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Aalto University publication series DOCTORAL DISSERTATIONS 43/2013
Organocatalysis and Continuous Flow Reactors as Enabling Tools in Organic Synthesis
Antti Kataja
A doctoral dissertation completed for the degree of Doctor of Science (Technology) (Doctor of Philosophy) to be defended, with the permission of the Aalto University School of Chemical Technology, at a public examination held at the Komppa Auditorium of the school on 6 April 2013 at 12.
Aalto University School of Chemical Technology Department of Chemistry Koskinen Research Group
Supervising professor Professor Ari Koskinen Preliminary examiners Professor Stephen J. Connon, Trinity College Dublin, Ireland Associate Professor Tore Bonge-Hansen, University of Oslo, Norway Opponent Professor David Tanner, DTU, Denmark
Aalto University publication series DOCTORAL DISSERTATIONS 43/2013 © Antti Kataja ISBN 978-952-60-5061-4 (printed) ISBN 978-952-60-5062-1 (pdf) ISSN-L 1799-4934 ISSN 1799-4934 (printed) ISSN 1799-4942 (pdf) http://urn.fi/URN:ISBN:978-952-60-5062-1 Unigrafia Oy Helsinki 2013 Finland
Abstract Aalto University, P.O. Box 11000, FI-00076 Aalto www.aalto.fi
Author Antti Kataja Name of the doctoral dissertation Organocatalysis and Continuous Flow Reactors as Enabling Tools in Organic Synthesis Publisher School of Chemical Technology Unit Department of Chemistry
Series Aalto University publication series DOCTORAL DISSERTATIONS 43/2013
Field of research Organic Chemistry
Manuscript submitted 29 October 2012 Date of the defence 6 April 2013
Permission to publish granted (date) 12 February 2013 Language English
Monograph Article dissertation (summary + original articles)
Abstract Enabling synthetic technologies are a collection of modern tools created to aid synthetic
organic chemists to achieve rapid and efficient synthesis and analysis of complex reaction products in the laboratory environment. These techniques include e.g. microwave reactors, heterogenized catalysts and continuous flow reactor systems. The application of enabling technologies to known methods of organic synthesis such as organocatalysis is paramount for chemists in adapting to a changing world where the ready availability natural resources is by no means a given.
The first part of this thesis describes studies towards elucidating the mechanism of cinchona alkaloid derived bifunctional thiourea organocatalysts. The activity of N-trityl substituted thiourea catalyst in the asymmetric Michael addition of Meldrum’s acid and other soft carbon nucleophiles to nitroalkenes was studied. The catalyst was found to be inactive with malonate diester nucleophiles, and subsequent studies revealed that the catalyst is unable to efficiently activate a non-enolic nucleophile, thus arresting the catalytic cycle.
The second part of this thesis focuses on the use of asymmetric organocatalytic ketone aldol addition in the total synthesis of marine alkaloid (–)-hennoxazole A. Two routes were investigated for the synthesis of the western pyran fragment. A prolineamide derivative was identified as the optimal catalyst. The addition of acetone to a bisoxazole aldehyde was then optimized in batch conditions and studied further in continuous flow conditions. Conditions for the O-methylation of the aldol addition product were also identified.
The final part of this thesis concentrates on the use of continuous flow reactors in industrially important aromatic nitration reactions. The nitration of vanillin was studied as the model reaction. Blockage of flow channels due to product precipitation was identified as a serious problem and the concentration of starting material stock solutions and reaction temperatures had to be adjusted accordingly. Reaction selectivity did not essentially differ from batch conditions in spite of radically different conditions, but product isolation was more difficult. Demethylation of the methoxy substituent of vanillin and subsequent nitration was identified to be the main side reaction, along with a deformylative ipso-nitration. The nitration protocol was studied with other substrates and it was found to function best for relatively electron rich aromatic compounds.
Keywords organocatalysis, continuous flow reactors, bifunctional thiourea catalysts, hydrogen bonding, proline, enamine catalysis, aldol reaction, Michael-addition, aromatic nitration
ISBN (printed) 978-952-60-5061-4 ISBN (pdf) 978-952-60-5062-1
ISSN-L 1799-4934 ISSN (printed) 1799-4934 ISSN (pdf) 1799-4942
Location of publisher Espoo Location of printing Helsinki Year 2013
Pages 171 urn http://urn.fi/URN:ISBN:978-952-60-5062-1
Tiivistelmä Aalto-yliopisto, PL 11000, 00076 Aalto www.aalto.fi
Tekijä Antti Kataja Väitöskirjan nimi Organokatalyysi ja jatkuvatoimiset virtausreaktorit mahdollistavina työkaluina orgaanisessa synteesissä Julkaisija Kemian tekniikan korkeakoulu Yksikkö Kemian laitos
Sarja Aalto University publication series DOCTORAL DISSERTATIONS 43/2013
Tutkimusala Orgaaninen kemia
Käsikirjoituksen pvm 29.10.2012 Väitöspäivä 06.04.2013
Julkaisuluvan myöntämispäivä 12.02.2013 Kieli Englanti
Monografia Yhdistelmäväitöskirja (yhteenveto-osa + erillisartikkelit)
Tiivistelmä Mahdollistavat synteesiteknologiat ovat kokoelma uudenaikaisia työkaluja, joiden
tavoitteena on auttaa orgaanisia kemistejä monimutkaisten reaktiotuotteiden nopeassa ja tehokkaassa synteesissä ja analysoimisessa. Näihin tekniikoihin kuuluvat mm. mikroaaltoreaktorit, immobilisoidut katalyytit sekä jatkuvatoimiset virtausreaktorit. Mahdollistavien synteesiteknologioiden soveltaminen tunnettuihin orgaanisiin synteesimenetelmiin kuten organokatalyysiin on ensiarvoisen tärkeää sopeuduttaessa muuttuvaan maailmaan, missä luonnonvarojen helppo saatavuus ei ole itsestäänselvyys.
Tämän väitöskirjan ensimmäisessä osassa on tutkittu kinkona-alkaloidien tioureajohdannaisia sekä niiden reaktiomekanismeja. N-Trityylisubstituoidun tioureakatalyytin aktiivisuutta tutkittiin Meldrumin hapon ja muiden pehmeiden hiilinukleofiilien asymmetrisessä Michael-additiossa nitroalkeeneihin. Katalyytin huomattiin olevan tehoton malonaattidiesterien suhteen, ja jatkotutkimukset osoittivat, ettei katalyytti pysty tehokkaasti aktivoimaan ei-enolimuotoisia nukleofiilejä, estäen siten katalyyttisen syklin.
Tämän väitöskirjan toisessa osakokonaisuudessa on tutkittu ketonin asymmetrisen organokatalyyttisen aldoliaddition käyttöä meriperäisen alkaloidin (–)-hennoksatsoli A:n kokonaissynteesissä. Kahta eri reittiä tutkittiin läntisen pyraanifragmentin synteesiä varten. Parhaaksi katalyytiksi osoittautui proliinin amidijohdannainen. Asetonin additio bisoksatsolialdehydiin optimoitiin ensin panosolosuhteissa ja sitä tutkittiin sen jälkeen virtausreaktorissa. Aldoliadditiotuotteen O-metyloinnille tutkittiin myös eri olosuhteita.
Tämän väitöskirjan viimeisessä osassa on tutkittu jatkuvatoimisten virtausreaktorien käyttöä teollisesti merkittävässä aromaattisessa nitrausreaktiossa. Vanilliinin nitrausta tutkittiin mallireaktiona. Virtauskanavien tukkeutuminen tuotteen saostumisen vuoksi osoittautui vakavaksi ongelmaksi, ja lähtöaineiden varastoliuosten konsentraatiota sekä reaktiolämpötilaa säädettiin tämän perusteella. Reaktion selektiivisyys ei olennaisesti eronnut panosolosuhteista huolimatta huomattavan erilaisista olosuhteista, mutta tuotteen eristäminen oli haasteellisempaa. Vanilliinin metoksiryhmän O-demetyloituminen ja sitä seurannut nitrautuminen tunnistettiin tärkeimmäksi sivureaktioksi deformyloivan ipso-nitrautumisen ohella. Nitrausmetodia sovellettiin myös muihin lähtöaineisiin ja sen todettiin toimivan parhaiten suhteellisen elektronirikkaiden aromaattisten yhdisteiden kohdalla.
Avainsanat organokatalyysi, jatkuvatoimiset virtausreaktorit, bifunktionaaliset tioureakatalyytit, vetysidokset, proliini, enamiinikatalyysi, aldolireaktio, Michael-additio, aromaattinen nitraus
ISBN (painettu) 978-952-60-5061-4 ISBN (pdf) 978-952-60-5062-1
ISSN-L 1799-4934 ISSN (painettu) 1799-4934 ISSN (pdf) 1799-4942
Julkaisupaikka Espoo Painopaikka Helsinki Vuosi 2013
Sivumäärä 171 urn http://urn.fi/URN:ISBN:978-952-60-5062-1
7
ACKNOWLEDGEMENTS
The research described in this thesis was carried out at the Department of Chemistry, Aalto University (Helsinki University of Technology until 1st January 2010) during 2007-2012. The research on the total synthesis of (–)-Hennoxazole A was carried out at the Department of Chemistry, University of Cambrige, during a research visit to Innovative Technology Centre and the group of Professor Steven V. Ley, from October 2009 to April 2010. The research on the continuous flow nitration of vanillin was carried out at Fermion Corporation, Espoo R&D facility from September 2011 to November 2011.
This work has been funded primarily by the National Technology Agency (TEKES) of Finland, by the project “Enabling Synthesis Technologies” (Pharma program) until February 2012. Funding for finishing the thesis was then received from the Magnus Ehrnrooth Foundation. In addition to the primary funders, Fermion Corporation, the Emil Aaltonen Foundation, Nordforsk network, Graduate School of Organic Chemistry and Chemical Biology, Aalto University and COST Action CM0804 are gratefully acknowledged for supplemental funding and conference travel grants.
I am especially grateful to my supervisor, Professor Ari Koskinen, for taking me in as a member to his research group in 2005, when I started on a research project on synthesizing potential FAAH inhibitors. Over the course of obtaining both M.Sc. and Ph.D. degrees under his supervision, I have come to admire his encyclopedic knowledge on organic chemistry, and his practical approach towards synthesis.
My warmest gratitude goes also to Professor Steven V. Ley, who accepted me as a visiting researcher to the Innovative Technology Centre at the University of Cambridge. It was both a wonderful and educational experience to visit one of the top universities in the world.
My sincere thanks to Mr. Leif Hildén and Mr. Martti Hytönen at Fermion for being able to spend two fascinating months in an industrial research environment, and to Mr. Jarkko Helminen for his insights on process engineering.
Professors Stephen J. Connon (Trinity College, Dublin) and Tore Bonge-Hansen (University of Oslo) are gratefully acknowledged for carefully revising this manuscript and for providing valuable and constructive criticism.
During the preparation of this thesis I have had the chance to consult with several experienced chemists and discuss my ideas. For these helpful and inspiring discussions I would like to thank especially Professor Dieter Seebach, Professor Petri Pihko and Dr. Pekka Joensuu.
The years spent in the laboratory were full of good times, discussions, exchange of ideas, jokes, problems etc. that we faced together as a reseach group. My big thanks to the current
8
and past members of Group Koskinen: Mikko P., Mikko M., Esa, Aki, Aapo, Annika, Essi, Andrejs, Christopher and Oskari. Our visiting post docs have also been of great help during my research, thank you to Damien, Katja and Peter. From the University of Cambridge I would like to thank especially Dr. Ian Baxendale (currently Professor at University of Durham) and Marcus Baumann for their collaboration on the hennoxazole project, and the whole Ley group for a memorable experience in the U.K.
For help in the laboratory, synthesis of starting materials and model studies I would like to thank the following students: Aleksi Tuokko, Laura Kolsi, Sami Tuomi, Päivi Kuosmanen, Simo Halonen and Janne Posti.
For analytical services in recording LC/MS and HRMS spectra and CHN analyses I would like to thank Tiia Juhala, Johanna Mareta (Aalto University) and Ilpo Laitinen (Fermion). For NMR consultation I would like to thank Dr. Jari Koivisto (Aalto) and Dr. Peter Grice (Cambridge). For HPLC services I am grateful to Dr. Richard Turner at Cambridge and especially to Mrs. Tarja Rissanen for ungrudgingly carrying out over 200 HPLC analyses during my brief stay at Fermion. For excellent technical aid and services I would especially like to thank Mr. Melvyn Orriss and Mr. Keith Parmenter at the University of Cambridge.
The years leading to this thesis have (luckily!) also been full of life outside the laboratory. I would like to thank all my dear friends from Dominante choir, Chamber choir Kaamos and Chamber choir Krysostomos, and especially conductors Seppo, Dani and Mikko for wonderful moments in music. Thank you also to all my fellow singers in our various respective vocal groups (especially SherryBeans). True friendship has also endured through the busy years and occasional long distances, thank you especially to Erika, Olli, Janne, Kristina and Tuomo.
My big thank you and love to my parents and close family for making a lot of things possible and enabling me to carve my own path in life, and to my siblings and their families for support and encouragement over the years.
Kun ei enää ulvo kuuta, tippuvat tähdet syliin (Once you stop howling for the moon, the stars may fall into your lap) wrote Kari Hotakainen. Thank you for everything, Iida!
9
TABLE OF CONTENTS
�ABSTRACT ............................................................................................................................... 3
TIIVISTELMÄ (Abstract in Finnish) ........................................................................................ 5
ACKNOWLEDGEMENTS ....................................................................................................... 7�
TABLE OF CONTENTS ........................................................................................................... 9�
ABBREVIATIONS .................................................................................................................. 11�
AUTHOR’S CONTRIBUTION ............................................................................................... 13�
1 INTRODUCTION ................................................................................................................. 15�
2 ASYMMETRIC ORGANOCATALYTIC MICHAEL ADDITIONS ................................. 17�
2.1 The Advent of Asymmetric Organocatalysis .............................................................. 18�
2.2 Hydrogen Bonding in Catalysis .................................................................................. 19�
2.2.1 Non-Covalent Organocatalysis ......................................................................... 19�
2.2.2 Hydrogen Bonds ............................................................................................... 20�
2.2.3 Urea and Thiourea Catalysts ............................................................................. 23�
2.2.4 Cinchona Alkaloid Derived Catalysts ............................................................... 26�
2.2.5 Thiourea Type Organocatalysts in Target-Oriented Synthesis ......................... 32�
2.3 Addition of Meldrum’s Acid to Nitroalkenes ............................................................. 34�
2.4 Results and Discussion ................................................................................................ 38�
2.5 Conclusions ................................................................................................................. 52�
3 STUDIES TOWARDS THE TOTAL SYNTHESIS OF (–)-HENNOXAZOLE A ............. 53�
3.1 Continuous Flow Technologies ................................................................................... 54�
3.1.1 Benefits and Disadvantages of Continuous Flow Conditions ........................... 54�
3.1.2 General Strategies for Continuous Flow Synthesis ........................................... 56�
3.2 Covalent Organocatalysis ............................................................................................ 59�
3.2.1 Enamine Catalysis ............................................................................................. 59�
3.2.2 Asymmetric Organocatalytic Aldol Reactions ................................................. 61�
10
3.2.3 Asymmetric Organocatalysis in Continuous Flow Conditions ......................... 68�
3.3 Total Synthesis of (–)-Hennoxazole A ........................................................................ 73�
3.3.1 Comparison of Previous Syntheses ................................................................... 73�
3.3.2 Previous studies by the Ley group .................................................................... 77�
3.3.3 First Approach to the Synthesis of the Western Fragment ............................... 78�
3.3.4 Second Approach to the Synthesis of the Western Fragment ........................... 80�
3.3.5 Optimization of the Bisoxazole Synthesis ........................................................ 81�
3.3.6 Catalyst Screening ............................................................................................. 83�
3.3.7 Organocatalytic Aldol Step under Continuous Flow Conditions ...................... 87�
3.3.8 Methylation studies ........................................................................................... 89�
3.4 Diastereoselectivity of �-Hydroxy Ketone Reduction with Solid Supported Borohydrides ..................................................................................................................... 90�
3.5 Conclusions ................................................................................................................. 94�
4 NITRATION OF AROMATIC SUBSTRATES UNDER CONTINUOUS FLOW CONDITIONS ......................................................................................................................... 96�
4.1 Common aspects of aromatic nitration ....................................................................... 96�
4.2 Nitration of Vanillin .................................................................................................... 97�
4.2.1 Preliminary studies ............................................................................................ 98�
4.2.2 Pulse experiments ........................................................................................... 102�
4.2.3 Identification of impurities .............................................................................. 104�
4.2.4 Continuous experiments in 5 mL reactor ........................................................ 106�
4.2.5 Continuous experiments in 10 mL reactor ...................................................... 110�
4.2.6 Isolation studies and comparison between batch and flow modes .................. 113�
4.3 Reaction profile and formation of impurities ............................................................ 116�
4.4. Nitration of other substrates ..................................................................................... 119�
4.5 Conclusions ............................................................................................................... 121�
5 EXPERIMENTAL SECTION ............................................................................................ 123�
5.1 General Experimental Considerations ....................................................................... 123�
5.2 Asymmetric Organocatalytic Michael Additions ...................................................... 124�
5.3 Total Synthesis of (–)-Hennoxazole A ...................................................................... 142�
5.4 Continuous Flow Nitration of Aromatic Substrates .................................................. 156�
6 REFERENCES .................................................................................................................... 158�
�
11
�
ABBREVIATIONS
Ac acetyl
app apparent
aq. aqueous
BEMP 2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorine
Bn benzyl
Boc tert-butoxycarbonyl
bpr back pressure regulator
Bz benzoyl
cat. catalytic amount
Cbz carboxybenzyl
CDI N,N’-carbonyldiimidazole
CPME cyclopentylmethyl ether
Cy cyclohexyl
DAST diethylaminosulfur trifluoride
dba dibenzylideneacetone
DBU 1,8-diazabicyclo[5.4.0]undec-7-ene
DCC dicyclohexylcarbodiimide
DDQ 2,3-dichloro-5,6-dicyano-1,4-benzoquinone
DEPC diethyl cyanophosphonate
(DHQD)2PHAL hydroquinidine 1,4-phthalazinediyl ether
DIAD diisopropyl azodicarboxylate
DIPEA diisopropylethylamine
DME 1,2-dimethoxyethane
DMF dimethyl formamide
DMSO dimethyl sulfoxide
DPPA diphenylphosphoryl azide
EDG electron donating group
ee enantiomeric excess
EWG electron withdrawing group
12
HMTA hexamethylenetetramine
HT-PFA high temperature resistant perfluoroalkoxy polymer
KHMDS potassium hexamethyldisilazane
LDA lithium diisopropylamide
MCA monochloroacetic acid
MTPA �-methoxy-�-(trifluoromethyl)phenylacetic acid
PIFA phenyliodonium bis(trifluoroacetate)
PMP p-methoxyphenyl
PMB p-methoxybenzyl
PPTS pyridinium p-toluenesulfonate
PS polymer supported
PyBroP bromo-tris-pyrrolidino phosphoniumhexafluorophosphate
QP-SA QuadraPureTM sulfonic acid resin
rt room temperature
tR retention time
Rrt relative retention time
TBAF tetra-n-butylammonium fluoride
TBS tert-butyldimethylsilyl
TBDPS tert-butyldiphenylsilyl
TES triethylsilyl
Tf trifluoromethanesulfonyl
TFA trifluoroacetic acid
TFAA trifluoroacetic anhydride
THF tetrahydrofuran
TIPS triisopropylsilyl
TMS trimethylsilyl
13
AUTHOR’S CONTRIBUTION
The author designed and carried out the experiments, recorded the analytical data (with exceptions mentioned in Acknowledgments), and interpreted the results that are presented in this thesis. Publications relevant to this thesis were written by the author.56
14
15
1 INTRODUCTION
Organic synthesis is a fundamental branch of chemistry upon which many givens of modern
life are built. The production and development of existing and new pharmaceuticals, modern
polymer and material sciences, and the production of industrial fine chemicals such as
perfumes and other cosmetics are strongly dependent on organic synthesis and skillful people
who are able to apply the corresponding technologies to use. In the modern world of
dwindling natural resources, this science is ever more important as the industry and academia
need to learn to achieve more with less.
The origin of synthetic technologies traces back to the 19th century and to the great leaps
taken then by experimental chemists in constructing specialized glassware for use in the
laboratory. However, the development of these technologies nearly came to a standstill in the
20th century. Still today undergraduate students are taught to perform organic syntheses in
round bottomed flasks not unlike those e.g. Gustaf Komppa used in the first total synthesis of
a stereochemically elaborate natural product, camphor in 1903. Whereas these basic skills are
important in themselves, the development of new and efficient tools is paramount in facing
the challenges of a changing world. Enabling synthetic technologies comprise a collection of
modern tools to aid the synthetic organic chemist in the laboratory environment.1 To mention
a few, the late 20th and early 21st centuries have seen the rise of solid phase synthesis,
combinatorial chemistry, automation, microwave reactors, continuous flow technologies, new
solvent systems such as ionic liquids and supercritical fluids, and heterogenized chiral
catalysts and biocatalysts as new chemical tools. The purpose of these technologies is to
enable the chemist to reliably synthesize and analyze complex products with high efficiency
and speed, so that the needs of the fast paced industrial and academic research environments
are met.
The importance of asymmetric synthesis and catalysis to modern chemical industry and
academic research cannot be overemphasized, as was shown by awarding the 2001 Nobel
Prize in Chemistry to Ryoji Noyori, William Knowles and K. Barry Sharpless for their
16
development of asymmetric hydrogenation and oxidation reactions. The term Organocatalysis
was recoined2 in the early 2000s as a way to describe the general transformation of substrates
to new compounds catalyzed by small molecules usually consisting only of carbon, hydrogen,
oxygen, nitrogen, sulfur, and/or phosphorus. While in the strictest sense a huge portion of
standard organic chemistry falls into this category (all reactions catalyzed by organic acids
and bases), in terminological sense ‘organocatalysis’ is used especially to describe synthetic
transformations catalyzed by small molecules, with the main focus of modern research being
on asymmetric catalysis. The most common source of chirality in organocatalysis is the chiral
pool provided by Nature. A great variety of organocatalysts is synthesized from amino acids
or other common chiral molecules readily available from natural sources. Depending on the
exact mode of the catalyst, chiral information in organocatalysis may be transferred to the
products either by relayed asymmetric induction (e.g. via covalent intermediates in enamine
and iminium catalysis) or by external asymmetric induction (e.g. via non-covalent
organization of transition states in hydrogen bond catalysis).
This thesis describes my efforts to use asymmetric organocatalysis as an enabling tool in
organic synthesis, from both method development and target oriented points of view. I have
investigated the scope of asymmetric organocatalysis by hydrogen bonding catalysts in
connection with the synthesis of (S)-pregabalin, and proline derivatives in the construction of
stereocenters via enamine aldol reaction in the total synthesis of marine alkaloid (–)-
hennoxazole A. The application of commercial laboratory scale continuous flow reactors to
organocatalytic aldol reaction was also investigated. Finally I will discuss the use of
continuous flow reactors in the nitration of aromatic substrates as a possible tool for industrial
setting.
17
2 ASYMMETRIC ORGANOCATALYTIC MICHAEL
ADDITIONS
The conjugate addition of a stabilized carbanion nucleophile to an �,�-unsaturated carbonyl
compound is called the Michael addition (or Michael reaction), and it is regarded as one of
the fundamental C-C-bond forming reactions in organic chemistry.3 The Michael addition is
an elegant step in the route to synthesizing more complex molecular frameworks. Classical
nucleophiles in the reaction include e.g. malonate diesters, �-ketoesters, �-ketonitriles, and
standard electrophiles are e.g. acrylonitriles, acrylate esters, or vinyl ketones (Scheme 1).
Currently, however, the term is sometimes used to encompass a wide variety of conjugate
addition reactions to C-C double bonds. In modern applications, N-, O-, S- and P-nucleophiles
have also garnered significant attention, especially in asymmetric synthesis.4 The acceptor can
be virtually any double or triple bond in �,�-relation to a resonance stabilizing electron
withdrawing group. The challenging addition into �,�-disubstituted alkenes is likewise of
particular interest for the formation of all carbon quaternary stereocenters.5 Current methods
for carrying out stereoselective Michael additions range from well known metal catalysis to
the blooming field of organocatalysis.6 Due to the focus of this thesis, we shall refrain from
reviewing metal catalyzed methods in any further detail and will concentrate on recent
advances and our own studies in organocatalytic Michael additions.
18
Scheme 1. The Michael manifold
2.1 The Advent of Asymmetric Organocatalysis
Although asymmetric organocatalytic reactions were first documented in early 20th century by
Bredig and Fiske in the form of enantioselective cyanohydrin synthesis,7 with a few seminal
examples appearing in the intervening decades (such as the Hajos-Parrish reaction, discussed
further in Chapter 3), the current avalanche of research was launched in 2000 after the
publications of List and MacMillan.2c,8 By the beginning of the second decade of the 21st
century, several extensive reviews and books have already been published on different aspects
of asymmetric organocatalysis.9-11
Based on the mechanisms utilized by different organocatalysts, a division into two categories
follows quite naturally (Scheme 2). These categories are aptly termed covalent catalysis and
non-covalent catalysis.9b Catalysts belonging to the first category mediate their effect through
formation of new bonds between catalyst and substrate. Examples of this category include the
discoveries of List and MacMillan, who used (S)-proline and imidazolidinones as enamine10
and iminium11 forming catalysts, respectively. Catalysts of the latter category direct the
19
substrates to react with each other through e.g. hydrogen-bond (H-bond) or ion pair formation
and subsequent advantageous spatial arrangement of transition states. Classical examples of
non-covalent catalysts include the Jacobsen and Takemoto thiourea catalysts, and quaternary
ammonium type phase transfer catalysts. Bifunctional catalysts12 may simultaneously activate
both nucleophile and electrophile, resulting in a highly organized transition state assembly,
especially if there are covalent interactions with catalyst and substrate, which usually
increases both reaction rate and stereoselectivity.9c In this thesis, experimental results
concerning both categories will be presented, with Chapter 2 focusing on the use of
bifunctional H-bonding organocatalysis, and Chapter 3 focusing on enamine catalysis,
respectively.
Scheme 2. Division of organocatalytic reactions according to catalysts
2.2 Hydrogen Bonding in Catalysis
2.2.1 Non-Covalent Organocatalysis
Non-covalently functioning organocatalysts can be divided into subcategories according to
their mode of action (Figure 1).9b Several non-covalent organocatalysts mediate their effect
20
via H-bond formation, thus carrying out a formal Lewis acid activation of an electrophile.
Brønsted acids, such as chiral phosphoric acids, are usually considered to belong in this
category, although there usually is momentary complete acid-base dissociation between
catalyst and substrate during the reaction. A catalyst may also function as a Lewis base and
thus trigger a Lewis acidic substrate to react, such as allyl silanes or silyl enol ethers. Another
widely explored category is phase-transfer catalysis, in which an ionic catalyst species
(usually a quaternary ammonium salt) acts as a carrier for reactive ions (e.g. hydroxide ions)
between an aqueous and an organic phase.
Figure 1. Examples of non-covalent organocatalysts: bifunctional H-bond catalyst 1 (Takemoto’s catalyst), chiral Brønsted acid 2, phase transfer catalyst 3.
2.2.2 Hydrogen Bonds
Hydrogen bond is an attractive interaction between an electronegative heteroatom (H-bond
acceptor) and a hydrogen atom (H-bond donor) bound covalently to another electronegative
(hetero)atom. The H-bond donor and acceptor may be parts of the same molecule
(intramolecular H-bond) or belong to separate molecules (intermolecular H-bond). Hydrogen
bonding has a profound impact on the chemical and conformational properties of molecules,
and they have an important role in molecular recognition and supramolecular chemistry.
Hydrogen bonds may encompass a wide variety of bond strengths up to 40 kcal/mol,
depending on the steric and electronic properties of the acceptor atom and the heteroatom of
the donor fragment. Based on this, a division into three subcategories is usually made (Table
1).13 Most commonly occurring H-bonds belong to the lower moderate and weak categories,
bond strengths being typically less than 5-6 kcal/mol. The exact strength and extent of
21
hydrogen bonding between two substrates is also strongly dependent on the surrounding
solvent.
Table 1. Classification of hydrogen bonds according to Jeffrey13
Strong Moderate Weak Type of bonding Mostly covalent Mostly electrostatic Electrostatic Length of H-bond (Å) 1.2–1.5 1.5–2.2 2.2–3.2 Bond angles (°) 175–180 130–180 90–150 Bond energy (kcal/mol) 14–40 4–15 <4
Hydrogen bonding may have several effects that are crucial to successful catalysis. They may
spatially preorganize the substrates prior to reaction, or activate bonds via polarization by
lowering the LUMO of electrophiles through a Lewis acid-base interaction between the H-
bond donor and acceptor moieties, or stabilize charges that are formed in the transition state
of the reaction.14 An early seminal example of H-bond catalysis is given in the works of Hine,
who used biphenylenediol compounds such as 5 to catalyze the epoxide opening of 4 with
diethylamine (Scheme 2).15 Another early example of achiral synthesis was published by
Curran, who used the aromatic urea 8 to catalyze the Claisen rearrangement of allyl vinyl
ether 7.16 The studies of Schreiner established that aromatic thioureas such as 12 are efficient
organic Lewis acid catalysts in e.g. Diels-Alder reactions.17
22
Scheme 3. Examples of achiral H-bond catalysis by Hine, Curran and Schreiner
The excellent activity of urea and thiourea catalysts has been explained by their ability to act
as bidentate H-bond donors, forming two explicit hydrogen bonds with a single substrate. The
crystallization studies of Etter showed that a (thio)urea may indeed form two hydrogen bonds
with e.g. the oxygen atom in THF (Figure 2).18 Through computational studies Schreiner
postulated that in urea/thiourea structures there is also an intramolecular rigidification of the
structure due to S-H-bonding between the thiourea and the aromatic ring, which forces both
N-protons to be in S-trans conformation.17b This effect is pronounced when there are electron
withdrawing groups in meta or para position with respect to the nitrogen. Due to inductive
effects, the Csp2-H bond at the ortho position becomes more polarized, and the acidified
proton can thus function as an H-bond donor to the urea/thiourea oxygen or sulfur. Therefore
the formation of two explicit H-bonds to a carbonyl oxygen is possible, and they may
synergistically activate the substrate towards nucleophilic attack.
23
Figure 2. The bidentate coordination of urea/thiourea with oxygen according to Etter and Schreiner. X-ray structure from Ref. 18c.
The role of hydrogen bonding in synthesis and catalysis has been under intense scrutiny
during the last decade, and the state of the art has been reviewed several times.19 Whereas it is
not practical to repeat the whole history of H-bonding in catalysis here, some seminal
developments are mentioned in the following sections.
2.2.3 Urea and Thiourea Catalysts
In 1998, the Jacobsen group reported an asymmetric Strecker reaction catalyzed by chiral
thiourea 15, derived from tert-leucine, (R,R)-1,2-diaminocyclohexane and a substituted
salicylaldehyde.20 The original aim of their research was the combinatorial synthesis and high
throughput screening of novel tridentate ligands for metal catalysts. They discovered that the
ligands themselves were able to catalyze the Strecker reaction of N-allyl benzaldimine 14 and
TBSCN or HCN in the absence of metals. The N-acylated aminonitriles 16 were formed in
good yields and enantioselectivities in the presence of the optimized catalyst 15 (Scheme 4).
Over the following decade, the Jacobsen group went on to publish a family of different urea
and thiourea catalysts for several reaction types, such as Mannich and acyl-Mannich
reaction,21a,b nitro-Mannich reaction,21c imine hydrophosphonylation,21d acyl-Pictet-Spengler
reaction,21e aza-Morita-Baylis-Hillman reaction,21f and ketone cyanosilylation,21g thus creating
a family of organocatalysts of an almost unprecedented generality (Figure 3).
24
Scheme 4. The first organocatalytic asymmetric Strecker reaction catalyzed by thiourea 15
Figure 3. Jacobsen’s urea/thiourea catalyst family
In 2003, Takemoto reported the asymmetric Michael addition of malonates and other 1,3-
dicarbonyl compounds to nitroalkenes catalyzed by the bifunctional thiourea 1, which
similarly incorporates (R,R)-1,2-diaminocyclohexane, doubling as a chiral scaffold and a
tertiary amine base (Scheme 5).22 The acidity and ease of deprotonation of the pronucleophile
strongly affects the reaction rate, as is shown by the difference in reaction times with diethyl
malonate 23, acetylacetone 24, and malononitrile 25. Takemoto also investigated the thiourea
N-substituent, finding that the electronic properties of the substituent clearly affected the
reaction rate and selectivity. Interestingly, an unsubstituted benzene gave a poorer conversion
�
25
than both EDG- or EWG-substituents at 3-position of the aromatic ring (Scheme 6), although
the increase in enantioselectivity correlates with decreasing electron density. As a general rule,
electron poor aromatic rings function best as the N-substituent, since they acidify the thiourea
N-protons and hence enhance their H-bond donating ability. It is noteworthy that a catalyst
otherwise identical to 1 but carrying a urea group with less acidic N-protons has a practically
identical activity in this reaction. A usual supposition has been that the lower pKa values of
urea usually correlate with decreasing catalytic activity and selectivity.23 Takemoto’s
observation highlights the importance of the bidentate H-bond formation for catalytic
efficiency. In other instances a urea catalyst has been noted to outperform a corresponding
thiourea in terms of selectivity.24
NH
NH
S
NMe2
CF3
F3C
1 (10 mol %)
toluene, rtPhNO2
26a
PhNO2
Nu+NuH (23-25)
EtO
O
OEt
O
23, 24 h, 86%, 93% ee
O O
24, 1 h, 80%, 89% ee
CNNC
25, 0.25 h, 85%, 25% ee
27a-29a
Scheme 5. Michael additions with Takemoto’s catalyst 1
Scheme 6. Variation of thiourea N-substituent
26
A significant increase in the catalyst activity is observed when the number of H-bond donors
is increased, even though the electron-deficient aromatic substituent is discarded in the
process, as was reported by Wang’s group.25 The thiourea 34 catalyzed addition of cyclic �-
ketoester to nitroalkenes 26a-c proceeded with high yields and selectivities. The aromatic
substituent of the nitroalkene had little effect on the selectivity of the reaction, and aliphatic
substituents were also very well tolerated. The addition of a small H-bond donor may lead to
a tighter transition state assembly, thus explaining the excellent activity and selectivity. A
bulkier sulfonamide group in place of OH showed significantly poorer diastereo- and
enantioselectivity.
Scheme 7. Wang’s catalyst 34 featuring multiple H-bonding sites
2.2.4 Cinchona Alkaloid Derived Catalysts
The highly specialized molecular scaffold of cinchona alkaloids is considered to be a
privileged structure in both organic synthesis and pharmacology.26 In themselves, the
alkaloids have historically been used for their pharmacological properties as antimalarial
(quinine) and antiarrhythmic agents (quinidine). In addition to being held in high regard as
flavoring agents for certain refreshments, the 20th and 21st centuries have seen the widespread
application of cinchona alkaloids to asymmetric synthesis as chiral reagents, ligands for metal
mediated synthesis or as scaffolds for creating new organocatalysts. The good availability and
the relatively easy functionalization of cinchona alkaloids make them attractive and useful
starting materials for methods development. Since the chemistry and scope of cinchona
alkaloid derived catalysts has been recently reviewed,19a,27 we shall consider only a few select
and important examples here.
27
The history of cinchona alkaloids in asymmetric catalysis goes back to the first reported
asymmetric organocatalytic reaction by Bredig and Fiske in 1912. The hydrocyanation of
benzaldehyde 36 catalyzed by quinine 37 (or quinidine) gave a chiral product, with
enantiomeric excess below 10%, however (Scheme 8).7 The next landmark was achieved in
1960, when Pracejus published the asymmetric addition of alcohols to phenyl ketene 39
catalyzed by O-acetylquinine 40.28 The reaction proceeded in good yields and, in context of
the date, in very good enantioselectivities, up to 74% ee (Scheme 9).
Scheme 8. Hydrocyanation of benzaldehyde by Bredig and Fiske
Scheme 9. Addition of methanol to phenyl ketene 39 by Pracejus
Pioneering work in both asymmetric Michael additions and H-bond catalysis was done in the
1970s and 1980s by Wynberg and his group. They reported the stereoselective Michael
additions of �-ketoesters and thiophenols to unsaturated ketones catalyzed by unmodified
cinchona-alkaloids.29 In the single best example of the latter reaction, the addition of 4-tert-
butylthiophenol 42 to 5,5-dimethylcyclohex-2-enone 43 proceeded in good yield (>80%) with
an ee of 75% when catalyzed by cinchonidine 44 (Scheme 10). Wynberg postulated that the
28
alkaloid had a bifunctional role in the reaction. The basic quinuclidine nitrogen functions as a
base and the alkaloid thus forms an unstable ion pair with the deprotonated thiol. The enone is
then directed via H-bond formation between the C9-hydroxyl and carbonyl oxygen into the
optimal position for conjugate addition to take place via a highly structured transition state.
Any modification of the C9-hydroxyl (removal, substitution with chlorine, acetylation,
inversion) led to nearly complete deterioration of stereoselectivity.
Scheme 10. Conjugate addition of phenyl thiols to cyclohexenones by Wynberg
In 2005, the groups of Chen, Soós, Dixon and Connon independently reported the use of
cinchona-derived bifunctional thiourea catalysts 45 and 46 in different asymmetric conjugate
and Michael additions.30 Chen found high activity but poor enantioselectivities in the addition
of phenylthiol to �,�-unsaturated imide, Soós reported a highly enantioselective Michael
addition of nitromethane to chalcones, and the groups of Connon and Dixon reported high
selectivities in the Michael addition of malonate nucleophiles into nitroalkenes (Scheme 11).
All the catalysts incorporate an epi-9-amino-(9-deoxy)cinchona skeleton, and this inversion of
stereochemistry was also proven to be crucial by Soós and Connon. In their studies they
showed that thiourea catalysts having the natural configuration at C9 had little or no activity.
In another interesting coincidence, following Takemoto’s example,22 all four groups also
independently incorporated the highly electron poor 3,5-bis(trifluoromethyl)phenyl moiety as
the other thiourea N-substituent.
29
N
NHN NHS
CF3F3C
N
HNNHN S
F3C CF345 46
OMe
Chen & Dixon Soós & Connon
Ph NH
O
Ph
O
PhSH +45 (10 mol %)
4 Å MS, CH2Cl2, 20 °C, 2 hPh N
H
O
Ph
OPhS
Chen, Ref. 30a
Ph
O
PhMeNO2 + Ph
O
Ph46 (10 mol %)
toluene, 25 °C, 110 h
O2N
99%, ee 17%
94%, ee 96%
Soós, Ref. 30b
47 48
49 50
PhNO2
26a
MeO OMe
OO
51
+46 (2 mol %)
toluene, –20 °C, 30 h PhNO2
(R)-52a
OMe
O
MeO
O
94%, ee 96%
Connon, Ref. 30c
PhNO2
26a
MeO OMe
OO
51
+45 (10 mol %)
CH2Cl2, –20 °C, 30 h PhNO2
(S)-52a
OMe
O
MeO
O
95%, ee 94%
Dixon, Ref. 30d
9 9
Scheme 11. The first cinchona derived thiourea catalysts in conjugate additions
The chemical modification required for the reversal of C9 stereochemistry was originally
reported by Brunner in 1995.31 He developed a one-pot protocol for sequential Mitsunobu
reaction32 and Staudinger reduction33 to avoid isolation of the intermediate azide (Scheme 12).
Practically all subsequent published syntheses of epi-C9-cinchona alkaloids are based on this
protocol, although diphenyl phosphory azide (DPPA) has mostly replaced the use of HN3 as
the azide source.
30
Scheme 12. The inversion of C9 stereocenter of cinchona alkaloids
The groups of Hiemstra and Deng have explored the positioning of the H-bond donor moiety
in cinchona derived catalysts. In 2004, Deng reported the first efficient organocatalytic
Michael addition of malonates into nitroalkenes using 6’-OMe-demethylated quinine 55
(cupreine) as the catalyst.34 In spite of longish reaction times (up to 106 hours), both aromatic
and aliphatic nitroalkenes gave excellent ee:s, and good to excellent yields (Scheme 13). In a
similar fashion, Hiemstra reported the application of catalyst 56 to the asymmetric Henry
reaction.35 In the catalyst structure the thiourea is likewise attached to the 6’-position of the
quinoline ring. No inversion of configuration at C9 was required in this case. Good activity
and selectivity was attained in the addition of nitromethane to aromatic aldehydes, but
aliphatic aldehydes were in general quite unreactive under similar conditions and gave poor
enantioselectivities (Scheme 14). In spite of promising results, catalyst 56 has not found
similar popularity in the literature as 45 or 46, similar catalysts having been used only for
nitroalkene cyanosilylation,36 conjugate addition of thiols to �,�-unsaturated oxazolidin-2-
ones,37 and desymmetrization-fragmentation of cyclic ketoepoxides and ketocyclopropanes.38
Recently, Connon et al also reported studies on C5’-urea-functionalized catalysts and their
use in Henry reaction and sulfa-Michael additions.39
N
OHN
OH
55 (10 mol %)R
NO2MeO OMe
OO
51
+R
NO2
OMe
O
MeO
O
26a: R = Ph26c: R = n-C5H11
52a: R = Ph52c: R = n-C5H11
THF, –20 °C
97%, ee 99%81%, ee 94%
Scheme 13. Conjugate additions by Deng’s C6’-modified cinchona catalyst
31
Scheme 14. Henry reaction by Hiemstra’s catalyst
In 2008, Rawal published a highly active cinchona derived squaramide catalyst 58 for the
Michael-addition of soft nucleophiles to nitroalkenes.40 The addition of acetylacetone 24 into
�-nitrostyrene 26a was carried out with a very low catalyst loading of 0.1 mol % in excellent
yield of 97% and 96% enantioselectivity (Scheme 15). The optimal catalyst loading was
found to be 0.5 mol %, with the ee climbing above 99%. The yields and enantioselectivities
were consistently high for aromatic nitroalkenes, but aliphatic nitroalkenes were for some
reason not tested. For asymmetric acyclic 1,3-diketo- or �-ketoester nucleophiles the
diastereoselectivity was rather poor (at maximum 5:1), but for cyclic substrates the ratio
climbed to 50:1.
NNH
N
NH
OO
58O O
24
PhNO2
26a
+ PhNO2
28a
O O
CH2Cl2, rt
0.5 mol % 58: 8 h, 94%, ee >99%0.1 mol % 58: 20 h, 97%, ee 96%
CF3
F3C
Scheme 15. Rawal’s squaramide catalyst 58 in nitro-Michael addition
The properties of squaramide group in anion recognition have been well studied, and it shows
better H-bond donating abilities than e.g. the corresponding urea compounds.41 This has been
32
explained by the geometry of the squaramide group (wider N-H bite angle) and the better
anion stabilizing characteristics, which ensue from a net gain in aromaticity of the four-
membered ring upon complexation with anions.40,42 Jorgensen calculated the H-bond lengths
between nitroalkene 26a and squaramide N-H:s to be 1.97-2.22 Å,43 but no rigorous
computational and mechanistic studies on the effect of squaramide moiety in organocatalytic
reactions have been published as of yet.
2.2.5 Thiourea Type Organocatalysts in Target-Oriented Synthesis
Since most method development papers concentrate on simple substrates, some examples of
target-oriented examples should be presented.44 An impressive example is the concise and
effective synthesis of (R)-rolipram 62 by Dixon et al. (Scheme 16).45 The key step in the
synthesis of rolipram was the Michael addition of dimethyl malonate 51 into the highly
functionalized aromatic nitroalkene 59, carried out in excellent yield and enantioselectivity,
furnishing the practically enantiopure key intermediate 60 after recrystallization.
O
MeO
NO2
59
N
HNN
45 (10 mol %)
SHN
CF3F3C
CH2Cl2, 48 h at –20 °C, 48 h at 0 °CMeO OMe
OO
51
+O
MeO
NO2
OMeMeO
O O
60 87%, ee >99%afterrecrystallization
2 steps from isovanillin
NiCl2·6H2ONaBH4, EtOH
O
MeO
NH
OEtO
O
61
1) LiOH·H2O, THF
2) toluene, rfxO
MeO
NH
O
(R)-rolipram, 6263% over 6 steps, ee >99%
Scheme 16. Synthesis of (R)-rolipram 62 by Dixon
33
Takemoto used his catalyst 1 in the total synthesis of (–)-epibatidine 66 (Scheme 17).46 The
reaction between �,�-unsaturated �-ketoester 63 and nitroalkene 64 proceeded in a good yield
of 90%, but the ee was only 75%, still being an impressive result considering the challenging
substrates and target-oriented nature of the reaction.
Scheme 17. Michael addition in the synthesis of (–)-epibatidine 66 by Takemoto
Jacobsen has used his thiourea catalysts in the total syntheses of indole alkaloids (+)-
harmicine 69 and (+)-yohimbine 73 via a Pictet-Spengler strategy.47 The synthesis of (+)-
harmicine included an acyl-Pictet-Spengler cyclization of hydroxylactam 67 mediated by
thiourea 68 (Scheme 18), which proceeded in excellent enantioselectivity of 97%.47a
Reduction of the intermediate with LiAlH4 gave (+)-harmicine. The tetrahydro-�-carboline
structure of (+)-yohimbine was obtained from 70 and 71 via an acyl-Pictet-Spengler reaction
in 81% yield over two steps and 94% ee (Scheme 19). 47b
Scheme 18. Synthesis of (+)-harmicine by Jacobsen
34
Scheme 19. Synthesis of (+)-yohimbine 73 by Jacobsen
Takemoto’s catalyst was also used in the synthesis of (+)-esermethole 77 by Barbas III
(Scheme 20).48 Conjugate addition of N-Boc-6-methoxy-4-methyl-3-oxindole 75 to
nitroethene proceeded in moderate yield and goodish ee of 83%, which was improved to 96%
by recrystallization. Further three steps gave the final product 77, which can further be
elaborated to the important parasympathomimetic compound (+)-physostigmine.
Scheme 20. Synthesis of (+)-esermethole 77 by Barbas III
2.3 Addition of Meldrum’s Acid to Nitroalkenes
In 2009, our laboratory published an organocatalytic enantioselective synthesis of (S)-
pregabalin, also known by its trade name Lyrica® (Scheme 21).49 The key step in the
35
synthesis involves the asymmetric addition of Meldrum’s acid 78 to a readily available
aliphatic nitroalkene 26d. After extensive screening of different catalysts, the quinidine-
derived thiourea 79 incorporating a bulky trityl substituent was recognized as the best source
of asymmetric induction, giving an ee of 75%. It is noteworthy that the benchmark catalyst 45
gave a meager enantiomeric excess of 32% and did not give full conversion in 16 hours at a
catalyst loading of 5 mol %.
Scheme 21. Organocatalytic synthesis of (S)-pregabalin 82 from our laboratory
Meldrum’s acid is a synthetically useful building block due to its easy deprotection and
possibilities for further functionalization, and along with its derivatives it has found use e.g. in
the synthesis of natural products.50 It has an intriguingly high acidity, with pKa values of 7.32
in DMSO and 4.83–4.97 in H2O.51 While this is widely regarded as an anomaly, there are
several explanations. The density functional theory calculations based on the reactive hybrid
orbital (RHO) theory developed by Ohwada have shown clear correlation between the energy
levels of unoccupied RHOs of the acidic �-C-H bonds of cyclic 1,3-dicarbonyl compounds,
including Meldrum’s acid, and their corresponding experimental deprotonation energies.52 A
classical explanation invokes the conformational stabilization of esters. An acyclic ester is
stabilized into trans conformation by several interactions between filled and unfilled orbitals:
36
there is donation from free electron pairs of the ‘alcohol’ oxygen to the carbonyl �* and �*
orbitals, and simultaneously donation from carbonyl oxygen free pair to the C-O sigma star
(Figure 4). Meldrum’s acid has a boat like ground state conformation, and the donation effect
of alcohol oxygen lone pair to carbonyl �* is prevented by the cyclic cis arrangement. Hence
the methylene group experiences the heightened reactivity from both carbonyl groups and is
significantly acidified. Thus, Meldrum’s acid is able to form defined ion pairs with practically
any mild base available.
Figure 4. Conformational and stereoelectronic stabilization of esters and Meldrum’s acid
The use of Meldrum’s acid as a nucleophile in asymmetric synthesis has been rather limited,
and more examples exist on e.g. the use of its 5-alkylidene derivatives as electrophiles.53 At
the time of our study, the few published results on the asymmetric addition of 78 to
electrophiles were not very encouraging. Kleczkowska and Sas attempted the asymmetric
Michael-addition of 78 to �-nitrostyrene 26a by using a stoichiometric amount of different
natural alkaloids and their derivatives as catalysts (Table 2).54 In spite of high or good yields,
the enantioselectivities were uniformly low (entries 1-6 and 9-10), and no selectivity was
detected in the presence of hydrocupreidine, �-isocupreidine and (–)-brucine (entries 7-8, 11).
No rationale was given for the low selectivity. Takemoto’s catalyst 1 performed a little better,
giving the Michael adduct 80a in 88% yield and 46% ee (Entry 12).22b The thiourea
derivatives of chiral Tröger’s base were likewise reported to give practically no
stereoselectivity in the same reaction.55
37
Table 2. Asymmetric Michael-additions of Meldrum’s acid prior to our studies.
�
Entrya Catalyst Yield (%) ee (%) Ref. 1 Cinchonine 88 21 (S) 54 2 Cinchonidine 92 18 (R) 54 3 Quinine 27 22 (R) 54 4 Quinidine 70 25 (S) 54 5 Hydroquinidine 70 19 (S) 54 6 (DHQD)2PHAL 63 5 (S) 54 7 Hydrocupreidine 54 0 54 8 �-Isocupreidine 71 0 54 9 L-proline 63 7 (S) 54
10 (–)-Sparteine 72 15 (R) 54 11 (–)-Brucine 82 0 54 12b 1 88 46 22b
a) The reactions were conducted with a stoichiometric amount of catalyst for 3 hours in CH2Cl2. b) 10 mol % 1, toluene, rt, 24 h
Since the publication of our study (results described below),56 only a few reports on the
asymmetric organocatalytic Michael addition of Meldrum’s acid have surfaced.57 The group
of Ellman reported a highly enantioselective addition of both 78 and cyclohexyl-Meldrum’s
acid 84 to nitroalkenes catalyzed by N-sulfinyl urea catalysts 83 and 85 (Scheme 22).57b They
applied this protocol likewise to the synthesis of (S)-pregabalin, obtaining the intermediate 86
in full conversion and ee of 92% in the key step.
38
Scheme 22. Highly selective additions of Meldrum’s acid 78 and cyclohexyl-Meldrum’s acid 84 to nitroalkenes by Ellman
2.4 Results and Discussion
As follow-up studies to our synthesis of (S)-pregabalin, we set out to further screen the
properties of our catalyst 79. Since it outperformed the widely used 45 in the key step, it was
our aim to study whether this represented a general trend in activity and selectivity. In
addition, we wanted to investigate whether catalyst 79 would outperform the benchmark
catalyst 45 with other substrates as well. Thus, following the general procedure described
previously, a solvent screen was conducted using nitroalkene 26d as a model substrate (Table
3). For the determination of enantioselectivity, the Meldrum’s acid adducts 80 were
transformed into the corresponding anilides 87 by treatment with 1:10 mixture of aniline in
DMF at 100 °C.53c
39
Table 3. The effect of solvent on addition of Meldrum’s acid 78 to nitroalkene 26d
Entry Solvent Time (h) Conversion (%)a ee (%)b 1 CH2Cl2 10 >95 72 2 Et2O 21 >95 69 3 THF 18 >95 72 4 PhCl 16 >95 78 5 MeCN 17 >95 56 6 DMF 18 >95 16
Reaction conditions: 0.8 mmol nitroalkene, 1.6 mmol of Meldrum’s acid, 10 mol % of 79, 0.5 mL solvent, rt. a) Determined by 1H NMR spectroscopy. b) Determined by chiral HPLC from the anilide derivative 87d.
The solvent screen showed little significant difference in enantioselectivity between CH2Cl2,
Et2O or THF, with chlorobenzene giving a maximum ee of 78% (entries 1-4). The
enantioselectivity was slightly suppressed in acetonitrile, and nearly completely eroded in
DMF (entries 5-6). This would be expected for solvents that function as good H-bond
acceptors or donors, as the solvent disrupts the optimal H-bond binding between the catalyst
and substrates. Similar tendencies have been observed with thiourea catalysts by Takemoto
and Soós.22a,30b
Although chlorobenzene gave the best enantioselectivity in the solvent screen, we chose to
complete substrate screening in the original conditions using CH2Cl2 as a solvent, due to the
lower solubility of Meldrum’s acid into chlorobenzene. Results from the substrate studies are
presented in Table 4. There is little difference in activity and selectivity between EDG- and
EWG-substituted aromatic substrates (entries 1-5), a fact noted also by Takemoto and
Wang.22b,25 Heteroaromatic substrates behave in a similar manner (entries 6-7). Surprisingly,
the best enantioselectivities were attained with the original substrate 26d. Aliphatic substrates
in general gave higher selectivities than aromatic nitroalkenes (entries 8-11). This goes
against the common trends reported in connection with bifunctional thiourea catalyzed
Michael additions. In Takemoto’s studies, the enantioselectivities dropped to 81% when
aliphatic nitroalkenes were used as substrates for the Michael-addition of diethyl malonate
23.22b Similar erosion in enantioselectivity was noted by Connon and Dixon in their respective
studies.30c,d
40
Table 4. Addition of Meldrum’s acid to nitroalkenes 26a- l
Entry R Time (h) Conversion (%)a ee (%)b 1 Ph (26a) 8 >95 49 2 4-MeO-C6H4 (26b) 9 >95 53 3 3-MeO-C6H4 (26e) 12 >95 55 4 4-BrC6H4 (26f) 17 >95 57 5 3-BrC6H4 (26g) 8 >95 47 6 2-furyl (26h) 9 >95 47 7 3-furyl (26i) 9 >95 48 8 Cy (26j) 49 91 59 9 n-C4H9 (26k) 19 >95 68
10 i-Bu (26d) 10 >95 72 11 BnOCH2 (26l) 7 >95 62
Reaction conditions: 0.8 mmol nitroalkene, 1.6 mmol of Meldrum’s acid, 10 mol % of 79, 0.5 mL CH2Cl2, rt. a) Determined by 1H NMR. b) Determined by chiral HPLC from the anilide derivative 87a-l.
To compare the performance of our catalyst to the studies of Takemoto, Connon and Dixon,
we turned to other nucleophiles such as dimethyl malonate 51 and acetylacetone 24 (Scheme
23). To our considerable surprise, 79 was unreactive in the simple model reaction between
26a and dimethyl malonate 51, giving a racemic product in 14% yield. Using 24 as the
nucleophile showed slight improvement, giving the product 28a in 37% yield with an ee of
46%.
Scheme 23. The addition of different C-nucleophiles catalyzed by 79
41
These results raised some questions concerning the mechanism of bifunctional thiourea
catalysts. According to the commonly accepted mechanistic hypothesis, the thiourea moiety
of the catalyst associates with the electrophile (e.g. nitroalkene), while the deprotonated
nucleophile forms an ion pair with the tertiary amine. Takemoto determined that the
organocatalytic Michael addition of a malonate nucleophile into nitrostyrene 26a follows
pseudo first order kinetics with respect to all reaction partners. No nonlinear effect was
observed with respect to the enantiomeric purity of the catalyst. Based on the kinetic data and 1H NMR titration experiments of 26a in the presence of the Schreiner thiourea 12, they
proposed a ternary complex to operate in the transition state of the reaction (Figure 5).22b The
groups of Soós and Papai carried out theoretical studies on Takemoto’s catalyst.58 Their
conclusion was that while the coordination scheme proposed by Takemoto soundly explains
the observed selectivity, a reversed situation where the nucleophile (acetylacetone) is
coordinated to the thiourea and the nitroalkene to the quaternary ammonium N-H is in fact
energetically more favorable by 2.7 kcal/mol (Figure 5, gas-phase calculations, 1.9 kcal/mol
with solvation energies accounted for). Based on their calculations, they also confirmed
Takemoto’s mechanistic speculation that the formation of an ion pair between the
deprotonated enolate form of the nucleophile, and protonated catalyst is the first step in the
catalytic cycle. It would also intuitively follow that the nucleophile stays close to its optimal
geometry due to extensive H-bond stabilization from both thiourea and quaternary ammonium
N-Hs. They also found that the same alternative route gives similar results in the cinchona
derived thiourea catalyzed addition of nitromethane into chalcones.58
Figure 5. Proposed transition states of thiourea catalyzed nitro-Michael addition by Takemoto (left) and Pápai (right) (bond lengths exaggerated for clarity)
Comparison of the pKa values of the substrates and catalyst suggests that the quinuclidine
nitrogen alone (pKaH 9.8 in DMSO)59 is by far not basic enough to deprotonate dimethyl
42
malonat
deproto
malonat
pronucl
ternary
the thio
computa
or �-dik
calculat
nucleop
nucleop
enolizat
exists s
extent i
Figure
form.62
bonding
slower t
Figure Compouand 3.56form.
In the c
bonding
te, whereas
nated by n
te51a) in D
eophile, the
complex pr
ourea as sh
ational stud
ketone, is de
tions.22b,58,61
phile activa
philic in com
tion constan
solely in its
n nonpolar
6), and is t
This differ
g catalysts,
than those o
6. 1H NMund 51 show6 ppm are
ase of dime
g of one or
s the unusu
nearly any b
DMSO. Wh
e complete
roposed by
hown on th
dies, the 1,3
epicted in it1 For 1,3-d
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mparison to
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s diketo for
solvents (r
thus much
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with react
of acetylace
MR spectra ws no enol 1.90:1 (CH
ethyl malon
both carbon
ually acidic
base. Acety
hile the re
lack of rea
Takemoto
he left in F
-dicarbonyl
ts enol form
dicarbonyl
the enol O
o the uneno
onate dieste
rm (Figure
roughly 4:1
more easily
activity has
tion times
etone.22b,57a,6
of dimethcontent, butvs. CH2), r
ate, it is mo
nyl groups
Meldrum’s
ylacetone ha
eactivities w
activity in t
et al. In bo
Figure 5. In
l nucleophil
m prior to de
compound
O-H is mu
olized form
ers, and acc
6). In cont
enol:diketo
y deproton
been obser
of malonat63
hyl malonatut 24 is 80%roughly cor
ost likely th
to the thiou
s acid (pKa
as a pKa of
with 79 d
the case of
oth cases th
n Takemot
le, whether
eprotonation
s the enol
uch more a
. However,
cording to
trast, acetyl
o according
ated by ter
rved in seve
te diesters
te 51 and % enolized, trresponding
hat the depro
urea moiety
a 7.32 in D
f 13.360 (vs
o reflect t
51 does no
e nitroalken
o’s model
a malonate
n in mechan
form is m
acidic and
little or no
our observ
lacetone is
g to 1H NMR
tiary amine
eral studies
usually bei
acetylacetothe ratio of
to a 3.8:1 r
otonation st
y, thus acidi
DMSO)51a is
s. 15.9 of d
the acidity
ot sit well
ne is coordi
and corres
diester, �-k
nistic propo
more desir
the a-carbo
o data exist
vation, in C
enolized to
MR spectra s
es alone in
on bifunct
ing four to
one 24 in signals at 5ratio of eno
tep is assiste
ifying the �
s readily
dimethyl
y of the
with the
inated to
sponding
ketoester
osals and
able for
on more
ts on the
CD2Cl2 it
o a high
shown in
its enol
ional H-
o tenfold
CD2Cl2. 5.52 ppm ol-diketo
ed by H-
�-protons
and assi
of Schre
and a d
same tim
anilinic
malonat
accordin
in its dik
Figure thioureamol % 1
Based o
N-H-pro
substitu
ability o
which i
Schrein
carbon s
of pKa
substitu
values a
isting the ba
einer thiour
downfield sh
me a maxim
nitrogen.
te pronucleo
ng to 1H NM
keto form.
7. 1H NMRa 12 in CD212. All spec
on these pre
otons of 79
uent preven
of catalyst
is supporte
ner’s measur
substituents
8.5, and t
uted 79 wou
about 19.6 i
asic amine
rea 12 in CD
hift of 0.00
mum shift o
This sugge
ophiles for
MR spectro
R shifts of 2Cl2. Blue: pctra calibrat
emises, two
9 do not co
nts this thro
45 is highl
d by Takem
rements, th
s are alkyl g
the catalyst
uld be closer
in DMSO (F
in the enoli
D2Cl2 show
05 ppm for
of 0.17 ppm
ests that th
the deproto
oscopy in th
dimethyl mpure 51; Reed relative t
different p
ordinate str
ough steric
y assisted b
moto’s, Sch
he thiourea
groups. The
t 88 lies in
r to the Jaco
Figure 8).21e
ization step
w a downfie
the O-Me
m was obser
he bidentat
onation step
he enol cont
malonate 51ed: ~10 mol to CD2Cl2 i
possibilities
rongly enou
interaction
by the elect
hreiner’s an
N-H pKa:s
symmetric
n between
obsen-List te,65
p. 1H NMR
eld shift of 0
protons wa
rved for the
te H-bond
p. However,
tent of 51, w
CH2- and O% 12; Gree
internal sign
now arise i
ugh to the n
ns. In comp
tron withdr
nd Cheng’s
are around
thiourea 12
with pKa
type catalys
titrations of
0.03 ppm fo
as observed
e thiourea p
coordinatio
there is no
which rema
OMe-groupen: ~20 molnal before o
in our case:
nucleophile
parison, the
rawing arom
s studies.17,
d 20 in DM
2 has an inc
value at 1
t 89 in thiou
f 51 in the p
for the CH2-
d (Figure 7)
protons orth
on is impo
o observable
ains practica
p in the prel % 12, Pur
overlaying.
: either the
e or the bul
e H-bond d
matic N-sub,22b,23 Acco
MSO when
credibly high
12.4.64 The
urea acidity
43
presence
-protons,
). At the
ho to the
ortant to
e change
ally fully
sence of rple: ~30
thiourea
lky trityl
donating
bstituent,
rding to
both N-
h acidity
N-trityl
y, having
44
Figure 8. Thiourea N-H acidities of common catalysts according to Schreiner
To test this, we first synthesized catalyst 92 from epi-9-amino-(9-deoxy)quinidine 90 and
cyclohexyl isothiocyanate 91. Compound 90 was synthesized according to literature
procedures via the Mitsunobu-Staudinger protocol.31,49 In the model reaction between 26a and
51 catalyzed by 92, a yield of 73% and an ee of 73% was achieved (Scheme 24). Hence, the
catalyst retained its activity even though the acidity of the thiourea N-H groups was severely
perturbed. This would suggest that the steric interactions between the N-trityl moiety of 79
and dimethyl malonate suppress the required nucleophile enolization step (Figure 9). It is
likewise conceivable that the bulky trityl group forces the thiourea N-H bonds to be in
unfavorable cis/trans conformation with respect to the central thiocarbonyl moiety instead of
the trans/trans conformation usually presented in drawn schemes. At the time of our studies,
less than 20% published crystal structures of thiourea compounds show the trans/trans
conformation.66 An example of cis/trans thiourea conformation within a catalyst was
observed by X-ray crystallography during our studies towards the synthesis of (S)-pregabalin:
a catalyst otherwise analogous to 79 but carrying a N-9-phenylfluorenyl substituent (in
principle a rigidified trityl) adopted said conformation in crystal structure (Figure 10).49,66
�
45
N H
HN
HN SN
O
92
+O O 92 (10 mol %)
CH2Cl2, rt, 24 hPh
NO2
O O
MeO OMeMeO OMe
73%, ee 73%
51 52a
PhNO2
26a
N H
H2NN
O
+
90
NCS
THF, rt
48%91
Scheme 24. Synthesis of catalyst 92 and its performance in the model reaction
Figure 9. Plausible model of malonate deprotonation by thiourea catalysts and possible steric interactions between N-trityl substituent and malonate nucleophiles with catalyst 79
46
Figure 10. X-ray structure of a 9-phenylfluorenyl substituted thiourea catalyst (from Ref. 49)
A sulfonamide derivative 94 based on the same cinchona scaffold was reported by Lu et al.
during the course of our studies.67 This catalyst was active in the Michael additions of mono-
and bicyclic �-ketoesters into nitroalkenes, indicating that a bidentate H-bond donor is not
always a crucial feature of the catalyst structure in these reactions (Scheme 25). We decided
to investigate further whether a bidentate hydrogen bonding is essential in our case. To this
end we synthesized catalysts 96 and 97, in which one of the thiourea N-H groups is in turn
replaced by an N-Me group (Figure 11).
Scheme 25. Monodentate cinchona derived H-bond catalyst by Lu
47
Figure 11. Catalysts 96 and 97 with a perturbed thiourea moiety
Catalyst 96 was synthesized as shown in Scheme 26. Monomethylation into 99 was carried
out by carbamoylation with EtOCOCl and subsequent LiAlH4-reduction of 98, and the
desired product was isolated after SiO2 chromatography. The standard thiourea formation was
then accomplished by reacting 99 with 3,5-bis(trifluoromethyl)phenyl isothiocyanate 100 to
give 96.
Scheme 26. Synthesis of monomethylated thiourea 96
The counterpart catalyst 97 was achieved by reversing the scaffolds of the isocyanate and the
amine.49 First, 90 was treated with CS2 in the presence of DCC to give the isothiocyanate 101
48
in good yield (Scheme 27). Compound 101 and its other cinchona relatives are versatile
synthons in themselves, and can be used to synthesize a variety of different
organocatalysts.49,68 It was our hope that we could add a methylated aniline into 101 to give
catalyst 97 in a straightforward manner. Monomethylation of 3,5-bis(trifluoromethyl)aniline
102 was attempted by an analogous carbamoylation-LiAlH4-reduction route, but partial
defluorination of carbamate 103 was observed after the reduction step (Scheme 28).69
N
H2NN
OMe
90
CS2, DCC
THF, –15 °C to rt
N
NN
OMe
101
CS
74%
Scheme 27. Synthesis of isothiocyanate 101
Scheme 28. Attempted synthesis of monomethylated aniline 104
Eventually, 104 was synthesized via a three step reaction sequence.70 Aniline 102 was first
acylated with TFAA in CH2Cl2, then treated with K2CO3 and MeI in acetone, and finally
hydrolyzed with K2CO3 in a 5:1 mixture of MeOH:H2O. The crude product was obtained in
90% yield over three steps with acceptable purity, and was used as such (Scheme 29).
49
CF3
F3C NH2
102
TFAACH2Cl2, 0 °C to rt
CF3
F3CHN
105
CF3
OMeI, K2CO3
Acetone, rfx.
CF3
F3C N
106
CF3
O
Me
K2CO3
5:1 MeOH:H2OCF3
F3CHN
104
Me90% over 3 steps, used without purification
Scheme 29. Synthesis of monomethylated aniline 104
Whereas the thiourea formation usually proceeds at ambient temperature without external
catalysts, direct coupling between 101 and 104 to give 97 was in this case unsuccessful, most
likely due to a combination of low nucleophilicity of the highly electron poor aniline and
steric shielding of the isothiocyanate 101. A copper(II)-mediated coupling was attempted but
with no success. Deprotonation of 104 with NaH both with and without the presence of 15-
crown-5 was equally unsuccessful. In both cases, most of the aniline was recovered, but
decomposition of the isothiocyanate was observed. A crossed thiophosgene coupling between
101 and 104 was likewise unsuccessful. The coupling was eventually achieved by
deprotonating 104 with n-BuLi at –78 °C, after which a solution of 101 in THF:DMF was
added to the mixture, which was then gradually warmed to room temperature (Scheme 30).
The reaction gave two products of identical mass which were highly similar according to 1H
NMR spectra. The correct product was assigned by thorough comparison with literature
data.30b
Scheme 30. Synthesis of monomethylated thiourea 97
50
Both catalysts 96 and 97 were nearly completely unreactive in the model reaction, giving little
product with poor enantioselectivity of 13% (Scheme 31). Hence, the bidentate thiourea
moiety is an essential feature of the catalyst structure, and its perturbation leads to loss of
reactivity. The methylation of the anilinic nitrogen also reversed the selectivity, giving the
opposite enantiomer than previously observed.
Scheme 31. Addition of dimethyl malonate 51 into nitroalkene 26a catalyzed by 96 or 97
The inactivity of 96 and 97 supports the proposition that bidentate coordination between 51
and thiourea is necessary for the deprotonation of the nucleophile. To further investigate the
nucleophile deprotonation in the reaction, 1H NMR titration of 51 was performed in the
presence of 7 to 40 mol % of catalyst 88 in CDCl3. In contrast with the Schreiner thiourea 12,
no expected downfield shift was observed for the methylene protons in the presence of 88.
When the 1H NMR spectrum of 51 was recorded in the presence of D2O alone (in MeCN-d3),
there was no significant shift or peak deformation. After addition of Et3N, the CH2 peak was
shifted upfield by 0.22 ppm, indicating a Lewis-basic solvation behavior between Et3N and 51.
No immediate deprotonation was observed, which correlates with the pKa differences between
51 and Et3N. The deprotonation of dimethyl malonate in the presence of the Schreiner
thiourea 12 is very quick. In the presence of 35 mol % of 12 and D2O, the CH2-peak of
dimethyl malonate disappears completely and immediately after the addition of Et3N.
In subsequent experiments we loaded a solution of 51 in MeCN-d3 to an NMR tube in the
presence of 20 mol % of 88. After addition of 0.1 mL of deuterium oxide and quick vigorous
shaking, the first 1H NMR measurement showed the disappearance of the sharp methylene
CH2 peak at 3.38 ppm, and the appearance of a broad singlet at 3.28 ppm. The integrals
matched roughly the intensity relationship 3:1 with the methyl ester peak. The experiment
was repeated in acetone-d6 using MeOD-d4 as the deuterium source. This time we observed a
gradual disappearance of the CH2 signal and the formation of a small amount of
monode
12).
Figure MeOD-50 minpresenta
The exp
observe
40% of
trityl su
moiety
Figure MeOD-addition
euterated 51
12. 1H NM-d4. From bon after addation.
periment wa
ed in 20 min
monodeute
ubstituent ef
of catalyst 7
13. 1H NM-d4. From bn of MeOD-
1, identified
MR spectraottom to top
dition of M
as repeated
nutes. After
erated 51 pr
ffectively b
79, and sub
MR spectraottom to to-d4. Spectra
d by the trip
a of dimethp: 51 and 8
MeOD-d4. S
with 51 in
12 hours, r
resent in the
blocks malo
sequently th
a of dimethop: 51 and 7a have been
plet signal a
hyl malonat88 without MSpectra hav
n the presen
roughly 60%
e mixture (F
onate nucleo
he catalytic
hyl malonat79 without offset manu
t 3.41 ppm
te 51 in theMeOD-d4; 2ve been of
nce of cataly
% of 51 had
Figure 13). H
ophiles from
cycle is als
te 51 in theMeOD-d4; ually for cla
next to the
e presence 2 min; 5 miffset manu
yst 79, but
been depro
Hence we c
m coordinat
so disrupted
e presence 5 min; 20 m
arity of pres
CH2 signal
of catalystin; 10 min;
ually for cl
no deuterat
otonated, wi
conclude tha
ting to the
d.
of catalystmin; 12 hosentation.
51
l (Figure
t 88 and 20 min;
larity of
tion was
ith about
at the N-
thiourea
t 79 and urs after
52
2.5 Conclusions
We have explored the properties of the N-trityl substituted thiourea catalyst 79 and its
applicability to nitro-Michael reaction. The catalyst performs best in the original reaction to
which it was optimized, giving otherwise mediocre enantioselectivities in the Michael
addition of Meldrum’s acid into aromatic and heteroaromatic nitroalkenes. It is noteworthy
that the catalyst gives better enantioselectivities for alkyl substituted than for aryl substituted
nitroalkenes, whereas the reverse trend is commonly observed in method development.
Catalyst 79 also suffers from substrate limitations. It was unable to catalyze the reaction
between dimethyl malonate and aromatic nitroalkenes, possibly due to steric hindrance caused
by the bulky N-trityl substituent. Malonate nucleophiles are ostensibly not able to effectively
coordinate to the thiourea moiety for assisted methylene proton acidification and
deprotonation by the tertiary amine. NMR experiments confirm that the catalyst 79 is unable
to deprotonate malonate like nucleophiles. This was also investigated with thiourea N-
methylated analogues 96 and 97 of Chen-Soós-Connon-Dixon type catalyst. When the
bidentate thiourea moiety was perturbed, the activity and selectivity of both catalysts in the
model reaction was significantly poorer than the original catalyst. The activity of 79 with
Meldrum’s acid would then seem to be mediated through a chiral acid-base ion pair formation.
Whether the thiourea moiety in 79 directs the nitroalkene via two explicit hydrogen bonds
remains unclear, since the bulky trityl substituent may force the N-Hs to adopt a cis/trans-
conformation with respect to central thiocarbonyl group.
53
3 STUDIES TOWARDS THE TOTAL SYNTHESIS OF (–)-
HENNOXAZOLE A
Hennoxazoles (Figure 14) constitute a family of biologically active marine alkaloids isolated
from Polyfibrospongia sp. in the early 1990s.71 Of these, (–)-hennoxazole A (107a) has
shown the most potent antiviral activity against herpes simplex 1 virus with an IC50 of 0.6
�g/mL. The distinctive bisoxazole core combined with a stereochemically elaborate
tetrahydropyran ring and a skipped triene containing a single distant stereocenter at C22 make
107 an interesting target for total synthesis. A similar directly joined bisoxazole moiety has
thus far been identified only in muscorides and diazonamides. To date, four different total
syntheses for (–)-hennoxazole A have been reported, and these are briefly reviewed in section
3.3.1.72
Figure 14. The hennoxazole family of marine natural products. Only the stereochemistry of (–)-hennoxazole A has been confirmed to be that shown here.
54
During the last decade, the Ley group has been developing laboratory scale continuous-flow
reactors and technologies and their application to organic synthesis.73 Their goal was to create
a total synthesis of (–)-hennoxazole A in which all or most of the steps would be carried out
in continuous-flow conditions. An overview of continuous-flow technologies, benefits and
disadvantages is given in below in Section 3.1.
3.1 Continuous Flow Technologies
During the last decade, the application of micro- and mesofluidic continuous flow conditions
in laboratory scale has been developed into a powerful enabling technology for synthetic
chemists.74 Several research groups both in the academic world and in the industry are
currently in the process of exploring the limitations and possibilities of continuous flow
conditions in organic synthesis. Whereas a “do it yourself” mentality has served well in the
early development of continuous flow methodologies, the 2000s have seen the launch of
commercial laboratory scale equipment that can be used in a highly modular fashion.75 These
technologies range from microfluidic chips to fully integrated reactor systems which are
usually based on commercial HPLC equipment, with specific modifications to answer specific
needs. A standard example is the ThalesNano H-Cube® flow hydrogenator, in which a
solution of the substrate is pumped through a cartridge filled with an immobilized
hydrogenation catalyst, e.g. Pd/C.76 Hydrogen is produced on demand in an integrated
electrolytic cell and mixed into the substrate stream before the cartridge, thus circumventing
the problem of storing and handling hazardous gases (although at a nontrivial energy cost).
Below we shall consider the benefits and disadvantages of carrying out organic synthesis in
continuous flow conditions using microreactors.
3.1.1 Benefits and Disadvantages of Continuous Flow Conditions
The mechanism of a reaction obviously does not change when transferred from batch to flow
systems. However, the differences in mass and heat transfer properties of the reactor system
may have a profound effect on the rate and selectivity of the reaction in question. Some recent
reviews shed light on these issues in a highly lucid fashion.74e,f Overall, one of the greatest
advantages of continuous flow conditions is the precise control over reaction parameters due
to the enhanced mass and heat transfer properties.
55
One of the most important issues of carrying out a chemical reaction is the proper and
efficient mixing of reagents. In microreactors (reactor channel diameter 10-500 �m), laminar
flow conditions usually exist (Re <2000), and mixing of reagents takes place via diffusion. It
has been calculated that for a molecule of typical diffusivity, it takes 30 seconds to achieve
complete mixing in a reaction channel of 400 �m i.d. With specifically fabricated
micromixers, this mixing time can be reduced to the order of 10 milliseconds. This is highly
beneficial for extremely fast reactions for which the rates are controlled by mass transfer. For
reactions in which substrates may react further than to the desired product, fast mass transfer
usually results in better selectivities.77
The volume-area relationship of continuous-flow reactors is usually very high, on the order of
5000-50000 m3/m2, which makes heat transfer into and from the reaction system very
efficient, depending on the thermal conductivity of the reactor material. This is highly
beneficial for reactions that release powerful exotherms, such as lithiation reactions. The
group of Yoshida has made significant contributions in this field, carrying out highly
exothermic and fast lithium-halogen exchange reactions with residence times of less than a
second in a cooled glass chip reactor.78 Even though the released energy per reactant mole is
impressive, in a microfluidic environment there are only small amounts of reacting materials
at a given moment, and hence the exotherm may be compensated by the high thermal
conductivity.
The contained environment and relative ease of pressurizing a continuous flow reactor
enables the superheating of reaction solvents above their boiling point in atmospheric pressure
in a safe manner.74g,79 Thus reactions that are accelerated by high pressures (reactions with
negative volume of activation/volume change) and temperatures, such as Diels-Alder
reactions, may be beneficially transferred to continuous flow conditions.80 Unstable,
hazardous and noxious reagents and intermediates are likewise contained in the reactor
system, and thus carrying out certain reactions may be significantly safer.81
The most obvious problem of microfluidic technologies lies in the intrinsic micro aspect.
Reaction channels that are usually less than 0.5 mm in diameter are highly prone to clogging
by salts and products crystallizing out from a reaction mixture.82 At worst this can lead to
powerful pressure buildup in the system and subsequent rupturing of the reactor vessel, coil or
chip, or other damage to the pumps and valves. When dealing with the issue of precipitation
and clogging, the reaction conditions in question usually need to be modified to suit the
microfluidic system. Lowering the concentration and changing the solvent system are obvious
56
methods, which however may lead to suboptimal performance of the reaction and increased
amounts of solvent waste.
When continuous flow conditions are applied to multistep synthesis, reaction monitoring and
coordination of further steps may become problematic (so-called “third stream problem”). In
tubular reactors where the fluid flow is laminar there is always some diversion from an ideal
plug-flow, which leads to axial dispersion and a bell curve shaped reactant concentration with
respect to time and reactor length.83 The injection of subsequent reactant streams has to be
coordinated so that there is minimum loss of substrates. In a continuous process this is an
issue only in the beginning, before reaching an equilibrium state. If a multistep process is
performed in a plug flow manner (e.g. in discovery chemistry for pharmaceuticals), there is a
need for robust in line monitoring and automation so that the injection of further reactant
streams may be triggered when a desirable concentration of product is observed.
3.1.2 General Strategies for Continuous Flow Synthesis
Transferring a reaction from batch to continuous flow conditions often requires a change in
the overall philosophy of chemistry.84 As will also be shown in Chapter 4, homogeneity of the
reaction becomes a major consideration and affects directly reactant concentration in solution.
In line quenching and purification of the reaction mixture is another important consideration.
Solid supported reagents, such as acidic and basic resins have been widely used for both
purposes. However, solid supported reagents suffer from the obvious drawback that they have
a specific loading capacity, and for large scale synthesis, which in flow conditions translates
to long operating time, such reagents should periodically be either replaced with new material
or regenerated with a washing sequence.
Catalysis in continuous flow conditions can be approached with several strategies.
Homogeneous catalysis may be carried out in continuous flow conditions in an analogous
manner to flask chemistry just by injecting the catalyst into the reaction stream.85 Product
isolation and catalyst separation then become the crucial issues. These may be solved by
scavenging reagents, catch and release techniques (of either catalyst or product), or by
incorporating a reactive tag in the catalyst structure which enables further operations.
Immobilizing a catalyst on a solid support is one of the ideal solutions, but it is usually
associated with both benefits and disadvantages.86 Immobilization forces reactions to take
place on the catalyst surface, which usually has a detrimental effect on reaction kinetics.
Another adverse kinetic effect may be caused by the improper porosity of the catalyst, since
57
the diffusion time for substrates to reach a catalytic site within the support matrix is
lengthened. If the porosity is suboptimal, some of the catalyst might be completely occluded
and cannot come into contact with the substrates. In the case of asymmetric catalysis, the
steric effects caused by the structure of the solid support may also deteriorate catalyst
selectivity. Further issues are e.g. the mechanical, thermal and chemical stability of the
support and its swelling properties in different solvents. Most of these issues depend on the
synthesis of the solid support (degree of cross linking in a polymer, polymer beads vs.
monolithic column, sol-gel synthesis of SiO2 with controlled pore size, etc.) and the method
of catalyst immobilization (co-polymerization, grafting, etc.). This is a science in itself and
beyond the scope of this thesis.
The highly automated synthesis of racemic oxomaritidine illustrates several key issues and
strategies in flow chemistry (Scheme 32).87 A solution of bromide 110 in 1:1 CH3CN:THF
was passed through an ion exchange resin to give the azide 111, which was subsequently
immobilized as the corresponding iminophosphorane on a butylphosphine functionalized
resin. Aldehyde 113, obtained by oxidation of the corresponding alcohol by passing a THF
solution through a column packed with immobilized tetra-N-alkylammonium perruthenate,
was pumped with 111 through a phosphine column to yield the aza-Wittig product 114. The
imine was then reduced to the amine 115 with a flow hydrogenator equipped with a 10% Pd/C
catalyst cartridge. After a manual solvent exchange from THF to CH2Cl2, the amine was
trifluoroacetylated in a chip reactor, and then passed through a column loaded with a PIFA-
functionalized resin to effect the oxidative phenolic coupling to give the intermediate 117.
Treatment of 117 with a strongly basic resin in the presence of a 4:1 MeOH:H2O side stream
hydrolyzed the amide, which then underwent a spontaneous conjugate addition to give
racemic oxomaritidine 118 in an overall yield of 40%. Most impurities were scavenged by the
basic resin, and the natural product was obtained with excellent purity.
58
Scheme 32. Continuous flow synthesis of racemic oxomaritidine
The time taken by the synthesis was 8 hours, which is significantly faster than performing the
same synthesis with traditional methods, albeit the scale of the flow synthesis is rather small.
Planning and optimizing each step of a multistep synthesis like oxomaritidine obviously is
quite time consuming. However, providing that a great number of known robust
transformations can be carried out in flow conditions, chemists should be able to perform
multistep flow syntheses routinely in the near future. The synthesis of oxomaritidine also
illustrates one of the greatest benefits of continuous flow systems. With each step telescoped
into the next one, the number of required unit operations is reduced significantly, since there
are no extraction or chromatography steps included, with only two evaporation steps. This
equates directly to reducing waste and saving consumables such as solvents and SiO2, but
even more importantly, time and manpower.
59
3.2 Covalent Organocatalysis
As stated in section 2.1, the other major category in organocatalysis is usually called covalent
catalysis.9b For carbonyl containing substrates this includes e.g. the enamine and iminium
manifolds, which are usually accessed by using chiral primary and secondary amines as
catalysts (Figure 15). Catalysis achieved by structures such as 119-121 is also commonly
called aminocatalysis. Reactions carried out this way include e.g. aldol reactions, Mannich
reactions, conjugate additions, and Diels-Alder reactions among other cyclizations. Other
examples of covalent organocatalysis include the use of tertiary amines or
phosphines/phosphites such as 123 as nucleophilic catalysts, such as in Morita-Baylis-
Hillman reactions. Umpolung type reactions of aldehydes such as Stetter reaction or benzoin
condensation are usually carried out with thiazolium catalysts or other nitrogen containing
heterocycles such as the precatalyst 122 that may form a stable ylide (or carbene).
Figure 15. Representative examples of catalysts in covalent organocatalysis
3.2.1 Enamine Catalysis
Aliphatic aldehydes and ketones are able to form enamines in the presence of primary and
secondary amines under dehydrating conditions. Enamine formation enhances the
nucleophilicity of the parent carbonyl �-carbon, thus making enamines highly useful specific
enol equivalents in organic synthesis.10b Being unstable species and prone to rapid hydrolysis
in aqueous environment, most enamines are difficult to isolate and separate from reaction
mixtures. However, the catalytic formation of enamines in the presence of an amine has
enabled a wide variety of reactions to be carried out under mild organocatalytic conditions.10a
When a chiral amine is used as the catalyst, the resulting enamine carries the chiral
information of the catalyst, and a stereoselective reaction with an electrophile ensues. The
60
topic of enamine catalysis has been widely reviewed recently,9b,c,10 and herein we shall only
consider some crucial theoretical aspects and examples.
The formation of an enamine raises the HOMO energy of the enolate C=C bond and thus
enhances the �-carbon nucleophilicity of a ketone or an aldehyde in comparison to the bare
enol form. The classical enamine catalysis cycle is presented in Scheme 33. The origin of
enantioselectivity in the reactions of e.g. proline has been explained by the Houk-List model
which accounts for intermolecular hydrogen bonding/Brønsted acid-base interactions to take
place between the catalyst-enamine species and the electrophile (Figure 16, I).88 The
minimum energy transition state has the Re-face of the E-enamine attacking the aldehyde
from the Re-face, with coordination assisted by H-bonding, leading to the usually observed
anti selectivity. For catalysts without a directing H-bond donor or Brønsted acid, such as the
Hayashi-Jørgensen type diarylprolinol silyl ethers,89 the bulky substituent blocks the other
side of the enamine, directing the attack to take place from the unhindered side (Figure 16,
II).90
Scheme 33. Enamine catalytic cycle shown for aldol reactions
61
Figure 16. Origin of enantioselectivity in enamine catalysis
3.2.2 Asymmetric Organocatalytic Aldol Reactions
The importance of aldol reactions to organic synthesis cannot be overemphasized, and since
its discovery in the 1800s it has been developed into a versatile tool for C-C bond formation.91
In Nature, the aldol reaction is mediated by class I and II aldolase enzymes. Class I aldolases
contain a lysine residue in the active site, and they mediate their effect via iminium/enamine
formation.92 Class II aldolases incorporate a bivalent metallic Lewis acid cofactor, usually
Zn2+, which assists in the deprotonation of the nucleophile (e.g. dihydroxyacetone
phosphate).93 The studies into catalytically active aldolase antibodies carried out by Barbas
and Lerner in the late 1990s were one of the key factors leading to the discovery of proline-
catalyzed intermolecular direct aldol reactions.94
The first asymmetric organocatalytic aldol reaction was discovered in 1971 by two industrial
research groups independently. The intramolecular aldol reaction of 124a catalyzed by (S)-
proline 125 is known as the Hajos-Parrish reaction (Scheme 34).95 The Hajos-Parrish protocol
proceeds with good yields and enantioselectivities to give the bicyclic aldol addition product
126a, which is then dehydrated to give the versatile synthetic intermediate 127a. Using 124b
as a starting material gives the nonracemic version of the Wieland-Miescher ketone 127b,
albeit in slightly lower enantioselectivity. The concurrently published protocol used by Eder,
Sauer and Wiechert includes a strong acid component, which gives the dehydration product
directly.
62
Scheme 34. Hajos-Parrish reaction
The first proline catalyzed asymmetric intermolecular organocatalytic aldol reaction was
reported by Barbas, List and Lerner in 2000.8 The aldol addition of acetone to 4-
nitrobenzaldehyde 128 in DMSO, catalyzed by 30 mol % (S)-proline gives the product 129 in
68% yield and 76% ee (Scheme 35). Out of simple easily available proline analogues, 4-
trans-hydroxyproline 133 gives a significantly better yield in this model reaction,8 but only
5,5-dimethyl thiazolidine-4-carboxylic acid 134 was able to clearly outperform proline in
enantioselectivity.96 However, the studies by Barbas revealed that proline gives consistently
better yields and is applicable to a wider range of substrates.96
63
Scheme 35. Proline-catalyzed aldol reactions by Barbas & List
One of the greatest challenges of organocatalytic aldol reactions is the control of selectivity in
the intermolecular crossed aldol reaction between two reactive aliphatic aldehyde species.
Unsubstituted aliphatic aldehydes perform rather poorly as acceptors, since they are likewise
apt to form the catalytic enamine species with the catalyst. The situation becomes even more
challenging when ketones are used as the nucleophilic species due to faster enamine
formation between aldehydes and amines. Due to this, most methods development papers
concentrate on using reliable and reactive acceptors such as electron poor aromatic aldehydes.
The first crossed organocatalytic aldol reactions of aliphatic aldehydes were reported by
MacMillan in 2002.97 In their procedure, the donor aldehyde species was slowly added to the
reaction mixture with a syringe pump to suppress self-condensation. As an example,
propionaldehyde 136 and isobutyraldehyde 137 gave the addition product 138 in good yield
and excellent diastereoselectivity and enantioselectivity (Scheme 36).
Scheme 36. Crossed aldol reaction between aliphatic aldehydes by MacMillan
64
The evolution of catalysts for organocatalytic aldol reactions has been rapid ever since the
first publications by List and MacMillan, and the developments have been recently
reviewed.98 Application of these methods to more challenging syntheses and targets has,
however, been modest. Therefore some target oriented examples of organocatalytic aldol
reactions from the literature are highlighted below.
As a classic example, the Hajos-Parrish-Eder-Sauer-Wiechert protocol was applied to the total
synthesis of erythromycin by Woodward et al. (Scheme 37).99 The racemic precursor 139 was
subjected to (R)-proline, which gave the aldol products 140 and 141 in good yield but a
meager ee of 36%. Being an early step in the synthesis, this could be done on large scale, and
the material was recrystallized until optically pure. All stereochemical information of
erythromycin was derived from this step, the rest of the synthesis containing mostly internal
asymmetric induction and diastereoselective methods.
Scheme 37. Proline catalysis in the total synthesis of erythromycin
One of the earliest examples of proline catalyzed crossed aldol reaction in natural product
synthesis is the reaction between propionaldehyde and isobutyraldehyde as reported by Pihko
in 2003.100 The reaction proceeded to give the TBS protected aldol product 142 in 61% yield
over two steps (one pot aldol reaction and TBS protection) in an impressive ee of over 99%
and 40:1 anti:syn diastereoselectivity (Scheme 38). A further Mukaiyama aldol reaction and
lactonization gave the natural product (–)-prelactone B in three operations.
65
Scheme 38. Synthesis of (–)-prelactone B 145
In 2006 Wang et al. published a total synthesis of trichostatin A 147, in which 4-
nitrobenzaldehyde 128 was surprisingly used in a target-oriented setting (Scheme 39).101
Proline was used according to the MacMillan protocol to catalyze the reaction between
propionaldehyde and 128 in good yield over two steps and excellent selectivities (16:1
diastereomeric ratio, >99% ee). The aldol product was immediately protected as the dimethyl
acetal 146 due to the instability of the aldol intermediate, which was prone to decompose on
SiO2. A further 7 steps gave optically pure 147 with a 17% overall yield.
Scheme 39. Organocatalytic aldol reaction in the synthesis of trichostatin A 147
66
An aldol/oxa-Michael reaction cascade was used in a short total synthesis of �-tocopherol by
Woggon and co-workers.102 Diarylprolinol 150 catalyzed the cyclization between phytenal
149 and the highly substituted salicylaldehyde 148 to give the lactol 151 in 97%
diastereomeric excess (Scheme 40). The reaction proceeds via a dienamine pathway, the
phytenal skeleton first adding to 148, and a subsequent ring closure through 1,4-addition of
the phenolic group to the conjugated iminium intermediate. Completion of the synthesis gave
the C2-epimeric �-tocopherol. Synthesis of natural �-tocopherol was achieved by using the R-
enantiomer of the diarylprolinol catalyst. Other chromane and chromanone derivatives have
also been accessed with this method.103
Scheme 40. Aldol/oxa-Michael cascade in the synthesis of �-tocopherol
The MacMillan group used both (S)- and (R)-proline in their total synthesis of Callipeltoside
C (Scheme 41).104 The first step in the tetrahydropyran fragment synthesis was the aldol
reaction between propionaldehyde and Roche aldehyde 152. In spite of poor yield (48%), the
selectivities were once more admirably high (12:1 d.r., 99% ee). A second aldol reaction was
used in the construction of the sugar fragment. TIPS-protected �-hydroxyacetaldehyde 154
was dimerized using (R)-proline in good yield and 99% ee in the synthesis of the mannose
fragment. The NMR spectroscopic data of the finished product did not match with the natural
product. To correct this, the enantiomeric mannose was synthesized by using (S)-proline in
the first step with identical yield and enantioselectivity.
67
PMBO H
O
+
152
H
O
136
PMBO
OH
H
O
153
NH
CO2H
(S)-125 (10 mol %)
DMSO, 4 °CSlow addition (100 h)
48%, ee 99%anti:syn 12:1
H
OOTIPS
154
(R)- or (S)-125H
O
OTIPS
OHOTIPSorH
O
OTIPS
OHOTIPS
155 ent-155
O O NH
CCl3OMeHO
TIPSOor
O O NH
CCl3OMeHO
TIPSO
156 ent-156
DMF, 75%, ee 99%anti:syn not given
Scheme 41. Proline catalyzed aldol reactions in the synthesis of Callipeltoside C
A rare and early example of ketone addition to an �-unsubstituted aldehyde was presented in
the synthesis of (+)-ipsenol 160 by List.105 The addition of acetone to isovaleraldehyde 157
gave enone 158 as the main product via a formal aldol condensation in 42% yield, and the
aldol addition product 159 in 34% yield and 73% ee (Scheme 42). The poor yield and
enantioselectivity may be justified by considering that the reaction is the first step of a
synthesis, and cheap starting materials and catalysts are used. Overall, a substrate screen
carried out by List revealed that the condensation product tends to become the main reaction
product in proline catalyzed ketone aldol additions to unsubstituted aldehydes. Furthermore,
they postulated that the mechanism for the enone formation proceeds through a Mannich-type
addition of the ketone into the iminium species formed from the aldehyde and proline.
68
Scheme 42. Addition of acetone into an unsubstituted aldehyde in the synthesis of (+)-ipsenol
160
In conclusion, the application of organocatalytic aldol reactions into large scale synthesis and
target oriented synthesis is still rather underdeveloped. In most examples, the organocatalytic
step is placed in the early phases of the synthesis, and constricted to simple starting materials.
Taking into consideration the easy availability and low cost of e.g. proline, this approach is
perfectly justified. However, as the current state of the art catalysts require some synthetic
effort and often expensive enantiopure materials, the benefits may quickly be balanced out by
the cost and lost time.
3.2.3 Asymmetric Organocatalysis in Continuous Flow Conditions
Organocatalytic reactions in continuous-flow conditions are still something of a rarity, but
some interesting examples have already been reported.106 More research has been done with
immobilized ligand-metal complexes, e.g. Co(salen)-complexes have been used in dynamic
kinetic resolution107 and Ru-complexes in e.g. cyclopropanation reactions.108 The alkylation
of aryl aldehydes with diethyl zinc has been reported to proceed with good
enantioselectivities when immobilized chiral amino alcohols are used as ligands.109
Enantioselective Michael-addition of malonate nucleophiles to nitroalkenes has been achieved
with an immobilized CaCl2-PyBox-complex.110 Immobilized enzymes have also been used to
carry out e.g. kinetic resolution111 and oxidative dimerization-intramolecular cyclization in a
natural product synthesis setting.112 Asymmetric hydrogenation protocols have also been
investigated recently.113
69
An interesting early example of organocatalysis comes from the group of Lectka.114 They
synthesized �-lactams by gravity assisted flow of substrates through sequential packed
columns (Scheme 43). Acid chloride 161 was used as a ketene precursor, and let flow through
a cooled column packed with PS-BEMP 162 to form the ketene 163 in situ. Imine 164 was
then added in a side stream, and the mixture was let flow through a column packed with
immobilized quinine ester 165 to form the �-lactam via a [2+2] ketene cycloaddition. A third
column was packed with a nucleophilic primary amine resin to scavenge excess reagents and
byproducts. The lactam 167 was obtained in 65% yield and 93% ee after evaporation of
solvents, with a cis/trans ratio of 10:1.
N NMePN NEt2
t-Bu
PS-BEMP 162
PhCl
OPh C
O
–78 °C –40 °C
PS-O-acylquinine 165
EtO2C H
NTs
164
NH2
PS-Benzylamine
NTs O
PhEtO2C
167 65%, 10:1 dree 93%
O
O
O
O
N
N
OMe
161 163
166
Scheme 43. Lectka’s synthesis of �-lactams
The immobilized quinine 165 has also been used in an asymmetric �-chlorination of acid
chlorides by the Lectka group.115 The reaction was a part of a convergent multi-step gravity
driven flow through synthesis of the metalloproteinase inhibitor BMS-275291 (Scheme 44).
Chlorinating agent 168 and acid chloride 169 were fed through a column packed with 165,
and then through an immobilized piperazine-packed column to remove excess acid chloride.
Simultaneously through the other channel was fed a mixture of peptide precursors 172 and
70
173, which were coupled with an immobilized carbodiimide 174 to give the amide 175.
Fmoc-deprotection was then carried out in a column packed with tris-(2-aminoethyl)amine
resin 176. The streams were connected at this point to carry out the amide coupling between
activated acid 171 and deprotected peptide 177. The final step was an SN2 substitution of the
�-chloride with a hydrogen sulfide anion, which was preloaded on a quaternary ammonium
resin. The final product 179 was obtained in 34% overall yield and 83% diastereomeric
excess.
PS-Quinine 165
MeN N
O
O
Cl
O
OCl
ClCl
Cl
ClCl
+
168 169
MeN N
O
O
O
O
Cl ClCl
ClCl
Cl
NNH
PS-Piperazine 170
171
FmocHN
s-BuOH
O
H2N+t-Bu
NHMe
O
172 173
PS-Carbodiimide 174
N C N HN
FmocHN
s-Bu HN
O
175
t-BuNHMe
O PS-Amine 176H2N
s-Bu HN
O
177
t-BuNHMe
O
N
NH2
NH2
171
177
Celite NH
s-Bu HN
O
178
t-BuNHMe
OOCl
N
MeN
OO
NMe3SH
NH
s-Bu HN
O
BMS-275291 179
t-BuNHMe
OOHS
N
MeN
OO
Scheme 44. Solid-phase flow synthesis of BMS-275291 by Lectka
At the time of our studies there was only one published report on asymmetric organocatalytic
aldol reactions in continuous flow conditions by Seeberger’s group.116 They showed the proof
of principle of carrying out an organocatalytic aldol reaction in flow conditions. The addition
of acetone to substituted benzaldehydes could be carried out at elevated temperatures with no
significant deterioration in enantioselectivity when compared to batch conditions (Scheme 45).
However, no in line scavenging or purification procedures were considered, and the reactions
were worked up under standard conditions and purified by SiO2 chromatography after
collection.
71
Scheme 45. Continuous flow aldol reaction with homogeneous catalysis
The current state of asymmetric organocatalytic chemistry in continuous flow is progressing
rapidly, and several research groups are investigating the use of polymer or solid supported
reagents. The Pericàs group has recently made impressive advances in aldol and Mannich
reactions in continuous flow conditions with polymer supported prolines.117 Both
propionaldehyde and isovaleraldehyde could be added to glyoxalate imine 182 with high
selectivities by pumping the starting material stock solutions through a column packed with
triazole linked 4-trans-hydroxy proline 183 on a Merrifield resin (Scheme 46).117a
Scheme 46. Continuous flow Mannich reaction catalyzed by resin bound proline 183
The Pericàs group has also reported the use of a slightly different proline derivative 186 in the
aldol addition of cyclic ketones to aromatic aldehydes. In batch screening they found that
electron poor aromatic aldehydes gave best yields and selectivities. In a continuous-flow
setting, a mixture of 4-nitrobenzaldehyde 128 and cyclohexanone 185 in DMF:H2O (60:40)
was pumped through a column packed with 600 mg of swollen resin containing 186. The flow
rate was 25 �L/min, and residence time 26 minutes. Nearly 20 millimoles of 187 was
72
produced over the course of 30 hours at a constant conversion of above 80% (Scheme 47).117b
As a downside, the product had to be purified by SiO2 chromatography after the reaction to
separate it from possible side products and excess starting material.
Scheme 47. Continuous flow aldol reaction catalyzed by resin bound proline 186
In addition to silica or polymer supported reagents, non-covalent immobilization techniques
have been explored. In 2011 the group of Sels reported the use of chiral primary amino acid
derived diamines immobilized on solid acids as catalysts in the aldol reaction between
aliphatic ketones and aromatic aldehydes.118 The optimal catalyst system was determined in
batch conditions and consisted of phenylalanine derived diamine 190 and sulfonated
fluoropolymer Nafion® NR50. 4-(Trifluoromethyl)benzaldehyde 188 and 2-butanone 189
were pumped through a fixed bed at a flow rate of 1 mL/h (Scheme 48). Over the course of 11
hours, the cumulative yield of the aldol product 191 showed some signs of deterioration, and
the enantiomeric excess peaked at 4 hours at 97% ee, after which it also started to show some
erosion, although staying above 90% during the whole experiment.
Scheme 48. Non-covalent immobilized organocatalyst in continuous-flow aldol reaction
73
3.3 Total Synthesis of (–)-Hennoxazole A
3.3.1 Comparison of Previous Syntheses
Wipf’s synthesis of (+)-Hennoxazole A
The first total synthesis of hennoxazoles was published in 1995 by Wipf.72a The
stereochemistry of the pyranacetal ring and bridging chain was derived from two separate
Sharpless asymmetric epoxidations. The sole stereocenter in the triene fragment was attained
with a Corey-Itsuno reduction of stannane 192 (Scheme 49). A key step in the synthesis was a
Pd-catalyzed coupling between stannane 194 and bromide 195. The final molecular backbone
was constructed via an amide coupling between ester 196 and amine 197 to give the �-
hydroxy amide 198. The bisoxazole structure was then finished via sequential Dess-Martin
oxidation, cyclization, and dehydrohalogenation. Deprotection with TBAF gave the (+)-
enantiomer of hennoxazole A in 23% yield from 198. Overall the synthesis is rather long,
providing key fragments for the final coupling in 21 steps and 3% yield (for 196), and 15
steps and 3% yield (for 197). The stereochemistry of (–)-hennoxazole A was thus confirmed
to be the opposite of the final product attained by Wipf, based on the opposite optical rotation
while other spectral data was identical to (–)-107a.
74
Scheme 49. Key steps in the synthesis of (+)-hennoxazole A by Wipf
Synthesis of (–)-Hennoxazole A by Williams
The second total synthesis of (–)-107a was reported by Williams et al. in 1999.72b The
synthesis is slightly more convergent, with a bisoxazole core 202 synthesized first and then
coupled with pyranacetal precursor 200, and with a late stage Julia-Kocienski olefination to
append the triene tail (Scheme 50). The bisoxazole coupling partner 202 was constructed by a
double sequential mixed anhydride amide coupling, DAST-mediated cyclization and
dehydrogenation, and a final DIBAL-H reduction. The coupling to stannane 200 was
mediated by (R,R)-borane 201 with a 10.5:1 diastereomeric ratio. Stannane 200 was obtained
by transmetalation of the corresponding silane, which in turn was synthesized by copper-
catalyzed Grignard addition of 2-bromo-3-trimethylsilylpropene into epoxide 199. The
stereochemistry at C4 of the pyranacetal 206 was thus derived from (S)-epichlorohydrin which
was used as a starting material, and at C6 from a Terashima reduction of intermediate 206.
The triene precursor 207 for the Julia-Kocienski reaction was synthesized in 11 steps from 3-
butyn-2-one.
75
Scheme 50. William’s synthesis of (–)-hennoxazole A
Synthesis by Shioiri
In their synthesis from 2000, Yokokawa and Shioiri followed Wipf’s strategy of a late stage
amide coupling of amine 211 and acid 212, and subsequent oxidation/cyclization/dehydration
sequence to furnish (–)-hennoxazole A (Scheme 51).72c,d A key feature is a Mukaiyama-aldol
reaction between keteneacetal 209 and aldehyde 208 in the construction of the stereocenter at
C6, giving �-hydroxy ketone 210 as a 88:12 mixture of diastereomers. The remote
stereocenter in the skipped triene is derived from (S)-Roche ester. The first oxazoline
formation was carried out with Deoxo-Fluor mediated cyclization and subsequent
dehydrogenation with BrCCl3/DBU in good yield, but it is very surprising that the same
method was not attempted in the final cyclization, or at least no mention of a failed attempt
was given. The fragments 211 and 212 were synthesized in 18 and 17 steps, respectively, and
a further 6 steps were needed to obtain the final product, rendering the synthesis rather
inefficient. A suprising feature of the synthesis is that the skipped triene moiety is carried
along unchanged for several steps during the endgame, whereas concerns for its stability have
been a directing factor e.g. in the syntheses of Wipf and Williams.
76
Scheme 51. Late stages of Shioiri’s synthesis of (–)-hennoxazole A
Synthesis by Smith
The synthesis published by Smith in 2007 features some of the most elegant solutions to the
construction of (–)-hennoxazole.72e,f The TBS-protected bisoxazole core 217 was synthesized
in 9 steps, beginning with a condensation of serine methyl ester hydrochloride and ethyl
acetimidate to give the first oxazoline 215 (Scheme 52). Sequential dehydrogenation,
saponification and amide coupling with another serine methyl ester gave the amido alcohol
216, which was then cyclized using Deoxo-Fluor. Reduction, acetalization and TBS-
protection of the most labile C-H bond gave 217 in 5 steps. The coupling-ready bromide 222
containing the full triene portion was synthesized in 6 steps from commercial starting
materials with high enantioselectivity (98% ee), using an asymmetric Hoffman pentenylation
and a 2,3-Wittig rearrangement. A drawback in the synthesis is the use of chiral auxiliaries,
which are used to sequentially introduce the stereocenters at C6 and C8 in the pyran ring, and
not without issues with diastereoselectivity (Scheme 53). The key aldol coupling to create the
stereochemistry at C8 proceeded in 6:1 diastereomeric ratio, with a 53% purified yield of 225,
and the second aldol reaction gave 227 in 3:1 dr and 46% purified yield, respectively. The
triene portion was installed by direct alkylation with a strong base, which predicated the
earlier TBS protection of the oxazole. All in all, starting from a rather expensive commercial
carboxylic acid 223 (synthesized in two steps), the longest linear sequence of this synthesis is
14 steps, and overall yield of 4% along the LLS.
77
EtO
NH2Cl SerOMe·HCl, Et3N MeO
ON
O
214 215
1) CuBr2, DBU, HMTA, CH2Cl22) NaOH, MeOH, H2O
3) SOCl2, rfx, then SerOMe·HCl
HN
ON
O
216HO
MeO
O
1) Deoxo-Fluor, CH2Cl2, –20 °C2) DBU, BrCCl3, 0 °C3) DIBAL-H, CH2Cl2, –78 °C4) TMSOMe, TMSOTf, CHCl3, –30 °C5) n-BuLi, TBSOTf, THF, –78 °C
217
N
ON
O
H
OMeMeO TBS
36% from 216
O
H+
218
B O
OCy
Cy
219
OH
220 81%, ee 98%
hexanes, 0 °C
KH, Bu3SnCH2I, THF,then n-BuLi, –78 °C
HO
221
4 steps
222
Br
HO
ON
O
223
Alternative starting material100 EUR/g at Sigma-Aldr ich
CH2Cl2, rfx
Scheme 52. Synthesis of key intermediates by Smith
�
Scheme 53. Key stereochemical steps by Smith.
3.3.2 Previous studies by the Ley group
The Ley group first generation retrosynthetic analysis of (–)-hennoxazole A is presented in
Scheme 54, consisting of a sp2-sp3 coupling119 to install the triene portion 231 to the
bisoxazole core 230, and a Paterson-type 1,5-anti-aldol reaction120 to couple the pyran
precursor 229 to the nearly complete hennoxazole scaffold in a stereoselective fashion. The
pyran ring would then be finished with OH-directed stereoselective reduction,
78
transacetalization, methylation and deprotection. However, early studies towards the triene
synthesis indicated that the sp2-sp3 coupling is unfeasible,119b and an olefin metathesis
strategy was later adopted.121 As will be shown below, the general strategy to synthesize the
pyranacetal ring was conserved, but the direction of approach was altered.
Scheme 54. Retrosynthesis and first generation approach to pyran ring
3.3.3 First Approach to the Synthesis of the Western Fragment
Our preliminary plan to synthesize and couple the pyranacetal ring was based on an
organocatalytic aldol addition of acetone to the aliphatic aldehyde 237. To synthesize the
substrate, we first attempted a redox neutral selective deprotection of a corresponding diacetal
235, but all attempts with normal acidic deprotection led to dioxolane migration (Scheme 55).
The selective deprotection could be carried out in principle by using TESOTf and 2,6-lutidine,
but this was deemed to be too wasteful due to necessary large scale chromatography.122 The
synthesis of 237 was finally carried out in a straightforward manner over two steps from
ethylacetoacetate 238 by acetal protection and DIBAL-H reduction (Scheme 56).
79
Scheme 55. Attempts at synthesis of 237
O
OEt
O
HO OH
p-TsOH (cat.)CH(OEt)3 (1 equiv)
toluene, rfx OEt
OOO DIBAL-H (1.2 equiv)CH2Cl2, –78 °C
OOOH
238 239 23774% 90%
Scheme 56. Synthesis of aldehyde substrate 237
The organocatalytic aldol addition of ketones to �-unsubstituted aliphatic aldehydes is a
highly challenging process, and in our hands it did not yield promising results. We used
known published catalysts according to literature procedures (Figure 17). Catalysts 125 and
180 were available at hand, and 240 and 241 were synthesized according to published
procedures.123,124 However, none of these gave the desired aldol addition product 242 in any
useful manner (Table 5). Proline was inactive in the reaction (entry 1). The tetrazole analogue
180 was more active (entries 2-3) but upon workup no product was isolated. Catalysts 240
and 241 also performed disappointingly (entries 4-9). Ostensibly the �-unsubstituted aldehyde
competes with acetone in enamine formation with the catalyst, thus possibly leading to self-
condensation products. Previous studies in the group had not yielded very promising results
either for this step. Hence, we decided to revise the synthetic plan.
80
Figure 17. Catalysts screened for the addition of acetone to 237
Table 5. Screening results
Entry Catalyst / Mol % Conditions Result 1 125 / 20 acetone, H2O, rt, 48 h No rxn 2 180 / 10 1:1 acetone:DMF, rt, 48 h Mostly 237, no product 3 180 / 10 4:1 DMSO:acetone, rt, 48 h Full conv., no 242 isolated 4 240 / 10 acetone, rt, 72 h Mostly 237 5 240 / 7 7 mol % TFA, acetone, rt, 72 h Full conv., no 242 isolated 6 240 / 10 acetone, premixing 2 h, rt, 72 h Mostly 237 7 240 / 10 AcOH, acetone, premixing 2 h, rt, 72 h Mostly 237 8 241 / 10 acetone, rt, 72 h Mostly 237 9 241 / 7 7 mol % TFA, acetone, rt, 72 h Almost full conv., no 242
3.3.4 Second Approach to the Synthesis of the Western Fragment
The revised plan is presented in Scheme 57. We decided to use the bisoxazole aldehyde 243
as the aldol acceptor partner in the addition of acetone, as this would better correspond to the
good results in proline-derivative catalyzed aldol reactions. The addition product would then
be alkylated to give 244, which would then be coupled to 237 according to the Paterson 1,5-
anti-aldol protocol.120 The fully functionalized pyran ring would then be achieved in a matter
of 1,3-anti-diastereoselective reduction125 of �-hydroxy ketone 245 and subsequent
transacetalization according to Williams.72b If a protecting group would be needed, an Evans-
Tishchenko reaction could be used to both stereoselectively reduce 245 in 1,3-anti fashion
and install an ester protecting group in one step.126 The presence of a protecting group at C4
hydroxyl might be necessary due to the challenging olefin metathesis that would install the
triene portion. If the pyran ring synthesis could be carried out on the whole bisoxazole-triene-
backbone, no protecting group would be needed.
81
O
O
NH
243
methylation
1,5-anti-aldol
1,3-anti-reduction
OO O
H237
R = H or Pg
transacetalization
N
O acetone aldol
OH
O
N
244
N
O
O OMe
O
N
245
N
O
O
OMe
O
N
246
N
O
OOO OHOMe
O
N
247
N
O
OHOO OR
OMe
O
N
N
OO
OR
HMeOMe
248
44
4
Scheme 57. Revised synthetic plan
3.3.5 Optimization of the Bisoxazole Synthesis
Aldehyde 243 was deemed to be a suitable model substrate, since it could also be used for
screening for olefin metathesis conditions (or the preceding ester 255). The synthesis of 243
was yet unoptimized, and gave the desired product with a 12% yield over 8 steps. By
tweaking the conditions slightly, we were able to raise the overall yield to 36% over the same
route, showing that high throughput would be possible (Scheme 58). The synthesis started
with a CDI mediated coupling of DL-serine methyl ester hydrochloride to 4-pentenoic acid
249 in acetonitrile to give the amide 250. This was then subjected to cyclization conditions
with DAST and K2CO3 in CH2Cl2 at –78 °C and dehydrogenation with BrCCl3 and DBU at
0 °C to give the oxazole 252. The bisoxazole core was obtained by repeating this three
reaction sequence after saponification of 252 with LiOH in THF/H2O. Selective DIBAL-H
reduction of the ester 255 gave the desired aldehyde 243 in good yield after chromatography.
The DAST-mediated cyclizations initially gave poorer yields than those shown below, but
with a fresh reagent the reactions proceeded with excellent yields. The crude products were
also deemed to be pure enough according to 1H NMR analysis for use in the following steps
with no further purification.
82
HO
O
NH
OHO
MeO
O
O
N
MeO
O
O
N
MeO
O
ON
O
NH
O
MeO
O
N
N
O
HMeO
OO
N
N
O
MeO
OO
N
N
O
O
H
DL-SerOMe•HCl,DIPEA, CDIMeCN, rt
89%
DAST, K2CO3
97% crude
BrCCl3, DBUCH2Cl2, 0 °C to rt
84% from 250
1) LiOH2) DL-SerOMe•HClEt3N, CDI, MeCN, rt
79%
crude 95%used as such
78% from 253(42% from 249)
DIBAL-HCH2Cl2, -78 °C
85%, (36% from 249)
HO
249 250 251
CH2Cl2, –78 °C to rt
252253DAST, K2CO3,CH2Cl2, –78 °C
254
BrCCl3, DBUCH2Cl2, 0 °C to rt
255 243
Scheme 58. Optimized synthesis of bisoxazole aldehyde 243
As a test for flow synthesis, we produced 3.2 grams of oxazoline 251 with a continuous flow
DAST-mediated cyclization according to the method developed in the Ley group (Scheme
59).127 The synthesis was carried out by sequential injections of 2-3 mmols of amide 250 and
DAST as stock solutions in anhydrous CH2Cl2 through separate injection loops. The
combined reagent stream was heated to 80 °C in a coil reactor with a residence time of 30
minutes. After the coil the mixture was directed into sequential columns packed with CaCO3
and SiO2. Since colored impurities would eventually leach through the SiO2, we repacked the
SiO2 column after three consecutive runs. The oxazoline 251 was deemed pure enough by 1H
NMR spectroscopy to be carried to the next reaction without further purification.
Scheme 59. Synthesis of 251 with a continuous-flow reactor
83
3.3.6 Catalyst Screening
Our first goal was to find the optimal organocatalyst for our model compound before
transferring the reaction to continuous-flow conditions. Hence, the catalyst screening was
carried out in small scale in batch conditions. The catalysts that were tested are presented in
Figure 18, and the results from the catalyst screening in Table 6. Catalysts 256, 257 and 258
were synthesized according to literature, and others were available from previous experiments
or from commercial sources.123,128
Figure 18. Organocatalysts used in screening for revised route
84
Table 6. Screening results in the addition of acetone to aldehyde 243
Entry Catalyst / Mol % Conditions Time Yield / ee 1 125 / 20 Neat, rt 5 d 11% / 3% 2 180 / 10 Neat, rt 5 d 36% / 9% 3 240 / 10 Neat, rt 5 d 36% / 27% 4 241 / 10 Neat, rt 5 d 73% 243 5 256 / 10 Neat, rt 5 d 33% / 56% 6 256 / 20 Neat, rt 5 d 33% / 47% 7 256 / 100 Neat, rt 2 h 43% / 34% 8 256 / 20 1:1 i-PrOH:acetone, rt 5 d 22% / 24% 9 257 / 10 Neat, rt 6 d 43% / 80%
10 257 / 20 Neat, rt 22 h 48% / 60% 11 258 / 20 Neat, rt 4 d 59% / 46% 12 258 / 20 Neat, rt, 10 mol % AcOH 4.5 h 58% / 57% 13 258 / 20 Neat, rt, 10 mol % MCA 6 h 68% / 83% 14 259 / 20 Neat, rt, 10 mol % AcOH 4 d ee < 10% 15 259 / 20 Neat, rt, 10 mol % AcOH, Na2SO4 4 d ee < 10% 16 260 / 20 Neat, rt 5 d no rxn 17 119 / 20 Neat, rt 2 d no rxn 18 119 / 20 Neat, rt, slow addition 5 d no rxn 19 119 / 20 Neat, rt, 10 mol % AcOH, slow add 5 d no rxn
As a general trend, the heterocyclic aldehyde 243 seemed to be less reactive than most
aromatic aldehydes. Decent reactivity was obtained only with organic acids as co-catalysts.
For entries 1-8, complete conversion was observed only in the cases of 5 and 6. The
prolinamides 257 and 258 reported by Singh128 were shown to be the most active by the initial
experiments without co-catalysts (entries 9-13), the reaction going to completion in 22 hours
when 20 mol % of 257 was used. Entries 14 and 15 gave both condensation and addition
products, obtained in a roughly 1:2 ratio, and the catalyst 259 did not show any asymmetric
induction. Hayashi-Jørgensen-type diphenyl-prolinol derivatives showed no reactivity in these
screening conditions (entries 16-19). Pleasingly, there was little difference whether the
reaction was done in rigorously dried anhydrous acetone or in distilled acetone, which
contains some moisture. The aldol addition product 244 is crystalline, and the enantiomeric
excess could be enhanced by crystallization. As an experiment, crops from several low ee
entries were combined and crystallized to give 244 with an ee of 70%. Generally in the test
conditions small amounts of intensively coloured impurities followed through with the
85
product in column chromatography. However, these could at least partially be removed via
crystallization of the product when larger amounts were handled.
Based on the results from the catalyst screen, the Singh prolinamide 257 was chosen for
further studies. At this time, more of the catalyst was also synthesized (Scheme 60). The Boc-
deprotection was originally attempted with TFA:CH2Cl2, but partial hydrolysis of the amide
was observed.
Scheme 60. Synthesis of catalyst 255
The results from the optimization of the acetone aldol step are presented in Table 7. The
reaction was investigated by varying reaction temperature, co-solvents, catalyst loading, and
the use of a co-catalyst.
86
Table 7. Optimization of organocatalytic conditions for the synthesis of 244
Entry 257 (mol %) Conditions Time Yield / ee 1 10 Neat, rt 6 d 43% / 80% 2 20 Neat, rt 22 h 48% / 60% 3 30 Neat, rt 6 h 50% / 73% 4 20 Neat, rt, 10 mol % TFA 5 d 18% / 90% 5 20 Neat, rt, Na2SO4 22 h 50% / 69% 6 20 1:1 i-PrOH:acetone, rt 6 h 45% / 42% 7 20 1:1 MeCN:acetone, rt 2 d 47% / 76% 8 30 Neat, 0 °C 1 d 53% / 52% 9 20 Neat, rt, 10 mol % AcOH 1 h 50% / 70%
10 20 Neat, 0 °C, 10 mol % AcOH 1.5 h 40% / 81% 11 20 Neat, 0 °C, 10 mol % MCA 3 h 59% / 90% 12 10 Neat, rt, 10 mol % MCA 1 d 68% / 90% 13 20 Neat, rt, 20 mol % HCOOH 1 h 59% / 85%
Catalyst loading had a significant effect on reaction speed (entries 1-3). For entry 4 the
reaction time is inaccurate, since only after work-up and purification it was realized that the
aldol condensation product 263 completely overlaps on TLC with 243, and the reaction in the
presence of TFA was ostensibly a lot faster. The presence of a dehydrating agent had no great
effect (entry 5), and changing the solvent system mostly had a detrimental effect, if any
(entries 6-7). In 0 °C the reaction became sluggish in spite of high catalyst loading, and ee
suffered (entry 8). The presence of acetic acid greatly accelerated the reaction, and yields and
enantioselectivities were further improved by the use of MCA as a co-catalyst (entries 9-12).
Under the best conditions we were able to isolate 244 in 68% yield, with ee slightly above
90%. Entry 13 describes an experiment that was carried out after it was realized that HCOOH
performed better as the co-catalyst under continuous flow conditions.
We attempted to verify the expected absolute configuration 244 by Mosher’s ester analysis,129
but the results were inconclusive (Scheme 61). The first derivatization attempt with (S)-(+)-
MTPA-Cl resulted in complete conversion to the elimination product 263. Another attempt
with DCC-coupling of (R)-(–)-MTPA was successful, and the corresponding crude ester 264
was analyzed by 1H NMR. Downfield shift of 1H NMR signal in the closer oxazole moiety
was observed, along with an upfield shift of the terminal methyl group, giving tentative proof
to the desired R-configuration according to the procedure by Mosher. However, the �-
87
methylene did not completely follow this trend: the group exhibited downfield shift of one
diastereotopic H, and a slight upfield shift of the other.
Scheme 61. Attempt at determination of absolute configuration of 244
3.3.7 Organocatalytic Aldol Step under Continuous Flow Conditions
We began our screening for continuous flow conditions with an approach similar to
Seeberger’s (see Scheme 45).116 A solution of the catalyst 257 and acid co-catalyst in acetone
was injected through one injection loop, and the aldehyde 243 through another according to
the scheme below. The mixture was pumped through the coil reactor at desired temperature
and analyzed with TLC and crude 1H NMR spectroscopy after evaporation. If the conversion
was good enough, the product was isolated after chromatography and analyzed by HPLC to
determine the enantioselectivity. The results of the screening are presented in Table 8.
88
Table 8. Continuous flow studies in organocatalytic aldol addition
Entrya 257 / Cocat (mol %) c (243)b Flow ratec tR Temp 243:244:263d Yield / ee 1 10 / - 0.05 0.5 mL/min 10 min rt 1:0.1 n.d. 2 10 / - 0.05 0.18 mL/min 30 min rt 1:0.1 n.d. 3 10 / 10 MCA 0.05 0.2 mL/min 25 min rt 1:0.3 n.d. 4 20 / 10 MCA 0.05 0.34 mL/min 15 min rt 1:0.75 n.d. 5 10 / 10 MCA 0.15 0.2 mL/min 25 min rt 1:0.3 n.d. 6 10 / 10 MCA 0.05 0.2 mL/min 25 min 50°C 1:0.3:0.05 n.d. 7 10 / 10 MCA 0.05 0.2 mL/min 25 min 70°C 1:0.4:0.1 n.d. 8 20 / 10 MCA 0.10 0.2 mL/min 25 min 60°C 1:1:0.2 n.d. 9 20 / 10 MCA 0.15 0.2 mL/min 25 min rt 1:1 n.d. 10 20 / 20 HCOOH 0.15 0.2 mL/min 25 min 50°C 1:45:trace 60% / 75% 11 20 / 20 HCOOH 0.15 0.1 mL/min 50 min rt 1:6 59% / 80% 12 20 / 20 HCOOH 0.25 0.5 mL/min 40 min 40°C nd 40% / 70% 13 20 / 15 MCA 0.33 0.33 mL/min 60 min rt 1:3.5:0.2 45% / >90%
a) The reactions were carried out by injecting 1 mL of stock solutions via injection loops into the flow reactor. b) Refers to total concentration of 243. c) Total flow rate, individual pumps functioning at 50% of shown rate. d) Determined by 1H NMR of evaporated crude output mixture.
As shown in the table, MCA did not perform well as the co-catalyst under continuous flow
conditions, and it took several attempts to see any significant amount of product (entries 1-9).
Better results were achieved when 20 mol % of formic acid was used (entries 10-12). The
reaction had to be heated to attain good conversion, and quite pleasingly we were able to
determine that the enantioselectivity was nearly as good as in homogeneous reactions, with
some expected erosion occurring. The best yield was achieved when 20 mol % of both 257
and HCOOH were used and the reaction was run at 50 °C with a residence time of 25 minutes
(entry 10). However, a nearly identical yield was achieved when the residence time was
doubled and the reaction was run at room temperature (entry 11). The enantioselectivity was
slightly higher in the latter case. To test whether the poor results with MCA were attributed to
the loading, one more test was run with 15 mol % of co-catalyst, and this time a slightly better
conversion was achieved, and the reaction again gave an ee of 90% (entry 13). The aldol
condensation product 263 could also be detected in the analyses of crude mixtures especially
at higher temperatures.
89
3.3.8 Methylation studies
The methylation of the aldol addition product 244 was briefly investigated in batch and flow
conditions. Several common methylation methods were attempted (Scheme 62). Treatment of
244 with sodium hydride in DMF led to decomposition of the starting material. Reaction with
Meerwein’s salt gave full conversion, but after work-up only the pyridine base was recovered,
indicating either decomposition or methylation of the heterocycle core to form a charged
oxazolium species which would remain in the aqueous phase. Treatment of 244 with dimethyl
sulfate gave no reaction. In the end, methylation with an excess of methyl iodide in the
presence of Ag2O gave a clean conversion in small scale reactions. For optimal reactivity
Ag2O had to be freshly prepared. Due to time restraints, only a proof of principle experiment
was done in continuous-flow conditions. A glass column was filled with a dispersion of Ag2O
in celite, with a small plug of celite in each end. A solution of 244 and an excess of MeI in
CH2Cl2 was pumped through the column, and the product was analyzed by 1H NMR
spectroscopy, showing a 2:1 mixture of unreacted 244 and the desired product 245 (Scheme
63), with no side products. It was also determined by chiral HPLC analysis that the
methylation step with MeI/Ag2O proceeds with no racemization, and the enantiopurity of 245
may likewise be enhanced by recrystallization.
Scheme 62. Methylation attempts of 244
90
Scheme 63. Methylation of 244 in continuous flow
3.4 Diastereoselectivity of �-Hydroxy Ketone Reduction with Solid Supported
Borohydrides
One of the endgame steps in the synthesis would have included a diastereoselective 1,3-anti-
reduction of a �-hydroxy ketone (Scheme 57). While there are established and well-tested
methods for 1,3-anti-reductions, such as the Evans-Carreira-Chapman modification of
Saksena reduction,125 and Evans-Tishchenko reduction,126 at the time of our studies there
were no reports on the diastereoselectivity in the reduction of �-hydroxy ketones with
immobilized borohydrides. Formally, the resin bound borohydride would correspond to a
quaternary ammonium borohydride compound (Scheme 64). Further modification to a
triacetoxyborohydride would then give an immobilized version of the Evans-Saksena reagent
that might be applicable to continuous flow conditions. Hence, we set out to briefly
investigate the matter.
Scheme 64. Reduction of �-hydroxyketone with immobilized borohydrides and the corresponding transition state leading to 1,3-anti-enriched product via complexation and intramolecular hydride attack.
For model compounds we synthesized 265-267 by standard aldol reactions between
corresponding ketones and aldehydes (Figure 19). A commercial polymer supported
borohydride was purchased from SigmaAldrich, but after it showed rather poor activity in the
model reaction, we carried out the immobilization ourselves.130 The borohydride ion was
91
immobilized on Amberlite IRA-400 (Cl– form) by washing the resin first with 1 M HCl and
distilled H2O, and then stirring it in a 1 M aqueous solution of NaBH4 and then drying the
resin cautiously in vacuum.
Figure 19. Model substrates for reduction studies
Reactions with solid supported borohydride were carried out by dissolving 1 mmol of �-
hydroxyketone into an alcoholic solvent, adjusting to desired temperature and then adding 1
gram of borohydride resin (2-3 equivalents based on theoretical loading). The Rychnovsky
cyclic acetonide method was used for determining the diastereoselectivity, and the 1H NMR
signals of CHOH protons at 3.37 (anti) and 3.45 (syn) were used for integration according to
Cohen.131,132 The products were isolated by filtering the reaction mixture and evaporating
solvents to dryness. An example of the reaction is shown in Scheme 65.
Scheme 65. Reduction of 265 with solid supported borohydride
The model reaction gave a syn-selective product, as usually does a standard reduction with
NaBH4 (a control experiment characterized with crude 1H NMR spectroscopy). Pretreating
the resin with glacial AcOH should give the triacetoxyborohydride species.134 The
borohydride resin was stirred in THF at 0°C with 3 equivalents of AcOH for 45 minutes, then
filtered and washed. However, the activity of the treated resin was lower, and still gave a syn-
enriched product with practically same selectivity as the untreated resin (Scheme 66). We also
attempted to perform the reaction in a mixture of AcOH and MeOH, but observed no reaction
92
taking place after strong initial bubbling during which the acid reacted with the borohydride
ions.
Scheme 66. Reduction of 265 with resin pretreated with glacial AcOH
To see how the selectivity could be tuned, we briefly investigated the effect of temperature
and solvents. Scheme 67 highlights the effect of temperature in the model reaction. By
heating the reaction we were able to boost the reaction speed significantly, with no great
effect to diastereoselectivity. This indicates also that the polymer supported borohydride
could theoretically be used in a continuous flow fashion as a packed column reactor, although
resin based borohydrides have been previously reported to be unreliable in flow conditions.76
However, this problem has been solved recently by using a monolithic quaternary ammonium
polymer loaded with borohydride ions.134
Scheme 67. The effect of temperature on reaction speed and selectivity
The effect of solvents is depicted in Table 9. For borohydride reductions, MeOH is usually
the best solvent with respect to reaction speed, since a precomplexation between the solvent
and the borohydride ion apparently results in a more active reagent. When the reaction was
run in i-PrOH, we observed an anti-enriched product although the reaction was very slow and
not as clean as in MeOH (entry 1). A non-alcoholic solvent gave no reaction (entry 2).
Mixtures of MeOH and other solvents gave slower reaction times and varying selectivities
93
(entries 3-6). Mixing i-PrOH with MeOH reversed the selectivity once more towards the syn-
isomer. Heating the reaction in i-PrOH gave a faster conversion (not shown in table), but after
filtration no product was isolated, which may be due to the instability of the resin in higher
temperatures. In entry 6 we carried out a hydrolytic and oxidative work-up with NaOH/H2O2,
which gave a further 50% yield of recovered product after extraction. The product thus
recovered consisted only of the syn-isomer, bringing the total yield to about 80% and
selectivity to 3:1 syn:anti. Keeping in mind the original goal of achieving an anti-selective
diastereoselective reduction in continuous flow conditions, these results were less than
promising, due to the slow kinetics and synthetically unusable selectivities even in the case of
i-PrOH.
Table 9. Effect of solvents on the reduction of 265
Entry Solvent Time Conversion syn:antia Yield 1 i-PrOH 6 d Full 1:~2.5b n.d 2 THF 6 d – – n.d 3 1:1 MeOH:THF 21 h Full 3:1 95% 4 4:1 i-PrOH:MeOH 16 h Full 1-1.5:1 n.d 5 1:1 i-PrOH:MeOH 16 h Full 2.5:1 n.d 6 4:1 s-BuOH:MeOH 5 d Full 1:1.5 30% a) The diastereoselectivity was determined via Rychnovski acetonide method. b) Approximated from crude product 1H NMR spectrum.
Finally, we attempted a simple substrate experiment to determine the effect of substitution.
Whereas compound 267 gave a diastereoselectivity of 2:1 syn:anti, reversing the position of
the ketone and hydroxyl groups gave a completely nonselective reaction (Scheme 68). In the
case of 267 we also treated the remaining resin with NaOH/H2O2 and recovered further 27%
of pure syn-product.
94
Scheme 68. Substrate experiments
3.5 Conclusions
We investigated the application of an organocatalytic aldol reaction into the total synthesis of
(–)-Hennoxazole A, and the possible transfer of the reaction into continuous flow conditions.
Organocatalytic reactions may not be ideally suited to continuous conditions due to the
intrinsic slow kinetics. To increase the rate suitably, the reaction needs to be heated which
leads to increased formation of side products and erosion of enantioselectivity. The best
catalyst for the reaction was 257, previously reported by Singh. The addition of acetone to
bisoxazole aldehyde 243 could be carried out in 60-70% yield and over 90% enantiomeric
excess. The methylation of the aldol product 244 was also investigated and suitable conditions
determined
The reaction was also successfully tested in continuous flow conditions, but further
optimization and development would be needed. It would be beneficial to develop either in
line quenching and scavenging methods for purification of the intermediate product, and to
investigate telescoping the aldol addition to the following methylation step. Another approach
would be the immobilization of the organocatalyst, of which there were no precedents at the
time of our study. The methylation step was also tested in continuous flow conditions, but no
optimization studies were yet carried out.
We briefly investigated the diastereoselectivity of �-hydroxy ketone reductions with polymer
supported borohydride resins. The reduction may be carried out with simple substrates, but
the diastereoselectivities did not show great promise in application to asymmetric synthesis.
In most cases the undesired syn-diastereomer was obtained, and while i-PrOH was the only
solvent that provided the desired anti-diastereomer, the reactions were very slow and of poor
purity. Another issue is the potential formation of six-membered boronate esters between the
95
substrate and the reducing agent, which remains complexed on the polymer beads. Thus,
based on our results we are unable to confirm the validity of using immobilized borohydrides
in a diastereoselective reduction, let alone apply it to the total synthesis of (–)-Hennoxazole A.
96
4 NITRATION OF AROMATIC SUBSTRATES UNDER
CONTINUOUS FLOW CONDITIONS
4.1 Common aspects of aromatic nitration
Nitration of aromatic compounds is a classic reaction, which is still a standard tool of modern
day chemical industry. Nitration reactions are usually carried out using either concentrated
nitric acid or a mixture of concentrated sulfuric acid and nitric acid (generally called the
mixed acid method), depending on the reactivity of the substrate. For electron rich aromatic
substrates even dilute nitric acid may be sufficient, as will be shown below. For unsubstituted
aromatic compounds such as benzene, or electron poor aromatic substrates, forcing conditions
with mixed acid is usually needed. Nitration reactions are frequently carried out in neat
conditions using only the acid mixture as solvent. Acetic acid is a frequently used solvent,
being safe to handle in the presence of concentrated HNO3. Other approaches and reagents
towards nitration include e.g. the in situ formation of acetyl nitrate from acetic anhydride and
concentrated HNO3, ionic complexes of nitronium cation [NO2]+ such as nitronium
tetrafluoroborate, and metal nitrates.
The kinetics of nitration are complex and depend on several factors, e.g. the nitration medium,
solvent, nitronium ion formation and activity of the substrate towards electrophilic aromatic
substitution.135 When electron-rich aromatic subtrates are used, zero order kinetics are usually
observed in respect to the substrate, and first order kinetics with respect to the concentration
of HNO3, or rather the [NO2]+-ion. For unreactive aromatic compounds nitration usually
follows first order kinetics with respect to the substrate. For compounds of intermediate
reactivity, the reaction can be forced towards either zero or first order kinetics based on the
exact conditions used, e.g. acidity of nitration medium and solvent. The nitration of electron
rich aromatic substrates may proceed also via electrophilic attack by nitrosonium ion [NO]+,
and a subsequent oxidation of the nitroso group to nitro group.136
97
4.2 Nitration of Vanillin
Nitration of vanillin 271 is a well-known reaction (Scheme 69).137,138 The highly activated
aromatic ring is reactive enough for the reaction to be carried out by using e.g. a
stoichiometric amount of 60 w-% aqueous nitric acid. In addition to traditional methods,137
the nitration of vanillin has been investigated e.g. with benzoyl nitrate,138a gaseous NO2,138b
SiO2-absorbed acetyl nitrate,138c and different metal nitrate complexes.138d-g The resulting 5-
nitrovanillin 272 has been used in medicinal chemistry as a precursor for e.g. catechol O-
methyltransferase inhibitors,137j,l combretastatin A analogues,137m and HIV-1 integrase
inhibitors.137k
H
OMeO
HO
271
Et2O, 10 °C
HNO3, HNO2H
OMeO
HO
272
NO2
95%, Vogl 1899 (Ref. 137b)
HNO3
AcOH, 0 °C to 20 °C272 83%, Klein 2011 (Ref. 137n)
ZrO(NO3)2·H2Oacetone, rt
272 94%, Venkateswarlu 2006 (Ref. 138e)
272 100%, Francis 1906 (Ref. 138a)BzONO2
CCl4
272 88%, Rodrigues 1999 (Ref. 138c)AcONO2 / SiO2
CHCl3
NO2 (g) 272
84% 272, 10% 273, 6% 274
H
OMeO
HO
273
+
NO2
H
OMeO
HO
274
+NO2
Kaupp 1995 (Ref. 138b)
Scheme 69. Examples of nitration of vanillin 271
In connection with studies for an enhanced process towards an important pharmaceutical
intermediate, it was in our interest to examine whether the reaction could be carried out in
continuous flow conditions, and to see if it would result in improved selectivity, yield, and/or
98
suppression of unwanted side reactions. In general, the reaction is usually carried out as a
semi-batch reaction by slowly adding concentrated pure or aqueous nitric acid into a solution
of vanillin in glacial acetic acid or another solvent. The strongly exothermic reaction is cooled
during the addition of HNO3 to keep the internal temperature as low as possible. The product
precipitates out of the reaction, and is usually isolated by further precipitation from cold water
or via direct filtration of the reaction mixture, depending on the solvent system used. Yields
are generally around 80–85% and the HPLC purity of the isolated material is over 99%.
Higher yields have been reported when the reaction is carried out in diethyl ether.137b
According to literature, the nitration of vanillin is usually highly regioselective, and 272 is
usually isolated in excellent purity. Known side products include 275 and 276, both arising
from a formal ipso-nitration-deformylation cascade (Scheme 70).137f Another reported side
product 277 ostensibly results from a dehydrogenative homocoupling at the 5-position.137c In
our previous studies, an analogous dinitration product to 276 was noted to be the most
common impurity when a slightly different aldehyde was used in large scale experiments. It
was unknown whether this side product was formed via a parallel reaction path, or whether it
was the result of overreaction of the desired product. Determining this was a secondary goal
in our studies.
Scheme 70. Previously known side products 276 and 277 observed by Bentley, and 275 observed by Stostkii in the presence of HNO2.
4.2.1 Preliminary studies
The equipment used for continuous-flow experiments was a commercial Uniqsis FlowSyn
reactor equipped with either a 5 mL HT-PFA reactor coil or a 10 mL stainless steel reactor
99
coil. The internal diameter of both coils is roughly 0.5 millimeters, and it was anticipated that
transferring an essentially heterogeneous reaction to these surroundings might result in
blockages in either the reaction coil or the back pressure regulator which is attached to the end
of the coil. As the nitrating reagent we used 60 w-% aqueous HNO3, the nitrous acid content
of which was not analyzed. The acid was colorless, indicating a low presence of other NOx
species. The reactions were analyzed qualitatively by HPLC, and all subsequent mentions of
HPLC analyses and numerical values in charts and tables refer to area percentages of the
crude chromatograph. The UV-extinction coefficients of 271 and 272 are ostensibly not equal
and hence some error is most likely included in the raw HPLC values.
Our first objectives were to discover reaction conditions that would be as close to
homogeneous as possible, if a completely solution-phase reaction would turn out to be
impossible to attain. These studies were carried out in batch conditions according to published
procedures. The use of co-solvents was also considered. The solubility of 272 into THF,
CH2Cl2, CHCl3, MeCN or PhCl is roughly 5-15 mg/mL at room temperature (on average 0.05
M). The solubility of 272 into glacial acetic acid as a function of temperature was plotted
roughly to get an idea of a workable temperature range (Chart 1). The solubility was
determined by adding measured amounts of 272 into 15 mL of AcOH at determined
temperature until no more dissolved. It was our anticipation that the continuous-flow
conditions for successful nitration would differ drastically from batch conditions, namely that
the reaction concentration would have to be a lot smaller, and conversely temperatures would
have to be higher. After preliminary experiments, we eventually decided to use glacial acetic
acid as the sole solvent to prevent possible (though unlikely) competitive side reactions of
HNO3 with other solvents. Hence all subsequent mentions of stock solutions refer to
concentration of reagents in AcOH unless otherwise stated.
100
� Chart 1. Rough solubility curve of 5-nitrovanillin 272 in glacial acetic acid
Table 10 shows the results from our preliminary experiments. The initiation of the reaction
was screened in a reaction concentration of 0.1–0.5 M. To see if the absence of acetic acid is
important, the reaction was run in THF, with the result that it is a necessary component
(entries 1-2). In several cases the reaction had to be incubated for a long period before
initiation (e.g. entries 3-7). Increasing the amount of HNO3 did not always result in a faster
reaction (entries 4 vs. 5) but eventually led to significant overreaction, and thus no desired
product was isolated in the experiment of entry 5. Cooling the reaction mixture severely
inhibits the initiation in low concentrations (entries 6 and 7). In the case of entry 8, the
reaction did not first proceed at all, but after stirring for 4 hours the characteristic change of
color of the reaction mixture was suddenly observed, and the reaction was over in a matter
moments. Raising the temperature above ambient conditions shows that even in low
concentrations the reaction starts almost immediately after adding HNO3 (entries 9-10). The
reaction could also be carried out by adding a 0.2 M solution of HNO3 in AcOH into a 0.2 M
solution of vanillin in AcOH. However, the reaction only took place after all of HNO3 had
been added (entry 11). As a benchmark, we ran the reaction in typical process concentration
and temperature (entry 12). We observed that the conversion of 271 was incomplete, most
likely due to cocrystallization with the product during the course of the reaction. The product
contained 0.9% of 271, and the filtrate nearly 18% (44% of product, high amounts of
impurities).
0
10
20
30
40
50
60
70
80
20 40 60 80 100
mg/mL
T (°C)
Solubility
101
Table 10. Preliminary experiments into reaction initiation and speed
Entry 271 (g) HNO3 (eq.) Solvent c (M) T (°C) t (init.) Yield (%) HPLC (%)
1 5 1.2 THF 0.55 rt n.d. n.d. n.d.
2 5 1.2 1:1 THF:AcOH 0.55 rt 5 min 77 99.6
3 1 6 1:1 THF:AcOH 0.11 rt n.d. n.d. n.d.
4 1 1.2 1:1 tol:AcOH 0.11 rt o.n. 65 99.9
5 1 6 1:1 tol:AcOH 0.11 rt o.n. n.d. n.d.
6 2 1.1 1:1 tol:AcOH 0.22 0 o.n. 76 99.6
7 2 1.1 1:1 tol:AcOH 0.26 15 o.n. 75 99.8
8 3.3 1.1 1:1 tol:AcOH 0.38 0 4 h 78 99.3
9 2 1.1 1:1 tol:AcOH 0.26 35 1 min 73 99.9
10 2 1.1 AcOH 0.33 50 0 s 75 99.6
11 1.85 1.1 AcOH 0.11 rt 40 min 57 99.9
12 10 1.05 1:2 tol:AcOH 1.5 5 0 s 75 98.8
In a stress experiment, vanillin was dissolved into 1:1 toluene:AcOH, and HNO3 was added to
the cooled reaction mixture (Scheme 71). After the addition of 6 equivalents the reaction had
not yet started. Cooling was stopped and the reaction let slowly warm to ambient temperature.
The reaction took place 15 minutes after the removal of cooling, and it went to completion
immediately. However, only 15% of product was isolated, and according to HPLC it
contained 4.6% of 276 whereas the mother liquor contained 64% of 276. Hence, the use of
excess nitric acid is detrimental to the reaction.
H
O
HO
MeOHNO3 (60 w-%)
1:1 toluene:AcOH, 0 °C to rt
H
O
HO
MeO
NO2
271, 0.2 M, 13 mmol 272
Addition of HNO3:0.2 mL aliquots at 30 s intervals until 2 mL (2 equiv) added0.5 mL aliquots at 60 s intervals until 6 mL (6 equiv) added
15%
Scheme 71. Stress test of reaction initiation at low concentration and temperature
102
In most of the experiments in Table 10, 272 could be seen precipitating in the course of the
reaction. As the concentrations would be lowered for continuous-flow experiments, the yields
could be anticipated to suffer as well. Hence, we briefly experimented on an isolation of a
second crop of precipitated product (Table 11). Carrying out the reaction in room temperature
at a concentration of 0.1 M, simple filtration of the reaction mixture gave a yield of 51–60%
(entries 1-3). Concentration of the mother liquor and subsequent second filtration gave a
further 15%. Both crops were of almost equal purity. In another experiment (entry 4), we first
concentrated the reaction mixture and added some toluene before cooling the mixture to 0 °C.
Filtration then gave a yield of 74%, with a slightly poorer purity of 98.9%, with dinitrated
product 276 being the dominant impurity (0.8%).
Table 11. Isolation of 272 from dilute reaction mixtures
Entry c (271/M) 1st crop HPLC 2nd crop HPLC 1 0.10 51% 99.902 15% 99.663 2 0.10 58% n.d. – – 3 0.10 60% 99.917 15% 99.409 4 0.10 74% 98.876 – –
4.2.2 Pulse experiments
Having observed that the nitration of 271 could be initiated at low concentration and high
temperatures in batch, we began screening for continuous-flow conditions. As a first step we
investigated the range of temperature, concentration, and residence time required for the
initiation and completion of the reaction within the reactor coil. The experiments were carried
out as pulse experiments (or plug flow) by injecting stock solutions of vanillin and HNO3 in
glacial AcOH via injection loops into the reactor coil. A schematic diagram of the setup is
presented in Figure 20. These experiments were carried out using a 5 mL HT-PFA (high-
temperature resistant perfluoroalkoxy polymer) coil. The coil material is transparent, and the
103
starting point of the reaction could thus be observed visually. The results are presented in
Table 12.
271 in AcOH
HNO3 in AcOH
Pump A
Pump B
PV
PV
PV = priming valve
Injector
Injectorreactor coil
BPR
bpr = back pressure regulator
AcOH
Selection valves
collection flask
Figure 20. Schematic representation of the continuous-flow system
Table 12. Pulse studies for the initiation of nitration reaction
Series 1a tR (min) T (°C) Init. Series 2b tR (min) T (°C) Init. 1 5 r.t. - 1 5 30 - 2 10 r.t. - 2 5 40 beaker 3 5 30 - 3 5 55 beaker 4 5 40 - 4 10 55 beaker 5 5 50 - 5 5 70 beaker 6 5 60 - 6 5 85 beaker 7 5 75 beaker 7 2,5 85 bpr
Series 3c tR (min) T (°C) Init. Series 4d tR (min) T (°C) Init. 1 2,5 45 beaker 1 3,3 30 beaker 2 2,5 60 beaker 2 5 40 bpr 3 5 60 beaker 3 10 40 bpr 4 2,5 40 bpr
Series 5e tR (min) T (°C) Init. 5 5 60 bpr 1 5 35 coil 6 10 60 bpr 2 2,5 50 coil 7 10 80 coil 3 2,5 70 coil 8 5 80 coil 4 1,67 70 coil 5 5 70 coil
a) c(271) 0.10 M, c(HNO3) 0.11 M; b) c(271) 0.20 M, c(HNO3) 0.21 M; c) c(271) 0.30 M, c(HNO3) 0.31 M; d) c(271) 0.40 M, c(HNO3) 0.41 M; e) c(271) 0.50 M, c(HNO3) 0.51 M
104
In several cases, the reaction only took place in the collection flask after all of the mixture had
been collected (series 1-3). Going up in concentration and temperature, the reaction could be
seen taking place right after the back pressure regulator, as the exiting mixture had turned
bright yellow (series 4). If the concentration was high enough, the reaction then went to
completion in the beaker and the product could be seen precipitating. When concentration was
increased to 0.4-0.5 M, the reaction could be seen taking place within the coil (series 4-5). If
the temperature was too low (series 5, experiment 1), the product precipitated within the coil,
leading to an immediate blockage at the joint between the back pressure regulator and the
reactor coil. Hence, the pulse experiments led us to conclude that a workable concentration
range would be 0.3-0.5 M and that temperatures should be above 70°C, but care should be
taken to avoid possible blockages.
4.2.3 Identification of impurities
After deciding on a proper range of conditions, we were ready to begin studying the reaction
in earnerst with continuous experiments. First we analyzed and identified the most prominent
impurities that were detected in the reaction mixture and products. A typical HPLC
chromatogram of a test run is presented in Figure 21. The impurity at retention time 11.2 min
was identified to be the ipso-nitration product of vanillin, and this was confirmed with an
authentic sample of 4-nitroguaiacol. We also subjected 4-nitroguaiacol 275 to the standard
batch nitration conditions and thus obtained an authentic sample of 4,6-dinitroguaiacol 276
(Scheme 72). This was then identified as the impurity at retention time 13.2 min, and it was
observed in small amounts e.g. the 1H NMR spectrum of previous experiments. In screening
for other potential impurities, both 271 and 272 were treated with AcCl (Scheme 73) in the
presence of Et3N, but upon HPLC analysis of the crude product, the corresponding acetates
did not give previously identified peaks. Hence, esterification of the phenolic OH does not
take place during the reaction.
Figure and pro
Scheme
Scheme
21. Typicalduct 272 at
HO
MeO
2
e 72. Nitrati
HO
MeO
27
e 73. Synthe
l HPLC chr9.75 min. S
NO2
275
ion of 4-nitr
O
H
R
71, 272
esis of aceta
omatogramSee Experim
1 equiv HNO
AcOH, r
roguaiacol 2
AcCl,
CH2Cl2
ates 278 and
m from a testmental Secti
O3 (60-w%)
rt, 5 min
p
275
, Et3N
2, 0 °C
N
d 279
t run. Startinion for HPL
HO
MeO
precipitated p
2
AcO
MeO
2
22
Neither detec
ng material LC details.
NO2
NO2
product pure
276
278, 279
O
H
R
278: R = H279: R = NO2
cted in HPLC
271 is at tR
on HPLC
H
2
C analyses
105
R 6.6 min
106
HPLC/M
vanillin
mononi
treated w
HPLC a
of 3,4-d
and thu
regioiso
correspo
HO
HO
Scheme
4.2.4 Co
The firs
reactor
The rea
through
system
decided
reaction
MS experim
n, 3,4-dihyd
trated prod
with HNO3
analysis of t
dihydroxy-5
us the corres
omer was n
onding carb
280
O
H
e 74. Nitrati
ontinuous ex
st continuo
in order to
actions wer
h the pump
are cerami
d to use HNO
n stream wa
ments revea
droxybenza
ducts of 280
3, and corre
the reaction
5-nitrobenza
sponding 2
not determ
boxylic acid
1 equiv HN
AcOH,
ion of 3,4-d
experiments
ous experim
be able to
re carried o
s into the
ic and high
O3 as a dilu
as analyzed
aled that th
aldehyde 2
0. To confir
sponding p
n mixture (S
aldehyde 28
- or 6-nitra
ined. HPLC
ds of 281 an
NO3 (60-w%)
rt, 5 min
222
dihydroxybe
in 5 mL rea
ments were
visually mo
out by feed
heated reac
hly resistant
ute solution
d by HPLC
he impurity
280. Impur
rm the resu
eaks of mo
Scheme 74)
81 was analy
ated isomer
C/MS expe
nd 282, but i
)
HO
HO
282: 25 (A)%281: 13% at2,6-dinitratio
enzaldehyde
actor
carried out
onitor both
ding stock
ctor coil. A
t to a wide
in AcOH to
. Temperatu
at 4.14 is
rities at 7
ults, an auth
ononitrated p
. In a simila
yzed and co
282 is the
eriments al
in minor am
NO2281
O
H
% on HPLC art 7.7; isome
on product (p
e 280
t with a tra
reaction in
solutions o
Although th
e range of
o minimize
ure, concen
the demeth
7.7 and 8
hentic samp
products we
ar manner, a
onfirmed as
impurity at
lso indicate
mounts.
HO
HO
2
+
analysis of rxeric 282 (putautative): 17%
ansparent 5
nitiation and
of vanillin a
he pump he
conditions
possible co
ntration of s
hylation pro
8.5 were i
ple of 280 w
ere observe
an authentic
the impurit
at 8.5, but t
ed the pres
282
O
H
NO2 (2- o
xn mixture atative): 12% a% at rt 12.0
5 mL HT-P
d possible b
and HNO3
eads in the
and chemi
orrosive effe
stock soluti
oduct of
isomeric
was also
ed via an
c sample
ty at 7.7,
he exact
sence of
or 6-)
rt 8.5at rt 9.4
�
PFA coil
blocking.
directly
Uniqsis
cals, we
ects. The
ions and
107
residence time were varied during the experiments. The temperature was varied from 65 °C to
105 °C and residence time from 1 to 5 minutes. The concentration of stock solutions was
varied from 0.30 M to 0.55 M. Some variation in HNO3 stoichiometry was explored, but
mostly a small excess was enough to ensure full conversion. Thus, in a general experiment,
flow rates of both lines were kept equal, and the stoichiometry was determined by the
concentration of the stock solutions.
Chart 2 presents the results according to constant residence time and variable temperature.
The concentration of stock solutions was 0.30 M (271) and 0.32 M (HNO3), and the residence
time 3.33 minutes, equating to a combined flow rate of 1.50 mL/min. From the chart it may
be seen that the conversion of vanillin is enhanced at higher temperature from 98.3% to above
99%, and the amount of 272 is raised correspondingly. The main impurities are the
demethylation product 280, isomeric nitration-demethylation product 282, and 275. Curiously,
the amount of 280 is higher at higher temperatures, and correspondingly the amount of
nitration product 282 decreases.
Chart 2. Nitration of 271 in 5 mL coil at constant residence time of 3.33 min and varying temperature at stock solution concentrations of 0.30 M (271) and 0.32 M (HNO3).
Chart 3 shows the variation of the crude reaction mixture according to residence time at a
constant temperature of 70°C. The stock solution concentrations were 0.35 M 271 and 0.38 M
HNO3. The conversion of vanillin stays nearly constant at over 99.5% under these conditions,
0
1
2
3
4
5
6
7
8
87
88
89
90
91
92
93
70 80 90 100 110
Impurities A-%272 A-%
T(°C)
272
271
280
282
275
276
108
and the longer residence time also seems to be beneficial for the selectivity of 272.
Correspondingly, the main impurity 282 is found in smaller amounts at longer residence times.
The reason for this remains unclear, but it may be due to the change of encounter velocity of
the reactant streams at the T-piece and subsequent diffusion-controlled mixing during the
flow through the reactor. Due to the integrated pressure sensor of the Uniqsis FlowSyn system,
we were not able to test differently shaped mixing pieces, as the pressure data was crucial for
monitoring the condition of the system.
Chart 3. Nitration of 271 at 70 °C and varying residence time at stock solution concentrations of 0.35 M (271) and 0.38 M (HNO3).
Further selected results from continuous experiments in 5 mL coil are presented in Table 13.
The best selectivity from a single experiment is shown in Entry 1, with stock solution
concentrations of 0.40 and 0.43 M. The conversion of 271 was 99.2% and selectivity of 272
94.2%, with 282 being the most significant impurity. From entries 1-4 it can be seen that
increasing the temperature too high may be detrimental to the selectivity. Entries 5-8 highlight
the stoichiometry of HNO3, with the surprising result that going from 1.3 equivalents to 1.7
equivalents at 70 °C has no significant effect on product distribution. The presence of 5% of
H2O in the stock solution of 271 has a slight detrimental effect on conversion at lower
temperatures, but at 90–100 °C the conversions and selectivities are once again at around 99.9%
and 92.2% (entries 9-12). When the reaction is run at 105 °C, shortening the residence time
once again has the effect of lowering selectivity (entries 13-16). Entries 17 and 18 are
performed at the same temperature and with the same residence time, but the reactor coil was
0
1
2
3
4
5
6
7
8
88
89
90
91
92
93
94
0 2 4 6
Impurities A-%272 A-%
Residence time (min)
272
271
280
281
282
275
109
changed from a 5 mL HT-PFA coil to 10 mL stainless steel coil in the latter experiment. The
conversion and selectivity were improved upon changing to the longer coil. The flow rates are
doubled, which might be beneficial for mixing. Likewise, the thermal properties of the reactor
change significantly based on the material, steel being a much better heat conductor than
perfluoroalkoxy polymers. Indeed, the coil and back-pressure regulator were blocked almost
immediately after obtaining the HPLC sample due to rapid cooling of the reaction mixture
and subsequent precipitation of 272. The working concentrations were judged to be nearing
their practical limits within our reactor setup.
Table 13. Selected results from continuous reactions in 5 mL reactor coil
Entry c(271/M) tR (min) T(°C) 271 272 280 281 282 275 276
1 0.40 2 80 0.753 94.22 0.902 0.871 1.517 0.678 0.189
2 0.40 2 90 0.273 92.994 1.297 1.217 1.887 0.845 0.18
3 0.40 1.7 90 0.083 91.901 1.327 1.355 2.207 0.988 0.176
4 0.40 1.7 100 0.085 91.449 1.703 1.503 1.556 1.335 0.137
5 0.35a 2.9 70 20.409 73.853 0.948 n.d. 3.449 0.035 0.043
6 0.35b 2.5 70 3.3 89.438 0.927 n.d. 5.102 0.059 0.065
7 0.35c 2.2 70 0.765 91.792 1.036 n.d. 5.195 0.091 0.084
8 0.35d 2.5 70 0.117 91.953 1.099 n.d. 5.237 0.108 0.119
9 0.35 3.3 70 42.284 53.87 0.79 n.d. 2.198 0.064 0.04
10 0.35 3.3 80 11.955 81.766 0.964 n.d. 3.934 0.072 0.092
11 0.35 3.3 90 0.085 92.189 1.81 1.419 2.331 0.344 0.179
12 0.35 3.3 100 0.114 92.112 2.155 1.515 1.702 0.521 0.147
13 0.30 3.3 105 0.878 91.293 2.303 n.d. 1.946 0.893 0.081
14 0.30 2.5 105 1.119 90.594 2.249 n.d. 1.358 0.847 0.089
15 0.30 1.7 105 0.852 90.179 2.029 n.d. 2.805 0.862 0.119
16 0.30 1 105 0.931 89.818 1.928 n.d. 3.488 0.84 0.092
17 0.55 5 90 9.182 88.949 0.99 1.547 1.656 0.903 0.211
18 0.55 5 90 2.412 91.546 0.802 1.151 1.284 0.677 0.365 a) 0.80 equivalents of HNO3. b) 1.05 equivalents of HNO3. c) 1.30 equivalents of HNO3. d) 1.75 equivalents of HNO3.
110
Experiments performed with stock solutions of 0.45 M 271 and 0.50 M HNO3 are shown in
Table 14. Within this parameter range (temperature 75-95 °C, residence time 1.5-3.5 minutes)
the reaction was functioning quite well in a robust fashion (entries 1-7). The conversion was
excellent in all cases, and selectivity of 272 was nearly constant, with parameter variation
leading mostly to changes in the composition of impurities – even with 2 equivalents of
HNO3 (entry 8). This was the optimal and most consistent series of experiments in the 5 mL
coil. At higher concentrations the conversion of 271 started to suffer, and in many cases full
conversion was not reached.
Table 14. Continuous experiments in 5 mL coil with 0.45 M and 0.50 M stock solutions
Entry tR (min) T(°C) 271 272 280 281 282 275 276
1 3.3 75 0.17 91.87 1.01 0.223 5.475 0.248 0.094
2 2 75 0.284 91.296 1.065 0.149 5.724 0.204 0.085
3 3.3 85 0.126 91.992 1.663 1.071 2.954 0.577 0.151
4 2 85 0.146 91.375 1.477 0.901 3.774 0.587 0.136
5 3.3 95 0.125 92.567 1.839 1.374 1.342 0.764 0.143
6 2 95 0.095 92.142 1.853 1.339 1.878 0.795 0.132
7 1.4 95 0.129 92.124 1.771 1.308 2.247 0.757 0.130
8a 2.2 95 0.156 92.132 0 0.629 0.317 1.89 0.765 a) 2 equivalents of HNO3 were used, and 2.189% of a previously disregarded impurity at Rrt 1.22 observed.
4.2.5 Continuous experiments in 10 mL reactor
Further experiments were carried out in the 10 mL stainless steel reactor coil. The
conversions and selectivities were consistently slightly improved upon this change of setup.
However, the precipitation of the product often became a serious problem at the end of the
coil due to rapid cooling of the long (about 10 cm) tail without heating. This problem was
partly solved by wrapping insulating cloth around the tail of the reactor coil, but as shown
below, the system could be kept running at stable conditions only for a maximum of about 40
minutes before significant pressure fluctuations started to occur due to accumulation of
precipitated material.
111
In a fashion similar to continuous experiments in the 5 mL coil, the reaction was observed at
constant temperature and at constant residence time (Charts 4 & 5). When the reaction was
run at 90 °C at varying residence times, the conversion of 271 was consistently above 99%,
and selectivity of 272 varied from 92.4% to 93.8%, thus giving slightly better overall results.
All impurities remained below 1.5%. A residence time of 4 minutes gave the best selectivity
of 272 and the least amount of impurities.
Chart 4. Nitration of 271 in 10 mL coil at constant temperature at stock solution concentrations of 0.40 M (271) and 0.44 M (HNO3). Lines indicating 280 and 282 overlap each other.
Interestingly, when the residence time was kept constant and the temperature varied from
85 °C to 105 °C, we observed deterioration of conversion and selectivity in higher
temperatures. The optimum temperature was 90 °C. We were unable to determine whether
this effect of high temperature was an artifact, since correlations to both directions could be
seen between separate experiments (See Table 15, Entries 1-2, 3-4 and Chart 5).
0
1
2
3
4
5
90
91
92
93
94
95
2 3 4 5 6 7
Impurities A-%272 A-%
Residence time (min)
272
271
280
281
282
275
276
112
Chart 5. Nitration of 271 in 10 mL coil at constant residence time at stock solution concentrations of 0.45 M (271) and 0.50 M (HNO3).
Table 15 presents selected results from other continuous experiments with 10 mL coil. The
best single run gave a maximum selectivity of 94.4% for 272, which was obtained with
concentrations of 0.50 M and 0.60 M of 271 and HNO3 respectively (entry 1). The residence
time was 3.3 minutes at 95 °C. Small variations of temperature and residence time did not
increase the selectivity (entries 2-4). Again we were close to the practical limits of our reactor
setup, and precipitation and pressure fluctuations were constantly occurring incidents.
Table 15. Selected results from continuous reactions in 10 mL coil
Entry c(271/M) tR (min) T(°C) 271 272 280 281 282 275 276
1 0.50 3.3 95 0.027 94.369 0.553 1.134 1.081 0.812 0.331
2 0.50 3.3 105 0.727 92.871 0.936 1.245 1.04 0.988 0.336
3 0.50 4 95 0.484 93.524 0.616 1.269 1.211 0.889 0.338
4 0.50 4 105 0 94.126 0.756 1.069 0.946 0.912 0.371
By following the reaction for a longer period of time, we determined that the reaction stays at
equilibrium with no significant fluctuations, as long as the pumps are performing smoothly
0
1
2
3
4
5
88
89
90
91
92
93
94
95
80 85 90 95 100 105 110
Impurities A-%272 A-%
T (°C)
272
271
280
281
282
275
276
113
and no precipitation issues occur. A 30 minute run is shown in Chart 6. Stock solutions of
0.43 M (271) and 0.50 M (HNO3) were used with a 10 mL steel coil, at a temperature of
95 °C and residence time of 4 minutes. It can be seen that the conversion of 271, reaction
selectivity, and amount of impurities all stay practically constant during the run.
Chart 6. A continuous nitration equilibrium run
Pressure fluctuations and blockages due to accumulated precipitation into the back pressure
regulator and coil were a constant nuisance during most of the longer experiments performed
in the 10 mL reactor coil. The solution for this, however, lies more in engineering than
chemistry, as the main problem was the rapid dissipation of heat from the unheated part of the
steel coil.
4.2.6 Isolation studies and comparison between batch and flow modes
Due to limited time given to the project we did not carry out rigorous optimization studies for
the isolation of 272. However, some experiments were carried out to see whether the yield
and purity of the product would correspond to results from batch conditions. The isolation
was carried out by collecting the output stream into distilled H2O for a calculated time. The
mixture was then cooled to 0 °C for 1 hour in an ice bath, filtered, washed with cold toluene
and EtOH, dried and analyzed with HPLC. The yields and HPLC purities are presented in
0
1
2
3
4
5
85
86
87
88
89
90
91
92
93
0 5 10 15 20 25 30
Impurities A-%272 A-%
Time (min)
272
280
271
281
282
275
276
114
Table 16. Varying the conditions slightly the yields were from 55% to 76% (entries 1-6). The
purity of the isolated material was overall slightly poorer than in batch conditions (on average
98.5%). The best purity (99.5%) was obtained when the output was collected into toluene
(entry 7), but the yield was significantly lower, only 46%. The fact that the yields are overall
lower than in batch conditions can be directly attributed to the greater amount of solvent used
in continuous flow conditions. When the concentration was raised, precipitation problems
occurred and disrupted the collection (entry 8). The longest collection times were 30 minutes,
the collection starting about 2-3 minutes after reaching equilibrium conditions (entries 9-10).
Although the experiments were ended at 30 minutes, the accumulated solids and remaining
material in the coil were already starting to cause significant precipitation, and pressure
fluctuations were observed by the time clear solvent was flowing through the whole coil.
Table 16. Isolation studies in continuous flow conditions
Entrya c(271/M) tR (min) T(°C) 271 272 281 275 276 Y Coll. t.
1 0.55 5 90 0.22 98.373 0.743 0.499 0.098 60% 13 min
2 0.55 5 95 0.231 97.894 0.954 0.712 0.12 55% 11 min
3 0.40 2.5 90 - 98.824 0.523 0.503 0.127 n.d. 5 min
4 0.45 4 95 0.058 98.706 0.566 0.495 0.15 76% 20 min
5 0.40 4 90 - 98.123 0.773b 0.791 0.135 69% 20 min
6 0.40 4 95 - 98.682 0.541 0.537 0.184 69% 20 min
7 0.40 4 95 - 99.49 0.313 0.098 0.099 46% 20 min
8 0.48 3.3 95 - 98.529 0.623 0.55 0.252 n.d. 13 min
9 0.43 4 95 - 98.384 0.671 0.739 0.065 69% 30 min
10 0.43 3.4 90 0.139 98.454 0.563 0.554 0.102 95% 30 min
a) All reactions were carried out in 10 mL coil except for entries 1-2, which were carried out in 5 mL coil; b) The isolated sample contained also 0.1% of isomeric 282.
Overall, the selectivity of nitration of vanillin was very similar in flow and batch conditions,
even though significantly higher reaction temperatures are used in flow conditions. In fact, the
conversion in flow conditions is usually better due to the fact that some vanillin tends to
cocrystallize with the mononitration product (See Table 10, entry 12). Especially in higher
concentrations this becomes more pronounced. No crystallization occurs in homogeneous
115
flow conditions, and thus all vanillin is able to react with HNO3. For comparison, we carried
out batch reactions at our highest working flow concentrations at different temperatures
(Table 17). Again we osberved high selectivities and the same impurities as in flow reactions
(entries 1-3). The highest selectivity (95.6%) was obtained when a 0.60 M solution of HNO3
was added into a 0.52 M solution of 271 at 80 °C (entry 4). However, at this temperature the
yields remain below 60%, most likely due to complete digestion of some organic material by
HNO3. At higher temperature, the dissociation of HNO3 into nitric oxide was also observed
by the formation of red fumes. When the reaction was run at a usual batch concentration of
1.4 M 271 in AcOH the conversion remained surprisingly low (entry 5). A greater amount of
impurities was also formed at higher temperatures, and new impurities were likewise present
in both filtrate and the product, but were left unidentified.
Table 17. Batch reactions in analogous flow concentrations and higher temperatures. Note: the precipitate was analyzed directly after filtration without washing.
Entry Sample T (°C) 271 272 280 281 282 275 276 Yield (%)
1a Reaction 20 0.128 94,709 1,005 0,118 3,014 - 0,314
Filtrate - 75,584 5,105 0,978 12,081 0,186 1,553
Product 0,148 99,654 - 0,029 0,052 - 0,116 73
2 a Reaction 50 - 94,422 0,967 0,514 2,191 0,193 0,338
Filtrate - 77,762 3,991 2,801 3,971 1,251 1,406
Product 0,013 99,784 - 0,059 0,028 0,008 0,09 69
3 a Reaction 80 0,27 94,572 0,29 0,824 0,775 0,68 0,522
Filtrate 0,545 80,071 0,578 2,358 1,772 2,832 1,674
Product - 99,509 - 0,241 0,032 0,089 0,129 59
4b Reaction 80 0,07 95,576 0,141 0,278 0,192 0,418 0,361
Filtrate - 84,674 - 0,613 0,418 2,016 0,864
Product - 99,768 - 0,089 - 0,089 0,03 58
5 c Reaction 80 15,445 72,806 0,323 0,671 1,043 0,417 2,143
Filtrate 47,333 26,503 0,759 1,528 3,085 1,219 4,15
Product 0,28 97,306 - 0,122 - 0,023 0,892 49 a) c(271) = 0.26 M, HNO3 added neat. b) A 0.60 M solution of HNO3 in AcOH was added into a 0.52 M solution of 271 in AcOH. c) c(271) = 1.4 M, HNO3 added neat.
116
4.3 Reaction profile and formation of impurities
In trying to determine the status of the side reactions (parallel vs. consecutive), we carried out
HPLC analyses over the course of a slow addition of HNO3 in batch conditions. The
conversion profile is presented in Chart 7. As stated before, the main nitration reaction is very
fast and as HNO3 was added in aliquots at regular intervals, the reaction proceeds
immediately, consuming the added HNO3. Thus the graphs are nearly linear, as would be
expected for a reaction of zero order kinetics, even though the experiment was not set up for
rigorous kinetic analysis. The background profile shows that the amount of 3,4-
dihydroxybenzaldehyde 280 stays nearly constant during the addition of HNO3, and the
amounts of mononitrated dihydroxybenzaldehyde isomers 281 and 282 increase.
Chart 7. Reaction conversion profile in batch. Initial concentration of 271 1.0 M in AcOH at 5 °C. 60 w% HNO3 added at a nearly constant rate over 67 minutes in small aliquots. The final vertical shift indicates a 60 minute delay between HPLC analyses after the addition of HNO3 was complete.
The side reaction to 281 can take place via either a nitration-demethylation, or a
demethylation-nitration pathway. To test this, we subjected 5-nitrovanillin to a stress test
under slightly forcing nitration conditions. In the presence of 1 equivalent of HNO3 at 55 °C
no significant demethylation or dinitration was observed during a digestion of 100 minutes
(Chart 8). When another equivalent of HNO3 was added, the amount of UV active material in
0
1
2
3
4
5
6
7
0102030405060708090
100
0 0,2 0,4 0,6 0,8 1 1,2
Impurities A-%271 & 272 A%
HNO3 (equiv)
271
272
280
281
282
275
Rrt 1,22
276
117
the HPLC analysis decreased dramatically, presumably meaning complete oxidation of the
carbon backbone. These results lead us to conclude that the demethylation step takes place as
a parallel reaction pathway with the main nitration. The resulting 3,4-dihydroxybenzaldehyde
ring is more electron rich and nucleophilic than vanillin, and hence is nitrated faster under the
reaction conditions (see Scheme 77). The impurity at relative retention time 1.22 remained
unidentified during the studies, but the most likely candidate would be 5-nitrovanillic acid
based on these results, as nitric acid is able to oxidize aromatic aldehydes to carboxylic acids.
Chart 8. Stress test of 272 with 1 equivalent of HNO3 at 55 °C
The fact that demethylation takes place was rather surprising, considering the relatively mild
reaction conditions. Whereas aromatic ethers are usually dealkylated in harsh conditions or
with strong reagents such as BBr3, HBr, or AlCl3/pyridine, this mild demethylation is
previously unreported in conjunction with the nitration of vanillin. However, a survey of the
literature reveals that the dealkylation of phenolic ethers under nitration conditions has been
reported previously.136,139 The studies by Ingold established that the concomitant dealkylation
is closely associated with the reactive nitration species, be it nitrosonium or nitronium ion, the
former being much more active in the dealkylation process. Ingold et al. were able to isolate
methyl acetate in a nearly quantitative yield corresponding to the amount of demethylation in
the nitration of anisoles. Corresponding phenyl ethyl ethers did not yield more than trace
amounts of ethyl acetate, detectable by olfactory analysis but unisolable from the reaction
0
1
2
3
4
5
88
89
90
91
92
93
94
95
0 20 40 60 80 100 120
Impurities A-%272 A-%
Time (min)
272
281
Rrt 1,22
276
118
mixture. Based on this they proposed that the methyl cation separates as the free cation and is
then attacked by acetic acid (or another available nucleophile in the mixture). They also
proposed that with ethyl ethers, significant oxidation takes place under the same conditions,
oxidizing the ethyl cation eventually to acetic acid, which is then indistinguishable from the
solvent. They ruled out an ordinary acid promoted demethylation process on the basis of a
model experiment in which no significant amounts of dealkylation took place in the presence
of an equimolar amount of H2SO4. Also, 2,6-disubstitution of anisoles effectively inhibited
the demethylation, presumably via steric effects. No kinetic studies have been carried out to
determine whether the demethylation is in fact a unimolecular process, but considering the
stability of primary cations, a bimolecular process would seem more likely (Scheme 75).
Scheme 75. Possible mechanisms for demethylation of vanillin
The ipso-substitution of aromatic compounds under nitration conditions has been reported on
several occasions.140 For example, the substitution of an isopropyl group with a nitro group
has been observed in the nitration of p-cymene.141 When an alkyl substituted carbon
undergoes ipso-attack, the usual outcomes may be a nucleophilic trapping of the cationic
intermediate, or a 1,2-migration of the nitro group, thus giving a formal ortho-nitration
product. The decarbonylative and decarboxylative nitration of electron rich substrates has also
been studied when using dilute nitric acid.142 Bentley reported the formation of 2,4-
dinitroguaiacol 276 from 5-nitrovanillin 272 when subjected to dilute nitration conditions,137c
but in our test experiment we had to use forcing conditions (several equivalents of HNO3,
high temperature) before we saw an increase in the amount of 276. As mentioned above, the
HPLC analysis also showed the disappearance of UV-active material at the same time,
ostensibly via complete oxidation by nitric acid. Hence, based on the actual calculated area,
the increase of 276 in the reaction mixture is rather modest, although clear. Hence we
119
conclude the dominating mechanism for the formation to be first an ipso-substitution of
vanillin to give 275, then via a second nitration to give 276 (Scheme 76).
�Scheme 76. Competing reactions in the nitration of vanillin. Species 275, 276, 280, 281, 282, 287 and 288 were observed experimentally by HPLC or MS.
4.4. Nitration of other substrates
The high-throughput continuous-flow nitration of aromatic compounds has been presented
recently.143 It is no surprise that these publications come from pharmaceutical companies,
since a safe method of nitration using hazardous reagents is of significant interest and
importance. For example, researchers at Novartis performed the nitration of bromo-
quinolinone 289 in good yield and at high production rate (Scheme 77).143a The starting
material was pumped through the reactor as 1.0 M solution in AcOH, and through the other
120
pump was fed fuming HNO3. The mixture was pumped through four consecutive 10 mL
reactor coils which were heated to 90 °C, and then cooled down and quenched by collecting
into H2O. The overall output was 7 mmol/min, corresponding to a production rate of 2.3 kg
per day.
Scheme 77. Continuous-flow nitration of bromoquinolinone 289 by Novartis
We carried out a brief investigation into the applicability of our relatively mild nitration
procedure to other substrates. In general, all procedures were carried out by pumping stock
solutions of starting material and 65 w-% aqueous HNO3 through a heated coil reactor.
However, in all cases the high dilution also hinders the work-up process, and it was difficult
to obtain good yields via either extraction or precipitation. The best results were achieved
with methyl 4-hydroxybenzoate 291. The mononitration product 292 could be isolated by
simple filtration from H2O in 75–85% yield and good purity. The limiting factor was the
solubility of methyl 4-hydroxybenzoate into acetic acid. In a large scale example run, the
reaction was run at steady state for a period of 2.5 hours, producing 18 grams of material
(Scheme 78).
Scheme 78. Continuous-flow nitration of methyl 4-hydroxybenzoate 291
121
With other substrates we were not so successful. With salicylaldehyde we obtained a
maximum yield of only 35% in similar conditions, with an expected mixture of regioisomers.
Anisaldehyde, 4-methoxyacetophenone and 4-methylacetophenone did not react under similar
conditions, and would obviously need more forcing conditions, e.g. fuming nitric acid or
mixed acid as the nitration reagent. While this is possible and precedented, as shown in
Scheme 77, we decided not to explore the subject further as it would stray away from our
original aim of relatively mild nitration in continuous flow conditions.
4.5 Conclusions
We have investigated the nitration of vanillin 271 under continuous flow conditions and
compared the performance of the reactor to standard batch conditions. Overall it was noted
that a highly exothermic nitration could be safely carried out in a continuous flow reactor with
no concerns of a runaway reaction. Moreover, the reaction optimization can be carried out
rapidly, providing that a fast and robust analysis method is at hand. The nitration of 271 is
basically a reactive crystallization, the product 272 precipitating out from the reaction mixture
very early on. This forces severe limitations on the applicability of the reaction into micro-
and mesofluidic conditions. The concentrations need to be lower and temperatures high
enough to ensure that the product does not prematurely precipitate and block the reaction line.
As an upside, a higher conversion can be obtained in the nitration of 271 since it will not
cocrystallize with the product. The isolation of 272 from flow conditions was left unoptimized.
As the main side reaction we identified the O-demethylation of vanillin and subsequent
nitration of the catecholic aldehyde into different regioisomers. Another unpreventable side
reaction arises from the ipso-substitution of the vanillin formyl group, and subsequent
nitration of the still active intermediate 4-nitroguaiacol. The formation of corresponding
carboxylic acids was also detected by LC/MS-experiments, but these were present in
significantly smaller proportions.
Since the usual benefits of continuous processing do not arise from converting a single
nitration step from batch to flow, it should be considered that if vanillin was used as a starting
material in a multistep process, the telescoping of following step(s) into a continuous process
should also be investigated. This could then lead to saving of time, materials and reactor
equipment since several unit operations could be skipped entirely.
122
The continuous flow nitration with a stoichiometric amount of dilute nitric acid is mostly
applicable to highly reactive substrates, as shown by our brief substrate studies. The high
throughput continuous nitration of less reactive aromatic substrates has been illustrated by
several industrial groups, thus confirming that there is pressure towards rethinking and
steering industrial processes towards greener and safer avenues with continuous processing.
123
5 EXPERIMENTAL SECTION
5.1 General Experimental Considerations
Moisture sensitive reactions were carried out under an argon atmosphere, and glassware was
dried with flame in vacuum or in an oven. Dry solvents (CH2Cl2, THF, Et2O, MeCN, toluene)
were obtained with MBraun MB-SPS 800 solvent drying system. Chlorobenzene was distilled
from P2O5 on 4 Å molecular sieves. DMF was distilled from ninhydrin/molecular sieves (4 Å).
Commercial reagents were used without further purification unless otherwise indicated.
Nonaqueous reagents were transferred under argon via syringe or cannula. Analytical TLC
was performed using SiO2 (silica gel 60, F254, 230-400 mesh, precoated aluminum sheets or
glass plates, Merck). TLC analyses were visualized with UV light, or with aqueous KMnO4,
ninhydrin or vanillin solutions. Flash chromatography was carried out on SiO2 (silica gel 60,
F254, 230-400 mesh, Merck). Continuous flow reactions were performed with Vapourtec
R2+/R4 or Uniqsis FlowSyn reactors.
The 1H and 13C NMR spectra were recorded with Bruker Avance DPX-400 spectrometer (1H
399.98 MHz; 13C 100.59 MHz). The chemical shifts are reported in ppm relative to TMS
internal standard (� = 0.00) or residual solvent signal (1H NMR: CDCl3 7.26, DMSO-d6 2.50,
MeCN-d3 1.94, MeOD-d4 3.31, CD2Cl2 5.32; 13C NMR: CDCl3 77.0, DMSO-d6 39.50,
MeOD-d4 49.0). Enantiomeric excesses were determined by HPLC using chiral stationary
phase columns with Waters 501 pump and Waters 2487 UV dual absorbance detector (Aalto
University), Agilent HP 1100 chromatograph (Cambridge), or Waters Alliance 2695 HPLC
system with PDA 996 detector (Fermion). Mass spectra described in Chapter 4 were recorded
with Waters 2960, PDA 996 + EMD 1000 apparatus. IR spectra were recorded with Perkin
Elmer One FTIR spectrometer. Optical rotations were measured with Perkin Elmer 343
polarimeter ( = 589 nm) using a 1 dm cuvette. Elemental analyses were performed with
Perkin Elmer 2400 Series II CHNS/O Analyzer. Melting points (uncorrected) were
determined in open capillaries using either a Stuart SMP3 (Aalto) or SRS OptiMelt apparatus
(Cambridge). HRMS were recorded with Waters Micromass LCT Premier (ESI) spectrometer.
124
For compounds 243 and 250-255 described in section 5.3, CHN analyses had been recorded
previously in the Ley group, and thus were not redetermined, as all other spectral data were in
agreement. The syntheses of known compounds (such as 26a-l, 45, 79, 88, 90, 101, 237, 239,
265-267) were carried out according to published procedures and are not reported here. Due
to low enantiopurity of model reactions and organocatalyst screening, optical rotation was
measured only for stereoisomerically pure compounds such as catalysts and their
intermediates.
5.2 Asymmetric Organocatalytic Michael Additions
5.2.1 General Organocatalytic Screening Procedure
Nitroalkene (0.8 mmol, 100 mol %) was loaded in a small vial equipped with a magnetic
stirrer. Compound 78 (230 mg, 1.6 mmol, 200 mol %) was added, and the mixture was
dissolved in CH2Cl2 (0.5 mL). Catalyst 79 (50 mg, 0.08 mmol, 10 mol %) was added, the vial
was tightly capped and the mixture was stirred at room temperature until completion as shown
by TLC. The solvents were evaporated and the crude mixture analyzed by 1H NMR and used
as such in the derivatization step.
5.2.2 5-(1-(3-Methoxyphenyl)-2-nitroethyl)-2,2-dimethyl-1,3-dioxane-4,6-dione (80e)
Compound 80e was prepared according to the general procedure. Purification of a small
sample for analytical purposes by flash chromatography (10% MeOH in EtOAc) gave 80e as
a yellowish oil. Rf = 0.21 (EtOAc); IR (neat): 2997, 2941, 1734, 1572, 1403, 1375, 1261 cm-1; 1H NMR (MeOD-d4, 400 MHz): (Partial, dicarbonyl H presumably exchanges to D) � 7.12
(app t, J = 7.9 Hz, 1H), 7.03 (s, 1H), 6.98 (d, J = 7.6 Hz, 1H), 6.69 (dd, J = 8.1, 2.0 Hz, 1H),
125
5.21 (dd, J = 12.0, 8.7 Hz, 1H), 5.07 (dd, J = 11.9, 7.5 Hz, 1H), 4.74 (t, J = 8.1 Hz, 1H), 3.74
(s, 3H), 1.54 (s, 6H); 13C NMR (MeOD-d4, 100 MHz): � 169.2, 160.9, 145.3, 129.9, 121.2,
114.4, 112.8, 102.8, 79.2, 76.5, 55.5, 41.3, 25.8; HRMS m/z 346.0906 [C15H17NO7 (M+Na)+
requires 346.0903].
5.2.3 5-(1-(4-Bromophenyl)-2-nitroethyl)-2,2-dimethyl-1,3-dioxane-4,6-dione (80f)
Compound 80f was prepared according to the general procedure. Purification of a small
sample for analytical purposes by flash chromatography (10% MeOH in EtOAc) gave 80f as a
yellow oil. Rf = 0.26 (50% EtOAc in hexane); IR (neat): 2994, 1716, 1579, 1488, 1399, 1374,
1262 cm-1; 1H NMR (MeOD-d4, 400 MHz): (Partial, dicarbonyl H presumably exchanges to
D) � 7.35 (s, 4H), 5.17 (dd, J = 12.1, 8.6 Hz, 1H), 5.09 (dd, J = 12.1, 7.7 Hz, 1H), 4.73 (dd, J
= 8.4, 8.0 Hz, 1H), 1.53 (s, 6H); 13C NMR (MeOD-d4, 100 MHz): � 169.1, 161.2, 143.1,
132.0, 130.9, 120.7, 102.9, 78.8, 76.3, 61.5, 40.9, 25.8; HRMS m/z 415.9742/417.9731
[C14H14BrNO6 (M-H+2Na)+ requires 415.9722/417.9702].
5.2.4 5-(1-(3-Bromophenyl)-2-nitroethyl)-2,2-dimethyl-1,3-dioxane-4,6-dione (80g)
126
Compound 80g was prepared according to the general procedure. Purification of a small
sample for analytical purposes by flash chromatography (10% MeOH in EtOAc) gave 80g as
a yellow oil. Rf = 0.19 (50% EtOAc in hexane); IR (neat): 2994, 2941, 1719, 1578, 1402,
1375, 1262 cm-1; 1H NMR (MeOD-d4, 400 MHz): (Partial, dicarbonyl H presumably
exchanges to D) � 7.61 (t, J = 1.8 Hz, 1H), 7.39 (d, J = 7.7 Hz, 1H), 7.28 (ddd, J = 8.0, 1.9,
1.0 Hz, 1H), 7.14 (t, J = 7.8 Hz, 1H), 5.19 (dd, J = 12.2, 8.6 Hz, 1H), 5.10 (dd, J = 12.1, 7.7
Hz, 1H), 4.74 (t, J = 8.1 Hz, 1H), 1.54 (s, 6H); 13C NMR (MeOD-d4, 100 MHz): � 169.1,
146.4, 131.9, 130.7, 130.2, 127.7, 123.0, 102.9, 78.8, 76.1, 41.1, 25.8; HRMS m/z
415.9731/417.9722 [C14H14BrNO6 (M-H+2Na)+ requires 415.9722/417.9702].
5.2.5 5-(1-(Furan-2-yl)-2-nitroethyl)-2,2-dimethyl-1,3-dioxane-4,6-dione (80h)
Compound 80h was prepared according to the general procedure. Purification of a small
sample for analytical purposes by flash chromatography (10% MeOH in EtOAc) gave 80h as
a yellow oil. Rf = 0.27 (50% EtOAc in hexane); IR (neat): 2995, 2943, 1731, 1578, 1411,
1375, 1262 cm-1; 1H NMR (MeOD-d4, 400 MHz): (Partial, dicarbonyl H presumably
exchanges to D) � 7.31 (m, 1H), 6.26 (dd, J = 3.2, 1.9 Hz, 1H), 6.08 (dt, J = 3.1, 0.9 Hz, 1H),
5.06 (dd, J = 11.9, 8.8 Hz, 1H), 5.02 (dd, J = 11.8, 6.9 Hz, 1H), 4.89-4.84 (m, 1H), 1.58 (s,
6H); 13C NMR (MeOD-d4, 100 MHz): � 169.0, 161.2, 156.3, 141.9, 111.1, 106.5, 102.9, 77.4,
73.8, 35.9, 25.8; HRMS m/z 306.0582 [C12H13NO7 (M+Na)+ requires 306.0590].
127
5.2.6 5-(1-(Furan-3-yl)-2-nitroethyl)-2,2-dimethyl-1,3-dioxane-4,6-dione (80i)
Compound 80i was prepared according to the general procedure. Purification of a small
sample for analytical purposes by flash chromatography (10% MeOH in EtOAc) gave 80i as a
yellow oil. Rf = 0.31 (50% EtOAc in hexane); IR (neat): 2994, 1737, 1578, 1555, 1377, 1261
cm-1; 1H NMR (MeOD-d4, 400 MHz): (Partial, dicarbonyl H presumably exchanges to D) �
7.32 (m, 2H), 6.46 (s, 1H), 5.05 (dd, J = 11.6, 8.7 Hz, 1H), 4.94 (dd, J = 11.6, 7.6 Hz, 1H),
4.66 (t, J = 8.1 Hz, 1H), 1.55 (s, 6H); 13C NMR (MeOD-d4, 100 MHz): � 169.0, 161.2, 143.3,
140.5, 126.9, 111.7, 102.8, 79.1, 75.6, 33.0, 25.8; HRMS m/z 306.0601 [C12H13NO7 (M+Na)+
requires 306.0590].
5.2.7 5-(1-Cyclohexyl-2-nitroethyl)-2,2-dimethyl-1,3-dioxane-4,6-dione (80j)
Compound 80j was prepared according to the general procedure. Purification of a small
sample for analytical purposes by flash chromatography (10% MeOH in EtOAc) gave 80j as a
clear oil. Rf = 0.13 (50% EtOAc in hexane); IR (neat): 2994, 2926, 2852, 1731, 1575, 1406,
1373, 1260 cm-1; 1H NMR (MeOD-d4, 400 MHz): (Partial, dicarbonyl H presumably
exchanges to D) � 4.90 (app. t, J = 10.8 Hz, 1H), 4.62 (dd, J = 10.8, 5.0 Hz, 1H), 3.25-3.17 (m,
1H), 1.84-1.66 (m, 5H), 1.65-1.60 (m, 1H), 1.55 (s, 6H), 1.31-1.10 (m, 3H), 1.10-0.90 (m,
128
2H); 13C NMR (MeOD-d4, 100 MHz): � 169.5, 102.6, 78.2, 74.0, 42.6, 39.9, 32.9, 32.1, 27.6,
27.6, 27.5, 25.9; HRMS m/z 322.1254 [C14H21NO6 (M+Na)+ requires 322.1266].
�
5.2.8 2,2-Dimethyl-5-(1-nitrohexan-2-yl)-1,3-dioxane-4,6-dione (80k)
O O
O O78
+NO2
26k
79 (cat.) NO2
80k
OO
O O
CH2Cl2, rt
Compound 80k was prepared according to the general procedure. Purification of a small
sample for analytical purposes by flash chromatography (10% MeOH in EtOAc) gave 80k as
a clear oil. Rf = 0.26 (50% EtOAc in hexane); IR (neat): 2956, 2930, 2863, 1782, 1741, 1718,
1553, 1383, 1311, 1206 cm-1; 1H NMR (CDCl3, 400 MHz): � 4.98 (dd, J = 13.3, 10.2 Hz, 1H),
4.57 (dd, J = 13.4, 4.4 Hz, 1H), 3.89 (d, 2.4 Hz, 1H), 3.31-3.22 (m, 1H), 1.81 (s, 3H), 1.79 (s,
3H), 1.64-1.53 (m, 1H), 1.51-1.41 (m, 1H), 1.40-1.27 (m, 4H), 0.94-0.87 (m, 3H); 13C NMR
(CDCl3, 100 MHz): � 164.0, 105.5, 75.8, 46.9, 36.4, 29.5, 29.0, 28.2, 26.9, 22.4, 13.8; HRMS
m/z 296.1106 [C12H19NO6 (M+Na)+ requires 296.1110].
5.2.9 5-(1-(Benzyloxy)-3-nitropropan-2-yl)-2,2-dimethyl-1,3-dioxane-4,6-dione (80l)
Compound 80l was prepared according to the general procedure. Purification of a small
sample for analytical purposes by flash chromatography (10% MeOH in EtOAc) gave 80l as a
yellowish oil. Rf = 0.14 (50% EtOAc in hexane); IR (neat): 2865, 1709, 1579, 1551, 1412,
1376, 1260 cm-1; 1H NMR (MeOD-d4, 400 MHz): (Partial, dicarbonyl H presumably
exchanges to D) � 7.35-7.21 (m, 5H), 4.93 (dd, J = 11.3, 9.2 Hz, 1H), 4.74 (dd, J = 11.3, 5.5
Hz, 1H), 4.50 (q, J = 11.6 Hz, 2H), 3.91-3.76 (m, 2H, overlapping signals), 3.55 (dd, J = 9.1,
129
4.8 Hz, 1H), 1.55 (s, 6H); 13C NMR (MeOD-d4, 100 MHz): � 169.3, 139.9, 129.3, 128.8,
128.5, 102.9, 77.4, 73.7, 72.5, 71.5, 37.1, 25.7; HRMS m/z 360.1064 [C16H19NO7 (M+Na)+
requires 360.1059].
5.2.10 General Procedure for Derivatization
The evaporated crude reaction mixture (100 mg) was loaded in a 5 mL flask and dissolved in
dry DMF (2.5 mL). Distilled aniline (0.25 mL) was added and the mixture was heated to
100 °C for 3 hours. The mixture was partitioned between 10 mL EtOAc and 10 mL 1 M HCl,
and washed further 3 times with 1 M HCl (3 * 10 mL). The organic phase was dried over
MgSO4, filtered and evaporated. The residue was purified by flash chromatography (EtOAc in
hexane). Enantioselectivity was determined by chiral HPLC from the chromatographed
product. For determination of elemental composition, the product was then crystallized from
boiling hexanes by adding a minimum amount of EtOAc for dissolving the product. The yield
was measured from the crystallized product, thus accounting for the low values.
5.2.11 4-Nitro-N,3-diphenylbutanamide (87a)
Compound 87a was prepared according to the general procedure, purified by flash
chromatography (50% EtOAc in hexane) and crystallized from EtOAc:hexane to give 80a as
white crystals (10 mg): Rf = 0.45 (50% EtOAc in hexane); mp. 107-109 °C; IR (neat): 3302,
3138, 3063, 3032, 1661, 1599, 1551, 1498, 1443 cm-1; 1H NMR (CDCl3, 400 MHz): � 7.40-
7.23 (m, 9H), 7.15-7.06 (m, 2H), 4.85 (dd, J = 12.6, 6.4 Hz, 1H), 4.73 (dd, J = 12.6, 7.9 Hz,
1H), 4.07 (app d, J = 7.1 Hz, 1H), 2.83 (dd, J = 15.0, 7.3 Hz, 1H), 2.75 (dd, J = 15.0, 7.1 Hz,
1H); 13C NMR (CDCl3, 100 MHz): � 167.9, 138.4, 137.2, 129.2, 129.0, 128.1, 127.3, 124.7,
120.1, 79.3, 40.7, 40.6; HPLC: Chiralcel OD column (0.46 cm 25 cm), 25% i-PrOH in
130
hexane, 1.0 mL/min, = 254 nm, tR(major) 17.9 min, tR(minor) 23.8 min; Anal. Calcd. for
C16H16N2O3: C, 67.59; H, 5.67; N, 9.85. Found: C, 67.50; H, 5.74; N, 9.85.
5.2.12 3-(4-Methoxyphenyl)-4-nitro-N-phenylbutanamide (87b)
NO2
80b
OO
O O 1:10 aniline:DMF
100 °C NH
ONO2
87bMeO
OMe
Compound 87b was prepared according to the general procedure. Purified by flash
chromatography (50% EtOAc in hexane) and crystallized from EtOAc:hexane to give 87b as
white crystals (12 mg). Rf = 0.38 (50% EtOAc in hexane); mp. 97-99 °C; IR (neat): 3309,
3199, 3138, 3061, 3038, 2969, 2837, 1664, 1600, 1551, 1514, 1499, 1443, 1379, 1303, 1251
cm-1; 1H NMR (CDCl3, 400 MHz): � 7.37 (d, J = 7.6 Hz, 2H), 7.28 (t, J = 7.9 Hz, 2H), 7.19
(br s, 1H), 7.16 (d, J = 8.5 Hz, 2H), 7.10 (t, J = 7.4 Hz, 1H), 6.85 (d, J = 8.7 Hz, 2H), 4.80 (dd,
J = 12.5, 6.5 Hz, 1H), 4.67 (dd, J = 12.5, 7.9 Hz, 1H), 4.06-3.97 (m, 1H), 3.77 (s, 3H), 2.79
(dd, J = 15.0, 7.2 Hz, 1H), 2.71 (dd, J = 15.0, 7.2 Hz, 1H), 13C NMR (CDCl3, 100 MHz): �
168.0, 159.2, 137.2, 130.2, 129.0, 128.4, 124.7, 120.1, 114.5, 79.6, 55.2, 40.8, 39.9; HPLC:
Chiralcel OD column (0.46 cm 25 cm), 25% i-PrOH in hexane, 1.0 mL/min, = 254 nm,
tR(major) 26.1 min, tR(minor) 46.7 min; Anal. Calcd. for C17H18N2O4: C, 64.96; H, 5.77; N,
8.91. Found: C, 64.81; H, 5.63; N, 8.86.
5.2.13 3-(3-Methoxyphenyl)-4-nitro-N-phenylbutanamide (87e)
NO2
80e
OO
O O 1:10 aniline:DMF
100 °C NH
ONO2
87e
MeOOMe
131
Compound 87e was prepared according to the general procedure. Purified by flash
chromatography (50% EtOAc in hexane) and crystallized from EtOAc:hexane to give 87e as
white crystals (16 mg). Rf = 0.39 (50% EtOAc in hexane); mp. 101-103 °C; IR (neat): 3303,
3139, 3059, 2919, 2837, 1661, 1600, 1551, 1498, 1443, 1378, 1260 cm-1; 1H NMR (CDCl3,
400 MHz): � 7.41-7.34 (m, 2H), 7.32-7.23 (m, 3H), 7.14-7.07 (m, 2H), 6.86-6.76 (m, 3H),
4.84 (dd, J = 12.6, 6.4 Hz, 1H), 4.72 (dd, J = 12.6, 7.9 Hz, 1H), 4.09-4.00 (m, 1H), 3.77 (s,
3H), 2.81 (dd, J = 15.1, 7.2 Hz, 1H), 2.75 (dd, J = 15.0, 7.0 Hz); 13C NMR (CDCl3, 100 MHz):
� 167.8, 160.1, 140.0, 137.2, 130.3, 129.0, 124.7, 120.0, 119.4, 113.5, 113.2, 79.2, 55.2, 40.7,
40.6; HPLC: Chiralcel OD column (0.46 cm 25 cm), 25% i-PrOH in hexane, 1.0 mL/min,
= 254 nm, tR(major) 16.6 min, tR(minor) 21.3 min; Anal. Calcd. for C17H18N2O4: C, 64.96; H,
5.77; N, 8.91. Found: C, 64.80; H, 5.50; N, 8.88.
5.2.14 3-(4-Bromophenyl)-4-nitro-N-phenylbutanamide (87f)
Compound 87f was prepared according to the general procedure. Purified by flash
chromatography (40% EtOAc in hexane) and crystallized from EtOH:H2O to give 87f as
white crystals (10 mg). Rf = 0.42 (50% EtOAc in hexane); mp. 127-130 °C; IR (neat): 3302,
3139, 3062, 2918, 1662, 1599, 1551, 1498, 1443, 1377 cm-1; 1H NMR (CDCl3, 400 MHz): �
7.47 (d, J = 8.4 Hz, 2H), 7.39 (d, J = 7.7 Hz, 2H), 7.31 (t, J = 7.9 Hz, 2H), 7.18-7.08 (m, 4H),
4.84 (dd, J = 12.8, 6.3 Hz, 1H), 4.71 (dd, J = 12.8, 8.0 Hz, 1H), 4.11-4.01 (m, 1H), 2.82 (dd, J
= 15.3, 7.3 Hz, 1H), 2.73 (dd, J = 15.3, 6.9 Hz, 1H); 13C NMR (CDCl3, 100 MHz): � 167.5,
137.5, 137.1, 132.3, 129.1, 124.9, 122.1, 120.1, 79.0, 40.3, 39.9; HPLC: Chiralcel OD column
(0.46 cm 25 cm), 25% i-PrOH in hexane, 1.0 mL/min, = 254 nm, tR(major) 14.5 min,
tR(minor) 17.7 min; Anal. Calcd. for C16H15BrN2O3: C, 52.91; H, 4.16; N, 7.71. Found: C,
52.93; H, 3.84; N, 7.55.
132
5.2.15 3-(3-Bromophenyl)-4-nitro-N-phenylbutanamide (87g)
Compound 87g was prepared according to the general procedure. Purified by flash
chromatography (40% EtOAc in hexane) and crystallized from EtOAc:hexane to give 87g as
white crystals (13 mg). Rf = 0.45 (50% EtOAc in hexane); mp. 110-111 °C; IR (neat): 3302,
3199, 3139, 3061, 2918, 1661, 1598, 1551, 1498, 1443, 1376 cm-1; 1H NMR (CDCl3, 400
MHz): � 7.45-7.36 (m, 4H), 7.30 (t, J = 7.9 Hz, 2H), 7.24-7.16 (m, 3H), 7.12 (t, J = 7.3 Hz,
1H), 4.84 (dd, J = 12.8, 6.3 Hz, 1H), 4.71 (dd, J = 12.8, 8.0 Hz, 1H), 4.10-4.01 (m, 1H), 2.81
(dd, J = 15.4, 7.5 Hz, 1H), 2.73 (dd, J = 15.4, 6.9 Hz, 1H); 13C NMR (CDCl3, 100 MHz): �
167.5, 140.8, 137.1, 131.3, 130.7, 130.4, 129.1, 126.2, 124.9, 123.1, 120.1, 78.9, 40.2, 40.0;
HPLC: Chiralcel OD column (0.46 cm 25 cm), 25% i-PrOH in hexane, 1.0 mL/min, =
254 nm, tR(major) 16.3 min, tR(minor) 18.8 min; Anal. Calcd. for C16H15BrN2O3: C, 52.91; H,
4.16; N, 7.71. Found: C, 52.99; H, 3.82; N, 7.71.
5.2.16 3-(Furan-2-yl)-4-nitro-N-phenylbutanamide (87h)
Compound 87h was prepared according to the general procedure. Purified by flash
chromatography (40% EtOAc in hexane) and crystallized from EtOAc:hexane to give 87h as
white crystals (10 mg). Rf = 0.48 (50% EtOAc in hexane); mp. 111-124 °C; IR (neat): 3304,
3141, 2918, 1662, 1600, 1552, 1499, 1444, 1376 cm-1; 1H NMR (CDCl3, 400 MHz): � 7.43 (d,
J = 8.1 Hz, 2H), 7.37 (d, J = 1.1 Hz, 1H), 7.31 (t, J =7.9 Hz, 2H), 7.22 (br. s, 1H), 7.12 (t, J =
133
7.3 Hz, 1H), 6.31 (dd, J = 3.1, 1.8 Hz, 1H), 6.21 (d, J = 3.3 Hz, 1H), 4.84 (dd, J = 12.6, 5.9
Hz, 1H), 4.76 (dd, J = 12.6, 7.1 Hz, 1H), 4.23-4.15 (m, 1H), 2.87 (dd, J = 15.0, 6.6 Hz, 1H),
2.82 (dd, J = 15.1, 7.4 Hz, 1H), 13C NMR (CDCl3, 100 MHz): � 167.6, 151.3, 142.5, 137.2,
129.1, 124.8, 120.1, 110.6, 107.5, 77.1, 38.1, 34.5; HPLC: Chiralcel OD column (0.46 cm
25 cm), 25% i-PrOH in hexane, 1.0 mL/min, = 254 nm, tR(major) 12.0 min, tR(minor) 15.1
min; Anal. Calcd. for C14H14N2O4: C, 61.31; H, 5.14; N, 10.21. Found: C, 61.26; H, 4.98; N,
10.16.
5.2.17 3-(Furan-3-yl)-4-nitro-N-phenylbutanamide (87i)
Compound 87i was prepared according to the general procedure. Purified by flash
chromatography (40% EtOAc in hexane) and crystallized from EtOAc:hexane to give 87i as
white crystals (10 mg). Rf = 0.42 (50% EtOAc in hexane); mp. 101-107 °C; IR (neat): 3302,
3136, 2918, 1664, 1599, 1551, 1499, 1443, 1377 cm-1; 1H NMR (CDCl3, 400 MHz): � 7.44 (d,
J = 7.7 Hz, 2H), 7.40 (t, J = 1.6 Hz, 1H), 7.37 (br s, 1H), 7.32 (app t, J = 7.9 Hz, 2H), 7.19 (br
s, 1H), 7.12 (app t, J = 7.4 Hz, 1H), 6.34 (br s., 1H), 4.80 (dd, J = 12.5, 6.0 Hz, 1H), 4.67 (dd,
J = 12.5, 7.3 Hz, 1H), 4.02 (app d, J = 6.8 Hz, 1H), 2.79 (dd, J = 15.2, 7.3 Hz, 1H), 2.72 (dd,
J = 15.1, 6.7 Hz, 1H); 13C NMR (CDCl3, 100 MHz): � 167.8, 143.9, 139.8, 137.2, 129.1,
124.8, 122.7, 120.0, 108.8, 78.8, 40.1, 31.8; HPLC: Chiralcel OD column (0.46 cm 25 cm),
25% i-PrOH in hexane, 1.0 mL/min, = 254 nm, tR(major) 13.0 min, tR(minor) 16.0 min;
Anal. Calcd. for C14H14N2O4: C, 61.31; H, 5.14; N, 10.21. Found: C, 61.07; H, 5.10; N, 10.18.
134
5.2.18 3-Cyclohexyl-4-nitro-N-phenylbutanamide (87j)
Compound 87j was prepared according to the general procedure. Purified by flash
chromatography (0 to 15% EtOAc in hexane) and recrystallization to give traces of 87j as
white crystals. Rf = 0.61 (50% EtOAc in hexane); IR (neat): 3302, 3139, 3061, 2958, 2931,
2861, 1661, 1600, 1548, 1499, 1443, 1380 cm-1; 1H NMR (CDCl3, 400 MHz): � 7.50 (d, J =
7.7 Hz, 2H), 7.33 (t, J = 7.9 Hz, 2H), 7.28-7.23 (br. s, 1H), 4.62 (dd, J = 12.4, 6.3 Hz, 1H),
4.53 (dd, J = 12.3, 5.1 Hz, 1H), 2.65-2.56 (m, 2H), 2.43 (dd, J = 16.5, 9.5 Hz, 1H), 1.85-1.73
(m, 4H), 1.72-1.65 (m, 1H), 1.55-1.46 (m, 1H), 1.32-1.19 (m, 2H), 1.19-1.10 (m, 1H), 1.09-
0.96 (m, 2H); 13C NMR (CDCl3, 100 MHz): � 169.2, 137.5, 129.1, 124.6, 119.9, 76.8, 40.0,
38.9, 36.5, 30.3, 29.9, 26.2, 26.2; HPLC: Chiralcel OD column (0.46 cm 25 cm), 10% i-
PrOH in hexane, 0.7 mL/min, = 254 nm, tR(major) 22.9 min, tR(minor) 26.8 min; HRMS
m/z 313.1540 [C16H22N2O3 (M+Na)+ requires 313.1528].
5.2.19 3-(Nitromethyl)-N-phenylheptanamide (87k)
Compound 87k was prepared according to the general procedure. Purified by flash
chromatography (0 to 15% EtOAc in hexane) and crystallized from EtOAc:hexane to give
87k as white crystals (9 mg). Rf = 0.59 (50% EtOAc in hexane); mp. 75-76 °C; IR (neat):
3307, 3200, 3139, 3061, 2926, 2854, 1711, 1661, 1600, 1549, 1499, 1443, 1379 cm-1; 1H
NMR (CDCl3, 400 MHz): � 7.51 (d, J = 7.7 Hz, 2H), 7.36-7.28 (m, 3H), 7.13 (t, J = 7.4 Hz,
135
1H), 4.60 (dd, J = 12.1, 5.9 Hz, 1H), 4.53 (dd, J = 12.0, 5.0 Hz, 1H), 2.74-2.63 (m, 1H), 2.52
(dd, J = 15.2, 5.9 Hz, 1H), 2.48 (dd, J = 15.2, 7.7 Hz, 1H), 1.53-1.45 (m, 2H), 1.42-1.29 (m,
4H), 0.91 (t, J = 7.0 Hz, 3H); 13C NMR (CDCl3, 100 MHz): (partial, anilide quaternary C not
seen) � 168.8, 129.1, 124.6, 119.9, 78.4, 39.1, 34.9, 31.1, 28.8, 22.5, 13.9; HPLC: Chiralcel
OD column (0.46 cm 25 cm), 15% i-PrOH in hexane, 1.0 mL/min, = 254 nm, tR(major)
18.6 min, tR(minor) 23.0 min; Anal. Calcd. for C14H20N2O3: C, 63.62; H, 7.63; N, 10.60.
Found: C, 63.59; H, 8.06; N, 10.60.
5.2.20 4-(Benzyloxy)-3-(nitromethyl)-N-phenylbutanamide (87l)
Compound 87l was prepared according to the general procedure. Purified by flash
chromatography (40% EtOAc in hexane) and crystallized from EtOH:H2O to give 87l as
white crystals (17 mg). Rf = 0.51 (50% EtOAc in hexane); mp. 82-85 °C; IR (neat): 3310,
3138, 3062, 3031, 2864, 1663, 1600, 1550, 1498, 1443, 1380 cm-1; 1H NMR (CDCl3, 400
MHz): � 7.43 (d, J = 7.7 Hz, 2H), 7.37-7.27 (m, 8H), 7.12 (t, J = 7.4 Hz, 1H), 4.61 (d, J = 6.4
Hz, 2H), 4.51 (dd, AB system, J = 13.5, 11.9 Hz, 2H), 3.60 (app d, J = 5.3 Hz, 2H), 3.10-3.00
(m, 1H), 2.57 (dd, J = 15.2, 6.8 Hz, 1H), 2.51 (dd, J = 15.2, 6.8 Hz, 1H); 13C NMR (CDCl3,
100 MHz): � 168.3, 137.5, 137.4, 129.0, 128.5, 128.0, 127.8, 124.6, 119.9, 76.3, 73.5, 69.4,
36.4, 35.3; HPLC: Chiralpak AS column (0.46 cm 25 cm), 10% i-PrOH in hexane, 1.0
mL/min, = 254 nm, tR(major) 75.7 min, tR(minor) 86.8 min.; Anal. Calcd. for C18H20N2O4:
C, 65.84; H, 6.14; N, 8.53. Found: C, 65.79; H, 6.35; N, 8.53.
136
5.2.21 1-Cyclohexyl-3-((R)-(6-methoxyquinolin-4-yl)((2R,4S,5R)-5-vinylquinuclidin-2-
yl)methyl)thiourea (92)
To a solution of 90 (180 mg, 0.56 mmol, 100 mol %) in dry THF (2 mL) was added freshly
distilled cyclohexyl isothiocyanate (90 �L, 0.63 mmol, 110 mol %) at room temperature.
Mixture was stirred under Ar overnight. Solvents were evaporated, and purification by flash
chromatography (8% to 10% MeOH in CH2Cl2) gave 92 as white foam (124 mg, 48%). Rf =
0.30 (10% MeOH in CH2Cl2); [�]20D = +218.5 (c = 1.0, CHCl3); IR (neat): 3247 (broad),
3067, 2999, 2933, 2856, 2669, 2212, 1622, 1589, 1542, 1509, 1474, 1452, 1433, 1364, 1337,
1321, 1227 cm-1; 1H NMR (CDCl3, 400 MHz): � 8.75 (d, J = 4.6 Hz, 1H), 8.03 (d, J = 9.1 Hz,
1H), 7.63 (d, J = 1.8 Hz, 1H), 7.50-7.45 (br s, 1H), 7.45 (d, J = 4.6 Hz, 1H), 7.41 (dd, J = 9.2,
2.7 Hz, 1H), 5.89 (ddd, J = 17.2, 10.7, 6.3 Hz), 5.24-5.15 (m, 2H), 3.99 (s, 3H), 3.34-3.20 (m,
1H), 3.20-2.90 (m, 5H), 2.45-2.34 (m, 1H), 1.99-1.87 (m, 1H), 1.83-1.70 (m, 2H), 1.70-1.46
(m, 4H), 1.46-1.37 (m, 1H), 1.37-1.16 (m, 4H), 1.16-0.97 (m, 3H), 0.97-0.79 (m, 1H); 13C
NMR (CDCl3, 100 MHz): � 180.9, 158.1, 147.6, 144.8, 139.3, 131.8, 127.6, 122.4, 120.1,
115.4, 101.3, 61.1, 55.7, 53.3, 48.8, 46.8, 38.5, 32.5, 32.3, 27.1, 25.8, 25.3, 24.8, 24.3; HRMS
m/z 487.2510 [C27H36N4OS (M+H)+ requires 487.2508].
5.2.21 Ethyl (R)-(6-methoxyquinolin-4-yl)((2R,4S,5R)-5-vinylquinuclidin-2-
yl)methylcarbamate (98)
137
To a solution of 90 (715 mg, 2.2 mmol, 100 mol %) in dry THF (10 mL) was added Et3N
(330 �L, 2.4 mmol, 110 mol %), followed by slow addition of ethyl chloroformate (230 �L,
2.4 mmol, 110 mol %). The mixture was stirred at room temperature under Ar for 2 hours.
The solvent was partly evaporated, and the mixture was partitioned between H2O (30 mL) and
Et2O (30 mL). The aqueous phase was washed with Et2O (3 20 mL). The organic phases
were combined and washed with brine, then dried over MgSO4, filtered and evaporated.
Purification by flash chromatography gave 98 as a white foam (463 mg, 53%). Rf = 0.23 (10%
MeOH in CH2Cl2); [�]20D = +176.6 (c = 1.0, CHCl3); IR (neat): 3185, 3075, 2936, 2870, 1709,
1622, 1590, 1508, 1474, 1433, 1365, 1298, 1252, 1227 cm-1; 1H NMR (C2D2Cl4, 400 MHz,
85 °C): � 8.74 (d, J = 4.6 Hz, 1H), 8.06 (d, J = 9.3 Hz, 1H), 7.62 (d, J = 2.7 Hz, 1H), 7.41 (dd,
J = 11.9, 2.7 Hz, 1H), 7.40 (br s, 1H), 6.09 (br s, 1H), 6.01-5.91 (m, 1H), 5.18 (d, J = 1.5 Hz,
1H), 5.11 (dt, J = 6.3, 1.5 Hz, 1H), 5.10 (dd, J = 10.5, 3.0 Hz, 1H), 4.00 (s, 3H), 3.99 (q, J =
7.1 Hz, 2H), 3.09-2.90 (m, 5H), 2.39-2.31 (m, 1H), 1.73-1.68 (m, 1H), 1.65-1.48 (m, 2H),
1.39-1.31 (m, 1H), 1.10 (t, J = 7.1 Hz, 3H), 1.07-.098 (m, 1H); 13C NMR (CDCl3, 100 MHz,
60°C): 157.9, 156.5, 147.6, 145.8, 145.0, 140.5, 131.9, 128.4, 121.7, 119.5, 114.7, 101.7, 60.8,
60.4, 55.5, 49.4, 47.3, 39.3, 27.6, 26.8, 25.5, 14.3; HRMS m/z 396.2293 [C23H30N3O3 (M+H)+
requires 396.2287].
5.2.22 9-N-Methylamino-(9-deoxy)-epi-quinidine (99)
Lithium aluminum hydride (100 mg, 2.6 mmol, 260 mol %) was suspended in dry THF (4 mL)
at 0 °C under Ar. Compound 98 (390 mg, 1.0 mmol, 100 mol %) was added as a solution in
dry THF (8 mL). The reaction was stirred at 0 °C for 6 hours, then allowed to warm to room
temperature and stirred overnight. LiAlH4 added as THF suspension (1 mmol, 100 mol %) to
drive the reaction to completion. The reaction was quenched by adding H2O (1.4 mL), 10 M
NaOH (0.15 mL) and H2O (0.6 mL) sequentially to give a yellow mixture. The organic phase
was dried over MgSO4, filtered and evaporated to give a yellow foam. Purification by flash
138
chromatography (9% MeOH in CH2Cl2, 1% NH4OH) gave 99 as a yellow oil (170 mg, 51%).
Rf = 0.31 (10% MeOH in CH2Cl2); [�]20D = +56.6 (c = 1.0, CHCl3); IR (neat): 3317, 3075,
2937, 2870, 2787, 1666, 1621, 1588, 1508, 1473, 1454, 1432, 1357, 1257, 1240, 1226 cm-1; 1H NMR (CDCl3, 400 MHz, partial spectra due to heavy rotamerism): � 8.77 (br s, 1H), 8.03
(d, J = 9.5 Hz, 1H), 7.77-7.41 (m, 2H), 7.38 (dd, J = 9.2, 2.7 Hz, 1H), 5.92 (ddd, J = 17.5,
10.1, 6.6 Hz, 1H), 5.12-5.05 (m, 2H), 4.36 (br s, 1H), 3.97 (s, 3H), 3.08-2.80 (m, 5H), 2.32-
2.23 (m, 1H), 2.20 (s, 3H), 1.62-1.46 (m, 3H), 1.24-1.15 (m, 1H), 0.89-0.73 (m, 1H); 13C
NMR (CDCl3, 100 MHz, 55°C, partial spectra due to heavy rotamerism): � 157.5, 147.8
(broad, possibly 2 signals), 144.9, 140.9, 131.8, 129.6, 121.3, 114.4, 102.1, 55.5, 49.6, 47.8,
39.7, 34.3, 27.7, 26.8, 25.0; HRMS m/z 338.2227 [C21H28N3O (M+H)+ requires 338.2232].
5.2.23 3-(3,5-Bis(trifluoromethyl)phenyl)-1-((R)-(6-methoxyquinolin-4-yl)((2R,4S,5R)-5-
vinylquinuclidin-2-yl)methyl)-1-methylthiourea (96)
To a solution of 16 (140 mg, 0.42 mmol, 100 mol %) in dry THF (3 mL) was added 3,5-
bis(trifluoromethyl)phenyl isothiocyanate (90 �L, 0.49 mmol, 110 mol %). The mixture was
stirred overnight at room temperature under Ar. The solvents were evaporated and the residue
purified by flash chromatography (5% to 10% MeOH in CH2Cl2) to give 12 as a whitish foam
(181 mg, 71%). Rf = 0.39 (10% MeOH in CH2Cl2); [�]20D = �3.8 (c = 1.0, CHCl3); IR (neat):
3237 (broad), 3070, 2938, 2872, 1622, 1510, 1474, 1370, 1311, 1278, 1242, 1175, 1134 cm-1; 1H NMR (MeOD-d4, 400 MHz): � 8.72 (d, 1H, J = 4.8 Hz), 8.53 (d, 1H, J = 1.8 Hz), 7.98 (s,
2H), 7.93 (d, 1H, J = 9.3 Hz), 7.74 (d, 1H, J = 4.8 Hz), 7.67 (s, 1H), 7.41 (dd, 1H, J = 9.1, 2.7
Hz), 7.36 (d, 1H, J = 11.0 Hz), 5.84 (ddd, 1H, J = 17.2, 10.7, 6.4 Hz), 5.22 (dt, 1H, J = 17.3,
1.6 Hz), 5.03 (dt, 1H, J = 10.6, 1.5 Hz), 4.09-4.00 (m, 1H), 4.00-3.90 (m, 1H), 3.98 (s, 3H),
3.19-3.11 (m, 1H), 3.05 (s, 3H), 3.05-2.91 (m, 2H), 2.36 (q, 1H, J = 7.8 Hz), 1.89-1.79 (m,
139
1H), 1.77-1.66 (m, 2H), 1.59-1.49 (m, 1H), 1.10-1.01 (m, 1H); 13C NMR (MeOD-d4, 100
MHz): � 184.4, 160.2, 147.7, 145.7, 144.4, 143.4, 141.3, 132.2 (q, 2JCF = 33.3 Hz), 131.3,
131.1, 127.2, 124.8 (q, 1JCF = 271 Hz), 124.3, 123.0, 118.7, 115.2, 105.7, 61.0, 57.7, 56.4,
54.8, 50.8, 50.0, 40.3, 32.8, 28.9, 27.6, 27.2. HRMS m/z 609.2133 [C30H31F6N4OS (M+H)+
requires 609.2123].
5.2.24 N-Methyl-3,5-bis(trifluoromethyl)aniline (104)
3,5-Bis(trifluoromethyl)aniline 102 (1.0 mL, 6.4 mmol, 100 mol %) was dissolved in CH2Cl2
(14 mL) and cooled to 0 °C. Trifluoroacetic anhydride (2.7 mL, 19 mmol, 300 mol %) was
added, and the mixture was stirred at 0 °C for 20 minutes. The solvents were evaporated, and
the residue was dissolved in acetone (15 mL). Anhydrous K2CO3 (1.77 g, 12.8 mmol, 200
mol %) and iodomethane (1.2 mL, 19 mmol, 300 mol %) were added, and the mixture was
heated to mild reflux for 2 hours. The mixture was filtered and evaporated, the residue was
dissolved in H2O:MeOH (5 mL : 25 mL), and anhydrous K2CO3 (880 mg, 6.4 mmol, 100
mol %) was added. The mixture was stirred at room temperature for one hour. The solvents
were partly evaporated, and the residue partitioned between H2O (25 mL) and CH2Cl2 (30
mL). The aqueous phase was extracted with CH2Cl2 (30 mL). The combined organic phases
were dried over MgSO4, filtered and evaporated to give 104 as a yellowish oil (1.41 g, 90%).
The product was practically pure with some solvent residues present. No further purification
was done since the compound was somewhat volatile at reduced pressures and could be
partially lost in high vacuum. Rf = 0.23 (5% EtOAc in hexane); IR (neat): 3465, 2927, 1623,
1523, 1485, 1385, 1273, 1168, 1116, 1100, 1072 cm-1; 1H NMR (CDCl3, 400 MHz): � 7.15 (s,
1H), 6.92 (s, 2H), 4.16 (br s, 1H), 2.91 (s, 3H); 13C NMR (CDCl3, 100 MHz): � 150.1, 132.8
(q, 2JCF = 33.0 Hz), 124.0 (q, 1JCF = 272.0 Hz), 111.8, 110.4, 30.7; HRMS m/z 244.0557
[C9H7F6N (M+H)+ requires 244.0561].
140
5.2.25 1-(3,5-Bis(trifluoromethyl)phenyl)-3-((R)-(6-methoxyquinolin-4-yl)((2R,4S,5R)-5-
vinylquinuclidin-2-yl)methyl)-1-methylthiourea (97)
Compound 104 (130 mg, 0.5 mmol, 100 mol %) was dissolved in dry THF (2 mL) under Ar
and cooled to –78 °C. n-BuLi (2.2 M, 230 �L, 0.5 mmol, 100 mol %) was added and the
resulting yellow mixture was stirred for 15 minutes. Isothiocyanate 101 (180 mg, 0.5 mmol,
100 mol %) dissolved in DMF (3 mL) was added, and the mixture was stirred at –78 °C for 40
minutes, then allowed to warm to room temperature and stirred for further one hour. The
reaction was quenched by adding sat. NH4Cl (1.0 mL), and the mixture was partitioned
between H2O (15 mL) and EtOAc (15 mL). The organic layer was washed with H2O (3 x 10
mL), dried over MgSO4, filtered and evaporated. The residue was purified by flash
chromatography (3% to 10% MeOH in CH2Cl2) to give 97 as an amorphous solid (158 mg,
52%). Another product was also isolated (50 mg) which had identical HRMS spectra and
highly similar 1H NMR spectra. The correct product was assigned by thorough comparison
with NMR data reported by Soós (Ref. 29b). Rf = 0.34 (10% MeOH in CH2Cl2); [�]20D =
+220.7 (c = 1.0, CHCl3); IR (neat): 3241 (broad), 3076, 2939, 2876, 1622, 1590, 1508, 1474,
1382, 1278, 1226, 1180, 1138 cm-1; 1H NMR (CDCl3, 400 MHz, 40°C): � 8.62 (d, J = 4.7 Hz,
1H), 8.02 (d, J = 2.2 Hz, 1H), 7.93 (d, J = 9.2 Hz, 1H), 7.87 (br s, 1H), 7.81 (br s, 2H), 7.47 (d,
J = 4.7 Hz, 1H), 7.42 (dd, J = 9.2, 2.7 Hz, 1H), 6.35 (br d, J = 10.7 Hz), 5.95 (ddd, J = 17.3,
10.6, 6.1 Hz, 1H), 5.21 (dt, J = 17.4, 1.6 Hz, 1H), 5.13 (dt, J = 10.6, 1.5 Hz, 1H), 4.01 (s, 3H),
3.56 (s, 3H), 3.36-3.21 (m, 2H, overlapping signals), 2.99 (dd, J = 14.0, 10.6 Hz, 1H), 2.95-
2.85 (m, 2H), 2.40-2.30 (m, 1H), 1.64-1.49 (m, 3H), 1.26-1.17 (m, 1H), 1.04-0.94 (m, 1H); 13C NMR (MeOD-d4, 100 MHz): � 184.5, 159.6, 148.5, 148.2, 148.0, 145.2, 141.7, 134.0 (q, 2JCF = 34.0 Hz), 131.2, 130.2, 129.3, 124.4, (q, 1JCF = 272.7 Hz), 123.7, 121.7, 121.1, 121.1,
115.2, 104.3, 61.2, 56.5, 50.0, 42.6, 40.2, 28.7, 27.4, 26.5; HRMS m/z 609.2137
[C30H31F6N4OS (M+H)+ requires 609.2123].
141
5.2.26 1H NMR Titration Experiment of 51 in the presence of 12
To an NMR tube was loaded a solution of 51 (10 mg, 0.08 mmol) in CD2Cl2 (0.75 mL), and
the 1H NMR spectrum was recorded. A stock solution of 12 (23 mg, 0.05 mmol) in CD2Cl2
(1.5 mL) was added in three increments (0.2 mL, 0.2 mL and 0.3 mL). The tube was shaken
vigorously and the 1H NMR spectrum was recorded after the addition of each increment. The
amount of 12 corresponded roughly to 10, 20 and 30 mol %.
Table 18. 1H NMR shifts of dimethyl malonate 51 and thiourea 12 in titration experiment
Run 51 CH2 51 OMe 12 H2,H6 12 H4 12 N-H
1 3.3698 3.7158 7.9311 7.8031 merged w/ H2,H6
2 3.3790 3.7176 8.1022 7.7462 8.6377 3 3.3871 3.7188 8.0831 7.7515 8.5673 4 3.3953 3.7200 8.0620 7.7577 8.4879
5.2.27 1H NMR Titration Experiment of 51 in the presence of 79 or 88 and MeOD-d4
To an NMR tube was loaded a solution of 51 (7.3 mg, 0.06 mmol, 100 mol %) in acetone-d6
(0.75 mL). Solution of catalyst 79 (3.5 mg, 0.006 mmol, 10 mol %) or 88 (3.3 mg, 0.006
mmol, 10 mol %) in acetone-d6 (0.6 mL for 79, 0.15 mL for 88) was added and the tube was
shaken vigorously. 1H NMR spectrum of the mixture was recorded to show the mixture of 51
142
and catalyst. MeOD-d4 (0.05 mL, 1.2 mmol) was added and the NMR tube was shaken
vigorously for 1 minute. 1H NMR spectra were recorded at time points of 2, 5, 10, 15, 20, 30
and 50 minutes for 88, and at 2, 5, 10, 20 min and 12 h for 79. Formation of 51-d1 and 51-d2
was determined by the appearance of a new signal at 3.41 (t, J = 2.4 Hz, 1H) and the gradual
disappearance of both the signal at 3.43 (s, 2H) and the triplet at 3.41.
5.3 Total Synthesis of (–)-Hennoxazole A
5.3.1 2-(2,2-Dimethoxyethyl)-2-methyl-1,3-dioxolane (235)
3-Oxobutyraldehyde dimethyl acetal (10.0 mL, 72 mmol, 100 mol %) was loaded in a 250 mL
flask and dissolved in toluene (80 mL). Anhydrous ethylene glycol (12.5 mL, 215 mmol, 300
mol %), triethyl orthoformate (12 mL, 72 mmol, 100 mol %) and PPTS (1.5 g, 6 mmol, 8
mol %) were added. The stirred mixture was heated to reflux for 100 minutes, then let cool to
room temperature. Excess solvents were evaporated, the residue dissolved in Et2O (60 mL),
washed with sat. aq. NaHCO3 (50 mL) and brine (50 mL). The organic phase was dried over
MgSO4, filtered and evaporated to give crude 235 as a yellowish oil (9.66 g, 76%). Pure
product was obtained by high vacuum distillation (92 °C, 0.6 mmHg) of the crude product. Rf
= 0.34 (1:3 EtOAc:Hex); IR (neat) 2984, 2884, 1116, 1036; 1H NMR (CDCl3) � 4.97 (t, J =
4.8 Hz, 1H), 4.0-3.8 (m, 8H), 3.82 (s, 2H), 2.04 (d, J = 4.8 Hz, 2H), 1.39 (s, 3H); 13C NMR
(CDCl3) � 108.0, 101.7, 64.7, 64.5, 43.1, 24.4; HRMS m/z 199.0949 [C8H16O4 (M+Na)+
requires 199.0941].
�
143
5.3.2 4-Hydroxy-5-(2-methyl-1,3-dioxolan-2-yl)pentan-2-one (242)
Racemic: Commercial LDA solution (1.8 M in THF/heptane/ethylbenzene, 0.65 mL, 1.1
mmol, 110 mol %) was added into a flask containing THF cooled to -78 °C under N2.
Acetone (90 �L, 1.2 mmol, 120 mol %) was added and mixture stirred at -78 °C for 30
minutes. Aldehyde 5 (in 1.5 mL THF, 130 mg, 1.0 mmol, 100 mol %) was added dropwise to
this solution and stirring was continued at –78 °C. After 35 minutes TLC showed no aldehyde,
and the reaction was quenched with sat. aq. NH4Cl, then let warm to room temperature. The
mixture was extracted with EtOAc (5 x 7 mL), and the organic phases were dried over
MgSO4, filtered and evaporated to give crude product as a brownish oil. Purification by flash
chromatography (75% EtOAc in hexanes to 100% EtOAc) gave 242 as a thick colourless oil
(110 mg, 59%). Rf = 0.12 (1:1 EtOAc:Hex); IR (neat): 3495, 2983, 2890, 1709, 1376; 1H
NMR (CDCl3) � 4.39-4.31 (m, 1H), 3.98 (s, 4H), 3.57 (br s, OH), 2.65 (dd, J = 16.2, 7.8 Hz,
1H), 2.51 (dd, J = 16.2, 4.6 Hz, 1H), 2.19 (s, 3H), 1.84 (d, J = 5.9 Hz, 2H), 1.37 (s, 3H). 13C
NMR (101 MHz; CDCl3): � 208.0, 109.9, 64.6, 64.3, 50.6, 44.5, 30.9, 24.0; HRMS m/z
211.0953 [C9H15O4 (M+Na)+ requires 211.0946].
Example of organocatalyst screening reaction: Catalyst 240 (11 mg, 0.027 mmol, 10
mol %) was dissolved in distilled acetone (0.5 mL) in a capped vial, and aldehyde 237 (35 mg,
0.27 mmol, 100 mol %) was added to the solution. The reaction was stirred at room
temperature for 72 hours, then quenched with sat. aq. NH4Cl. The mixture was extracted with
EtOAc (5 x 5 mL), and the combined organic phases were dried over MgSO4, filtered and
evaporated to give crude product, which was analyzed by 1H NMR.
�
144
5.3.3 Methyl 3-hydroxy-2-(pent-4-enamido)propanoate (250)
Pent-4-enoic acid 249 (6.5 mL, 61.7 mmol, 100 mol %) was dissolved in MeCN (100 mL)
and CDI (11.4 g, 70 mmol, 110 mol %) was added. The mixture was stirred at rt for 1 hour,
and then added to a mixture of DL-SerOMe-HCl (11.5 g, 74 mmol, 120 mol %) and DIPEA
(14 mL, 85 mmol, 140 mol %) prepared 1 hour previously. The solution was stirred at rt
overnight, then washed with 1 M HCl (150 mL) and extracted with EtOAc (200 mL + 4*100
mL). Purification by flash chromatography (75% EtOAc in hex) afforded the amide 250 as a
thick clear oil (10.9 g, 88%). Rf = 0.17 (75% EtOAc in hex); IR (neat): 3352, 3309, 3078,
2955, 1739, 1641, 1531, 1437, 1209; 1H-NMR (400 MHz; CDCl3): � 6.47-6.45 (m, 1H), 5.89-
5.79 (m, 1H), 5.09 (dq, J = 17.1, 1.5 Hz, 1H), 5.04-5.01 (m, 1H), 4.68 (dt, J = 7.3, 3.7 Hz,
1H), 3.97 (dd, J = 11.2, 3.9 Hz, 1H), 3.91 (dd, J = 11.2, 3.4 Hz, 1H), 3.79 (s, 3H), 2.43-2.36
(m, 5H); 13C NMR (100 MHz, CDCl3): � 172.8, 171.0, 136.7, 115.7, 63.4, 54.7, 52.7, 35.6,
29.4; HRMS m/z 202.1079 [C9H15NO4 (M+H)+ requires 202.1079].
5.3.4 Methyl 2-(but-3-enyl)-4,5-dihydrooxazole-4-carboxylate (251)
To a stirred solution of 250 (10.5 g, 52 mmol, 100 mol %) in dry CH2Cl2 (110 mL) at –78 °C
was added DAST (8.0 mL, 61 mmol, 120 mol %) dropwise over 15 minutes. The resulting
mixture was stirred at –78 °C for 30 minutes, then cooling was removed and the mixture
stirred for 40 minutes while it was gradually warming towards rt. K2CO3 (10.0 g, 72 mmol,
mol %) was added, and the mixture stirred for a further 1 hour, then cannulated to 110 mL of
vigorously stirred saturated aqueous NaHCO3. Phases were separated, and the aqueous phase
was extracted with CH2Cl2 (150 mL). The combined organic phases were washed with brine,
dried over MgSO4, filtered through SiO2 and evaporated to give the crude oxazoline 251 in
145
excellent purity and yield (9.28 g, 97%). The product was used as such in the next step. Rf =
0.39 (80% EtOAc in hex); IR 2955, 1739, 1659, 1437, 1204, 1176, 982, 914; 1H NMR (400
MHz, CDCl3): � 5.87-5.77 (m, 1H), 5.08-5.03 (m, 1H), 5.01-4.98 (m, 1H), 4.71 (dd, J = 10.6,
7.8 Hz, 1H), 4.47 (dd, J = 8.7, 7.8 Hz, 1H), 4.37 (dd, J = 10.6, 8.7 Hz, 1H), 3.77 (s, 3H), 2.43-
2.37 (m, 4H); 13C NMR (100 MHz, CDCl3): � 184.1, 165.8, 156.4, 143.4, 141.5, 139.3, 135.9,
129.4, 116.2, 30.6, 27.5; HRMS m/z 184.0974 [C9H13NO3 (M+H)+ requires 184.0974].
Preparation of 251 in flow conditions: Vapourtec R2+/R4 was equipped with 5 mL
Rheodyne injection loops and a 10 mL convection heated flow coil reactor. Two OmniFit
glass columns (� 10 mm) were packed with CaCO3 (2.6 g) and SiO2 (2.4 g). The system was
pressurized with a 100 psi back pressure regulator. The combined system was dried by
pumping anhydrous CH2Cl2 through for 30 minutes. Before carrying out the reaction, the
temperature of the reactor coil was adjusted to 80 °C. Stock solutions (0.4-0.6 M) of 250 and
DAST were injected via injection loops through the reactor with a residence time of 30
minutes (flow rates 0.167 mL/min, both channels). The product was collected into a flask
after the CaCO3 and SiO2 columns and the solvents evaporated to give crude oxazoline 251 in
acceptable purity to be used in the following steps. The columns were emptied and repacked
after 3 runs, when colored impurities had almost reached through the SiO2 plug. In 10
sequential runs 3.15 g (17.2 mmols, 66% combined yield) of 251 was obtained.
5.3.5 Methyl 2-(but-3-enyl)-oxazole-4-carboxylate (252)
To a stirred solution of 251 (9.28 g, 50.7 mmol, 100 mol %) in dry CH2Cl2 (110 mL) at 0 °C
was added DBU (11.3 mL, 75.7 mmol, 150 mol %) and BrCCl3 (10 mL, 101 mmol, 200
mol %) dropwise. The mixture was stirred overnight while slowly allowing it to warm to rt.
The mixture was washed with 1 M HCl and the phases were separated. The aqueous phase
was extracted with CH2Cl2 (2 * 100 mL + 90 mL). The combined organic phases were
washed with brine, dried over MgSO4, filtered through SiO2 and evaporated to give the crude
product as a brown oil. Purification by flash chromatography (33% to 50% EtOAc in hex)
146
gave 252 as a yellow oil (7.89 g, 84% from 250). Rf = 0.63 (80% EtOAc in hex); IR 3166,
2953, 1742, 1642, 1586, 1437, 1322, 11??; 1H NMR (400 MHz; CDCl3): � 8.14 (s, 1H), 5.83
(ddt, J = 17.0, 10.3, 6.6 Hz, 1H), 5.07 (dq, J = 17.1, 1.6 Hz, 1H), 5.01 (dq, J = 10.2, 1.4 Hz,
1H), 3.90 (s, 3H), 2.91 (dd, J = 8.2, 7.0 Hz, 2H), 2.57-2.51 (m, 2H); 13C NMR (100 MHz,
CDCl3): � 165.2, 161.7, 143.7, 136.0, 133.1, 116.2, 52.0, 30.7, 27.6; HRMS m/z 182.0819
[C9H11NO3 (M+H)+ requires 182.0817].
5.3.6 Methyl 2-[2-(but-3-enyl)-oxazole-4-carboxamido]-3-hydroxypropanoate (253)
Oxazole 252 (7.89 g, 43.5 mmol, 100 mol %) was dissolved in THF (60 mL) and treated with
2 M LiOH (39 mL, 78 mmol, 180 mol %). The mixture was stirred at rt for 2 hours, then
poured into 1 M HCl (100 mL). Concentrated HCl (2 mL) was added to ensure full
acidification. The phases were separated, and the aqueous phase was extracted with EtOAc (3
* 100 mL). Combined organic phases were washed with brine, dried over Na2SO4, filtered
and evaporated to give the crude acid, which was then dissolved in MeCN (100 mL), treated
with CDI (9.0 g, 55.5 mmol, 130 mol %) and stirred at rt for 1 hour. The mixture was then
added to a previously prepared mixture of DL-SerOMe-HCl (8.34 g, 53.6 mmol, 120 mol %)
and DIPEA (9.5 mL, 57.5 mmol, 130 mol %) in MeCN (70 mL). The resulting solution was
stirred at rt overnight, then washed with 1 M HCl (120 mL) and extracted with EtOAc (200
mL + 2 * 100 mL). The combined organic phases were washed with brine, dried over Na2SO4,
filtered and evaporated. The crude product was purified by flash chromatography (60% to 100%
EtOAc in hex) to give 253 as a yellow oil (8.1 g, 69%). Rf = 0.60 (EtOAc); IR 3400, 2956,
1742, 1655, 1600, 1513, 1214; 1H NMR (400 MHz, CDCl3): � 8.10 (s, 1H), 7.72 (br d), 5.82
(ddt, J = 17.0, 10.3, 6.6 Hz, 1H), 5.07 (dq, J = 17.1, 1.6 Hz, 1H), 5.01 (dq, J = 10.2, 1.4 Hz,
1H), 4.79 (dt, J = 7.8, 3.9 Hz, 1H), 4.08-3.96 (m, 2H), 3.78 (s, 3H), 2.85 (dd, J = 8.2, 7.1 Hz,
2H), 2.53-2.48 (m, 2H); 13C NMR (100 MHz, CDCl3): � 184.1, 165.8, 156.4, 143.4, 141.5,
139.3, 135.9, 129.4, 116.2, 30.6, 27.5; HRMS m/z 269.1133 [C12H16N2O5 (M+H)+ requires
269.1137].
�
147
5.3.7 Methyl 2-[2-(but-3-enyl)-oxazol-4-yl]-4,5-dihydrooxazole-4-carboxylate (254)
To a solution of 253 (8.0 g, 30 mmol, 100 mol %) in dry CH2Cl2 (100 mL) at –78 °C was
added DAST (4.7 mL, 35 mmol, 120 mol %) dropwise over 40 minutes. The cooling was
stopped and the resulting mixture stirred for 40 minutes while letting it slowly warm up.
K2CO3 was added and the mixture stirred vigorously for further 2 hours, then cannulated into
vigorously stirred saturated aqueous NaHCO3 (100 mL). The mixture was diluted with 100
mL H2O, the phases were separated, and the aqueous phase was extracted with CH2Cl2 (100
mL). The combined organic phases were washed with brine, dried over MgSO4, filtered and
evaporated. The crude product was filtered through SiO2 with EtOAc and the solvents were
evaporated to give a cloudy yellow oil, which was then redried with Na2SO4 to remove
suspected water. Filtration and evaporation gave 254 as a cloudy yellow oil (7.1 g, 95%),
which was of excellent purity by 1H NMR, and the product was used as such in the next step.
Rf = 0.32 (80% EtOAc in hex); IR 2954, 1739, 1676, 1583, 1206, 1104; 1H NMR (400 MHz,
CDCl3): � 8.10 (s, 1H), 5.83 (ddt, J = 17.0, 10.4, 6.6 Hz, 1H), 5.06 (dq, J = 17.1, 1.6 Hz, 1H),
5.01 (q, J = 1.4 Hz, 1H), 4.99 (q, J = 1.4 Hz, ), 4.92 (dd, J = 10.5, 8.0 Hz, 1H), 4.67 (t, J = 8.3
Hz, 1H), 4.57 (dd, J = 10.5, 8.7 Hz, 1H), 3.79 (s, 3H), 2.90 (dd, J = 8.2, 7.1 Hz, 2H), 2.57-
2.51 (m, 2H); 13C NMR (100 MHz, CDCl3): � 171.1, 165.3, 160.1, 141.1, 136.1, 129.8, 116.0,
69.6, 68.4, 52.6, 30.6, 27.5; HRMS m/z 464.2011 [C12H14N2O4 (M+H)+ requires 251.1032].
5.3.8 Methyl 2'-(but-3-enyl)-2,4'-bioxazole-4-carboxylate (255)
To a solution of 254 (7.1 g, 28 mmol, 100 mol %) in dry CH2Cl2 (100 mL) at 0 °C was added
DBU (6.4 mL, 43 mmol, 150 mol %) and BrCCl3 (5.5 mL, 56 mmol, 200 mol %) dropwise.
148
The solution was stirred at 0 °C for 80 minutes, then washed with 1 M HCl (50 mL). The
phases were separated and the aqueous phase was extracted with CH2Cl2 (3 * 50 mL). The
combined organic phases were washed with brine, dried over Na2SO4, filtered and evaporated.
The crude product was purified by flash chromatography (5% to 80% EtOAc in CH2Cl2) to
give 255 as a yellowish solid (5.83 g, 78% from 253). Mp. 118-119 °C; Rf = 0.55 (80%
EtOAc in hex); IR 3148, 2952, 1719, 1637, 1570, 1436, 1317; 1H NMR (400 MHz, CDCl3): �
8.28 (s, 1H), 8.28 (s, 1H), 5.85 (ddt, J = 17.0, 10.3, 6.6 Hz, 1H), 5.09 (dq, J = 17.1, 1.6 Hz,
1H), 5.03 (dq, J = 10.2, 1.3 Hz, 1H), 3.94 (s, 3H), 2.97-2.93 (m, 2H), 2.60-2.55 (m, 2H); 13C
NMR (100 MHz; CDCl3): � 165.6, 161.3, 143.5, 139.2, 135.9, 134.2, 129.5, 116.2, 52.2, 30.6,
27.5; HRMS m/z 271.0688 [C12H12N2O4Na (M+H)+ requires 271.0695].
5.3.9 But-3-enyl-2,4'-bisoxazole-4-carbaldehyde (243)
To a solution of 255 (1.6 g, 6.4 mmol, 100 mol %) in dry CH2Cl2 (35 mL) at –78 °C was
slowly added Dibal-H (1 M in CH2Cl2, 13 mL, 13 mmol, 200 mol %) while keeping the
internal temperature below –65 °C. After addition the mixture was stirred for 1 hour, then
quenched by adding MeOH (3 mL) dropwise. The mixture was stirred for 10 minutes at –
78 °C, then solid Rochelle’s salt (5.6 g) and 2 mL of saturated aqueous Rochelle’s salt were
added. The mixture was stirred vigorously and let warm to rt, then filtered through celite,
washed with H2O, dried over MgSO4, filtered and evaporated. The crude product was purified
by flash chromatography (50% to 66% EtOAc in hex) to give the aldehyde 243 as a yellowish
solid (1.19 g, 85%). Mp. 106-107 °C; Rf = 0.52 (80% EtOAc in hex); IR 3126, 3082, 2830,
1684, 1641, 1553; 1H NMR (400 MHz, CDCl3) 10.00 (s, 1 H), 8.29 (s, 1 H), 8.24 (s, 1 H),
5.87 (ddd, 1 H, J = 17.0, 10.3, 6.6 Hz), 5.10 (dq, 1 H, J = 17.1, 1.6 Hz), 5.04 (dq, 1 H, J =
10.2, 1.4 Hz), 2.97 (dd, 2 H, J = 8.1, 7.1 Hz), 2.62-2.59 (m, 2H); 13C NMR (100 MHz,
CDCl3): � 184.1, 165.8, 156.4, 143.4, 141.5, 139.3, 135.9, 129.4, 116.2, 30.6, 27.5; HRMS
m/z 219.0775 [C11H10N2O3 (M+H)+ requires 219.0770].
149
5.3.10 (S)-2-Amino-4-methyl-1,1-diphenylpentan-1-ol (262)
Commercial PhMgBr (3.0 M in Et2O, 60 mL, 180 mmol, 670 mol %) was loaded in a dry 250
mL flask and diluted with 60 mL dry Et2O to form a roughly 1.8 M solution, which was
cooled to 0 °C. L-Leucine methyl ester hydrochloride (4.9 g, 27 mmol, 100 mol %) was added
portionwise to the flask, and the resulting mixture was stirred overnight while letting it warm
to rt. The reaction was cooled to 0 °C and quenched by slowly adding saturated aqueous
NH4Cl (60 mL). The resulting suspension was partitioned between H2O (200 mL) and EtOAc
(150 mL), and the aqueous phase was extracted with EtOAc (2 *100 mL). The organic phases
were combined and washed with brine, dried over Na2SO4, filtered and evaporated. The crude
product was purified by crystallizing twice from EtOH, and by sequentially precipitating the
remaining product from EtOAc by partially evaporating the solvent and filtering out the
precipitated solid. The crops were combined and washed with cold hexane to give the amino
alcohol as a white solid (5.37 g, 74%). [�]25D = –108 (c = 1.0, CHCl3); Rf = 0.20 (80%
EtOAc:hex); 1H-NMR (400 MHz; CDCl3): � 7.62 (dd, J = 8.4, 1.2 Hz, 2H), 7.48 (dd, J = 8.4,
1.2 Hz, 2H), 7.31 (dd, J = 15.7, 7.4 Hz, 4H), 7.21-7.14 (m, 2H), 3.99 (dd, J = 10.2, 2.1 Hz,
1H), 1.61-1.55 (m, 1H), 1.27 (ddd, J = 14.1, 10.3, 3.8 Hz, 1H), 1.08 (ddd, J = 14.1, 10.7, 2.1
Hz, 1H), 0.90 (d, J = 6.5 Hz, 3H), 0.87 (d, J = 6.6 Hz, 3H). Data in agreement with literature
values.144
5.3.11 (S)-N-[(S)-1-hydroxy-4-methyl-1,1-diphenylpentan-2-yl]pyrrolidine-2-carboxamide
(257)
150
To a solution of L-Boc-proline (3.37 g, 15.7 mmol, mol %) in dry CH2Cl2 at 0 °C was added
Et3N (2.6 mL, 18.8 mmol, mol %) and EtOCOCl (1.7 mL, 17.9 mmol, mol %) dropwise. The
mixture was stirred at 0 °C for 30 minutes followed by addition of 262 (3.95 g, 14.7 mmol,
100 mol %) in one portion. The reaction was let warm to rt and stirred overnight. The mixture
was diluted with CH2Cl2 (90 mL), then filtered to give a white residue and a clear filtrate. The
residue was redissolved in CH2Cl2 and combined with the filtrate. The mixture was washed
with H2O (2 * 150 mL) and brine, dried over Na2SO4, filtered and evaporated to give 293 as a
white solid, which was used without further purification.
Deprotection: HCOOH (20 mL) was slowly added to 293 (2.1 g, 4.5 mmol) at 0 °C, and the
mixture was let warm to rt and stirred overnight. HCOOH was evaporated to give a viscous
oil, which was dissolved in CH2Cl2 and basified to strongly basic with 1 M NaOH. The
mixture was diluted with 50 mL H2O, the phases were separated, and the aqueous phase was
extracted with CH2Cl2 (2 * 50 mL). The combined organic phases were washed with brine,
dried over Na2SO4, filtered and evaporated. Purification by flash chromatography (10%
MeOH in CH2Cl2, 1% NH4OH) gave 257 as a white solid (1.14 g, 69%). NB! Standard
TFA:CH2Cl2 deprotection conditions led to partial hydrolysis of the catalyst, and only 25% of
the desired product was isolated. Mp. 185-190°C; [�]25D = –48 (c = 1.0, CHCl3); Rf = 0.1 (10%
MeOH in CH2Cl2); 1H NMR (400 MHz, CDCl3): � 7.94-7.92 (br d, 1H), 7.57-7.53 (m, 4H),
7.32-7.28 (m, 2H), 7.24-7.22 (m, 4H), 7.20-7.16 (m, 1H), 7.14-7.10 (m, 1H), 4.59 (ddd, J =
11.1, 8.7, 2.2 Hz, 1H), 3.49 (dd, J = 9.4, 4.7 Hz, 1H), 2.83 (m, 1H), 2.58 (m, 1H), 1.91-1.83
(m, 2H), 1.82-1.66 (m, 2H), 1.61-1.52 (m, 1H), 1.49-1.43 (m, 2H), 1.26-1.19 (m, 2H), 0.92 (d,
J = 6.5 Hz, 3H), 0.86 (d, J = 6.7 Hz, 3H); 13C NMR (100 MHz; CDCl3): � 175.8, 146.6, 145.1,
128.2, 127.9, 126.6, 126.4, 125.7, 125.6, 80.9, 60.3, 56.8, 47.0, 37.4, 30.5, 25.7, 25.4, 23.8,
21.5; HRMS m/z 367.2377 [C23H30N2O2 (M+H)+ requires 367.2386].
5.3.12 (R)-4-[2'-(but-3-en-1-yl)-(2,4'-bisoxazol)-4-yl]-4-hydroxybutan-2-one (244)
Representative example of organocatalytic reaction: Catalyst 257 (37 mg, 0.1 mmol, 20
mol %) and MCA (4.7 mg, 0.05 mmol, 10 mol %) were loaded in a small flask and dissolved
151
in acetone (3 mL). The mixture was stirred for 30 minutes at 0 °C. Aldehyde 243 (110 mg, 0.5
mmol, 100 mol %) was added to the flask, and the reaction was stirred overnight while letting
the cooling bath slowly reach room temperature. The reaction was quenched with saturated
aqueous NH4Cl, and the mixture extracted with EtOAc (3 x 5 mL). The combined organic
phases were washed with brine, dried over Na2SO4, filtered and evaporated. The residue was
purified by flash chromatography (60% to 100% EtOAc in hex) to give 244 as a slowly
crystallizing oil. Enantiomeric excess was analyzed by HPLC from a sample dissolved in 1:1
i-PrOH:hexane: ChiralPak AS column (0.46 * 25 cm), 15% i-PrOH in hexane, 1 mL/min, =
254 nm, tR(major) 29.1 min, tR(minor) 36.1 min.
Representative example of flow reaction: The reaction was performed with Uniqsis
FlowSyn reactor. A stock solution of aldehyde 243 in acetone (0.33 M) and catalyst 257 and
MCA in acetone (0.066 M + 0.045 M) were prepared. 1 mL of stock solutions was injected in
sample loops. The streams were mixed in a T-piece and then pumped through a 20 mL
stainless steel reactor coil at room temperature with a residence time of 60 minutes (individual
flow rates 0.16 mL/min). The product stream was collected on saturated aqueous NH4Cl
solution and worked up as in batch conditions.
A racemic sample of 244 was prepared by standard LDA procedure: To a solution of
diisopropylamine (100 μL, 0.7 mmol, mol %) in dry THF (1 mL) at 0 °C was added n-
butyllithium (2.5 M in hexane, 400 μL, 0.8 mmol, mol %). The mixture was stirred at 0 °C for
a few minutes, and then cooled to –78 °C. Anhydrous acetone (60 μL, 0.8 mmol, mol %) was
added, and the mixture stirred for few minutes before the aldehyde 243 (137 mg, 0.63 mmol,
100 mol %) was added dropwise in dry THF (2 mL).
Mp. 59-61 °C (rac) / 69-78 °C (ee 70%); Rf 0.27 (80% EtOAc:hex); IR (neat): 3369, 3109,
2900, 1710, 1632, 1585, 1529, 1407, 1357, 1302, 1104, 1066, 989, 975, 919; 1H NMR (400
MHz; CDCl3): � 8.09 (s, 1H), 7.63 (d, J = 1.2 Hz, 1H), 5.85 (ddt, J = 17.0, 10.3, 6.6 Hz, 1H),
5.18 (ddd, J = 8.7, 3.3, 1.2 Hz, 1H), 5.08 (dq, J = 17.1, 1.6 Hz, 1H), 5.02 (dq, J = 10.2, 1.4 Hz,
1H), 3.15 (dd, J = 17.9, 3.3 Hz, 1H), 2.98 (d, J = 8.7 Hz, 1H), 2.94 (dd, J = 8.2, 7.0 Hz, 3H),
2.60-2.54 (m, 2H), 2.20 (s, 3H). 13C NMR (100 MHz; CDCl3): � 209.0, 165.6, 155.4, 143.6,
138.0, 136.1, 134.6, 130.3, 116.1, 64.1, 48.9, 30.77, 30.70, 27.6; HRMS m/z 277.1175
[C14H16N2O4 (M+H)+ requires 277.1188].
152
5.3.13 Attempted determination of absolute stereochemistry:
Attempt with (S)-(+)-MTPA-Chloride:
To a dry 5 mL flask was sequentially loaded Et3N (150 μL, 110 mg), DMAP (1 mg, 0.01
mmol), (S)-(+)-MTPA-Cl (13 μL, 17 mg, 0.07 mmol), CH2Cl2 (200 μL) and 244 (13 mg, 0.05
mmol). The mixture was stirred at rt overnight, then diluted with Et2O and washed with cold
0.03 M HCl, cold saturated NaHCO3 and brine. The organic phase was dried over Na2SO4,
filtered and evaporated to give a whitish solid, which was directly analyzed by 1H NMR.
Analysis showed the product to consist solely of the corresponding alkene 263. 1H NMR (400
MHz, CDCl3): � 8.17 (s, 1H), 7.84 (s, 1H), 7.36 (d, J = 15.7 Hz, 1H), 7.07 (d, J = 15.7 Hz,
1H), 5.86 (ddt, J = 17.0, 10.3, 6.6 Hz, 1H), 5.09 (dq, J = 17.1, 1.6 Hz, 1H), 5.03 (dq, J = 10.2,
1.4 Hz, 1H), 2.96 (t, J = 7.6 Hz, 2H), 2.61-2.56 (m, 2H), 2.34 (s, 3H).
Attempt with (R)-(–)-MTPA acid:
To a dry 5 mL flask was loaded (R)-(–)-MTPA (34 mg, 0.14 mmol, 140 mol %) which was
then dissolved in dry CH2Cl2 (0.5 mL). To this solution was added 244 (27 mg, 0.1 mmol,
100 mol %) and DMAP (6.7 mg, 0.05 mmol, 50 mol %). The mixture was stirred and cooled
to 0 °C, followed by addition of DCC (47 mg, 0.23 mmol, 230 mol %). The mixture was
stirred at rt overnight, then diluted with Et2O, filtered, and washed with 0.5 M HCl (2 x 5 mL),
saturated NaHCO3 (2 x 5 mL). The organic phase was dried over Na2SO4, filtered and
evaporated to give the crude ester ent-264, along with roughly 10% of the alkene, and some
153
leftover N,N-dicyclohexylurea. 1H NMR (400 MHz, CDCl3): � 8.10 (s, 1H), 7.71 (s, 1H),
7.56-7.30 (m, 6H), 6.47 (dd, J = 8.6, 4.7 Hz, 1H), 5.85 (ddt, J = 17.0, 10.3, 6.6 Hz, 1H), 5.11-
5.00 (m, 2H), 3.45 (s, 3H), 3.35 (dd, J = 17.6, 3.4 Hz, 1H), 3.21-3.15 (m, 1H), 3.11 (dd, J =
17.6, 4.7 Hz, 1H), 2.97-2.93 (m, 2H), 2.59-2.54 (m, 2H), 2.08 (s, 3H).
5.3.14 (R)-4-(2'-(but-3-en-1-yl)-[2,4'-bisoxazol]-4-yl)-4-methoxybutan-2-one (245)
To a solution of 244 (77 mg, 0.28 mmol, 100 mol %) in CH2Cl2 (3 mL) was added MeI (1 mL)
and Ag2O (130 mg, 0.56 mmol, 200 mol %), and the mixture was protected from light and
stirred at rt until completion. The mixture was filtered through celite and the solvents
evaporated. Purification by flash chromatography (60% to 90% EtOAc in hex) gave pure 245
as a slowly crystallizing yellowish oil (29 mg, 36%). HPLC: ChiralPak AS column (0.46 * 25
cm), 5% i-PrOH in hexane, 1 mL/min, = 254 nm, tR(major) 34 min, tR(minor) 55 min; Mp.
62-66 °C; Rf = 0.47 (80% EtOAc in hex); IR (neat): 3133, 2930, 2880, 2823, 1709, 1633,
1585, 1531, 1435, 1362, 1098; 1H NMR (400 MHz; CDCl3): � 8.15 (s, 1H), 7.64 (d, J = 0.6
Hz, 1H), 5.87 (ddt, J = 17.0, 10.3, 6.6 Hz, 1H), 5.11 (dq, J = 17.1, 1.6 Hz, 1H), 5.04 (dq, J =
10.2, 1.4 Hz, 1H), 4.77 (dd, J = 8.3, 4.5 Hz, 1H), 3.35 (s, 3H), 3.09 (dd, J = 16.7, 8.4 Hz, 1H),
2.98-2.90 (m, 3H), 2.62-2.56 (m, 2H), 2.20 (s, 3H); 13C NMR (100 MHz, CDCl3): � 205.9,
165.5, 155.8, 141.2, 138.1, 136.1, 135.5, 130.3, 116.1, 71.9, 57.2, 48.5, 30.8, 27.6; HRMS m/z
313.1166 [C15H18N2O4 (M+Na)+ requires 313.1164].
Proof of principle flow reaction: Through an OmniFit column (� 6.6 mm) packed with a
bed of Ag2O dispersed in celite and capped with celite plugs was pumped a premixed solution
of 244 (27 mg, 0.1 mmol) in 1:1 CH2Cl2:MeI (1 mL) at a flow rate of 0.1 mL/min. The crude
product was collected, evaporated and analyzed by 1H NMR to show a 2:1 mixture of 244:245
with little impurities.
154
5.3.15 Representative Reaction for �-Hydroxy Ketone Reduction With Polymer Supported
Borohydride: (3RS,5RS)-2,6-Dimethylheptane-3,5-diol (268) and (3RS,5SS)-2,6-
Dimethylheptane-3,5-diol (269)
To a 5 mL flask was loaded �-hydroxy ketone 265 (167 mg, 1.05 mmol, 100 mol %) and
dissolved in MeOH (5 mL). Borohydride resin (1.0 g) was added, and the mixture was stirred
for 8 hours until TLC showed no more 265. The mixture was filtered and solvents evaporated
to give the crude product (154 mg, 93%) as a mixture of diastereomers 268 and 269. Spectral
data of compounds was determined to correspond to literature values.125b,132,145
268: 1H NMR (400 MHz; CDCl3): � 3.62 (ddd, J = 10.2, 5.0, 1.3 Hz, 2H), 2.95 (br s, 2H),
1.73-1.62 (m, 2H), 1.59 (dt, J = 14.4, 2.0 Hz, 1H), 1.41 (dt, J = 14.4, 10.3 Hz, 1H), 0.92 (d, J
= 6.8 Hz, 12 H); 13C NMR (100 MHz, CDCl3): � 78.2, 35.8, 34.3, 18.3, 17.4. 269: 1H NMR
(400 MHz; CDCl3): � 3.65 (app q, 2H), 2.21 (br s, 2H), 1.70 (spt, J = 6.7 Hz, 2H), 1.59 (dd, J
= 6.4, 5.1 Hz, 2H), 0.96 (d, J = 6.7 Hz, 6H), 0.90 (d, J = 6.8 Hz, 6H); 13C NMR (100 MHz,
CDCl3): � 74.2, 36.5, 33.7, 18.7, 18.0.
5.3.16 Analysis of Diastereoselectivity
OHOH OO
268 294
p-TsOH, Na2SO4OO
295
+
OMeMeO
Crude 268 (23 mg, 0.14 mmol, 100 mol %) was dissolved in distilled 2,2-dimethoxypropane
(2 mL), and a small amount of Na2SO4 was added, and then a catalytic amount of p-TsOH (8
mg, 0.04 mmol, 30 mol %) was added. The reaction was quenched with NaHCO3 (aq), and
the resulting mixture extracted with Et2O (3 x 10 mL). The organic phases were washed with
brine, dried over Na2SO4, filtered and evaporated to give a crude mixture of 294 and 295,
which was analyzed by 1H and 13C NMR. NMR spectral data of compounds was determined
to correspond to literature values.132,145
294: 1H
1.45 (dt
J = 11.9
CDCl3)
3.36 (ap
0.92 (d,
34.4, 33
5.3.17 R
phenylp
Prepare
literatur
NMR si
the crud
Figure diastere
H NMR (400
t, J = 12.6, 2
9 Hz, 1H),
: � 98.1, 74
pp q, J = 7.
J = 6.6 Hz
3.0, 24.3, 18
Reduction of
pentan-3-on
OH
266
O
267
d according
re values.14
ignals of 27
de reaction m
22. Redeoselectivity
0 MHz; CD
2.4 Hz, 1H)
0.91 (d, J =
4.1, 33.1, 30
.9 Hz, 2H),
, 6H), 0.86
8.9, 17.6.
f 3-hydroxy
e (270 and
Ph
O
6
Ph
OH
7
g to the pro45b,146 Analy
70 at 4.94 p
mixture (Fig
duction of y
Cl3): � 3.44
), 1.38 (d, J
= 6.8 Hz, 6
0.2, 30.2, 19
1.66-1.55
(d, J = 6.8 H
y-4-methyl-1
296)
NMe3B
MeOH
NMe3B
MeOH
ocedure des
ysis of dias
ppm (dd, J =
gures 22 &
f 266 wit
4 (ddd, J =
J = 6.6 Hz, 6
6H), 0.87 (d
9.8, 18.5, 1
(m, 2H), 1
Hz, 6H); 13
1-phenylpen
BH4
BH4
scribed in 5
stereoselect
= 9.0, 3.8 H
23).
th solid
11.5, 6.6, 2
6H), 1.39 (s
d, J = 6.8 H
17.7. 295: 1H
.57 (app t, J
C NMR (10
ntan-3-one a
Ph
OHOH
270
Ph
OH OH
270
5.3.15. NM
tivity was
Hz, 1H) and
supported
.3 Hz, 2H),
, 3H), 1.37
Hz, 6H); 13C
H NMR (40
J = 7.9 Hz,
00 MHz, CD
and 1-hydro
O
+
O
+
MR spectral
determined
d 296 at 5.0
borohydrid
, 1.66-1.56
(s, 3H), 1.0
C NMR (10
00 MHz; C
, 2H), 1.32
DCl3): � 100
oxy-4-methy
Ph
OHOH
296 �
Ph
OHOH
296
data corres
d by integra
07 (app q, 1
de, 1:1 s
155
(m, 2H),
08 (app q,
00 MHz,
DCl3): �
(s, 6H),
0.1, 72.0,
yl-1-
spond to
ating 1H
H) from
syn:anti-
156
Figure diastere
5.4 Con
5.4.1 5-
Represe
mol %)
mL 3-n
monitor
added d
turned b
precipit
kept at
toluene:
272 as a
(d, J =
the mate
23. Redeoselectivity
ntinuous Fl
-Nitrovanill
entative ba
was dissol
neck flask e
ring the int
dropwise wi
brownish im
tating rapidl
that tempe
:AcOH (3:1
a yellow po
1.8 Hz, 1H)
erial to be 9
duction of y
low Nitratio
in (272)
HO
MeO
271
atch proce
lved in a m
quipped wi
ternal tempe
ith an addit
mmediately
ly. After th
erature for
1). The prec
owder (9.7 g
), 3.98 (s, 3
98.8% pure.
f 267 wit
on of Arom
H
O
edure (Tab
mixture of gl
ith a mecha
erature. HN
tion funnel
after the ad
he addition
45 minutes
cipitate was
g, 75%). 1H
3H), corresp
th solid
matic Subst
HNO3
AcOH
ble 10, Ent
lacial AcOH
anical stirre
NO3 (60 w-
over a per
ddition was
was compl
s. The mix
s dried in a
H NMR: � 9
ponding to l
supported
trates
HO
MeO
try 12): Va
H (30 mL)
r. The mixt
-%, 5.5 mL
riod of 3.5 m
HNO3 was
lete, the mi
xture was f
vacuum ov
.88 (s, 1H),
literature da
borohydrid
H
O
NO2
272
anillin (10.0
and toluene
ture was co
L, 69 mmol
minutes. Th
begun, and
xture was c
filtered and
ven overnig
8.11 (d, J =
ata.135n HPL
de, 2:1 s
H
0 g, 66 mm
e (15 mL)
ooled to 5 °
l, 105 mol
he reaction
d the produc
cooled to 0
d washed w
ght at 60 °C
= 1.8 Hz, 1
LC analysis
syn:anti-
mol, 100
in a 250
°C while
%) was
mixture
ct started
0 °C and
with cold
C to give
H), 7.64
showed
157
Representative pulse experiment in flow conditions: Uniqsis FlowSyn reactor was
equipped with a transparent 5 mL HT-PFA reactor coil and a 100 psi back pressure regulator,
and then the system completely flushed with glacial AcOH which was used as the system
solvent. Stock solutions of vanillin and HNO3 of desired concentrations in AcOH were
prepared to separate volumetric flasks. The reactor was primed to the desired temperature and
flow rate, after which 1 mL of both stock solutions was injected to the reactor via injection
ports equipped with proper injection loops. After the indicated residence time, the reaction
mixture was collected to a separate beaker. The initiation of the reaction was observed by a
color change to yellow either in the beaker after collection was ended, right after the reaction
stream exited the bpr, or in the reactor coil.
Representative continuous experiment: Stock solutions of vanillin and HNO3 in AcOH
were prepared in separate volumetric flasks. Uniqsis FlowSyn reactor was equipped with a 10
mL stainless steel reactor coil and a 100 psi back pressure regulator, and then the system was
completely flushed with glacial AcOH which was used as the system solvent. The reactor was
primed to the desired temperature and flow rate, after which the stock solutions were fed
through the pumps into the reactor. The exiting reacted mixture was collected to a separate
beaker partially filled with H2O. The outbound stream was analyzed with HPLC by collecting
the mixture into a 10 mL volumetric flask for a few seconds, and then diluting to indicated
volume with 1:1 H2O:MeCN. The output stream was collected for an indicated time, then
cooled to 0 °C in an ice bath for 1 hour, filtered, and washed with ice cold H2O and EtOH.
The yellow powder was dried in a vacuum oven and analyzed with HPLC.
HPLC analyses: The reactions were characterized by reverse phase HPLC analyses with
Waters Alliance 2695 system uding a Symmetry Shield RP8 column (3.5 �m, 4.6 x 150 mm)
and PDA 996 UV detector ( = 284 nm). Eluent A for gradient elution was H2O:MeCN:TFA
850:150:1, and eluent B was MeCN:TFA 1000:1, and elution speed was 1.5 mL/min. The
gradient was as follows:��
Minutes A(%) B(%) 0-2 100 0 2-20 50 50 20-22 15 85 22-27 15 85 27-29 100 0 29-35 100 0
158
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