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Aldrich
VOLUME 11 NUMBER 1 2011
Asymmetricc S Synynththhesesesiisisis
Catalysis
ChChememiciccicicalalalalal BB BBiioioiiololologygg
Organonomemetatatalllllliciciccssss
BuB ilding Bloockckss
SySyntnnthehetititicc c ReReReagagagenentsts
Sttabablele I Isosotopes
StStockroom m ReReagagagenenentststs
LaLaLabwb are NoNotetess
VOLUME 11 NUMBER 1 20201111
Cyclopropylboronic acid MIDA ester: a useful building block for use in
Suzuki-Miyaura reactions.
Missing out on
the latest research
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* Thomson Reuters; Journal Citation Reports®, Science Edition.
Introduction 3
Haydn Boehm, Ph. D.Global Marketing Manager: Chemical Synthesis
Dear Chemists,
Welcome to the fi rst edition of the Aldrich ChemFiles for 2011.
Aldrich ChemFiles is our FREE quarterly newsletter written by
our experts in Product Management and R&D. Our aim is to
keep you keep informed of new Aldrich Chemistry products that facilitate the latest
research methodologies and trends, and allow you to access key starting materials and
reagents more effi ciently.
As well as introducing all the latest innovations across all our product lines, each
2011 edition of Aldrich ChemFiles will be themed to a product line. Aldrich ChemFiles
11.1 focuses on Organometallic Reagents, which is very timely as it aff ords me the
opportunity to welcome Dr. Aaron Thornton as our new Organometallic Reagents
Product Manager. Our cover molecule is cyclopropylboronic acid MIDA ester, which
is a new addition to our ever-growing MIDA boronate portfolio. Aaron also highlights
our latest trifl uoroborates, a complementary strategy to MIDA boronates for selective
Suzuki-Miyaura coupling reactions. This “Organometallics issue” also features our
latest organotin reagents for Stille couplings, as well as TurboGrignards for selective
metallations.
Aldrich ChemFiles 11.1 also introduces our new iridium catalysts (Catalysis),
indoles and thiazoles (Building Blocks), reagents for organometallic chemistry in water
(Synthetic Reagents) and ChemMatrix Resin for solid phase peptide synthesis (Chemical
Biology).
We hope that Aldrich ChemFiles enables you to expand your research toolbox and
advance your chemistry more eff ectively by implementing the latest innovative
synthetic strategies.
Kind Regards,
Haydn Boehm, Ph. D.
Global Marketing Manager: Chemical Synthesis
Table of Contents
Asymmetric Synthesis ...............................................................................................................................4
Catalysis ................................................................................................................................................................8
Chemical Biology ....................................................................................................................................... 10
Organometallic Reagents .................................................................................................................... 14
Building Blocks ............................................................................................................................................ 22
Synthetic Reagents ................................................................................................................................... 24
Stable Isotopes ............................................................................................................................................ 26
Stockroom Reagents ............................................................................................................................... 28
Labware Notes .............................................................................................................................................. 30
Volume 11, Number 1
Sigma-Aldrich Corporation
6000 N. Teutonia Ave.Milwaukee, WI 53209, USA
Editorial Team
Haydn Boehm, Ph.D.Wesley SmithDean LlanasSharbil J. Firsan, Ph.D.Weimin Qian, Ph.D.
Production Team
Cynthia SkaggsCarrie SpearChris LeinTom BeckermannChristian HagmannDenise de Voogd
Chemistry Team
Aaron Thornton, Ph.D.Daniel Weibel, Ph.D.Josephine Nakhla, Ph.D.Matthias Junkers, Ph.D.Mark Redlich, Ph.D.Troy Ryba, Ph.D.Todd Halkoski Paula FreemantleMike Willis
Aldrich ChemFiles Subscriptions
To request your FREE subscription to Aldrich ChemFiles, either
visit our website at: aldrich.com/chemfi les or contact your local
Sigma-Aldrich offi ce (see back cover).
Aldrich ChemFiles Online
Aldrich ChemFiles is also available in PDF format on the Internet at
aldrich.com/chemfi les.
Aldrich Chemistry Products
Aldrich brand products are sold through Sigma-Aldrich, Inc.
Sigma-Aldrich, Inc. warrants that its products conform to the
information contained in this and other Sigma-Aldrich publications.
Purchaser must determine the suitability of the product for its
particular use. See reverse side of invoice or packing slip for addi-
tional terms and conditions of sale. All prices are subject to change
without notice.
To Place Orders or Contact Customer/
Technical Services
Please contact your local Sigma-Aldrich offi ce (see back cover).
Aldrich ChemFiles (ISSN 1933–9658) is a publication of Aldrich
Chemical Co., Inc. Aldrich is a member of the Sigma-Aldrich Group.
© 2011 Sigma-Aldrich Co.
Aldrich
TO ORDER: Contact your local Sigma-Aldrich offi ce (see back cover), or visit Aldrich.com/chemicalsynthesis.Aldrich.com
4
BASF’s ChiPros®: Optically Active Intermediates
on an Industrial Scale
In recent years, single-enantiomer drugs and drug candidates have
become more and more important in the pharmaceutical and agro-
chemical industry. Therefore, effi cient methods for the synthesis of small,
homochiral intermediates, which are frequently used as building blocks
for many pharmaceuticals and crop protection agents like herbicides,
fungicides and insecticides, but also resolving agents and chiral auxilia-
ries, are of central interest.
With its ChiPros portfolio1, BASF off ers a broad and growing range of
chiral amines, alcohols, epoxides and carboxylic acids. The ChiPros tool-
box holds the best-in-class technologies of enzyme-based biocatalysis
including lipases, dehydrogenases, nitrilases, esterases, oxygenases, etc.
In addition, chemical methods such as catalytic asymmetric hydrogena-
tions and CBS reductions are utilized to further strengthen the technol-
ogy portfolio.2
ChiPros Chiral Amines
Chiral amines play an important role in stereoselective organic synthesis.
They are used directly as resolving agents, building blocks or chiral
auxiliaries. While classically available through racemic resolution with
optically active acids, biotechnological approaches also open a way to
chiral amines.3 BASF’s optimized lipase-catalyzed route to optically active
amines (Scheme 1) can be run at a scale of several thousand tons. Due
to the wide range of substrates tolerated by the enzymes, a large variety
of diff erent chiral amines and chiral aminoalcohols are commercially
available.
CH3
NH2
CH3
NH2
CH3
HN CH3
O
Lipase+
Scheme 1: Lipase-catalyzed resolution of racemic amines.
CH3
NH2
H3CO
H3CO
CH3
NH2
H3CO
H3CO
H3CCH3
NH2
CH3H3C
NH2
CH3Cl
NH2
CH3
NH2
OCH3
H3C CH3
NH2
CH3
NH2
F
CH3Br
NH2
H3C CH3
NH2
CH3
HN
CH3H3C
NH2
CH3
H3CCH3
CH3
NH2
CH3H3C
H3C CH3
NH2
CH3
NH2
CH3
CH3
NH2
CH3
NH2
H2N CH3
H3C
CH3
NH2
CH3
NH2
Cl
CH3
NH2
Cl
CH3
NH2
CH3H3C
H3C CH3
NH2
CH3
NH2
NH2
O
NH2
NH2NH2
O
NH2
O
NH2
O
H2N CH3
NH2
727288
727229
727172
727164 727156
727148
727105
727024
726974
726931
726915
726907
726850
726559
726583
726591
726621
726648726664
726680
726702
726710
726729
726737726796
726826
726540
726532 726524
726516
726494
726486
Asymmetric SynthesisDaniel Weibel, Ph.D. European Market Segment Manager, Chemical [email protected]
Ready to scale up? For competitive quotes on larger quantities or custom synthesis, contact your local Sigma-Aldrich offi ce, or visit safcglobal.com.
Asymmetric Synthesis 5
ChiPros Chiral Acids
Enantiopure α- and ß-hydroxy acids and esters are versatile building
blocks for the preparation of a wide range of active pharmaceutical
ingredients by incorporating them as esters, amides or ethers, or after
further derivatization, as diols, amino alcohols, thioethers.
Hydroxy acids are accessible via a range of biotransformations, among
them are the stereoselective hydrolysis of the racemic ester precursor or
reduction of the corresponding keto esters. Hydroxynitrile lyase (HNL)
processes catalyze the stereoselective addition of HCN to aldehydes and
ketones yielding single-enantiomeric nitriles.3 Application of nitrilases or
a combination of nitrile-hydratase plus amidase allows the transforma-
tion of the starting material into the desired enantiomer of the corre-
sponding acid in a dynamic kinetic resolution fi nally yielding mandelic
acid derivatives.
BASF developed proprietary processes based on dehydrogenases to off er
access to a wide range of α- and ß-hydroxy esters, starting from readily
available keto esters. Due to the large range of enzymes available, both
enantiomers can normally be made. Another established technology is
enzymatic resolution using lipases which only acylate one enantiomer.
OH
O
OH
H3C
726990
SO3
CH3
OH
O
H3C
NH3
727350
Cl OH
O
OH
727067
ChiPros Chiral Alcohols
Chiral alcohols form a versatile class of chiral synthons, since they can
be incorporated into the API structures directly as esters or ethers. They
can be starting materials for the formation of amines, amides, thiols,
thioethers. In addition, after transforming the hydroxyl function into a
leaving group by way of mesylation, tosylation or trifl ation, they can be
used to form new C–C bonds.
Many manufacturing routes make use of asymmetric hydrogenation
methods.4 The two most important biocatalytical processes for the forma-
tion of chiral alcohols apply lipases and dehydrogenases, respectively.3
The latter off ers the advantage that only the requested enantiomer is
obtained. Enzyme-catalyzed acylations using lipases, however, achieve
the resolution of racemic mixtures of alcohols but with an inherent 50
percent maximum yield of the total amount of starting material. One
enantiomer of the racemic mixture remains unchanged while the antipo-
dal enantiomer is esterifi ed (Scheme 2).
H3COO
O
CH3CH3
OH
R
CH3
OH
R
CH3
O
R
OOCH3
Lipase+ +
Scheme 2: Lipase-catalyzed resolution of aryl-substituted alcohols.
Thanks to a variety of commercial and proprietary enzymes at its disposal,
BASF off ers a wide range of aliphatic and cycloaliphatic and aryl-substituted
single-enantiomer alcohols under the ChiPros brand.
726753 726672
726567
727059
CH3
OH
CH3H3C
OH
CH3H3C
OH
CH3H3C
OH
O
O
CH3
OH
727210
H3C CH3
NH2
H3C CH3
NH2
NH2
CH3
CH3Br
NH2
CH3
NH2
CH3H3C
NH2
CH3H3C
NH2
Br
CH3
NH2
H3CO
CH3
NH2
CH3
NH2
CH3
NH2
H3CO
CH3
NH2
CH3
HN
NH2
CH3
NCO
727342
727180
727083
727032
726958
726923
726893
726885
726869
726842
726605
726613
726656
726818
726761
TO ORDER: Contact your local Sigma-Aldrich offi ce (see back cover), or visit Aldrich.com/chemicalsynthesis.Aldrich.com
6
ChiPros Chiral Epoxides
Oxiranes are very valuable building blocks which allow
derivatization:
by forming C-X bonds (through reactions with alcohols, • ammonia, amines, phenolates etc.)
or by forming new C–C bonds (through reactions with cyanide, • malonates, allyl silyl reagents, metal-organic reagents, e.g. Mg, Zn,
Li organyls)
There are several alternative routes towards chiral aryl-substituted epox-
ides, among them Jacobsen’s asymmetric epoxidation5 or his hydrolytic
kinetic resolution6 method, Sharpless’s asymmetric epoxidation7 using
catalytic titan(IV)- isopropylate/diethyl tartrate complexes and tert-butyl-
hydroperoxide, complemented by Shi’s reaction8 using peroxomonosul-
fate with a chiral ketone as catalyst, or among the enzymatic methods,
application of epoxide hydrolases, lipases or monooxygenases. The ste-
reoselective reduction of α-chlorinated acetophenones using dehydro-
genases, however, aff ords a very versatile and more cost-effi cient access
to a wide range of oxiranes, including both enantiomers of styrene oxide
as well as very diff erently substituted phenyl oxiranes (Scheme 3).
CH3
O OX
O
RR
OHX
R R
Base
Scheme 3: Stereoselective synthesis of oxiranes.
O
726508
OCl
726699
O
726834
OF
727253
Aldrich Chemistry is proud to off er ChiPros in small quantities (up to
kilograms). A total of 79 products from the ChiPros portfolio are available
from Aldrich Chemistry, including chiral amines, alcohols, epoxides and
carboxylic acids.
References:
(1) http://www.chipros.com (2) Karl, U.; Simon, A. Chimica Oggi/Chemistry Today 2009,
27, 5. (3) Breuer, M.; Ditrich, K. et al. Angew. Chem. Int. Ed. 2004, 43, 788-824. (4) Blaser, H.
U.; Schmidt, E. Asymmetric Catalysis on Industrial Scale, Wiley-VCH. 2004 (5) Zhang, W.;
Loebach, J. L. et al. J. Am. Chem. Soc. 1990, 112, 2801-2803. (6) White, D. E.; Jacobsen, E. N.
Tetrahedron: Asymmetry 2003, 14, 3633-3638. (7) (a) Katsuki, T.; Sharpless, K. B. J. Am. Chem.
Soc. 1980, 102, 5974-5976. (b) Review: Hüft, E. Top. Curr. Chem. 1993, 164, 63-77.
(8) (a) Wang, Z.-X.; Tu, Y. et al. J. Am. Chem. Soc. 1997, 119, 11224-11235; (b) Ager, D.;
Anderson, K. et al., Org. Proc. Res. Dev. 2007, 11, 44-51; (c) Aldrich Chemfi les 2010, 3, 4-5.
For a complete list of Chiral Building Blocks available from
Aldrich Chemistry, visit Aldrich.com/chiralbb
Q-Tubes are affordable alternatives to a microwave synthesizer
and feature a safe pressure-release system (patent pending) that
prevents accidental explosions due to overpressurization. Starter
kits contain all items needed for immediate use.
New Q-Tube™ Pressure Reactors
Q-Tube Benefi ts:
Better yield•
Cleaner product•
Reduced reaction time•
Higher reproducibility•
Scalability (up to 20 grams)•
Safer automatic pressure release•
Aff ordability•
Maintenance-free•
Q-Tube Starter Kits:
Kits contain all items needed for immediate use.
View accessory product listings and technical information
about Q-Tubes on our website at
sigma-aldrich.com/qtube
Q-Tube Size Cat. No.
12 mL Z567671
35 mL Z567736
Q-Block™ Heating BlocksThese anodized-aluminum heating blocks are designed for
use with 12-mL and 35-mL Q-Tubes. The maximum working
temperature is 204 °C. Blocks have a safety locking plate, safety
shield, thermally stable silicone tubing, and an internal cooling
channel for fast cooling (nitrogen, compressed air, or vacuum).
There is also a thermocouple well for accurate temperature
measurement.
Q-Tube Size Cat. No.
12 mL Z567914
35 mL Z567922
TO ORDER: Contact your local Sigma-Aldrich offi ce (see back cover), or visit Aldrich.com/chemicalsynthesis.Aldrich.com
8
Ir(I)-Catalyzed C–H
Borylation
Arylboronic acids and esters are invaluable tools for the chemical com-
munity. These powerful reagents are used for a variety of transformations,
most notably the Suzuki-Miyaura cross-coupling reaction. This reaction
is used to selectively construct C–C bonds through the combination of
an organo-boron nucleophile with a suitable aryl, alkenyl, or alkyl halide
or trifl ate. While the Suzuki-Miyaura reaction has become commonplace
within the synthetic community, one limitation of this method is the
limited ability to access the requisite organo-boron species.
Historically, methods for the synthesis for aryl C–B bonds have relied
upon the use of harshly basic reaction conditions or substrates contain-
ing prefunctionalized carbon centers. These shortcomings require that
additional steps must be taken to either protect sensitive functionality
or install the necessary functional handle prior to C–B bond formation
(Scheme 1).
RX
X = Cl, Br, I
R'MXR
MX B(OR'')3R
B(OR'')2
RDG
R'LiR
DG B(OR'')3R
DG
H
RX
X = Br, I, OTf
Pd(0), BaseR
B(OR'')2
HB(OR'')2
(OR'')2B B(OR'')2
or
Li B(OR'')2
• Harshly basic reaction conditions• Multiple steps and manipulations• Requires prefunctionalized starting materials
Scheme 1: Classical methods for C–B bond formation.
The direct formation of aryl C–B bonds from aryl C–H bonds thus repre-
sents a powerful strategy for streamlining the synthesis of these useful
reagents (Scheme 2).1
RH
RB(OR'')2
HB(OR'')2
(OR'')2B B(OR'')2
or
[M]
• No harsh reagents or reaction conditions
• Atom economical• No need for prefunctionalization
Scheme 2: Metal-catalyzed direct C–H borylation.
CatalysisJosephine Nakhla, Ph.D.Market Segment ManagerOrganometallics and [email protected]
Building upon their previous work within the area,2 Professor John F.
Hartwig has disclosed a method for the direct conversion of aryl C–H
bonds to aryl C–B bonds through the use of an Ir(I) catalyst and B2pin2
(Table 1).3 This powerful system displays excellent regioselectivity that
can be easily predicted by sterics and leads to the rapid synthesis of
highly useful arylboronic esters.
arene product
RH
RBpin1/2[IrCl(COD)]2/bpy
B2pin2, 80 oC, 16 h.
Bpin95 %
Bpin
83 %
Bpin
86 %
Bpin
83 %
Bpin58 %
Bpin
86 %
Bpin
72 %
Bpin
73 %
CH3
H3C
CH3
H3C
H3COOCH3 OCH3
H3CO
ClCl Cl
Cl
CH3
H3C
CH3
H3C
CH3
H3CO
Br
H3CO
H3C
CH3
H3C
CH3
CH3
H3CO
H3CO
Br
arene productyield yield
H
H
H
H H
H
H
H
Table 1: Ir(I)-Catalyzed aryl C–H borylation.
This method provides a simple and direct route to arylboronic esters that
fully avoids the use of harshly basic reaction conditions and does not
require multiple reaction steps and manipulations. Importantly, this reac-
tion employs catalysts and reagents that are all readily accessible, and
now available from Aldrich.
Reference: (1) Cho, J. Y.; Tse, M. K.; Holmes, D.; Maleczka Jr., R. E.; Smith III, M. R.
Science, 2002, 295, 305 (2) (a) Chen, H.; Hartwig, J. F. Angew. Chem. Int. Ed. Engl. 1999, 38,
3391. (b) Chen, H.; Schlecht, S.; Semple, T. C.; Hartwig, J. F. Science 2000, 287, 1995.
(3) Hartwig, J. F. et al. J. Am. Chem. Soc. 2002, 124, 390. (4) Hartwig, J. F.
et al. Chem. Rev. 2010, 110, 890.
Ready to scale up? For competitive quotes on larger quantities or custom synthesis, contact your local Sigma-Aldrich offi ce, or visit safcglobal.com.
9Catalysis
Iridium(I) Catalysts, Bipyridine Ligands, and Borylation Reagents from Aldrich:
For a complete list of C–H borylation reagents available from Aldrich
Chemistry, please visit Aldrich.com/borylation
Carboranes as Superweak Anions
The chemistry of weakly coordinating anions, or superweak anions,
continues to be actively investigated within many laboratories for a
variety of purposes. These useful molecules often allow for the isolation
of extremely reactive salts of cations, making them applicable to the ever
growing list of chemical tasks that require highly reactive cations. These
uses include the catalytic polymerization of olefi ns, the catalytic formation
of C–C bonds, the manufacture of high-current-density lithium batteries,
and the activation of C–H bonds. Discover how carboranes from Aldrich
can advance your research.
Carboranes from Aldrich:
BB
B
B
B
B
BB
B
B
B
B
F
F
F
F
F
FF
F
FF
F F
Cs
CsBB
B
B
B
B
BB
B
B
B
B
F
F
F
F
F
FF
F
FF
F F
K
K
723509 720887
N N
t-Bu t-Bu
515477
N N
H3C CH3
569593
N N
513040
H3C CH3
N N
H3CO OCH3
536040
N N
36759 473294
655856
473286
188913
518808
B BO
OO
O
H3CH3C
H3CH3C
CH3
CH3
CH3
CH3
BO
OCH3
CH3
CH3
CH3
H
B BO
OO
O
BO
OH
OB
OB
O
O CH3
CH3
H3C
H3C
683094
685062
377155
685011
Ir(I) Catalysts Bipyridine Ligands Borylation Reagents
IrIrCl
Cl
Ir
IrOCH3
OCH3
Ir
[Ir(COE)2Cl]2
Frustrated Lewis Pairs as Hydrogenation
Catalysts
The hydrogenation of organic substrates with molecular hydrogen (H2)
has been used for purposes ranging from the large-scale upgrading of
crude-oil, to the synthesis of fi ne chemicals used in food, agriculture, and
the pharmaceutical industry. While the majority of methods rely on the
use of costly precious metal catalysts, recent work from the lab of Profes-
sor Douglas W. Stephan has illustrated the use of frustrated Lewis pairs
for the same purpose.1,2 These powerful non-metallic catalysts contain
both Lewis acidic (borane) and Lewis basic (phosphine) moieties that
cannot be quenched internally due to steric constraints. Because of this
unquenched reactivity, these organic catalysts are used to activate a vari-
ety of small molecules, including the heterolytic cleavage of H2, leading to
a powerful catalyst system for the hydrogenation of imines and aziridines
(Scheme 3).
Scheme 3: Frustrated Lewis pairs for the hydrogenation of imines
and aziridines.
Reference: (1) Welch, G. C.; San Juan, R. R.; Masuda, J. D.; Stephan, D. W. Science 2006, 314,
1124. (2) (a) Chase, P. A.; Welch, G. C.; Jurca, T.; Stephan, D. W. Angew. Chem., Int. Ed. 2007,
46, 8050. (b) Chase, P. A.; Welch, G. C.; Jurca, T.; Stephan, D. W. Angew. Chem., Int. Ed. 2007,
46, 9136.
Frustrated Lewis Pairs from Aldrich:
For a complete list of Frustrated Lewis pairs available from Aldrich
Chemistry, please visit Aldrich.com/fl p
B
H
FF
F
FF F
F
PF
FF
F
FF
F
H+
t-Bu
t-Bu
BH
F
FF
FF
F FF
FF
F
FF
F
P
H3C CH3
CH3
CH3
H3C CH3
H+
703087 703095
N
PhH
t-Bu NH
PhH
t-Bu
H2
703087 5 mol %
10 mol %
5 atm H
25 atm HPh
N
Ph
PhNH
Ph
Ph703095
Ph
98 %
98 %
TO ORDER: Contact your local Sigma-Aldrich offi ce (see back cover), or visit Aldrich.com/chemicalsynthesis.Aldrich.com
10
ChemMatrix® Resin – A major advance in solid
phase peptide synthesis
ChemMatrix® is a proprietary, 100% PEG (polyethylene glycol) based
resin from PCAS BioMatrix. It combines the strengths of two major
resin systems — the chemical stability of polystyrene resins and the
superior performance of PEG grafted resins making it the ultimate
choice for the solid supported synthesis of large or hydrophobic
peptides and even proteins.
In the past decades polystyrene resins have been the primary choice for
solid supported peptide synthesis due to their good results in the syn-
thesis of small peptides. Nevertheless, with the growing amino acid chain
during the synthesis, the tendency of the peptide to form secondary
structures increases. The hydrophobic environment of the polystyrene
resin amplifi es the aggregational behavior of the peptide making the
synthesis of large peptides extremely diffi cult or even impossible. Crude
products of large peptides synthesized on polystyrene resins exhibit a
mixture of deletion sequences and uncompleted fragments. PEG grafted
resins have helped to reach better crude peptide purities by making the
resin more polar and improving the swelling properties in both polar
and unpolar solvents. As a drawback such PEG grafted resins only allow
smaller loadings and are less chemically stable leading to potential leach-
ing during the cleavage step.
ChemMatrix resin was designed from scratch starting with a new type of
monomer building block. The fi nal polymer resin is built exclusively on
primary ether bonds and therefore exhibits high chemical stability, avoid-
ing leaching (Figure 1).1
Figure 1: The scaff old of Aminomethyl-ChemMatrix resin is built completely on
chemically stable polyether bonds (left). Microscopic image of ChemMatrix beads
(right).
H2N OO
O NH2
H2N OO
O NH2
H2N OO
O NH2
n
n
n
OO
On
Chemical BiologyMatthias Junkers, Ph.D.Product [email protected]
At the same time, the increased polarity of the resin allows the use of var-
ious polar solvents, including: water, THF, DMF, methanol and acetonitrile,
in which the resin displays excellent swelling properties (Figure 2). High
swelling properties should be considered during practical use as the wet
ChemMatrix resin will consume considerably more space in the reaction
vessel than conventional polystyrene resins. Typical loading ranges are
between 0.4 and 0.7 mmol/g which is a comparable binding capacity as
polystyrene resins.
Aceto
nitrile
DCMDMF
NMP
DMSO
Methanol
TFAWater
Polystyrene
Aminomethyl-ChemMatrix
Swel
ling
(mL/
g)
1816141210
86420
Figure 2: Swelling properties of ChemMatrix resin compared to
polystyrene resin.
Two recent independent publications give remarkable evidence for
the unmatched performance of ChemMatrix resin. For the synthesis of
HIV–1 protease, a large peptide of 99 amino acids, ChemMatrix resin
was compared directly to polystyrene.2 As the following chromatograms
clearly show, the desired peptide is the main component of the crude
product using ChemMatrix as the solid support (Figure 3). Polystyrene
resins only deliver crude mixtures preventing the direct, linear synthesis
of long peptides.
Ready to scale up? For competitive quotes on larger quantities or custom synthesis, contact your local Sigma-Aldrich offi ce, or visit safcglobal.com.
11Chemical Biology
1.00 2.00 3.00 4.00 5.00 6.00 7.00 8.00 9.00 10.00 11.00 12.00
7.02
5
Minutes
Minutes
1.00 2.00 3.00 4.00 5.00 6.00 7.00 8.00 9.00 10.00 11.00 12.00
Figure 3: HPLC chromatograms of HIV–1 protease (99 amino acids) after
78 amino acids. The synthesis on ChemMatrix resin yields the desired peptide
directly without further purifi cation (top) whereas polystyrene
resin only yields a very crude mixture (bottom).2
In a second amazing example, Bacsa et al. reported in 2010, the solid
supported, microwave assisted synthesis of the polypeptide Aβ(1–42).3
Aβ (1–42) plays a crucial role in the pathogenesis of Alzheimer’s disease
in that it forms β–sheet structures and amyloid fi brils which induce
neurotoxicity. Thus, it is a key material needed to further investigate the
molecular mechanisms of Alzheimer’s disease and potential drugs for its
treatment. Due to its aggregational behavior this peptide is highly diffi cult
to synthesize. ChemMatrix resin allows the direct, linear synthesis with a
standard Fmoc/t–Bu synthesis strategy applying DIC/HOBt as a simple
and inexpensive coupling reagent. Except for the coupling of three
racemization sensitive histidine residues which was carried out at room
temperature the synthesis was achieved under controlled microwave
conditions at 86 °C. ChemMatrix resin remained completely stable under
these conditions.4 Finally, Aβ(1–42) was obtained within a 15h overall
processing time in high yield and purity (78% crude yield).3
Apart from peptide synthesis ChemMatrix resin has also been used suc-
cessfully in combinatorial synthesis,5 for the synthesis of oligonucleotide
derivatives,6 PNA,7 asymmetrically substituted phthalocyanines,8 and
peptide hybrids incorporating non-natural chemical residues.9
In summary, ChemMatrix overcomes the challenges of synthesizing
longer and more complex therapeutic peptides. Peptides produced with
ChemMatrix have higher purity and can be obtained with better yields.
Peptides that were hitherto achievable only by ligation or recombinant
techniques can now be synthesized directly on solid support.
For the synthesis of peptide acids, we recommend using the ChemMatrix
with a HMPB anchor as this resin will provide high crude purity and a
recovery yield of 90–95%. The Wang-ChemMatrix will produce similar
crude peptide purity, but the recovery yield is lower (60–70%). HMPB–Ch-
emMatrix resins are also off ered preloaded with the most common amino
acids. A number of protocols for the application of ChemMatrix resin have
been published recently in the literature.10
Features of ChemMatrix Resin
• Exceptional Stability
ChemMatrix resin is made exclusively from primary ether bonds which
are highly chemically stable. No leaching occurs during synthesis and
cleavage.
• High Loading
ChemMatrix resins have a loading of 0.4–0.7 mmol/g.
• Solvent Compatibility
ChemMatrix allows the use of almost any kind of solvent, even water.
High swelling properties of ChemMatrix in water allows high throughput
post-synthetic downstream screening.
• Versatile Choices
ChemMatrix resin is off ered with an extensive range of linkers for
peptide acids, amides and fragments. For peptide synthesis, preloaded
resins are also available for your convenience.
• Demonstrated Superiority
ChemMatrix resin has been fi eld proven for easier and faster develop-
ment of long, complex and hydrophobic peptides. The longer, the more
complex or hydrophobic your peptide is, the more improvement you
will see with ChemMatrix.
• Microwave assisted synthesis
No leaching is observed on microwave synthesizers at 80 °C.
References: (1) García-Martin, F.; Albericio, F. Chem. Today 2008, 26, 29. (2) Frutos, S.;
Tulla-Pucha, J.; Albericio, F.; Giralt, E. Intern. J. of Pept. Res. Ther. 2007, 13, 221. (3) Bacsa, B.;
Bösze, S.; Kappe. C. O. J. Org. Chem. 2010, 75, 2103. (4a) Subiros-Funosas, R.; Acosta, G. A.;
El-Faham, A.; Albericio, F. Tet. Lett. 2009, 50, 6200. (4b) Galanis, A. S.; Albericio, F.; Grøtli,
M. Org. Lett. 2009, 11, 4488. (5) Marani, M.M.; Martínez-Ceron, M. C.; Giudicessi, S. L.; de
Oliveira, E.; Côté S.; Erra-Balsells, R.; Albericio, F.; Cascone, O.; Camperi, S. A. J. Comb. Chem.
2009, 11, 146. (6) Mazzini, S.; García-Martin, F.; Alvira, M.; Aviñó, A.; Manning, B.; Albericio, F.;
Eritja, R. Chem. Biodiv. 2008, 5, 209. (7) Fabani, M. M.; Abreu-Goodger, C.; Williams, D.; Lyons,
P. A.; Torres, A. G.; Smith, K. G. C.; Enright, A. J.; Gait, M. J.; Vigorito., E. Nucl. Acids Res. 2010, 38,
4466. (8) Erdem, S. S.; Nesterova, I. V.; Soper, S. A.; Hammer, R. P. J. Org. Chem. 2008, 73, 5003.
(9) Spengler, J.; Ruíz-Rodríguez, J.; Yraola, F.; Royo, M.; Winter, M.; Burger, K.; Albericio. F. J.
Org. Chem. 2008, 73, 2311. (10) García-Ramos Y.; Paradís-Bas, M.; Tulla-Puchea, J.; Albericio, F.
J. Pept. Science 2010, 16, 675.
TO ORDER: Contact your local Sigma-Aldrich offi ce (see back cover), or visit Aldrich.com/chemicalsynthesis.Aldrich.com
12
ChemMatrix resins
NH
OO
NHFmoc
OCH3
OCH3Rink amide CM
NH
OO
HMPB-CMOH
OCH3
NH
O
Trityl-OH CM OH
NH
OO
OHWang-CM
NH
OO
Ramage-CM
NHFmocNH
O
PAL-CM
O
NHFmoc
OCH3
OCH3
H2N OO
O NH2
H2N OO
O NH2
H2N OO
O NH2
n
n
n
68571
727768727741
64191 727776
727792 727784
Aminomethyl CM
ChemMatrix HMPB preloaded resins
NH
OO
O
OCH3
H-Gly-HMPB-CM H-Ala-HMPB-CMO
NH2
NH
OO
O
OCH3
OCH3
NH2
NH
OO
O
OCH3
O
NH2
H-Arg(Pbf)-HMPB-CM
NH
OO
O
OCH3
O
NH2
H-Lys(Boc)-HMPB-CM
NH
OO
O
OCH3
O
NH2
CH3
H-Leu-HMPB-CM
CH3 NH
OO
O
OCH3
O
NH2
CH3
H-Val-HMPB-CM
CH3
H-Phe-HMPB-CM
NH
OO
O
OCH3
O
NH2 NH
OO
O
OCH3
O
H-Pro-HMPB-CM
HN
727806 727822
727849 727865
727814 727830
727857 727873
NH
NHPbf
HNBocHN
For a complete list of ChemMatrix products available from Aldrich
Chemistry, please visit Aldrich.com/chemmatrix
Custom Packaged Reagents (CPR)
To register for an online ordering account or to submit inquiries, visit Discoverycpr.com
Our CPR Service provides a cost eff ective strategy to
procure one to thousands of unique, custom packaged
building blocks and screening compounds for use in
research programs.
CPR is optimized to support several discovery activities:
The chemist looking to identify and procure sets of building blocks for their high • throughput synthetic reactions
The chemical biologist or biologist interested in the diversity of the world’s largest • selection of screening compounds
Customized packaging allows you to receive samples in a ready-to-use format, allowing
you to focus on your research rather than spending time weighing out building blocks or
tracking down vendors.
CPR from Aldrich provides:
Widest selection of building blocks, reagents, and screening compounds through • hundreds of managed vendors worldwide
Internet-based chemical database and procurement functionality• Custom packaging of over 200,000 off -the-shelf products from global sources• Availability and pricing in a single quotation with consolidation of invoicing• Standard or client-supplied custom packaging in vials or plates• Customized labeling, including 1-D or 2-D barcoding to your specifi cations• Normalization of electronic data with shipment including SD fi le generation•
TO ORDER: Contact your local Sigma-Aldrich offi ce (see back cover), or visit Aldrich.com/chemicalsynthesis.Aldrich.com
14
OrganometallicsAaron Thornton, Ph.D.Product [email protected]
MIDA Boronates for Suzuki–Miyaura
Cross-Couplings
Professor Martin Burke and coworkers recently prepared retinal using
key MIDA building block BB1 in iterative Suzuki-Miyaura cross coupling
reactions (Scheme 1). The MIDA unit of BB1 is unreactive under these
conditions, allowing for the selective cross-coupling of BB1 with triene
(1). Subsequent hydrolysis of the MIDA unit of (2) followed by a second
Suzuki-Miyaura reaction provided all-trans-retinal.
CH3
CH3H3C CH3
B(OH)2
BO
N
OOBr
BB1
BO
N
OO
CH3
CH3
H3C CH3
Pd(OAc)2, SPhos, K3PO4
23 °C, 78%toluene
1. aq. NaOH, THF, 23 °C
2.
23 °C, 66%
CH3
CH3
H3C CH3CH3 H
OBr
CH3
O
H
Pd(OAc)2, SPhos, K3PO4, THF
703478
H3C
H3C
O
O
all-trans-retinal
1 2
Scheme 1: Iterative Suzuki-Miyaura cross-couplings in the synthesis of
all-trans-retinal.
Reference: Lee, S. J. et al. J. Am. Chem. Soc. 2008, 130, 466.
The many advantages of the MIDA boronate platform include air and
moisture stability, stability under anhydrous cross-coupling conditions,
compatibility with a range of common and harsh reagents, solubility
in various organic solvents, silica gel compatibility, and the ability to
undergo slow release cross-couplings.
MIDA Boronates from Aldrich:
BO
N
OOO
H3C
697311
H2CB
O
N
OOO
H3C
698709 700231
B
O
N
O
OO
H3C
B
O
N
O
OO
H3C
H2C
704415
BO
N
OOO
H3C
CH2
707252
H3CB
O
N
O
OO
H3C
S
708828
HC
For complete list of MIDA boronates available from
Aldrich Chemistry, visit Aldrich.com/mida
Slow-Release of Unstable Boronic Acids from
MIDA Boronates
In addition to attenuated reactivity towards anhydrous cross-coupling
conditions, MIDA boronates also possess the capacity for in situ slow-
release of boronic acids under aqueous basic conditions (Scheme 2).
Harnessing this phenomenon, boronic acids that are notoriously unstable
can be eff ectively utilized in cross-coupling when employed as MIDA
boronates. While aqueous solutions of NaOH promote the fast hydrolysis
of MIDA boronates to their corresponding boronic acids, the use of aque-
ous K3PO4 allows for the slow-release of relatively unstable boronic acids,
preventing decomposition of the organometallic species and improving
overall yields for many Suzuki-Miyaura reactions.
Slow Release of Unstable Boronic Acids
Scheme 2: Slow-release of unstable boronic acids from MIDA boronates.
Burke and coworkers examined this slow-release concept by comparing
various freshly prepared boronic acids with their corresponding MIDA
boronates. The study revealed that many boronic acids decompose
signifi cantly via various pathways, including protodeborylation, oxidation,
and polymerization, after just 15 days of benchtop storage under air. On
the other hand, the corresponding MIDA boronates were remarkably
stable, with >95% of each MIDA remaining after ≥60 days of benchtop
storage under air. In addition to complications related to storage, the
overall effi ciency of cross-coupling for these reagents is also impacted
by the nature of the boron unit. For example, while isolated yields are
RB
O
N
OOO R B(OH)2
mild aqueous base (e.g. K3PO4)
Cl R'
Pd-catalyst
R R'
H3C
Ready to scale up? For competitive quotes on larger quantities or custom synthesis, contact your local Sigma-Aldrich offi ce, or visit safcglobal.com.
15Organometallics
generally low to moderate even when freshly-prepared boronic acids are
employed in Suzuki-Miyaura cross-couplings, employing the correspond-
ing MIDA boronate results in excellent yields of the desired cross-coupled
products (Table 1).
RB
O
N
OOO
Ot-Bu
Cl
Pd(OAc)2, SPhos
Ot-Bu
RK3PO4, dioxane:H2O (5:1)
60 °C, 6 h
R B(OH)2 or
1 eq 1 eq
1 mmol
O
BocN
5 >95a
<5 >95
7 >95
R
% remaining after benchtopstorage under air
A B
A (15 days) B (>60 days)
Cross Coupling Isolated Yield (%)
BocN
Ot-Bu
C
C
Ot-Bu
with A with B
68 94
61 90
79 98
Entry
1
2
3
4NN
SO2Ph SO2Ph
<5 >9514 93
across coupling conducted at 100 °C
H3C
Ot-Bu
OOt-Bu
Table 1: Stability and slow-release cross-coupling studies of MIDA boronates vs.
boronic acids.
MIDA Boronates for Classically Challenging
Suzuki-Miyaura Cross-Couplings
The power of this slow-release concept has been further illustrated by
utilizing various MIDA boronates of which the corresponding boronic
acids have historically exhibited challenges with respect to either storage
or use, including 2-heterocyclic, vinyl and cyclopropyl boronic acids.
Because these organoboron species readily decompose through a variety
of pathways, the effi ciency with which their corresponding MIDA bor-
onates may be coupled is particularily noteworthy (Table 2).
RB
O
N
OOO
ClPd(OAc)2, SPhos, K3PO4
dioxane/H2O (5:1), 60 °C, 6 h
Entry
1
2
3
4
BO
N
OOOS
BO
N
OOO
Cl
H3C CH3
CH3
N
NCl
R
R'
R' ClMIDA Isolated Yield (%)Product
H3C CH3
79
97
CH3
N
NS
R R'
BO
N
OOON
Boc98N
Boc
N
O
ClCH3 N
OCH3
BO
N
OOO
N
Cl
NH2
76N NH2
H3C
H3C
H3C
H3C
H3C
Table 2: Slow-release cross-coupling of MIDA boronates with historically challeng-
ing substrates.
2-Pyridinylboronic Acid MIDA Ester as a Stable
2-Pyridinyl Boron Anion Equivalent
The development of a viable air-stable surrogate for the notoriously
unstable 2-pyridinylboronic acid has been a long-standing challenge
in the fi eld of cross-coupling. This motif is ubiquitous in drug-like small
molecules, and therefore of particular importance to the synthetic com-
munity. While 2-pyridinylboronic acid surrogates exist, their use is often
complicated by air- and moisture-sensitivity as well as their somewhat
variable and impure compositions. In contrast, Burke and coworkers
found that 2-pyridinyl MIDA boronate is isolable, benchtop and chroma-
tography stable, and under slow-release conditions can be successfully
coupled with a variety of aryl and heteroaryl chlorides (Table 3).
BO
N
OOON
Cl
Pd2(dba)3, XPhos, K3PO4
DMF/IPA (4:1), 100 °C, 4 h
R
Cu(OAc)2, K2CO3
N R
Entry Cl R Product Isolated Yield (%)
1
2
3
Cl
C
Cl
CN
N
N
Cl
C
CN
N
N
N
72
60
79N
N
719390
H3C
OCH3
OCH3
Table 3: Slow-release cross-coupling of 2-pyridinylboronic acid MIDA ester.
References: (1) Gillis, E. P.; Burke, M. D. Aldrichimica Acta 2009, 131, 17. (2) Knapp, D. M.;
Gillis, E. P.; Burke, M. D. J. Am. Chem. Soc. 2009, 131, 6961.
Pyridinyl MIDA Boronates from Aldrich
BO
N
OO
O
H3C
NH3CO
BO
N
OO
O
H3C
N
723053
723959
BO
N
OOO
H3C
N OCH3
701084
BO
N
OOO
H3C
NH3CO
699845
BO
N
OOO
N
Br
H3C
703370
BO
N
OOO
NCl
H3C
700908
BO
N
OOO
NBr
H3C
702269
BO
N
OO
O
H3C
N
719390
H3C BO
N
OOO
H3C
N
704563
For a complete list of MIDA boronates available from
Aldrich Chemistry, visit Aldrich.com/mida
TO ORDER: Contact your local Sigma-Aldrich offi ce (see back cover), or visit Aldrich.com/chemicalsynthesis.Aldrich.com
16
Heterocyclic Organotin Reagents for
Stille Coupling
Stille reactions remain one of the most viable methods for the formation
of C–C bonds in organic chemistry.1 Their use has been highlighted in
various areas, including countless natural product syntheses, material sci-
ence applications, and in numerous synthetic methodology studies. The
coupling of imidazolyl stannane 718793 with heterocycle (4) by process
chemists at Pfi zer was reported in 2003 (Scheme 3).2 This coupling
employed Pd(PPh3)4 as the catalyst and was carried out in 67% isolated
yield. Addition/elimination on the resulting functionalized thienopyri-
dine provided bulk material of the desired VEGFR kinase inhibitor (5). It
is worth noting that of several cross-couplings which were examined,
the Stille coupling employing stannane 718793 was the only reaction
feasible on scales >50g.
N
Cl
SI
N
N
CH3
SnBu3
718793Pd(PPh3)4 (5 mol%)
DMF, 95 C40 h, 67%
N
Cl
S
N
NH3C
N
NH
S
N
NH3C
HN
H3C
NH2
HN
H3C
t-BuOH/DCE100 C
52%4 5
Scheme 3: Stille reaction in the preparation of VEGFR kinase inhibitors (5).
References: (1) Mascitti, Vincent. Stille coupling. Name Reactions for Homologations 2009,
(Pt. 1), 133–162. (2) Ragan, J. A.; Raggon, J. W.; Hill, P. D.; Jones, B. P.; McDermott, R. E.;
Munchhof, M. J.; Marx, M. A.; Casavant, J. M.; Cooper, B. A.; Doty, J. L.; Lu, Y. Org. Proc. Res.
Dev. 2003, 7, 676.
Organotin Reagents from Aldrich:
683930 719366
678333 698598
SBu3Sn SnBu3
SBu3Sn N
H3C
Bu3Sn
NBu3Sn N
Bu3Sn
718807
719730 706868 707031
706981
N
N
Cl Cl
Bu3Sn
N
NBu3Sn
N
NBu3Sn
Cl
N
N
OCH3Bu3Sn
ONBu3Sn
OCH2CH3
O
707813 717630
638617 642541 706965
NN
CH3
Bu3Sn
N
N
CH3
Bu3Sn
O
N
Bu3Sn S
N
Bu3Sn
S
NSnBu3
Br
675679 719501 718793
NCH3
Bu3SnN
N
CH3
Bu3Sn
N
N
CH3
Bu3Sn
717703
For a complete list of Organotin Reagents available from
Aldrich Chemistry, visit Aldrich.com/organotin
Selective 1,2-Additions with LaCl3·2LiCl
While the 1,2-addition of Grignard reagents to ketones is undoubtedly
a powerful transformation, oftentimes selectivity issues arising from
competitive alpha-deprotonation detract from the use of these reagents.
Various methods have been developed to address this shortcoming,
including the use of CeCl3 and other Lewis acidic salts. However, because
of the heterogeneous nature of these reagents, it is often diffi cult to
obtain adequate selectivity. With this in mind, the lab of Professor Paul
Knochel has shown that LaCl3•2LiCl (703559) may be used to attenuate
the basicity of Grignard reagents, in turn preventing competitive enoliza-
tion side reactions while leading to a powerful method for the selective
1,2-addition of Grignard reagents to ketones. In addition to enolizable
ketones, even sterically hindered ketones, as well as Michael acceptors
and unactivated imines can undergo 1,2-additions selectively to provide
the desired addition products (Table 4).1
i-PrMgCl
KetoneGrignardReagentEntry
1
2
3
Productwith
LaCl3 2LiClc
92
92
81
•
N
MgCl LiCl•
Br
OPh Ph EtO2C
Bn
OHBn
PhO Ph
OH
N
Br
withno additives
a
5
with CeCl3b
72
39 11
35 __
•
Yield (%)
aIsolated yield of product based on reaction between ketone and Grignard reagentbIsolated yield of product in the presence of 1.5 eq CeCl3 (Dimitrov Method)cIsolated yield of product in the presence of 1.0 eq LaCl3 2LiCl
OOH
i-Pr
MgCl LiCl
EtO2C
R1MgCl +R3
OR2
R3
OMgClR2
0 °C, 10 min-6h
703559
LaCl3 2LiCl•
R1
Table 4: LaCl3•2LiCl mediated addition to ketones.
Ready to scale up? For competitive quotes on larger quantities or custom synthesis, contact your local Sigma-Aldrich offi ce, or visit safcglobal.com.
17Organometallics
Subsequent to these initial studies with LaCl3•2LiCl, Knochel and cowork-
ers reported that sub-stoichiometric quantities of the lanthanide salt are
suffi cient to promote the desired 1,2-addition, as demonstrated by the
addition of i-PrMgCl•LiCl to unactivated imines (Scheme 4). This protocol
is amenable to the use of alkyl, aryl, and heteroaryl Grignard reagents.2
OMe
N
Ph
•+
LaCl3 2LiCl•
(10 mol%)
THF, rt, 12h
OMe
HN
Ph i-Pr
84%i-PrMgCl LiCl
Scheme 4: 1,2-Addition of organomagnesium reagents in the presence of catalytic
LaCl3•2LiCl.
Advantages of LaCl3•2LiCl:
No pretreatment procedures necessary• Easy handling of reagents and reaction setup• Homogeneous reaction conditions • Improved selectivity and reactivity providing better yields and • decreased reaction times
References: (1) Krasovskiy, A.; Kopp, F.; Knochel, P. Angew. Chem. Int. Ed. 2006, 45, 497. (2)
Metzger, A.; Gavryushin, A.; Knochel, P. SynLett 2009, 1433.
For a complete list of selective metallation reagents available from
Aldrich Chemistry, visit Aldrich.com/metallations
Chiral Silacycles for Enantioselective
Allylation and Crotylation Reactions
The asymmetric allylation and crotylation of aldehydes and other carbo-
nyl compounds remains one of the most fundamental reactions for the
construction of chiral building blocks. While numerous methods for this
challenging task have been examined previously, including the use of
chiral auxiliaries, chiral reagents and catalytic systems, still today a truly
convenient and broadly reaching method remains elusive. With this goal
in mind, the group of Professor James Leighton has developed a versatile
system that has proven to be uniquely eff ective. Leighton and co-workers
have harnessed the power of strained silacycles for use as allylation re-
agents without the need for any further catalysts or reagents (Scheme 5).
OSi
N
Cl
Me
OSi
N
Cl
Me
Ph
Me
Ph
Me
NSi
N
Cl
H
H
Br
Br
NSi
N
Cl
H
H
Br
Br
Scheme 5: Leighton’s chiral allyl silanes.
These bench-stable and non-toxic reagents undergo enantioselective ad-
dition to a range of carbonyl compounds, including aldehydes, ketones,
and hydrazones1 (Table 5). Notably, all of these reactions are carried out at
convenient reaction temperatures without the need for external activat-
ing reagents, thereby simplifying reaction set-up and manipulation.
OSi
N
Cl
Me
Ph
Me
706671
+O
R H R
OH
R T (oC) yield % e.e. %
-10
-10
-10
80
59
84
81
78
88
OSi
N
Cl
Me
Ph
Me
+N
R R' R
NHBzR' NHNHBz
706671R' T (oC) yield % e.e. %
CH3-10
-10
-10
80
59
84
81
78
88
R
CO2Me
CH3
Table 5: Enantioselective allylation of various aldehydes and hydrazones with
706671.
In addition to enantioselective allylation reactions, Leighton and
co-workers have extended this concept to the enantioselective crotyla-
tion of carbonyl compounds2 (Table 6). Importantly, these diamine
derived silacycles are bench-stable crystalline solids, providing the added
benefi t of simple reaction setup and purifi cation.
NSi
N
Cl
H
H
Br
Br
CH3
+O
R H
R
OH
CH3
R
OH
CH3
R yield % e.e. %
H3C
CH3
BnO
NSi
N
Cl
H
H
Br
Br
CH3
or or
B
A
Silane product
AB
AB
AB
1
2
12
12
12
8381
9798
7071
9697
8283
9699
AB
12
6752
9594
DBU
CH2Cl2, 0 oC
Table 6: Enantioselective crotylation of aldehydes.
References: (1) (a) Kinnaird, J. W. H.; Ng, P. Y.; Kubota, K.; Wang, X.; Leighton, J. L. J.Am.
Chem. Soc. 2002, 124, 7920. (b) Berger, R.; Duff , K.; Leighton, J. L. J. Am. Chem. Soc. 2004, 126,
5686. (2) Hackman, B. M.; Lombardi, P. J.; Leighton, J. L. Org. Lett. 2004, 23, 4375.
TO ORDER: Contact your local Sigma-Aldrich offi ce (see back cover), or visit Aldrich.com/chemicalsynthesis.Aldrich.com
18
Chiral Allyl and Crotylsilanes:
For a complete list of allylation reagents available from
Aldrich Chemistry, visit Aldrich.com/allylations
Selective Metalations using i-PrMgCl·LiCl and
s-BuMgCl·LiCl
While halogen-metal exchange reactions are among the most common
methods for preparing reactive organometallic reagents, Li-halogen
exchange reactions typically require low temperatures and off er limited
compatibility with other functionalities. On the other hand, Mg-halogen
exchange reactions require higher temperatures and are often prone to
elimination side reactions. To address these issues, Knochel and cowork-
ers have found that the use of salt additives increase both the rate and
the effi ciency of this Mg-halogen exchange reaction. The most eff ec-
tive reagents are generated with R-MgCl (R = i-Pr, s-Butyl) and 1.0 equiv
of LiCl. The increased reactivity of these aptly named TurboGrignards
may be due to the breakup of polymeric aggregates known to exist in
classical solutions of Grignard reagents. TurboGrignards allow for the
conversion of a variety of functionalized and highly sensitive substrates,
including those containing CO2R, CN, OMe, and halogen moieties, to
their corresponding functionalized organometallic derivatives. While rate
enhancements are observed with TurboGrignards, this increased reactiv-
ity does not have a negative impact on the overall scope of the reaction,
permitting transformations to occur in the presence of a broad range of
functional groups (Table 7).1
OSi
N
Cl
Me
706671
OSi
N
Cl
Me
719056
Ph
Me
Ph
Me
NSi
N
Cl
705098
H
H
Br
Br
NSi
N
Cl
704725
H
H
Br
Br
NSi
N
Cl
733075
H
H
Br
Br
NSi
N
Cl
733199
H
H
Br
Br
CH3CH3
Br
FG
MgCl LiCl
FG
•
(TurboGrignard)
FG = CO2R', CN, OMe, halogen
i-PrMgCl LiCl•
THF, -15 °C to 25 °CE
E
FG
656984
or heteroaryl halide
MgCl LiCl•
i-PrO O OO
Ph 80a
N
MgCl LiCl•Br
MgCl LiClN
S
•
N
AllylBr
N
S
OH
ElectrophileReagentEntry
2
3
Product IsolatedYield
93b
87
Allyl Bromide
PhCHO
PhCHO
1
aThe halogen-metal exchange was conducted in THF/DMPU.bGrignard was transmetalated with CuCN 2LiCl before addition of E.•
Ph
Table 7: Aryl/heteroaryl Grignard reagents prepared using i-PrMgCl·LiCl and reac-
tions with electrophiles.
Advantages of TurboGrignards:
Increased functional group compatibility• Mild reaction conditions• Minimal side reactions• Allows for the large-scale production of reactive • Grignard reagents
References: (1) Krasovskiy, A.; Knochel, P. Angew. Chem. Int. Ed. 2004, 43, 3333.
(2) P. Knochel, E P 1582 524 A1.
TurboGrignard Reagents from Aldrich:
For more information on these new reagents, visit
Aldrich.com/metalations
Sold in collaboration with
H3C
CH3
MgCl.LiCl
656984
H3CCH3
MgCl.LiCl
703486
Ready to scale up? For competitive quotes on larger quantities or custom synthesis, contact your local Sigma-Aldrich offi ce, or visit safcglobal.com.
19Organometallics
Organotrifl uoroborates as Coupling Partners in Suzuki-Miyaura ReactionsSuzuki-Miyaura cross-coupling reactions are some of the most common
methods for the formation of C–C bonds in organic chemistry. The use of
organotrifl uoroborate salts as boronic acid surrogates has lead to signifi -
cant advancement in the fi eld of Suzuki-Miyaura reactions. Trifl uorobo-
rates exhibit excellent functional group tolerance and stability towards
common reagents, in turn leading to a truly versatile class of reagents.1, 2
Our platform of trifl uoroborate salts is continually growing, with new
product introductions occurring regularly.
Benefi ts of Organotrifl uoroborates:
Stable tetracoordinate species• Less prone to protodeboronation• Air-and moisture-stable•
Potassium Vinyltrifl uoroborate as a Versatile Dianion PrecursorMolander and co-workers have developed a powerful strategy for the
production of a unique 1,2-dianion equivalent using potassium vinyl-
trifl uoroborate.1 This useful organotrifl uoroborate undergoes selective
hydroboration with 9-BBN to generate (3), a 1,2-dianion equivalent that
can then undergo a variety of selective transformations (Scheme 6).
BF3K
Potassium vinyltrifluoroborate
655228
BF3KB
9-BBN
3
Scheme 6: Hydroborated intermediate (3) as a 1,2-dianion equivalent.
This versatile 1,2-dianion equivalent undergoes sequential Suzuki-Miyaura
cross-coupling with a range of organic electrophiles, including aryl-,
heteroaryl-, and alkenyl halides (Table 8).
BF3K
1.) 9-BBN2.) Pd(OAc)2, DavePhos, KF,
3.) RuPhos, K2CO3,toluene/H2O
R' Br
R'' Br
R''R'
R'-Br R''-Br yield %
OMe
MeO BrN
Br OMe82
OMe
MeO Br
SCl O
H
84
O ClO
H
N
NBr
60
Br
OMe
MeO Br
74
Me
MeBr
N
Br OMe80
Me
OMe
MeO
N
OMe
OMe
MeOS
H
O
OMe
MeO
Me
Me
Me
N
OMe
N
NO
H
O
Table 8: Sequential Suzuki-Miyaura cross-couplings to build molecular complexity
from potassium vinyltrifl uoroborate.
References: Molander. G. A.; Sandrock, D. L. Org. Lett. 2009, 11, 2369.
Alkenyl Potassium Trifl uoroborates from Aldrich:
BF3K
655228
BF3K
684937
BF3K
723916
BF3K
720682
BF3K
683590
BF3K
720933
BF3K
720747
Br
CH3
CH3
H3C
H3CO
CH3
H3CCH3
CH3
H3C
TO ORDER: Contact your local Sigma-Aldrich offi ce (see back cover), or visit Aldrich.com/chemicalsynthesis.Aldrich.com
20
Ni-Catalyzed Cross-Coupling of
Heteroaryltrifl uoroborates with Unactivated
Alkyl Halides
Recently the lab of Professor Gary Molander disclosed a method for the
eff ective cross-coupling of air and moisture stable heteroaryltrifl uo-
roborates with unactivated alkyl halides.3 While previous methods for
this same transformation have been developed, still today a number of
shortcomings remain. Most notable is the need for excess organoboron
coupling partner, and the limited scope of organoboron reagents that
can be used for this transformation (generally restricted to aryl boronic
acids only). To address these issues, Molander has taken advantage of
the increased stability of organotrifl uoroborates as well as the increased
reactivity of Ni catalysts. Under the optimized conditions a range of
heteroaryltrifl uoroborates can be coupled effi ciently with both alkyl
bromides and iodides (Table 9).
OBF3K
or
N
BF3K+ Alkyl X
OAlkyl
or
N
Alkyl
NiBr2.glyme (10 mol %)
bathophenanthroline (10 mol %)LiHMDS (3 eq), s-BuOH
A
B
Alkyl-X
BnOBr
O
O
Br
ICl
Br
Br
I
Alkyl-Xyield % yield %
A, 80B, 76
A, 76B, 78
A, 84B, 63
A, 67B, 68
A, 63B, 68
A, 60B, 71
(X = Br, I)
Table 9: Cross-coupling of 2-benzofuranyl- and 4-pyridinyltrifl uoroborates with
various alkyl halides.
References: (1) Molander, G. A.; Ellis, N. Acc. Chem. Res. 2007, 40, 275.
(2) Molander, G. A.; Figueroa, R. Aldrichimica Acta 2005, 38, 49. (3) Molander, G. A.;
Argintaru, O. A.; Aron, I.; Dreher, S. D. Org. Lett. 2010, 24, 5783.
NNH
BF3K
711144
N
NKF3B
711098
N
BF3K
711101
SH3C CH3
BF3K
711136
NO
NKF3B
706116
NBr
BF3K
717517
NF
BF3K
717487
SBF3K
717509
NN
722588
O
KF3B
NBoc
BF3K
719420
Heteroaryltrifl uoroborates from Aldrich:
For a complete list of organotrifl uoroborates available from Aldrich
Chemistry, visit Aldrich.com/tfb
Materials ScienceMaterials Science
Nano-layers of metals, semiconducting and dielectric materials are
crucial components of modern electronic devices, high-effi ciency
solar panels, memory systems, computer chips and a broad variety of
high-performance tools.
The technique of choice for depositing nano-fi lms on various surfaces
is Atomic Layer Deposition (ALD), which uses consecutive chemical
reactions on a material’s surface to create nanostructures with
predetermined thickness and chemical composition (Figure 1).
Aldrich Materials Science off ers high-quality precursors for ALD safely
packaged in steel cylinders suitable for use with a variety of
deposition systems.
We continue to expand our portfolio of ALD precursors to include
new materials. For an updated list of our deposition precursors, please
visit aldrich.com/ald
Precursors for Atomic Layer DepositionHigh-Tech Solutions for Your Research Needs
(a)
(b)
Figure 1. Schematic of the ALD method based on sequential, self-limiting
surface reactions.
For additional vapor deposition precursors prepacked in cylinders, please contact us by email at [email protected]
Precursors Packaged for Deposition Systems
Atomic
No. Description Molecular Formula Form Prod. No.
Water packaged for use in deposition systems
H2O liquid 697125
13 Trimethylaluminum (CH3)3Al liquid 663301
14 (3-Aminopropyl)triethoxysilane H2N(CH2)3Si(OC2H5)3 liquid 706493
14 Silicon tetrachloride SiCl4 liquid 688509
14 Tris(tert-butoxy)silanol ((CH3)3CO)3SiOH solid 697281
14 Tris(tert-pentoxy)silanol (CH3CH2C(CH3)2O)3SiOH liquid 697303
22 Tetrakis(diethylamido)titanium(IV) [(C2H5)2N]4Ti liquid 725536
22 Tetrakis(dimethylamido)titanium(IV)
[(CH3)2N]4Ti liquid 669008
22 Titanium tetrachloride TiCl4 liquid 697079
22 Titanium(IV) isopropoxide Ti[OCH(CH3)2]4 liquid 687502
30 Diethylzinc (C2H5)2Zn liquid 668729
31 Triethylgallium (C3H2)3Ga liquid 730726
31 Trimethylgallium Ga(CH3)3 liquid 730734
39 Tris[N,N-bis(trimethylsilyl)amide]yttrium
[[(CH3)3Si]2N]3Y solid 702021
40 Bis(methyl-η5-cyclo-pentadienyl)methoxymethylzirconium
Zr(CH3C5H4)2CH3OCH3 liquid 725471
Atomic
No. Description Molecular Formula Form Prod. No.
40 Tetrakis(dimethylamido)zirconium(IV)
[(CH3)2N]4Zr solid 669016
40 Tetrakis(ethylmethylamido)zirconium(IV)
C12H32N4Zr liquid 725528
44 Bis(ethylcyclopentadienyl)ruthenium(II)
C7H9RuC7H9 liquid 679798
72 Bis(methyl-η5-cyclopentadienyl) dimethylhafnium
Hf[C5H4(CH3)]2(CH3)2 solid 725501
72 Bis(methyl-η5-cyclopentadienyl)methoxymethylhafnium
HfCH3(OCH3)[C5H4(CH3)]2 liquid 725498
72 Tetrakis(dimethylamido)hafnium(IV)
[(CH3)2N]4Hf low-melting solid
666610
72 Tetrakis(ethylmethylamido)hafnium(IV)
[(CH3)(C2H5)N]4Hf liquid 725544
73 Tris(diethylamido)(tert-butylimido)tantalum(V)
(CH3)3CNTa(N(C2H5)2)3 liquid 668990
74 Bis(tert-butylimino) bis(dimethylamino)tungsten(VI)
((CH3)3CN)2W(N(CH3)2)2 liquid 668885
78 Trimethyl(methylcyclo-pentadienyl)platinum(IV)
C5H4CH3Pt(CH3)3 low-melting solid
697540
TO ORDER: Contact your local Sigma-Aldrich offi ce (see back cover), or visit Aldrich.com/chemicalsynthesis.Aldrich.com
22
Indoles and Indole Isosteres
Substituted indoles have frequently been referred to as “privileged struc-
tures” since they are capable of binding to multiple receptors with high
affi nity, and thus have applications across a wide range of therapeutic
areas.1 However, recent publications often demonstrate the need for a
researcher to attenuate or amplify the activity of their target compound
without altering the steric bulk of the structure; thus, isosteres of the in-
dole ring have proven very valuable to synthetic and medicinal chemists.
The azaindole and indazole moieties diff er only by the addition of an
extra ring nitrogen, and thus exhibit excellent potential as bioisosteres
of the indole ring system. Although more rare in nature, interest in these
structures has surged over the past decade and they comprise essential
subunits in many pharmaceutically relevant compounds.2,3 Indazoles
have been widely reported to display signifi cant activity as antifungals,
anti-infl ammatory agents, antiarrhythmic agents, analgesics, and nitric
oxide synthase inhibitors.2a Of the various azaindoles, 7-azaindoles are of
particular interest because of their ability to mimic purines in their roles
as hydrogen-bonding partners. Similarly, imidazopyridines have proven
eff ective as purine mimics in several recent studies.4
When two ring nitrogens are added to the indole subunit, it results in
7-deazapurines, an important class of compounds found in a wide vari-
ety of biological niches. Various ribonucleosides containing 7-deazapu-
rines demonstrate a broad spectrum of biological activity, even at
nanomolar concentrations.5
Aldrich is pleased to off er a wide variety of these useful building blocks
for your research.
New Indoles
For a complete list of indoles from Aldrich Chemistry, visit
Aldrich.com/indole
NH
H2N
NH
H3CO
F3CNH
CH3
HO
NH
Br O
OCH3
NH
H3CO
733040 723789 716529
724718 724378
Building BlocksMark RedlichProduct [email protected]
New Azaindoles
For a complete list of azaindoles available from
Aldrich Chemistry, visit Aldrich.com/azaindole
New Indazoles
For a complete list of indazoles available from
Aldrich Chemistry, visit Aldrich.com/indazole
New Imidazopyridines
685755 721050 732141
N
N
NH2
N
N
Br
NN
Br
For a complete list of imidazopyridines available from
Aldrich Chemistry, visit Aldrich.com/imidazopyridine
New Purines and Deazapurines
For a complete list of purines and deazapurines available from Aldrich
Chemistry, visit Aldrich.com/purine
NH
N
Br
N
NH
H3CO N
NH
OSiH3CCH3
CH3
732168 707953 723770
NNH
Br
NN
CH3
Br
717525 717215
722332 717592
N
N NH
NH2
N
N N
HN
NH2
Cl
Ready to scale up? For competitive quotes on larger quantities or custom synthesis, contact your local Sigma-Aldrich offi ce, or visit safcglobal.com.
23Building Blocks
Thiazoles
Thiazoles have been frequently discovered as a vital component of novel
and structurally diverse natural products that exhibit a wide variety of
biological activities. Their presence in peptides, their ability to bind to
proteins, DNA, and RNA, as well as the exceptional range of antitumor,
antiviral, and antibiotic activities of thiazole-containing compounds have
directed numerous synthetic studies and new applications. The thiazole
ring has been identifi ed as a central feature of myriad natural products,
and synthetic variants have been pursued by pharmaceutical companies
due to their signifi cant activity.6
Additionally, thiazoles are important features of various peptides and
pseudopeptides that function as potent antineoplastic agents,7 or have
demonstrated signifi cant cytotoxicity or antibiotic properties.8 Thiazoles
can also serve as a protected formyl group that can be liberated in the
late stages of a complex natural product synthesis.9
New Thiazoles
For a complete list of thiazoles available from
Aldrich Chemistry, visit Aldrich.com/thiazole
Other New Building Blocks
N
S NH
Boc N
S Br
t-BuN
S NH2
H3C
O
HO
N
SH3C NH2
BrN
S
BrOH3C
O N
723649 724122 722375
717851 717258
718076
729442
725293
723282
722316
722340
722464
721530
722359
OHCl Br
BocN
HN
BocCH3
O
OO
CH3
O
OCH3 O OH
O
NH
O
O CH3
O
NH
NO CH3
O
NN
CH3
CH3
O
HO
NN
OH
O
CH3
H3C
724890 722367 724149
NH2
NH2
NOH
OH
H3CO NH2
SO
OCl
Cl NO2
Other New Building Blocks — cont'd
For a comprehensive list of Building Blocks available form Aldrich
Chemistry, visit Aldrich.com/bb
References: (1) Horton, D. A. et al. Chem. Rev. 2003, 103, 893 and references therein.
(2) Recent reviews of indazoles: a) Schmidt, A. et al. Eur. J. Org. Chem. 2008, 4073. (b)
Cerecetto, H. et al. Mini-Rev. Med. Chem. 2005, 5, 869. (c) Stadlbauer, W.; Camp, N. In
Science of Synthesis: Houben-Weyl Methods of Molecular Transformations; Bellus, D., Ley,
S. V., Noyori, R., Regitz, M., Schaumann, E., Shinkai, E., Thomas, E. J., Trost, B. M., Reider, P.
J., Eds.; Thieme: Stuttgart, Germany, 2002; Vol. 12, p 227. (3) Recent reviews of azaindoles:
(a) Popowycz, F. et al. Tetrahedron 2007, 63, 1031. (b) Popowycz, F. et al. Tetrahedron
2007, 63, 8689. (c) Song, J. J. et al. Chem. Soc. Rev. 2007, 36, 1120. (4) Huang, W.-S. et al.
J. Med. Chem. 2010, 53, 4701. (b) Buckley, G. M. et al. Bioorg. Med. Chem. Lett. 2008, 18,
3656. (c) Buckley, G. M. et al. Bioorg. Med. Chem. Lett. 2008, 18, 3291. (5) (a) Suhadolnik,
R. J. Pyrrolopyrimidine Nucleosides in Nucleoside Antibiotics; Wiley-Interscience: New York,
1970; 298 and references therein. (b) Kasai, H. et al. Biochemistry 1975, 14, 4198. (c) Nauš,
P. et al. J. Med. Chem. 2010, 53, 460. (6) Jin, Z. Nat. Prod. Rep., 2005, 22, 196. (7) Pettit, G. R.
et al. J. Am. Chem. Soc. 1987, 109, 6883. (8) (a) Davidson, B. S. Chem. Rev. 1993, 93, 1771.
(b) Fusetani, N.; Matsunaga, S. Chem. Rev. 1993, 93, 1793. (c) Wipf, P. Chem. Rev. 1995, 95,
2115. (d) Aulakh, V. S.; Ciufolini, M. A. J. Org. Chem. 2009, 74, 5750. (9) Dondoni, A.; Marra,
A. Chem. Rev. 2004, 104, 2557.
722073
722022
725048
720321
715646
720844
720917
714372
724165
697966
719722
730343
O
H
OHNO2
H3CO
N
HN
CH3
BocN
OO
CH3
CH3
N
O H
Boc
NN
N
ClON CH3
O
H
NN
NH2
N
NCl
ClN
N
Br
Br Br
N
N
Cl
NH2
O2N
N
N
CF3O
H3CO
ClN
N
S
NH2
727598
724254
722243
694770
722251
724157
O
NNH2
O
NH3CO
F
SO
OCl
O
O
OH
SO
OClCl
TO ORDER: Contact your local Sigma-Aldrich offi ce (see back cover), or visit Aldrich.com/chemicalsynthesis.Aldrich.com
24
Cross-Couplings in Water
Conducting transition metal-catalyzed cross-coupling chemistry in water
instead of organic solvent has a number of potential benefi ts in terms of
cost, environmental impact, safety, and impurity profi les. Increasing focus
on the “green-ness” of chemical processes has further promoted recent
developments in this fi eld. The actual means of implementing reactions
in water, however, especially at room temperature and for water-insolu-
ble organic substrates, has not always been clear. One solution that has
been applied to a broad range of transition metal-catalyzed processes is
the use of small amounts of a nanomicelle-forming amphiphile in water,
which provides a lipophilic medium in which cross-coupling reactions
can take place.
Micellar Catalysis
Beginning in 2008, Lipshutz et al. published a series of papers demon-
strating the viability of surfactant promoted, transition metal-catalyzed
chemistry in water at room temperature. Using a variety of commercially
available surfactants, a number of palladium- and ruthenium-catalyzed
processes were found to be amenable to mild, room temperature reac-
tions in water. Products can be recovered from the aqueous phase using
standard extraction procedures and in high isolated yields.
Synthetic ReagentsTroy Ryba, Ph.D.Product [email protected]
TPGS–750–M: Second Generation Amphiphile for Organometallic Chemistry in Water @ RT
TPGS–750–M: A Second Generation
Amphiphile
Lipshutz and co-workers have recently developed a second
generation technology to their original PTS-enabling surfactant based
on a polyoxyethanyl-α-tocopheryl succinate derivative, TPGS-750-M
(733857) (Figure 1). This designer surfactant is composed of a lipophilic
α-tocopherol moiety and a hydrophilic PEG-750-M chain, joined by an
inexpensive succinic acid linker, and spontaneously forms micelles upon
dissolution in water. The balance and composition of TPGS-750-M’s
lipophilic and hydrophilic components has been tailored to promote a
broader array of chemistry in water more effi ciently than that seen in PTS.
Furthermore, this new, more practical surfactant can be readily substi-
tuted for older amphiphiles, usually with equal or greater
effi ciency in terms of both yield and reaction times.
Figure 1: TPGS–750–M.
O
O
3
OO
OO
OMe
16
*Special thanks to Professor Bruce Lipshutz, Zarko V. Boskovic and Alex R. Abela of
University of California, Santa Barbara for contributing this article on TPGS-750-M.
Ready to scale up? For competitive quotes on larger quantities or custom synthesis, contact your local Sigma-Aldrich offi ce, or visit safcglobal.com.
25Synthetic Reagents
Olefi n Metathesis
Employing the second generation Grubbs catalyst (2 mol %) a variety of
lypophillic substrates successfully undergo ring-closing or cross-meta-
thesis in water at room temperature to produce high isolated yields of the
desired products (Scheme 1). Reactions were conducted in 2.5% TPGS-
750-M/water, with yields equal to or slightly better than those performed
using various other surfactant-water combinations.
O
OOTBS
Grubbs-2 (2 mol %)
2.5% TPGS-750-M, water22 oC, 12 hOTBS
O
O
91%
NTs
Grubbs-2 (2 mol %)
2.5% TPGS-750-M, water22 oC, 12 hN
Ts88%
Scheme 1: Selected olefi n metathesis.
Pd-Catalyzed Cross-Coupling Reactions
A variety of widely used palladium-catalyzed cross-coupling reactions can
now be run under mild room temperature conditions in water with TPGS-
750-M, using a variety of commercially available palladium complexes
and ligands. These transformations, including Suzuki-Miyaura, Sono-
gashira, Buchwald-Hartwig aminations, and Heck, are amongst the most
heavily used bond forming reactions, both industrially and academically
(Scheme 2).
Scheme 2: Selected Pd-catalyzed cross coupling reactions.
Operationally extremely simple Suzuki-Miyaura reactions using micellar
catalysis and bis(di-tert-butylphosphino)ferrocene palladium chloride
complex provide access to highly sterically congested substrates at room
temperature using triethylamine as base.
B(OH)2
OMeBr
OMe
88%
Br
99%
Br NH2HN
93%
+
+
+
2 mol % Pd(dtbpf)Cl2Et3N (3 equiv)
2% TPGS-750-M, water20 °C, 24 h
KOH (1.5 equiv) 2% TPGS-750-M, water
22 oC, 19 h
[(allyl)PdCl]2 (0.5 mol %)
Takasago's cBRIDP (2 mol %)
3% TPGS-750-M, water 22 oC, 21 h
PdCl2(CH3CN)2 (1 mol %)X-Phos (2.5 mol %)
Et3N (2 eq.)
OMeI
OMe
95%
+ 5% TPGS-750-M, water
22 oC, 12 h
(PtBu3)2Pd (2 mol %)
Et3N (3 equiv)
Sonogashira reactions and Buchwald-Hartwig aminations are also
amenable to reaction in water with TPGS-750-M using the palladium
chloride/X-Phos combination in the former, and allyl palladium chlo-
ride/cBRIDP in the latter (Figure 2).
Figure 2: Selected ligand examples.
Heck cross-couplings with aryl iodides can be successfully performed
using Pd(P(t-Bu)3)2 as the palladium source in the bulk aqueous environ-
ment containing TPGS-750-M (5 wt. %), obviating the need for high
temperatures commonly associated with Heck reactions.
Zinc-mediated Negishi-like couplings between aryl and alkyl
halides can be performed in aqueous TPGS-750-M (Scheme 3).
Under these conditions, typically highly moisture sensitive organozinc
halides are formed in situ from an alkyl halide and zinc dust, and react
with an aryl halide under palladium catalysis. With the aid of a surfac-
tant and a stabilizing ligand for RZnX, such as tetramethylethylenedi-
amine (TMEDA), this entire process takes place in water, leading to a
variety of primary and secondary alkyl-substituted aromatics. The choice
of catalyst is crucial for the success of the reaction; Pd(Amphos)2Cl2
(Bis(di-tert-butyl (4-dimethylaminophenyl)phosphine) palladium(II)
chloride) was found to be the optimal catalyst.
Scheme 3: Selected Negishi-like cross-coupling example.
C–H Activation Reactions
Cationic palladium in combination with stoichiometric oxidant benzo-
quinone and silver nitrate successfully catalyzes ortho-functionalization
of a variety of aryl acetamides in water at room temperature using this
amphiphile (Scheme 4).
Scheme 4: Selected C–H activation reaction.
Reference: Lipshutz, B. H.; Ghorai, S. Aldrichimica Acta 2008, 41, 59.
For more information on TPGS–750–M, visit
Aldrich.com/tpgs750m
i-Pr
i-Pr
PCy2
i-PrMe
P(t-Bu)2Ph
Ph
X-Phos cBRIDP
685151638064
Br
Br
EtO2CEtO2C
0.5% Pd(Amphos)2Cl2TMEDA (1 equiv)Zn dust (3 equiv)
2% TPGS-750-M, water, rt
80%
+
[Pd(MeCN)4](BF4)2 (10 mol %)BQ, AgNO3
OMe
HN
CO2n-Bu
2% TPGS-750-M, water, rt
HN
O
OMe
O
On-Bu
H
O+
83%
TO ORDER: Contact your local Sigma-Aldrich offi ce (see back cover), or visit Aldrich.com/chemicalsynthesis.Aldrich.com
26
Stable Isotope Labeled
Reagents from ISOTEC®
Stable isotope containing compounds are used in a variety of applica-
tions including tracers in clinical studies,1 labeled amino acids for use in
protein quantifi cation2 and standards for metabolic research.3 Historically,
the introduction of stable isotopes has been a diffi cult, time consum-
ing and costly process requiring the specialized skill of a stable isotope
chemist. The reagents below were designed to introduce stable isotopes
using standard chemical procedures.
13C Labeled Olefi nation Reagents
The 13C labeled olefi nation reagents4 were developed to simplify the
labeling process by providing a set of substrates ready to be incorpo-
rated into precedented chemical syntheses.5 These olefi nation reagents
provide access to a fi xed 13C label within the alkene as well as site-vari-
able deuterium incorporation (Scheme 1). This methodology effi ciently
provides a densely labeled compound ready for further functionalization.
PhS
13CH2
O O
K2CO3, CH2OH2O/DMSO
1. K2CO3H2O/DMSO
2. RI, 3. R'CHO
K2CO3, CD2OH2O/DMSO
K2CO3, CD2OD2O/DMSO
K2CO3, CH2OD2O/DMSO
PhS
13CH
O O
CH2
PhS
13C
O O
R
R'
PhS
13C
O O
DD
PhS
13C
O O
CH2
D
PhS
13CH
O O
DD
P
O
OEt
OEt
D
Scheme 1: Olefi nation reagents labeling strategies.
The availability of all three sulfur oxidation states allows control of the
reaction conditions including base type and strength as well as access to
a preferred sulfur removal strategy.6 By providing access to mild reaction
conditions, fewer compatibility issues arise between reaction conditions,
olefi nation reagent and substrate.
New 13C Labeled Olefi nation Reagents
715832 715816715824
PhS
13CH2
O O
P
O
OEt
OEtPhS
13CH2
O
P
O
OEt
OEtPhS
13CH2
P
O
OEt
OEt
Stable IsotopesLisa Roth, Ph.D.Product [email protected]
D and/or 13C Labeled 1,3–Dithiane Unlabeled 1,3–Dithiane is a versatile reagent able to act as an acyl anion
equivalent when submitted to Corey-Seebach reaction conditions.7
This well known chemistry can also be carried out when 1,3–Dithiane
is labeled at the 2 position providing labeled and protected aldehydes,
ketones, α-hydroxyketones, 1,2–diketones and α-keto acid derivatives.
Deprotection can be facilitated using standard methods to give the
appropriately labeled substrates (Scheme 2).8
Scheme 2: 1,3–Dithiane for the introduction of D and/or 13C.
New Labeled D and/or 13C 1,3–Dithiane
S
13CS
716111S
13CS D
D
716073
HH
References: (1) Brown, L. D.; Cheung, A.; Harwood, J. E. F.; Battaglia, F. C.; J. Nut. 2009,
139, 1649. (2) Hanke, S.; Besir, H.; Oesterhelt, D.; Mann, M.; J. Proteome. Res. 2008, 7, 1118.
(3) Li, C.; Hill, R.W.; Jones, A. D.; J. Chrom. B 2010, 878, 1809. (4) Licensed from Highlands
Stable Isotopes Corp. (5) a) Capela, R.; Oliveira, R.; Gonçalves, L. M.; Domingos, A; Gut, J.;
Rosenthal, P. J.; Lopes, F.; Moreira, R.; Biorg. Med. Chem. Lett. 2009, 19, 3229. (b) Verissimo,
E.; Berry, N.; Gibbons, P.; Cristiano, M. L. S.; Rosenthal, P. J.; Gut, J.; Ward, S. A.; O’Neill, P. M.;
Biorg. Med. Chem. Lett. 2008, 18, 4210. (6) a) Beye, G. E.; Ward, D. E.; J. Am. Chem. Soc. 2010,
132, 7210. (b) Pellissier, H.; Tetrahedron 2006, 62, 5559. (7) a) Seebach, D.; Corey, E. J.; J. Org.
Chem. 1975, 40, 231. (b) Mundy, P. B.; Ellerd, M. G.; Favaloro, F. G., Jr.; Name Reactions and
Reagents in Organic Synthesis, 2nd ed.; Wiley & Sons: New York, 2005; p 186, 745. (8) Wutz, P.
G. M.; Greene, T. W.; Protection for the Carbonyl Group, Greene’s Protective Groups in Organic
Synthesis, 4th ed.; Wiley & Sons: New York, 2007; p 482.
For more information on these products avaliable from
Aldrich Chemistry, visit Aldrich.com/sinext
or contact:
Stable Isotope Technical Services
Phone: (937) 859-1808
(800) 448-9760 (US and Canada)
Fax: (937) 859-4878
E-mail: [email protected]
S
13CS R
R
O13C
R'R R13C
R'
O OH
R13C R'
O
OR
13C OHO
O
R = H or D
For more information on our
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TO ORDER: Contact your local Sigma-Aldrich offi ce (see back cover), or visit Aldrich.com/chemicalsynthesis.Aldrich.com
28
Aldrich NMR Solvents
Challenge Us... and see why our Quality is
Unsurpassed!
High quality NMR solvents are essential for satisfying the most rigorous
demands of NMR-based research and analyses. At Aldrich, we are pas-
sionate about providing this high level of quality to our customers and
work continuously to meet these requirements. We off er the widest
range of NMR solvents with the highest isotopic enrichment available
along with excellent chemical purity. We consistently review and im-
prove our methods for solvent purifi cation and for the reduction of water
content in our already high quality NMR solvents. All of our NMR solvents
undergo thorough quality control testing during the manufacturing and
packaging processes to verify that the product quality is preserved.
Most deuterated NMR solvents readily absorb moisture. To minimize the chance of water contamination, use carefully dried NMR tubes and handle NMR solvents in a dry atmosphere.
How to Obtain a Nearly Moisture-free Surface
1. Dry glassware at ~150 °C for 24 hours and cool under an inert atmosphere.
2. Rinse the NMR tube with the deuterated solvent prior to preparing the sample. This allows for a complete exchange of protons from any residual moisture on the glass surface.
3. For less demanding applications, a nitrogen blanket over the sample prepara-tion setup may be adequate.
How to Avoid Sources of Impurities and Chemical Residues
1. Use clean, dry glassware and PTFE accessories.
2. Use a vortex mixer instead of shaking the tube contents. The latter action can introduce contaminants from the NMR tube cap.
3. Residual chemical vapor from equipment can be a source of impurities; residual acetone in pipette bulbs is a common example.
How to Remove Solvent Residue
1. Protonated solvent residue can be removed by co-evaporation.
2. Use a small quantity of the desired deuterated solvent, a brief high vacuum drying (5–10 min), and then prepare the NMR sample.
3. Solvents such as chloroform-d, benzene-d6, and toluene-d8, also remove residual water azeotropically.
How to Avoid TMS Evaporation
1. Extended storage of TMS-containing solvents can lead to some loss of TMS. Storing these solvents in Sure/Seal™ bottles virtually eliminates such a loss.*
2. Purchase TMS-containing solvents in single-use ampules.
* To dispense the product from Sure/Seal™ bottle or septum vials, use standard syringe needle techniques. For details and recommended procedures, please refer to Aldrich Technical Bulletin AL-134 or visit our Web site at Aldrich.com.
Use and Handling of NMR Solvents
Stockroom ReagentsTodd HalkoskiMarket Segment [email protected]
Aldrich also off ers unparalleled convenience and service. Our award-
winning website allows for quick product searching, easy ordering, and a
wealth of valuable tools and information to aid your research eff orts. We
also off er on-site stocking programs for NMR solvents so they are available
to you for immediate use. If you have technical questions, you can feel
comfortable knowing our knowledgeable and well-trained technical
service specialists can answer your toughest questions.
Try our NMR Solvents today to see their high quality
for yourself.
For a complete listing of all NMR-related products and information,
visit Aldrich.com/nmr
Ready to scale up? For competitive quotes on larger quantities or custom synthesis, contact your local Sigma-Aldrich offi ce, or visit safcglobal.com.
29Stockroom Reagents
Specialty NMR Solvents
Aldrich off ers a wide range of high purity deuterated solvents for the
NMR community. In addition, we also off er various specialty solvents for
more demanding applications. Whether you need the highest enriched
deuterium oxide available, or solvents with a reduced HOD peak, we
have what you need.
“Special HOH” Solvents
When customers requested NMR solvents with a suppressed HOD peak
we listened, and developed NMR solvents called “Special HOH”. These
solvents have an HOD peak which is less than 1% of the HOH peak, to
minimize potential exchange with an analyte. “Special HOH” solvents also
meet our standard water specifi cation for NMR solvents.
1H-NMR Spectrum of DMSO-d6 “Special HOH”
Anhydrous NMR Solvents
When water content is of paramount concern, try our anhydrous
solvents that contain reduced levels of water.
“Extra” Enriched D2O
With an enrichment of 99.994 atom % D, this is the highest enriched
deuterium oxide available.
For additional information visit us at Aldrich.com/nmr
or contact:
Stable Isotope Technical Services
Phone: (937) 859-1808
(800) 448-9760 (US and Canada)
Fax: (937) 859-4878
E-mail: [email protected]
11.5 11.0 10.5 10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 –0.5ppm
2.5 2.4ppm
3.3ppm
HOH
DMSO-d6 residual peak
HOD
Deuterium oxide, Extra, 99.994 atom % D
613398-10G serum bottle 10 g
613398-50G serum bottle 50 g
Acetonitrile-d3, 99.8 atom % D, Anhydrous (water < 10 ppm)
569550-10X1ML ampule 10 x 1 mL
Benzene-d6, 99.6 atom % D, Anhydrous (water < 10 ppm)
570680-50G glass bottle 50 g
Chloroform-d, 99.8 atom % D, Anhydrous (water < 10 ppm)
570699-50G glass bottle 50 g
Dimethyl sulfoxide-d6, 99.9 atom % D, Anhydrous (water < 50 ppm)
570672-50G glass bottle 50 g
569585-5X1ML ampule 5 x 1 mL
569585-10X1ML ampule 10 x 1 mL
Methanol-d4, 99.8 atom % D, Anhydrous (water < 50 ppm)
570729-50G glass bottle 50 g
569534-5X1ML ampule 5 x 1 mL
569534-10X1ML ampule 10 x 1 mL
Toluene-d8, 99.6 atom % D, Anhydrous (water < 10 ppm)
570710-50G glass bottle 50 g
Acetonitrile-d3, 99.8 atom % D, "Special HOH"
699543-10G glass bottle 10 g
699543-25G glass bottle 25 g
699543-50G glass bottle 50 g
Dimethyl sulfoxide-d6, 99.9 atom % D, "Special HOH"
612324-25G glass bottle 25 g
612324-50G glass bottle 50 g
612324-100G glass bottle 100 g
716731-10x0.75ML ampule 10 x 0.75 mL
716731-10ML serum vial 10 mL
716731-50ML serum vial 50 mL
Data acquired on a Varian 400 MHz instrument.
TO ORDER: Contact your local Sigma-Aldrich offi ce (see back cover), or visit Aldrich.com/chemicalsynthesis.Aldrich.com
30
Inert Atmosphere Glove-Boxes
Sigma-Aldrich® off ers a wide range of Plas-Labs™ glove boxes for most
oxygen and moisture-sensitive applications .
The boxes are manufactured with a clear, one piece acrylic top and a
molded base section. Gaskets are double layered for a reliable, airtight
seal. The 8 in. ports with ambidextrous Hypalon® glove with SS O-rings
give easy access to all parts of the glove box. The transparent transfer
chamber has an adjustable vacuum gauge.
Nitrogen Dry Box
The Plas-Labs™ nitrogen Dry Box is a completely enclosed chamber
designed for working in nitrogen, argon and plasma-type atmospheres
and ideal for handling oxygen sensitive materials.
Drying train removal without disturbing internal atmosphere• Two vacuum/pressure pumps to speed purging.• Fluorescent light system with illuminated controls•
Single-station model - Internal H×W×D - 26 in.×41 in.×26 in.
Z562920 AC input 120 V
Z563285 AC input 240 V, Euro plug
Z562939 AC input 240 V, UK plug
Multi-station model - Internal H×W×D - 28 in.×60 in.×38 in.
Z562947 AC input 120 V
Z563293 AC input 240 V, Euro plug
Z562955 AC input 240 V, UK plug
Labware NotesPaula FreemantleProduct [email protected]
Basic Glove Box
The Plas-Labs Basic glove
boxes are engineered to
fi t general laboratory iso-
lation applications. They
can be easily modifi ed
for specifi c uses and are
very handy for isolating
sensitive research studies
from a hostile exterior
environment.
These economical units are compact, portable, lightweight and
self-contained.
Three tier suspended clear acrylic shelves • White leveling tray for transferring the transfer chamber.• Four purge valves• Multiple electrical outlet strip•
Single-station model - Internal H×W×D - 26 in.×41 in.×28 in.
Z563013 AC input 120 V
Z563307 AC input 240 V, Euro plug
Z563021 AC input 240 V, UK plug
Multi-station model - Internal H×W×D - 28 in. × 60 in. × 38 in.
Z563048 AC input 120 V
Z563315 AC input 240 V, Euro plug
Z563056 AC input 240 V, UK plug
Ready to scale up? For competitive quotes on larger quantities or custom synthesis, contact your local Sigma-Aldrich offi ce, or visit safcglobal.com.
31Labware Notes
Eliminating Static
from Glove Boxes
Static in plastic glove boxes
and bags can be a problem in
many applications. The anti-
static ionizer from Plas-Labs™
is an eff ective way to eliminate
all static charges within 36
inches (90 cm) of unit.
Ion balance adjustment• Compact footprint• Virtually maintenance free•
Z563064 120 V
Z563072 240 V, UK plug
Z563323 240 V, Euro plug
For more information about these products or to place an order visit
Aldrich.com
The AtmosBag™
An Economical Solution for ControlledAtmosphere Applications. AtmosBag is a fl exible, infl atable
polyethylene chamber with built-in
gloves that lets you work in a totally
isolated and controlled environ-
ment. Our customers use it for a
wide variety of applications from
providing an emergency isolation environment for inspecting unknown
materials to the transfer of air- and moisture-sensitive materials when
sampling or weighing. AtmosBag even permits weighing operations
inside a fume hood for added safety. Air currents that would interfere with
weighing are eliminated inside of AtmosBag.
Z106089 Two-hand, non-sterile, size L, Tape-seal
Z108405 Four-hand, non-sterile, Tape-seal
Z112828 Two-hand, non-sterile, size M, Tape-seal
Z112836 Two-hand, non-sterile, size S, Tape-seal
Z118354 Two-hand, sterile, size L, Tape-seal
Z118362 Two-hand, sterile, size M, Tape-seal
Z118370 Two-hand, sterile, size S, Tape-seal
Z530204 Two-hand, size S, Zipper-lock
Z530212 Two-hand, size M, Zipper-lock
Z530220 Two-hand, size L, Zipper-lock
Z555525 Four-hand, Zipper-lock
Full details can be found in our Technical Bulletin AL 211 which can be
downloaded from Aldrich.com
NMR Tube Holders
Unbreakable, NMR tube car-
rier provides protection for
the tube and lab personnel
when transporting samples.
The clear, shatter-resistant
polycarbonate case allows
for visual sample identifi ca-
tion and inspection prior
to opening. Natural rubber
plugs on both ends of the
case provide impact absorp-
tion if accidentally dropped. NMR tubes are held securely in place inside
the PC case by the bottom loading rubber plug. Carrier holds one 5 mm
diameter tube, 7 or 8 in. L.
Z567078-5EA
News and Innovation
Chemrus® Disposable Filter Funnels
Convenient and inexpensive, these disposable fi lter funnels have
polypropylene bodies with tapered stems that fi t 7/10 joints with-
out seals. The funnels are available in two styles, Buchner and Hirsch,
and a choice of 10 micron polyethylene frit, Celite, or perforated
plate for use with fi lter paper.
Maximum use temperature is 110 °C. Order vacuum adapters, fi lter
paper, vials and 20–400 to 24–400 vial connector separately not
given below.
Cat. No. Style Filter type Capacity (mL)
Z679798 Buchner PE frit, 10 micron 18
Z679801 Buchner PE frit, 10 micron 40
Z679828 Buchner PE frit, 10 micron 110
Z679860 Buchner Celite® (0.5g) 18
Z679860 Buchner Celite® (1.5g) 40
Z679836 Hirsch Perforated Plate 20
Z679844 Hirsch Perforated Plate 60
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