Upload
others
View
2
Download
0
Embed Size (px)
Citation preview
„BABES-BOLYAI” UNIVERSITY CLUJ-NAPOCA
FACULTY OF CHEMISTRY AND CHEMICAL
ENGINEERING
Organic Chemistry Department
Ph.D. THESIS
ABSTRACT
CCoonnttrriibbuuttiioonnss ttoo tthhee SSyy nntthheessiiss ooff NNeeww FFuunnccttiioonnaalliizzeedd
QQuuiinnuucclliiddiinneess UUssiinngg TTwwoo SSeemmii--NNaattuurraall CCiinncchhoonnaa
AAllkkaallooiiddss aass PPrreeccuurrssoorrss ((QQuuiinnccoorriinnee aanndd QQuuiinnccoorriiddiinnee))
aanndd ttoo tthhee CCoonnffoorrmmaattiioonnaall AAnnaallyy ssiiss ooff SSoommee 11,,33--
DDiiooxxaannee DDeerriivv aattiivv eess
Scientific Adviser Ph.D. Student
Prof. dr. ION GROSU STEFANIA TÖTÖS
CLUJ-NAPOCA
2003
„BABES-BOLYAI” UNIVERSITY CLUJ-NAPOCAFaculty of Chemistry and Chemical Engineering
Organic Chemistry Department
STEFANIA TÖTÖS
CCoonnttrriibbuuttiioonnss ttoo tthhee SSyynntthheessiiss ooff NNeeww FFuunnccttiioonnaalliizzeedd
QQuuiinnuucclliiddiinneess UUssiinngg TTwwoo SSeemmii--NNaattuurraall CCiinncchhoonnaa AAllkkaallooiiddss aass
PPrreeccuurrssoorrss ((QQuuiinnccoorriinnee aanndd QQuuiinnccoorriiddiinnee)) aanndd ttoo tthhee
CCoonnffoorrmmaattiioonnaall AAnnaallyyssiiss ooff SSoommee 11,,33--DDiiooxxaannee DDeerriivv aattiivv eess
Ph.D. THESIS
ABSTRACT
Scientific AdviserProf. dr. ION GROSU
JURY
PRESIDENT
Prof. Univ. Dr. LUMINITA SILAGHI-DUMITRESCU – Dean of the Faculty of Chemistry
and Chemical Engineering, Universitatea “BABES-BOLYAI” Cluj-Napoca
REVIEWERS
Prof. Univ. Dr. MANFRED FILD – Technische Univesität Braunschweig (Germany)
Prof. Univ. Dr. GÉRARD PLÉ – Université de Rouen, IRCOF (France)
Priv. Doz. Dr. CARSTEN THÖNE – Technische Univesität Braunschweig (Germany)
Prof. Univ. Dr. SORIN ROSCA – Universitatea “POLITEHNICA” Bucuresti
Prof. Univ. Dr. SORIN MAGER – Universitatea “ BABES-BOLYAI” Cluj-Napoca
Defence: 28 October 2003
2
CONTENTS
PART A1. Introduction
2. The Synthesis and Functionalization of 10,11-didehydro-Quincorine and
10,11-didehydro-Quincoridine2.1. Synthesis of 10,11-didehydro-Quincorine and 10,11-didehydro-
Quincoridine2.2. Sonogashira Cross-Coupling Reactions of 10,11-didehydro-Quincorine and 10,11-didehydro-Quincoridine2.3. Synthesis of (E)-and (Z)-Chloroenynes as well as (E)- and (Z)- Enediynes from 10,11-didehydro-Quincorine and 10,11-didehydro- Quincoridine2.4. Eglinton Reaction of 10,11-didehydro-Quincorine and 10,11-didehydro-
Quincoridine2.5. Addition of Terminal Alkynes 10,11-didehydro-Quincorine and 10,11- didehydro-Quincoridine to Internal Alkynes
3. [2+2+2] Cross-Benzannulation Reactions3.1. [2+2+2] and [4+2] Approaches to the Regioselective Synthesis of Polysubstituted Benzenes3.2. [2+2+2] and [4+2] Cycloaddition Reactions of Some Quinuclidine
Derivatives
4. Metal Complexes of Pd(II) and Pt(II) with Quincorine, Quincoridine and
their Derivatives4.1. N,O-Chelate and bis-N,O-Chelate Complexes of Pd(II) with Quincorine, Quincoridine and their Corresponding Saturated Derivatives4.2. The Synthesis of New bis-Aminophosphinite Ligands Derived from Quincorine and Quincoridine4.3. Platinum (II) and Palladium (II) Complexes Using the bis-Amino-
phosphinites 120 and 121 as Ligands
5. Experimental Section5.1. General Remarks5.2. The Synthesis of Palladium and Platinum Complexes5.3. The Synthesis of Compounds from Chapter 25.4. The Synthesis of Compounds from Chapter 35.5. The Synthesis of Compounds from Chapter 4
6. Conclusions
7. References
8. Appendix
3
PART B9. Introduction
10. Study on the Atropisomerism of Some New 1,3-Dioxane Derivatives 10.1. Synthesis and Stereochemistry of 1,3-Dioxane Derivatives Obtained from 2-Acetylpyridine10.2. Synthesis and Stereochemistry of 1,3-Dioxane Derivatives Obtained from o,o’-Diformylbiphenyl
11. Experimental Section11.1. General Remarks11.2. General Procedure for the Preparation of 128-13011.3. General Procedure for the Preparation of 13111.4. General Procedure for the Preparation of 132 and 133
12. Conclusions
13. References
14. List of Synthesized Compounds
4
General Introduction
In the present PhD thesis the research work was foccused on two main fields,
represented one side by the synthesis and structural analysis of new quinuclidine derivatives
using Quincorine and Quincoridine as precursors and on the other side by the synthesis and
stereochemistry of some new 1,3-dioxane derivatives. Part A of the thesis was developed at
the Institut für Anorganische und Analytische Chemie, TU Braunschweig, in the research
group of Prof. Dr. Manfred Fild. Part B was made at the “Babes-Bolyai” University in the
research group of Prof. Dr. Ion Grosu.
The objective of Part A was the synthesis and structural analysis of new
functionalized quinuclidines derived from Quincorine and Quincoridine. Optimization of the
process described in the literature33 for the preparation of 10,11-didehydro Quincorine 20 and
10,11-didehydro Quincoridine 21 has allowed the synthesis of these alkynes, in high yields, as
white solids, in two steps using a lipophilic phase transfer catalyst. These terminal alkynes
turned out to be versatile key intermediates as they afforded the desired products in
Sonogashira cross-coupling reactions and addition reactions catalyzed by Pd. The addition
process exhibited high chemoselectivity and excellent regio- and diastereoselectivity, the E-
enynes being obtained as single products in almost all cases. 10,11-Didehydro Quincorine 20
has failed as donor, but its O-acylated analogue 64 gave very good results in the cross-
coupling reactions. Eglinton reaction for the oxidative homocoupling of 20 and 21 allowed
the formation of the desired dimers in very good yields. Moreover, the formal [2+2+2]
intermolecular trimerization of alkynes via palladium catalyzed cross-benzannulation
reactions afforded tetra- and pentasubstituted benzenes, which are not easily available using
conventional methods and the proposed methodology provides a synthetically useful way to
multifunctinal quinuclidine derivatives.
On the other hand, a series of Pd(II) complexes in which Quincorine and Quincoridine
coordinated via N,O donor atoms were obtained. The syntheses of two new bis-P,N-
aminophosphinite ligands, derived from Quincorine and Quincoridine, have been developed
and the coordinating properties to Pd(II) and Pt(II) were pointed out.
Part B of this thesis deals with the synthesis and stereochemistry of some 1,3-dioxane
derivatives obtained from 2-acetylpyridine and biphenyl-2,2’-dicarbaldehyde. The peculiar
structural aspects of these compounds such as axial chirality and the anancomeric behavior
were pointed out.
5
PART A
2. The Synthesis and Fuctionalization of 10,11-didehydro-Quincorine and 10,11-didehydro-Quincoridine
2.1. Synthesis of 10,11-didehydro-Quincorine and 10,11-didehydro-Quincoridine
Quincorine 18 and Quincoridine 19, synthesized for the first time by Hoffmann and
co-workers33, are two new scalemic β-amino alcohols containing four stereogenic centers
each, including the N-chiral 1(S)-configurated bridgeheads.10,11-Didehydro-Quincorine 20
and 10,11-didehydro-Quincoridine 21 were also obtained for the first time by Hoffmann’s
group through the conversion of the olefinic double bond of the Quincorine 18 and
Quincoridine 19 into the corresponding alkynes 20 and 21.35
Trying to synthesize the acetylenic derivatives 20 and 21 after the described literature
procedure led to the desired products in small amounts and in very poor yields (<20 %).
Optimization of the procedure allowed the synthesis of the alkynes 20 and 21 in large
amounts. The optimized method is based on the known literature procedure and involves two
steps:
i) bromination using 1.25 eq. Br2 at 0 °C in CHCl3 as solvent, instead 1.8 eq.Br2 and CCl4,
and the isolation of the corresponding dibromoderivatives 18a-b and 19a-b in quantitative
amounts (Scheme 2.2)
N N N
N N N
HO HO HO
HO HO HO
Br
Br
Br
Br
Br
Br
Br
Br
Br2
CHCl3
Br2
CHCl3
+
+
QCI 18
QCD 19
18a 18b
19a 19b
Scheme 2.2: The bromination of QCI 18 and QCD 19
6
ii) double-dehydrobromination in a simple one-pot procedure using 0.2 eq. Aliquat 336, 3.5
eq. solid NaOH in anhydrous t-BuOH at reflux 3 h (Scheme 2.3)
N N
N N
HO HO
HO HO
Br
Br
Br
Br
Br
Br
Br
Br
+
+
18a 18b
19a 19b
N
N
HO
HO
NaOH, Aliquat 336
t-BuOH
NaOH, Aliquat 336
t-BuOH
Didehydro-QCI 20
Didehydro-QCD 21
Scheme 2.3: Dehydrobromination of 18a-b and 19a-b
Essentially changes were done in the work-up steps, these being described in the
Experimental Section of this work. Thus, the desired acetylenic derivatives 20 and 21 could
be isolated as white solids in good yields.
2.2. Sonogashira Cross-coupling Reactions of 10,11-didehydro-Quincorine and 10,11-
dideydro-Quincoridine
Carbon-carbon bond-forming reactions are the most important processes in chemistry,
as they represent key steps in the building of more complex molecules from simple
precursors.36
Two types of transition-metal-mediated cross-coupling reactions to sp carbon atoms
are available. These are cross-couplings of alkynylmetal reagents with unsaturated organic
halides, and of alkynyl halides with alkynyl- or arylmetals reagents. Among them the Stille
couplings36,37 (using alkynyltin reagents), the Suzuki couplings36,38 (using alkynylboranes
reagents) and Sonogashira couplings36,39-40 are the most known.
7
The Pd-catalyzed coupling of aryl and alkenyl halides with terminal alkynes was developed in
1975 by Sonogashira39,40. The coupling reaction is carried out in the presence of catalytic
amounts of Pd(II)-complex and CuI in an amine as solvent (Scheme 2.4).39,40 The use of
cosolvents like THF or DMF has also been reported.45
HC CR'Pd(PPh3)2Cl2, CuI
NHEt2, Et3N or piperidineRX +
R = aryl, alkenylX = Cl, Br, I, OTf
RC CR'
Scheme 2.4: Sonogashira cross-coupling reaction
To explore the application of the Sonogashira cross-coupling reaction to semi-natural
Cinchona alkaloids, 10,11-didehydro Quincorine 20 and 10,11-didehydro Quincoridine 21
were used as precursors. A wide variety of bromo- and chloro(het)arenes were used as
coupling partners. The substitution of bromine or chlorine atoms was achieved using different
palladium catalysts, namely, Pd(PPh3)2Cl2, Pd(PPh3)4 and Pd(PhCN)2Cl2. No systematic
relation between the type of aryl halides or the type of alkyne and the best-suited catalyst was
observed. The reactions were carried out in anhydrous THF at room temperature. The
elimination of the HX formed during the substitution reactions was performed using various
amines (Scheme 2.8).
N N
N N
HO HO
HO HO
Pd(PPh3)2Cl2, CuI
Pd(PPh3)2Cl2, CuI
Et3N, n-BuNH2 orpiperidine, THF, r.t.
Et3N, n-BuNH2 orpiperidine, THF, r.t.
+ ArX
+ ArX
20 31 a-k
21 32 a-k
Ar
Ar
Scheme 2.8: Sonogashira coupling of 10,11-didehydro Quincorine 20 and 10,11-didehydro
Quincoridine 21
8
The structure of new compounds 31a-k and 32a-k was deduced from 1H-, 13C- and
C,H-COSY spectra and mass spectrometry investigations. All derivatives show the expected
fragmentation pattern and the molecular ions in their EI mass spectra. For all compounds the
H-3endo signals are shifted downfield compared with the corresponding H-3exo signals. The
H-3endo signals of the 31a-k are shifted downfield relative to those of the 32a-k. In contrast,
the H-3exo signals of the 31a-k are shifted to higher field compared with those of the 32a-k.
Based on these guidelines, it can easily distinguish between the quincorine derivatives 31a-k
and quincoridine derivatives 32a-k. As example in Fig. 2.1 and Fig. 2.2 are presented details
from the 1H NMR spectra of the 31h and 32h, both isomers showing characteristic signals for
the quinuclidine moiety.
N
HO
N
N
Hendo
Hexo Hexo
Hendo
HexoHendo
0.20.40.60.81.01.21.41.61.82.02.22.42.62.83.03.23.43.63.84.0
H-3exo
H-8H-4
H-3endoH-7H-5
H-6 H-7
H-2
OH
H-10
H-9
Fig. 2.1: 1H NMR spectrum of the bicyclic part of 31h
N
N
N
12
3 4
5
6
7
8
9
Hendo
Hexo
Hendo
HexoHendo
HO
Hexo
1.41.61.82.02.22.42.62.83.03.23.43.63.8
H-3exoH-3endoH-8H-8H-4
H-5
H-7H-7OH
H-6H-2H-6
H-9 H-9
Fig. 2.2: 1H NMR spectrum of the bicyclic part of 32h
9
2.3. Synthesis of (E)- and (Z)-Chloroenynes as well as (E)- and (Z)-Enediynes from
10,11-didehydro Quincorine and 10,11-didehydro Quincoridine
The synthesis of conjugated enynes, a moiety incorporated in a number of natural
products, has been the subject of many studies during the past years. An efficient way to
enynes has been realized by reaction of vinylmetals with haloalkynes63,64 or by reaction of
vinyl halides with metallated terminal alkynes.65,66 The utilization of commercially available
(E)- and (Z)-dichloroethenes appears to be interesting since it would lead, by sequential
substitution, to chloroenynes67 and then to enediynes.68
The cross-coupling of simple 10,11-didehydro Quincorine 20 and 10,11-didehydro
Quincoridine 21 with an excess of (E)- or (Z)-1,2-dichloroethene in the presence of Pd(PPh3)4
(5 %), CuI (10 %), piperidine (2 eq.) in THF as solvent afforded the corresponding (E)- and
(Z)-chloroenynes 36, 37, 40 and 41 in very good yields without by-products (Scheme 2.11 and
2.12). These exhibited in the 1H NMR spectra two type of signals corresponding to the vinylic
hydrogen atoms: a doublet for the proton geminal to chlorine atom and a doublet of doublet
for the other one (Table 2.3).
Table 2.3: NMR Data (δ (ppm) and J (Hz)) for the Vinylic Protons of (E)- and (Z)-
Chloroenynes
Compound H-13 (d) H-12 (dd)36 6.38, 13.6 5.86, 13.6, 2.237 6.26, 7.3 5.79, 7.3, 2.240 6.38, 13.6 5.85, 13.6, 2.141 6.26, 7.3 5.78, 7.3, 2.2
Moreover, further spacers could be introduced giving the symmetrical (E)- and (Z)-
enediynes 38, 39, 42 and 43 with an excess of alkynes 20 and 21 using PdCl2(PhCN)2 (5 %)
and CuI (10 %) as catalysts and piperidine as amine (Scheme 2.11 and 2.12). The formation
of the enediyne moieties is pointed out in the 1H NMR spectra by the appearance of a singlet
for the vinylic protons (Table 2.4).
Table 2.4: NMR Data (δ (ppm)) for the Vinylic Protons of (E)- and (Z)-Enediynes
Compound δ(ppm)38 5.8539 5.7042 5.8343 5.69
10
N
HO
Cl
Cl
Cl Cl
N N
Cl
OH
Cl
OH
NN
HO
OH
NHO
N
HO
20
i) 60%
ii) 88% ii) 64%
36 37
39
i) 66%
38
Scheme 2.11: Reaction of (E)- and (Z)-dichloroethene with 10,11-didehydro Quincorine 20. Reagents and conditions: i) Pd(PPh3)4 5 %, CuI 10 %, piperidine (2 eq.), (E)- or (Z)-1,2-dichloroethene (3 eq.), in THF, r.t., 3-5 h; ii) PdCl2(PhCN)2 5 %, CuI 10 %, piperidine (2 eq.), 10,11-didehydro Quincorine 20 (1.2 eq.), in THF, r.t.,3-10 h.
N
Cl
Cl
Cl Cl
N N
Cl
Cl
HO
HO HO
N
OH
N
HO
N
OH
N
HO
21
40 41
42 43
i) 88% i) 78%
ii) 69% ii) 60%
Scheme 2.12: Reaction of (E)- and (Z)-dichloroethene with 10,11-didehydro Quincoridine 21. Reagents and conditions: i) Pd(PPh3)4 5 %, CuI 10 %, piperidine (2 eq.), (E)- or (Z)-1,2-dichloroethene (3 eq.), in THF, r.t., 3-5 h; ii) PdCl2(PhCN)2 5 %, CuI 10 %, piperidine (2 eq.), 10,11-didehydro Quincoridine 21 (1.2 eq.), in THF, r.t.,3-5 h.
11
Colourless crystals of 43 suitable for X-ray analysis were obtained through slow
diffusion of n-hexane into a concentrated solution of 43 in CH2Cl2. The X-ray structure of
(Z)-enediyne 43 is shown below (Fig. 2.5). Compound 43 crystallizes with four molecules in
the unit cell (Z = 4) and belongs to the orthorhombic space group P212121.
Fig. 2.5: The molecular structure of 43 in the crystal. H-atoms omitted for clarity
2.5. Addition of Terminal Alkynes 10,11-didehydro Quincorine and 10,11-didehydro
Quincoridine to Internal Alkynes
The presence of enynes in natural compounds and their utility as building blocks for
further structural elaboration stimulate the interest in seeking simple synthetic routes to them.
Trost et.al.75 demonstrated that 1,2,4-trisubstituted enynes could be efficiently prepared via
selective “syn”-addition of a terminal alkyne (donor alkyne) to an internal alkyne (acceptor
alkyne) in the presence of a catalytic amount of palladium acetate and an electron rich
sterically encumbered ligand tris-(2,6-dimethoxyphenyl)phosphine (TDMPP).
To explore the application of this addition reaction to semi-natural Cinchona
alkaloids, the 10,11-didehydro derivatives 20, 21, 64, and 65 of Quincorine 18 and
Quincoridine 19 were used as terminal alkynes. As activated internal alkynes for cross-
coupling (the acceptor alkynes), alkynes that bear ester or ketone as electron withdrawing
groups were used.
When one equivalent of 21 or 65 was treated with one equivalent of acceptor alkynes
in the presence of 2 mol% Pd(OAc)2 and 2 mol% of TDMPP in THF at room temperature, the
corresponding 1,2,4,-trisubstituted enynes 66a-e and 67a-b were obtained in very good yields
(Scheme 2.24, Table 2.5). Excepting, entry 4 and 5 (Table 2.5) all reactions proceeded
smoothly and gave a single geometric isomer assigned E on the basis of 1H NMR spectra and
the mechanism.75,79,80
12
N
NRO
RO
R''
H
R'
+R'
R''2 % Pd(OAc)22 % TDMPP
THF, r.t.21 R = H65 R = Ac
66a-e R = H67a-b R = Ac
Scheme 2.24
Table2.5: Cross-Couplings of 10,11-didehydro Quincoridine 21 and 65 with Alkyl- and Aryl-
Substituted Acceptor Alkynes
Entry
Donor alkyne
R
Acceptor alkyne
R' R''
Yield
% Compound
1
2
3
4a
5b
6
7
H
H
H
H
H
Ac
Ac
CH3
C6H5
C6H5
C6H5
C2H5
C6H5
C2H5
CO2C2H5
CO2C2H5
CO2CH3
COCH3
COCH3
CO2CH3
COCH3
94
73
84
67
not isolated
81
53
66a
66b
66c
66d, 66f
66e
67a
67ba) A mixture of E/Z isomers was obtained.b) Reaction performed 24 h at r.t. and 3 h at reflux, the transposition product 66g was
obtained, 80%.
Changing the donor alkynes from 21 and 65 to 20 and 64 the cross-coupling reactions
with acceptor alkynes furnished the desired enynes in moderate yields, the results being
slightly different in comparison with their isomers (Scheme 2.28, Table 2.7).
N N
R''
H
R'
+
R'
R''2 % Pd(OAc)22 % TDMPP
THF, r.t.
20 R = H64 R = Ac
68a-b R = H69a-e R = AcRO RO
Scheme 2.28
13
Table 2.7: Cross-Couplings of 10,11-didehydro Quincorine 20 and 64 with Alkyl- and Aryl-
Substituted Acceptor Alkynes
Entry
Donor alkyne
R
Acceptor alkyne
R' R''
Yield
% Compound
1
2a
3
4
5
6
7
H
H
Ac
Ac
Ac
Ac
Ac
CH3
C6H5
CH3
C6H5
C6H5
C2H5
C6H5
CO2C2H5
CO2C2H5
CO2C2H5
CO2C2H5
CO2CH3
COCH3
COCH3
26
31
70
67
68
59
61
68a
68b, 68c
69a
69b
69c
69d
69e
a) A mixture of E and Z isomers was obtained.
In the case of alkyne 20 O-protection of the 1,2-aminoalcohol was necessary. Low
conversions were recorded (Table 2.7, entries 1 and 2) even at high temperatures or
increasing the mole percent of the catalyst. A part of the effect derived from the presence of
the free OH-group, because the O-acylated derivative 64 participated without complications
to the addition reactions (Table 2.7, entries 3-7). A plausible explanation could be the
formation of a N,O-chelate complex (Fig.2.12) that inhibits the catalytic activity of the
palladium. Unfortunately this supposition was not demonstrated.
N
Pd
O
OAc
TDMPP
Fig. 2.12
14
3. [2+2+2] Cross-Benzannulation Reactions
3.2. [2+2+2] and [4+2] Cycloaddition Reactions of some Quinuclidine Derivatives
Homodimerization of terminal alkynes and subsequent [4+2] benzannulation with
diynes allowed the formation of tetrasubstituted benzenes as a single reaction product in
moderate to good yields.99
To examine the application of this formal [2+2+2] intermolecular trimerization of alkynes via
palladium catalyzed sequential homodimerization/[4+2] benzannulation reaction to the
Cinchona alkaloid derivatives the dimers 44 and 45 were used as diynes. These were
efficiently prepared as was described in Chapter 2.4, using 10,11-didehydro Quincorine 20
and 10,11-didehydro Quincoridine 21 as precursors.
Reactions of terminal alkynes 96 and 97 with diynes 44 and 45 in the presence of 5
mol % of Pd(PPh3)4 in THF at reflux furnished the tetrasubstituted 98a-b and 99a-b benzenes
in moderate yields (Scheme 3.11 and Scheme 3.12). These compounds were obtained as
single reaction products and the 1H NMR, 13C NMR and mass spectra were in full agreement
with the proposed structures. Thus, in the 1H NMR spectra of 98a and 99a the H5’ atom
suffers a downfield shift of more than 0.8 ppm in comparison with the H5’’ atom due to the
anisotropy of the benzene ring, the signal being a multiplet lying at δ = 3.66-3.60 ppm for 98a
and δ = 3.49-3.45 ppm for 99a, respectvely. The H5’’ atom exhibits a multiplet at δ = 2.60-
2.58 ppm for 98a and at δ = 2.58-2.54 ppm for 99a, respectively. The 13C NMR spectra of
98a and 99a show six signals for the quaternary aromatic carbon atoms at δ = 146.43, 145.88,
141.55, 140,51, 139.88 and 121.65 for 98a and at δ = 146.04, 145.48, 141.48, 140.55, 139.78
and 121.72 for 99a, respectively. In the EI mass spectra of 98a and 99a the molecular ions are
observed. In the case of derivatives 98b and 99b again the H5’ atom suffers a downfield shift
in comparison with H5’’ due to the anisotropy of the benzene ring. The benzene ring exhibits
two singlets at δ = 7.24 and δ = 7.22 ppm for 98b and at δ = 7.20 ppm and δ = 7.13 ppm for
99b, respectively. The corresponding singlets of the methylene groups are lying at δ = 4.51
and δ = 4.40 ppm for 98b and at δ = 4.50 and δ = 4.38 ppm for 99b. The methoxy groups
exhibit also two singlets at δ = 3.33 and δ = 3.32 ppm for 98b and at δ = 3.36 and δ = 3.31 for
99b. The 13C NMR spectra of 98b and 99b show four signals for the quaternary aromatic
carbon atoms at δ = 145.49, 140.92, 137.57 and 121.65 for 98b and at δ = 144.61, 141.05,
15
137.41 and 121.63 for 99b, pointed out the formation of the tetrasubstituted benzene
derivatives. The EI mass spectra of 98b and 99b present the expected molecular ions.
NN
Ph Ph
N
N
N
N
OCH3H3CO
i)
H2CH3COPh
98a 98b
44
OH
HO
HO
HO
HO
HO
9697
2 2
H5'
H5"
H5'
H5"
Scheme 3.11: The synthesis of tetrasubstituted benzenes 98a-b. Reagents and conditions: i) 1 eq. of diyne 44, 2 eq. of terminal alkyne, 5 mol % Pd(PPh3)4, THF, reflux
N
N
OH
HO
Ph Ph
N
N
HO
HO
N
N
HO
HO
OCH3H3CO
i)
H2CH3COPh
99a 99b
45
96 9722
H5' H5'
H5"H5"
Scheme 3.12: The synthesis of tetrasubstituted benzenes 99a-b. Reagents and conditions: i) 1 eq. of diyne 45, 2 eq. of terminal alkyne, 5 mol % Pd(PPh3)4, THF, reflux
16
When the mixture of E/Z conjugated enynes 66d/66f was employed as partner for the
[4+2] cross-benzannulation reaction with 2,4-hexadiyne 100, the pentasubstituted benzene
101 was obtained in very low yield (Scheme 3.13).
N
Ph
H
H3COC
HO H3C
CH3
+5% Pd(PPh3)4
THF, 100 °C
H3C
H3COC
H3C
N
HO66d/66f
101100
Scheme 3.13
The 1H NMR spectrum of 101 exhibits a singlet at δ = 7.02 ppm corresponding to the
pentasubstituted benzene ring. The H5’ atom is again deshielded due to the anisotropy of the
benzene ring in comparison with the starting material 66f, the corresponding multiplet lies at
δ = 3.48-3.42 ppm. The 13C NMR spectrum of 101 presents five signals for the quaternary
aromatic carbon atoms at δ = 144.63, 140.17, 139.73, 136.63 and 136.59 ppm. The EI mass
spectrum of 101 shows the molecular ion 387[M+] as base peak.
Slow diffusion of diethyl ether into a concentrated CH2Cl2 solution of 101 produced
colourless crystals and a single X-ray analysis showed the pentasubstituted benzene (Fig. 3.1).
Compound 101 crystallizes with four molecules in the unit cell (Z = 4) and belongs to the
monoclinic space group C2. The torsion of the biphenyl unit is C(25)–C(24)–C(31)–C(36)
42.2(5) (Fig. 3.1).
Fig. 3.1: The molecular structure of 101 in the crystal. H-atoms omitted for clarity.
17
4. Metal Complexes of Pd(II) and Pt(II) with Quincorine, Quincoridine and
their Derivatives
4.1. N,O-Chelate and bis-N,O-Chelate Complexes of Pd(II) with Quincorine,
Quincoridine and their Corresponding Saturated Derivatives
The synthesis of new chiral ligands for transition metals is an essential tool for the
development of novel catalytic systems exhibiting high reactivity and enantioselectivity.
Quincorine 18 and Quincoridine 19 contain four stereogenic centers, including the N-chiral
(1S-configurated) bridgehead, and also possess three potential donor sites: the –OH group, a
tertiary N-atom and an olefinic C=C bond. For the synthesis and characterization of new
metal complexes Quincorine 18, Quincoridine 19 and their corresponding saturated
derivatives 102 and 103 were used as ligands.
Reactions of two equivalents of ligands 18, 19, 102 or 103 with one equivalent of the
chloro-bridge complex (Ph3P)(Cl)Pd(µ-Cl)2Pd(Cl)(PPh3) 104 in the presence of NaOMe in
methanol/dichloromethane gave the corresponding five membered ring chelate complexes
105-108 (Scheme 4.1).158
N
N
HO
R
HO
R
+1/2 {PdCl2[P(C6H6)3]}2
+
N
R
OPd
P
Cl
Ph PhPh
N
R
O
Pd
PCl
Ph
PhPh
R = C2H3 (18), C2H5 (102)
R = C2H3 (19), C2H5 (103)
R = C2H3 (105),C2H5 (107)
R = C2H3 (106),C2H5 (108)
NaOMeCH2Cl2/MeOH r.t.
1/2 {PdCl2[P(C6H6)3]}2
NaOMeCH2Cl2/MeOH r.t.
Scheme 4.1: The synthesis of phosphane Pd(II)-Quincorine and Quincoridine complexes
18
All of the complexes 105-108 present the expected molecular ions in their positive FAB mass
spectra. In the 31P{1H}NMR spectra of 105-108 all compounds display two nearby singlets of
different intensities (Table 4.1). The signal with the high intensity was assigned to the trans-
P-M-N isomer and another, with low intensity (< 5%), to the cis-P-M-N isomer.
Table 4.1: 31P{1H}NMR Data for the complexes 105-108
PCompound trans-P-M-N cis-P-M-N
105106107108
26.8426.8326.7426.64
23.9523.9626.8226.78
The formation of the five-membered chelate ring in 105-108 was also confirmed in 1H NMR
spectra by the diastereotopicity of H9 atoms. An upfield shift with ca. 0.5 ppm was observed
for one of them. The H6 and H7 atoms suffer a small downfield shift, perhaps, due to the
interaction with dz2 orbital of the metal and the coordination of the tertiary N-atom. Single-
crystal X-ray determinations of 107 and 108 (Fig. 4.1 and Fig. 4.3) have proved that the trans-
P-M-N isomers were formed as main products. Deep yellow crystals suitable for X-ray
analysis were obtained from Et2O and n-hexane.
Compound 107 crystallizes with four molecules in the unit cell (Z = 4) and belongs
to the orthorhombic space group P212121. The coordination geometry around Pd is square
planar, with N and P lying in the trans positions (Fig. 4.1).
Fig. 4.1: The molecular structure of 107 in the crystal. H-atoms omitted for clarity.
19
The five-membered ring has a half-chair conformation, the torsion angles being
N(1)–Pd(1)–O(1)–C(8) 17.59(15) and O(1)–Pd(1)–N(1)–C(1) 10.91(13) (Fig.4.2).
Fig. 4.2: The half-chair conformation of the five-memberd ring
When one equivalent of (PhCN)2PdCl2 was reacted with two equivalents of 18, 19,
102 or 103 in the presence of NaOMe in methanol/dichloromethane the bis-N,O-chelate
complexes 109-112 were obtained in excellent yields (> 90%) (Scheme 4.2).158
(PhCN)2PdCl2
2 NaOMeMeOH / CH2Cl2
r.t.
NN
HO
R
HO
R
22
R = C2H3 (18),C2H5 (102) R = C2H3 (19), C2H5 (103)
N
N
O
O
R
R
Pd
N
N
R
R
O
OPd
R = C2H3 (111), C2H5 (112)
R = C2H3 (109), C2H5 (110)
Scheme 4.2: The synthesis of homoleptic Pd(II) Quincorine and Quincoridine complexes
All compounds 109-112 show the molecular ions in their EI mass spectra. 1H NMR spectra
confirmed the formation of the spiro-complexes 109-112 due to the diastereotopicity of H9
atoms. These atoms exhibit a downfield and an upfield signals due to the different
20
environment obtained through the closure of the five-membered chelate rings. The H6 and H7
atoms suffer a small downfield shift due to the coordination of the tertiary N-atom to Pd and
the interaction with the dz2 orbital of the metal.158
Yellow crystals of 109 and 111 suitable for X-ray analysis were obtained from Et2O
and n-hexane. Compound 109 crystallized with two molecules of water and has four
molecules in the unit cell (Z = 4). It belongs to the orthorhombic space group P212121. The
coordination geometry around Pd is square planar, with N1 and N2 occupying the trans
positions. The water molecules form hydrogen bonds with the oxygen atoms O1 and O2
(Fig.4.5). The five-membered rings of the spirane system have different conformation, one is
envelope on C(10) (torsion angle N(2)–Pd(1)–O(1)–C(17) 4.86(13)) and the other one is
twisted on C(20)–C(27) (torsion angles O(2)–Pd(1)–N(1)–C(20) 12.34(11) and N(1)–Pd(1)–
O(2)–C(27) 14.44(13)) (Fig. 4.6).
Fig. 4.5: The molecular structure of 109 in the crystal. H-atoms omitted for clarity.
Fig. 4.6: The envelope and half-chair conformations of the five-membered rings
21
4.2. The Synthesis of New bis-Aminophosphinite Ligands Derived from Quincorine and
Quincoridine
Chiral phosphorus-containing ligands that incorporate an additional nitrogen donor
center acquire a progressively growing importance in the development of asymmetric
catalysis and coordination chemistry. In the 1990’s, the concept, which involves the
asymmetric induction by electronic differentiation, has been extensively studied.122-124 P,N-
Bidentate ligands, structurally dissymmetric, are also characterized by marked electronic non-
symmetry, these possessing a soft electron-donating atom such as phosphorus and a hard
electron-donating atom such as nitrogen.124 It is possible to vary widely both the steric and
electronic parameters of the two donor centers and the structure of the bridge between them.
In this context a remarkable number of amino-phosphine, -phosphite, -phosphonite and –
phosphinite ligands were developed leading to complexes used for asymmetric catalytic
reactions, such as allylic alkylation125-129, hydrogenation130, cross-coupling131, hydro-
silylation132-134, hydroformylation135 and hydroboration124,136. One of the possible ways to
enhance the efficiency of P,N-ligands is to increase the π-acceptor character of the
phosphorus donor center by using a phosphite (amidophosphite) fragment in the ligand
structure.137-142 Another principally important parameter is the stereochemical characteristics
of the donor centers. In particular, growing interest in enantioselective catalysts with ligands
that contain chiral donor atoms is currently observed.143
Two new chiral P,N-tetradentate ligands containing two quinuclidine cores bridged
through a cis enediyne fragment were designed using 10,11-didehydro Quincorine 20 and
10,11-didehydro Quincoridine 21 as precursors.158 The symmetrical (Z)-enediynes 39 and 43
were synthesized in good yields, in two steps procedure (see Chapter 2.2) involving two
sequential Pd(PPh3)4 and PdCl2(PhCN)2 catalyzed coupling reactions starting from (Z)-1,2-
dichloroethene and 20 and 21. Treatment of 39 and 43 with diphenylphosphine chloride in
dichloromethane, in the presence of triethylamine, gave the bis-aminophosphinites 120 and
121 in very good yields (Scheme 4.5). These compounds are pale yellow oils, which are
stable under nitrogen atmosphere for a long time. 31P{1H}NMR spectra exhibit a singlet at δP
= 115.29 for 120 and δP = 114.60 for 121, respectively. Both ligands 120 and 121 show the
molecular ions in their EI mass spectra.
22
Cl Cl
N N
HO
HO
NN
HO
HO
ClCl
N N
HO
HO
NHO
N
HO
N N
Ph2PO
Ph2PO
NPh2PO
N
Ph2PO
20 21
3741
39 43
120 121
5%Pd(PPh3)4, 10%CuI2eq. C5H11N, THF
1.2 eq. 211.2 eq. 205% (PhCN)2PdCl210% CuI2eq. C5H11N, THF
5% (PhCN)2PdCl210% CuI2eq. C5H11N, THF
2eq. Ph2PCl,Et3N, CH2Cl2
2eq. Ph2PCl,Et3N, CH2Cl2
Scheme 4.5: The synthesis of the aminophosphinites 120 and 121 from the acetylenic
Quincorine and Quincoridine derivatives 20 and 21
23
4.3. Platinum (II) and Palladium (II) Complexes Using bis-Aminophosphinites 120 and
121 as Ligands
It was considered of interest to study the complexation ability of novel bis-P,N-
aminophosphinites 120 and 121. When a solution of [PtCl2(SMe2)2] in dichloromethane was
added to a solution of 120 or 121 in the same solvent, in a 1:1 molar ratio, the cis-complexes
122 and 123 were obtained (Scheme 4.6).158
PtCl2(SMe2)2
N
N
O
O
P
PPh
Ph
Ph Ph
Pt
Cl
ClN
N
O
O
P
P
PhPh
Ph
Ph
Pt
Cl
Cl
120 121
CH2Cl2, r.t.
122 123
Scheme 4.6: Platinum (II) chelate complexes of the aminophosphinites 120 and 121
They show in the 31P{1H}NMR spectra one singlet with its associated 195Pt satellites at δP =
83.89 (1JPt,P = 4198.5 Hz) for 122 and at δP = 85.10 (1JPt,P = 4152.0 Hz) for 123. The FAB
mass spectra present the molecular ions corresponding to the monomeric forms. Slow
diffusion of diethyl ether into a concentrated THF/dioxane solution of 122 produced
colourless crystals and a single crystal X-ray analysis (Fig. 4.10) show the complex to be the
cis-metallamacrocycle. Compound 122 crystallizes with two molecules in the unit cell (Z = 2)
and belongs to the triclinic space group P1. The geometry about the Pt center shows a slight
tetrahedral distortion away from a regular square planar environment. The angles between
P1–Pt1–Cl2 and P2–Pt1–Cl1 are 173.38(8)° and 178.40(9)°, respectively. The PtCl2 group
24
lies exterior to the metallamacrocycle and the Pt–P bonds are shorter and Pt–Cl bonds longer,
consistent with the different trans influences.
Fig. 4.10: The molecular structure of 122 in the crystal
In view of the interesting complexes 122 and 123, the synthesis of the corresponding
complexes with Pd(II) was taken into consideration. When one equivalent of ligand 120 or
121 was allowed to react with two equivalents of η4-C7H8PdCl2 in dichloromethane again
yellow solids were obtained.158 The 31P{1H}NMR spectra of these products exhibit only one
signal around δP = 103 ppm. The ESI mass spectra indicate that the compounds are bis-P,N-
chelate complexes 124 and 125 (Scheme 4.8), the corresponding molecular ions being
observed. The formation of the six-membered chelate rings in 124 and 125 is also confirmed
in the 1H NMR spectra. The H-6 and H-7 atoms are strongly deshielded after complexation, in
comparison with the free ligands due to the coordination of the tertiary N-atom to Pd and the
anisotropy of the phenyl groups (Table 4.2).
25
Table 4.2: 1H NMR Data (δ (ppm)) for the free ligands 120, 121 and their Pd(II) complexes
124 and 125
δ (ppm) δ(ppm)
Compound H-6 H-7 Compound H-6 H-7
120 3.04-2.74 2.82-2.74
2.31-2.24
124 5.09
3.24-3.19
4.31-4.25
3.01-2.94
121 3.12
2.93-2.86
2.48-2.31 125 4.86
2.83-2.78
4.64-4.56
3.29-3.27
2 η4−C7H8PdCl2
N
N
O
N
N
O
120
CH2Cl2, r.t.
P Ph
Ph
Pd
Cl
O
P
Pd
Ph
Ph
ClCl
P
Pd
PhPh
Cl
Cl
O P
Pd
PhPh
Cl
Cl
Cl
124 125
121
Scheme 4.8: Binuclear Palladium(II) complexes of the phosphinites 120 and 121
In contrast to Pt(II), Pd(II) show marked preference to form bis-P,N-chelate
complexes with the ligands 120 and 121.
26
PART B
10. Study on the Atropisomerism of Some New 1,3-Dioxane Derivatives
10.1. Synthesis and Stereochemistry of 1,3-Dioxane Derivatives Obtained from 2-
Acetylpyridine
The studies concerning the conformational analysis of 1,3-dioxane compounds
displaying aromatic substituents in the acetal part of the heterocycle revealed some interesting
aspects.1-4
The acetalisation reaction of the 2-acetylpyridine with several 1,3-propanediols using
PTSA in excess afforded the new 1,3-dioxane derivatives 128-130 in very good yields
(Scheme 10.1). 12
N CH3
O HO
HO R
R
O
OH3C R
RN
1
2
3 4
5
6
R = CH3 128R = COOCH3 129R = CH2Br 130
+
Scheme 10.1
Compound 128 was further reacted with C2H5I to obtain the N-alkylated derivative 131
(Scheme 10.2).
O
OH3C CH3
CH3N
+ C2H5I
O
OH3C CH3
CH3N+
C2H5 I-
128 131
Scheme 10.2
All investigated compounds 128-131 exhibit anancomeric 1,3-dioxane rings, the
conformational equilibria being shifted towards the conformer that displays the aromatic
substituent in axial orientation (structure I, Scheme 10.3).12
27
OO
OO
H3C
R
R
CH3
R
RX
X
I II
X = N, N-C2H5]+I-
Scheme 10.3
The NMR spectra (Table 10.1) exhibit different signals for the equatorial and axial protons of
the 1,3-dioxane rings and for the axial and equatorial similar groups located at the alkyl part
of the saturated heterocycles.
Table 10.1: 1H NMR Data (δ ppm) of Compounds 132, 133
Compound Position 5: CH3, CH2Br, OCH2-
axial equatorial ∆ax-eq
Positions 4 ,6
equatorial axial ∆eq-ax
128 1.25 0.62 0.63 3.49 3.42 0.07
129 3.88 3.63 0.25 4.55 3.99 0.56
130 3.96 3.13 0.83 3.91 3.63 0.28
131 1.19 0.77 0.42 3.62 3.44 0.18
10.2. Synthesis and Stereochemistry of 1,3-Dioxane Derivatives Obtained from
o,o’-Diformylbiphenyl
The acetalisation reaction of o,o’-diformyl-biphenyl with two 1,3-propanediols using PTSA
as catalyst allowed the synthesis of new derivatives containing two 1,3-dioxane rings (Scheme
10.5).
CHO CHO
+
HO
HO R
R
O O O O
RR RR
R = CH3 132R = COOC2H5 133
Scheme 10.5
28
The o,o’-diformyl-biphenyl was obtained through the ozonolysis of phenantherene, based on
the procedure described in the literature.11
Both new compounds exhibit anancomeric structures, the conformational equilibrium
being shifted towards the conformer that displays the aromatic substituent in equatorial
orientation. The “rigid” structures determine the recording in the NMR spectra of different
signals for the axial and equatorial protons of the 1,3-dioxane ring (positions 4 and 6) and for
the protons and carbon atoms belonging to the axial and equatorial groups in position 5. It is
also known that biphenyls containing large groups in the ortho positions cannot freely rotate
about the central bond because of the steric hindrance, and this generates the atropisomery of
these compounds (Scheme 10.6).
D D
D D
D = 2-dioxanyl
mirror
Scheme 10.6
At room temperature, the free rotation around the axis C1–C1’, the chiral axis, is frozen and
the 1H NMR spectra showed four different signals for the diastereotopic protons of positions 4
and 6 (Table 10.2).
Table 10.2: 1H NMR Data (δ ppm) of Compounds 132, 133
Compound
Positions 4 and 6
4-ax 6-ax ∆4ax-6ax 4-eq 6-eq ∆4eq-6eq
132 3.22 3.11 0.11 3.53 3.45 0.08
133 3.82 3.68 0.14 5.04 4.93 0.11
In comparison with the 2-acetylpyridine derivatives in this case was interesting to investigate
these compounds using high temperature 1H NMR experiments. The experiments with 132
([D8]-toluene) did not showed modifications of the shape of the spectra with the rising of the
temperature even at 353 K.
29
Conclusions
1. The synthesis method for the preparation of 10,11-didehydro Quincorine 20 and
10,11-didehydro Quincoridine 21 was optimized and these compounds are now
comercially available from Buchler GmbH Braunschweig.
2. Sonogashira cross-coupling allowed the synthesis of a wide variety of functionalized
quinuclidines (30 compounds) starting from 10,11-didehydro Quincorine and 10,11-
didehydro Quincoridine.
3. Eglinton reaction for the oxidative homocoupling of 20 or 21 afforded the desired
dimers 44 and 45 in very good yields without occurance of by-products.
4. Palladium catalyzed addition of terminal alkynes 20, 21, 64 or 65 to internal alkynes
allowed the synthesis of 1,2,4-trisubstituted (E)-enynes (17 compounds) in very good
yields.
5. Tetra- and pentasubstituted benzenes (5 compounds) were obtained through the formal
[2+2+2] intermolecular trimerization of alkynes via palladium catalyzed cross-
benzannulation reactions.
6. N,O-Chelate and bis-N,O-chelate complexes of Pd(II) with Quincorine, Quincoridine
and their corresponding saturated derivatives were synthesized (8 compounds).
7. The synthesis of two new chiral P,N-tetradentate ligands containing two quinuclidine
cores bridged through a cis enediyne fragment was developed. These new ligands,
having two soft electron-donating atoms and two hard electron-donating atoms
showed different coordinating properties towards Pt(II) and Pd(II). They prefer to
form with Pt(II) cis-P-M-P monomeric metallamacrocycles and bis-P,N-chelate
complexes with Pd(II).
8. For ten compounds the molecular structure in monocrystal were determined by X-ray
diffractometry.
9. New 1,3-dioxane derivatives were obtained by acetalysation of 2-acetyl pyridine with
several 1,3-propanediols using PTSA in excess. The stereochemistry investigations by
NMR in solution revealed the axial orientation of the aromatic substituent and its
orthogonal rotameric behaviour. The hindrance of the rotation of the aryl group around
its bond with the 1,3-dioxane ring introduces the axial chirality of the molecules.
30
10. The acetalysation reaction of o,o’-diformyl-biphenyl with two 1,3-propanediols using
PTSA as catalyst allowed the synthesis of new derivatives containing two 1,3-dioxane
rings. The hindering of the free rotation around the central bond, the chiral axis,
generates the atropisomery of these compounds. This peculiar aspect was pointed out
in 1H NMR spectra four different signals for the diastereotopic protons at positions 4
and 6 were recorded.
31
Selective References
PART A
33. H. M. R. Hoffmann, T. Plessner, C. Von Riesen, Synlett 1996, 689.
35. O. Schrake, W. Braje, H. M. R. Hoffmann, R. Wartchow, Tetrahedron: Asymmetry 1998,
9, 3717.
36. F. Diederich, P. J. Stang, Metal-Catalyzed Cross-coupling Reactions, Wiley-VCH,
Weinheim, Ney York, 1998.
37. D. E. Rudisill, J. K. Stille, J. Org. Chem. 1989, 54, 5856.
38. N. Miyaura, A. Suzuki, Chem. Rev. 1995, 2457.
39. K. Sonogashira, Y. Tohda, N. Hagihara, Tetrahedron Lett. 1975, 16, 4457.
40. S. Takahashi, Y. Kuroyama, K. Sonogashira, N. Hagihara, Synthesis 1980, 627.
45. S. Thorand, N. Krause, J. Org. Chem. 1998, 63, 8551.
63. N. Miyaura, K. Yamada, H. Suginome, A. Suzuki, J. Am. Chem. Soc. 1985, 109, 972.
64. I. Beaudet, J. L. Parrain, J. P. Quintard, Tetrahedron Lett. 1992, 33, 3647.
65. J. K. Stille, J. H. Simpson, J. Am. Chem. Soc. 1987, 109, 2138.
66. Y. Hatanaka, T. Hiyama, J. Org. Chem. 1988, 53, 918.
67. V. Ratovelomanata, G. Linstrumelle, Tetrahedron Lett. 1981, 22, 315.
68. D. Guillerm, G. Linstrumelle, Tetrahedron Lett. 1985, 26, 3811.
75. B. M. Trost, M. T. Sorum, C. Chan, A. E. Harms, G. Ruhter, J. Am. Chem. Soc. 1997,
119, 698.
99. V. Grevorgyan, U. Radhakrishnan, A. Takeda, M. Rubina, M. Rubin, Y. Yamamoto, J.
Org. Chem. 2001, 66, 2835.
122. A. Ohashi, T. Imamoto, Tetrahedron Lett. 2001, 42, 1099.
123. T. V. RajanBabu, T. A. Ayers, G. A. Halliday, K. K. You, J. C. Calabrese, J. Org. Chem.
1997, 62, 6012.
124. A. Schnyder, L. Hintermann, A. Togni, Angew. Chem. Int. Ed. Engl. 1995, 34, 931.
125. B. M. Trost, D. L. Van Vraken, Chem. Rev. 1996, 96, 395.
126. A. M. Porte, J. Reibenspies, K. Burgess, J. Am. Chem. Soc. 1998, 120, 9180.
127. P. Von Matt, A. Pfaltz, Angew. Chem. Int. Ed. Engl. 1993, 32, 566.
128. Y. Sprinz, G. Helmchen, Tetrahedron Lett. 1993, 34, 1769.
129. T. Mino, Y. Tanaka, M. Sakamoto, T. Fujita, Heterocycles 2000, 53, 1485.
130. V. I. Tararov, R. Kadyrov, T. H. Riermeier, J. Holz, A. Borner, Tetrahedron: Asymmetry
32
1999, 10, 4009.
131. G. Chelucci, M. A. Cabras, C. Botteghi, M. Marchetti, Tetrahedron: Asymmetry 1994, 5,
299.
132. T. Langer, J. Janssen, G. Helmchen, Tetrahedron: Asymmetry 1996, 7, 1599.
133. H. Brunner, H. Weber, Chem. Ber. 1985, 118, 3380.
134. A. Togni, R. Dorta, C. Kollner, G. Pioda, Pure Appl. Chem. 1998, 70, 1477.
135. I. D. Kostas, C. G. Screttas, J. Organomet. Chem. 1999, 585, 1.
136. A. Schnyder, A. Togni, U. Wieshi, Organometallics 1997, 16, 255.
137. J. M. Brunel, T. Constantieux, G. Buono, J. Org. Chem. 1999, 64, 8940.
138. R. Prétôt, A. Pfaltz, Angew. Chem. Int. Ed. Engl. 1998, 37, 323.
139. J. M. Brunel, T. Constantieux, A. Labante, F. Lubatti, G. Buono, Tetrahedron Lett. 1998,
38, 5971.
140. A. Alexakis, J. Vastra, J. Burton, C. Benhaim, P. Mangeney, Tetrahedron Lett. 1998,
7869.
141. D. K. Heldmann, D. Seebach, Helv. Chim. Acta 1999, 82, 1096.
142. A. K. Knobel, I. H. Escher, A. Pfaltz, Synlett 1997, 1429.
143. V. V. Dunina, E. B. Golovan’, N. S. Gulyukina, Yu K. Grishin, I. P. Beletskaya, Russ.
Chem. Bull. 1997, 1385.
158. M. Fild, C. Thöne, S. Tötös, Eur. J. Inorg. Chem 2003, accepted for publication.
PART B
1. M. J. O. Anteunis, D. Tavernier, F. Borremans, Heterocycles 1976, 4, 293.
2. F. W. Nader, E. L. Eliel, J. Am. Chem. Soc. 1970, 92, 3050.
3. A. Terec, L. Muntean, S. Tötös, N. Bogdan, C. Florian, D. Margineanu, S. Mager, I. Grosu,
Studia Univ „Babes-Bolyai“ Chemia 2002, 47, 187.
4. S. Mager, M. Horn, I. Grosu, M. Bogdan, Monatsh. Chem. 1989, 120, 735.
11. P. S. Bailey, R. E. Erickson, Organic Synthesis, Vol. 41, 1961, 41.
12. M. Balog, S. Tötös, C. Florian, I. Grosu, G. Plé, L. Toupet, Y. Ramondenc, N. Dinca,
Monatsh. Chem. 2003, submitted for publication.