Chiral amines in the diastereoselective Mannich-related multicomponent synthesis of diarylmethylamines, 1,2-diarylethylamines, and β- arylethylamines

Article abstract of DOI:10.1016/j.tet.2010.10.058

The multicomponent synthesis of diarylmethylamines, 1,2-diarylethylamines and β-arylethylamines has been undergone starting from aryl- or benzylzinc reagents, aldehydes, and primary or secondary chiral amines. Good to high diastereoselectivities have been obtained from both l-proline ester derivatives 1 and (±)-trans-1-allyl-2,5-dimethylpiperazine (4). The use of R-(+)-1-phenylethylamine (7) provides important diastereoisomeric excesses (～60%) in conjunction with very high chemical yields. This work constitutes a preliminary entry to the intended development of a more flexible reaction system, involving easily cleavable chiral amines.

Full text of DOI:10.1016/j.tet.2010.10.058

Tetrahedron 66 (2010) 9902e9911
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Chiral amines in the diastereoselective Mannich-related multicomponent
synthesis of diarylmethylamines, 1,2-diarylethylamines, and b-arylethylamines
*
ꢀ
Caroline Haurena, Erwan LeGall , Stephane Sengmany, Thierry Martens
ꢀ
ꢁ
ꢀ
ꢀ
ꢀ
Electrochimie et Synthese Organique, Institut de Chimie et des Materiaux Paris-Est, ICMPE, UMR 7182 CNRSdUniversite Paris-Est Creteil, 2-8 rue Henri Dunant, 94320 Thiais, France
a r t i c l e i n f o
a b s t r a c t
Article history:
The multicomponent synthesis of diarylmethylamines, 1,2-diarylethylamines and b-arylethylamines has
Received 23 September 2010
Received in revised form 19 October 2010
Accepted 21 October 2010
been undergone starting from aryl- or benzylzinc reagents, aldehydes, and primary or secondary chiral
amines. Good to high diastereoselectivities have been obtained from both -proline ester derivatives 1
and (ꢀ)-trans-1-allyl-2,5-dimethylpiperazine (4). The use of R-(þ)-1-phenylethylamine (7) provides
important diastereoisomeric excesses (w60%) in conjunction with very high chemical yields. This work
constitutes a preliminary entry to the intended development of a more flexible reaction system, in-
volving easily cleavable chiral amines.
L
Available online 28 October 2010
Keywords:
Multicomponent reactions
Organozinc compounds
Diastereoselectivity
Cobalt
Ó 2010 Elsevier Ltd. All rights reserved.
Zinc
1. Introduction
aryl halides and primary or secondary amines has already been
evaluated in the process (Scheme 1). However, despite the common
Multicomponent reactions (MCRs)1,2 are known to constitute
a powerful synthetic tool since they allow the straightforward
formation of complex structures starting from simple substrates.
Moreover, recent works have demonstrated that they represent
very reliable processes for the preparation of important synthetic
intermediates or natural products.3 In this context, procedures re-
lated to the Mannich reaction4 have been the subject of a tremen-
dous development in the past few years. While thoroughly
examined topics were regarding the development of unusual ver-
sions of the original reaction, in particular those employing orga-
noboronic acids5 or organometallic compounds6,7 as nucleophiles
equivalents, a particular emphasis was also placed on the de-
velopment of diastereoselective MCRs involving (at least) one chiral
substrate.8
As part of our work devoted to the development of MCRs
employing organometallic reagents, we described recently a Man-
nich-type three-component reaction between amines, aldehydes
and preformed or in situ-generated arylzinc or benzylzinc reagents
(Barbier-like conditions). It was demonstrated that this reaction can
provide a straightforward access to various molecular scaffolds like
creation of an asymmetric carbon at the position a to the nitrogen,
none of the starting compounds used were chiral.10 Thus, the po-
tential asymmetric induction provided by one of the reaction
substrates was not assessed. Therefore, we found interesting to
initiate
a novel campaign of experiments focused on the
Arylglycines
Diarylmethylamines
R
R'
R
R'
N
N
Ar
CO2R
GF
GF
O
H
R' R"
N
R1 ZnBr +
+ R2
H
R
R'
R
R'
N
N
GF
GF
CO2R
β-Arylethylamines
Arylalanines
e.g., diarylmethylamines, 1,2-diarylethylamines,
b-arylethylamines
R
N
R'
or
a
-amino esters.9 To date, a rather important range of aldehydes,
GF
Ar
1,2-Diarylethylamines
* Corresponding author. Tel.: þ33 (0)149781135; fax: þ33 (0)149781148; e-mail
Scheme 1. Structural motifs accessible through a Mannich-type reaction between
organozinc compounds, aldehydes and amines.
address: legall@glvt-cnrs.fr (E. LeGall).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.10.058

C. Haurena et al. / Tetrahedron 66 (2010) 9902e9911
9903
development of diastereoselective versions of the reaction. As
a first disclosure of this current research interest, we report herein
the possibility of operating from some primary or secondary chiral
amines to obtain coupling products with satisfactory to very good
diastereoisomeric excesses.
additional equivalent of the organozinc reagent upon acidebase
reaction with CO2H, we decided to start with 3 equiv of this species.
Unfortunately, these experiments resulted in failures and no cou-
pling products were detected in the reaction medium, even after
24 h heating at 60 ꢁC. We then decided to start from the corre-
sponding ester derivatives. Thus, ethyl and methyl esters of L-pro-
2. Results and discussion
line12 were engaged in three-component reactions with a range of
aromatic or aliphatic aldehydes and organozinc compounds,13 in
situ-preformed from the corresponding benzyl bromides to avoid
the formation of the N-benzylated product (resulting from the di-
rect addition of the amine onto the starting benzyl bromide). Re-
sults are presented in Table 1.
In the first part of the study, we focused our attention on the
reactivity of chiral cyclic secondary amines. Due to its wide com-
mercial availability and its potential relevant integration into bio-
active compounds,11,12
L-proline derivatives 1 were first tested.
A preliminary experiment was realized starting from -proline,
L
It could be observed that the ethyl and the methyl ester function
of proline provide comparable results, both in terms of diaster-
eoselectivity and chemical yield (Table 1, entries 1 and 2). Then, we
did not try to further expand the steric hindrance of the ester
function and decided to undergo the following experiments start-
ing from 1a. The following results indicated that both a function-
alized organozinc reagent and a functionalized aromatic aldehyde
can be successfully used in the process (Table 1, entries 3e5). With
2- or 3-chlorobenzaldehyde as the starting aldehyde, we could
notice that similar diastereoselectivities are obtained. However, the
benzylzinc bromide, and benzaldehyde, without protection of the
carboxylic acid function. Indeed, it was assumed that after a prob-
able deprotonation by the organozinc and under its carboxylate
anion form, L-proline should be able to present interesting stereo-
differentiating abilities and allow the formation of coupling prod-
ucts with important diastereoselectivities. In previous works, we
had demonstrated that the presence of 2 equiv of the organozinc
was necessary, even starting from non-functionalized secondary
amines. Thus, in order to prevent the probable consumption of an
Table 1
Multicomponent couplings starting from benzylzinc reagents,
L
-proline esters 1 and aldehydesa
CO2R
N
CO2R
Ar
ZnBr
+
N
+ R' CHO
Ar
CH3CN, r.t.
H . HCl
R'
2a-h
1
Entry
1
Benzylzinc bromide
Proline ester 1
Aldehyde
Time (h)
Product
Diastereoisomeric
excessb (de)
Yieldc (%)
3
3
3
3
2a
2b
2c
2d
54
64
72
50
45
2
3
4
60
51
32
5
3
2e
54
42
6
7
2.5
3
2f
72
76
64
65
2g
8
3
2h
20
23
a
Reactions were conducted with 15 mL of acetonitrile, 7 mmol of the benzyl bromide, 2 mmol of the amine 1, 2.4 mmol of the aldehyde, and 0.7 g (10.7 mmol) of zinc dust,
pre-activated in the presence of TFA.
b
Determined by 1H NMR.
Isolated yields.
c

9904
C. Haurena et al. / Tetrahedron 66 (2010) 9902e9911
presence of the chloride at the ortho position provides a lower re-
action yield (Table 1, entry 4). An aliphatic aldehyde is usable and
provides coupling products in reasonable yields and di-
astereoisomeric excess (Table 1, entries 5 and 6). However, with
ethyl glyoxylate as the carbonyl derivative, worse results are ob-
served (Table 1, entry 8). A possible reason to this failure should rely
in an unfavorable effect of both ester functions. Unfortunately, we
were not able to interpret these observations on the basis of a re-
action mechanism proposal.
In all experiments, moderate to excellent diastereoselectivities
were observed, with diastereoisomeric excesses ranging from 46%
(Table 2, entry 4) to>90% (Table 2, entries 7 and 9). While the yields
proved to be generally comparable to those observed with ben-
zylzinc bromides, the reaction of aromatic organozinc reagents
required longer reaction times (w24 h) than the reaction of ben-
zylic organozinc reagents (w3 h). This result is not surprising since
the increased reactivity of benzylzinc reagents in this multicom-
ponent procedure had already been reported elsewhere.9c
We then investigated the outcome of the reactions involving
aromatic organozinc reagents. Some preliminary experiments had
revealed that their couplings with amines and aldehydes were
more efficient when this reagent is used in the absence of zinc
powder. Consequently, the organozinc reagent was preformed and
transferred into the reaction flask containing the other reaction
substrates, then allowed to react overnight at room temperature.
Results are reported in Table 2.
In a following set of experiments, we envisaged assessing the
reactivity of (ꢀ)-trans-1-allyl-2,5-dimethylpiperazine (rac-4) in the
three-component coupling with benzylzinc bromide and benzal-
dehyde. This choice was motivated by the presence of this nitrogen-
containing motif in the analgesic diarylmethylamines SNC-8014 and
BW373U86,15 which are highly selective non-peptidic agonists of
the
the reaction was more difficult to carry out than expected. Indeed, it
d
-opioid receptor.16 Preliminary experiments had indicated that
Table 2
Multicomponent couplings starting from arylzinc reagents, L
-proline methyl ester (1a), and aromatic aldehydesa
CO2Me
Ar1 ZnBr
+
Ar2 CHO
CO2Me
+
N
N
CH3CN, r.t.
Ar1 Ar2
H . HCl
1a
3a-j
Entry
1
Arylzinc bromide
Aldehyde
Time (h)
Product
Diastereoisomeric excess (de)b
Yieldc (%)
41
21
15
3a
3b
d
2
3
4
74
70
46
36
33
41
20
15
3c
3d
5
6
7
8
20
20
22
20
3f
80
52
23
61
47
3g
3h
3i
78
>90
72
9
20
3j
>90
70
a
Reactions were conducted with 40 mL of acetonitrile, 15 mmol of the aryl bromide, 0.83 g (5 mmol) of proline methyl ester hydrochloride, 5 mmol of the aldehyde, 0.66 g
(3 mmol) of cobalt bromide, and 6 g (92 mmol) of zinc dust, pre-activated in the presence of methanesulfonic acid.
b
Determined by 1H NMR.
Isolated yields.
c

C. Haurena et al. / Tetrahedron 66 (2010) 9902e9911
9905
was observed the concomitant formation of the three-component
coupling product and the alcohol 6 resulting from the addition of
the organozinc onto benzaldehyde (Scheme 2).
of two closely related benzyl CeN bonds in most of the formed
compounds, these methods should be difficultly applicable here.
Some preliminary experiments were realized though and in-
dicated, as reported above with the amine 4, that the formation of
the alcohol 6 could constitute a significant limitation of the process.
We then screened a set of reaction parameters and mainly chose to
place a particular focus on the reaction temperature modulation.
Main results are reported in Table 4.
H3C
N
H3C
N
N
H3C
Ph
N
N
N
H
CH3
Ph ZnBr
4
rac-
CH3
CH3
Ph
Table 4
Ph
Multicomponent coupling starting from benzylzinc bromide, R-(þ)-1-phenylethyl-
5
amine (7), and benzaldehyde: optimization of the reaction conditionsa
Ph CHO
CH3
CH3
H
H
OH
Ph
OH
Ph
N
Ph ZnBr
Ph ZnBr
N
H
+
+ Ph CHO
+
Ph
Ph
Ph
CH3CN
Ph
8a
6
7
6
Ph Br
Entry Temperature (ꢁC) Time (h) 8a/6 ratio Diastereoisomeric Yieldc (%)
Scheme 2. Concurrent reaction pathways.
excess (de)b
1
2
3
4
0
10
25
60
2
1.5
1
82:18
90:10
72:25
50:50
60
72
50
40
62
82
56
53
This effect might be the consequence of a limited nucleophilicity
of the amine, thus indirectly favoring such direct organometallic
addition rather than the formation of a formal iminium and it’s
trapping by the organozinc reagent. Consequently, we tried to ex-
plore some experimental adaptations devoted to the optimization
of the reaction conditions. Main results are highlighted in Table 3.
Unfortunately, these experiments did not produce a satisfactory
improvement of the three-component coupling. Indeed, similar
limited yields were obtained, regardless of the reaction tempera-
ture (Table 3, entries 1 and 2), the mode of the organozinc com-
pound formation (Table 3, entry 3) or the experimental technique,
which was applied for the addition (Table 3, entry 4). However, we
were satisfied to notice the very interesting excesses, which were
observed in all cases, thus revealing the excellent stereo-differen-
tiating abilities of the piperazine derivative in the three-component
reaction. In addition, since the conversion of the starting amine was
not quantitative at room temperature, the results reported in entry
4 should be prone to a sensible improvement, for instance by
working at a slightly higher temperature.
1
a
Reactions were conducted with 15 mL of acetonitrile, 0.85 g (5 mmol) of benzyl
bromide, 0.25 g (2 mmol) of the benzylamine 7, 0.25 g (2.4 mmol) of benzaldehyde,
and 0.5 g (7.6 mmol) of zinc dust, pre-activated in the presence of TFA.
b
Determined by 1H NMR.
Isolated yields of 8a.
c
Very reliable reactions conditions, both in terms of chemical
yield and diastereoselectivity, could be obtained by working at
10 ꢁC (Table 4, entry 2), whereas other experiments suffered from
a lack of diastereoselectivity (Table 4, entry 4) or worse reaction
yields (Table 4, entries 1, 3, and 4). Thus, with these optimized
conditions in hand, we decided to proceed further and chose to
examine the reaction of R-(þ)-1-phenylethylamine (7) with some
benzylzinc reagents and aldehydes. Results are reported in Table 5.
These results confirmed those obtained with proline derivatives,
particularly by demonstrating that a range of aromatic aldehydes
are usable in the reaction. Interesting diastereoisomeric excesses,
ranging from 50 to 72%, were obtained in all cases. However, as
Table 3
Multicomponent coupling starting from benzylzinc bromide, (ꢀ)-trans-1-allyl-2,5-dimethylpiperazine (4), and benzaldehydea
H3C
+
N
H3C
Ph
N
N
Zn
OH
Ph
+
Ph CHO
Ph Br
+
Ph
N
H
CH3
CH3
Ph
CH3CN
5
4
6
Entry
Phenylzinc bromide
Temperature (ꢁC)
Time (h)
5/6 ratio
Diastereoisomeric excess (de)b
Yieldc (%)
1
2
3
4
Preformed
Preformed
In situ-generated
Preformed, dropwise addition
25
10
25
25
3
15
5
57:43
68:32
51:49
82:18
74
80
78
80
36
34
29
23d
3
a
Reactions were conducted with 15 mL of acetonitrile, 0.85 g (5 mmol) of benzyl bromide, 0.31 g (2 mmol) of the piperazine 4, 0.25 g (2.4 mmol) of benzaldehyde, and 0.5 g
(7.6 mmol) of zinc dust, pre-activated in the presence of TFA.
b
Determined by 1H NMR.
Isolated yields of 5.
The conversion of the starting amine was only partial.
c
d
In a following part of the study, we focused our attention to the
examination of reactions involving primary chiral amines. To this
end, R-(þ)-1-phenylethylamine (7) was chosen as the model sub-
strate. Indeed, this amine does not only constitute one of the most
reliable chiral inductors, both in terms of price and stereo-differen-
tiating abilities,17 it also generally provides the further opportunity of
cleaving the N-benzyl bond either by e.g., hydrogenolysis18 or nu-
cleophilic substitution by iodide.19 Nevertheless, due to the presence
mentioned above (Table 1, entry 8), ethyl glyoxylate conducted to
a lower reaction yield (Table 5, entry 5).
With the final aim of increasing the diastereoselectivity of the
reaction, we tried to use a more bulky primary amine related to R-
(þ)-1-phenylethylamine (7). To this end, it was chosen to replace
the phenyl by a naphtyl group. It can be noted that a strategy based
on the use of ortho-naphtol to interact with an imine function and
provide improved diastereoselectivities was employed by Alfonsov

9906
C. Haurena et al. / Tetrahedron 66 (2010) 9902e9911
Table 5
Multicomponent couplings starting from benzylzinc reagents, R-(þ)-1-phenylethylamine (7) and aldehydesa
CH3
R
CH3
H
H
N
Ar
ZnBr
+
N
H
+ R CHO
Ar
CH3CN, 10°C
7
8a-e
Entry
1
Benzylzinc bromide
Aldehyde
Time (h)
1.5
Product
Diastereoisomeric excess (de)b
Yield (%)c
82
8a
72
54
60
64
50
2
3
4
2
8b
8c
8d
8e
93
84
86
30
0.5
0.5
2
5
a
Reactions were conducted with 15 mL of acetonitrile, 5 mmol of the benzyl bromide, 0.25 g (2 mmol) of the benzylamine 7, 2.4 mmol of the aldehyde, and 0.5 g (7.6 mmol)
of zinc dust, pre-activated in the presence of TFA.
b
Determined by 1H NMR.
Isolated yields.
c
and co-workers in the synthesis of
a
-aminophosphonic acids.20
the major diastereoisomer arising from primary chiral amines
(Scheme 4).
However, this strategy might not be applicable here due to the
ease of deprotonation of phenol derivatives and the probable in-
efficiency of phenolates in the process.
Thus, (S)-1-(naphthalen-1-yl)ethylamine (9) was allowed to
react with benzylzinc bromide and benzaldehyde, providing the
three-component coupling product in 47% yield and 80% de
(Scheme 3).
In this case, we assume that the formation of the (R,R) di-
astereoisomer might be prevalent. However, only a selective
debenzylation giving rise to the formation of a known enantiomer
or a chemical correlation by the unambiguous preparation of one
diastereoisomer should corroborate this hypothesis.
CH3
CH3
H3C
N
H
H
H
CH3
N
Ph ZnBr
N
H
+
+ Ph CHO
Ph
CH3CN, 10°C, 3.5 h
47%
H
Ph
N
H
+
R CHO
9
10
R
H
d.e. = 80
Scheme 3. Effect of the use of a more bulky aromatic group.
7
BrZn
Ar
H
R
In spite of a notable decrease of the chemical yield, this exper-
iment revealed that a more important steric discrimination be-
tween the methyl and the aryl group should result in a notable
improvement of the diastereoselectivities. Consequently, this
H
H3C
H H3C
N
H
N
R
strategy might be extended to a larger range of a-methyl benzyl-
amine derivatives, which may ideally both supply steric hindrance
and deprotection opportunities by smooth and selective cleavage of
the proper benzylic CeN bond. Ideally, the phenyl should bear one
or more substituents, which could additionally provide activation
of the CeN bond, in regard with the ease of deprotection. The
search for such a reliable chiral auxiliary is currently in progress.21
While the assignment of the configurations of the asymmetric
carbons could neither be done by conventional NMR methods nor
crystallization and subsequent X-ray analysis, a predictive model
close to that of Yamamoto22 should be used to imagine the nature of
Ph
H
H3C
H
N
(R,R) diastereoisomer
Ar
H
R
Scheme 4. Prediction of the major diastereoisomer.

C. Haurena et al. / Tetrahedron 66 (2010) 9902e9911
9907
3. Conclusion
4.3. Typical procedure for the coupling of an aryl bromide
with (S)-methyl pyrrolidine-2-carboxylate and an aldehyde
(Table 2, preparation of compounds 3aej)
In conclusion, this work shows that a range of chiral amines
should be usable in the diastereoselective Mannich-related multi-
component synthesis of some model diarylmethylamines, 1,2-dia-
A dried 100 mL round-bottomed flask was flushed with argon
and charged with acetonitrile (40 mL). Cobalt bromide (0.7 g,
3 mmol), zinc bromide (0.66 g, 3 mmol), zinc dust (6 g, 92 mmol),
and methanesulfonic acid (0.02 mL) were successively added under
vigorous stirring. After 5 min, aryl bromide (15 mmol) was added
and the mixture was stirred for 30 min. After decantation, the clear
arylzinc solution was transferred dropwise using a syringe to
a mixture of the amine (5 mmol) and the aldehyde (5 mmol) in
ethylene glycol dimethyl ether (5 mL). The solution was stirred at
room temperature overnight. The reaction was quenched with
a saturated sodium carbonate solution (50 mL) and the organic
solution extracted with dichloromethane (2ꢂ100 mL). After re-
moval of the solvent, a chromatographic purification on a silica gel
column using a pentane/diethyl ether mixture as the eluent affor-
ded the pure product.
rylethylamines, and
b-arylethylamines, providing coupling
products in generally good yields and diastereoisomeric excesses.
While in this work, only harshly- or non-cleavable amines were
used, it would be highly valuable to employ easily convertible chiral
amines in the process, thus providing an access to enantioenriched
primary or secondary amines after subsequent deprotection. Con-
sequently, the design of a cleavable chiral amine, able to provide
high yields and diastereoisomeric excesses of coupling products,
would be highly desirable. The work presented herein thus con-
stitutes a first entry to the conception of a more flexible reaction
system, which will be the purpose of a further study.
4. Experimental
4.1. General
4.4. Typical procedure for the coupling of benzyl bromide
with ( )-trans-1-allyl-2,5-dimethylpiperazine and
benzaldehyde (Table 3, preparation of compound 5)
Solvents and reagents were purchased from commercial
suppliers and used without further purification. All reactions
were monitored by gas chromatography (GC) using a Varian
3400 chromatograph fitted with an SGE BP1 capillary column
A dried 25 mL round-bottomed flask was flushed with argon and
charged with acetonitrile (15 mL). Zinc dust (0.5 g, 7.6 mmol) and
trifluoroacetic acid (0.03 mL) were added under vigorous stirring.
After 5 min, benzyl bromide (0.85 g, 5 mmol) was added and
the mixture was stirred for 10 min. If required, the mixture was
cooled down and (ꢀ)-trans-1-allyl-2,5-dimethylpiperazine (0.31 g,
2 mmol) and benzaldehyde (0.25 g, 2.4 mmol) were added. The
resulting solutionwas stirred for 3e15 h. The reactionwas quenched
with a saturated ammonium chloride solution (50 mL) and the or-
ganic products extracted with dichloromethane (2100 mL). After
removal of the solvent, a chromatographic purification on a silica gel
column using a pentane/dichloromethane/triethylamine mixture as
the eluent (88/10/2) afforded the pure product.
(l¼5 m, ؼ0.32 mm, df¼0.4
mm). Infrared spectra were recorded
in ATR mode on a Bruker TENSOR 27 spectrometer and treated
via OPUS software. NMR spectra were recorded in CDCl3 (com-
pounds 3aej) or CD3OD (compounds 2aeh, 5, 8aee, 10) at
400 MHz (1H), 100 MHz (13C), and 376 MHz (19F) on a Bruker
Avance II 400 spectrometer. Chemical shifts (d) of the major
diastereoisomer are reported in parts per million (ppm) relative
to the residual solvent signal. Coupling constant values (J) are
given in hertz (Hz) and refer to apparent multiplicities, in-
dicated as follows: s (singlet), d (doublet), t (triplet), q (quartet),
m (multiplet), dd (doublet of doublets). Mass spectra were
recorded in ESIþ mode on a Trace 200 chromatograph fitted
with a CPSIL5CB/MS capillary column (l¼25 m, ؼ0.25 mm,
4.5. Typical procedure for the coupling of a benzyl bromide
with (R)-1-phenylethylamine (7) or (S)-1-(naphthalen-1-yl)
ethylamine (9) and an aldehyde (preparation of compounds
8aee and 10)
df¼0.12
mm). High Resolution Mass Spectrometry (HRMS) were
performed by the Mass Spectrometry service of the ICSN
(Institut de Chimie des Substances Naturelles), Gif-sur-Yvette,
France. Compounds, which have been previously described in
the literature are linked to the corresponding bibliographic
A dried 25 mL round-bottomed flask was flushed with argon and
charged with acetonitrile (15 mL). Zinc dust (0.5 g, 7.6 mmol) and
trifluoroacetic acid (0.03 mL) were added under vigorous stirring.
After 5 min, the benzyl bromide (5 mmol) was added and the solu-
tion stirred for 10 min. The mixture was then cooled to 10 ꢁC and the
amine (2 mmol) and the aldehyde (2.4 mmol) were added. The
resulting solution was stirred for 0.5e3 h at 10 ꢁC. The reaction was
quenched witha saturatedammoniumchloride solution(50 mL)and
the organic products extracted with dichloromethane (2ꢂ100 mL).
After removal of the solvent, a chromatographic purification on
a silica gel column using a pentane/dichloromethane/triethylamine
mixture as the eluent (93/5/2) afforded the pure product.
references whereas compounds labeled by asterisk (
best of our knowledge, new compounds.
*
) are, to the
4.2. Typical procedure for the coupling of a benzyl bromide
with (S)-methyl pyrrolidine-2-carboxylate (1a) or (S)-ethyl
pyrrolidine-2-carboxylate (1b) and an aldehyde (Table 1,
preparation of compounds 2aeh)
A dried 25 mL round-bottomed flask was flushed with argon
and charged with acetonitrile (15 mL). Zinc dust (0.7 g, 10.7 mmol)
and trifluoroacetic acid (0.04 mL) were added under vigorous stir-
ring. After 5 min, the benzyl bromide (7 mmol) was added and the
mixture stirred for 10 min. The amine (2 mmol) and the aldehyde
(2.4 mmol) were added and the resulting solution was stirred for
2.5e3 h at room temperature. The reaction was quenched with
a saturated ammonium chloride solution (50 mL) and the organic
products extracted with dichloromethane (2ꢂ100 mL). After re-
moval of the solvent, a chromatographic purification on a silica gel
column using a pentane/dichloromethane/triethylamine mixture
as the eluent (88/10/2) afforded the pure product.
4.6. Characterization data
4.6.1. (2S)-Ethyl 1-(1,2-diphenylethyl)pyrrolidine-2-carboxylate
yellow oil FT-IR (neat, cmꢃ1):
3062, 3028, 2975, 1727, 1602,
1495, 1453, 1369, 1269, 1174, 1080, 1028, 747, 698. 1H NMR:
7.16e7.14 (m,
*
(2a). Pale
n
d
1H), 7.13 (d, J¼4.4 Hz, 2H), 7.12e7.10 (m, 2H), 7.06e7.04 (m, 2H),
7.04e7.00 (m, 1H), 6.85e6.81 (m, 2H), 3.75 (dd, J¼10.8, 4.0 Hz, 1H), 3.53
(dd, J¼6.1, 3.5 Hz, 1H), 3.50 (q, J¼7.0 Hz, 2H), 3.37 (dd, J¼13.2, 4.1 Hz, 1H),
3.30e3.25 (m, 1H), 2.91 (dd, J¼12.7, 10.6 Hz, 1H), 2.71e2.64 (m, 1H),
2.18e2.01 (m, 2H), 1.97e1.76 (m, 2H), 1.19 (t, J¼7.0 Hz, 3H). 13C NMR:

9908
C. Haurena et al. / Tetrahedron 66 (2010) 9902e9911
d
177.0, 142.6, 140.1, 130.5, 130.3, 128.9, 128.4, 126.8, 72.8, 65.1, 61.5, 53.8,
2.70e2.62 (m, 1H), 2.42e2.33 (m, 1H), 1.85e1.77 (m, 2H), 1.76e1.68
(m, 2H),1.30e1.24 (m, 3H),1.18e1.11 (m, 2H),1.11e1.02 (m, 5H), 0.75
51.2, 42.7, 31.1, 24.7,14.5. MS, m/z (relative intensity): 250 ([MꢃCO2C2H5]þ,
8), 232 ([MꢃC7H7]þ, 100), 204 (60), 181 ([C14H13]þ, 8), 135 (15), 91
([C7H7]þ, 6), 70 (39). HRMS calcd for C21H25NO2 [MþH]þ: 324.1964,
found: 324.1976.
(t, J¼7.3 Hz, 3H). 13C NMR:
d 177.6, 142.0, 130.3, 129.4, 126.9, 63.7,
62.6, 52.2, 47.1, 36.7, 33.3, 33.0, 30.6, 30.2, 27.1, 25.1, 23.7,14.5. MS, m/
z (relative intensity): 226 ([MꢃC7H7]þ, 100), 166 (24), 70 (8). HRMS
calcd for C20H31NO2 [MþH]þ: 318.2433, found: 318.2429.
4.6.2. (2S)-Methyl 1-(1,2-diphenylethyl)pyrrolidine-2-carboxylate
(2b). Yellow oil. FT-IR (neat, cmꢃ1):
3062, 3025, 2974, 1729, 1600,
1495, 1453, 1171, 1079, 747, 698. 1H NMR:
7.15e7.09 (m, 5H),
*
n
4.6.7. (2S)-Methyl 1-(1-(p-tolyl)octan-2-yl)pyrrolidine-2-carboxyl-
d
ate
*
(2g). Yellow oil. FT-IR (neat, cmꢃ1):
n 3047, 2926, 2855, 1733,
7.06e7.01(m, 3H), 6.85e6.81 (m, 2H), 3.72 (dd, J¼10.9, 4.4 Hz, 1H),
3.53 (dd, J¼9.8, 3.6, 1H), 3.43 (s, 3H), 3.36 (dd, J¼12.8, 4.1 Hz, 1H),
2.95e2.88 (m, 1H), 2.71e2.63 (m, 1H), 2.14e2.07 (m, 1H), 1.99e1.77
1704, 1515, 1457, 1436, 1276, 1194, 1165, 803, 758, 724. 1H NMR:
d
7.10e7.02 (m, 4H), 3.68 (s, 3H), 3.56 (dd, J¼8.2, 4.2 Hz, 1H),
3.00e2.94 (m, 1H), 2.92e2.83 (m, 2H), 2.80e2.72 (m, 1H), 2.43 (dd,
J¼12.3, 8.2 Hz, 1H), 2.30 (s, 3H), 2.02e1.95 (m, 1H), 1.94e1.86 (m,
2H), 1.85e1.78 (m, 1H), 1.40e1.35 (m, 3H), 1.26e1.22 (m, 2H),
(m, 4H). 13C NMR:
d 177.3, 142.3, 140.2, 130.5, 130.3, 129.0, 128.9,
128.4, 126.8, 72.8, 65.0, 53.7, 52.0, 42.9, 31.1, 24.7. MS, m/z (relative
intensity): 250 ([MꢃCO2CH3]þ, 5), 218 ([MꢃC7H7]þ, 100), 181
([C14H13]þ, 7), 121 (92), 91 ([C7H7]þ, 10), 70 (7). HRMS calcd for
C20H23NO2 [MþH]þ: 310.1807, found: 310.1804.
1.21e1.14 (m, 5H), 0.86 (t, J¼6.9 Hz, 3H). 13C NMR:
d 177.3, 138.8,
136.4, 130.2, 130.0, 63.6, 62.5, 52.2, 47.1, 36.3, 33.3, 32.9, 30.5, 30.2,
27.1, 25.0, 23.7, 21.1, 14.4. MS, m/z (relative intensity): 226
([MꢃC8H9]þ, 100), 166 (46), 70 (13). HRMS calcd for C21H33NO2
[MþH]þ: 332.2590, found: 332.2581.
4.6.3. (2S)-Methyl 1-(2-(2-cyanophenyl)-1-phenylethyl)pyrrolidine-
2-carboxylate
2949, 2843, 2223, 1731, 1599, 1486, 1451, 1434, 1273, 1195, 1167,
1086, 759, 701. 1H NMR:
7.54e7.50 (m, 1H), 7.30e7.26 (m, 1H),
*
(2c). Yellow oil. FT-IR (neat, cmꢃ1):
n 3062, 3029,
4.6.8. (2S)-Methyl 1-(1-ethoxy-1-oxo-3-phenylpropan-2-yl)pyrroli-
d
dine-2-carboxylate
2926, 2851, 1726, 1488, 1437, 1310, 1165, 1004, 749, 700. 1H NMR:
7.28e7.23 (m, 2H), 7.22e7.17 (m, 2H), 7.20e7.17 (m, 1H), 3.98 (q,
*
(2h). Colorless oil. FT-IR (neat, cmꢃ1):
n 2974,
7.23e7.19 (m, 1H), 7.16e7.14 (m, 1H), 7.16e7.12 (m, 1H), 7.15e7.10
(m, 2H), 6.89 (d, J¼7.6 Hz,1H), 3.90 (dd, J¼11.6, 3.8 Hz,1H), 3.62 (dd,
J¼13.0, 4.8 Hz,1H), 3.49 (dd, J¼9.6, 3.7 Hz,1H), 3.41 (s, 3H), 3.10 (dd,
J¼12.9, 11.2 Hz, 1H), 2.84e2.75 (m, 2H), 2.20e2.08 (m, 1H),
d
J¼7.3 Hz, 2H), 3.83 (dd, J¼9.1, 6.7 Hz, 1H), 3.61 (s, 3H), 3.19e3.03 (m,
1H), 3.09e3.03 (m, 1H), 3.03e2.98 (m, 1H), 2.83e2.76 (m, 2H),
2.20e2.06 (m, 1H), 1.95e1.89 (m, 1H), 1.87e1.80 (m, 2H), 1.14 (t,
2.00e1.87 (m, 2H), 1.86e1.77 (m, 1H). 13C NMR:
d 177.4, 144.0, 141.4,
133.6, 133.5, 132.2, 130.2, 129.1, 128.8, 127.9, 119.3, 114.0, 71.6, 65.3,
53.7, 52.1, 41.3, 31.2, 24.8. MS, m/z (relative intensity): 327 (7), 281
(23), 275 ([MꢃCO2CH3]þ, 10), 253 (18), 225 (7), 218 ([MꢃC8H6N]þ,
100), 207 (76), 191 (16), 179 (9), 121 (43), 91 (8), 70 (6). HRMS calcd
for C21H22N2O2 [MþH]þ: 335.1760, found: 335.1758.
J¼8.7 Hz, 3H). 13C NMR:
d 176.2, 173.3, 139.5, 130.2, 129.3, 127.4,
65.8, 63.9, 61.4, 52.4, 52.3, 37.8, 30.4, 24.7, 14.6. MS, m/z (relative
intensity): 246 ([MꢃCO2Me]þ, 41), 232 ([MꢃCO2Et]þ, 95), 214
([MꢃC7H7]þ, 100), 186 (24), 172 (40), 158 (6), 135 (6), 103 (5), 70
(10). HRMS calcd for C17H23NO4 [MþH]þ: 306.1705, found:
306.1708.
4.6.4. (2S)-Methyl 1-(1-(2-chlorophenyl)-2-phenylethyl)pyrrolidine-
2-carboxylate
2949, 2843, 1732, 1495, 1471, 1435, 1354, 1262, 1194, 1167, 1051,
1034, 756, 699. 1H NMR:
7.63e7.58 (m, 2H), 7.14e7.10 (m, 2H),
*
(2d). Yellow oil. FT-IR (neat, cmꢃ1):
n
3062, 3028,
4.6.9. (S)-Methyl 1-benzhydrylpyrrolidine-2-carboxylate
oil. FT-IR (neat, cmꢃ1):
2949, 1731, 1659, 1450, 1276, 1196, 1168, 698.
1H NMR:
*
(3a). Colorless
n
d
d
7.55 (t, J¼7.1 Hz, 4H), 7.33 (q, J¼7.2 Hz, 4H), 7.24 (q,
7.06e7.03 (m, 3H), 6.91e6.87 (m, 2H), 4.55 (dd, J¼10.7, 4.5 Hz, 1H),
3.57e3.51 (m, 2H), 3.42 (s, 3H), 3.41e3.35 (m, 1H), 2.92 (dd,
J¼13.0, 10.8 Hz, 1H) 2.72e2.74 (m, 1H), 2.18e2.07 (m, 1H),
J¼6.9 Hz, 2H), 4.98 (s, 1H), 3.58 (dd, J¼9.0, 3.0 Hz, 1H), 3.51 (s, 3H),
3.11 (q, J¼4.8 Hz, 1H), 2.70 (q, J¼8.8 Hz, 1H), 2.23e2.14 (m, 1H),
2.05e1.93 (m, 3H). 13C NMR:
d 175.2, 143.5, 143.1, 128.4, 128.3, 128.1,
2.00e1.78 (m, 4H). 13C NMR:
d
177.2, 139.9, 139.1, 135.9, 131.7, 130.5
128.0, 127.1, 127.1, 72.8, 63.3, 52.1, 51.1, 30.2, 23.7. MS, m/z (relative
intensity): 295 ([M]þ, 10), 237 (5), 236 ([MꢃCO2Me]þ, 32), 168 (15),
167 ([MꢃPro-OMe]þ, 100), 166 (8), 165 (21), 152 (10). HRMS calcd for
C19H21NO2 [MþH]þ: 296.1651, found: 296.1649.
(two peaks), 130.1, 129.5, 129.4, 128.8, 127.7, 127.0, 66.1, 64.9, 53.6,
52.0, 42.4, 31.2, 24.8. MS, m/z (relative intensity): 284
([MꢃCO2CH3]þ, 7), 252 ([MꢃC7H7]þ, 100), 215 ([MꢃC6H10NO2]þ,
5), 157 (13), 155 (39). HRMS calcd for C20H22ClNO2 [MþH]þ:
344.1417, found: 344.1424.
4.6.10. (2S)-Methyl 1-((4-methoxyphenyl)(phenyl)methyl) pyrroli-
dine-2-carboxylate
*
(3b). Pale yellow oil. FT-IR (neat, cmꢃ1):
n
2950,
4.6.5. (2S)-Methyl 1-(1-(3-chlorophenyl)-2-phenylethyl)pyrrolidine-
1731, 1609, 1509, 1453, 1245, 1169, 1030, 700. 1H NMR:
d 7.34 (d,
2-carboxylate
2949, 2841, 1731, 1595, 1573, 1474, 1454, 1194, 1166, 1077, 787, 750,
698. 1H NMR:
7.17 (s, 1H), 7.15e7.13 (m, 1H), 7.13e7.12 (m, 1H),
*
(2e). Yellow oil. FT-IR (neat, cmꢃ1):
n
3062, 3027,
J¼7.5 Hz, 2H), 7.24 (d, J¼8.3 Hz, 2H), 7.16 (t, J¼7.5 Hz, 2H), 7.06 (q,
J¼7.2 Hz, 1H), 6.70 (d, J¼8.3 Hz, 2H), 4.64 (s, 3H), 3.38e3.36 (m, 1H),
3.35 (s, 3H), 2.91e2.86 (m, 1H), 2.56e2.50 (m, 1H), 2.06e2.01 (m,
d
7.11e7.07 (m, 2H), 7.07e7.04 (m, 1H), 6.99e6.95 (m, 1H), 6.85 (d,
J¼7.5 Hz, 2H), 3.75 (dd, J¼11.5, 4.9 Hz, 1H), 3.51 (dd, J¼9.6, 3.3 Hz,
1H), 3.48 (s, 3H), 3.37 (dd, J¼13.4, 4.7 Hz, 1H), 3.29e3.22 (m, 1H),
2.90e2.82 (m, 1H), 2.68 (q, J¼7.4 Hz, 1H), 2.16e2.05 (m, 1H),
1H), 1.87e1.74 (m, 3H). 13C NMR:
d 175.3, 158.6, 143.8, 135.3, 129.0,
128.2, 127.9, 126.9, 113.7, 71.9, 63.3, 55.2, 51.9, 51.1, 30.1, 23.6. MS, m/
z (relative intensity): 325 ([M]þ, 9), 266 ([MꢃCO2Me]þ,11),198 (15),
197 ([MꢃPro-OMe]þ, 100), 182 (7), 166 (5), 165 (8). HRMS calcd for
C20H23NO3 [MþH]þ: 326.1756, found: 326.1759.
1.93e1.95 (m, 2H), 1.85e1.78 (m, 1H). 13C NMR:
d 177.2, 145.2, 139.6,
134.9, 130.5, 130.3, 130.1, 129.0, 128.7, 128.4, 127.1, 72.2, 65.2, 53.5,
52.0, 42.7, 31.1, 24.0. MS, m/z (relative intensity): 284
([MꢃCO2Me]þ, 8), 252 ([MꢃC7H7]þ, 100), 179 (9), 155 (41), 130 (5).
HRMS calcd for C20H22ClNO2 [MþH]þ: 344.1417, found: 344.1421.
4.6.11. (2S)-Methyl 1-((4-chlorophenyl)(phenyl)methyl) pyrrolidine-
2-carboxylate
*
(3c). Colorless oil. FT-IR (neat, cmꢃ1):
n
2949, 1731,
1660, 1488, 1273, 1197, 1169, 1088, 698. 1H NMR:
d
7.43 (t, J¼8.5 Hz,
4H), 7.32e7.18 (m, 5H), 4.79 (s, 1H), 3.51e3.48 (m, 1H), 3.49 (s, 3H),
3.05e2.99 (m, 1H), 2.67e2.2.61 (m, 1H), 2.20e2.14 (m, 1H),
4.6.6. (2S)-Methyl 1-(1-phenyloctan-2-yl)pyrrolidine-2-carboxylate
(2f). Pale yellow oil. FT-IR (neat, cmꢃ1):
2957, 2927, 2855, 1732,
1704, 1495, 1455, 1435, 1194, 1165, 1102, 744, 699. 1H NMR:
7.16e7.13 (m, 1H), 7.07e7.04 (m, 4H), 3.58 (s, 3H), 3.46 (dd, J¼8.2,
4.3 Hz,1H), 2.91e2.85 (m,1H), 2.84e2.81 (m,1H), 2.80e2.76 (m,1H),
*
n
2.00e1.78 (m, 3H). 13C NMR:
d 175.11, 142.93, 141.71, 132.68, 129.19,
128.58, 128.41, 127.90, 127.32, 71.98, 63.11, 52.08, 51.20, 30.18, 23.55.
MS, m/z (relative intensity): 329 ([M]þ, 8), 294 ([MꢃCl]þ, 8), 272
(14), 271 (9), 270 ([MꢃCO2Me]þ, 42), 203 (34), 202 (15), 201
d

C. Haurena et al. / Tetrahedron 66 (2010) 9902e9911
9909
([MꢃPro-OMe]þ, 100), 167 (5), 166 (37), 165 (38), 164 (5). HRMS
calcd for C19H20ClNO2 [MþH]þ: 330.1261, found: 330.1272.
100), 216 (5), 215 (16), 166 (12), 165 (12). HRMS calcd for
C
20H20F3NO2 [MþH]þ: 364.1524, found: 364.1517.
4.6.12. (2S)-Methyl 1-(((4-ethoxycarbonyl)phenyl) (phenyl)methyl)
4.6.17. (2S)-Methyl 1-(phenyl(4-(m-tolyl)methyl))pyrrolidine-2-car-
boxylate 2949, 1731, 1659,
(3j). Colorless oil. FT-IR (neat, cmꢃ1):
1279, 1197, 1160, 705. 1H NMR:
(m, 4H), 7.23e7.16 (m, 2H), 7.02 (d, J¼6.9 Hz, 1H), 4.77 (s, 1H),
3.53e3.49 (m,1H), 3.50 (s, 3H), 3.07e3.02 (m,1H), 2.67 (q, J¼8.9 Hz,
1H), 2.34 (s, 3H), 2.21e2.13 (m, 1H), 2.02e1.90 (m, 3H). 13C NMR:
pyrrolidine-2-carboxylate
*
(3d). Colorless oil. FT-IR (neat, cmꢃ1):
n
*
n
2951, 1714, 1609, 1271, 1100, 1020, 710. 1H NMR:
d
7.96 (t, J¼6.1 Hz,
d
7.49 (d, J¼7.3 Hz, 2H), 7.32e7.29
2H), 7.55 (t, J¼6.1 Hz, 2H), 7.44e7.39 (m, 3H), 7.25e7.15 (m, 2H),
4.90 (s, 1H), 4.31 (q, J¼6.9 Hz, 2H), 3.51e3.47 (m, 1H), 3.46 (s, 3H),
2.99e2.96 (m, 1H), 2.67e2.60 (m, 1H), 2.15e2.11 (m, 1H), 1.92e1.83
(m, 3H), 1.33 (t, J¼6.9 Hz, 3H). 13C NMR:
d
174.9, 166.3, 148.7, 142.6,
d 175.3, 143.4, 143.2, 137.7, 128.7, 128.4, 128.2, 128.1, 127.4, 127.0,
129.6, 128.5, 128.0, 128.0, 127.7, 127.3, 71.9, 62.9, 60.7, 52.1, 51.1, 30.0,
23.4, 14.3. MS, m/z (relative intensity): 367 ([M]þ, 7), 309 (11), 308
([MꢃCO2Me]þ, 57), 240 (18), 239 ([MꢃPro-OMe]þ, 100), 167 (18),
166 (15), 165 (20). HRMS calcd for C22H25NO4 [MþH]þ: 368.1862,
found: 368.1880.
125.1, 72.9, 63.4, 52.2, 51.1, 30.2, 23.6, 21.6. MS, m/z (relative in-
tensity): 309 ([M]þ, 9), 251 (7), 250 ([MꢃCO2Me]þ, 28),182 (15),181
([MꢃPro-OMe]þ, 100), 166 (20), 165 (18). HRMS calcd for
C20H23NO2 [MþH]þ: 310.1807, found: 310.1801.
4.6.18. (2S,5R)-1-Allyl-4-(1,2-diphenylethyl)-2,5-dimethylpiperazine
(5). Yellow oil. FT-IR (neat, cmꢃ1):
3061, 3023, 2971, 2926, 2818,
1493, 1450, 1375, 1338, 1176, 1151, 1070, 1055, 997, 915, 744, 726,
694. 1H NMR:
*
4.6.13. (2S)-Methyl 1-(phenyl(thiophen-3-yl)methyl)pyrrolidine-2-
n
carboxylate
*
(3f). Colorless oil. FT-IR (neat, cmꢃ1):
n
2948, 2842,
7.48 (d,
1730, 1651, 1452, 1434, 1275, 1196, 1158, 704. 1H NMR:
d
d
7.39 (d, J¼7.5 Hz, 2H), 7.26 (t, J¼7.5 Hz, 2H),
J¼7.4 Hz, 2H), 7.32 (t, J¼7.4 Hz, 2H), 7.25e7.17 (m, 2H), 7.12 (d,
J¼4.9 Hz, 1H), 4.87 (s, 1H), 3.53 (s, 3H), 3.46 (dd, J¼9.4, 4.1 Hz, 1H),
3.08e3.04 (m, 1H), 2.56 (q, J¼9.0 Hz, 1H), 2.16e2.09 (m, 1H),
7.21e7.17 (m, 1H), 7.17e7.15 (m, 2H), 7.15e7.13 (m, 2H), 7.08e7.05
(m, 1H), 5.96e5.84 (m, 1H), 5.29e5.25 (m, 1H), 5.25e5.20 (m, 1H),
4.44 (t, J¼7.6 Hz, 1H), 3.51e3.44 (m, 1H), 3.19 (d, J¼7.3 Hz, 2H),
3.00e2.94 (m, 1H), 2.93e2.88 (m, 1H), 2.88e2.84 (m, 1H), 2.66 (dd,
J¼11.5, 2.7 Hz, 1H), 2.36 (t, J¼10.1 Hz, 1H), 2.26e2.18 (m, 1H), 2.11 (t,
J¼10.1 Hz, 1H), 1.27 (d, J¼6.5 Hz, 3H), 1.02 (d, J¼5.9 Hz, 3H). 13C
1.99e1.79 (m, 3H). 13C NMR:
d 175.2, 144.5, 142.3, 128.4, 128.0,
127.7, 127.2, 125.3, 122.2, 68.3, 63.4, 52.2, 51.3, 30.2, 23.6. MS, m/z
(relative intensity): 301 ([M]þ, 19), 243 (6), 242 ([MꢃCO2Me]þ,
33), 175 (6), 174 (12), 173 ([MꢃPro-OMe]þ, 100), 172 (5), 171 (8),
129 (17). HRMS calcd for C17H19NO2S [MþH]þ: 302.1215, found:
302.1226.
NMR:
d 141.6, 141.3, 134.2, 130.9, 130.2, 129.3, 128.9, 128.0, 126.8,
119.9, 64.0, 60.7, 57.5, 57.1, 53.5, 52.9, 30.8, 17.9, 16.9. MS, m/z (rel-
ative intensity): 243 (100), 228 (12), 201 (36), 91 ([C7H7]þ, 15).
HRMS calcd for C23H30N2 [MþH]þ: 335.2487, found: 335.2483.
4.6.14. (2S)-Methyl
carboxylate
(3g). Brown oil. FT-IR (neat, cmꢃ1):
1666, 1596, 1413, 1279, 1198, 1170, 700. 1H NMR:
1-(phenyl(pyridin-4-yl)methyl)pyrrolidine-2-
*
n
3028, 2950, 1730,
4.6.19. 1,2-Diphenyl-N-((R)-1-phenylethyl)ethylamine23
d
8.50 (d, J¼5.9 Hz,
(8a). Yellow oil. FT-IR (neat, cmꢃ1):
n
3061, 3026, 2924, 2852, 1493,
2H), 7.40 (d, J¼5.9 Hz, 2H), 7.36 (d, J¼7.3 Hz, 2H), 7.29 (t, J¼7.2 Hz,
2H), 7.23 (t, J¼7.2 Hz, 1H), 4.88 (s, 1H), 3.51 (s, 3H), 3.48e3.36 (m,
1H), 2.96e2.92 (m, 1H), 2.68 (q, J¼8.2 Hz, 1H), 2.18e2.12 (m, 1H),
1452, 1155, 1129, 1070, 1028, 758, 696. 1H NMR:
d
7.33e7.30 (m, 2H),
7.29e7.27 (m, 1H), 7.27e7.24 (m, 2H), 7.24e7.22 (m, 2H), 7.22e7.19
(m, 2H), 7.19e7.17 (m, 1H), 7.15e7.11 (m, 2H), 7.10e7.07 (m, 1H),
6.92e6.88 (m, 2H), 3.83 (dd, J¼8.9, 5.6 Hz, 1H), 3.76 (q, J¼6.5 Hz,
1H), 3.18 (dd, J¼13.2, 5.6 Hz, 1H), 2.87 (dd, J¼13.2, 8.9 Hz, 1H), 1.32
1.97e1.83 (m, 3H). 13C NMR:
d 174.9, 152.3, 150.0, 140.9, 128.6, 128.2,
127.7, 122.8, 70.7, 62.7, 51.2, 51.0, 29.8, 23.4. MS, m/z (relative in-
tensity): 296 ([M]þ, 6), 238 (10), 237 ([MꢃCO2Me]þ, 63), 195 (5),
169 (14), 168 ([MꢃPro-OMe]þ, 100), 167 (35). HRMS calcd for
C18H20N2O2 [MþH]þ: 297.1603, found: 297.1594.
(d, J¼6.5 Hz, 3H). 13C NMR:
d 146.4, 144.0, 140.1, 130.4, 129.6, 129.3,
129.1, 128.8, 128.2, 128.1, 127.9, 127.1, 63.7, 56.2, 44.1, 22.4. MS, m/z
(relative intensity): 210 (94), 165 (9), 106 (100), 91 ([C7H7]þ, 9), 79
(38), 77 ([C6H5]þ, 21), 51 (5). HRMS calcd for C22H23N [MþH]þ:
302.1909, found: 302.1916.
4.6.15. (2S)-Methyl
dine-2-carboxylate
1731, 1597, 1487, 1451, 1434, 1279, 1257, 1159, 1041, 704. 1H NMR:
1-((3-methoxyphenyl)(phenyl)methyl)pyrroli-
*
(3h). Yellow oil. FT-IR (neat, cmꢃ1):
n
2949,
4.6.20. 1-Phenyl-N-((R)-1-phenylethyl)-2-(o-tolyl)ethylamine
(8b). Colorless oil. FT-IR (neat, cmꢃ1):
3061, 3025, 2962, 2924,
2860, 1492, 1451, 1369, 1118, 1070, 1054, 1026, 844, 756. H NMR:
7.33e7.26 (m, 2H), 7.26e7.23 (m, 1H), 7.23e7.21 (m, 2H), 7.21e7.19
*
d
7.34 (d, J¼7.3 Hz, 2H), 7.15 (t, J¼7.3 Hz, 2H), 7.12e7.05 (m, 2H),
n
1
6.96e6.91 (m, 2H), 6.61e6.58 (m, 2H), 4.65 (s, 1H), 3.64 (s, 3H),
3.39e3.34 (m, 4H), 2.93e2.87 (m, 1H), 2.55 (q, J¼8.9 Hz, 1H),
d
2.05e2.00 (m, 1H), 1.86e1.68 (m, 3H). 13C NMR:
d
175.4, 159.6,
(m, 2H), 7.19e7.16 (m, 1H), 7.11e7.07 (m, 2H), 6.99e6.96 (m, 1H),
6.91e6.89 (m, 1H), 6.89e6.87 (m, 1H), 6.79e6.75 (m, 1H), 3.83 (dd,
J¼9.0, 5.5 Hz, 1H), 3.78 (q, J¼6.7 Hz, 1H), 3.20 (dd, J¼13.3, 5.5 Hz,
1H), 2.87 (dd, J¼13.3, 9.0 Hz, 1H), 2.02 (s, 3H), 1.31 (d, J¼6.7 Hz, 3H).
145.2, 129.2, 128.3, 127.9, 127.1, 120.4, 113.5, 112.5, 72.7, 63.2, 55.1,
52.1, 51.1, 30.2, 23.6. MS, m/z (relative intensity): 325 ([M]þ, 17),
267 (9), 266 ([MꢃCO2Me]þ, 42), 198 (17), 197 ([MꢃPro-OMe]þ,
100), 182 (14), 181 (6), 179 (5), 169 (9), 166 (6), 165 (16), 154 (5), 153
(7). HRMS calcd for C20H23NO3 [MþH]þ: 326.1756, found:
326.1764.
13C NMR:
d 146.6, 144.3, 138.3, 137.7, 131.4, 131.1, 129.6, 129.3, 128.7,
128.2, 128.1, 127.9, 127.3, 126.6, 62.4, 56.5, 41.6, 22.7, 19.6. MS, m/z
(relative intensity): 210 ([MꢃC8H9]þ, 100), 165 (5), 106 (100), 79
(28), 77 ([C6H5]þ, 16). HRMS calcd for C23H25N [MþH]þ: 316.2065,
found: 316.2074.
4.6.16. (2S)-Methyl
1-(phenyl(4-(trifluoromethyl)phenyl)methyl)
pyrrolidine-2-carboxylate
*
(3i). Yellow oil. FT-IR (neat, cmꢃ1):
n
2992, 1732, 1618, 1323, 1198, 1160, 1119, 1065, 700. 1H NMR:
d
7.64
4.6.21. 1-(2-Fluorophenyl)-2-phenyl-N-((R)-1-phenylethyl)ethyl-
(d, J¼8.1 Hz, 2H), 7.55 (d, J¼8.1 Hz, 2H), 7.44 (d, J¼7.5 Hz, 2H), 7.31
(t, J¼7.5 Hz, 2H), 2.24 (t, J¼7.4 Hz, 1H), 4.94 (s, 3H), 3.53 (dd, J¼9.0,
2.7 Hz, 1H), 3.49 (s, 3H), 3.04e2.99 (m, 1H), 2.69 (q, J¼8.4 Hz, 1H),
amine
*
(8c). Colorless oil. FT-IR (neat, cmꢃ1):
n 3062, 3027, 2963,
2924, 1487, 1453, 1216, 1128, 1077, 1029, 824, 755, 697. 1H NMR:
d
7.22e6.80 (m, 14H), 4.14 (dd, J¼8.9, 5.7 Hz, 1H), 3.62 (q, J¼6.6 Hz,
2.21e2.16 (m, 1H), 2.02e1.90 (m, 3H). 13C NMR:
d
(ppm): 175.1,
1H), 3.11e3.04 (m,1H), 2.85e2.78 (m,1H), 1.20 (d, J¼6.6 Hz, 3H). 13C
147.6, 141.9, 129.2 (q, J¼32.0 Hz), 128.6, 128.2, 128.0, 127.5, 125.3 (q,
NMR:
d
165.3 (d, J¼243.2 Hz), 146.2, 139.7, 130.3, 130.1 (d, J¼4.7 Hz),
J¼3.0 Hz), 124.2 (q, J¼270.0 Hz), 71.7, 63.0, 51.5, 51.2, 30.0, 23.4. 19F
129.8 (d, J¼8.4 Hz), 129.5, 129.1, 128.2, 127.9, 127.7, 127.2, 125.3 (d,
NMR:
d
ꢃ63.00. MS, m/z (relative intensity): 363 ([M]þ, 6), 344 (5),
J¼3.4 Hz), 116.1 (d, J¼23.0 Hz), 56.7, 56.6, 43.0, 22.5. 19F NMR:
305 (13), 304 ([MꢃCO2Me]þ, 67), 236 (14), 235 ([MꢃPro-OMe]þ,
d
ꢃ123.42. MS, m/z (relative intensity): 216 ([MꢃC7H7]þ, 100), 153

9910
C. Haurena et al. / Tetrahedron 66 (2010) 9902e9911
(7), 112 (86), 105 ([C8H9]þ, 62), 103 (15), 85 (14), 79(14), 77 ([C6H5]þ,
5. (a) Prakash, G. K. S.; Mandal, M.; Schweizer, S.; Petasis, N. A.; Olah, G. A. J. Org.
Chem. 2002, 67, 3718e3723; (b) Petasis, N. A.; Boral, S. Tetrahedron Lett. 2001,
42, 539e542; (c) Petasis, N. A.; Zavialov, I. A. J. Am. Chem. Soc. 1998, 120,
11798e11799; (d) Petasis, N. A.; Akritopoulou, I. Tetrahedron Lett. 1993, 34,
11). HRMS calcd for C22H22FN [MþH]þ: 320.1815, found: 320.1819.
583e586.
ˇ
4.6.22. 2-Phenyl-N-((R)-1-phenylethyl)-1-(thiophen-3-yl)ethyl-
ꢀ
amine
2922, 2850, 1493, 1452, 1127, 1077, 1028, 780, 761, 697, 653. 1H
NMR: 7.24e7.18 (m, 3H), 7.17e7.11 (m, 3H), 7.05e6.96 (m, 3H),
*
(8d). Colorless oil. FT-IR (neat, cmꢃ1):
n 3061, 3026, 2961,
6. (a) Desrosier, J.-N.; Cote, A.; Charette, A. B. Tetrahedron 2005, 61, 6186e6192;
ˇ
ꢀ
(b) Cote, A.; Charette, A. B. J. Org. Chem. 2005, 70, 10864e10867; (c) Akullian, L.
C.; Snapper, M. L.; Hoveyda, A. H. Angew. Chem., Int. Ed. 2003, 42, 4244e4247;
(d) Porter, J. R.; Traverse, J. F.; Hoveyda, A. H.; Snapper, M. L. J. Am. Chem. Soc.
2001, 123, 10409e10410.
d
6.88 (dd, J¼5.1, 1.3 Hz, 1H), 6.82 (dd, J¼2.8, 1.0 Hz, 1H), 6.82e6.77
(m, 2H), 3.97 (dd, J¼9.1, 5.3 Hz, 1H), 3.82 (q, J¼6.6 Hz, 1H), 3.19 (dd,
J¼13.1, 5.3 Hz, 1H), 2.87 (dd, J¼13.1, 9.1 Hz, 1H), 1.35 (d, J¼6.6 Hz,
7. (a) Fan, R.; Pu, L.; Qin, L.; Wen, F.; Yao, G.; Wu, J. J. Org. Chem. 2007, 72, 3149e3151;
(b) Aschwanden, P.; Stephenson, C. R. J.; Carreira, E. M. Org. Lett. 2006, 8,
2437e2440; (c) Gommermann, N.; Knochel, P. Tetrahedron 2005, 61,
11418e11426; (d) Dube, H.; Gommermann, N.; Knochel, P. Synthesis 2004,
2015e2025; (e) Bieber, L. W.; Da Silva, M. F. Tetrahedron Lett. 2004, 45,
8281e8283; (f) Estevam, I. H. S.; Bieber, L. W. Tetrahedron Lett. 2003, 44, 667e670;
(g) Wei, C.; Li, Z.; Li, C.-J. Org. Lett. 2003, 5, 4473e4475; (h) Wei, C.; Li, C.-J. J. Am.
Chem. Soc. 2003, 125, 9584e9585; (i) Gommermann, N.; Koradin, C.; Polborn, K.;
Knochel, P. Angew. Chem., Int. Ed. 2003, 42, 5763e5766; (j) Sakaguchi, S.; Kubo, T.;
3H). 13C NMR:
d 146.2, 145.0, 140.1, 130.3, 129.6, 129.1, 128.2, 127.9,
127.5, 127.2, 126.7, 123.1, 59.1, 56.5, 43.4, 22.5. MS, m/z (relative
intensity): 216 ([MꢃC7H7]þ, 100), 153 (7), 112 (86), 105 ([C8H9]þ,
62), 103 (15), 85 (14), 79 (14), 77 ([C6H5]þ, 11). HRMS calcd for
C20H21NS [MþH]þ: 308.1473, found: 308.1458.
ꢀ
ꢀ
Ishii, Y. Angew. Chem., Int. Ed. 2001, 40, 2534e2536; (k) Choucair, B.; Leon, H.; Mire,
M.-A.; Lebreton, C.; Mosset, P. Org. Lett. 2000, 2, 1851e1853.
8. For systems employing the Petasis reaction, see: (a) Petasis, N. A.; Goodman,
A.; Zavialov, I. A. Tetrahedron 1997, 53, 16463e16470; (b) Petasis, N. A.; Za-
vialov, I. A. J. Am. Chem. Soc. 1997, 119, 445e446; (c) Jiang, B.; Xu, M. Org. Lett.
2002, 4, 4077e4080; (d) Southwood, T. J.; Curry, M. C.; Hutton, C. A. Tetra-
hedron 2006, 62, 236e242 For systems based on the Ugi reaction, see: (e)
Martquarding, D.; Hoffman, P.; Heitzer, H.; Ugi, I. J. Am. Chem. Soc. 1970, 92,
1969e1971; (f) Kunz, H.; Sager, W. Angew. Chem., Int. Ed. Engl. 1987, 26,
557e559; (g) Ross, G. F.; Herdtweck, E.; Ugi, I. Tetrahedron 2002, 58,
6127e6133; (h) Kunz, H.; Perengle, W. J. Am. Chem. Soc. 1988, 110, 651e652; (i)
Owens, T. D.; Araldi, G.-L.; Nutt, R. F.; Semple, E. J. Tetrahedron Lett. 2001, 42,
6271e6274; (j) Gulevich, A. V.; Balenkova, E. S.; Nenajdenko, V. G. J. Org. Chem.
2007, 72, 7878e7885 For the use of Mannich and related reactions, see: (k)
Loh, T.-P.; Chen, S.-L. Org. Lett. 2002, 4, 3647e3650; (l) Delaye, P.-O.; Vasse, J.-L.;
Szymoniak, J. Org. Biomol. Chem. 2010, 8, 3635e3637; (m) Rondot, C.; Zhu, J.
Org. Lett. 2005, 7, 1641e1644; (n) Saidi, M. R.; Azizi, N. Tetrahedron: Asymmetry
2003, 14, 389e392.
4.6.23. Ethyl
(8e). Yellow oil. FT-IR (neat, cmꢃ1):
1453, 1179, 1136, 1027, 759, 698. 1H NMR:
3-phenyl-2-(((R)-1-phenylethyl)amino)propanoate
3062, 3030, 2932, 1729, 1494,
7.20e7.18 (m, 1H),
*
n
d
7.18e7.17 (m, 2H), 7.16e7.14 (m, 2H), 7.13e7.11 (m, 1H), 7.11e7.08
(m, 2H), 7.05e7.01 (m, 2H), 3.80e3.66 (m, 2H), 3.65 (q, J¼6.7 Hz,
1H), 3.36 (dd, J¼8.2, 5.9 Hz, 1H), 2.94e2.88 (m, 1H), 2.80e2.73 (m,
1H), 1.21 (d, J¼6.7 Hz, 3H), 0.89 (t, J¼7.1 Hz, 3H). 13C NMR:
d 144.3,
138.3, 137.7, 131.4, 131.1, 129.6, 129.3, 128.7, 128.2, 127.9, 127.3, 126.6,
62.6, 61.2, 57.9, 40.3, 23.3, 14.3. MS, m/z (relative intensity): 224
([MꢃCO2Et]þ, 20), 206 ([MꢃC7H7]þ, 53), 120 (35), 105 ([C8H9]þ,
100), 102 (25), 91 ([C7H7]þ, 42), 79 (17), 74 (5). HRMS calcd for
C19H23NO2 [MþH]þ: 298.1807, found: 298.1816.
9. (a) Haurena, C.; Le Gall, E.; Sengmany, S.; Martens, T.; Troupel, M. J. Org. Chem.
2010, 75, 2645e2650; (b) Le Gall, E.; Decompte, A.; Martens, T.; Troupel, M.
Synthesis 2010, 249e254; (c) Le Gall, E.; Haurena, C.; Sengmany, S.; Martens, T.;
Troupel, M. J. Org. Chem. 2009, 74, 7970e7973; (d) Sengmany, S.; Le Gall, E.;
Troupel, M. Synlett 2008, 1031e1035; (e) Haurena, C.; Sengmany, S.; Huguen, P.;
Le Gall, E.; Martens, T.; Troupel, M. Tetrahedron Lett. 2008, 49, 7121e7123; (f)
4.6.24. N-((S)-1-(Naphthalen-2-yl)ethyl)-1,2-diphenylethylamine
(10). Colorless oil. FT-IR (neat, cmꢃ1):
3027, 2925, 2848, 1510,
1494, 1452, 1169, 1118, 1071, 1028, 799, 777, 757, 697. 1H NMR:
*
n
d
7.77e7.69 (m, 2H), 7.63 (d, J¼7.8 Hz, 1H), 7.45 (d, J¼7.3 Hz, 1H),
ꢀ
ꢀ
Sengmany, S.; Le Gall, E.; Le Jean, C.; Troupel, M.; Nedelec, J.-Y. Tetrahedron
7.39e7.26 (m, 3H), 7.22e7.15 (m, 6H), 7.13e7.09 (m, 2H), 6.97e6.92
(m, 2H), 4.42 (q, J¼6.6 Hz, 1H), 3.99 (t, J¼6.6 Hz, 1H), 2.87e3.03 (m,
2007, 63, 3672e3681; (g) Le Gall, E.; Troupel, M.; Nedelec, J.-Y. Tetrahedron
ꢀ
ꢀ
2006, 62, 9953e9965; (h) Le Gall, E.; Troupel, M.; Nedelec, J.-Y.- Tetrahedron
Lett. 2006, 47, 2497e2500.
2H), 1.33 (d, J¼6.6 Hz, 3H). 13C NMR:
d 137.8, 132.9, 130.0, 128.3,
10. A single experiment involving the use of 1-phenylethylamine had been dis-
closed, see Ref. 9c for details.
11. Nanda, K. K.; Trotter, B. W. Tetrahedron Lett. 2005, 46, 2025e2028.
12. Trotter, N. S.; Brimble, M. A.; Harris, P. W. R.; Callis, D. J.; Sieg, F. Bioorg. Med.
Chem. 2005, 13, 501e517.
127.8,127.3, 127.1,126.4, 126.2,126.1, 125.1,124.6,124.5,124.3,122.2,
122.0, 61.0, 49.9, 43.5, 20.7. MS, m/z (relative intensity): 260
([MꢃC7H7]þ, 81), 155 ([C12H11]þ, 100), 128 (7), 106 (18). HRMS calcd
for C26H25N [MþH]þ: 352.2065, found: 352.2056.
13. Proline esters were obtained as hydrochlorides thus 3 equiv of the organozinc
reagent were used.
14. Furness, M. S.; Zhang, X.; Coop, A.; Jacobson, A. E.; Rothman, R. B.; Dersch, C. M.;
Xu, H.; Porreca, F.; Rice, K. C. J. Med. Chem. 2000, 43, 3193e3196.
15. Bishop, M. J.; McNutt, R. W. Bioorg. Med. Chem. Lett. 1995, 5, 1311e1314.
16. Calderon, S. N.; Coop, A. Curr. Pharm. Des. 2004, 10, 733e742.
17. (a) Siwicka, A.; Wojtasiewicz, K.; Leniewski, A.; Maurin, J. K.; Zawadzka, A.;
Czarnocki, Z. Can. J. Chem. 2007, 85, 1033e1036; (b) Levinger, S.; Nair, R.;
Hassner, A. Beilstein J. Org. Chem. 2008, 4, No. 32; (c) Abraham, H.; Stella, L.
Tetrahedron 1992, 48, 9707e9718; (d) Boga, C.; Savoia, D.; Umani-Ronchi, A.
Acknowledgements
Financial support of this work by the CNRS and the University
ꢀ
Paris-Est Creteil (Ph.D. grant) is gratefully acknowledged.
References and notes
ꢀ
Tetrahedron: Asymmetry 1990, 1, 291e294; (e) Zio1kowski, M.; Czarnocki, Z.;
Leniewski, A.; Maurin, J. K. Tetrahedron: Asymmetry 1999, 10, 3371e3380; (f)
Soe, T.; Fukui, N.; Hino, T.; Nakagawa, M. Heterocycles 1996, 42, 347e358; (g) Xu,
D.; Prasad, K.; Repic, O.; Blacklock, T. J. Tetrahedron: Asymmetry 1997, 8,
ꢀ
1. For a reference book, see:Multicomponent Reactions; Zhu, J., Bienayme, H., Eds.;
Wiley-VCH: Weinheim, 2005.
ꢂ
1445e1451; (h) de Parrodi, C. A.; Juaristi, E.; Quintero, L.; Clara-Sosa, A. Tetra-
hedron: Asymmetry 1997, 8, 1075e1082.
18. For some miscellaneous examples, see: (a) Bajwa, J. S.; Slade, J.; Repic, O. Tet-
2. For recent reviews on multicomponent reactions (MCRs) and asymmetric
MCRs (AMCRs), see: (a) Arndtsen, B. A. Chem.dEur. J. 2009, 15, 302e312;
(b) Isambert, N.; Lavilla, R. Chem.dEur. J. 2008, 14, 8444e8454; (c) Guillena,
G.; Ramon, D. J.; Yus, M. Tetrahedron: Asymmetry 2007, 18, 693e700; (d)
ꢂ
rahedron Lett. 2000, 41, 6025e6028; (b) Liotta, L. J.; Ganem, B. Tetrahedron Lett.
1989, 30, 4759e4762; (c) Czech, B. P.; Bartsch, R. A. J. Org. Chem. 1984, 49,
4076e4078; (d) Marzi, M.; Misiti, D. Tetrahedron Lett. 1989, 30, 6075e6076; (e)
Bernotas, R. C.; Cube, R. V. Synth. Commun. 1990, 20, 1209e1212; (f) Cheng, C.;
Sun, J.; Xing, L.; Xu, J.; Wang, X.; Hu, Y. J. Org. Chem. 2009, 74, 5671e5674.
19. (a) Balducci, D.; Contaldi, S.; Lazzari, I.; Porzi, G. Tetrahedron: Asymmetry 2009,
20, 1398e1401; (b) Ferioli, F.; Piccinelli, F.; Porzi, G.; Sandri, S. Tetrahedron:
Asymmetry 2002, 13, 1181e1187.
€
€
D’Souza, D. M.; Muller, T. J. J. Chem. Soc. Rev. 2007, 36, 1095e1108; (e) Domling,
ꢀ
A. Chem. Rev. 2006, 106, 17e89; (f) Ramon, D. J.; Yus, M. Angew. Chem., Int. Ed.
2005, 44, 1602e1634; (g) Simon, C.; Constantieux, T.; Rodriguez, J. Eur. J. Org.
Chem. 2004, 4957e4980; (h) Zhu, J. Eur. J. Org. Chem. 2003, 1133e1144; (i)
Orru, R. V. A.; De Greef, M. Synthesis 2003, 1471e1499; (j) Hulme, C.; Gore, V.
Curr. Med. Chem. 2003, 10, 51e80; (k) Balme, G.; Bossharth, E.; Monteiro, N.
€
Eur. J. Org. Chem. 2003, 4101e4111; (l) Domling, A.; Ugi, I. Angew. Chem., Int. Ed.
€
20. Metlushka, K. E.; Kashemirov, B. A.; Zheltukhin, V. F.; Sadkova, D. N.; Buchner,
2000, 39, 3168e3210.
B.; Hess, C.; Kataeva, O. N.; McKenna, C. E.; Alfonsov, V. A. Chem.dEur. J. 2009,
15, 6718e6722.
3. (a) Kalinski, C.; Lemoine, H.; Schmidt, J.; Burdack, C.; Kolb, J.; Umkehrer, M.;
Ross, G. Synthesis 2008, 4007e4011; (b) Endo, A.; Yanagisawa, A.; Abe, M.;
Tohma, S.; Kan, T.; Fukuyama, T. J. Am. Chem. Soc. 2002, 124, 6552e6554.
4. (a) Arend, M.; Westermann, B.; Risch, N. Angew. Chem., Int. Ed. 1998, 37,
1044e1070; (b) Heaney, H. In Comprehensive Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 2, pp 953e973; (c) Overman, L.
E.; Ricca, D. J. In Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
Pergamon: Oxford, 1991; Vol. 2, pp 1007e1046.
21. One can envisage the possible use of e.g., 4-methoxybenzyl or 2,4-dimethoxy-
benzyl groups, which might be selectively removed by different pathways, for
€
some miscellaneous examples see: (a) Lechner, R.; Konig, B. Synthesis 2010,
1712e1718; (b) Yang, B. V.; O’Rourke, D.; Li, J. Synlett 1993, 195e196; (c) Trost,
B. M.; Krische, M. J.; Radinov, R.; Zanoni, G. J. Am. Chem. Soc. 1996, 118,
6297e6298; (d) Williams, R. M.; Kwast, E. Tetrahedron Lett. 1989, 30, 451e454

C. Haurena et al. / Tetrahedron 66 (2010) 9902e9911
9911
For a review on protecting groups, see: (e) Jarowicki, K.; Kocienski, P. J. Chem.
Soc., Perkin Trans. 1 1998, 4005e4037 For a leading book, see: (f) Greene, T. W.;
Wuts, P. G. M. In Protective Groups in Organic Synthesis Wiley: New York, NY,
1999.
22. (a) Yamamoto, Y.; Komatsu, T.; Maruyama, K. J. Am. Chem. Soc. 1984, 106,
5031e5033; (b) Yamamoto, Y.; Nishii, S.; Maruyama, K.; Tomatsu, T.; Ito, W.
J. Am. Chem. Soc. 1986, 108, 7778e7786.
23. Bytschkov, I.; Doye, S. Eur. J. Org. Chem. 2001, 4411e4418.