Synthesis of substituted 5-(pyrrolidin-2-yl)tetrazoles and their application in the asymmetric Biginelli reaction

Article abstract of DOI:10.1002/ejoc.200801046

A series of chiral substituted 5-(pyrrolidin-2-yl)tetrazoles have been synthesized and evaluated as organocatalysts for the asymmetric Biginelli reaction. The relationship between catalytic activity and the different catalyst structures is briefly discussed. By using the optimized catalyst C¹⁰ (10 mol-%), a series of 3,4-dihydropyrimidin-2(1H)-one (DHPM) derivatives have been obtained in 63-88% yields and 68-81 % ee values within 24 h at room temperature.

Full text of DOI:10.1002/ejoc.200801046

FULL PAPER
DOI: 10.1002/ejoc.200801046
Synthesis of Substituted 5-(Pyrrolidin-2-yl)tetrazoles and Their Application in
the Asymmetric Biginelli Reaction
Yong-Yong Wu,[a,b] Zhuo Chai,[a] Xin-Yuan Liu,[a] Gang Zhao,*[a] and Shao-Wu Wang*[b]
Keywords: Enantioselectivity / Asymmetric catalysis / Organocatalysis / Biginelli reaction / Tetrazoles
A series of chiral substituted 5-(pyrrolidin-2-yl)tetrazoles
have been synthesized and evaluated as organocatalysts for
the asymmetric Biginelli reaction. The relationship between
catalytic activity and the different catalyst structures is
(10 mol-%), a series of 3,4-dihydropyrimidin-2(1H)-one
(DHPM) derivatives have been obtained in 63–88% yields
and 68–81% ee values within 24 h at room temperature.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
briefly discussed. By using the optimized catalyst C10 Germany, 2009)
Introduction
Chiral tetrazoles as organocatalysts have received in-
creasing interest since the pioneering works of Yama-
moto,[1] Ley,[2] and Arvidsson[3] and their co-workers in
2004. So far tetrazole catalysts have been applied success-
fully to a variety of organic reactions, including Mannich-
type reactions,[4] Michael additions,[5] and aldol[6] and o-
nitroso-aldol/Michael reactions.[7] Meanwhile, Barbas[8] and
Ward[9] and their co-workers have also successfully utilized
tetrazole catalysts in the total synthesis of BIRT-377 and
serricornin, respectively. Tetrazoles were initially synthe-
sized out of consideration for a better solubility in conven-
tional organic solvents than the corresponding amino acids
while retaining their properties. In fact, it has been well
documented[1–9] that in many cases tetrazoles are more ef-
ficient catalysts than the parent amino acids, which makes
them a valuable member of the organocatalyst family. How-
ever, until now, in contrast to the huge number of amino
acid catalysts available, only a handful of chiral tetrazole
catalysts[10] (Figure 1, A–E) have been synthesized and in-
vestigated in asymmetric reactions.
As one of the most useful multicomponent reactions and
originally described by Biginelli in 1891,[11] the Biginelli re-
action offers an efficient way to obtain pharmacologically
and biologically important 3,4-dihydropyrimidin-2(1H)-
ones (DHPMs) through the simple condensation reaction
of an aldehyde, a urea or thiourea, and an easily enolizable
carbonyl compound.[12] However, besides chemical resolu-
Figure 1. Structures of known organocatalysts.
tion and enzymatic strategies,[13] procedures for the enantio-
selective synthesis of DHPMs are rather limited,[14] espe-
cially by the catalytic asymmetric Biginelli reaction.[15–17]
In 2005, a catalytic highly enantioselective version of the
Biginelli reaction was realized by Zhu and co-workers using
a recyclable new chiral ytterbium catalyst.[15] In the field of
organocatalysis, Gong and co-workers successfully applied
BINOL-derived phosphoric acids to this reaction with ex-
cellent enantiocontrol.[16] Feng and co-workers utilized a
readily available trans-4-hydroxyproline-derived secondary
amine Brønsted acid as a catalyst to catalyze this reaction,
however, an organic amino salt was usually required as an
additive to obtain good results in this case.[17] In view of
these few successful examples, it is still desirable to develop
other new organocatalysts for this important transforma-
tion. As a part of our continued interest in the development
of novel asymmetric organocatalytic reactions,[18] we report
herein the synthesis of a series of novel proline-derived
tetrazole catalysts and their application in these reactions.
[a] Laboratory of Modern Organic Synthetic Chemistry, Shanghai
Institute of Organic Chemistry, Chinese Academy of Sciences,
354 Fenglin Lu, Shanghai 200032, P. R. China
Fax: +86-21-64166128
E-mail: zhaog@mail.sioc.ac.cn
swwang@mail.ahnu.edu.cn
[b] Institute of Organic Chemistry, School of Chemistry and Mate-
rials Science, Anhui Normal University,
Wuhu, Anhui 241000, P. R. China
904
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 904–911

Asymmetric Biginelli Reaction
Table 2. Optimization of the reaction conditions with catalyst C1.[a]
Results and Discussion
Our study began with a preliminary screening of several
different known catalysts (Figure 1). By using benzaldehyde
(1.1 mmol), ethyl acetoacetate (1.0 mmol), and urea
(1.5 mmol) as the probing substrates, the reactions were
performed in DMSO at room temperature and the results
are summarized in Table 1. Although -proline could cata-
lyze this reaction to provide the desired product 4a in mod-
erate yield, the enantioselectivity was rather poor (Table 1,
entry 1). Moreover, the N-Boc-protected -proline F, the di-
phenyl prolinol G, and prolinamide H, in which the carbox-
ylic acid group of -proline is replaced by less acidic groups,
all failed to catalyze this reaction (Table 1, entries 4–6). Al-
though the desired product could be obtained in good
yields when catalysts I and J with a stronger acidic moiety
were used, the enantioselectivities were poor (Table 1, en-
tries 7–9). These results suggested that both the basic amine
and the acidic moieties in -proline are essential to effect
this reaction. Encouragingly, we found that 5-(pyrrolidin-2-
yl)tetrazole (C1) could catalyze this reaction effectively to
provide 4a in 65% yield and 23% ee. Consequently, we di-
rected our optimization efforts towards both the structural
modification of C1 and the optimization of the reaction
conditions.
Entry
Solvent
Yield [%][b]
ee [%][c]
1
MeOH
DMSO
THF
75
65
73
84
58
68
55
65
30
23
20
44
52
51
32
27
2
3[d]
4
EtOH
5
iPrOH
iPrOH
iBuOH
tBuOH
6[d,e]
7
8
[a] The reaction was performed with C1 (0.05 mmol), 1a
(0.27 mmol), 2a (0.30 mmol), and 3a (0.25 mmol) in 1 mL of sol-
vent at room temperature for 24 h. [b] Isolated yields. [c] Deter-
mined by HPLC using chiral columns. [d] A reaction time of 48 h
was used. [e] 10 mol-% of catalyst C1 was used.
model reaction. Disappointingly, none of the three catalysts
led to any significant improvement in the enantioselectivity
compared with C1 (Table 3, entries 1–4). With the intention
of achieving better enantioselectivity, we continued our en-
deavors in the synthesis of novel catalysts based on C1.
Starting from the commercially available 4-hydroxy--pro-
line, the known compound 5a was prepared according to
literature procedures.[1,19] The reaction of 5a with TsCl pro-
vided compound 6a, which was subjected to a sequence of
ammonolysis, dehydration with POCl3, and a click reaction
with sodium azide to afford the desired catalyst C4
(Scheme 1). In a similar way, C5, the N-methylated ana-
logue of C4, was also prepared. To ascertain whether the
relative stereochemistry of the catalyst would have an influ-
ence on the enantioselectivity, we also synthesized the 2,4-
trans-disubstituted catalysts C6 and C7, namely the 2-epi-
mers of C4 and C5 (Figure 2). Subsequently, the newly pre-
pared catalysts C4–C7 were tested in the model reaction. It
was found that the 2,4-trans-disubstituted pyrrolidinyltetraz-
oles C6 and C7 provided higher enantioselectivities than
their syn counterparts C4 and C5 with an inverted absolute
configuration of the product 4a. In addition, no consider-
able difference in the enantioselectivity was observed be-
tween C6 and C7, which suggests that the hydrogen atom
Table 1. Preliminary catalyst screening for the asymmetric Biginelli
reaction.[a]
Entry
Catalyst
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
9
-proline
57
65
8
23
C1
D
F
Ͻ5
Ͻ5
n.d.
n.d.
[d]
[d]
G
H
I1
I2
J
–
–
[d]
[d]
–
–
75
81
87
4
2
11
[a] 1a:2a:3a = 1.1:1:1.5. [b] Isolated yields. [c] Determined by HPLC
using a chiral column. [d] No reaction was detected.
First, solvent effects were evaluated with the catalyst C1 on the N-4 atom might not participate in the enantiodiscri-
and the results are shown in Table 2. In terms of both yield minating process.
and enantioselectivity, iPrOH as the solvent gave the best
Next we changed the protecting group of C6 from tosyl
results (Table 2, entry 5). Longer- and shorter-chained to a mesyl (C8) or mesityl (C9) group to examine the steric
alcohols all gave inferior results. In addition, reducing the effect of this position. Moreover, because some proline-de-
catalyst loading to 10 mol-% led to a longer reaction time rived organocatalysts with long alkyl chains on the nitrogen
without any significant change in the enantioselectivity atom have recently been found to be highly effective in aldol
(Table 2, entry 6).
and Michael reactions,[20] we also modified the N-4 atom
In the meantime, our efforts to structurally modify the of C6 with four-, eight- and twelve-carbon alkyl chains,
tetrazole catalyst C1 commenced with the synthesis of the namely catalysts C10–C12 (Scheme 2). Then the five novel
known catalysts C2, C3, and E1 (Figure 1). For reasons of catalysts C8–C12 were examined in the model reaction: C10
solubility, these three catalysts together with C1 were inves- with a four-carbon alkyl chain gave the highest enantio-
tigated in a co-solvent of DMSO/iPrOH (1:5, v/v) in the selectivity (63%) and the ee values of the product dropped
Eur. J. Org. Chem. 2009, 904–911
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Y.-Y. Wu, Z. Chai, X.-Y. Liu, G. Zhao, S.-W. Wang
FULL PAPER
Table 3. Further evaluation of catalysts for the asymmetric Biginelli as the alkyl chain became longer (Table 3, entries 10–13).
reaction.[a]
Although the catalyst C8 provided the best chemical yield,
the ee was poor (Table 3, entry 9).
Entry Catalyst
Time [h] Yield [%][b] ee [%][c] Config.[d]
1
2
3
4
5
6
7
8
C1
C2
C3
E1
48
48
48
48
24
24
24
24
24
48
24
24
24
68
75
84
48
80
63
85
78
90
77
74
68
72
47
51
49
49
42
45
59
58
50
58
63
54
51
S
S
S
S
S
Figure 2. Structures of catalysts C6–C9.
C4
C5
C6
C7
C8
C9
C10
C11
C12
S
R
R
R
R
R
R
R
To optimize the reaction conditions further, the solvent
effect was reinvestigated with the optimum catalyst C10, and
the best result was obtained in EtOH (Table 4, entry 4).
Similar to the instance of catalyst C1, DMSO and THF
again gave very poor enantioselectivity (Table 4, entries 3
and 6). When the reaction was performed in DCM, a very
low yield was obtained even with a prolonged reaction time,
probably due to low catalyst solubility, although the ee was
comparable to that of EtOH. Thus, the optimal reaction
conditions for this transformation were determined to be
10 mol-% of C10 in EtOH at room temperature (Table 4,
entry 4).
9
10
11
12[e]
13[f]
[a] The reaction was performed with catalyst (0.025 mmol), 1a
(0.27 mmol), 2a (0.30 mmol), and 3a (0.25 mmol) in 1.2 mL of sol-
vent at room temperature. [b] Isolated yields. [c] Determined by
HPLC using a chiral column. [d] The absolute configuration was
determined by comparison of the optical rotation value with litera-
ture values.[17] [e] DMSO/iPrOH = 1:3 was used as the solvent due
to poor catalyst solubility. [f] DMSO/iPrOH = 1:2 was used as the
solvent due to poor catalyst solubility.
With the optimized conditions in hand, the substrate
scope of this reaction was probed (Table 5). In general, all
the examined substrates could furnish the desired products
in good yields and with moderate-to-good enantioselectivi-
ties. Notably, although the enantioselectivities are not very
satisfying, the catalytic system described in this work re-
quired a markedly shorter reaction time (24 h) compared
with two previous organocatalytic systems (36–72 h).[16,17]
Changes to the substituents in both the aldehyde and the
acylacetate components seemed not to have any striking ef-
fect on either the yields or the ee values. In addition, a com-
parable result was obtained when thiourea 2b was employed
instead of urea 2a (Table 5, entry 10).
Based on previous studies of the mechanism of the Bigi-
nelli reaction[12,15–17] and the experimental results, a pos-
sible transition state with catalyst C10 as an example has
Scheme 1. Synthesis of catalysts C4 and C5.
Scheme 2. Synthesis of catalysts C10–C12.
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Eur. J. Org. Chem. 2009, 904–911

Asymmetric Biginelli Reaction
Table 4. Screening of solvents for catalyst C10.[a]
tetrazole moiety, which is supported by the following two
observations: (a) The inversion of the absolute configura-
tion of the product when catalysts C1–C5 were used
(Table 3) and (b) modification of the substituents at the 4-
position of the catalysts had no remarkable influence on
product enantioselectivity.
Entry
1
Solvent
Time [h] Yield [%][b]
ee [%][c]
DMSO/iPrOH,
1:5
24
74
63
2
3
4
MeOH
DMSO
EtOH
EtOH
THF
24
24
24
24
48
70
73
75
55
73
22
65
35
72
70
20
69
5[d,e]
6[e]
7[e]
CH2Cl2
120
[a] The reaction was performed with C10 (0.025 mmol), 1a
(0.27 mmol), 2a (0.30 mmol), and 3a (0.25 mmol) in 1.2 mL of sol-
vent at room temperature. [b] Isolated yields. [c] Determined by
HPLC using a chiral column. [d] Catalyst C11 was used. [e] The
catalyst did not dissolve completely.
Figure 3. Possible catalytic transition state for the present catalytic
system.
Conclusions
We have synthesized a series of novel chiral substituted
5-(pyrrolidin-2-yl)tetrazoles for application in the enantio-
selective Biginelli reaction. The optimization of catalyst
structures, including different absolute and relative configu-
rations and different substituents with varied electronic and
steric properties, furnished C10 as the best catalyst, which
provides the corresponding 3,4-dihydropyrimidin-2(1H)-
one (DHPM) derivatives in good yields and enantio-
selectivities under mild reaction conditions. These novel
tetrazole catalysts allow facile adjustments to both elec-
tronic and steric properties for further optimization and ex-
pand the existing library of tetrazole catalysts.
Table 5. Scope of the asymmetric Biginelli reaction catalyzed by
C10.[a]
Entry
Ar (1)
R1/R2 (3)
4
Yield [%][b] ee [%][c]
1
2
3
4
5
6
7
8
C6H5 (1a)
4-BrC6H4 (1b)
4-CNC6H4 (1c)
4-NO2C6H4 (1d) Me/Et (3a)
3-NO2C6H4 (1e) Me/Et (3a)
C6H5 (1a)
C6H5 (1a)
C6H5 (1a)
C6H5 (1a)
4-CNC6H4 (1c)
Me/Et (3a)
Me/Et (3a)
Me/Et (3a)
4a
4b
4c
4d
4e
4f
4g
4h
4i
75
63
82
78
75
88
81
78
76
71
72
69
75
76
78
81
69
68
72
80
Ph/Et (3b)
Me/Me (3c)
Me/iPr (3d)
Me/tBu (3e)
Me/Et (3a)
Experimental Section
1
9
General Remarks: H NMR spectra were recorded with a Bruker
10[d]
4j
DPX-300 or Varian EM-360 (300 MHz) instrument. All chemical
shifts (δ) are given in ppm. 13C NMR spectra were recorded with
a Bruker DPX-300 (75 MHz) or DPX-400 (100 MHz) instrument.
IR spectra were recorded with a Perkin–Elmer 983G instrument.
Flash column chromatography was performed by using 300–400-
mesh silica gel. For thin-layer chromatography (TLC), silica gel
plates (HSGF 254) were used and compounds were visualized by
irradiation with UV light or by treatment with a solution of phos-
phomolybdic acid in ethanol followed by heating. Mass spectra
(EI) were recorded at an ionizing voltage of 70 eV.
[a] The reaction was performed with C10 (0.025 mmol),
1
(0.27 mmol), 2 (0.30 mmol), and 3 (0.25 mmol) in 1 mL of EtOH
at room temperature. [b] Isolated yields. [c] Determined by HPLC
using chiral columns. The absolute configuration was determined
by comparison of the optical rotation value or the sequence of
HPLC peaks with literature values.[17] [d] Thiourea was used in-
stead of 2a.
been proposed to explain the stereochemical results of the Synthesis of Esters 6a–d: A solution of p-toluenesulfonyl chloride
(1.14 g, 6.0 mmol) in dry DCM (5.0 mL) was slowly added to a
stirred solution of dibenzyl (2S,4R)-4-aminopyrrolidine-1,2-dicar-
boxylate (5a) (1.416 g, 4.0 mmol) and Et3N (1.12 mL, 8.0 mmol) in
dry DCM (20 mL) under cooling in an ice/water bath. The stirring
was continued for 12 h at room temperature. Then saturated
NaHCO3 (10 mL) was added to quench the reaction. The reaction
mixture was extracted with DCM (2ϫ10 mL). The combined or-
ganic portions were washed with saturated brine (20 mL), dried
with Na2SO4, and concentrated in vacuo. The crude product was
purified by flash column chromatography (PE/EA, 1:1) to give 6a
transformation described in this work (Figure 3). Similarly
to the widely accepted catalytic mode of the -proline-cata-
lyzed aldol reaction, the catalyst may catalyze the reaction
in a dual-activation way: The acidic tetrazole moiety acti-
vates the electrophilic imine formed from urea and aldehyde
by a hydrogen-bonding interaction and the secondary
amine moiety activated the nucleophilic keto ester via the
formation of an enamine intermediate. Such a transition
state implies that the enantiodetermining element in the cat-
alyst mainly resides in the stereochemistry of the acidic as a white solid.
Eur. J. Org. Chem. 2009, 904–911
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Y.-Y. Wu, Z. Chai, X.-Y. Liu, G. Zhao, S.-W. Wang
FULL PAPER
Dibenzyl (2S,4S)-4-(4-Methylphenylsulfonamido)pyrrolidine-1,2-di-
carboxylate (6a): Yield 1.585 g, 78%. [α]2D7 = –13.1 (c = 4.57,
CHCl3). 1H NMR (300 MHz, CDCl3): δ = 7.75–7.64 (m, 2 H),
7.35–7.12 (m, 12 H), 6.08 (d, J = 9.0 Hz, 1 H), 5.22–4.92 (m, 4 H),
4.36–4.17 (m, 1 H), 3.89 (br., 1 H), 3.63–3.50 (m, 1 H), 3.40–3.30
(m, 1 H), 2.34 and 2.32 (s, 3 H), 2.35–2.20 (m, 1 H), 2.00–1.75 (m,
1 H) ppm. 13C NMR (75 MHz, CDCl3, the signals in parentheses
refer to the rotamer): δ = 173.3 (173.1), 154.6 (153.9), 143.6, 137.6,
136.2 (136.1), 135.2 (135.0), 130.0 (129.9), 128.7, 128.5, 128.3,
128.2, 128.1, 127.8, 127.0, 67.4, 67.3, 57.9 (57.5), 52.5, 52.2 (51.7),
centrated in vacuo. The crude product was purified by flash column
chromatography (PE/EA, 3:1) to give 7a as a colorless oil.
Dibenzyl
(2S,4S)-4-(N,4-Dimethylphenylsulfonamido)pyrrolidine-
1,2-dicarboxylate (7a): Yield 2.558 g, 98%. [α]2D7 = –31.8 (c = 4.97,
1
CHCl3). H NMR (300 MHz, CDCl3): δ = 7.62 (d, J = 6.9 Hz, 2
H), 7.34–7.12 (m, 12 H), 5.15–4.88 (m, 4 H), 4.57–4.40 (m, 1 H),
4.36–4.17 (m, 1 H), 3.62 (dd, J = 10.5, 8.1 Hz, 1 H), 3.26–3.14 (m,
1 H), 2.61 and 2.57 (s, 3 H), 2.32 (s, 3 H), 2.30–2.12 (m, 1 H),
1.86–1.64 (m, 1 H) ppm. 13C NMR (75 MHz, CDCl3, the signals
in parentheses refer to the rotamer): δ = 171.9 (171.7), 154.5
(153.9), 143.8, 136.3 (136.2), 135.5 (135.3), 130.0, 128.5, 128.5,
128.4, 128.3, 128.2, 128.1, 127.8, 127.1, 67.2, 66.9, 57.5 (57.1), 54.7
36.5 (35.3), 21.5 ppm. IR (KBr): ν = 3271, 2953, 1709, 1417, 1354,
˜
1163, 698 cm–1. MS (ESI): m/z = 531.2 [M + Na]+. HRMS (ESI):
calcd. for C27H28N2O6SNa+ [M + Na]+ 531.1560; found 531.1575.
(54.1), 46.6, 32.2 (30.7), 29.3 (29.2), 21.4 ppm. IR (KBr): ν = 2954,
˜
1747, 1712, 1417, 1348, 1166, 663 cm–1. MS (ESI): m/z = 523.2
[M + H]+. HRMS (ESI): calcd. for C28H30N2O6SNa+ [M + Na]+
545.1717; found 545.1732.
Dibenzyl (2R,4S)-4-(4-Methylphenylsulfonamido)pyrrolidine-1,2-di-
carboxylate (6b): Yield 1.748 g, 86%. [α]2D7 = 23.0 (c = 4.27, CHCl3).
1H NMR (300 MHz CDCl3): δ = 7.68 (dd, J = 8.4, 4.5 Hz, 2 H),
7.32–7.12 (m, 12 H), 6.17 (dd, J = 9.9, 7.2 Hz, 1 H), 5.14–4.86 (m,
4 H), 4.46–4.32 (m, 1 H), 3.65 (br., 1 H), 3.66–3.56 (m, 1 H), 3.28
(m, 1 H), 2.33 and 2.31 (s, 3 H), 2.24–1.92 (m, 2 H) ppm. 13C NMR
(75 MHz, CDCl3, the signals in parentheses refer to the rotamer):
δ = 172.0 (171.8), 154.8 (154.2), 143.7, 137.3 (137.1), 136.2 (136.1),
135.5 (135.3), 130.0 (129.9), 128.6, 128.5, 128.4, 128.2, 128.1, 127.7,
127.0, 67.3, 67.1 (67.0), 57.8 (57.6), 51.8 (51.7), 51.6 (51.1), 36.8
Dibenzyl
(2R,4S)-4-(N,4-Dimethylphenylsulfonamido)pyrrolidine-
1,2-dicarboxylate (7b): Yield 2.480 g, 95%. [α]2D5 = 17.7 (c = 4.20,
CHCl3). 1H NMR (300 MHz, CDCl3): δ = 7.58 (dd, J = 8.1,
4.5 Hz, 2 H), 7.40–7.16 (m, 12 H), 5.22–4.96 (m, 4 H), 4.76–4.55
(m, 1 H), 4.48–4.34 (m, 1 H), 3.70–3.50 (m, 1 H), 3.24–3.13 (m, 1
H), 2.69 and 2.67 (s, 3 H), 2.40 and 2.38 (s, 3 H), 2.24–1.83 (m, 2
H) ppm. 13C NMR (75 MHz, CDCl3, the signals in parentheses
refer to the rotamer): δ = 171.7 (171.5), 154.6 (153.9), 143.8, 136.3
(136.2), 135.5 (135.4), 135.2, 130.0, 128.7, 128.5, 128.3, 128.2,
128.1, 127.8, 127.1, 67.2, 67.1, 57.9 (57.6), 54.8 (54.0), 46.9 (46.8),
(35.6), 21.5 ppm. IR (KBr): ν = 3255, 2954, 1745, 1708, 1420, 1162,
˜
698 cm–1. MS (ESI): m/z = 531.2 [M + Na]+. HRMS (ESI): calcd.
for C27H28N2O6SNa+ [M + Na]+ 531.1560; found 531.1574.
32.5 (31.0), 29.2 (29.1), 21.5 ppm. IR (KBr): ν = 2956, 1745, 1712,
˜
Dibenzyl (2R,4S)-4-(Methylsulfonamido)pyrrolidine-1,2-dicarboxyl-
ate (6c): Yield 1.123 g, 65%, m.p. 89–90 °C. [α]2D9 = 26.1 (c = 1.20,
CHCl3). 1H NMR (300 MHz, CDCl3): δ = 7.45–7.16 (m, 10 H),
5.73 (t, J = 7.2 Hz, 1 H), 5.20–4.95 (m, 4 H), 4.54–4.40 (m, 1 H),
4.10–4.00 (m, 1 H), 3.88–3.80 (m, 2 H), 3.48–3.34 (m, 1 H), 2.86
and 2.83 (s, 3 H), 2.30–2.14 (m, 1 H) ppm. 13C NMR (75 MHz,
CDCl3, the signals in parentheses refer to the rotamer): δ = 171.9
(171.8), 154.8 (154.2), 136.2 (136.1), 135.4 (135.2), 128.7 (128.6),
128.5, 128.2, 128.2 (128.1), 127.9, 127.7, 67.5 (67.4), 67.2, 57.8
1455, 1416, 1348, 1162, 663 cm–1. MS (ESI): m/z = 523.2 [M +
H]+. HRMS (ESI): calcd. for C28H30N2O6SNa+ [M + Na]+
545.1717; found 545.1729.
Synthesis of Compounds 9: nBuBr (0.65 mL, 6.0 mmol, 2.0 equiv.)
was slowly added to a stirred solution of 8 (1.20 g, 3.0 mmol,
1.0 equiv.), K2CO3 (0.496 g, 3.6 mmol, 1.2 equiv.), and nBu4NBr
(0.097 g, 0.3 mmol, 0.1 equiv.) in acetone (30 mL) and DMF
(5 mL). The stirring was continued for 5 d at room temperature.
Then the reaction mixture was concentrated in vacuo before water
(50 mL) was added. The mixture was extracted with DCM
(2ϫ25 mL). The combined organic portions were washed with sat-
urated brine (40 mL), dried with Na2SO4, and concentrated in
vacuo. The crude product was purified by flash column chromatog-
raphy (PE/EA, 3:1) to give 9 as a white solid.
(57.6), 52.1 (52.0), 51.8 (51.1), 41.1, 37.3 (36.1) ppm. IR (KBr): ν
˜
= 3281, 2927, 1747, 1498, 1463, 745, 697 cm–1. MS (ESI): m/z =
433.2 [M + H]+. HRMS (ESI): calcd. for C21H24N2O6SNa+ [M +
Na]+ 455.1239; found 455.1247.
Dibenzyl (2R,4S)-4-(2,4,6-Trimethylphenylsulfonamido)pyrrolidine-
1,2-dicarboxylate (6d): Yield 1.672 g, 78%. [α]2D7 = 24.2 (c = 3.95,
CHCl3). 1H NMR (300 MHz, CDCl3): δ = 7.36–7.12 (m, 10 H),
6.93 and 6.90 (s, 2 H), 5.18–4.90 (m, 5 H), 4.47–4.33 (m, 1 H),
3.94–3.84 (m, 1 H), 3.68–3.58 (m, 1 H), 3.28–3.20 (m, 1 H), 2.57
and 2.56 (s, 6 H), 2.29 and 2.26 (s, 3 H), 2.25–2.06 (m, 2 H) ppm.
13C NMR (75 MHz, CDCl3, the signals in parentheses refer to the
rotamer): δ = 172.0 (171.8), 154.7 (154.1), 142.6, 139.1, 136.2
(136.1), 135.4 (135.2), 133.8 (133.7), 132.2 (132.1), 128.6, 128.5,
128.4, 128.2, 128.1, 127.8, 67.3, 67.1, 57.8 (57.6), 51.6 (51.4), 51.3
Benzyl (2R,4S)-4-(N-Butyl-4-methylphenylsulfonamido)-2-cyanopyr-
rolidine-1-carboxylate (9a): Yield 1.228 g, 90%. [α]2D3 = 18.7 (c =
1.75, CHCl3). 1H NMR (300 MHz, CDCl3): δ = 7.67 (d, J =
8.4 Hz, 2 H), 7.38–7.22 (m, 7 H), 5.13 (d, J = 5.7 Hz, 2 H), 4.64–
4.47 (m, 2 H), 3.67–3.46 (m, 1 H), 3.23–3.10 (m, 1 H), 3.10–2.95
(m, 2 H), 3.05 (s, 3 H), 2.40–2.10 (m, 2 H), 1.56 (m, 2 H), 1.25 (q,
J = 7.5 Hz, 2 H), 0.87 (t, J = 7.5 Hz, 3 H) ppm. 13C NMR
(75 MHz, CDCl3, the signals in parentheses refer to the rotamer):
δ = 162.5, 154.0 (153.1), 144.0, 136.8 (135.6), 130.0, 128.6, 128.4,
128.2, 127.0, 118.0 (117.8), 68.1 (68.0), 55.7 (54.8), 47.3 (46.9), 45.5
(45.2), 45.1, 36.4 (34.3), 33.5 (33.4), 33.1 (31.4), 21.5 (20.0),
(50.6), 36.8 (35.7), 22.9, 21.0 ppm. IR (KBr): ν = 3276, 2939, 1747,
˜
1714, 1604, 1455, 1156, 746, 698, 659 cm–1. MS (ESI): m/z = 537.3
[M + H]+. HRMS (ESI): calcd. for C29H32N2O6SNa+ [M + Na]+
559.1873; found 559.1885.
13.7 ppm. IR (film): ν = 2957, 2927, 1713, 1455, 1410, 1353, 1162,
˜
550 cm–1. MS (ESI): m/z = 473.2 [M + NH4]+. HRMS (ESI): calcd.
for C24H29N3O4SNa+ [M + Na]+ 478.1771; found 478.1777.
Synthesis of Compounds 7a–d: MeI (1.4 mL, 15.0 mmol, 3.0 equiv.)
was slowly added to a stirred solution of 6a (2.54 g, 5.0 mmol,
1.0 equiv.) and K2CO3 (0.828 g, 6.0 mmol, 1.2 equiv.) in acetone
(40 mL) and DMF (6 mL). The stirring was continued for 2 d at
room temperature. Then the reaction mixture was concentrated in
vacuo before HCl (1.0 , 50 mL) was added. The mixture was ex-
tracted with EA (2ϫ40 mL). The combined organic portions were
washed with saturated brine (40 mL), dried with Na2SO4, and con-
Benzyl (2R,4S)-2-Cyano-4-(N-octyl-4-methylphenylsulfonamido)pyr-
rolidine-1-carboxylate (9b): Yield 1.318 g, 86%. [α]2D3 = 16.7 (c =
2.56, CHCl3). 1H NMR (300 MHz, CDCl3): δ = 7.61 (d, J =
9.0 Hz, 2 H), 7.42–7.17 (m, 7 H), 5.06 (d, J = 6.6 Hz, 2 H), 4.60–
4.40 (m, 2 H), 3.61–3.38 (m, 1 H), 3.18–3.03 (m, 1 H), 3.03–2.90
(m, 2 H), 2.34 (s, 3 H), 2.23–2.07 (m, 2 H), 1.50 (br., 2 H), 1.16
(m, 10 H), 0.80 (t, J = 6.6 Hz, 3 H) ppm. 13C NMR (75 MHz,
908
www.eurjoc.org
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 904–911

Asymmetric Biginelli Reaction
CDCl3, the signals in parentheses refer to the rotamer): δ = 162.4,
153.9 (153.1), 143.9, 136.8 (135.6), 130.0, 128.5, 128.4, 128.1, 126.9,
117.9 (117.8), 68.0 (67.9), 55.6 (54.8), 47.2 (46.9), 45.5 (45.3), 36.4,
34.3 (33.0), 31.7, 31.4 (31.3), 29.1, 29.0, 26.7, 22.5, 21.5, 14.0 ppm.
6.6 Hz, 1 H), 2.74–2.40 (m, 3 H), 1.96–1.26 (m, 8 H) ppm. IR
(KBr): ν = 2930, 2530, 1617, 1443, 1397, 1097, 889 cm–1.
˜
(S)-5-(Indolin-2-yl)-1H-tetrazole (C3): Yield 0.329 g, 88%. [α]2D4
=
–21.1 (c = 0.80, DMSO). 1H NMR (300 MHz, [D4]MeOH): δ =
7.16–7.02 (m, 2 H), 6.82–6.70 (m, 2 H), 5.29 (t, J = 9.0 Hz, 1 H),
IR (film): ν = 2927, 2856, 1716, 1455, 1410, 1353, 1161, 550 cm–1.
˜
MS (ESI): m/z = 529.2 [M + NH4]+. HRMS (ESI): calcd. for
3.68–3.57 (m, 1 H), 3.28–3.17 (m, 1 H) ppm. IR (KBr): ν = 3349,
˜
C28H37N3O4SNa+ [M + Na]+ 534.2397; found 534.2395.
2935, 2598, 1882, 1605, 1569, 1484, 1244, 1054, 747 cm–1.
Benzyl (2R,4S)-2-Cyano-4-(N-dodecyl-4-methylphenylsulfonamido)-
pyrrolidine-1-carboxylate (9c): Yield 1.361 g, 80%. [α]2D3 = 16.2 (c =
0.92, CHCl3). 1H NMR (300 MHz, CDCl3): δ = 7.62 (d, J =
8.7 Hz, 2 H), 7.30–7.16 (m, 7 H), 5.07 (m, 2 H), 4.63–4.42 (m, 2
H), 3.60–3.42 (m, 1 H), 3.22–3.05 (m, 1 H), 3.05–2.83 (m, 2 H),
2.35 (s, 3 H), 2.27–2.10 (m, 2 H), 1.51 (br., 2 H), 1.17 (m, 18 H),
0.81 (t, J = 6.6 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3, the
signals in parentheses refer to the rotamer): δ = 162.0, 153.9
(153.2), 144.0, 136.8 (135.7), 130.0, 128.6, 128.5 (128.4), 128.3
(128.1), 127.0, 117.9, 68.0, 55.7 (54.9), 47.3 (46.9), 45.5 (45.2), 34.4,
33.1, 31.9 (31.4), 29.6, 29.5, 29.3, 29.2, 26.8, 22.7, 21.5, 14.1 ppm.
(2S,4S)-5-[4-(4-Methylphenylsulfonamido)pyrrolidin-2-yl]-1H-tetra-
zole (C4): Yield 0.554 g, 90%, m.p. 169–170 °C. [α]2D5 = –11.4 (c =
1.05, DMSO). H NMR (300 MHz, [D6]DMSO): δ = 8.26 (br., 1
H), 7.73 (d, J = 8.1 Hz, 2 H), 7.43 (d, J = 8.1 Hz, 2 H), 4.76–4.62
(m, 1 H), 4.00–3.84 (m, 1 H), 3.34–3.20 (m, 1 H), 3.00–2.82 (m, 1
H), 2.40 (s, 3 H), 2.10–1.90 (m, 2 H) ppm. 13C NMR (75 MHz,
[D6]DMSO): δ = 157.8, 143.6, 138.2, 130.4, 127.2, 53.6, 51.9, 49.7,
1
36.5, 21.5 ppm. IR (KBr): ν = 3559, 3107, 2895, 2448, 1653, 1449,
˜
1312, 1152, 1093, 661 cm–1. MS (ESI): m/z = 309.2 [M + H]+.
HRMS (ESI): calcd. for C12H17N6O2S+ [M + H]+ 309.1128; found
309.1133.
IR (film): ν = 2925, 2854, 1716, 1456, 1410, 1353, 1161, 550 cm–1.
˜
MS (ESI): m/z = 585.4 [M + NH4]+. HRMS (ESI): calcd. for
(2S,4S)-5-[4-(N,4-Dimethylphenylsulfonamido)pyrrolidin-2-yl]-1H-
tetrazole (C5): Yield 0.547 g, 85%, m.p. 162–163 °C. [α]2D5 = –19.2
C32H45N3O4SNa+ [M + Na]+ 590.3023; found 590.3024.
1
(c = 0.95, DMSO). H NMR (300 MHz, [D6]DMSO): δ = 7.73 (d,
Synthesis of Catalysts C1–C12 and E1: A solution of the ester
(5 mmol) and MeOH saturated with NH3 (100 mL) in a tightly
sealed bottle (250 mL) at room temperature was stirred for 5 d.
The solvent was then removed under reduced pressure to give the
corresponding acylamide without further purification.
J = 8.4 Hz, 2 H), 7.45 (d, J = 8.4 Hz, 2 H), 4.93–4.80 (m, 1 H),
4.80–3.68 (m, 1 H), 3.29 (m, 1 H), 3.00–2.84 (m, 1 H), 2.72 (s, 3
H), 2.40 (s, 3 H), 2.26–2.14 (m, 1 H), 2.10–1.94 (m, 1 H) ppm. IR
(KBr): ν = 3548, 2972, 2451, 1657, 1597, 1343, 1153, 1091, 983,
˜
665 cm–1. MS (ESI): m/z = 323.2 [M + H]+. C13H18N6O2S: C 48.43,
Under dry N2, a solution of POCl3 (2.8 mL, 30 mmol) in DCM
(10 mL) was added dropwise to a stirred solution of the acylamide
(5 mmol) and pyridine (10 mL) in DCM (20 mL) under cooling
in an ice/water bath. Stirring was continued for 3 h at the same
temperature. The resulting mixture was poured into ice/water
(100 mL) and the water portion was extracted with DCM
(2ϫ30 mL). The combined organic portions were washed with sat-
urated Cu2SO4 (2ϫ80 mL) and saturated brine (40 mL), dried with
Na2SO4, and concentrated in vacuo. The crude product was puri-
fied by flash column chromatography (PE/EA, 4:1) to give the cor-
responding nitrile.
H 5.63, N 26.07; found C 48.20, H 5.44, N 26.31.
(2R,4S)-5-[4-(4-Methylphenylsulfonamido)pyrrolidin-2-yl]-1H-tetra-
zole (C6): Yield 0.536 g, 87%, m.p. 217–218 °C. [α]2D7 = –8.6 (c =
1
1.80, DMSO). H NMR (300 MHz, [D6]DMSO): δ = 8.18 (br., 1
H), 7.72 (m, 2 H), 7.42 (m, 2 H), 4.95–4.82 (m, 1 H), 3.93 (br., 1
H), 3.46–3.32 (m, 1 H), 3.10–2.97 (m, 1 H), 2.37 (s, 3 H), 2.30–2.07
(m, 2 H) ppm. 13C NMR (75 MHz, [D6]DMSO): δ = 157.9, 143.7,
137.8, 130.4, 127.2, 53.7, 52.3, 50.9, 36.8, 21.5 ppm. IR (KBr): ν =
˜
3543, 3112, 2430, 1594, 1450, 1314, 1159, 1094, 706 cm–1. MS
(ESI): m/z = 309.2 [M + H]+ . HRMS (ESI): calcd. for
C12H17N6O2S+ [M + H]+ 309.1128; found 309.1132.
NaN3 (0.52 g, 8 mmol) and NH4Cl (0.432 g, 8 mmol) were added
to a stirred solution of nitrile (4 mmol) in DMF (40 mL). Stirring
was continued for 1 d at 70 °C. The resulting mixture was concen-
trated in vacuo to remove most of the DMF, then water (100 mL)
was added, and the water phase was extracted with DCM
(2ϫ50 mL). The combined organic portions were washed with sat-
urated brine (2ϫ50 mL), dried with Na2SO4, and concentrated in
vacuo. The crude product was purified by flash column chromatog-
raphy (DCM/MeOH, 10:1) to give the Cbz-protected tetrazole.
(2R,4S)-5-[4-(N,4-Dimethylphenylsulfonamido)pyrrolidin-2-yl]-1H-
tetrazole (C7): Yield 0.560 g, 87%, m.p. 156–157 °C. [α]2D5 = –8.0 (c
= 1.45, DMSO). H NMR (300 MHz, [D6]DMSO): δ = 7.69 (d, J
= 8.4 Hz, 2 H), 7.45 (d, J = 8.4 Hz, 2 H), 4.92–4.80 (m, 2 H), 3.28
(m, 1 H), 3.05–2.96 (m, 1 H), 3.00 (s, 3 H), 2.40 (s, 3 H), 2.13–2.05
1
(m, 2 H) ppm. IR (KBr): ν = 3611, 3430, 2962, 2423, 1649, 1597,
˜
1337, 1158, 1087, 669 cm–1. MS (ESI): m/z = 323.2 [M + H]+.
C13H18N6O2S: C 48.43, H 5.63, N 26.07; found C 48.25, H 5.50,
N 26.19.
10% Pd/C (10 wt.-%) was added to a solution of the Cbz-protected
tetrazole (2 mmol) in methanol and the mixture was subjected to
hydrogenation under a pressure of 1 atmosphere at room tempera-
ture. The reaction was monitored by TLC. After completion of the
reaction, the reaction mixture was filtered and concentrated in
vacuo to afford the crude product. The pure catalysts C were ob-
tained by recrystallization from methanol.
(S)-5-(Pyrrolidin-2-yl)-1H-tetrazole (C1):[1] Yield 0.234 g, 84%.
[α]2D5 = –27.5 (c = 1.30, DMSO). 1H NMR (300 MHz, [D4]MeOH):
δ = 5.02–4.96 (m, 1 H), 3.55–3.42 (m, 2 H), 2.62–2.47 (m, 1 H),
(2R,4S)-5-(4-Methylsulfonamidopyrrolidin-2-yl)-1H-tetrazole (C8):
M.p. 204–205 °C. Yield 0.399 g, 86%. [α]2D6 = –26.4 (c = 1.05,
DMSO). 1H NMR (300 MHz, [D6]DMSO): δ = 7.69 (br., 1 H),
4.98 (m, 1 H), 4.26 (br., 1 H), 3.67–3.56 (m, 1 H), 3.22 (m, 1 H),
3.02 (s, 3 H), 2.55–2.45 (m, 1 H), 2.44–2.32 (m, 1 H) ppm. 13C
NMR (75 MHz, [D6]DMSO): δ = 158.1, 54.1, 52.3, 51.6, 40.8,
37.7 ppm. IR (KBr): ν = 3295, 3000, 2472, 1602, 1462, 1328, 1154,
˜
1029, 764 cm–1. MS (ESI): m/z = 233.1 [M + H]+. HRMS (ESI):
calcd. for C6H12N6O2SNa+ [M + Na]+ 255.0635; found 255.0643.
(2R,4S)-5-[4-(2,4,6-Trimethylphenylsulfonamido)pyrrolidin-2-yl]-
2.46–2.10 (m, 3 H) ppm. IR (KBr): ν = 2962, 2586, 2466, 1627,
˜
1H-tetrazole (C9): Yield 0.558 g, 83%, m.p. 238 °C (dec.). [α]2D5
=
1456, 1418, 1397, 954 cm–1.
–8.8 (c = 1.70, DMSO). 1H NMR (300 MHz, [D6]DMSO): δ = 8.03
(2S,3R,7R)-5-(Octahydro-1H-indol-2-yl)-1H-tetrazole (C2): Yield (br., 1 H), 7.10–7.00 (m, 2 H), 4.89 (t, J = 8.7 Hz, 1 H), 3.98 (t, J
0.317 g, 82%. [α]2D4 = –6.0 (c = 0.77, DMSO). 1H NMR (300 MHz,
[D4]MeOH): δ = 4.98 (t, J = 8.4 Hz, 1 H), 3.70 (dd, J = 15.3,
= 8.7 Hz, 1 H), 3.45 (m, 1 H), 3.05–2.95 (m, 1 H), 2.58 (s, 6 H),
2.27 (s, 3 H), 2.30–2.16 (m, 1 H), 2.16–1.99 (m, 1 H) ppm. 13C
Eur. J. Org. Chem. 2009, 904–911
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
909

Y.-Y. Wu, Z. Chai, X.-Y. Liu, G. Zhao, S.-W. Wang
FULL PAPER
NMR (75 MHz, [D6]DMSO): δ = 158.1, 142.5, 139.0, 134.4, 132.4,
Acknowledgments
53.7, 51.5, 50.5, 36.7, 23.1, 20.9 ppm. IR (KBr): ν = 3536, 3112,
˜
2974, 1604, 1456, 1328, 1160, 660 cm–1. MS (ESI): m/z = 337.1 [M
+ H]+. HRMS (ESI): calcd. for C14H20N6O2S+ [M + H]+ 337.1441;
found 337.1438.
Generous financial support from the National Natural Science
Foundation of China (Nos. 20172064, 203900502, and 20532040),
the QT Program of the Shanghai Natural Science Council, and
the Excellent Young Scholars Foundation of the National Natural
Science Foundation of China (No. 20525208) is gratefully acknowl-
edged.
(2R,4S)-5-[4-(N-Butyl-4-methylphenylsulfonamido)pyrrolidin-2-yl]-
1H-tetrazole (C10): Yield 0.612 g, 84%, m.p. 244–245 °C. [α]2D4
=
15.5 (c = 0.60, DMSO). 1H NMR (300 MHz, [D4]MeOH): δ = 7.80
(d, J = 8.4 Hz, 2 H), 7.45 (d, J = 8.1 Hz, 2 H), 5.20 (t, J = 6.9 Hz,
1 H), 4.96–4.80 (m, 1 H), 3.72–3.62 (m, 1 H), 3.43–3.30 (m, 1 H),
3.25–3.17 (m, 2 H), 2.57–2.40 (m, 2 H), 2.46 (s, 3 H), 1.69 (m, 2
H), 1.38 (q, J = 7.5 Hz, 2 H), 0.98 (t, J = 7.5 Hz, 3 H) ppm. 13C
NMR (75 MHz, [D6]DMSO): δ = 158.4, 144.0, 136.8, 130.5, 127.4,
[1] a) H. Torii, M. Nakadai, K. Ishihara, S. Saito, H. Yamamoto,
Angew. Chem. Int. Ed. 2004, 43, 1983–1986; b) Y. Yamamoto,
N. Momiyama, H. Yamamoto, J. Am. Chem. Soc. 2004, 126,
5962–5963.
[2] a) A. J. A. Cobb, D. M. Shaw, S. V. Ley, Synlett 2004, 3, 558–
560; b) C. E. T. Mitchell, S. E. Brenner, J. García-Fortanet,
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mun. 2004, 1808–1809.
56.0, 53.5, 46.7, 44.4, 34.0, 32.9, 21.4, 20.0, 14.1 ppm. IR (KBr): ν
˜
= 3169, 2925, 2855, 1597, 1468, 1345, 1160, 1091, 673, 571 cm–1.
MS (ESI): m/z = 365.2 [M + H]+. HRMS (ESI): calcd. for
C16H25N6O2S+ [M + H]+ 365.1754; found 365.1769.
[3] A. Hartikka, P. I. Arvidsson, Tetrahedron: Asymmetry 2004,
(2R,4S)-5-[4-(N-Octyl-4-methylphenylsulfonamido)pyrrolidin-2-yl]-
15, 1831–1834.
1H-tetrazole (C11): Yield 0.638 g, 76%, m.p. 183–184 °C. [α]2D4
=
[4] a) A. J. A. Cobb, D. M. Shaw, D. A. Longbottom, J. B. Gold,
S. V. Ley, Org. Biomol. Chem. 2005, 3, 84–96; b) N. S. Chow-
dari, M. Ahmad, K. Albertshofer, F. Tanaka, C. F. Barbas III,
Org. Lett. 2006, 8, 2839–2842; c) Y. Hayashi, T. Urushima, S.
Aratake, T. Okano, K. Obi, Org. Lett. 2008, 10, 21–24.
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2005, 5346–5348; b) K. R. Knudsen, C. E. T. Mitchell, S. V.
Ley, Chem. Commun. 2006, 66–68.
[6] a) A. Hartikka, P. I. Arvidsson, Eur. J. Org. Chem. 2005, 11,
4287–4295; b) I. Ibrahem, W. Zou, Y. Xu, A. Córdova, Adv.
Synth. Catal. 2006, 348, 211–222.
[7] a) S.-G. Kim, T.-H. Park, Tetrahedron Lett. 2006, 47, 9067–
9071; b) S. Kumarn, D. M. Shaw, S. V. Ley, Chem. Commun.
2006, 3211–3213; c) S. Kumarn, D. M. Shaw, D. A. Longbot-
tom, S. V. Ley, Org. Lett. 2005, 7, 4189–4191; d) N. Momi-
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129, 1190–1195.
–2.80 (c = 1.15, DMSO). 1H NMR (300 MHz, [D4]MeOH): δ =
7.81 (d, J = 8.1 Hz, 2 H), 7.45 (d, J = 8.1 Hz, 2 H), 5.24 (t, J =
6.9 Hz, 1 H), 4.94–4.82 (m, 1 H), 3.75–3.64 (m, 1 H), 3.43–3.35 (m,
1 H), 3.26–3.13 (m, 2 H), 2.55–2.42 (m, 2 H), 2.46 (s, 3 H), 1.69
(m, 2 H), 1.33 (m, 10 H), 0.94 (t, J = 6.9 Hz, 3 H) ppm. 13C NMR
(75 MHz, [D6]DMSO): δ = 158.3, 144.0, 136.8, 130.5, 127.4, 56.0,
53.5, 46.6, 44.6, 32.9, 31.8, 31.7, 29.1, 28.1, 26.7, 22.5, 21.4,
14.4 ppm. IR (KBr): ν = 2955, 2871, 2525, 1594, 1409, 1346, 1161,
˜
1137, 663, 548 cm–1. MS (ESI): m/z = 421.2 [M + H]+. HRMS
(ESI): calcd. for C20H33N6O2S+ [M + H]+ 421.2380; found
421.2390.
(2R,4S)-5-[4-(N-Dodecyl-4-methylphenylsulfonamido)pyrrolidin-2-
yl]-1H-tetrazole (C12): Yield 0.639 g, 67%, m.p. 190–191 °C. [α]2D4
=
–11.8 (c = 0.95, DMSO). 1H NMR (300 MHz, [D4]MeOH): δ =
7.80 (d, J = 8.4 Hz, 2 H), 7.44 (d, J = 7.8 Hz, 2 H), 5.19 (t, J =
6.6 Hz, 1 H), 4.96–4.82 (m, 1 H), 3.72–3.58 (m, 1 H), 3.46–3.35 (m,
1 H), 3.25–3.14 (m, 1 H), 2.55–2.36 (m, 2 H), 2.46 (s, 3 H), 1.69
(m, 2 H), 1.32 (m, 18 H), 0.93 (t, J = 6.6 Hz, 3 H) ppm. 13C NMR
(75 MHz, [D6]DMSO): δ = 158.4, 143.9, 136.8, 130.4, 127.3, 56.0,
53.4, 46.4, 44.6, 32.9, 31.7, 29.5, 29.5, 29.2, 26.7, 22.5, 21.3,
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14.3 ppm. IR (KBr): ν = 2924, 2854, 1598, 1459, 1341, 1159, 1091,
˜
814, 661 cm–1. MS (ESI): m/z = 477.3 [M + H]+. HRMS (ESI):
calcd. for C24H41N6O2S+ [M + H]+ 477.3006; found 477.3015.
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1.43, DMSO). 1H NMR (300 MHz, [D6]DMSO): δ = 8.03 (s, 1 H),
7.66–7.58 (m, 4 H), 7.50–7.40 (m, 6 H), 5.25 (t, J = 7.2 Hz, 1 H),
4.69–4.63 (m, 1 H), 3.42–3.29 (m, 2 H), 2.43–2.32 (m, 1 H), 2.24–
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2.16 (m, 1 H), 1.03 (s, 9 H) ppm. IR (KBr): ν = 3432, 2956, 1653,
˜
1471, 1428, 1090, 1020, 702 cm–1.
General Procedure for the Enantioselective Biginelli Reaction: Com-
pound 3 (0.26 mmol) was added to a stirred solution of catalyst
(10 mol-%, 0.25 mmol) and 2 (0.30 mmol) in EtOH (1.0 mL). The
reaction mixture was stirred at 25 °C for the time given in Tables 1,
2, 3, 4, and 5. After removal of the solvent, the crude product was
purified by flash column chromatography (PE/EA = 1:1) to afford
the corresponding product. The enantiomeric excesses were deter-
mined by HPLC using a chiral column (OD or OD-H).
Supporting Information (see also the footnote on the first page of
1
this article): H and 13C NMR spectra and HPLC chromatograms.
910
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© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 904–911

Asymmetric Biginelli Reaction
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Received: October 25, 2008
Published Online: December 19, 2008
Eur. J. Org. Chem. 2009, 904–911
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
911