Use of (S)-5-(2-methylpyrrolidin-2-yl)-1H-tetrazole as a novel and enantioselective organocatalyst for the aldol reaction

Article abstract of DOI:10.1002/ejoc.200700834

The novel organocatalyst (S)-5-(2-methylpyrrolidin-2-yl)-1H-tetrazole (4) catalyzes the aldol reaction between acetone and various aldehydes with superior enantioselectivity to the existing organocatalysts (S)-proline (1) and (S)-5-(Pyrrolidin-2-yl)-1H-tetrazole (3). Wiley-VCH Verlag GmbH & Co. KGaA, 2008.

Full text of DOI:10.1002/ejoc.200700834

FULL PAPER
DOI: 10.1002/ejoc.200700834
Use of (S)-5-(2-Methylpyrrolidin-2-yl)-1H-tetrazole as a Novel and
Enantioselective Organocatalyst for the Aldol Reaction
Sok-Teng (Amy) Tong,[a] Paul W. R. Harris,[a] David Barker,[a] and Margaret A. Brimble*[a]
Keywords: Aldol / Enantioselectivity / Methylproline / Organocatalysis / Tetrazole
The novel organocatalyst (S)-5-(2-methylpyrrolidin-2-yl)-1H-
tetrazole (4) catalyzes the aldol reaction between acetone
and various aldehydes with superior enantioselectivity to the
existing organocatalysts (S)-proline (1) and (S)-5-(pyrrolidin-
2-yl)-1H-tetrazole (3).
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
talyst, we decided to re-examine the effect of α-substitution
in proline-based catalysts on the efficiency and enantio-
selectivity of the aldol reactions of acetone.
Introduction
Asymmetric organocatalysis has recently emerged as a
“hot field” in synthetic chemistry providing an operation-
ally simple, economic and environmentally friendly strategy
to prepare enantioenriched compounds.[1] The aldol reac-
tion can now be carried out enantioselectively using a vari-
ety of organocatalysts, many of which are based on a pro-
line scaffold.[2,3] These proline-based catalysts contain the
minimum structural requirements required for organocata-
lytic activity namely a cyclic secondary amine and an acidic
proton in the correct spatial geometry as found in (S)-pro-
line 1.[2c,2h,2q]
Significantly, examples of organocatalysts based on an α-
alkylproline scaffold are rare. (S)-α-Methylproline (2) was
shown to be ineffective as an organocatalyst for the α-hy-
droxylation of cyclohexanone,[4] but proved better than pro-
line (1) for the α-hydroxylation of aldehydes.[5] In the inter-
molecular aldol reaction between acetone and p-nitrobenz-
aldehyde, use of 2 resulted in lower yields and enantio-
selectivity than proline,[2h] whilst the recently reported in-
tramolecular α-alkylation of aldehydes involving catalysis
by 2 proceeded in better yield and enantioselectivity than
when proline was used.[6]
The pyrrolidine derivative 3 has emerged as a useful or-
ganocatalyst for various reactions.[2j,3a–3c,7–11] Substitution
of the carboxylic acid group in proline for a tetrazole moi-
ety reduced the aldol reaction times from 1–2 days to less
than half a day.[2h,3a,3b] This dramatic improvement in effi-
ciency was attributed to the presence of a more acidic tetra-
zole proton in DMSO as solvent and the larger size of the
tetrazole unit resulting in a more favourable transition
state.[3a,12] Whilst proline is known to react with aliphatic
aldehydes and ketones to form oxazolidinones,[2c,13–15] and
with aromatic aldehydes to give azomethine ylides,[2c,16–17]
NMR studies by Hartikka and Arvidsson showed that 3
did not participate in these reactions.[3b] They attributed the
major reason for the enhanced efficiency of 3 over proline
1 to be due to the lack of side reactions between 3 and the
aldehyde and ketone substrates. Notably, however, 3 did not
improve the enantioselectivity of these aldol reactions.[3a]
We therefore envisaged that “α-methylproline tetrazole”
4 might prove to be a better organocatalyst in that it com-
bined the presence of an additional α-methyl substituent to
improve the stereoselectivity of the aldol reaction with the
incorporation of a tetrazole moiety to increase the reaction
rate. We therefore herein report the use of α-methylproline
(2) and the synthesis and use of the novel derivative 4 as
organocatalysts for intermolecular aldol reactions (Fig-
ure 1).
In general the aldol reactions between acetone and aro-
matic aldehydes catalysed by proline 1 only proceeded in
modest yield and enantiomeric excess (Ͻ80% ee).[2c,2d,2h]
There are, however, recent examples of aldol reactions with
other ketones and aromatic aldehydes in which higher ee
values are obtained.[2r,2s] Given the remarkable improve-
ment in the stereoselectivity of α-alkylation and α-hydroxyl-
ation of aldehydes using α-methylproline 2 as the organoca-
[a] Department of Chemistry, The University of Auckland,
23 Symonds Street, Auckland 1142, New Zealand
Fax: +64-9-373-7422
E-mail: m.brimble@auckland.ac.nz
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
Figure 1. Structures of the existing organocatalysts 1, 2 and 3 and
the novel organocatalyst 4.
164
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 164–170

Novel Proline-Derived Organocatalyst for Aldol Reactions
Table 1. Yields and ee values for the aldol reaction between acetone
and p-nitrobenzaldehyde (11) catalysed by 1–4.
Results and Discussion
α-Methylproline (2) was prepared via Wang and Ger-
manas’s modification[18] of Seebach’s method[19] for the
preparation of α-branched amino acids. Tetrazole 4 was
prepared by adaptations of previously reported methods for
the synthesis of tetrazole 3 or its intermediates,[3b,20–22]
starting from the readily available (S)-α-methylproline
methyl ester (5) (Scheme 1).[23]
Entry Catalyst Loading Time
% Yield
% ee[d]
[mol-%]
[h]
12
13 SM[c] 14
1[a]
2[a]
3[a]
4[b]
5[a]
6[a]
7
1
1
2
2
2
3
3
3
4
4
4
20
30
20
20
30
20
20
30
20
30
40
22
18
70
46
54
0.7
1.4
0.9
68
48
50
54
56
13
32
18
50
61
54
60
67
17
1
2
0
0
0
8
21
6
2
6
0
0
Ͻ1
Ͻ1
0
0
0
0
8
9
0
0
23
0
0
0
0
0
72
68
0[e]
2[e]
0[e]
76
76
76
88
86
80
8
9
11
26
24
10
11[a]
0
0
[a] Performed under anhydrous conditions. [b] The reaction was
performed in DMF with 555 mol-% of water. [c] Percentage of re-
covered aldehyde 11. [d] ee values of 12 as determined by 1H NMR
analysis for the Mosher ester derivative. [e] The ee value reported
by Barbas et al. was not reproduced.[2h]
reactions in an excess of acetone in order to circumvent this
undesired reaction.[2c] In our case, significant quantities of
14 were observed using proline and α-methylproline as cata-
lysts using their conditions. The fact that 14 was not ob-
served when using the tetrazoles 3 and 4 (Table 1) supports
the postulate that tetrazoles offer an additional benefit in
the catalytic aldol reactions by eliminating the oxapyrroliz-
idine side reaction which is observed using the carboxylic
acid based catalysts 1 and 2.
Scheme 1. Synthesis of (S)-5-(2-methylpyrrolidin-2-yl)-1H-tetrazole
(4).
Table 1 illustrates the observation that while catalyst
Catalysts 1, 2, 3 and 4 were initially examined as organo- loading had little influence on the reaction outcome, the
catalysts for the benchmark aldol reaction between acetone presence of water had a significant effect. The effect of
and p-nitrobenzaldehyde (11). The reactions were carried water on asymmetric aldol reactions using various organo-
out in DMSO as the standard solvent.[2c,2d,2h,2k,3a,24] Use of catalysts[3e–3g,25] including proline and tetrazole 3[2h,2l,2o,3c]
DMSO favours the 1H-tautomer of the tetrazole engaged has been well documented. In general, water promotes cata-
in the favoured transition state.[3a] Catalysis by proline and lytic efficiency but not the stereoselectivity, with use of ex-
tetrazole 3 afforded β-hydroxy ketone 12 in 60% yield, and cessive water leading to reduced stereoselectivity. Indeed in
as previously reported, the reaction proceeded much faster our case, the catalytic efficiency of α-methylproline doubled
using proline tetrazole 3 than (S)-proline but with similar when water was added, with no effect on the stereoselecti-
enantioselectivity (Table 1). The use of α-methylproline, vity (Table 1, entry 4). Water possibly serves to hydrolyse
however, only resulted in formation of racemic 12. Pleas- any iminium species that forms between substrate 11 and
ingly, tetrazole 4 afforded the highest enantioselectivity of the catalyst, such that they are free to react as intended
the four catalysts examined with the reaction proceeding in without participating in side reactions.
comparable yield albeit with a longer reaction time.
We next examined the effect of solvent on the catalysis of
An interesting observation was the formation of the oxa- the aldol reaction using tetrazole 4 (Table 2). The reaction
pyrrolizidine derivative 14 as a by-product in the reactions worked well in DMF (3% water) with minimal effect on
using proline and α-methylproline (2) as catalysts. The pyr- the stereoselectivity. Lowering the reaction temperature in
rolizidine 14 has previously been reported by Orsini et al.[16] DMF has been shown to increase stereoselectivity when
as a mixture of diastereomers from reaction of proline 1 using proline,[3a] however, using the tetrazole 4 in DMF at
with 11 in DMSO. List and Barbas III carried out their lower temperature only resulted in a low yield of product.
Eur. J. Org. Chem. 2008, 164–170
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165

S.-T. (A.) Tong, P. W. R. Harris, D. Barker, M. A. Brimble
FULL PAPER
Aldol reactions in dichloromethane and toluene using tetra- Table 3. Effect of temperature on the catalysis of the aldol reaction
between acetone and aldehyde 11 by α-methylproline tetrazole 4.
zole 4 proceeded slowly and less satisfactorily than in
DMSO, which proved to be the optimal solvent.
Table 2. The effect of solvent on the catalysis of the aldol reaction
between acetone and aldehyde 11 by tetrazole 4.
Entry Temperature
4 h
1 day
2 days
65%
3 days
1
2
3
room temp.
44%
(90% ee)
65%
(85% ee) (82% ee) (81% ee)
67%
60%
(88% ee)
67%
Entry
Solvent
Time
[h]
% Yield
13 SM[b]
% ee of 12
35 °C
15%
12
50 °C
1
2
3
4
5
DMF, H2O, room temp.
DMF, –50 °C
DCM
48
72
50
69
68
63
7
31
17 Ͻ1
60
3
0
0
20
71
69
68
11
82
86
(78% ee)
68
PhMe
DMSO
74[a]
88
2
[a] Notably, ee of 12 is still higher than those obtained with proline
1 (54% ee) and proline tetrazole 3 (61%).[3a] [b] Percentage of reco-
vered aldehyde 11.
With the optimal reaction conditions determined, several
aldehydes were screened to determine the generality of
Efforts to improve the catalytic efficiency of α-methylpro- tetrazole 4 as an organocatalyst (Table 4). α-Methylproline
line tetrazole 4 were next undertaken (Table 3). Several re- tetrazole 4 conferred excellent enantioselectivity using a
cent reports suggested a positive effect of microwave irradi- variety of aromatic aldehydes with much better enantio-
ation or heat on the aldol reaction catalysed by proline 1, meric excesses being obtained compared to the use of pro-
significantly shortening the reaction time whilst main- line 1 or proline tetrazole 3. Entry 4 demonstrates the posi-
taining the observed enantioselectivity.[26,27] Running the re- tive impact of water on the catalytic efficiency, where the
action at 35 °C instead of room temperature shortened the yield was four times higher than that obtained under anhy-
reaction time by one-third, with the same yield and slightly drous conditions. Notably, the potential for improvement in
lower selectivity (Table 3, entry 2). Unfortunately, further efficiency by heating the reaction at 35 °C was also sub-
increases in the temperature diminished the selectivity with- strate-specific. Whereas 16i was obtained in 87% yield at
out improving the yield (Table 3, entry 3). 1H NMR studies 35 °C after 1 day (Table 4, entry 9), heating did not improve
in [D6]DMSO showed that the conversion rate reached a the formation of 16e significantly (Table 4, entry 5). Disap-
plateau after 2 days (see electronic supporting information) pointingly, the increase in temperature appeared to facilitate
with the optimum yield and ee being obtained after 1 day undesired dehydration, giving more enone 17c than 16c
(Table 3, entry 2).
(Table 4, entry 3).
Table 4. Yields and ee values for the aldol reaction between acetone and various aldehydes 15 catalysed by 4.
Entry
R
Time [h], temp. [°C]
% Yield
% ee[c]
% ee[e]
% ee[f]
16, 17, SM[b]
1
2
3
4-NO2, a
2-Cl, b
4-MeO, c
68, room temp.
68, room temp.
143, room temp.
51, 35 °C
48, room temp.
48, room temp.[a]
88, room temp.
43, 35 °C
89, room temp.
69, room temp.
72, room temp.
67, room temp.
24, 35 °C
60, 2, 11
60, Ͻ2, 0
12, 0, 47
4, 9, 47
33, Ͻ5, 13
8, 0, 50
11, 8, 73
16, 9, 51
30, 18, 33
22, 0, 0
36, 6, 20
88, 4, 3
88[d]
90
85
–
87
83
70
–
81
80
86
91
89
90
72
70
76
77
62[3b]
4
5
4-Br, d
65[2h]
69[2h]
66[3b]
4-AcNH, e
6
7
8
9
2-naphthyl, f
H, g
4-Cl, h
2-NO2, i
77[2h]
60[2h]
65[3b]
87, 4, 0
71, 3, 9
10
3-NO2, j
68, room temp.
[a] Performed under anhydrous conditions. [b] Percentage of recovered aldehyde 15. [c] ee obtained with tetrazole 4 by chiral HPLC. [d]
1
Determined by H NMR analysis of the Mosher ester derivative. [e] ee obtained with proline. [f] ee obtained with tetrazole 3.
166
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Novel Proline-Derived Organocatalyst for Aldol Reactions
5-HB), 4.90–5.22 (m, 2 H, PhCH2O), 7.25–7.40 ppm (m, 5 H, Ar-
Conclusions
1
H), as a mixture of 1:1 rotamers. H NMR spectroscopic data was
consistent with literature values.[29]
In conclusion, we have examined the effect of α-methyl
substitution on proline-based catalysts 1 and 3 by investiga-
ting the potential of α-methylproline (2) and “α-methylpro-
line tetrazole” 4 as organocatalysts for the aldol reaction.
Tetrazole 4 affords remarkable stereoselectivity and this ob-
served enhancement may well be extended to the organocat-
alysis of other reactions. The detailed mechanistic basis for
these observations is currently under investigation.[28] Ad-
dition of an α-substituent to other existing proline-based
organocatalysts may also improve the observed stereoselec-
tivities. Studies on the use of tetrazole 4 as an organocata-
lyst for other reactions together with the introduction of α-
substituents onto other proline-based organocatalysts are
on-going.
(S)-1-(Benzyloxycarbonyl)-2-methylpyrrolidine-2-carboxylic
Acid
(7): A solution of ester 6 (578 mg, 2.08 mmol) in 5  NaOH/MeOH
(2:1, 12 mL) was heated at reflux for 2 hours. The mixture was then
diluted with water (30 mL) and washed with diethyl ether (20 mL).
The aqueous phase was acidified to pH 1 with 2  HCl and ex-
tracted with CHCl3 (3ϫ35 mL). The combined CHCl3 extracts
were washed with brine (40 mL), dried (MgSO4) and evaporated to
give a crude pale yellow oil (492 mg). The crude was recrystallised
with dichloromethane/hexane to yield the title acid as a colourless
solid (478 mg, 87%); m.p. 89–91 °C (lit.[29] m.p. 121 °C). [α]1D8 = –7
1
(c = 1.0, MeOH) [ref.[30] [α]2D0 = –8.8 (c = 1.0, MeOH)]. H NMR
(400 MHz, CDCl3): δ = 1.54 and 1.64 (s, 3 H, 2-CH3), 1.80–2.00
(m, 3 H), 2.20–2.43 (m, 1 H), 3.49–3.72 (m, 2 H, 5-HA and 5-HB),
5.00–5.20 (m, 2 H, PhCH2CO), 7.20–7.50 (m, 5 H, Ar-H), 9.38–
10.60 ppm (br. s, 1 H, OH), as an approximately 1:1 mixture of
1
rotamers. The H NMR spectroscopic data are consistent with lit-
erature values.[29] MS (EI): m/z (%) = 263 (0.015, M+), 218 (0.17,
M – CO2H), 174 (0.18), 128 (0.17, M–PhCH2CO2), 91 (1.0,
PhCH2). HMRS calculated for C14H17NO4 263.11576, found
263.11551.
Experimental Section
General: Reactions were monitored by TLC, using pre-coated silica
gel TLC plates obtained from Merck. Flash chromatography was
carried out on silica gel (Riedel-de Haën, particle size 0.032–
0.063 mm). Reactions that required anhydrous conditions were run
under an atmosphere of nitrogen. Evaporation of solvents was car-
ried out at reduced pressure. Dimethyl sulfoxide was distilled from
calcium hydride at reduced pressure and acetone was distilled from
anhydrous calcium sulfate. Hexane for flash chromatography was
distilled before use. HPLC analysis was performed on a Waters
Instrument (2487 dual wavelength absorbance detector with a 600
binary HPLC Pump). The Chiralpak AD-H column was purchased
from Daicel Chemical Industries Ltd. Optical rotations were mea-
sured on a Perkin–Elmer 341 polarimeter (λ = 589 nm, 0.1 dm cell).
Melting point determinations were performed on an Electrother-
mal® melting point apparatus. 1H NMR and 13C NMR spectra
were recorded on Bruker Avance DRX 300 MHz or 400 MHz spec-
trometers at ambient temperatures. Chemical shifts δ are expressed
in ppm and coupling constants J are reported in Hz. TMS served
Benzyl (S)-2-Carbamoyl-2-methylpyrrolidine-1-carboxylate (8): To a
solution of acid 7 (100 mg, 0.38 mmol) in dry chloroform (32 mL)
was added, under nitrogen at 0 °C, triethylamine (0.42 mL,
3.04 mmol) and ethyl chloroformate (0.29 mL, 3.04 mmol). The
mixture was stirred at 0 °C for 2 hours and aqueous ammonia solu-
tion (28%, 4.94 mL) was added, after which the mixture was stirred
for another 3 hours. The aqueous phase was separated and ex-
tracted with chloroform (2ϫ15 mL). The combined organics were
washed with cold 5% NaHCO3 solution (30 mL), dried (MgSO4)
and evaporated to afford a crude yellow oil, which was purified via
flash chromatography ( EtOAc/MeOH, 99:1) to furnish the title
amide as a sticky yellow gum (94 mg, 94%). [α]2D0 = –25 (c = 1.0,
1
MeOH). H NMR (300 MHz, CDCl3): δ = 1.53 and 1.64 (s, 3 H,
2-CH3, rotamers), 1.72–2.09 (m, 3 H), 2.09–2.78 (m, 1 H), 3.33–
3.78 (m, 2 H, 5-HA and 5-HB), 5.12 (s, 2 H, PhCH2), 6.08–6.56 (m,
1 H, NH), 6.83 (br. s, 1 H, NH), 7.06–7.60 ppm (m, 5 H, Ar-H),
as a mixture of rotamers. 13C NMR (100 MHz, CDCl3): δ = 22.2
(2-CH3), 22.5 (C-4), 38.9 and 41.2 (C-3, rotamers), 48.2 and 48.4
(C-5, rotamers), 65.9 and 67.0 (C-2, rotamers), 66.7 and 66.8
(PhCH2, rotamers), 127.5, 127.8, 128.3 (Ar-C), 136.0 and 136.3
(quat. Ar-C), 154.4 and 154.7 (C=O carbamate, rotamers), 177.0
1
as internal standard (δ = 0 ppm) for H NMR, and CDCl3 served
as internal standard (δ = 77.0 ppm) for 13C NMR spectroscopy.
Where CD3OD was used as the solvent, chemical shifts δ were re-
1
ported using residual CHD2OD (δ = 3.30 ppm for H NMR) and
CD3OD (δ = 49.05 ppm for 13C NMR) as internal standards,
respectively. Infrared spectra were recorded on a Perkin–Elmer
spectrum one FT-IR spectrometer.
and 177.5 ppm (C=O amide, rotamers). IR (NaCl): ν = 3401
˜
(amide N–H stretching), 2977 (C–H), 2874, 1691 (carbamate,
amide C=O stretching), 1606 (amide, N–H bending), 1497 cm–1.
MS (CI+, NH3): m/z (%) = 263 (0.20, M + H), 218 (0.40, M –
CONH2), 174 (0.23), 91 (1.0, PhCH2). HMRS calculated for
C14H19N2O3 263.13957, found 263.13897.
1-Benzyl 2-Methyl (S)-2-Methylpyrrolidine-1,2-dicarboxylate (6):
To a solution of methyl (S)-2-methylpyrrolidine-2-carboxylate hy-
drochloride (5) (600 mg, 3.10 mmol) in water/dioxane (1:1, 6 mL)
was added, at 0 °C, NaHCO3 (0.39 g, 4.65 mmol) in small portions,
followed by benzyl chloroformate (3.48 mL, 24.78 mmol) dropwise.
The mixture was stirred at 0 °C for 2 hours and then at room tem-
perature for 47 hours. The reaction mixture was concentrated under
reduced pressure to remove dioxane and the remaining aqueous
phase was extracted with chloroform (3ϫ6 mL). The organic ex-
tracts were dried (MgSO4) and concentrated to give a crude colour-
less liquid (4.2 g). The crude was subsequently distilled (20 mbar,
120 °C) to remove benzyl alcohol and the remaining residue was
purified by flash chromatography (toluene/EtOAc, 4:1) to furnish
Benzyl (S)-2-Cyano-2-methylpyrrolidine-1-carboxylate (9). Method
1: To a solution of amide 8 (1.09 g, 4.17 mmol) in dimethylform-
amide (14 mL) was added at 0 °C cyanuric chloride (0.58 g,
3.12 mmol) in one shot. The mixture was stirred for 3 hours, by
which time it had turned yellow. Water (30 mL) was added to
quench the reaction mixture, and the resultant yellow solution was
extracted with EtOAc (3ϫ30 mL). The combined organics were
washed with water (4ϫ15 mL), dried (MgSO4) and evaporated to
yield the title nitrile as a pale yellow oil (0.97 g, 95%). [α]2D0 = –35.58
the title ester as a pale yellow oil (0.62 g, 72%). [α]2D0 = –18 (c =
1.0, MeOH). H NMR (400 MHz, CDCl3): δ = 1.54 and 1.60 (s, 3 (c = 2.08, Et2O). 1H NMR (400 MHz, CDCl3): δ = 1.67 and 1.76 (s,
1
H, 2-CH3, rotamers), 1.82–1.98 (m, 3 H), 2.10–2.24 (m, 1 H), 3.46
3 H, 2-CH3, rotamers), 1.85–2.13 (m, 3 H), 2.41–2.61 (m, 1 H),
and 3.71 (s, 3 H, CO2CH3, rotamers), 3.50–3.71 (m, 2 H, 5-HA and
3.36–3.55 (m, 1 H, 5-HA), 3.55–3.75 (m, 1 H, 5-HB), 5.06–5.32 (m,
Eur. J. Org. Chem. 2008, 164–170
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167

S.-T. (A.) Tong, P. W. R. Harris, D. Barker, M. A. Brimble
FULL PAPER
2 H, PhCH2), 7.26–7.54 ppm (m, 5 H, Ar-H), as a 3:2 mixture of
rotamers. 13C NMR (100 MHz, CDCl3): δ = 22.3 and 22.8 (2-CH3,
rotamers), 24.2 and 25.4 (C-4, rotamers), 40.3 and 41.6 (C-3, rota-
mers), 47.2 and 48.0 (C-5, rotamers), 55.1 and 55.9 (C-2, rotamers),
66.9 and 67.5 (PhCH2, rotamers), 120.7 (CϵN), 127.8, 127.9,
(m, 1 H), 3.39–3.52 (m, 2 H, 5-HA and 5-HB) ppm. 13C NMR
(100 MHz, CD3OD): δ = 22.6 (C-4), 23.4 (2-CH3), 37.0 (C-3), 44.5
(C-5), 64.4 (C-2), 162.7 (CN) ppm. IR (NaCl): ν = 3347 (b), 2112
˜
(b), 1646 (b), 1381 cm–1. MS (EI): m/z (%) = 153 (0.08, M+), 138
(0.07, M – CH3), 110 (0.23, M – HN3), 84 (0.34, M – CN4H),
128.1, 128.3 (Ar-C, rotamers), 135.9 (quat. Ar-C), 153.4 ppm 43 (1.0, HN3+). HMRS calculated for C6H11N5 153.10145, found
(C=O, carbamate), as a 2:1 mixture of rotamers. IR (NaCl): ν =
153.10164.
˜
2979 (C–H), 2876, 2237 (CϵN), 1703 (carbamate C=O stretching),
1497 cm–1. MS (EI): m/z (%) = 263 (0.05, M+), 185 (0.04), 137
(0.05), 128 (0.19, M – PhCH2CO2), 91 (1.0, PhCH2). HMRS calcu-
lated for C14H16N2O2 244.12118, found 244.12098.
General Procedures for the Enantioselective Direct Aldol Reaction
Catalysed by Tetrazole 4
A. Under Anhydrous Conditions: A clean, dry round-bottomed flask
was charged with tetrazole 4 (7.66 mg, 0.05 mmol) and the flask
flushed with nitrogen and placed under an atmosphere of nitrogen.
Anhydrous dimethyl sulfoxide (2 mL) was added via syringe fol-
lowed by freshly distilled acetone (0.5 mL). The mixture was stirred
for 5 minutes. The aldehyde (0.25 mmol) was then added in one
shot. The mixture was stirred at room temperature for the reported
number of hours. The mixture was quenched with saturated ammo-
nium chloride (1 mL), after which it became warm. The mixture
was diluted with water (5 mL) and transferred to a separating fun-
nel where it was extracted with EtOAc or ether until no more prod-
uct was detected in the aqueous phase by TLC. The combined or-
ganics were dried (MgSO4) and evaporated in vacuo to furnish a
crude brown liquid, which was purified via flash chromatography
(hexane/EtOAc) to provide the aldol adduct.
Method 2: A solution of phosphorus oxychloride (0.18 mL) in dry
dichloromethane (0.37 mL) was added at –5 °C under nitrogen to
a solution of amide 8 (0.40 g, 1.53 mmol) in pyridine (1.91 mL,
0.024 mol). The mixture was stirred at –5 °C for 5 hours, after
which time no starting material was detected by TLC. The mixture
was poured onto ice (10 g). The resultant solution was then ex-
tracted with diethyl ether (3ϫ12 mL). The combined organics were
washed with saturated cupric sulfate solution (20 mL), brine
(20 mL) and dried (MgSO4) and evaporated to give the title nitrile
as a pale yellow oil (0.308 g, 83%). The NMR spectroscopic data
were identical to those obtained via method 1.
Benzyl (S)-2-Methyl-2-(1H-tetrazol-5-yl)pyrrolidine-1-carboxylate
(10): To a solution of triethylamine (0.46 mL, 3.27 mmol) in dry
toluene (2 mL), under an atmosphere of nitrogen, was added glacial
acetic acid (0.19 mL, 3.27 mmol) and the solution was allowed to
stir for two minutes. This solution was then transferred to a round-
bottomed flask containing nitrile 9 (200 mg, 0.82 mmol) and so-
dium azide (0.21 g, 3.27 mmol) was added. The mixture was heated
at reflux for 24 hours, after which time no nitrile was detected by
TLC. Water (4 mL) was added and the aqueous layer was sepa-
rated. The organic layer was again extracted with water, and the
combined aqueous extracts were treated with 2  HCl (3 mL). The
aqueous mixture was then extracted with EtOAc (3ϫ10 mL). The
combined organics were dried (MgSO4) and evaporated in vacuo
to furnish the title tetrazole as a viscous light brown oil (225 mg,
96%). [α]1D8 = –72.30 (c = 2.96, CHCl3). 1H NMR (400 MHz,
CDCl3): δ = 1.88 and 1.90 (s, 3 H, 2-CH3, rotamers), 1.90–2.92 (m,
4 H, rotamers), 3.54–3.82 (m, 2 H, 5-HA and 5-HB), 4.96 and 5.11
(m, 2 H, PhCH2, rotamers), 6.85–7.00 and 7.10–7.41 ppm (m, 5 H,
B. Under Ambient Conditions: To a solution of tetrazole 4 (7.66 mg,
0.05 mmol) in dimethyl sulfoxide (2 mL) acetone (0.5 mL) was
added. The mixture was stirred for 5 minutes, after which time the
aldehyde (0.25 mmol) was added in one shot. The mixture was
stirred at room temperature for the reported number of hours. The
mixture was quenched with saturated ammonium chloride (1 mL),
after which it became warm. The mixture was diluted with water
(5 mL) and transferred to a separating funnel where it was ex-
tracted with EtOAc or ether until no more product was detected
in the aqueous phase by TLC. The combined organics were dried
(MgSO4) and evaporated in vacuo to furnish a crude brown liquid,
which was purified via flash chromatography (hexane/EtOAc) to
provide the aldol adduct.
1
4-Hydroxy-4-(4-nitrophenyl)butan-2-one (16a): The H NMR spec-
troscopic data was consistent with literature values.[2h] The product
was obtained in 88% ee. The optical purity was determined via the
Ar-H, rotamers), as
a
3:1 mixture of rotamers. 13C NMR
synthesis of the corresponding Mosher ester (see below). [α]2D3
=
(100 MHz, CDCl3): δ = 22.2 and 22.6 (C-4, rotamers), 24.3 and
24.6 (2-CH3, rotamers), 40.0 and 43.0 (C-3, rotamers), 48.3 and
48.5 (C-5, rotamers), 59.5 and 59.6 (C-2, rotamers), 67.3 and 67.5
(PhCH2, rotamers), 127.5, 128.0, 128.3, 128.4 (Ar-C, rotamers),
135.1 and 135.7 (quat. Ar-C, rotamers), 154.5 and 155.2 (C=O,
carbamate, rotamers), 160.0 ppm (CN), as a 3:1 mixture of rota-
+37.5 (c = 0.48, CHCl3) [ref.[3l] (99% ee). [α]2D2 = +66.2 (c = 0.5,
CHCl3)].
4-(2-Chlorophenyl)-4-hydroxybutan-2-one (16b): The 1H NMR
spectroscopic data was consistent with literature values.[3k] The
product was obtained in 90% ee. The optical purity was determined
by HPLC with hexane/2-propanol (95:5) as eluent; flow rate
0.5 mL/min; tR = 24.94 min (R), 27.27 min (S). [α]2D3 86.7 (c = 0.6,
CHCl3) [ref.[3l] (96% ee). [α]2D2 = +101.7 (c = 0.58, CHCl3)].
4-Hydroxy-4-(4-methoxyphenyl)butan-2-one (16c): The 1H NMR
spectroscopic data was consistent with literature values.[31] The
product was obtained in 85% ee. The optical purity was determined
by HPLC with hexane/2-propanol (95:5) as eluent; flow rate
0.5 mL/min; tR = 52.87 min (R), 60.81 min (S). [α]2D3 = +30.0 (c =
0.4, CHCl3) [ref.[32] (67% ee). [α]1D6 = +25.51 (c = 0.24, CHCl3)].
4-(4-Bromophenyl)-4-hydroxybutan-2-one (16d): The 1H NMR spec-
troscopic data was consistent with literature values.[3k] The product
was obtained in 87% ee. The optical purity was determined by
HPLC with hexane/2-propanol (93:7) as eluent; flow rate 0.5 mL/
min; tR = 38.46 min (R), 41.12 min (S). [α]2D3 = +50.9 (c = 0.57,
mers. IR (NaCl): ν = 3600–2400, 1702 (carbamate C=O stretching),
˜
1548, 1411, 1354 cm–1. MS (EI): m/z (%) = 287 (0.14, M+), 217
(0.07), 201 (0.06), 181 (0.06), 111 (0.12), 91 (1.0, PhCH2). HMRS
calculated for C14H17N5O2 287.13822, found 287.13834.
(S)-5-(2-Methylpyrrolidin-2-yl)-1H-tetrazole (4): To a solution of
tetrazole 10 (652 mg, 2.269 mmol) in HOAc/H2O (9:1, 25 mL) was
added 10% palladium on charcoal (65.2 mg). The mixture was
placed under an H2 atmosphere and stirred for 72 hours. The mix-
ture was then filtered through a pad of celite and the pad washed
with methanol. The volatiles were removed in vacuo and the re-
maining brown solution was azeotroped with acetonitrile to yield
a cream solid which was recyrstallised from methanol/diethyl ether
to afford the title tetrazole as a colourless solid (308 mg, 89%);
m.p. 238–240 °C. [α]1D8 = –8 (c = 1.0, MeOH). 1H NMR (400 MHz,
CD3OD): δ = 1.82 (s, 3 H, 2-CH3), 2.05–2.28 (m, 3 H), 2.52–2.65 CHCl3) [ref.[3k] (90% ee). [α]1D8 = +53.3 (CHCl3)].
168 Eur. J. Org. Chem. 2008, 164–170
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Novel Proline-Derived Organocatalyst for Aldol Reactions
N-[4-(1-Hydroxy-3-oxobutyl)phenyl]acetamide (16e): 1H NMR
(300 MHz, CDCl3): δ = 2.17 (s, 3 H), 2.20 (s, 3 H), 2.73–2.93 (m,
2 H), 3.29 (br. s, 1 H), 5.00–5.19 (m, 1 H), 7.30 (d, J = 8.5 Hz, 2
H), 7.47 (d, J = 8.5 Hz, 2 H) ppm. The product was obtained in
70% ee. The optical purity was determined by HPLC with hexane/
2-propanol (90:10) as eluent; flow rate 0.5 mL/min; tR = 100.40 min
(R), 108.86 min (S). [α]2D3 = +15.9 (c = 0.44, CHCl3) [ref.[2h] (69%
ee). [α]D +12.5 (c = 1, CHCl3)].
Acknowledgments
We wish to thank the New Zealand Government for the NZ Inter-
national Doctoral Research Scholarship (STT) and the University
of Auckland for financial assistance.
[1] M. Gaunt, C. Johansson, A. McNally, N. Vo, Drug Discovery
Today 2007, 12, 8–27.
1
4-Hydroxy-4-(2-naphthyl)butan-2-one (16f): The H NMR spectro-
scopic data was consistent with literature values.[2h] The product
was obtained in 81% ee. The optical purity was determined by
HPLC with hexane/2-propanol (95:5) as eluent; flow rate 0.5 mL/
min; tR = 94.46 min (R), 109.57 min (S). [α]2D3 = +40.0 (c = 0.5,
CHCl3) [ref.[27] (74% ee). [α]2D0 = +34.8 (c = 0.525, CHCl3)].
[2] Examples of asymmetric aldol reactions catalysed by proline:
a) U. Eder, G. Sauer, R. Wiechert, Angew. Chem. Int. Ed. Engl.
1971, 10, 496–497; b) Z. Hajos, D. Parrish, J. Org. Chem. 1974,
39, 1615–1621; c) B. List, R. Lerner, C. Barbas III, J. Am.
Chem. Soc. 2000, 122, 2395–2396; d) W. Notz, B. List, J. Am.
Chem. Soc. 2000, 122, 7386–7387; e) C. Pidathala, L. Hoang,
N. Vignola, B. List, Angew. Chem. Int. Ed. 2003, 42, 2785–
2788; f) B. List, P. Pojarliev, C. Castello, Org. Lett. 2001, 3,
573–575; g) N. Mase, F. Tanaka, C. Barbas III, Angew. Chem.
Int. Ed. 2004, 43, 2420–2423; h) K. Sakthivel, W. Notz, T. Bui,
C. Barbas III, J. Am. Chem. Soc. 2001, 123, 5260–5267; i) J.
Suri, D. Ramachary, C. Barbas III, Org. Lett. 2005, 7, 1383–
1385; j) R. Thayumanavan, F. Tanaka, C. Barbas III, Org. Lett.
2004, 6, 3541–3544; k) A. Cordova, W. Notz, C. Barbas III,
J. Org. Chem. 2002, 67, 301–303; l) A. Cordova, W. Notz, C.
Barbas III, Chem. Commun. 2002, 3024–3025; m) A. Northrup,
D. MacMillan, J. Am. Chem. Soc. 2002, 124, 6798–6799; n) A.
Bogevig, N. Kumaragurubaran, K. A. Jorgensen, Chem. Com-
mun. 2002, 620–621; o) A. Nyberg, A. Usano, P. Pihko, Synlett
2004, 11, 1891–1896; p) G. Szollosi, G. London, L. Balaspiri,
C. Somlai, M. Bartok, Chirality 2003, 15, S90–S96; q) T. Bui,
C. Barbas III, Tetrahedron Lett. 2000, 41, 6951–6954; r) P. M.
Pihko, K. M. Laurikainen, A. Usano, A. I. Nyberg, J. A.
Kaavi, Tetrahedron 2006, 62, 317–328; s) Y. Hayashi, S. Ara-
take, T. Itoh, T. Okano, T. Sumiya, M. Shoji, Chem. Commun.
2007, 957–959.
1
4-Hydroxy-4-phenylbutan-2-one (16g): The H NMR spectroscopic
data was consistent with literature values.[3k] The product was ob-
tained in 80% ee. The optical purity was determined by HPLC
with hexane/2-propanol (93:7) as eluent; flow rate 0.5 mL/min; tR
= 39.13 min (R), 42.51 min (S). [α]2D3 = +31.1 (c = 0.45, CHCl3)
[ref.[33] (96% ee). [α]2D0 = +59.7 (c = 1.7, CHCl3)].
4-(4-Chlorophenyl)-4-hydroxybutan-2-one (16h): The 1H NMR
spectroscopic data was consistent with literature values.[3k] The
product was obtained in 86% ee. The optical purity was determined
by HPLC with hexane/2-propanol (96:4) as eluent; flow rate
0.5 mL/min; tR = 42.03 min (R), 45.77 min (S). [α]2D3 = +73.0 (c =
0.49, CHCl3) [ref.[33] (83% ee). [α]2D7 = +53.5 (c = 1.0, CHCl3)].
4-Hydroxy-4-(2-nitrophenyl)butan-2-one (16i): The 1H NMR spec-
troscopic data was consistent with literature values.[3f] The product
was obtained in 91% ee. The optical purity was determined by
HPLC with hexane/2-propanol (97:3); flow rate 0.5 mL/min; tR
=
80.84 min (R), 84.87 min (S). [α]2D3 –141.0 (c = 0.546, CHCl3) [ref.[33]
(75% ee). [α]2D7 –108.2 (c = 1.2, CHCl3)].
[3]
Examples of asymmetric aldol reactions catalysed by proline-
based organocatalysts: a) A. Hartikka, P. Arvidsson, Tetrahe-
dron: Asymmetry 2004, 15, 1831–1834; b) A. Hartikka, P. Arv-
idsson, Eur. J. Org. Chem. 2005, 4287–4295; c) H. Torri, M.
Nakadai, K. Ishihara, S. Saito, H. Yamamoto, Angew. Chem.
Int. Ed. 2004, 43, 1983–1986; d) A. Berkessel, B. Koch, J. Lex,
Adv. Synth. Catal. 2004, 346, 1141–1146; e) S. S. Chimni, D.
Mahajan, Tetrahedron: Asymmetry 2006, 17, 2108–2119; f) Y.-
Q. Fu, Z.-C. Li, L.-N. Ding, J.-C. Tao, S.-H. Zhang, M.-S.
Tang, Tetrahedron: Asymmetry 2006, 17, 3351–3357; g) S. Gu-
izzetti, M. Benaglia, L. Pignataro, A. Puglisi, Tetrahedron:
Asymmetry 2006, 17, 2754–2760; h) L. He, J. Jiang, Z. Tang,
X. Cui, A.-Q. Mi, Y.-Z. Jiang, L.-Z. Gong, Tetrahedron: Asym-
metry 2007, 18, 265–270; i) M. Nakadai, S. Saito, H. Yamam-
oto, Tetrahedron 2002, 58, 8167–8177; j) Z. Tang, F. Jiang, X.
Cui, L.-Z. Gong, A.-Q. Mi, Y.-Z. Jiang, Y.-D. Wu, Proc. Natl.
Acad. Sci. USA 2004, 101, 5755–5760; k) Z. Tang, F. Jiang, L.-
T. Yu, X. Cui, L.-Z. Gong, A.-Q. Mi, Y.-Z. Jiang, Y.-D. Wu,
J. Am. Chem. Soc. 2003, 125, 5262–5263; l) Z. Tang, Z.-H.
Yang, X.-H. Chen, L.-F. Cun, A.-Q. Mi, Y.-Z. Jiang, L.-Z.
Gong, J. Am. Chem. Soc. 2005, 127, 9285–9289; m) M. Vishnu-
maya, S. Ginotra, V. Singh, Org. Lett. 2006, 8, 4097–4099; n)
X.-Y. Xu, Y.-Z. Wang, L.-F. Cun, L.-Z. Gong, Tetrahedron:
Asymmetry 2007, 18, 237–242.
4-Hydroxy-4-(3-nitrophenyl)butan-2-one (16j): The 1H NMR spec-
troscopic data was consistent with literature values.[3k] The product
was obtained in 90% ee. The optical purity was determined by
HPLC with hexane/2-propanol (97:3) as eluent; flow rate 0.5 mL/
min; tR = 120.49 min (R), 129.38 min (S). [α]2D3 = +65.9 (c = 0.44,
CHCl3) [ref.[3k] (87% ee). [α]2D0 = +62.1 (CHCl3)].
Procedures for the Synthesis of the Mosher Ester of Adduct 16a: To
a solution of (S)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoic acid
(15.11 mg, 0.065 mmol) in dry dichloromethane (0.3 mL) was
added aldol adduct 16a (9 mg, 0.043 mmol) and DMAP (1.05 mg,
0.0086 mmol). The mixture was stirred and cooled to 0 °C and di-
cyclohexylcarbodiimide (22.18 mg, 0.11 mmol) was added. The
mixture was stirred overnight, at room temperature, after which
time the TLC indicated complete consumption of the starting ma-
terial. The reaction mixture was filtered, the filtrate was then evap-
orated in vacuo, the residue dissolved in diethyl ether (4 mL). The
solution was washed with 0.5  HCl (2ϫ2 mL), saturated
NaHCO3 (2ϫ2 mL), dried (MgSO4) and evaporated to yield the
Mosher ester as a yellow residue which was directly subjected to
1H NMR analysis: 1H NMR (400 MHz, CDCl3): δ = 2.09 and
2.17 (s, 3 H, CH3), 2.80 (dd, J = 3.8, 17.8 Hz, 1 H, CH2), 3.20 (dd,
J = 9.4, 17.8 Hz, 1 H, CH2), 3.51 (s, 3 H, OMe), 6.41 (dd, J = 4.0,
9.2 Hz, 1 H, CH) and 6.5 (dd, CH), 7.29–7.41 (m, 5 H, Ph-H), 7.70
(d, J = 9.0 Hz, 1 H, ArNO2-H), 8.16 (d, J = 8.6 Hz, 2 H, ArNO2-
H), 8.26 ppm (d, J = 9.0 Hz, 1 H, ArNO2-H).
[4]
[5]
M. Engqvist, J. Casas, H. Sunden, I. Ibrahem, A. Cordova,
Tetrahedron Lett. 2005, 46, 2053–2057.
A. Cordova, H. Sunden, M. Engqvist, I. Ibrahem, J. Casas, J.
Am. Chem. Soc. 2004, 126, 8914–8915.
N. Vignola, B. List, J. Am. Chem. Soc. 2004, 126, 450–451.
A. Cobb, D. Shaw, S. Ley, Synlett 2004, 3, 558–560.
A. J. Cobb, D. M. Shaw, D. Longbottom, J. Gold, S. V. Ley,
Org. Biomol. Chem. 2005, 3, 84–96.
[6]
[7]
[8]
Supporting Information (see also the footnote on the first page of
this article): Experimental details, 1H NMR and 13C NMR spectra
1
for all new compounds. H NMR spectra and HPLC traces for all
[9]
A. J. Cobb, D. Longbottom, D. M. Shaw, S. V. Ley, Chem.
Commun. 2004, 1808–1809.
aldol adducts.
Eur. J. Org. Chem. 2008, 164–170
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
169

S.-T. (A.) Tong, P. W. R. Harris, D. Barker, M. A. Brimble
FULL PAPER
[10] N. Momiyama, H. Torri, S. Saito, H. Yamamoto, Proc. Natl. [24] N. Mase, F. Tanaka, C. Barbas III, Angew. Chem. Int. Ed. 2004,
Acad. Sci. USA 2004, 101, 5374–5378. 43, 2420–2423.
[11] Y. Yamamoto, N. Momiyama, H. Yamamoto, J. Am. Chem. [25] T. Dickerson, K. Janda, J. Am. Chem. Soc. 2002, 124, 3220–
Soc. 2004, 126, 5962–5963.
[12] M. Arno, R. J. Zaragoza, L. Domingo, Tetrahedron: Asym-
metry 2005, 16, 2764–2770.
3221.
[26] M. Hosseini, N. Tiasni, V. Barbieri, C. O. Kappe, J. Org. Chem.
2007, 72, 1417–1424.
[13] B. List, L. Hoang, H. Martin, Proc. Natl. Acad. Sci. USA 2004,
101, 5839.
[14] D. Seebach, M. Boes, R. Naef, W. Schweizer, J. Am. Chem.
Soc. 1983, 105, 5390–5398.
[15] F. Orsinni, F. Pelizzoni, M. Forte, M. Sisti, G. Bombieri, F.
Benetollo, J. Heterocycl. Chem. 1989, 26, 837–841.
[16] F. Orsinni, F. Pelizzoni, M. Forte, R. Destro, P. Gariboldi, Tet-
rahedron 1988, 44, 519–541.
[17] G. Rizzi, J. Org. Chem. 1970, 35, 2069.
[18] H. Wang, J. Germanas, Synlett 1999, 33–36.
[19] A. Beck, S. Job, D. Seebach, T. Sommerfeld, Org. Synth., Coll.
Vol. 1998, 9, 626.
[27] S. Mosse, A. Alexakis, Org. Lett. 2006, 8, 3577–3580.
[28] It is postulated the incorporation of the α-methyl group in 4
alters the conformation of the pyrrolidine ring such that the
cyclic secondary amine and the acidic tetrazole proton are opti-
mally positioned to act as an organocatalyst.
[29] C.-O. Chan, C. Cooksey, D. Crich, J. Chem. Soc. Perkin Trans.
1 1992, 777–780.
[30] C. Overberger, Y. Jon, J. Polym. Sci.: Polymer Chem. Edition
1977, 15, 1413–1421.
[31] S. Chandrasekhar, N. Ramakrishna Reddy, S. Shameem Sul-
tana, Ch. Narsihmulu, K. Venkatram Reddy, Tetrahedron 2006,
62, 338–345.
[20] K. Koguro, T. Oga, S. Mitsui, R. Orita, Synthesis 1998, 910– [32] Y. Zhou, Z. Shan, Tetrahedron 2006, 62, 5692–5696.
914.
[33] Y. Zhou, Z. Shan, Tetrahedron: Asymmetry 2006, 17, 1671–
[21] R. G. Almquist, W.-R. Chao, C. Jennings-White, J. Med.
Chem. 1985, 28, 1067–1071.
[22] S. Shatzmiller, B.-Z. Dolithzky, E. Bahar, Liebigs Ann. Chem.
1991, 375–379.
1677.
Received: September 6, 2007
Published Online: November 15, 2007
[23] P. Harris, M. Brimble, V. Muir, M. Lai, N. Trotter, D. Callis,
Tetrahedron 2005, 61, 10018–10035.
170
www.eurjoc.org
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Eur. J. Org. Chem. 2008, 164–170