3-trifluoromethanesulfonamido-Pyrrolidine: A general organocatalyst for antf-selective mannich reactions

Article abstract of DOI:10.1021/ol8000975

Mannich-type reactions of a glyoxylate imine with carbonyl compounds catalyzed by 3-trifluoromethanesulfonamidopyrrolidine proceed with high yields and anfi-stereoselectivity. The catalyst is easily prepared and the transformation appears to be quite general accommodating aldehydes or ketones.

Full text of DOI:10.1021/ol8000975

ORGANIC
LETTERS
2008
Vol. 10, No. 5
1029-1032
3-Trifluoromethanesulfonamido-pyrrolidine:
A General Organocatalyst for
anti-Selective Mannich Reactions
Mickael Pouliquen, Je´roˆme Blanchet,* Marie-Claire Lasne, and Jacques Rouden
Laboratoire de Chimie Mole´culaire et Thio-organique, ENSICAEN, UniVersite´ de Caen
Basse-Normandie, CNRS, 6 bouleVard du Mare´chal Juin, 14050 Caen, France
jerome.blanchet@ensicaen.fr
Received October 19, 2007 (Revised Manuscript Received January 15, 2008)
ABSTRACT
Mannich-type reactions of a glyoxylate imine with carbonyl compounds catalyzed by 3-trifluoromethanesulfonamidopyrrolidine proceed with
high yields and anti-stereoselectivity. The catalyst is easily prepared and the transformation appears to be quite general accommodating
aldehydes or ketones.
With the aim of achieving reactions of high synthetic
potential, the search for asymmetric catalysts which are not
only highly reactive but stereoselective and easily available
from commercial sources is an ongoing quest for organic
chemists. The Mannich reaction, roughly the addition an
enolizable donor carbonyl compound with an imine to yield
â-amino carbonyl compounds, is one of these challenging
reactions (Scheme 1).1,2 Over the past years, the use of
with a preformed imine8 or in a three-component reaction9
have been described.
The first anti-selective asymmetric Mannich reaction of
unmodified aldehydes with an activated imine was reported
in 2002 using 20% mol of catalyst I (Figure 1).8a The
(1) Mannich, C. Arch. Pharm. 1912, 250, 647.
(2) For reviews, see: Arend, M.; Westermann, B.; Risch, N. Angew.
Chem., Int. Ed. 1998, 37, 1044-1070. For the enantioselective organo-
catalyzed Mannich reaction see: (a) Cordova, A. Acc. Chem. Res. 2004,
37, 102-112. (b) Marques, M. M. B. Angew. Chem., Int. Ed. 2006, 45,
348-352. (c) Verkade, J. M. M.; van Hemert, L. J. C.; Quaedflieg, P. J. L.
M.; Rutjes, F. P. J. T. Chem. Soc. ReV. 2008, 1, 29-41. (d) Ting, A.; Schaus
S. E. Eur. J. Org. Chem. 2007, 5797-5815. (e) Shibasaki, M.; Yoshikawa,
N. Chem. ReV. 2002, 102, 2187-2209. (f) Kobayashi, S.; Ishitami, H. Chem.
ReV. 1999, 99, 1069-1094.
Scheme 1. Direct Mannich Reaction with Preformed Imine
(3) With a preformed imine: (a) Yang, J. W.; Stadler, M.; List, B. Angew.
Chem., Int. Ed. 2007, 46, 609-611. (b) Cordova, A.; Barbas, C. F., III.
Tetrahedron Lett. 2003, 44, 1923-1926. (c) Zhuang, W.; Saaby, S.;
Jørgensen, K. A. Angew. Chem., Int. Ed. 2004, 43, 4476-4478. (d) Cobb,
A. J. A.; Shaw, D. M.; Longbottom, D. A.; Gold, J. B.; Ley, S. V. Org.
Biomol. Chem. 2005, 3, 84-96.
(4) Three-component Mannich reaction and miscellaneous: (a) List, B.
J. Am. Chem. Soc. 2000, 122, 9336-9337. (b) List, B.; Pojarliev, P.; Biller,
W. T.; Martin, H. J. J. Am. Chem. Soc. 2002, 124, 827-833. (c) Pojarliev,
P.; Biller, W. T.; Martin, H. J.; List, B. Synlett 2003, 1903-1905. (d)
Hayashi, Y.; Tsuboi, W.; Ashimine, I.; Urushima, T.; Shoji, M.; Sakai, K.
Angew. Chem., Int. Ed. 2003, 42, 3677-3680. (e) Cordova, A. Chem. Eur.
J. 2004, 10, 1987-1997. (f) Enders, D.; Grondal, C.; Vrettou, M.; Raabe,
G. Angew. Chem., Int. Ed. 2005, 44, 4079-4083. (i) Westermann, B.;
Neuhaus, C. Angew. Chem., Int. Ed. 2005, 44, 4077-4079.
organic molecules as catalysts has been intensively devel-
oped, thus avoiding expensive and/or toxic metals. High syn
diastereo- and enantioselectivity were achieved using natural
(S)-proline and its derivatives,3,4 cinchona alkaloids,5 Brøn-
sted6 and amino acids.7 However, only a few examples of
anti-selective, catalytic, asymmetric Mannich reactions either
(5) Lou, S.; Taoka, B. M.; Ting, A.; Schaus, S. J. Am. Chem. Soc. 2005,
127, 11256-11257.
10.1021/ol8000975 CCC: $40.75
© 2008 American Chemical Society
Published on Web 01/29/2008

A comparison of the data obtained with catalysts IIIa,b
and V suggests that only one hydrogen bond is necessary to
stabilize the postulated transition state8f leading to the anti-
diastereoisomer (A, Figure 2). According to the propensity
Figure 2. Postulated transition state.
Figure 1. Previously reported anti-selective Mannich catalysts.
of substituted 3-aminopyrrolidines to adopt an aza-norbornyl
conformation,13 a rigid transition state involving a three-
centered hydrogen bond is proposed (B, Figure 2).14 To check
this hypothesis we synthesized a set of pyrrolidine 3-sul-
fonamides.
Methanesulfonyl (Ms), 4-nitrobenzenesulfonyl (Ns), tri-
fluoromethanesulfonyl (Tf), and nonafluorobutane-sulfonyl
(Nf) 3-aminopyrrolidine 6a-6d were prepared in a two-step
procedure from commercially available 3-aminopyrrolidine
(R)-4 (Scheme 2).
identification of II8b led to a significant improvement in terms
of yields and enantioselectivity. Chiral amino sulfonamide
IV8c afforded high stereoselectivities with low catalyst
loading (0.5-2 mol %) as did IIIa.8e However, all of these
compounds are poor nucleophiles and are efficient in the
Mannich reaction mainly with linear aldehydes as donors.
To circumvent this limitation, pyrrolidine bis-sulfonamide
V8d and less hindered â-proline IIIb8f were successfully
developed for the reaction of ketones and hindered aldehydes.
Finally, â-amino acids VI have recently shown interesting
selectivities with cyclohexanone derivatives.8g However, most
of these catalysts did not match the broad scope of (S)-
proline. Moreover, efficient catalysts IIIa, IV, and V require
tedious multistep syntheses, and thus their use is limited.10
Scheme 2. Preparation of 3-Sulfonamidopyrrolidines
As a part of our ongoing project on the synthesis and
application of 3-substituted pyrrolidines,11 we report our
results concerning the development of a new and easily
available catalyst for the anti-selective direct Mannich
reaction.12
(6) (a) Akiyama, T.; Itoh, J.; Yokota, K.; Fuchibe, K. Angew. Chem.,
Int. Ed. 2004, 43, 1566-1568. (b) Uraguchi, D.; Terada, M. J. Am. Chem.
Soc. 2004, 126, 5356-5357.
(7) (a) Ibrahem, I.; Zou, W.; Engqvist, M.; Xu, Y.; Cordova, A. Chem.
Eur. J. 2005, 11, 7024-7029.
(8) (a) Cordova, A.; Barbas, C. F., III. Tetrahedron Lett. 2002, 43, 7749-
7752. (b) Franzen, J.; Marigo, M.; Fielenbach, D.; Wabnitz, T. C.;
Kjaersgaard, A.; Jorgensen, K. A. J. Am. Chem. Soc. 2005, 127, 18296-
18304. (c) Kano, T.; Yamaguchi, Y.; Tokuda, O.; Maruoka, K. J. Am. Chem.
Soc. 2005, 127, 16408-16409. (d) Kano, T.; Hato, Y.; Maruoka, K.
Tetrahedron Lett. 2006, 47, 8467-8469. (e) Mitsumori, S.; Zhang, H.; Ha-
Yeon, P.; Houk, K. N.; Tanaka, F.; Barbas, C. F., III. J. Am. Chem. Soc.
2006, 128, 1040-1041. (f) Zhang, H.; Mifsud, M.; Tanaka, F.; Barbas, C.
F., III. J. Am. Chem. Soc. 2006, 128, 9630-9631. (g) Dziedzic, P.; Cordova,
A. Tetrahedron: Asymmetry 2007, 18, 1033-1037. (h) Ramasastry, S. S.
V.; Zhang, H.; Tanaka, F.; Barbas, C. F., III. J. Am. Chem. Soc 2007, 129,
288-289.
The pyrrolidines 6a-d were first evaluated in a test
reaction with butanal 2a and imine 1 in DMF at 0 °C. As
shown in Table 1, the reaction proceeded smoothly, giving
(12) This work was presented at the Journe´es de Chimie Organique 2007,
Palaiseau, France, on 19th September 2007 (Socie´te´ Franc¸aise de Chimie).
During the submission of this manuscript, two related studies appeared :
Kano, T.; Hato, Y.; Yamamoto, A.; Maruoka, K. Tetrahedron 2008, 64,
1197-1203. (b) Zhang, H.; Mitsumori, S.; Utsumi, N.; Imai, M.; Garcia-
Delgado, N.; Mifsud, M.; Albertshofer, K.; Cheong, P. H.-Y.; Houk, K.
N.; Tanaka, F.; Barbas, C. F., III. J. Am. Chem. Soc. 2008, 3, 875-886.
(13) Corruble, A.; Davoust, D.; Desjardins, S.; Fressigne´, C.; Giessner-
Prettre, C.; Harrison-Marchand, A.; Houte, H.; Lasne, M.-C.; Maddaluno,
J.; Oulyadi, H.; Valnot, J.-Y. J. Am. Chem. Soc. 2002, 124, 15267-15279.
(14) To the best of our knowledge, such 3-centered hydrogen bonding
has not been proposed nor ruled out by computational studies. This unusual
interaction is a generally accepted concept. See Jeffrey, G. A.; Mitra, J. J.
Am. Chem. Soc. 1984, 106, 5546-5553 and Okamoto, I.; Nabeta, M.;
Hayakawa, Y.; Morita, N.; Takeya, T.; Masu, H.; Azumaya, I.; Tamura,
O. J. Am. Chem. Soc. 2007, 129, 1892-1893. One reviewer is aknowledged
to have drawn our attention on this point.
(9) (a) Guo, Q.-X.; Liu, H.; Guo, C.; Luo, S.-W.; Gu, Y.; Gong, L.-Z.
J. Am. Chem. Soc. 2007, 129, 3790-3791. (b) Cheng, L.; Wu, X.; Lu, Y.
Org. Biomol. Chem. 2007, 5, 1018-1020.
(10) â-Proline IIIb is not widely available, although protected derivatives
can be purchased at onerous cost. See : Blanchet, J.; Pouliquen, M.; Lasne,
M.-C.; Rouden, J. Tetrahedron Lett. 2007, 48, 5727-5730.
(11) (a) Jean, L.; Baglin, I.; Rouden, J.; Maddaluno, J.; Lasne, M.-C.
Tetrahedron Lett. 2001, 42, 5645-5649. (b) Jean, L.; Rouden, J.; Madd-
aluno, J.; Lasne, M.-C. J. Org. Chem. 2004, 69, 8893-8902. (c) Cabello-
Sanchez, N.; Jean, L.; Maddaluno, J.; Lasne, M.-C.; Rouden, J. J. Org.
Chem. 2007, 72, 2030-2039.
1030
Org. Lett., Vol. 10, No. 5, 2008

Table 1. Prelimary Study of Various Catalysts
Table 3. Influence of Temperature and 6c Loading on
Selectivities
temp
(°C)
6c
(mol %)
yieldb
(%)
eed
(%)
entrya
anti:sync
1
2
3
4
5
6
20
0
-20
-40
-40
-40
5
5
5
5
10
1e
97
92
96
86
87
92
8:1
9:1
9:1
12:1
15:1
10:1
97
97
98
98
99
95
time yieldb
ee antid ee synd
entrya catalyst
(h)
12
18
0.5
12
(%)
anti:sync
(%)
(%)
1
2
3
4
6a
6b
6ce
6d
84
72
92
54
2:1
4:1
9:1
1:1
18
24
97
7
8
11
nd
0
a Reaction conditions: 1 (1 equiv), butanal 2a (3 equiv), catalyst 6c (x
mol %) in DMF (0.15 M), 0.5-2 h. b Isolated yield. c Determined by H
1
NMR. d Determined by chiral HPLC. e Reaction time 8 h.
a Reaction conditions: 1 (1 equiv), butanal 2a (3 equiv), catalyst 6a-d
(10 mol %) in DMF (0.15 M), 0 °C. b Isolated yield. c Determined by H
1
NMR. d Determined by chiral HPLC. e 5 mol % 6c was used.
catalyst 6c gave high yields and stereoselectivities (entries
8-9, Table 2).
The effect of temperature was next studied (Table 3).
Temperatures higher than -20 °C shortened reaction times
with preserved selectivities (entries 1-4, Table 3). Lowering
the temperature to -40 °C improved the anti/syn ratio to
12:1 with a complete conversion in 2 h. With 10 mol % of
catalyst 6c the anti selectivity reached 15:1, and the ee
reached 99% (entry 5, Table 3). The catalyst is still efficient
using a 1 mol % amount, although a slight erosion of
selectivity was observed (entry 6, Table 3). As a compromise
we decided to use 5 mol % of catalyst 6c to study the scope
of the reaction with various linear and branched aldehydes
and ketones.
With the optimal conditions in hand, the scope of the
reaction was investigated (Table 4). Linear aldehydes gave
high dr and ee (entry 1-4, Table 4). Even hindered
3-methylbutanal reacted rapidly at -20 °C (entry 5). The
Mannich adduct was systematically found to be configura-
tionally stable enough to be isolated by standard chromato-
graphic purification. With hindered branched aldehydes, no
reaction occurred at low temperature but gave excellent
results at 0 °C (entries 6-9, Table 4). Importantly, 6c
afforded higher selectivity than proline with milder conditions
and a lower catalyst loading with the latter substrates.16
Cycloheptanone and pentan-2-one required a 20 mol %
loading of 6c to improve both yield and dr (entries 12 and
18, Table 4). Surprisingly, cyclopentanone failed to afford
the desired compound (entry 16, Table 4).
moderate to excellent yields of aminoaldehyde (2S,3R)-3a.15
A dramatic effect of the sulfonamido group was observed.
As the acidity of the sulfonamido proton increased, the
selectivity (absolute and relative) and the reactivity improved
(trifluorosulfonamide 6c being the best catalyst in the series
[entry 3, Table 1]). Surprisingly, the nonaflyl derivative 6d
proved to be poorly efficient, giving a 1:1 mixture of racemic
diasteroisomers (entry 4, Table 1).
Those results demonstrate the critical role of the acidity
of sulfonamide proton in the reaction and the importance of
the distance between the nucleophilic nitrogen and the proton,
a sluggish result being previously obtained with an homolo-
gated derivative of 6c.8e
Optimization of the reaction using 5 mol % (R)-6c to
afford (2S,3R)-3a in various solvents at -20 °C has shown
that methanol is not suitable: only hydrolysis of imine 1
was observed (entry 1, Table 2).
Table 2. Influence of Solvent on Selectivity with 6c
yieldb
(%)
ee antid
(%)
ee synd
(%)
entrya
solvent
anti:sync
1
2
3
4
5
6
7
8
9
MeOH
i-PrOH
THF
dioxane
CH2Cl2
toluene
Et2O
0
78
86
92
81
76
85
96
96
-
6:1
8:1
7:1
5:1
4:1
5:1
10:1
9:1
-
74
79
74
74
64
68
95
98
55
57
51
57
46
45
nd
nd
Finally, the optimized conditions were applied to a direct
three-component reaction involving glyoxaldehyde, 4-meth-
oxyaniline, and butanal. (2S,3R)-3a was formed in 79% yield
(anti/syn 13:1, ee 97%) similar to that obtained previously
(entry 1, Table 4). During the reaction, no cross-aldol side
product was detected.
MeCN
DMF
a Reaction conditions: 1 (1 equiv), butanal 2a (3 equiv), catalyst 6c (5
mol %) in appropriate solvent (0.15 M) at -20 °C. b Isolated yield.
(15) Relative configuration was assigned by comparison of 1H NMR
shifts, and absolute configuration was assigned by direct comparison of
the sign of optical rotation with reported data (see ref 8). HPLC peaks of
anti- and syn-diastereomers were attributed by carrying out syn-Mannich
reaction with proline. Absolute configuration of the syn-diastereomer was
not determined.
(16) Cyclohexane carboxaldehyde and cyclopentane carboxaldehyde gave
respectively 55% ee and 98% ee with 30 mol % proline in DMSO at room
temperature, see: Chowdari, N. S.; Suri, J. T.; Barbas, C. F., III. Org. Lett.
2004, 6, 2507-2510.
1
c Determined by H NMR. d Determined by chiral HPLC.
In isopropanol (entry 2, Table 2) the desired product was
formed in 78% with a moderate steroselectivity. Similar
results were observed in the THF, dioxane, dichloromethane,
toluene, and ether (entries 3-7). In acetonitrile or DMF,
Org. Lett., Vol. 10, No. 5, 2008
1031

Table 4. Scope of the Reaction
a Reaction conditions: 1 (1 equiv), aldehyde or ketone 2a (3 equiv), catalyst 6c (5 mol %) in DMF (0.15 M) at -40 °C. b Isolated yield. c Determined
1
by H NMR. d Determined by chiral HPLC. e 20 mol % 6c was used.
In summary, we have identified a new anti-selective
catalyst for the direct or three-component Mannich reaction
that achieved high yields and selectivities for various
substrates ranging from linear and branched aldehydes to
ketones at low temperatures and under three-component
conditions. The acidity of the trifluoromethylsulfonamide
group was critical to achieve high stereoselectivity. The
results confirmed our hypothesis and showed that C2 sym-
metry of catalyst V is not a key structural feature for a high
stereoselectivity. The broad scope of the reaction associated
to the availability of catalyst 6c will trigger applications in
enantioselective synthesis of complex molecules.
Acknowledgment. We gratefully acknowledge the
“Poˆle Universitaire Normand de Chimie Organique”
for a fellowship to MP and CNRS, Re´gion Basse-Normandie,
and the European Union (FEDER funding) for financial
supports.
Supporting Information Available: Experimental pro-
cedure, characterization data, HPLC charts, and copies of
NMR spectra for all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL8000975
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Org. Lett., Vol. 10, No. 5, 2008