First organocatalyzed asymmetric Michael addition of aldehydes to vinyl sulfones

Article abstract of DOI:10.1021/ol051488h

(Chemical Equation Presented) The first asymmetric direct Michael addition of aldehydes to vinyl sulfones catalyzed by N-iPr-2,2′-bipyrrolidine is described. 1,4-Adducts are obtained in good yields and enantioselectivities. The determination of absolute c

Full text of DOI:10.1021/ol051488h

ORGANIC
LETTERS
2005
Vol. 7, No. 20
4361-4364
First Organocatalyzed Asymmetric
Michael Addition of Aldehydes to Vinyl
Sulfones
Sarah Mosse´ and Alexandre Alexakis*
Department of Organic Chemistry, UniVersity of GeneVa, Quai Ernest Ansermet 30,
CH-1211 GeneVa, Switzerland
alexandre.alexakis@chiorg.unige.ch
Received June 25, 2005
ABSTRACT
The first asymmetric direct Michael addition of aldehydes to vinyl sulfones catalyzed by N-iPr-2,2
′
-bipyrrolidine is described. 1,4-Adducts are
obtained in good yields and enantioselectivities. The determination of absolute configuration allowed us to postulate a Si,Si transition state
model, as shown previously for nitroolefins.
In the past few years, organocatalysis has shown its efficiency
in organic synthesis.1 Following the famous asymmetric
annulation developed by Wiechert,2 Hajos, and Parrish,3
L-proline brilliantly catalyzed asymmetric 1,2-additions as
aldol reactions, Mannich reactions, and R-amination reac-
tions. However, L-proline seems to be less selective in
asymmetric 1,4-additions4 compared to other amines.4d,5
Our laboratory has recently reported highly enantioselec-
tive Michael addition of aldehydes and ketones to nitroolefins
catalyzed by N-iPr-2,2′-bipyrrolidine (iPBP 4c).6 Therefore,
we directed our efforts toward applying our catalyst on new
Michael acceptors as vinyl sulfones.7 Although the reaction
of preformed enamine with vinyl sulfones has been known
for some time,8 only sporadic examples lead to chiral adducts.
Among them, d’Angelo has developed highly diastereose-
lective Michael additions of chiral imines, derived from
(5) For organocatalysts with a pyrrolidine’s backbone, see: (a) Betancort,
J. M.; Sakthivel, K.; Thayumanavan, R.; Barbas, C. F., III. Tetrahedron
Lett. 2001, 42, 4441. (b) Betancort, J. M.; Barbas, C. F., III. Org. Lett.
2001, 3, 3737. (c) Mase, N.; Thayumanavan, R.; Tanaka, F.; Barbas, C. F.,
III. Org. Lett. 2004, 6, 2527. (d) Betancort, J. M.; Sakthivel, K.;
Thayumanavan, R.; Tanaka, F.; Barbas, C. F., III. Synthesis 2004, 1509.
(e) Isshii, T.; Fujioka, S.; Sekiguchi, Y.; Kotsuki, H. J. Am. Chem. Soc.
2004, 126, 9558. (f) Planas, L.; Pe´rard-Viret, J.; Royer, J. Tetrahedon:
Asymmetry 2004, 15, 2399. (g) Wang, W.; Wang, J.; Li, H. Angew. Chem.,
Int. Ed. 2005, 44, 1369. (h) Cobb, A. J. A.; Longbottom, D. A.; Shaw, D.
M.; Ley, S. V. Chem. Commun. 2004, 1808. (i) Cobb, A. J. A.; Shaw, D.
M.; Longbottom, D. A.; Gold, J. B.; Ley, S. V. Org. Biolmol. Chem. 2005,
3, 84. (j) Mitchell, C. E. T.; Cobb, A. J. A.; Ley, S. V. Synlett 2005, 611.
For bifunctional thiourea organocatalysts, see: (k) Hoashi, Y.; Yabuta, T.;
Takemoto, Y. Tetrahedron Lett. 2004, 45, 9185. (l) Okino, T.; Hoashi, Y.;
Furukawa, T.; Xu, X.; Takemoto, Y. J. Am. Chem. Soc. 2005, 127, 119.
For MacMillan catalyst, see: (m) Paras, N. A.; MacMillan, D. W. C. J.
Am. Chem. Soc. 2001, 123, 4370. (n) Austin, J. F.; MacMillan, D. W. C.
J. Am. Chem. Soc. 2002, 124, 1172. (o) Paras, N. A.; MacMillan, D. W. C.
J. Am. Chem. Soc. 2002, 124, 7894. (p) Fonseca, M. T. H.; List, B. Angew.
Chem., Int. Ed. 2004, 43, 3958. For results reported by the Jørgensen group,
see: (q) Halland, N.; Aburel, P. S.; Jørgensen, K. A. Angew. Chem., Int.
Ed. 2004, 43, 1272 and references therein.
(1) For selected general reviews, see: (a) List, B. Synlett 2001, 1675.
(b) Gro¨ger, H.; Wilken, J. Angew. Chem., Int. Ed. 2001, 40, 529. (c) Dalko,
P. I.; Moisan, L. Angew. Chem., Int. Ed. 2001, 40, 3726. (d) Jarvo, E. R.;
Miller, S. J. Tetrahedron 2002, 58, 2481. (e) List, B. Tetrahedron 2002,
58, 5572. (f) Notz, W.; Tanaka, F.; Barbas, C. F., III. Acc. Chem. Res.
2004, 37, 580. (g) Houk, K. N.; List, B. Acc. Chem. Res. 2004, 37, 487.
(h) Dalko, P. I.; Moisan, L. Angew. Chem., Int. Ed. 2004, 43, 5138.
(2) Eder, U.; Sauer, G.; Wiechert, R. Angew. Chem., Int. Ed. Engl. 1971,
10, 496.
(3) Hajos Z. G.; Parrish D. R. J. Org. Chem. 1974, 39, 1615.
(4) (a) List, B.; Pojarliev, P.; Martin, H. J. Org. Lett. 2001, 3, 2423. (b)
Enders, D.; Seki, A. Synlett 2002, 26. (c) Hanessian, S.; Pham, V. Org.
Lett. 2000, 2, 2975. (d) Bui, T.; Barbas, C. F., III. Tetrahedron Lett. 2000,
41, 6951.
10.1021/ol051488h CCC: $30.25
© 2005 American Chemical Society
Published on Web 09/09/2005

cyclanones and optically active 1-phenylethylamine to vinyl
sulfones. This methodology represents one of the most
efficient methods for the stereocontrolled construction of
quaternary carbon centers.9 However, to the best of our
knowledge, there is no example of direct enantioselective
and/or catalytic conjugate addition of aldehydes to vinyl
sulfones.
entry 1), whereas the reaction was completed in 30 min with
1,1-bis(benzenesulfonyl)ethylene 2 (entry 2). The modest
yield obtained could be explained by the formation of
byproduct 6, arising from 1,4-addition of bis(phenylsulfonyl)-
methane, generated in situ, to 1,1-bis(benzenesulfonyl)-
ethylene 2 and the sensitivity of γ-sulfo aldehyde 5a toward
silica gel chromatography.
Herein we report the first asymmetric Michael addition
of aldehydes to vinyl sulfones catalyzed by 2,2′-bipyrrolidine
derivatives. Nowadays, the use of sulfones still remains an
important strategy, especially for making C-C bonds.10 After
appropriate transformation, the resulting 1,4-adducts could
be involved in reductive alkylation,11 Julia-type reaction,12
and remain also powerful nucleophilic reagents.13
We first performed the racemic version by using pyrro-
lidine 4a as catalyst for the addition of isovaleraldehyde 3a
to phenylvinyl sulfone 1 and 1,1-bis(benzenesulfonyl)-
ethylene14 2 at room temperature. No conversion was
observed with phenylvinyl sulfone 1 after 3 days (Table 1,
Therefore, we focused our attention on the vinyl sulfone
2 and carried out the asymmetric version with our previously
reported diamines.6 We ran the experiments at -60 °C to
decrease the reaction rate in order to increase stereoselectivity
(57% ee, entry 3). The influence of the substituents on the
2,2′-bipyrrolidine was very significant. A small group, such
as N-Me 4b (entry 4), or a too bulky one, such as N-c-Hex
4d (entry 6) or N-3-pentyl 4e (entry 7), were revealed to be
unselective. Moreover, the smaller the group, the higher was
the quantity of byproduct 6. Finally, the most interesting
results were obtained with the secondary group i-Pr 4c (71%
yield, 75% ee) (entry 5). This result, with iPBP, was
impressive, as neither L-proline 4f (entry 8) nor (S)-(+)-(1-
pyrrolidinylmethyl)pyrrolidine 4g (entry 9) gave as clean
reactions good yields or enantioselectivities.
Table 1. Asymmetric Conjugate Addition of Isovaleraldehyde
3a to Vinyl Sulfones 1-2 Catalyzed by Various Amines 4a-g
Screening of solvents with the best organocatalyst 4c has
shown that chlorinated solvents, CHCl3 (entry 5), and
anhydrous CH2Cl2 (entry 10) gave the highest yields and
enantioselectivities. The other solvents tested were dramati-
cally disappointing. No conversion was obtained with
anhydrous CH3CN. MeOH (entry 11) or anhydrous THF
(6) (a) Alexakis, A.; Andrey, O. Org. Lett. 2002, 4, 3611. (b) Andrey,
O.; Alexakis, A.; Bernardinelli, G. Org. Lett. 2003, 5, 2559. (c) Andrey,
O.; Vidonne, A.; Alexakis, A. Tetrahedron Lett. 2003, 44, 7901. (d) Andrey,
O.; Alexakis, A.; Tomassini, A.; Bernardinelli, G. AdV. Synth. Catal. 2004,
346, 1147.
(7) For a general review on vinyl sulfones, see: Simpkins, N. S.
Tetrahedron 1990, 46, 6951.
(8) (a) Risaliti, A.; Fatutta, S.; Forchiassin, M. Tetrahedron 1967, 23,
1451. (b) Forchiassin, M.; Risaliti, A.; Russo, C.; Calligaris, M.; Pitacco,
G. J. Chem. Soc., Perkin Trans. 1 1974, 660. (c) Benedetti, F.; Fabrissin,
S.; Risaliti, A. Tetrahedron 1984, 40, 977. (d) Modena, G.; Pasquato, L.;
DeLucchi, O. Tetrahedron Lett. 1984, 25, 3643.
(9) (a) d’Angelo, J.; Revial, G.; Costa, P. R. R.; Castro, R. N.; Antunes,
O. A. C. Tetrahedron: Asymmetry 1991, 2, 199. (b) d’Angelo, J.; Desmae¨le,
D.; Dumas, F.; Guingant, A. Tetrahedron: Asymmetry 1992, 3, 459. (c)
Pinheiro, S.; Guingant, A.; Desmae¨le, D.; d’Angelo, J. Tetrahedron:
Asymmetry 1992, 3, 1003. (d) Desmae¨le, D.; Delarue-Cochin, S.; Cave,
C.; d’Angelo, J.; Morgant, G. Org. Lett. 2004, 6, 2421.
(10) For general review, see: (a) The Chemistry of Sulfones and
Sulfoxides; Patai, S., Rapoport, Z., Stirling, C., Eds.; J. Wiley & Sons:
Chichester, U.K., 1988. (b) Trost, B. M. Bull. Chem. Soc. Jpn. 1988, 61,
107. (c) Simpkins, N. S. Sulphones in Organic Synthesis; Pergamon Press:
Oxford, 1993. (d) The Synthesis of Sulphones, Sulphoxides and Cyclic
Sulphides; Patai, S., Rapoport, Z., Eds.; J. Wiley & Sons: Chichester, U.K.,
1994. (e) Rayner, C. M. Contemp. Org. Synth. 1994, 1, 191. (f) Rayner, C.
M. Contemp. Org. Synth. 1995, 2, 409. (g) Rayner, C. M. Contemp. Org.
Synth. 1996, 3, 499. (h) Chinchilla, R.; Najera, C. Recent Res. DeV. Org.
Chem. 1997, 1, 437. (i) Najera, C.; Sansano, J. M. Recent Res. DeV. Org.
Chem. 1998, 2, 637. (j) Ba¨ckvall, J.-E.; Chinchilla, R.; Najera, C.; Yus, M.
Chem. ReV. 1998, 98, 2291.
(11) For recent reviews, see: (a) Na`jera, C.; Yus, M. Tetrahedron 1999,
55, 10547 and references therein. (b) Yus, M. Chem. Soc. ReV. 1996, 155.
(12) (a) Julia, M.; Paris, J. M. Tetrahedron 1973, 49, 4833. (b)
Dumeunier, R.; Marko, I. E. Modern Carbonyl Olefination; Wiley-VCH
Verlag GmbH & Co. KGaA: Weinheim, Germany, 2004, pp 104-150.
(13) For allylation reaction examples, see: (a) Tsuji, J. Palladium
Reagents: InnoVations in Organic Synthesis; J. Wiley & Sons: Chichester,
U.K., 1995; pp 290-340. And for Knoevenagel condensation, see: (b)
Jones, G. Org. React. 1967, 15, 204.
reaction
conditions 5a:6b (%)
yielda
eec
(%)
entry
R1
cat. solvent
1d
2d
3
4
5
H
4a
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
rt, 4 days
rt, 30 min
rt, 30 min
0:0
75:0 (53)e
65
SO2Ph 4a
SO2Ph 4c
SO2Ph 4b
SO2Ph 4c
57
-60 °C, 2 h 23:50
-60 °C, 2 h 71:13
-60 °C, 2 h 43:17
-60 °C, 2 h 69:6
-60 °C, 2 h n.d.g
-60 °C, 2 h 25:4
-78 °C, 2 h 50:23
-60 °C, 2 h 65:18
54
75
58
47
6
SO2Ph 4d CHCl3
7
SO2Ph 4e
SO2Ph 4f
SO2Ph 4g
SO2Ph 4c
SO2Ph 4c
SO2Ph 4c
SO2Ph 4c
CHCl3
CHCl3
CHCl3
CHCl2
MeOH
8f
n.d.
9f
19
66
35
n.d.
15
10
11
12f
13f
CH3CN -45 °C, 2 h n.d.
THF -78 °C, 2 h 15:19
a Isolated compounds after purification by column chromatography on
Florisil. b Proportion of compound 6 determined by 1H NMR of the crude
material. c Enantioselectivities were measured by chiral Super Fluid Chro-
matography (SFC). d Reaction performed with 0.5 equiv of pyrrolidine 4a.
e Isolated yield after purification by column chromatography on silica gel.
f The reaction was sluggish and led to many byproducts. g Not determined.
(14) For preparation of 1,1-bis(benzenesulfonyl)ethylene 2, see Support-
ing Information.
4362
Org. Lett., Vol. 7, No. 20, 2005

(entry 13) have provided lower yields and enantioselectivities
compared to those of CHCl3, which has given the greatest
results. Then, with the optimal organocatalyst iPBP 4c and
solvent (CHCl3) in hand, we examined several aldehydes
3a-g to generalize the scope of the reaction.
Scheme 1. Determination of Absolute Configuration of
1,4-Adduct 5a by Synthesis of Alcohol 8
As revealed in Table 2, the best results were obtained with
hindered aldehydes 3a-c (entries 1-3). Isovaleraldehyde 3a
Table 2. Asymmetric Conjugate Addition of Aldehydes 3a-g
to Vinyl Sulfone 2 Catalyzed by Diamine 4c
with the literature data (Scheme 1).16 Indeed, the crude
aldehyde 5a can be easily converted to the primary alcohol
7a in 69% overall yield and 73% ee.
We then tested several conditions to transform the sulfone
group into hydrogen,11a but most of them led either to the
recovery of the starting material17 or to the elimination of
only one sulfone,18 probably due to the presence of nonac-
tivated geminal bis-sulfones. Fortunately, the bis-desulfo-
nylation could be performed using activated magnesium
turnings in MeOH.19 Hence, alcohol 8 was obtained in 45%
yield without any loss of enantioselectivity (74% ee). We
deduced the absolute configuration of product 5a (R) by
measurement of the optical rotation of the derivative 8 (S),
with an inversion of CIP priority.20 It may be considered
that the configuration of the others adducts 5b-h is the same.
The determination of absolute configuration allowed us
to propose a transition state model to explain the selectivity
of the 1,4-addition. The acyclic synclinal model described
by Seebach,21 involving a trans enamine intermediate, could
be applied to the addition of aldehydes to vinyl sulfones, as
shown previously for nitroolefins.6 Actually, R-substituted
nitroolefins have displayed better enantioselectivities than
geminal bis-sulfone, implying that the selectivity depends
on steric hindrance. Consequently, the less hindered Si,Si
transition state is well favored compared to the Re,Re and
leads to the (R) adduct (Scheme 2).
aldehyde/
product
reaction
conditions
yielda
(%)
eeb
(%)
entry
R1
R2
1
2
3
4
5
6d
7
8
3a/5a
3b/5b
3c/5c
3d/5d
3e/5e
3f/5f
iPr
tBu
cHex
nPr
Me
Me
Et
H
H
H
H
H
-60 °C, 2 h 71
-60 °C, 2 h 78
-60 °C, 2 h 71
-60 °C, 2 h 76
-60 °C, 2 h 72c
75
80
70
53
0c
Me rt, 1 h
Me rt, 4 h
Me rt, 7 h
73
59
14(15)e
3g/5g
3h/5h
12
0
Ph
a Isolated yields after purification by column chromatography on Florisil.
b Enantioselectivities were measured by Super Fluid Chromatography (SFC).
c Determined on the reduced aldehyde 5e to the corresponding primary
alcohol 7e. d Reaction performed with 0.5 equiv of pyrrolidine 4a. e Con-
1
version determined by H NMR on the crude material.
and 2-cyclohexylacetaldehyde15 3c afforded their respective
adducts 5a and 5c in good yields (71%) and enantioselec-
tivities (75 and 70%, entries 1 and 3). Reaction with the more
bulky 3,3-dimethylbutyraldehyde 3b gave the highest yield
(78%) and enantioselectivity (80%) (entry 2). Valeraldehyde
3d produced adduct 5d in good yield (76%), but in modest
enantioselectivity (53%, entry 4). Smaller substrate 3e
showed similar reactivity, but no stereoselectivity was
observed (entry 5). Consequently, the more hindered the
aldehyde, the better was the enantioselectivity.
Scheme 2. Proposed Transition State Model for
Diamine-Catalyzed Michael Addition
The formation of quaternary carbon centers with R,R-
dialkyl-substituted aldehydes proved to be considerably less
easy and required higher temperature (25 °C) for complete
conversion (entries 6 and 7). The differentiation between
methyl and ethyl in 3-methylbutyraldehyde 3g was obviously
not enough to provide a good stereocontrol (12% ee, entry
7). Finally, 2-phenylpropionaldehyde 3h reacted very slowly
with no selectivity, probably due to the presence of a too
labile proton in the R-position of the carbonyl (entry 8).
The absolute configuration of the adduct 5a was deter-
mined by comparison of the optical rotation of alcohol 8
In conclusion, we have disclosed the first direct asym-
metric conjugate addition of aldehydes to vinyl sulfones
(16) (a) Gao, L.-J.; Zhao, X.-Y.; Vandewalle, M.; De Clercq, P. Eur. J.
Org. Chem. 2000, 2755. (b) Tsuda, K.; Kishida, Y.; Hayatsu, R. J. Am.
Chem. Soc. 1960, 82, 3396.
(15) For preparation of 2-cyclohexylacetaldehyde 3c, see: Rumbolt, G.;
Righi, G. J. Org. Chem. 1996, 61, 3557.
Org. Lett., Vol. 7, No. 20, 2005
4363

catalyzed by iPBP derived from 2,2′-bipyrrolidine. The
reaction proceeds with good yields and enantioselectivities.
The full scope of this reaction, including addition of ketones,
is presently being investigated. Further applications of this
methodology and developments of new organo-catalyzed
reactions are currently underway in our laboratory.
Acknowledgment. We thank Olivier Andrey for valuable
advice and constructive discussions, and the Swiss National
Science Foundation (Grant 200020-105368) for financial
support.
Supporting Information Available: Experimental pro-
cedures, 1H and 13C spectra, and chiral separations for
compounds 5a-h. This material is available free of charge
via the Internet at http://pubs.acs.org.
(17) Use of Raney Ni. (a) For a review, see: Petit, G. R.; van Tamelen,
E. E. Org. React. 1962, 12, 356. For an example, see: (b) Wenkert, E. Liu,
S. J. Org. Chem. 1994, 59, 7677. For ultrasound, see: (c) Alexakis, A.;
Lensen, N.; Mangeney, P. Synlett 1991, 625.
(18) Use of Al-Hg. For the preparation of aluminium amalgam, see:
(a) Corey, E. J.; Chaykovsky, M. J. Am. Chem. Soc. 1965, 87, 1345. For
examples, see: (b) Du Penhoat, C. H.; Julia, M. Tetrahedron 1986, 42,
4807. (c) Posner, G. H.; Asirvatham, E. J. Org. Chem. 1985, 50, 2589.
(19) (a) Ku¨ndig, E. P.; Cunningham, A. F., Jr. Tetrahedron 1988, 44,
6855. (b) Wu, J.-C.; Chattopadhyaya, J. Tetrahedron 1990, 46, 2587.
OL051488H
(21) (a) Blarer, S. J.; Seebach, D. Chem. Ber. 1983, 116, 3086. (b) Ha¨ner,
R.; Laube, T.; Seebach, D. Chimia 1984, 38, 255. (c) Seebach, D.; Beck,
A. K.; Golinski, J.; Hay, J. N.; Laube, T. HelV. Chim. Acta 1985, 68, 162.
(d) Seebach, D.; Golinski, J. HelV. Chim. Acta 1981, 64, 1413. (e) Fabrissin
S.; Fatutta S.; Risaliti A. J. Chem. Soc., Perkin Trans. 1 1981, 109.
(20) Optical rotation measured [R]25 ) -6.79 (c ) 0.118, CHCl3)
D
compared to literature data,16 [R]20 ) -9.47 (c ) 2.126, CHCl3).
D
4364
Org. Lett., Vol. 7, No. 20, 2005