Table 3. Diamine 10/TFA-Catalyzed Direct Michael Reactions for the Synthesis of Quaternary Carbon
a Determined by 1H NMR. b Determined by chiral HPLC analysis using CHIRALCEL OD-H, OJ-H, and/or CHIRALPAK AS-H columns. c Starting
material was recovered in 9% (entry 8), 25% (entry 9), 30% (entry 10), and 16% (entry 11) yields.
gave a better enantioselectivity than 10/TFA, but the reaction
was slow and the yield was low after 4 days (entries 9 and
10).
Using diamine 10/TFA as a catalyst, a series of different
solvent systems was evaluated as shown in Table 2.8 DMSO,
2-propanol, and diethyl ether were superior solvents in terms
of product yield (entries 4, 6, and 9). Diethyl ether gave the
highest ee of the solvents tested; however, the solubility of
diamine 10/TFA catalyst was poor in diethyl ether. Ionic
liquids such as [bmim]PF6 and [bmim]BF4 showed over 70%
ee, but yields were low (entries 12 and 13). Therefore, we
chose 2-PrOH as a solvent for further study. The Michael
reaction was carried out in 2-PrOH at 4 °C, rather than room
temperature, to give the Michael product in 87% yield with
80% ee (entry 14).9
(3) Recent direct organocatalyic reactions using aldehyde and ketone
donors: (a) Torii, H.; Nakadai, M.; Ishihara, K.; Saito, S.; Yamamoto, H.
Angew. Chem., Int. Ed. 2004, 43, 1983-1986. (b) Cobb, A. J. A.; Shaw,
D. M.; Ley, S. V. Synlett 2004, 558-560. (c) Hayashi, Y.; Yamaguchi, J.;
Sumiya, T.; Shoji, M. Angew. Chem., Int. Ed. 2004, 43, 1112-1115. (d)
Halland, N.; Braunton, A.; Bachmann, S.; Marigo, M.; Jørgensen, K. A. J.
Am. Chem. Soc. 2004, 126, 4790-4791. (e) Vignola, N.; List, B. J. Am.
Chem. Soc. 2004, 126, 450-451. (f) Bogevig, A.; Sunden, H.; Cordova,
A. Angew. Chem., Int. Ed. 2004, 43, 1109-1112. (g) Brochu, M. P.; Brown,
S. P.; MacMillan, D. W. C. J. Am. Chem. Soc. 2004, 126, 4108-4109. (h)
Notz, W.; Tanaka, F.; Watanabe, S.; Chowdari, N. S.; Turner, J. M.;
Thayumanavan, R.; Barbas, C. F., III J. Org. Chem. 2003, 68, 9624-9634.
(i) Ramachary, D. B.; Chowdari, N. S.; Barbas, C. F., III. Angew. Chem.,
Int. Ed. 2003, 42, 4233-4237. (j) Vogt, H.; Vanderheiden, S.; Brase, S.
Chem. Commun. 2003, 2448-2449. (k) Ramachary, D. B.; Chowdari, N.
S.; Barbas, C. F., III. Synlett 2003, 1910-1914. (l) Chowdari, N. S.;
Ramachary, D. B.; Barbas, C. F., III. Org. Lett. 2003, 5, 1685-1688. (m)
Chowdari, N. S.; Ramachary, D. B.; Barbas, C. F., III. Synlett 2003, 1906-
1909. (n) Cordova, A.; Notz, W.; Zhong, G.; Betancort, J. M.; Barbas, C.
F., III. J. Am. Chem. Soc. 2002, 124, 1842-1843. (o) Cordova, A.;
Watanabe, S.; Tanaka, F.; Notz, W.; Barbas, C. F., III. J. Am. Chem. Soc.
2002, 124, 1866-1867. (p) Watanabe, S.; Cordova, A., Tanaka, F.; Barbas,
C. F., III. Org. Lett. 2002, 4, 4519-4522. (q) Chowdari, N. S.; Suri, J. T.;
Barbas, C. F., III. Org. Lett. 2004, in press.
Encouraged by these results, we further examined the
scope of this class of Michael reactions with a series of R,R-
disubstituted aldehyde donors 13a-k using 10/TFA catalyst
under the same reaction conditions (Table 3). Cyclopentane-
(7) For additional studies of amine-acid combination catalysts in
organocatalytic reactions, see ref 1f and: Nakadai, M.; Saito, S.; Yamamoto,
H. Tetrahedron 2002, 58, 8167-8177.
(8) We used DMSO to dissolve the diamine 10/TFA catalyst. Ratio of
DMSO/solvent was 30/70.
(9) Typical Procedure for Table 2 entry 14 and Table 3. A catalyst
stock solution (1.0 M in 2-PrOH) was prepared as a mixture of (S)-(+)-
1-(2-pyrrolidinylmethyl)pyrrolidine (0.5 mmol) and trifluoroacetic acid (0.5
mmol) in 2-PrOH (0.5 mL, HPLC grade) before use. â-Nitrostyrene 14
(0.5 mmol) was dissolved in 2-PrOH (0.85 mL), and isobutyraldehyde 13a
(1.0 mmol) was added. To the mixture was added the catalyst stock solution
(1.0 M in 2-PrOH, 0.15 mL, 0.15 mmol) at 4 °C. The reaction mixture was
stirred at 4 °C for the indicated time and then purified by flash silica gel
column chromatography without further workup to provide Michael product
15a.
(4) Mase, N.; Tanaka, F.; Barbas, C. F., III. Angew. Chem., Int. Ed. 2004,
43, 2420-2423.
(5) Mase, N.; Tanaka, F.; Barbas, C. F., III. Org. Lett. 2003, 5, 4369-
4372.
(6) Fluorogenic Michael acceptor: (a) Tanaka, F.; Thayumanavan, R.;
Barbas, C. F., III. J. Am. Chem. Soc. 2003, 125, 8523-8528. (b) Tanaka,
F.; Thayumanavan, R.; Mase, N.; Barbas, C. F., III. Tetrahedron Lett. 2004,
45, 325-328. See also fluorogenic aldol acceptor: (c) Tanaka, F.; Mase,
N.; Barbas, C. F., III. J. Am. Chem. Soc. 2004, 126, 3692-3693.
Org. Lett., Vol. 6, No. 15, 2004
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