unsaturated ketones in moderate to good yields from
unmodified ketones and aldehydes under mild reaction
conditions.
Table 1. Effect of Solvents on Dehydration Reaction of
Cyclopentanone with p-Nitrobenzaldehydea
In recent years, small organic molecule-based organoca-
talysis has received considerable attention in organic syn-
thesis.6 One of the extensively studied oragnocatalyst-
catalyzed reactions is the aldol condensation of aldehydes
and ketones.7-11 In seeking new organocatalysts with struc-
tural diversity for catalyzing aldol reactions, we have
designed and prepared a novel organocatalyst pyrrolidine
imide I (Table 1).12,13 This bifunctional molecule having a
basic pyrrolidine and a significantly acidic imide moiety
could function the same way as L-proline does for promoting
reactions. In an initial study using 20 mol % of I for an
aldol condensation, the reaction of cyclopentanone with
p-nitrobenzaldehyde in DMSO, surprisingly, did not result
in the formation of the desired condensation product b (Table
1, entry 1). In contrast, the dehydration product, an R,â-
unsaturated ketone a, with (E) configuration was obtained
stereoselectively as the major product in high yield (93%)
(Table 1, entry 1). Based on the observation, we envisioned
that the compound I could serve as an effective catalyst for
direct preparation of the synthetically useful R,â-unsaturated
carbonyl compounds from simple aldehydes and ketones.
An initial investigation of a variety of reaction media for
the process revealed that reaction solvents played a signifi-
cant role in the formation of R,â-unsaturated ketone a and
condensation product b. It is noted that in DMSO, dehydra-
tion product a was produced exclusively in 93% yield
yield (%) for
yield (%) for
entry
solvent
DMSO
product ab
product bb,c
1
2
3
4
5
6
7
8
9
93
71
43
37
33
32
32
31
31
DMF
28
54
61
65
66
53
68
47
CH2Cl2
CHCl3
1,4-dioxane
EtOAc
i-PrOH
THF
CH3CN
a Reaction conditions: A mixture of aldehyde (0.15 mmol), ketone (0.30
mmol), and catalyst I (0.03 mmol) in 0.5 mL of anhydrous DMSO was
vigorously stirred for 21.5 h. The resulting mixture was then directly purified
by silica gel chromatography to provide a solid or clear oil. b Isolated yield.
c Stereoselectivity not determined.
without aldol product b (Table 1, entry 1). However, in the
other eight solvents tested, both products were formed, and
in many cases, the aldol product b was the major one (Table
1, entries 3-9). The results of the study prompted us to select
DMSO as reaction medium for the subsequent investigation
(Table 1, entry 3).
(6) For selected recent organocatalysis reviews, see: (a) Dalko, P. I.;
Moisan, L. Angew. Chem., Int. Ed. 2001, 40, 3726. (b) Dalko, P. I.; Moisan,
L. Angew. Chem., Int. Ed. 2004, 43, 5138. (c) List, B. Synlett 2001, 1675.
(d) List, B. Tetrahedron 2002, 58, 5573. (e) Special issue: Asymmetric
Organocatalysis. Acc. Chem. Res. 2004, 37, 487.
The effect of catalyst loading on the reaction efficiency
was evaluated next (Table 2). Reactions with 10 and 5 mol
(7) For L-proline-catalyzed aldol reactions, see: (a) List, B.; Lerner, R.
A.; Barbas, C. F., III. J. Am. Chem. Soc. 2000, 122, 2395. (b) List, B.;
Pojarliev, P.; Castello, C. Org. Lett. 2001, 3, 573. (c) Pidathala, D.; Hoang,
L.; Vignola, N.; List, B. Angew. Chem., Int. Ed. 2003, 42, 2785. (d)
Sakthivel, K.; Notz, W.; Bui, T.; Barbas, C. F., III. J. Am. Chem. Soc. 2001,
123, 5260. (e) Thayumanavan, R.; Tanaka, F.; Barbas, C. F., III. Org. Lett.
2004, 6, 3541. (f) Northrup, A. B.; MacMillan, D. W. C. J. Am. Chem.
Soc. 2002, 124, 6798. (g) Northrup, A. B.; Mangion, I. K.; Hettche, F.;
MacMillan, D. W. C. Angew. Chem., Int. Ed. 2004, 43, 2152. (h) Northrup,
A. B.; MacMillan, D. W. C. Science 2004, 305, 1752. (i) Pan, Q.; Zou, B.;
Wang, Y.; Ma, D. Org. Lett. 2004, 6, 1009.
Table 2. Effect of Catalyst Loading on Dehydration Reaction
of Cyclopentanone with p-Nitrobenzaldehydea
(8) For diamine catalyzed aldol reactions, see: (a) Mase, N.; Tanaka,
F.; Barbas, C. F., III. Angew. Chem., Int. Ed. 2004, 43, 2420. (b) Saito, S.;
Nakadai, M.; Yamamoto, H. Synlett 2001, 1245. (c) Nakadai, M.; Saito,
S.; Yamamoto, H. Tetrahedron 2002, 58, 8167.
(9) For amino alcohol catalyzed aldol reactions, see: (a) Tang, Z.; Jiang,
F.; Yu, L.-T.; Cui, X.; Gong, L.-Z.; Mi, A.-Q.; Jiang, Y.-Z.; Wu, Y.-D. J.
Am. Chem. Soc. 2003, 125, 5262. (b) Tang, Z.; Jiang, F.; Cui, X.; Gong,
L.-Z.; Mi, A.-Q.; Jiang, Y.-Z.; Wu, Y.-D. Proc. Natl. Acad. Sci. U.S.A.
2004, 101, 5755. (c) Zhong, G.; Fan, J.; Barbas, C. F., III. Tetrahedron
Lett. 2004, 45, 5681.
entry
catalyst (mol %)
time
% yieldb
1
2
3
20
10
5
21.5 h
7 d
7 d
93
70
31
(10) For peptide-catalyzed aldol reactions, see: Tang, Z.; Yang, Z.-H.;
Cun, L.-F.; Gong, L.-Z.; Mi, A.-Q.; Jiang, Y.-Z. Org. Lett. 2004, 6, 2285.
(11) For pyrrolidine tetrazole catalyzed aldol reactions, see: Torii, H.;
Nakadai, M.; Ishihara, K.; Saito, S.; Yamamoto, H. Angew. Chem., Int.
Ed. 2004, 43, 1983.
(12) For the preparation of catalyst I, see the Supporting Information.
(13) Recently, we have found pyrrolidine sulfonamide/amide as effective
catalysts for asymmetric organic transformations, see: Michael addition:
(a) Wang, W.; Wang, J.; Li, H. Angew. Chem., Int. Ed. 2004, in press.
R-Aminoxylation: (b) Wang, W.; Wang, J.; Li, H.; Liao, L.-X. Tetrahedron
Lett., 2004, 45, 7235. Mannich-type reaction: (c) Wang, W.; Wang, J.; Li,
H. Tetrahedron Lett. 2004, 45, 7243. R-Selenenylation: (d) Wang, W.;
Wang, J.; Li, H. Org. Lett. 2004, 6, 2817. R-Sulfenylation: (e) Wang, W.;
Li, H.; Wang, J.; Liao, L.-X. Tetrahedron Lett. 2004, 45, 8229.
a Reaction conditions (see footnote a in Table 1). b Isolated yield.
% catalyst I took place much slower, and a large amount of
starting materials remained. Therefore, the use of 20 mol %
of pyrrolidine imide I was optimal to ensure high reaction
efficiency (93% yield) while maintaining a reasonable
reaction time (Table 2, entry 1).
Having established optimal reaction conditions, we probed
the generality of the process (Table 3). The reaction between
602
Org. Lett., Vol. 7, No. 4, 2005