Table 1. Optimization of the Reaction Conditions for
NHC-Catalyzed Crossed Acyloin Condensation
Scheme 1. NHC-Catalyzed Regioselective Crossed Acyloin
Condensation
solvent
(M)a
time
(h)
yieldc
(%)
entry
catalyst
3a/4ab
1
2
3
4
5
6
7
I
THF (0.5)
THF (0.3)
THF (0.3)
THF (0.5)
THF (0.3)
m-xylene (0.5)
THF (0.5)
15
24
24
24
15
15
24
95:5
88
71
52
50
91
95
-
IIa
IIb
IIc
IId
IId
III
10:90
14:86
35:65
17:83
14:86
-
a Molar concentration of 4-chlorobenzaldehyde 1a. b Determined by
300 MHz 1H NMR of the unpurified reaction mixture after workup. c Isolated
yield of a 3a/4a mixture obtained after flash chromatography.
Mixed acyloin skeletons are often found as the key
structural motif for many natural products withinteresting
biological activities and synthetic therapeutics.4 Despite
the synthetic advantages of crossed acyloin condensations
between two carbonyl compounds,5 there are two draw-
backs, the undesired self-condensations and the uncon-
trolled regiochemistry of crossed condensations.
Given the importance of acetaldehdye as a simple nucleo-
phile in organocatalytic reactions,6 we hypothesized that
acetaldehdye could be employed as a surrogate for an active
acetaldehyde generated by a combination of pyruvate with
ThDP-dependent enzymes. Such an approach can eliminate
carbon dioxide emission and thus be of substantial benefit to
the development of an environmentally benign process.
Here, we report a facile method for the highly regiose-
lective crossed acyloin condensations between aromatic
Figure 1. NHC catalysts I-III examined in this study.
(4) (a) Kakeya, H.; Morishita, M.; Koshino, H.; Morita, T.-I.;
Kobayashi, K.; Osada, H. J. Org. Chem. 1999, 64, 1052–1053. (b) Fang,
Q. K.; Han, Z.; Grover, P.; Kessler, D.; Senanayake, C. H.; Wald, S. A.
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Jordan, F. Nat. Prod. Rep. 2003, 20, 184–201.
(5) For a single report so far on NHC-catalyzed nonasymmetric
intermolecular crossed acyloin condensations of aldehydes with ketones,
see: (a) Enders, D.; Henseler, A. Adv. Synth. Catal. 2009, 351, 1749–
1752. For NHC-catalyzed asymmetric intramolecular crossed acyloin
condensations of aldehydes with ketones, see: (b) Enders, D.; Niemeier,
O. Synlett 2004, 2111–2114. (c) Enders, D.; Niemeier, O.; Balensiefer, T.
Angew. Chem., Int. Ed. 2006, 45, 1463–1467. (d) Enders, D.; Niemeier,
O.; Raabe, G. Synlett 2006, 2431–2434. (e) Takikawa, H.; Hachisu, Y.;
Bode, J. W.; Suzuki, K. Angew. Chem., Int. Ed. 2006, 45, 3492–3494. (f)
Li, Y.; Feng, Z.; You, S.-L. Chem. Commun. 2008, 2263–2265. (g) Ema,
T.; Oue, Y.; Akihara, K.; Miyazaki, Y.; Sakai, T. Org. Lett. 2009, 11,
4866–4869. For NHC-catalyzed nonasymmetric intramolecular crossed
acyloin condensations of aldehydes with ketones, see: (h) Enders, D.;
Niemeier, O. Synlett 2004, 2111–2114. (i) Hachisu, Y.; Bode, J. W.;
Suzuki, K. J. Am. Chem. Soc. 2003, 125, 8432–8433.
aldehydes 1 and acetaldehyde 2 using N-heterocyclic car-
bene (NHC) catalysts I and II (Scheme 1). It is found that
the desired mixed acyloin product 3 or 4 can be obtained as
a major product when the formation of self-acyloin pro-
duct 5 except for acetoin 6 is suppressed by using excess
acetaldehyde. In addition, we found that the control of
regioselectivity in the crossed acyloin condensations of
aromatic aldehydes with acetaldehyde can be achieved by
properly choosing NHC catalysts.
We initiated our studies by reacting p-chlorobenzalde-
hyde 1a with 10 equiv of acetaldehyde 2 in the presence of
10 mol % NHC (pre)catalysts and 10 mol % Cs2CO3
(Scheme 1 and Table 1). Fortunately, thiazolium I and
triazolium II catalysts afforded the desired R-hydroxy
ketones 3a/4a as a mixture in high yield. Remarkably,
the change of regioselectivity in such crossed reactions was
accomplished by choosing between thiazolium and triazo-
lium as a catalyst. Fortunately, thiazolium catalyst I was
suitable for producing 1-(4-chlorophenyl)-2-hydroxy-
propan-1-one 3a, whereas triazolium catalyst II was sui-
table for producing its regioisomer, 1-(4-chlorophenyl)-1-
hydroxy-propan-2-one 4a. Recently, Zeitler and Connon
found that a similar regioselectivity in a crossed benzoin
ꢀ
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(6) (a) Yang, J. W.; Chandler, C.; Stadler, M.; Kampen, D.; List, B.
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H. Angew. Chem., Int. Ed. 2008, 47, 2082–2084. (c) Garcıa-Garcıa, P.;
´ ´
ꢀ ^
Ladepeche, A.; Halder, R.; List, B. Angew. Chem., Int. Ed. 2008, 47, 4719–
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Org. Lett., Vol. 13, No. 5, 2011
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