M. Sreenivasulu et al. / Tetrahedron Letters 52 (2011) 727–732
731
OH
Ph
% yield (Ligand)
89 (A)
72 (B)
55 (C)
46 (D)
Ph
MeOH
5h
O
Ligand
(5 mol %)
O
6
O
H
Ph
O
Ph
+
S
Et3N
25 oC
O
85 (A)
65 (B)
45 (C)
40 (D)
THF
6h
O
1b
5
Ph
S
Ph
O
7
Scheme 2. Keto-reduction and hydroacylation of benzil (5).
In order to explore the potential of NHC ligand A further we
examined the effect of ligands A–D in the reactions with enolizable
aldehydes or other activated ketones. Thus both the keto-reduction
and hydroacylation processes were examined using benzil and sev-
eral aldehydes such as thiophene-2-carbaldehyde (Scheme 2), 3-
phenylpropanal and propionaldehyde (see Supplementary data).
While the keto-reduction of benzil (5) proceeded well using thio-
phene-2-carbaldehyde (1b) in the presence of all the ligands
(Scheme 2), the reaction provided a mixture of unidentified prod-
ucts when enolizable aldehydes were used. A similar observation
was also noted during the hydroacylation process indicating that
the present method is not effective for enolizable aldehydes. Nev-
ertheless, once again A was found to be the best among the four
NHC ligands tested in terms of product yield.
MeOH that are present in excess) rather than alcohol 4 is more
likely in this case. The reason for THF to serve as a better solvent
than CH2Cl2 is perhaps due to its ability to facilitate the acyl group
transfer from Y to alcohol 4 via transient formation of a THF–acy-
lium complex (the oxygen of THF is very exposed and thus the lone
pairs can easily coordinate to the electron deficient centers).
In conclusion, we have demonstrated that the combination of
1,3-bis(2,4,6-trimethylphenyl)imidazolium chloride (A) and trieth-
ylamine facilitates hydroacylation/reduction of activated ketones
at ambient temperature via generating N-heterocyclic carbene in
situ. The advantages of the present process include the use of (i)
readily available, cheaper and lower quantity of catalyst/base and
(ii) shorter reaction time. Moreover, the hydroacylation reaction
can be carried out efficiently in a non-chlorinated solvent and
was found to be effective for both electron rich and deficient alde-
hydes. The methodology, therefore, has potential to become a prac-
tical alternative to the previously reported method and would find
wide applications.
Mechanistically, the hydroacylation/reduction process proceeds
via a generation of a tetrahedral intermediate X due to the interac-
tion of NHC with an aldehyde 1 (Scheme 3). The presence of bulky
and electron rich 2,4,6-trimethylphenyl moiety facilitated the gen-
eration of NHC in the presence of a milder base such as Et3N. A hy-
dride transfer from X to the
a-keto ester 2 (Cannizzaro-type
Acknowledgment
reaction) provides an acyl heteroazolium species Y and the alcohol
4 via regioselective reduction of the keto group of 2. The alcohol 4
is then O-acylated by Y possessing an acyl iminium moiety respon-
sible for the transfer of acyl group to the hydroxyl moiety. As a re-
sult the NHC is regenerated to complete the catalytic cycle yielding
the hydroacylation product 3. While the formation of alcohol 4 in-
stead of 3 in a protic solvent is not clearly understood at this stage
the transfer of acyl group from Y to the solvent molecules (e.g.
The authors (M.S., K.A.K., K.S.R. and K.S.K.) thank Dr. Vilas
Dahanukar for constant support and the analytical group of DRL
for spectral data.
Supplementary data
Supplementary data associated with this article can be found, in
H
References and notes
N
N
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O
Cl
Et3N
Et3N.HCl
O
H
R
H
R
O
OR3
1
O
R2
3
N
N
addition
acylation
R
H
O
N
R
O
2. Chan, A.; Scheidt, K. A. J. Am. Chem. Soc. 2006, 128, 4558.
3. Phan, D. H. T.; Kim, B.; Dong, V. M. J. Am. Chem. Soc. 2009, 131, 15608.
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V. Angew. Chem., Int. Ed. 2004, 43, 5130.
N
N
N
Y
X
O
5. Glorius, F. Top. Organomet. Chem. 2007, 21, 1.
6. He, M.; Bode, J. W. Org. Lett. 2005, 7, 3131.
O
H
hydride
transfer
O
H
HO
OR3
Et3N.HCl
Scheme 3. Proposed mechanism of NHC-mediated reduction/hydroacylation.2
O
OR3
O
7. Nair, V.; Sreekumar, V.; Bindu, S.; Suresh, E. Org. Lett. 2005, 7, 2297.
8. For a detailed structure analysis of A, see: Cole, M. L.; Junk, P. C. Cryst. Eng.
Commun. 2004, 6, 173.
9. The influence of steric and electronic properties of a ligand on its stability and
reactivity is enormous. See for example: Dorta, R.; Stevens, E. D.; Scott, N. M.;
OR3
R2
R2
4
R2
2