house fly.11 Very recently, Ruat reported N-acylureas have
acted as inhibitors of hedgehog signaling.12 For these rea-
sons, it is very important to develop an efficient synthesis of
N-acylurea derivatives. There are various examples in the
older literature of the formation of N-acyl derivatives from
reactions of carbodiimides with carboxylic acids in the
presence of bases.13 In 1995, reactions of substituted benzoic
acids with N,N0-dicyclohexylcarbodiimide (DCC) in the
presence of [Bu3NH][ClO4]/[Bu3N] buffer were shown to
afford N-acylurea derivatives, and several improved reactions
of DCC with carboxylic acids have been reported.14 Recently,
Srivastava reported the reaction of benzoic acid derivatives
and N,N0-disubstituted carbodiimides under solvent-free con-
ditions in a microwave oven in 2007.15 Asfarasweknow,there
are no examples of the catalytic synthesis of N-acylureas from
aldehydes and N,N0-disubstituted carbodiimides. Herein, we
present the first report on a highly effective coupling reaction of
aldehydes with N,N0-disubstituted carbodiimides catalyzed by
NHC under aerobic conditions using several N-heterocyclic
carbene precursors (Figure 1).
We began the optimization studies using benzaldehyde
(1a) and N,N0-dicyclohexylcarbodiimide (2a) as a model
substrate (Table 1).
Table 1. Effect of Precatalysts and Solvents
entry
precatalyst
solv.
yield (%)
1
4
5
6
7
8
9
4
4
4
4
4
ꢀ
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
THF
65
23
4
2
3
4
6
5
10
29
62
35
73
88
93
nr
6
7
8
toluene
MeCN
MeCN
MeCN
MeCN
9
10a
11a,b
12a,b
a Concentration was 1.0 M. b 1.2 equiv of 1a and 1.0 equiv of 2a were
used. Yield is calculated on the basis of 2a.
The initial experiments on the reaction between 1a and 2a
under aerobic conditions were performed using 20 mol % of
NHC precatalyst 4 and potassium carbonate (K2CO3) as a
base to generate the carbene catalyst in dichloromethane
(CH2Cl2). The corresponding N-acylurea 3aa was obtained
in 65% yield after 18 h. Encouraged by this result, further
studies were carried out by employing 20 mol % of 5ꢀ9 as a
precatalyst (entries 2ꢀ6). The reaction proceeded in all
cases; however, the reactivities were very low, affording
the product 3aa in low yields. From these results, precatalyst
4 was found to be more active than the other precatalysts
5ꢀ9. The reaction proceeded smoothly in both CH2Cl2 and
tetrahydrofuran (THF) to afford 3aa in good yields (entries
1 and 7). When toluene was used as a solvent, the reaction
was sluggish to afford 3aa in 35% yield (entry 8). Acetoni-
trile (MeCN) was the most effective solvent for this reaction,
affording 3aa in 73% yield (entry 9). When the reaction was
carried out at higher concentration (1.0 M), the product 3aa
was obtainedin 88% yield (entry 10). A significant increase
in yield was observed when 1.2 equiv of 1a and 1.0 equiv of
2a were used, and the product 3aa was isolated in 93%
yield (entry 11). In the absence of the precatalyst 4, the
reaction did not proceed at all (entry 12).
Figure 1. Structures of N-heterocyclic carbene precursors.
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Under the optimized reaction conditions using the highly
active precatalyst 4, the scope of the catalytic oxidative
coupling was explored with various aromatic and aliphatic
aldehydes (Table 2). We were delighted to find that our
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ꢀ
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B
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