imidazolium ylides (or carbenes) have been postulated for
some time.8 In fact, the first stable, crystalline imidazolium
carbene was isolated and characterized by X-ray crystal-
lography in 1991.9 Furthermore, Regel and Buchel proposed
an imidazolium ylide as the reactive intermediate leading to
2-aroylimidazoles in the reaction of imidazole with benzoyl
chlorides.4 In a previous work, we found that imidazo[1,5-
a]pyridine could be similarly acylated with benzoyl chlorides
(at the 3-position) but that it did not react with sterically
hindered 2,4,6-trimethylbenzoyl chloride.10
On the basis of this information, we decided to design a
novel reaction for the synthesis of 2-substituted imidazoles.
By way of example, a sterically hindered acyl chloride, such
as diisopropylcarbamyl chloride, should react with 1-ben-
zylimidazole at the 3-position to afford an intermediate
imidazolium salt, which would be deprotonated in the
presence of an amine base to form ylide III. Trapping with
a suitable electrophile would then produce the target
2-substituted-1-benzylimidazole (Scheme 2). In fact, this
Table 1. Preparation of 2-Substituted Imidazoles11
conditionsa
entry
R1R2CO
temp
time product yield (%)
1
2
3
4
5
(CH3)3CCHO
(CH3)2CHCHO
PhCH2CH2CHO
PhCH2CHO
PhCH2CHO
PhCHO
reflux 24 h
1
2
3
4
4
66
85
75
32b
78c
78
64
14d
rt
rt
66 h
29 h
reflux 20 h
reflux 44 h
reflux 24 h
6
5
7
PhCHO
rt
24 h
5
8
PhCHO
reflux 21 h
5
9
4-(OMe)-PhCHO
4-Cl-PhCHO
PhCOCF3
CHdCHCHO
EtOOCCH(CH3)- rt
COCOOEt
rt
rt
rt
rt
67 h
30 h
3 d
68 h
68 h
6
7
8
9
73
77
89
67
10
11
12
13
10
73e
Scheme 2. Reaction Design via an Imidazolium Ylide III
14
Ph-NdCdO
reflux 21 h
71f
a Reactions were run on a 2 mmol scale with 2.4 mmol of DIPC and 6.3
mmol of DIEA in 8 mL of acetonitrile. b Also obtained 55% of a 2:7 trans
to cis mixture of PhCHdCHOCON(i-Pr)2. c Three reagent charges. d No
base was used. e Obtained a 3:1 mixture of diastereomers. f The product
was 3-[(1-benzyl-imidazol-2-yl)carbonyl]-1,1-diisopropyl-3-phenyl-urea 11.
that the amine base is required, as expected from the
aforementioned reaction plan in which ylide III is an
intermediate. The reaction of 1-benzylimidazole with benzoyl
chloride and benzaldehyde gave R-(1-benzylimidazol-2-yl)-
benzyl benzoate 14 in only 2% yield, while 2-benzoyl-1-
benzylimidazole was the major product isolated in 39% yield
(Table 2, entry 5), indicating that a hindered acyl chloride
is required. The examples presented in Table 1 show that
an electrophile with significant reactivity is needed. Although
reaction proceeded as designed to afford 5 in 78% yield!
Herein, we describe our initial study of the scope and
generality of this new reaction.
Omission of diisopropylethylamine from the reaction
resulted in a low yield of 5 (Table 1, entry 8), indicating
(7) Breslow, R. J. Am. Chem. Soc. 1958, 80, 3719-3726. Holzer, H.
Angew. Chem. 1961, 73, 721-729.
Table 2. Acylator Modifications11
(8) Wanzlick, H. W. Angew. Chem. 1962, 74, 129-134; Angew. Chem.,
Int. Ed. Engl. 1962, 1, 75-80 is a good leading reference.
(9) Arduengo, A. J., III; Harlow, R. L.; Kline, M. J. Am. Chem. Soc.
1991, 113, 361-363.
(10) Hlasta, D. J.; Silbernagel, M. J. Heterocycles 1998, 48, 1015-1022.
Hlasta, D. J. Tetrahedron Lett. 1990, 31, 5833-5834.
(11) All compounds gave satisfactory C, H, N analysis ((0.4%), and
mass spectra and NMR spectra were consistent. Isolated yields are after
flash chromatography on silica. Typical Experimental Procedure: To a
suspension of 315 mg (2.0 mmol) of 1-benzylimidazole in 3 mL of
acetonitrile at 0 °C and under nitrogen was added rapidly dropwise a solution
of 396 mg (2.4 mmol) of diisopropylcarbamyl chloride in 5 mL of
acetonitrile. To the slightly cloudy solution was added 0.31 mL (3.0 mmol)
of benzaldehyde, followed by 1.1 mL (6.3 mmol) of diisopropylethylamine.
The ice bath was removed, and after 10 min of stirring, the cloudy yellow
solution was refluxed for 24 h, cooled to room temperature, and concentrated
in vacuo. The residue was dissolved in ethyl acetate and washed successively
with 2 N NaOH, water, and saturated brine. The organic layer was dried
over magnesium sulfate, filtered, and concentrated to 1.01 g of a pale yellow
oil. Flash chromatography on silica (50 mm × 18 cm column) eluted with
ethyl acetate-hexanes (1:1) gave 611 mg (78%) of 5 as white crystals:
mp 106-109 °C.; MS (ESP) m/z 392 [MH+].
conditionsa
entry
RCOX
temp
time
product
yield (%)
1
2
3
4
5
ClCON(i-Pr)2
O(COO-t-Bu)2
O(COOEt)2
(CH3)3CCOCl
PhCOCl
reflux
reflux
reflux
reflux
rt
24 h
21 h
21 h
21 h
4 d
5
12
78
52
b
32
2c
13
14
a Reactions were run on a 2 mmol scale with 2.4 mmol of RCOX and
6.3 mmol of DIEA in 8 mL of acetonitrile. b A mixture was obtained by
TLC, and the product was not detected by MS. c The major product obtained
in 39% yield was 2-benzoyl-1-benzyl-imidazole.
(12) Pratt, R. F.; Kraus, K. K. Tetrahedron Lett. 1981, 22, 2431-2434.
158
Org. Lett., Vol. 3, No. 2, 2001