Novel use of imidazolium ylides in an efficient synthesis of 2-substituted imidazoles

Article abstract of DOI:10.1021/ol006734y

equation presented A new reaction of imidazoles was discovered involving the formation of an imidazolium ylide, which on trapping with various electrophiles afforded diverse 2-substituted imidazoles. The facile, convenient reaction conditions when compared to the existing procedures make this reaction the method of choice in the preparation of 2-substituted imidazoles. Moreover, the reaction differs from the reported methods since the products (viz., 1) contain an α-substituent that is transformed by solvolysis chemistry into further functionalized derivatives.

Full text of DOI:10.1021/ol006734y

ORGANIC
LETTERS
2001
Vol. 3, No. 2
157-159
Novel Use of Imidazolium Ylides in an
Efficient Synthesis of 2-Substituted
Imidazoles
Dennis J. Hlasta*
Drug DiscoVery, The R.W. Johnson Pharmaceutical Research Institute,
Welsh and McKean Roads, Spring House, PennsylVania 19477-0776
dhlasta@prius.jnj.com
Received October 15, 2000
ABSTRACT
A new reaction of imidazoles was discovered involving the formation of an imidazolium ylide, which on trapping with various electrophiles
afforded diverse 2-substituted imidazoles. The facile, convenient reaction conditions when compared to the existing procedures make this
reaction the method of choice in the preparation of 2-substituted imidazoles. Moreover, the reaction differs from the reported methods since
the products (viz., 1) contain an r-substituent that is transformed by solvolysis chemistry into further functionalized derivatives.
Imidazoles are important as heterocyclic components of many
drugs and biologically active molecules.1,2 Consequently,
new, efficient methodology for the preparation of imidazole
derivatives would provide a valuable tool to synthetic organic
chemists. Relative to functionalizing imidazole at the 2-posi-
tion, 2-lithioimidazoles are generated with strong bases (e.g.,
BuLi) at low temperatures and under anhydrous conditions
and then captured by electrophiles.1,3 Imidazoles can be
directly acylated at the 2-position4 or thermally condensed
with aldehydes or isocyanates, although the yields in the
aldehyde reaction can be highly variable and substrate-
dependent.5 2-Substituted imidazoles are also prepared by
reacting 2-trimethylsilyl-1-alkylimidazoles with aldehydes,
typically in good yields.6
We sought to establish a new reaction of imidazoles
involving formation of an imidazolium ylide species (viz.,
II in Scheme 1), which is isoelectronic to carbene species I,
Scheme 1
(1) Grimmett, M. R. In ComprehensiVe Heterocyclic Chemistry; Katritz-
ky, A. R., Rees, C. W., Scriven, E. F. V., Eds.; Pergamon Press: Oxford,
1996; Vol. 3, pp 77-220.
(2) Roehrle, A. N.; Schmidhammer, H. HelV. Chim. Acta 1998, 81,
1070-1076. Davies, D. H.; Haire, N. A.; Hall, J.; Smith, E. H. Tetrahedron
1992, 48, 7839-7856. Gordon, T.; Hansen, P.; Morgan, B.; Singh, J.;
Baizman, E.; Ward, S. Bioorg. Med. Chem. Lett. 1993, 3, 915-20. Reid,
R. C.; March, D. R.; Dooley, M. J.; Bergman, D. A.; Abbenante, G.; Fairlie,
D. P. J. Am. Chem. Soc. 1996, 118, 8511-8517. von Geldern, T. W.; Kester,
J. A.; Bal, R.; Wu-Wong, J. R.; Chiou, W.; Dixon, D. B.; Opgenorth, T. J.
J. Med. Chem. 1996, 39, 968-81. Pridgen, L. N.; Mokhallalati, M. K.;
McGuire, M. A. Tetrahedron Lett. 1997, 38, 1275-1278.
(3) Merino, P. Prog. Heterocycl. Chem. 1999, 11, 21-44 and references
therein.
with subsequent trapping by electrophiles to afford diverse
2-substituted imidazoles. The related thiazolium ylides have
long been known from the mechanism of thiamine,7 and
(5) Roe, A. M. J. Chem. Soc. 1963, 2195-2200. Papadopoulos, E. P. J.
Org. Chem. 1977, 42, 3925-3929. Papadopoulos, E. P.; Schupbach, C. M.
J. Org. Chem. 1979, 44, 99-104.
(6) Pinkerton, F. H.; Thames, S. F. J. Heterocycl. Chem. 1972, 9, 67-
72.
(4) Regel, E.; Buchel, K.-H. Liebigs Ann. Chem. 1977, 145-158, 159-
168.
10.1021/ol006734y CCC: $20.00 © 2001 American Chemical Society
Published on Web 12/29/2000

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

aldehydes, trifluoromethyketones, R-ketoesters, and isocy-
anates gave good yields of the desired products, the less
reactive ketones, such as acetophenone and benzophenone,
were not successful. Instead, the Bamberger degradation12
product was obtained on aqueous workup.13 Phenylacetal-
dehyde, which contains highly enolizable R-hydrogens,
required special conditions to obtain a good yield of
imidazole 4. Under typical conditions (entry 4), phenylac-
etaldehyde competed for reaction with the ylide and diiso-
propylcarbamyl chloride, and desired product 4 was obtained
in only 32% yield, along with the O-carbamoyl enol ether
of phenylacetaldehyde. When the reaction was conducted
with two additional charges of reagents at 6 and 24 h, and
after a total reaction time of 44 h, a 78% yield of the
imidazole 4 was obtained (entry 5).
A comparison of five acyl chlorides and anhydrides in the
reaction of 1-benzylimidazole with benzaldehyde (Table 2)
confirmed that a sterically hindered acyl chloride is required
for good yields. As previously mentioned, benzoyl chloride
afforded the 2-benzoyl imidazole in moderate yield and trace
amounts of the desired product 14 (entry 5). Diethyl
dicarbonate gave a complex mixture in this reaction (entry
3), while the more sterically encumbered di-tert-butyl
dicarbonate gave the imidazole 12 in 52% yield (entry 2).
Diisopropylcarbamyl chloride gave the best results.
Table 3. Solvolysis Reactions of the Carbamate 511
entry
Nuc-H
H2O
H2O
CH3OH
CH3CH2OH
CH3CONH2
CH3SO2NH2
rxn timea
product
yield (%)
1
2
3
4
5
6
11 h
21 h
52 h
8 h
18 h
18 h
15
15
16
17
18
19
84
quantb
60c
84d
63
75
a Reactions were run on a 2 mmol scale with 20 equiv of the nucleophile
in 10 mL of THF containing 0.5 mL of TFA at reflux. b A quantitative
yield was obtained on a 15 mmol scale. c Isolated 11% of the alcohol 15.
d Isolated 12% of the alcohol 15.
shown in Table 3. For example, treatment of 5 with
methanesulfonamide and trifluoroacetic acid in THF at reflux
gave the methanesulfonamido derivative 19 in 75% yield
(entry 6). Similar results were obtained with acetamide,
methanol, ethanol, and water (entries 1-5).
The new reaction described herein has tremendous po-
tential in the synthesis of imidazoles bearing a wide diversity
of substitution patterns. The facile, convenient reaction
conditions when compared to the existing procedures make
this reaction the method of choice in the preparation of
substituted imidazoles. Furthermore, the reaction differs from
the reported methods since the products contain an R-sub-
stituent that can be readily transformed by solvolysis
chemistry into further functionalized derivatives. Studies on
additional heterocycles and electrophiles, as well as asym-
metric and solid-phase methods, are being pursued.
Since the carbamoyl group of 5 is a good leaving group,
we anticipated that various solvolysis reactions would
provide imidazoles with a range of R-substituents. Imidazole
5 was converted to modified 2-substituted imidazoles as
(13) The reaction of acetophenone under typical conditions gave on
workup the Bamberger degradation product 20 in 52% yield with none of
the desired product detected.
OL006734Y
Org. Lett., Vol. 3, No. 2, 2001
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