Reaction of N-acetylimidazole with enamines

Article abstract of DOI:10.1016/S0040-4039(03)01688-5

N-Acetylimidazole is a commonly used acylating reagent. When it is allowed to react with several typical enamines, amides are produced rather than the expected acylated enamines.

Full text of DOI:10.1016/S0040-4039(03)01688-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 6923–6925
Reaction of N-acetylimidazole with enamines
Gilbert Cook* and Julie L. Waddle
Department of Chemistry, Valparaiso University, Valparaiso, IN 46383, USA
Received 13 May 2003; revised 30 June 2003; accepted 4 July 2003
Abstract—N-Acetylimidazole is a commonly used acylating reagent. When it is allowed to react with several typical enamines,
amides are produced rather than the expected acylated enamines.
© 2003 Elsevier Ltd. All rights reserved.
Acylation of enamines using acid chlorides, acid anhy-
drides and ketenes has been well documented.1,2 N-
Acetylimidazole (2) is an azolide which has been used
extensively for acylation of amines and alcohols.3 How-
ever, there has not previously been a report of it being
used to acylate enamines. We have found that N-
acetylimidazole (2) does not simply acylate an enamine,
but it undergoes a rearrangement to form an amide
(Scheme 1). For example, when 1-(1-pyrro-
lidino)cyclohexene (1b) is allowed to react with N-
Scheme 1.
Keywords: enamines; acylation; imidazole; amides.
* Corresponding author. Tel.: 219-464-5389; fax: 219-464-5489; e-mail: gil.cook@valpo.edu
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01688-5

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G. Cook, J. L. Waddle / Tetrahedron Letters 44 (2003) 6923–6925
Table 1. Reaction times, yields and physical properties of amides
Compounda
Ratio (endo(3):exo(4))
Yield (%)
bp °C (mm)
Time (min)
a
b
c
d
e
f
3:1
3:1
3:1
4:1
3:1
4:1
40
59
33
53
37
56
122–125 (0.3)
104–106 (0.6)
180 (3)
135–140 (0.45)
113–117 (0.3)
158 (0.3)
45
30
40
30
40
45
a a is X=bond, n=0; b is X=bond, n=1; c is X=CH2, n=0; d is X=CH2, n=1; e is X=O, n=0; f is X=O, n=1.
acetylimidazole at reflux temperatures, the only prod-
ucts isolated were 1-(1-cyclohexen-1-ylacetyl)pyrrolidine
(3b) and 1-(2-cyclohexylidine-1-ylacetyl)pyrrolidine
(4b)4 in an overall yield of 59% and an isomer ratio of
3:1 of endo (3b) to exo (4b) (Table 1).
The structural identities of the amide products 3 and 4
were made as follows. One of the amide products,
4-(1-cyclohexen-1-ylacetyl)morpholine (3f), has previ-
ously been reported,5 and the physical properties of 3f
correspond to those reported.6 The amide products
were hydrolyzed to produce the corresponding mixtures
of previously reported acids, namely 1-cyclohexenyl-
acetic acid7 (6, n=1)/cyclohexylidene acetic acid8 (5,
n=1) and 1-cyclopentenylacetic acid9 (6, n=0)/
cyclopentylideneacetic acid10 (5, n=0) (Scheme 1).
These acids were synthesized by us using the known
pathway of the Horner–Wadsworth–Emmons phospho-
noacetate reagent11 followed by hydrolysis of the ester.
These independently synthesized unsaturated acids were
then transformed into the desired amides using the
standard technique of acyl halide production followed
by treatment with a required secondary amine (Scheme
1). The products of these reactions had identical physi-
cal and spectroscopic properties as the products
obtained from the reaction of N-acetylimidazole and
the enamines.
Scheme 2.
The use of N-acylimidazoles with no hydrogen on the
a-carbon of the acyl group results in a normal acylation
of the enamine. This is demonstrated by the treatment
of 1-(1-pyrrolidino)cyclohexene (1b) with N-benzoylim-
idazole (7) to produce the simple acylated compound 8
in a 91% yield (Scheme 2). In a similar demonstration
of this, the reaction of enamine 1b with N-trifl-
uoroacetylimidazole (9) produced addition compound
10 via an exothermic reaction at room temperature in a
47% yield. An acylation reaction of 1-(1-morpho-
line)cyclohexene with trifluoroacetic anhydride has been
previously described.12
Scheme 3.
(14) in a 4:1 ratio (Scheme 4). The positioning of the
amide group relative to the methyl group on the cyclo-
hexane ring was shown by 13C NMR.16 This demon-
strates that ipso substitution is taking place in this
reaction.
A proposed mechanism for the formation of amide 3 is
as shown in Scheme 5 using formation of 3b as the
example. There is a complete cleavage of the car-
bonylꢀimidazole CꢀN bond in the first step of the
mechanism producing imidazole anion 15 as a leaving
group.17 This anion is a strong enough base (pKa
14.17)18 to remove the a-proton from the acyl group
attached to a positive nitrogen in the second step. This
is followed by a rearrangement to give the final product
amide 3b.
One possible pathway for this reaction to follow would
be for the initial formation of acylated enamine 1113,14
followed by reaction with imidazole. However, allowing
acylated enamine 11 to react with imidazole under
identical reaction conditions did not produce the rear-
rangement products (Scheme 3).
Treatment of 4-methyl-1-pyrrolidinocyclohexene15 (12)
with N-acetylimidazole (2) produced amides (13) and

G. Cook, J. L. Waddle / Tetrahedron Letters 44 (2003) 6923–6925
6925
Scheme 4.
Scheme 5.
IR spectrum (neat) wmax 1643 cm−1
;
1H NMR spectrum
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