A facile synthesis of structurally novel 1-aryl-2-arylamino-4-alkyl/phenyl-5-aroyl-1H-imidazoles from amidinothioureas

Article abstract of DOI:10.1016/j.tetlet.2008.10.012

We report here a convenient and efficient two-step synthesis of 1-aryl-2-arylamino-4-alkyl/phenyl-5-aroyl-1H-imidazoles from easily available amidinothioureas. Guanylation of amidinothioureas 1 using mercury(II) chloride as a thiophile yielded amidinoguanidines 2, which reacted with various phenacyl bromides under mild conditions to afford the corresponding diversely functionalized imidazoles 3 in moderate to good yields.

Full text of DOI:10.1016/j.tetlet.2008.10.012

Tetrahedron Letters 49 (2008) 7220–7222
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Tetrahedron Letters
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A facile synthesis of structurally novel 1-aryl-2-arylamino-4-alkyl/phenyl-
5-aroyl-1H-imidazoles from amidinothioureas
*
Jitendra C. Kaila, Arshi B. Baraiya, Kamala K. Vasu , V. Sudarsanam
Department of Medicinal Chemistry, B.V. Patel Pharmaceutical Education and Research Development (PERD) Centre,
Thaltej-Gandhinagar Highway, Thaltej, Ahmedabad, Gujarat 380 054, India
a r t i c l e i n f o
a b s t r a c t
Article history:
We report here a convenient and efficient two-step synthesis of 1-aryl-2-arylamino-4-alkyl/phenyl-5-
aroyl-1H-imidazoles from easily available amidinothioureas. Guanylation of amidinothioureas 1 using
mercury(II) chloride as a thiophile yielded amidinoguanidines 2, which reacted with various phenacyl
bromides under mild conditions to afford the corresponding diversely functionalized imidazoles 3 in
moderate to good yields.
Received 18 August 2008
Revised 30 September 2008
Accepted 3 October 2008
Available online 7 October 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
2-Aminoimidazoles
Amidinothioureas
Thiophile
Desulfurization
The imidazole moiety which incorporates both
p
-excessive and
tion occurs upon complexation of the basic imidazole with the
Lewis acid.9 Therefore, a general synthetic methodology which
would result in diversely functionalized 1-aryl-2-arylamino-4-al-
kyl/aryl-5-aroyl-1H-imidazoles could find applications in medici-
nal chemistry. Imidazoles possessing structural features of the
title compound, to our knowledge, are unknown in the literature.
The synthesis of biologically active 2-aminothiazoles from
amidinothioureas has been reported by our group.10 In
continuation of this work, we reasoned that the title compounds
could be prepared from amidinothioureas via guanylation and
p
-deficient characteristics1 has proven to be a master key in a
range of drug target families.2 Compounds incorporating the imid-
azole scaffold are known as inhibitors of p38 MAPK,3a JNK3,3b B-Raf
kinase,3c transforming growth factor b-1 (TGF-b1) type 1 activin
receptor-like kinase,3d acyl-CoA: cholesterol O-acyl transferase
(ACAT)3e and anti-amoebic agents.3f Imidazoles substituted with
a 2-arylamino functionality have been reported to have potent
and selective agonist activity at a
2-adrenoceptors.4 Pharmacologi-
cal evaluation of diversely functionalized imidazoles against a de-
sired target can lead to meaningful structure—activity relationship
(SAR) to facilitate the discovery and design of drug-like candidates.
Due to this high level of importance and utility, an ever increasing
amount of research has been focused on the preparation and func-
tionalization of the imidazole moiety.5
Recently, several alkaloids possessing the 2-aminoimidazole
moiety have been isolated and found to be biologically active.6
Even though several methodologies for synthesis of 2-aminoimid-
azoles have been reported in the literature, only few describe the
efficient synthesis of polysubstituted 2-aminoimidazoles, in partic-
ular, 4,5-disubstituted-2-aminoimidazoles.7 A recent microwave-
assisted protocol gives easy access to substituted 2-aminoimidaz-
oles.8 A convenient method for the synthesis of closely related
2-arylimidazoles might lead to a biologically important novel class
of heterocycles. The synthesis of 5-aroyl imidazoles can be prob-
lematic, particularly using the Friedel–Crafts reaction as deactiva-
cyclization with a-bromo carbonyl compounds. Herein, we report
a general protocol for the synthesis of highly functionalized
2-aminoimidazoles.
Amidinothioureas can be obtained easily by reacting isothio-
cyanates with amidines. Amidinothioureas have been used as
synthetic precursors to 2-aminothiazoles via reaction with various
a
-haloketones.11 The corresponding amidinoguanidines can be
synthesized through guanylation of amidinothioureas. Various
mercury salts as well as other thiophiles have been used for the
guanylation of thioureas.12 Thus, we used various mercury salts
for the guanylation of amidinothioureas and achieved the best re-
sults using mercury(II) chloride as a thiophile. HgC12 promotes
desulfurization of thiourea to produce the corresponding carbodi-
imide intermediates; amines were then added to the carbodii-
mides to yield guanidine products.13 The desulfurization of the
substituted amidinothioureas was monitored visually based on
the formation of the black precipitate of HgS. The use of HgCl2
was limited to the guanylation of thiourea substrates having one
hydrogen on each nitrogen. Here, we have efficiently demonstrated
* Corresponding author. Tel.: +91 79 27439375; fax: +91 79 27450449.
E-mail addresses: perd@perdcentre.com, kamkva@gmail.com (K. K. Vasu).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.10.012

J. C. Kaila et al. / Tetrahedron Letters 49 (2008) 7220–7222
7221
Scheme 1.
Table 2
Table 1
Synthesis of amidinoguanidines 2 from amidinothioureas 1
Synthesis of 1-aryl-2-arylamino-4-alkyl/phenyl-5-aroyl-1H-imidazoles
R2
N
N
R1
N
N
R3
N
H
R2
R1
N
R1
NH
R1
O
R1
R2
Product
Mp (°C)
Yielda (%)
Entry
R1
R2
R3
Product
Mp (°C)
Yielda (%)
Entry
1
2
3
4
5
6
7
8
9
C6H5
C6H5
CH3
CH3
CH3
CH3
4-ClC6H4
4-MeC6H4
4-ClC6H4
4-MeC6H4
4-ClC6H4
4-MeC6H4
4-ClC6H4
4-MeC6H4
4-ClC6H4
4-MeC6H4
4-ClC6H4
3a
3b
3c
3d
3e
3f
3g
3h
3i
128–130
172–174
190–192
117–119
215–217
204–206
207–209
186–188
239–241
221–223
133–135
55
60
58
65
68
68
55
58
65
60
58
1
2
3
4
5
6
7
C6H5
CH3
CH3
C6H5
C6H5
C6H5
CH3
2a
2b
2c
2d
2e
2f
198–200
215–217
182–184
185–187
158–160
167–169
Oil
75
70
80
68
70
70
65
4-ClC6H4
4-MeC6H4
4-ClC6H4
C6H5
4-MeC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-MeC6H4
C6H5
4-ClC6H4
4-ClC6H4
4-MeC6H4
4-MeC6H4
4-ClC6H4
CH3
C6H5
C6H5
C6H5
C6H5
C6H5
C4H9
C4H9
2g
a
Isolated yield.
10
11
3j
3k
the HgCl2-promoted guanylation of amidinothioureas 1 to generate
a wide range of amidinoguanidines 2 (Scheme 1).
a
Isolated yield.
The scope of the guanylation reaction was explored for a variety
of amidinothioureas and the results are summarized in Table 1.
The reaction conditions were consistent and the yields ranged from
65% to 80%.
Our ultimate aim was to synthesize diversely functionalized
imidazoles using cheap and readily available reagents under mild
conditions. Initially, we performed the reaction of symmetrical
amidinoguanidines 2 with phenacyl bromide at room temperature
in the presence of KOBu-t. The formation of the imidazole moiety
was apparent from the dark yellow spot on the TLC and after col-
umn purification, it was identified as the desired compound by
LCMS. On confirmation of the feasibility of the cyclization reactions
of phenacyl bromides with substrate 2 to give imidazoles 3, we
undertook further investigations using different bases (DBU, NaH,
K2CO3, and KOBu-t) and solvents (THF, DMF, and acetonitrile) at
room temperature to optimize the conditions. In the reaction of
2 with phenacyl bromides, the best results were obtained when
DBU was used as the base in acetonitrile which is used as solvent
at room temperature for 12 h. (Scheme 1, Table 2).
The generality of this new synthetic method for the efficient
construction of 1,2,4,5-tetrasubstituted imidazoles was investi-
gated by employing these optimized conditions. The results are
summarized in Table 2. The reaction presumably proceeds through
N-alkylation of the phenacyl bromide followed by attack of the
carbanion on the amidino carbon and elimination of diethylamine
(Scheme 2). A variety of substrates, including functionalized aro-
matic for variation of the substituents at the imidazole one and
two positions, methyl/phenyl at the imidazole 4 position, and dif-
ferent aroyl groups at the 5 position were demonstrated. However,
our efforts to cyclize the corresponding amidinoguanidines for the
synthesis of imidazoles with alkyl substituents at positions 1 and 2
failed. The generality of this method for alkyl substituents at posi-
tion 4 was studied by synthesizing an imidazole with an n-butyl
group at this position (Table 2, entry 11).
Scheme 2.
inothioureas under mild conditions. The reaction is applicable to
a wide range of substituted anilines, phenacyl bromides, and ami-
dines. Work is underway in our laboratory to further explore the
scope of this reaction.
Acknowledgments
J.C.K. and A.B.B. thanks B. V. Patel PERD centre for the award of
research fellowship. We thank Prof. Harish Padh, Director, B.V. Pa-
tel PERD centre, for constant encouragement and support.
Supplementary data
General experimental procedures and spectral data for new
compounds. Supplementary data associated with this article can
be found, in the online version, at doi:10.1016/j.tetlet.2008.10.012.
References and notes
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aryl-5-aroyl-1H-imidazole derivatives from easily available amid-
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