A convenient synthesis of di- and trisubstituted 2-aminoimidazoles from 1-amidino-3-trityl-thioureas

Article abstract of DOI:10.1016/j.tetlet.2009.04.083

Convenient synthesis of 2-amino-1,5-disubstituted and 2-amino-1,4,5-trisubstituted imidazoles has been reported using readily available starting materials and simple reagents under mild conditions. Guanylation of 1-amidino-3-trityl-thioureas 1 and 7 using

Full text of DOI:10.1016/j.tetlet.2009.04.083

Tetrahedron Letters 50 (2009) 3955–3958
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A convenient synthesis of di- and trisubstituted 2-aminoimidazoles from
1-amidino-3-trityl-thioureas
*
Jitendra C. Kaila, Arshi B. Baraiya, Amit N. Pandya, Hitesh B. Jalani, Kamala K. Vasu , V. Sudarsanam
Department of Medicinal Chemistry, B.V. Patel Pharmaceutical Education and Research Development (PERD) Centre, Thaltej-Gandhinagar Highway, Thaltej, Ahmedabad 380 054,
Gujarat, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Convenient synthesis of 2-amino-1,5-disubstituted and 2-amino-1,4,5-trisubstituted imidazoles has been
reported using readily available starting materials and simple reagents under mild conditions. Guanyla-
tion of 1-amidino-3-trityl-thioureas 1 and 7 using mercury(II) chloride (Caution) as a thiophile resulted
Received 18 March 2009
Revised 16 April 2009
Accepted 22 April 2009
Available online 3 May 2009
in corresponding guanidines 2 and 8 which on reaction with a-bromo ketones yielded 2-tritylaminoim-
idazoles. Deprotection of 2-tritylaminoimidazoles using trifluoroacetic acid at room temperature fur-
nished desired 2-aminoimidazoles 4 and 10 in good to moderate yields.
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
2-Aminoimidazoles
Amidinothioureas
Thiophile
Guanidines
Heterocyclic moieties often provide framework for pharmaco-
phoric function and sometimes are part of pharmacophore itself.1
The assembly of various structural fragments to the heterocyclic
molecular scaffold can provide a facile framework as binding epi-
topes to macromolecular targets. Five-membered heterocycles in
particular have proved to be productive and popular in the design
of drugs. These rings can pack a relatively large number of polarized
bonds in a relatively small molecular space and also can offer a con-
venient framework to which necessary side chains can be attached.2
As representatives of these compounds, 2-aminoimidazoles have
been identified as an important class of heterocycles due to their
presence in many pharmacologically active substances and marine
natural products.3 Compounds incorporating 2-aminoimidazoles
have been reported to possess potential anti-cancer,4 anti-fungal,5
and nitric oxide synthase inhibitory activities.6 Therefore, develop-
ment of simple and convenient synthetic procedures for such nitro-
gen-containingheterocyclesrepresentsanattractiveandinteresting
area of research in synthetic organic and medicinal chemistry.
There are onlya few approachesthat describethe direct synthesis
of 1-substituted 2-aminoimidazoles. The earliest method involves
sequential functionalization of 1,2-diprotected imidazole ring with
different electrophiles.12 Nevertheless, to match the increasingly
scientific and practical demands for functionalized 2-aminoimidaz-
oles, itisstillofcontinuedinterestandofgreatimportancetoexplore
novel and efficient synthetic approaches for such heterocycles. The
synthesis of 2-amino-5-aroyl/acyl imidazoles can be problematic,
particularly using the Friedel–Crafts reaction, as deactivation occurs
upon complexation of the basic imidazole with the Lewis acid.13 Be-
cause of this limitation, a convenient method for the synthesis of
2-amino-1-aryl-4-substituted/unsubstituted-5-aroyl/acyl-imida-
zoles would find applications in medicinal chemistry.
Amidinothioureas have been studied by our group for the synthe-
sis of biologically important 2-aminothiazoles.14 We have recently
explored amidinothioureas for the synthesis of highly substituted
2-arylamino imidazoles,15 but this methodology was unable to give
free amino group at the imidazole 2 position. We required a general
method that would be amenable to preparation of analogues of dif-
ferent bioactive marine alkaloids possessing a 2-aminoimidazole
skeleton. Therefore, we wish to report the development of a new
method meeting these requirements. This method would result in
medicinally useful compound library to study their biological activ-
ities and structure–activity relationships.
condensation of
a-aminocarbonyl compounds with cyanamide or
their synthetic equivalents.7,8 This method is most commonly used
for the direct construction of the 2-aminoimidazole ring. Other gen-
eral applicable strategies are cyclocondensation of 2-aminopyrimi-
Reaction of trityl isothiocyanate with excess of amidines in
diethyl ether furnished 1-amidino-3-trityl-thioureas 1 as white
solids. As described in our previous communication, the corre-
sponding guanidines 2 were obtained through the reaction of
thioureas 1 with various anilines in presence of mercury(II)
chloride as thiophile (Scheme 1, Table 1, entries 1–4).15 In compar-
ison with p-substituted anilines, the reaction with o-substituted
dines with a-bromocarbonyl compounds followed by the cleavage
of the intermediary imidazo[1,2-a]pyrimidin-1-ium salts with an
excess of hydrazine,9 iminophosphorane-mediated cyclization of
a
-azido esters,10 ammonolysis of 2-amino-1,3-oxazol-3-ium salts,11
* Corresponding author. Tel.: +91 79 27439375; fax: +91 79 27450449.
E-mail addresses: perd@perdcentre.com, kamkva@gmail.com (K.K. Vasu).
Caution.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.04.083

3956
J. C. Kaila et al. / Tetrahedron Letters 50 (2009) 3955–3958
Scheme 1.
Table 1
obtained in lowest yield (Table 1, entry 5, 25%). Synthesis of guani-
Synthesis of N-amidino-N0-aryl-N00-trityl-guanidines
dines 8a–c was achieved starting from the thiourea (Scheme 2.).
Monocondensation of thiourea with dimethylformamide dimethyl
acetal (DMFDMA) was achieved to give thiourea 6 in 90% yield when
methanol was employed as the solvent.16 In agreement with the re-
ported studies, our efforts failed to produce corresponding guani-
dines using N-monosubstituted (terminal) thiourea 6.17 Therefore,
we protected the terminal amino group by reacting thiourea 6 with
trityl chloride in dichloromethane using triethylamine as the base to
give 1-amidino-3-trityl-thiourea 7. Reaction of amidinothiourea 7
with anilines in presence of mercury(II) chloride afforded guanidine
8a–c in good yield (Scheme 2, Table 1, entries 6–8).
We performed several experiments for reaction of guanidines 2
or 8 with phenacyl bromides using different bases (NaH, KOBu-t,
DBU, and K2CO3) and solvents (acetonitrile, THF, acetone, and
1,4-dioxane) at room temperature to obtain the desired imidazoles
3 or 9. Our experiments failed to achieve imidazoles 3 through
cyclization of guanidines 2 with phenacyl bromides using hindered
base like t-KOBu in acetonitrile at room temperature. Due to the
presence of bulky trityl group in the guanidines 2 or 8, t-KOBu
invariably failed to abstract the proton from nitrogen atom. we ob-
N
N
N
N
Ph
Ph
N
Ph
Ph
N
R1
R1
NH
NH
Ph
Ph
R2
R2
2
8
Entry
Product
R1
R2
Yielda
1
2
3
4
5
6
7
8
2a
2b
2c
2d
2e
8a
8b
8c
CH3
CH3
CH3
CH3
4-OMeC6H4
4-MeC6H4
2-ClC6H4
2-MeC6H4
4-ClC6H4
4-FC6H4
65
67
48
50
25
78
70
65
4-MeC6H4
H
H
H
4-ClC6H4
C6H5
a
Isolated yield.
anilines afforded the corresponding guanidines in slightly lower
yield (Table 1, entries 3 and 4). Guanidine 2e (R1 = 4-MeC6H4) was
Scheme 2.

J. C. Kaila et al. / Tetrahedron Letters 50 (2009) 3955–3958
3957
Scheme 3.
tained the best results for the cyclization of substituted guanidines
2 or 8 with various phenacyl bromides to give imidazoles 3 or 9
when K2CO3 (3 equiv) was used as the base in acetonitrile as sol-
vent at room temperature (Schemes 1 and 2). Due to the presence
of bulky trityl group, the reaction presumably proceeds through
selective N-alkylation of the phenacyl bromides at the nitrogen
atom directly attached to the aryl ring. The formation of the het-
erocycle takes place by the attack of carbanion on amidino carbon
and elimination of diethylamine (Scheme 3). Deprotection of 2-tri-
tylamino imidazoles using trifluoroacetic acid at room tempera-
ture resulted in desired 1,4,5-trisubstituted 2-aminoimidazoles 4
(Table 2). All the reactions between guanidines and phenacyl bro-
mides, with systematic variation of R1, R2, and R3 proceeded
smoothly to afford the corresponding imidazole 3 or 9, which were
detritylated to give desired imidazoles 4a–d, 4f, 10a–d, and 10f in
good to moderate yields (Table 2, entries 1–4, 6, 9–12, and 14).
Previously we had reported that the oxime moiety plays an
important role in modulating anti-inflammatory activity.18 It is
noteworthy that the alkoxyimino feature is also present in many
cephalosporin side chains and has given rise to cephalosporin
drugs with not only better therapeutic index but also much better
and broader spectrum of activity. Therefore, in the present work
we were interested in studying the reaction of 4-bromo-2-
alkoxyimiono-3-oxo-butyric acid ethyl ester side chain with
substituted guanidines using general reaction conditions. This
reaction resulted in biologically interesting imidazoles 4g and
10g in 55% and 65% yields, respectively (Table 2, entries 7 and 15).
In summary, we have developed a convenient method for syn-
thesis of biologically interesting 1,5- and 1,4,5-substituted 2-ami-
noimidazoles. This reaction is applicable to a wide range of
substituted anilines, a-bromo ketones, and amidines. Synthesis of
1,5-disubstituted 2-aminoimidazoles was achieved starting from
inexpensive and readily available reagents. The total synthesis of
marine alkaloids using this strategy is under investigation in our
laboratory.
Reaction of guanidines 2b and 8b with a-bromo-4-acetyl pyridine
hydrobromide, when subjected to the identical reaction conditions
mentioned previously, furnished 2-aminoimidazole 4e and 10e as
novel entries (Table 2, entries 5 and 13).
Acknowledgments
Table 2
We thank Professor Harish Padh and Professor C. J. Shisoo,
Directors, B.V. Patel PERD centre, for their constant encouragement
and support. Reviewers’ useful comments are gratefully
acknowledged.
Synthesis of 2-amino-1,5-disubstituted imidazoles and 2-amino-1,4,5-trisubstituted
imidazoles
R1
N
R3
H2N
N
Supplementary data
R2
O
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.04.083.
Entry
Product
R1
R2
R3
Yielda
1
2
3
4
5
6
7
8
4a
4b
4c
4d
4e
4f
4g
4h
10a
10b
10c
10d
10e
10f
10g
CH3
CH3
CH3
CH3
CH3
CH3
CH3
4-MeC6H4
H
H
H
H
H
H
H
4-OMeC6H4
4-MeC6H4
2-ClC6H4
2-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-ClC6H4
4-FC6H4
4-FC6H4
4-FC6H4
4-ClC6H4
4-ClC6H4
C6H5
4-ClC6H4
65
60
52
50
60
62
55
60
75
71
68
63
55
54
65
4-OMeC6H4
4-MeC6H4
4-ClC6H4
4-Pyridyl
4-SO2Me
C@N(OnPr)COOEt
4-MeC6H4
4-MeC6H4
4-ClC6H4
4-OMeC6H4
4-MeC6H4
4-Pyridyl
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