An efficient, regioselective, versatile synthesis of N-fused 2- and 3-aminoimidazoles via Ugi-type multicomponent reaction mediated by zirconium(IV) chloride in polyethylene glycol-400

Article abstract of DOI:10.1055/s-0028-1087915

An Ugi-type multicomponent reaction of heterocyclic amidines with aldehydes and isocyanides catalyzed by zirconium(IV) chloride in PEG-400 was developed. The protocol offers the rapid, environment friendly, regioselective and versatile synthesis of medici

Full text of DOI:10.1055/s-0028-1087915

628
LETTER
An Efficient, Regioselective, Versatile Synthesis of N-Fused 2- and
3-Aminoimidazoles via Ugi-Type Multicomponent Reaction Mediated by
Zirconium(IV) Chloride in Polyethylene Glycol-400
Versatile
Synt
a
hesis of
N
-F
n
used 2-
a
nd
k
3-Aminoim
a
s
r K. Guchhait,* Chetna Madaan
Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), S. A. S. Nagar (Mohali)-
160062, Punjab, India
Fax +91(172)2214692; E-mail: skguchhait@niper.ac.in
Received 3 November 2008
MCR methodologies in the synthesis of library of N-fused
Abstract: An Ugi-type multicomponent reaction of heterocyclic
aminoimidazoles.
amidines with aldehydes and isocyanides catalyzed by zirconi-
um(IV) chloride in PEG-400 was developed. The protocol offers
the rapid, environment friendly, regioselective and versatile synthe-
sis of medicinally important N-fused 2- and 3-aminoimidazoles in
good to high yields. The combination of catalyst and solvent, that
was judiciously explored, was crucial for regioselectivity and ver-
satility of the method.
As a part of our research program focused on the synthesis
of polycyclic heterocyclic compounds for drug discovery,
we sought to develop a MCR protocol which would offer
the efficient formation of library of versatile N-fused
aminoimidazoles. Bradley12f reported that the reaction of
2-aminopyrimidines catalyzed by Sc(OTf)3, HClO4 or
AcOH in MeOH formed a regioisomeric mixture of 2- and
3-aminoimidazo[1,2-a]pyrimidines (I and II, Scheme 1)
in almost equimolar ratio, while ammonium chloride in
toluene led the reaction to form only 3-aminoimidazo[1,2-
a]pyrimidines (II) as developed by Krasavin.12e This regio-
selective variation in the reaction of 2-aminopyrimidine
can be speculated, as proposed by Krasavin,12e that MeOH
favors the formation of both of possible uncharged imine
and ionic iminium intermediates (A and B, Scheme 1),
while toluene being nonpolar solvent can stabilize only
imine intermediate (A).
Key words: multicomponent reaction, regioselective synthesis,
N-heterocycles, zirconium(IV) chloride, polyethylene glycol
Nitrogen-fused imidazoles1 have recently gained im-
mense attention because of their wide range of pharma-
ceutical activities such as antibacterial,2 antiviral,3
antifungal4 and anti-inflammatory5 agents, selective CDK
inhibitors,6 GABA receptor agonists,7 bradykinin B2 re-
ceptor antagonists8 and calcium channel blockers.9 These
classes of heterocycles are represented by launched drugs
in market like zolimidine (antiulcer), zolpidem (hypnotic)
and alpidem (anxiolytic). Significant approaches to the
synthesis of N-fused imidazoles include coupling of 2-
aminopyridines with a-halocarbonyl compounds,10 [3+2]-
cyclization of 2-aminopyridine with 1,2-bis(benzotri-
azolyl)-1,2-(dialkylamino)ethanes,11 Ugi-type multicom-
ponent reaction of heterocyclic 2-aminoazines with
aldehydes and isocyanides,12 five-step one-pot cascade
reaction starting from pyridine13 and Pd–Cu-catalyzed
Sonogashira coupling followed by in situ heterocycliza-
tion.14 As multicomponent reactions (MCRs)15 offer key
advantages of atom economy and feasibility of introduc-
ing maximum molecular diversity elements in a single
chemical event, the MCR processes have received pre-
ferred attention in context of organic and medicinal chem-
ist’s perspective in drug discovery. But the versatile
inefficiency of the MCR approaches for various hetero-
aromatic amidines and aldehydes leading to the diversity
in products is of real concern. Additionally, regioselectiv-
ity problem of reaction in case of 2-aminopyrimidine, for-
mation of side products, long reaction time and use of
expensive Lewis acid e.g., Sc(OTf)3 restrict the use of
N
N
R1
N
N
R2N
C
R1
N
H
N
[4+2]
N
NH2
R1CHO
A
NHR2
I
N
NH
N
N
N
N
H R2N
[4+2]
C
NHR2
N
R1
B
II
R1
Scheme 1 Plausible mechanism12e
Additionally, nucleophilic solvents like methanol were
found to promote the competitive side reaction of nucleo-
philic attack of 2-aminoazines as well as that of solvent it-
self on intermediates A and B. It is noteworthy that the use
of nonpolar solvent like toluene in reaction requires long-
er time at high temperature. We reasoned that the polar
protic but less nucleophilic solvent like polyethylene gly-
col could favor the formation of ionic iminium intermedi-
ate and avoid nucleophilic side reaction. Thus high
regioselectivity and versatility of the reaction could be
achieved if performed in PEG-400,16 with use of suitable
Lewis acid catalyst having high cationic charge potential.
Zr4+, with a high charge to size ratio (Z2/r is 22.22 e2m–10
has strong coordinating ability, and thus ZrCl4 shows high
)
SYNLETT 2009, No. 4, pp 0628–0632
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x.
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x.
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0
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Advanced online publication: 16.02.2009
DOI: 10.1055/s-0028-1087915; Art ID: G35908ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Versatile Synthesis of N-Fused 2- and 3-Aminoimidazoles
629
Table 1 Regioselective Synthesis of 2-Aminoimidazo[1,2-a]pyri-
midines
Table 2 Synthesis of Versatile N-Fused 3-Aminoimidazoles Span-
ning Diverse Heterocyclic Amidinesa
N
N
NH2
CHO
t-BuNC
N
ZrCl4 (10 mol%)
PEG-400, 50 °C
5-/6-
het
5-/6-
het
NHt-Bu
Ar
N
NH2
N
N
N
ZrCl4 (10 mol%)
Cl
III
RCHO
t-BuNC
R
NHt-Bu
N
PEG-400
50 °C
N
Productb
Time (h)
4.5
Yield (%)c
85
N
Entry
R
N
N
N
1
Ar
IV
NHt-Bu
NHt-Bu
Entry Substrate (R)
Time (h)
Isolated yield (%)
2
7
81
III
IV
N
Ar
N
1
1
2
83
9
Cl
NHt-Bu
N
3
4
5
6
2
83
90
85
72
2
80
78
10
11
Ar
N
N
NHt-Bu
Ar
3
4
1.5
2
MeO
NC
3
N
NHt-Bu
84
7
2.5
3.5
N
Ar
N
Cl
NHt-Bu
efficiency in catalytic activity.17 Additionally, the inex-
pensiveness and ease and safety of handling of ZrCl4
prompted us to choose it as catalyst for initial screening.
Herein, we report the results of this study.
Br
N
Ar
NHt-Bu
Ar
N
Br
N
In the initial experiment, the reaction of 2-aminopyridine
was carried out with 4-chlorobenzaldehyde and tert-butyl
isocyanide catalyzed by ZrCl4 (10 mol%) in PEG-400 as
solvent at 50 °C. It provided N-tert-butyl-2-(4-chlorophe-
nyl)imidazo[1,2-a]pyridin-3-amine in 85% isolated yield
in 4.5 hours. This result incited us to investigate the reac-
tion systematically to explore its potential utility. The use
of CeCl3·7H2O, ZnClO4·6H2O or InCl3 as catalyst effect-
ed the reaction in comparatively lower yields. Polar apro-
tic solvent like acetonitrile led the reaction very slowly
and the formation of side products was observed. ZrCl4
was necessary as the reaction in PEG-400 without catalyst
did not form product after five hours. A 10 mol% loading
of ZrCl4 gave the best result at optimal temperature and
reaction time. The experimental procedure is very simple
and straightforward.18
7
8
3
5
90
90
N
N
NHt-Bu
Ar
S
N
N
N
N
NHt-Bu
9
10
11
2
83
64
84
N
S
Ar
NHBut
7
S
N
N
Ar
NHt-Bu
S
4.5
N
N
The optimized protocol was then tested for its regioselec-
tive efficiency. Very interestingly, 2-aminopyrimidine in
this method catalyzed by ZrCl4 in PEG-400 afforded the
highly regioselective formation of 2-tert-butylaminoimi-
dazo[1,2-a]pyrimidines III over 3-amino regioisomeric
products IV in almost 8:1 ratio with high yields (Table 1).
The reason for regioselective formation of products III
can be speculated that PEG-400, being polar solvent, sta-
bilizes preferentially the ionic iminium intermediate B
and ZrCl4 acting as Lewis acid of high cationic charge po-
tential enhances the formation of pyrimidin-2(1H)-imine
tautomeric form of 2-aminopyrimidine and thus interme-
diate B. The structures of 2- and 3-aminoimidazo[1,2-
Ar
t-BuHN
EtO2C
12
5
79
N
Ar
N
N
H
NHt-Bu
a Reaction conditions: heterocyclic amidines, aldehydes and isocy-
anides in equimolar ratio, ZrCl4 (10 mol%), PEG-400, 50 °C.
b Ar = 4-chlorophenyl, and all products were characterized by
1H NMR, 13C NMR, IR, mass and elemental analyses.
c Isolated yields.
Synlett 2009, No. 4, 628–632 © Thieme Stuttgart · New York

630
S. K. Guchhait, C. Madaan
LETTER
a]pyrimidines were characterized by their spectroscopic as reasoned. While glyoxylic acid was explored19 to be an
data (IR, 1H NMR, 13C NMR, mass and elemental analy- efficient formaldehyde equivalent in MCR to afford 2-un-
ses) which, along with Rf value in TLC, were identical substituted 3-amino N-fused imidazoles, the reaction of
with those of respective isomers prepared by reported formaldehyde in Ugi-type MCRs for their synthesis are
method.12f
reportedly scarce, and those reported are low yielding.12d
Interestingly, the reaction of paraformaldehyde with 2-
aminopyridine and tert-butyl isocyanide (Table 3, entry
11) in this method offered the product in 75% yield, and
thus this protocol provides the convenient access of 2-un-
substituted 3-amino N-fused imidazoles. This process was
quite general for isocyanides. The reaction of 2-amino-
pyridine and 4-chlorobenzaldehyde with tert-butyl, cyclo-
hexyl and 1,1,3,3-tetramethylbutyl isocyanides afforded
the corresponding products in 85%, 88% and 90% yield
respectively. Significantly, the dealkylation of 1,1,3,3-tetra-
methylbutyl group of MCR product by TFA can convert it
into the corresponding primary amine product, which can
be as useful for further modification.20 Functional groups
on aromatic rings of aldehydes and heterocyclic amidines,
such as methoxy, chloro, bromo, cyano, N,N-dimethyl and
carboxyl were unaffected by the reaction conditions. This
method was straightforward. Reactions were sufficiently
fast and insensitive to oxygen and moisture. Preformation
of imine was found to be unnecessary.
Splendidly, the scope of this protocol was extensively
broad and versatile, spanning a wide range of heterocyclic
2-aminoazines, aldehydes and isocyanides. The hetero-
cyclic azine used included 2-aminopyridine, 2-aminopy-
razine, 2-aminothiazole, 2-aminothiadiazole, 2-amino-
benzthiazole and 3-amino-1H-pyrazole (Table 2). The al-
dehydes comprised electron-rich, electron-poor, sterically
hindered and metallocene-derived aromatic, heteroaro-
matic and aliphatic aldehydes (Table 3). The reactions of
all heterocyclic amidines other than 2-aminopyrimidine
(Tables 2 and 3) formed only one regioselective product,
N-fused 3-aminoimidazoles, which are likely to be
formed according to the reported MCR approaches. Less
reactive amidines such as aminopyrazine, aminothiazole
and aminothiadiazole in Ugi-type MCR in MeOH were
reported to suffer from a competing reaction through nu-
cleophilic attack of MeOH and amidine-amine on inter-
mediate Schiff bases.12a,e,f Significantly, the reaction of
these amidines in this process (Table 2, entries 8–11) af-
forded high yield of products suppressing side reactions,
Table 3 Synthesis of Versatile N-Fused 3-Aminoimidazoles (Imidazo[1,2-a]pyridines) Spanning a Wide Range of Aldehydesa,b
NH2
N
ZrCl4 (10 mol%)
PEG-400, 50 °C
R
t-BuNC
RCHO
+
+
N
N
NHt-Bu
Entry
1
Substrate (R)
Time (h)
4.5
Yield (%)c
85
Cl
2
3
4
5
6
3
80
6
78
88
82
80
NC
F
1.5
3
Me2N
2
7
8
5
95
95
Br
3.5
MeO
9
2.5
85
Synlett 2009, No. 4, 628–632 © Thieme Stuttgart · New York

LETTER
Versatile Synthesis of N-Fused 2- and 3-Aminoimidazoles
631
Table 3 Synthesis of Versatile N-Fused 3-Aminoimidazoles (Imidazo[1,2-a]pyridines) Spanning a Wide Range of Aldehydesa,b (continued)
NH2
N
ZrCl4 (10 mol%)
PEG-400, 50 °C
R
t-BuNC
RCHO
+
+
N
N
NHt-Bu
Entry
10
Substrate (R)
Time (h)
1.5
Yield (%)c
88
11
12
13
5
75
92
89
(CH2O)n
C3H7
2
2.5
N
O
14
15
2.5
2.5
81
83
N
H
16
17
1.5
2.5
86
78
S
Fe
a Reaction conditions: 2-aminopyridine, aldehydes and isocyanides in equimolar ratio, ZrCl4 (10 mol%), PEG-400, 50 °C.
b All products were characterized by 1H NMR, 13C NMR, IR, mass and elemental analyses.
c Isolated yields.
(3) (a) Hamdouchi, C.; de Blas, J.; del Prado, M.; Gruber, J.;
In conclusion, we have developed a novel method with
judicious choice of solvent and catalyst for the synthesis
of N-fused 2- and 3-aminoimidazoles. This new protocol
has enormous potential for preparing a large library of
regioisomerically pure, versatile nitrogen-fused 2- and 3-
aminoimidazoles in an expeditious and environmentally
friendly way in good to excellent yields from readily ac-
cessible starting materials. Further investigation on use of
this methodology in multistep synthesis of library of tar-
get molecules for drug discovery is ongoing.
Heinz, B. A.; Vance, L. J. Med. Chem. 1999, 42, 50.
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Acknowledgment
We gratefully acknowledge financial support from the DST, New
Delhi for this investigation.
References and Notes
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Spampinato, S.; Marinelli, L.; Novellino, E.; Chiarini, A.
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4935.
Synlett 2009, No. 4, 628–632 © Thieme Stuttgart · New York

632
S. K. Guchhait, C. Madaan
LETTER
(18) Representative Experimental Procedure for the
(12) (a) Bienayme, H.; Bouzid, K. Angew. Chem. Int. Ed. 1998,
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Tetrahedron Lett. 2008, 49, 3097; and references cited
therein.
Synthesis of N-tert-Butyl-2-(4-chlorophenyl)imidazo[1,2-
a]pyridin-3-amine (Table 2, entry 1): To a mixture of 2-
aminopyridine (0.19 g, 2 mmol) and 4-chlorobenzaldehyde
(0.28 g, 2 mmol) in PEG-400 (2 mL), tert-butyl isocyanide
(0.17 g, 2 mmol) and ZrCl4 (47 mg, 10 mol%) were added.
The mixture was allowed to stir at 50 °C under open air.
After completion of the reaction (4.5 h, monitored by TLC),
the resulting mixture was extracted with EtOAc and washed
with H2O. The organic layer was dried over anhyd Na2SO4,
filtered and concentrated under reduced pressure. The
column chromatographic purification of crude product over
silica gel (mesh size: 60–120) eluting with EtOAc–hexane
(1:1.5) afforded N-tert-butyl-2-(4-chlorophenyl)imidazo-
[1,2-a]pyridin-3-amine (0.48 g, 85%); white solid; mp 146–
149 °C. MS (ESI): m/z = 300 [M + 1]. 1H NMR (400 MHz,
CDCl3): d = 1.06 (s, 9 H), 3.00 (br, NH), 6.78 (t, J = 6.8 Hz,
1 H), 7.15 (t, J = 8.0 Hz, 1 H), 7.40 (d, J = 8.8 Hz, 2 H), 7.54
(d, J = 7.2 Hz, 1 H), 7.92 (d, J = 8.8 Hz, 1 H), 8.20 (d, J = 6.8
Hz, 1 H). 13C NMR (100 MHz, CDCl3): d = 30.3 (3 × Me),
56.4 (C), 111.5 (CH), 117.3 (CH), 123.3 (CH), 123.4 (C),
124.3 (CH), 128.4 (2 × CH), 129.3 (2 × CH), 133.1 (C),
133.7 (C), 138.3 (C), 142.0 (C). IR (KBr): 3457, 2972, 1635,
1194, 770 cm–1. Anal. Calcd for C17H18ClN3: C, 68.11; H,
6.05; N, 14.02. Found: C, 67.89; H, 6.07; N, 13.99.
All reactions (Tables 1– 3) were carried out following this
procedure.
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(20) Blackburn, C.; Guan, B. Tetrahedron Lett. 2000, 41, 1495.
Synlett 2009, No. 4, 628–632 © Thieme Stuttgart · New York

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