A highly flexible and efficient ugi-type multicomponent synthesis of versatile n-fused aminoimidazoles

Article abstract of DOI:10.1055/s-0029-1216916

A microwave-promoted highly flexible and efficient Ugi-type multicomponent reaction of heterocyclic amidines with aldehydes and isocyanides catalyzed by zirconium(IV) chloride was developed. The general protocol offered the very reliable synthesis of a li

Full text of DOI:10.1055/s-0029-1216916

PAPER
3293
A Highly Flexible and Efficient Ugi-Type Multicomponent Synthesis of
Versatile N-Fused Aminoimidazoles
Flexible
a
nd E
a
f
ficient Syn
n
thesis of N-
k
F
used Amino
a
imidazole
sr K. Guchhait,* Chetna Madaan, Balmukund S. Thakkar
Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, S. A. S. Nagar,
Punjab 160 062, India
Fax +91(172)2214692; E-mail: skguchhait@niper.ac.in
Received 1 May 2009; revised 12 May 2009
like zolimidine (antiulcer), zolpidem (hypnotic), and alp-
Abstract: A microwave-promoted highly flexible and efficient
idem (anxiolytic). To access such medicinally important
Ugi-type multicomponent reaction of heterocyclic amidines with al-
N-fused imidazoles, several MCR methods4,5 in addition
dehydes and isocyanides catalyzed by zirconium(IV) chloride was
to the multi-step synthesis,6a one-pot multi-reactions,6b
developed. The general protocol offered the very reliable synthesis
of a library of medicinally important, widely versatile N-fused ami- and two-component reactions,7 have been endeavored.
noimidazoles in excellent yields. Poorly reactive heterocyclic
MCR approaches, especially the Ugi-type multicompo-
amidines, functionally and sterically hindered aldehydes, which
nent reaction, which was simultaneously first discovered
suffer as troublesome reactants in earlier described methods, were
by Bienaymé,4j Groebke,4k and Blackburn4l et al. in 1998,
rendered as feasible substrates in this process. The efficient cataly-
have attracted attention because of their appealing at-
sis by ZrCl4 in addition to the effect of microwave irradiation was
tributes. But their inflexibility spanning over versatile re-
actants, especially low-reactive amidines and functional
aldehydes is found to be a crucial problem. The less reac-
tive amidines in these reactions reportedly suffer from
slow reaction and competing side reactions through nu-
cleophilic attack of protic solvent (like MeOH) and ami-
dine-amine to intermediate Schiff bases.4a,b,j,5b Moreover,
the MCR products derived from these 2-aminoazines are
significant in aspects of pharmacophoric features for bio-
activity studies. Likewise, the products resulting from
functional aldehydes offer the opportunity of preparing
larger compound libraries through diversity oriented syn-
thesis. In addition, the low yields, long reaction times, and
the use of expensive Lewis acids, for example, Sc(OTf)3,
are the issues of Ugi-type MCR methods, that need to be
resolved.
found crucial for gaining superior flexibility and efficiency of the
protocol.
Key words: multicomponent reaction, N-heterocycles, catalysis,
zirconium(IV) chloride, microwave
Multicomponent reactions (MCRs)1 offer the elegant per-
formance of multiple reactions into a sequence in one re-
action step without isolating the intermediates, atom-
economy, structural complexity of products (structural
economy), bond-forming efficiency (bond-forming econ-
omy), convergent synthesis, and the feasibility of intro-
ducing maximum chemical diversity elements in one
chemical event. They are being increasingly tailored and
fine tuned for synthesizing various heterocyclic scaffolds
that is particularly useful in the preparation of diverse
chemical libraries of bioactive molecules. The success of
introducing chemical diversity into MCR products lead-
ing to the formation of a library exclusively depends on
the efficiency of the reaction spanning over versatile reac-
tants. Thus, the development of novel multicomponent
process that can be reliable for versatile reactants to pro-
vide the high-yielding synthesis of a wide library of drug-
like products is of high demand, and is continually aug-
mented.2
Herein, we present a microwave-promoted robust and
much reliable multicomponent protocol catalyzed by zir-
conium(IV) chloride (Scheme 1). The protocol proved its
superior flexibility and efficiency for wide versatile reac-
tants including low reactive amidines, and functional and
sterically hindered aldehydes.
N
NH2
R2
NHR3
HetAr
ZrCl4 (10 mol%)
HetAr
N
N
R1
R1
R2 CHO
Nitrogen-fused imidazoles with scaffold versatility in sec-
ond heterocyclic ring have gained immense attention be-
cause of their wide range of pharmaceutical activities,3
such as antibacterial,3d antiviral,3e antifungal3f and anti-
inflammatory3g agents, selective CDK inhibitors,3h
GABA receptor agonists,3i bradykinin B2 receptor antag-
onists,3j and calcium channel blockers.3k These classes of
heterocycles are represented by launched drugs in market
PEG-400
μW, 140 °C, 7 min
72–97%
R3 NC
Scheme 1 Synthesis of versatile N-fused 3-aminoimidazoles
Recently, we have developed a protocol4a of multicompo-
nent synthesis of N-fused imidazoles exploring the effi-
cient catalysis of zirconium(IV) chloride in poly(ethylene
glycol). The method worked well for considerably large
versatile reactants. Considering the aspect of drug-like
properties and the structural significance of the MCR-
products derived from the reaction of 2-aminobenzimida-
SYNTHESIS 2009, No. 19, pp 3293–3300
x
x.
x
x
.
2
0
0
9
Advanced online publication: 23.07.2009
DOI: 10.1055/s-0029-1216916; Art ID: Z08609SS
© Georg Thieme Verlag Stuttgart · New York

3294
S. K. Guchhait et al.
PAPER
zole, which is a much less reactive amidine, we performed flexibility and efficiency of the protocol, as a general pro-
its reaction with 4-chlorobenzaldehyde and tert-butyl iso- cess, for other versatile heterocyclic-2-amidines, alde-
cyanide by our developed process. The reaction was hydes, and isocyanides. The reaction of 2-aminopyridine
found to be slow, and prolonging the reaction for 18 hours with 2-thiophenecarboxaldehyde and cyclohexyl isocya-
produced a mixture of products out of which 23% of the nide was carried out in this microwave-promoted method.
targeted product was isolated. Increasing the reaction tem- Very interestingly, the extraction of the resultant reaction
perature from 50 to 100 °C and screening of other sol- mixture with ethyl acetate, washing with water, and the
vents such as DMSO and t-BuOH did not improve the evaporation of the solvent provided a mixture of only the
reaction. To the best of our knowledge, there is no report product,
N-cyclohexyl-2-(2-thiophenyl)imidazo[1,2-
of use of this amidine in the Ugi-type MCR. The reactions a]pyridin-3-amine and poly(ethylene glycol) as revealed
were then performed following some reported efficient by 1H NMR spectroscopy. The reaction conversion as de-
1
methods, for example, catalysis by perchloric acid4f in termined by H NMR was quantitative, and quantitative
4h
MeOH, Sc(OTf)3 in CH2Cl2–MeOH, and catalysis by 1H NMR calculation showed 99.6% yield. The column
MgCl24c in MeOH under microwave irradiation (160 °C). chromatographic filtration of the reaction mixture on sili-
Although, Sc(OTf)3-catalyzed process improved the yield ca gel afforded the analytically pure product in 97% iso-
of the product (36%) in 48 hours, the other two methods lated yield (Table 2, entry 11).
disfavored the desired MCR, and the formation of many
Table 1 Synthesis of Versatile N-Fused 3-Aminoimidazoles Span-
ning Diverse Heterocyclic Amidines
side reaction products were observed in all the three meth-
ods. In addition, the reaction of 4-formylphenylboronic
acid and 4-formylbenzoic acid, which are important for
NH2
N
ZrCl4 (10 mol%)
tBuNC
follow up chemistry leading to diversity oriented synthe-
sis, when attempted in our described method, exhibited a
low reaction rate, and side products started to form after
15 hours. We then considered developing a robust method
to gain the wider flexibility for these low reactive hetero-
cyclic amidine and functional aldehydes, and additionally
the method could be general to provide a convenient high-
yielding synthesis of a library of versatile N-fused imida-
zoles. As microwave irradiation is continually being
proved as a convenient method of heating to offer en-
hanced chemical activation as revealed in many areas in-
cluding cycloaddition reactions8 we surmised that the
efficient catalysis by zirconium(IV) chloride, as explored
in our earlier developed method,4a in combination with
microwave irradiation could be beneficial.
Ar
HetAr
HetAr
ArCHO
N
N
PEG-400, μW
140 °C, 7 min
NHtBu
Entry
1
Product
Yield (%)a
H
N
N
75b
N
N
N
Cl
NHtBu
N
H
N
2
3
74b
72b
CN
NHtBu
N
H
N
In an initial experiment, the reaction of 2-aminobenzimi-
dazole was carried out with 4-chlorobenzaldehyde and
tert-butyl isocyanide catalyzed by ZrCl4 (10 mol%) in
PEG-400 as solvent under microwave irradiation at
140 °C (Biotage InitiatorTM 60) for 5 minutes. Although,
it afforded the desired MCR product, its complete isola-
tion by both chromatographic purification and crystalliza-
tion was problematic because of its high polarity and
association with PEG. The reaction was then performed in
t-BuOH. To our delight, the direct crystallization of the
product from the reaction mixture without workup and
chromatographic purification afforded N-tert-butyl-2-(4-
chlorophenyl)-1H-imidazo[1,2-a]benzimidazol-3-amine
in 75% yield (Table 1, entry 1). Inspired by the success of
the reaction with 2-aminobenzimidazole, we tested the ef-
ficiency of the protocol for 4-formylphenylboronic acid
and 4-formylbenzoic acid. Gratifyingly, the reaction of
these functional aldehydes with 2-aminopyridine and tert-
butyl isocyanide in PEG-400 provided the desired prod-
ucts in 82 and 92% isolated yield, respectively (Table 2,
entries 1 and 2). Isolation of these products by crystalliza-
tion without workup and chromatographic purification re-
sulted in considerable loss in yields. We then focused on
OCH3
NHtBu
N
Cl
4
5
91
92
N
N
NHtBu
N
Cl
Cl
Cl
Cl
NHtBu
N
6
7
8
92
82
94
N
Cl
NHtBu
N
N
Br
N
NHtBu
N
N
NHtBu
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Flexible and Efficient Synthesis of N-Fused Aminoimidazoles
3295
Table 1 Synthesis of Versatile N-Fused 3-Aminoimidazoles Span-
ning Diverse Heterocyclic Amidines (continued)
Table 2 Synthesis of N-Fused 3-Aminoimidazoles Spanning a
Range of Aldehydes and Isocyanides
NH2
NH2
N
N
ZrCl4 (10 mol%)
ZrCl4 (10 mol%)
CHO
NC
R1
R2
tBuNC
Ar
HetAr
HetAr
ArCHO
R1
N
N
R2
N
N
PEG-400, μW
PEG-400, μW
140 °C, 7 min
140 °C, 7 min
NHtBu
HN
Entry
9
Product
Yield (%)a
Entry Aldehyde
R1
Isocyanide
R2
Yield
(%)a
S
N
Cl
90
1
2
4-HCOC6H4B(OH)2 t-Bu
82
92
88
93
96
89
90
96
95
93
97
91
90
81
88
96
N
N
NHtBu
4-HCOC6H4CO2H
2,4,6-Me3C6H2
t-Bu
S
N
N
3
cyclohexyl
82c
82
Cl
10
11
4
3,4,5-(MeO)3C6H2 cyclohexyl
NHtBu
5
3-MeOC6H4
4-Me2NC6H4
2-BrC6H4
2-naphthyl
2-pyrrolyl
2-furyl
cyclohexyl
cyclohexyl
cyclohexyl
cyclohexyl
cyclohexyl
cyclohexyl
cyclohexyl
cyclohexyl
cyclohexyl
t-Bu
S
N
6
N
Cl
7
NHtBu
EtO2C
8
N
12
88
9
Cl
N
N
H
10
11
12
13
14
15
16
NHtBu
a Isolated yield.
2-thiophenyl
2-pyridyl
ferrocenyl
n-C5H11
b Reaction was performed in t-BuOH at 140 °C for 5 min.
c Reaction was performed at 140 °C for 3 min.
The scope of this process was broad and covers a wide
range of heterocyclic 2-azines, aldehydes, and isocya-
nides affording, in all cases, the products in excellent
yields. Heterocyclic azine includes 2-aminobenzimida-
zole, 2-aminopyridine, 2-aminopyrazine, 2-aminothia-
zole, 2-aminothiadiazole, 2-aminobenzthiazole, and 3-
amino-1H-pyrazole (Table 1). Less reactive amidines like
4-ClC6H4
4-ClC6H4
1,1,3,3-tetramethylbutyl
4-MeOC6H4
a Isolated yield.
aminothiazole and aminothiadiazole were reported4j,5b to tetramethylbutyl group of MCR product by TFA can con-
suffer from a slower reaction and competing reactions vert it into corresponding primary amine product, which
through nucleophilic attack of protic solvent (like MeOH) can be useful for further modification to afford more ver-
and amidine-amine to intermediate Schiff bases. Signifi- satile products.9 Functional groups on aromatic rings of
cantly, the reaction of these amidines (Table 1, entries 9– aldehydes and heterocyclic amidines, such as boronic ac-
11) afforded also excellent yields. The less reactive ami- id, carboxylic acid, ester, methoxy, chloro, bromo, cyano,
dine, 2-aminobenzimidazole, which gave in previous and N,N-dimethyl were unaffected by the reaction condi-
methods maximally 23% yield, provided in this new pro- tions, and it thus opens the avenue for diversity-oriented
cess the corresponding products in 72–75% isolated preparation of larger focused libraries. The MCR product
yields (Table 1, entries 1–3). These MCR products repre- containing a boronic acid is valuable for further modifica-
sent the compounds of significant drug-like properties for tion via the follow up C–C, C–O, and C–N bond forma-
our investigation of targeted bioactivity studies.
tion by carbon–boron bond cross-coupling processes such
as Suzuki, Heck, Sonogashira, and Buchwald–Hartwig
couplings and Petasis MCR. Similarly the MCR product
containing carboxylic acid can lead to a diverse library via
several reactions like Ugi and Passerini reactions.
Aldehydes including electron-rich, electron-poor, steri-
cally hindered and metallocene-derived aromatic, het-
eroaromatic, and aliphatic aldehydes can be used
(Table 2). 4-Formylphenylboronic acid, 4-formylbenzoic
acid, and sterically hindered 2,4,6-trimethylbenzaldehyde This multicomponent reaction proceeds consecutively
(Table 2, entries 1–3), which suffered problems to under- through the formation of imine (or iminium) intermediate
go the reaction in our earlier reported method, proceeded from 2-amidine and aldehyde, its [4+1] cycloaddition
well in the new process. The method was quite general for with the isocyanide, and the prototropic shift resulting in
isocyanides, as investigated with tert-butyl, cyclohexyl, N-fused 3-aminoimidazoles. As observed in our investi-
4-methoxyphenyl, and 1,1,3,3-tetramethylbutyl isocya- gations on the reaction of 2-aminobenimidazole, the re-
nides (Table 2). Significantly, the dealkylation of 1,1,3,3- ported methods of Sc(OTf)3- and HClO4-catalysis, and
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3296
S. K. Guchhait et al.
PAPER
lowing the above-mentioned procedure. The resultant mixture
obtained in each case was diluted with H2O (5 mL), and aq ammo-
nia (10%) was added dropwise till complete precipitation. The solid
was filtered, washed subsequently with ice-cold H2O (3 × 10 mL)
and EtOAc–petroleum ether (bp 60–80 °C) (1:1, 3 × 5 mL), and
dried under air. The complete removal of solvents was done under
vacuum pump.
MgCl2-catalysis under microwave irradiation (160 °C)
failed to provide successfully the corresponding MCR
products for this poorly reactive starting compound. Our
earlier developed process of ZrCl4-catalysis at conven-
tional heating (50 °C) was also found unsuccessful. On
the other hand, the present method involving microwave
irradiation (140 °C) and catalysis by ZrCl4 offered the
success for this poorly reactive 2-aminoazine. These im-
ply that the efficient Lewis acid-catalysis by ZrCl4, be-
cause of its high cationic charge potential (Z2/r is 22.22
e2m–10), in addition to the effect of microwave irradiation
was found crucial to promote the sufficient activation of
low reactive amidines, and functional and sterically hin-
dered aldehydes towards imine formation and subsequent
hetero [4+1] cycloaddition in MCR. This effect results in
a superior flexibility and efficiency of the protocol for
structurally versatile reactants, and provides the MCR-
products in excellent yields. To the best of our knowledge,
there is no report on both conventional and microwave-
promoted heating methods of using these less reactive 2-
aminobenzimidazole, 4-formylphenylboronic acid, 4-
formylbenzoic acid, and 2,4,6-trimethylbenzaldehyde in
Ugi-type multicomponent reactions.
N-tert-Butyl-2-(4-chlorophenyl)-1H-imidazo[1,2-a]benzimida-
zol-3-amine (Table 1, Entry 1)
Light yellow solid; mp 234–236 °C.
IR (KBr): 3309, 2969, 2868, 1629, 1470, 1187, 740 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 1.13 (s, 9 H), 3.58 (br s, 1 H,
NH), 4.68 (br s, 1 H, NH), 7.19 (t, J = 7.5 Hz, 1 H), 7.28 (t, J = 7.5
Hz, 1 H), 7.40–7.47 (m, 3 H), 8.01 (d, J = 7.8 Hz, 1 H), 8.17 (d,
J = 8.4 Hz, 2 H).
13C NMR (100 MHz, DMSO-d6): d = 30.3 (3 CH3), 56.0, 112.5,
119.2, 122.5, 123.1, 125.7, 128.1 (2 CH), 128.7 (2 CH), 129.0,
129.4, 130.52, 130.56, 133.0, 146.3.
MS (MALDI): m/z = 339 (MH+).
Anal. Calcd for C19H19ClN4: C, 67.35; H, 5.65; N, 16.54. Found: C,
67.51; H, 5.78; N, 16.49.
N-tert-Butyl-2-(4-cyanophenyl)-1H-imidazo[1,2-a]benzimida-
zol-3-amine (Table 1, Entry 2)
In conclusion, we have developed a highly efficient pro-
tocol of microwave-promoted multicomponent reaction
catalyzed by zirconium(IV) chloride. The tolerance of the
process towards functional moieties such as boronic acid,
carboxylic acid, ester, halogens, and nitrile offers the
feasibility of follow-up chemistry leading to diversity-
oriented synthesis.
Yellow solid; mp >300 °C.
IR (KBr): 3380, 2968, 2221, 1630, 1469, 1196, 851, 743 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 1.05 (s, 9 H), 7.12 (t, J = 7.6
Hz, 1 H), 7.22 (t, J = 7.6 Hz, 1 H), 7.33 (d, J = 8.0 Hz, 1 H), 7.75
(d, J = 8.0 Hz, 2 H), 7.95 (d, J = 8.0 Hz, 1 H), 8.29 (d, J = 8.0 Hz,
2 H).
13C NMR (100 MHz, DMSO-d6): d = 30.2 (3 CH3), 56.4, 107.8,
112.1, 112.8, 119.5, 119.8, 123.6, 124.3, 125.4, 127.3 (2 CH), 132.1
(2 CH), 133.5, 136.5, 141.2, 146.4.
The starting materials and solvents were used as received from
commercial suppliers without further purification. The 1H and 13
C
MS (MALDI): m/z = 330 (MH+).
spectra were recorded on Bruker Avance III 400 and DPX 300 spec-
trometers using TMS as internal standard. Mass spectra were ana-
lyzed on Finnigan MAT LCQ (ESI) and Bruker Daltonics Ultraflex
(MALDI). The IR spectra were taken on a Perkin-Elmer spectrom-
eter as KBr pellets for solid and neat for liquid samples. Elemental
analyses were done on Elementar Vario EL spectrometer.
Anal. Calcd for C20H19N5: C, 72.93; H, 5.81; N, 21.26. Found: C,
73.07; H, 5.92; N, 21.01.
N-tert-Butyl-2-(4-methoxyphenyl)-1H-imidazo[1,2-a]benzimi-
dazol-3-amine (Table 1, Entry 3)
Yellow solid; mp >300 °C.
IR (KBr): 3313, 2970, 1610, 1511, 1252, 1039, 833, 740 cm–1.
N-tert-Butyl-2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-amine
(Table 1, Entry 4); Typical Procedure
1H NMR (400 MHz, DMSO-d6): d = 1.02 (s, 9 H), 6.91 (d, J = 8.4
Hz, 2 H), 7.05 (t, J = 8.0 Hz, 1 H), 7.16 (t, J = 7.6 Hz, 1 H), 7.33 (d,
J = 8.0 Hz, 1 H), 7.89 (d, J = 7.6 Hz, 1 H), 7.93 (d, J = 8.0 Hz, 2 H).
13C NMR (100 MHz, DMSO-d6): d = 30.3 (3 CH3), 55.4, 55.7,
112.1, 113.2, 113.7 (2 CH), 118.7, 120.9, 122.6, 126.1, 127.7, 128.5
(2 CH), 131.0, 133.5, 146.7, 158.1.
To a mixture of 2-aminopyridine (94 mg, 1 mmol) and 4-chlorobenz-
aldehyde (140 mg, 1 mmol) in PEG-400 (1 mL) in a microwave vial
were added tert-butyl isocyanide (83 mg, 1 mmol) and ZrCl4 (23
mg, 10 mol%). The vessel was sealed with a cap and the mixture
was then irradiated in a monomode microwave synthesizer (Biotage
InitiatorTM 60) at 140 °C for 7 min. After cooling to r.t. in the mi-
crowave cavity, the crude mixture was extracted with EtOAc (60
mL) and the EtOAc layer was washed with H2O (3 × 10 mL). The
organic layer was dried (Na2SO4), filtered, and concentrated under
reduced pressure. The column chromatographic purification of the
crude product over silica gel (mesh size: 60–120) with EtOAc–hex-
ane (1:1.5) as eluent afforded N-tert-butyl-2-(4-chlorophenyl)imi-
dazo[1,2-a]pyridin-3-amine; yield: 273 mg (91%).
MS (MALDI): m/z = 335 (MH+).
Anal. Calcd for C20H22N4O: C, 71.83; H, 6.63; N, 16.75. Found: C,
72.07; H, 6.89; N, 16.59.
N-tert-Butyl-2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-amine
(Table 1, Entry 4)
White solid; mp 146–149 °C.
All reactions in Tables 1 and 2, except the reactions of 2-aminoben-
zimidazole (Table 1, entries 1–3) were carried out following this
procedure.
IR (KBr): 3457, 2972, 1635, 1493, 1194, 770 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.06 (s, 9 H), 6.78 (t, J = 6.8 Hz,
1 H), 7.15 (t, J = 8 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, 2 H), 8.20 (d, J = 6.8 Hz, 1 H).
Reactions of 2-Aminobenzimidazole (Table 1, Entries 1–3)
The reactions of 2-aminobenzimidazole with aldehydes and tert-bu-
tyl isocyanide in t-BuOH (replacing PEG-400) were conducted fol-
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Flexible and Efficient Synthesis of N-Fused Aminoimidazoles
3297
13C NMR (100 MHz, CDCl3): d = 30.3 (3 CH3), 56.4, 111.5, 117.3,
123.3, 123.4, 124.3, 128.4 (2 CH), 129.3 (2 CH), 133.1, 133.7,
138.3, 142.0.
13C NMR (100 MHz, CDCl3): d = 30.4 (3 CH3), 57.0, 116.2, 124.9,
128.6 (2 CH), 128.7, 129.0, 129.4 (2 CH), 131.3, 132.7, 134.1,
137.3, 141.1, 143.4.
MS (ESI): m/z = 300 (MH+).
MS (ESI): m/z = 301 (MH+).
Anal. Calcd for C17H18ClN3: C, 68.11; H, 6.05; N, 14.02. Found: C,
68.45; H, 6.29; N, 13.97.
Anal. Calcd for C16H17ClN4: C, 63.89; H, 5.70; N, 18.63. Found: C,
63.65; H, 5.88; N, 18.36.
N-tert-Butyl-2-(4-chlorophenyl)-8-methylimidazo[1,2-a]pyri-
din-3-amine (Table 1, Entry 5)
Light yellow solid; mp 147–148 °C.
N-tert-Butyl-6-(4-chlorophenyl)imidazo[2,1-b]thiazol-5-amine
(Table 1, Entry 9)
Cream solid; mp 167–168 °C.
IR (KBr): 3406, 2972, 1635, 1493, 757 cm–1.
IR (KBr): 3429, 2959, 1636, 1487, 651 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.03 (s, 9 H), 2.61 (s, 3 H), 3.00
(br s, 1 H, NH), 6.69 (t, J = 6.8 Hz, 1 H), 6.93 (d, J = 6.8 Hz, 1 H),
7.38 (d, J = 6.4 Hz, 2 H), 7.90 (d, J = 6.4 Hz, 2 H), 8.06 (d, J = 6.8
Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 16.5, 30.3 (3 CH3), 56.3, 111.4,
121.2, 123.0, 123.8, 127.1, 128.4 (2 CH), 129.5 (2 CH), 132.9,
134.1, 138.0, 142.4.
1H NMR (400 MHz, CDCl3): d = 1.08 (s, 9 H), 6.74 (d, J = 4.4, 1
H), 7.33–7.36 (m, 3 H), 7.89 (d, J = 6.8 Hz, 2 H).
13C NMR (100 MHz, CDCl3): d = 30.2 (3 CH3), 55.8, 111.7, 117.7,
125.4, 128.3 (2 CH), 128.4 (2 CH), 132.3, 133.7, 139.1, 145.7.
MS (ESI): m/z = 306 (MH+).
Anal. Calcd for C15H16ClN3S: C, 58.91; H, 5.27; N, 13.74; S, 10.48.
Found: C, 59.22; H, 5.20; N, 13.92; S, 10.29.
MS (ESI): m/z = 314 (MH+).
Anal. Calcd for C18H20ClN3: C, 68.89; H, 6.42; N, 13.39. Found: C,
69.17; H, 6.68; N, 13.32.
N-tert-Butyl-6-(4-chlorophenyl)imidazo[2,1-b][1,3,4]thiadiazol-
5-amine (Table 1, Entry 10)
White solid; mp 127–130 °C.
N-tert-Butyl-6-chloro-2-(4-chlorophenyl)imidazo[1,2-a]pyri-
din-3-amine (Table 1, Entry 6)
White solid; mp 192–194 °C.
IR (KBr): 3451, 2970, 1635, 1496, 779 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.05 (s, 9 H), 3.00 (br s, 1 H, NH),
7.11 (d, J = 7.2, 2.4 Hz, 1 H), 7.40 (d, J = 6.8 Hz, 2 H), 7.47 (d,
J = 8.8 Hz, 1 H), 7.86 (d, J = 6.8 Hz, 2 H), 8.23 (s, 1 H).
IR (KBr): 3349, 2960, 1664, 1602, 1493, 797 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 1.06 (s, 9 H), 4.53 (s, 1 H),
7.40 (d, J = 8.4 Hz, 2 H), 8.17 (d, J = 8.4 Hz, 2 H), 9.12 (s, 1 H).
13C NMR (100 MHz, DMSO-d6): d = 30.4 (3 CH3), 55.4, 127.6,
128.3 (2 CH), 128.4 (2 CH), 131.2, 134.4, 137.4, 140.6, 149.3.
MS (ESI): m/z = 307 (MH+).
13C NMR (100 MHz, CDCl3): d = 30.3 (3 CH3), 56.6, 117.8, 120.1,
121.3, 123.9, 125.7, 128.5 (2 CH), 129.3 (2 CH), 133.2, 133.5,
139.5, 140.3.
Anal. Calcd for C14H15ClN4S: C, 54.81; H, 4.93; N, 18.26; S, 10.45.
Found: C, 54.92; H, 5.22; N, 18.14; S, 10.23.
N-tert-Butyl-2-(4-chlorophenyl)imidazo[2,1-b]benzothiazol-3-
amine (Table 1, Entry 11)
MS (ESI): m/z = 334 (MH+).
Anal. Calcd for C17H17Cl2N3: C, 61.09; H, 5.13; N, 12.57. Found:
C, 60.96; H, 5.29; N, 12.62.
Light yellow solid; mp 171–174 °C.
IR (KBr): 3337, 2958, 1673, 1491, 757 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.06 (s, 9 H), 3.01 (br s, 1 H, NH),
7.28–7.32 (m, 1 H), 7.37 (d, J = 6.4 Hz, 2 H), 7.64–7.66 (m, 1 H),
7.65 (d, J = 7.6 Hz, 1 H), 7.74 (d, J = 6.4 Hz, 2 H), 8.30 (d, J = 8.2
Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 29.9 (3 CH3), 56.6, 114.4, 124.0,
124.3, 125.3, 128.2, 128.4 (2CH), 128.9 (2CH), 130.3, 130.7,
132.7, 133.6, 133.7, 140.0, 144.2.
6-Bromo-N-tert-butyl-2-(4-chlorophenyl)imidazo[1,2-a]pyri-
din-3-amine (Table 1, Entry 7)
Greenish yellow solid; mp 174–176 °C.
IR (KBr): 3291, 2966, 2922, 2857, 1488, 1402, 1207, 1093, 835,
797, 765 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.04 (s, 9 H), 7.20 (d, J = 9.6 Hz,
1 H), 7.38–7.43 (m, 3 H), 7.45 (J = 8.4 Hz, 2 H), 8.31 (s, 1 H).
13C NMR (100 MHz, CDCl3): d = 30.3 (3 CH3), 56.6, 106.5, 118.0,
123.6, 127.7, 128.5 (2 CH), 129.3 (2 CH), 133.1, 133.5, 139.3,
140.4.
MS (ESI): m/z = 356 (MH+).
Anal. Calcd for C19H18ClN3S: C, 64.12; H, 5.10; N, 11.81; S, 9.01.
Found: C, 64.31; H, 5.38; N, 11.44; S, 8.62.
MS (ESI): m/z = 378 (MH+).
Ethyl 3-(tert-Butylamino)-2-(4-chlorophenyl)-5H-imidazo[1,2-
b]pyrazole-7-carboxylate (Table 1, Entry 12)
Yellow solid; mp 181–183 °C.
Anal. Calcd for C17H17BrClN3: C, 53.92; H, 4.52; N, 11.10. Found:
C, 54.12; H, 4.68; N, 11.06.
IR (KBr): 3431, 2961, 1623, 1480, 704 cm–1.
N-tert-Butyl-2-(4-chlorophenyl)imidazo[1,2-a]pyrazin-3-amine
(Table 1, Entry 8)
Light yellow solid; mp 150–152 °C.
IR (KBr): 3425, 2972, 1646, 1493, 757 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.07 (s, 9 H), 7.43 (d, J = 6.8 Hz,
2 H), 7.86 (d, J = 4.4 Hz, 1 H), 7.92 (d, J = 6.8 Hz, 2 H), 8.10 (d,
J = 6 Hz, 1 H), 8.99 (s, 1 H).
1H NMR (400 MHz, CDCl3): d = 1.13 (s, 9 H), 1.62 (m, 3 H), 3.00
(br s, 1 H, NH), 7.38 (d, J = 8 Hz, 2 H), 7.76 (d, J = 8 Hz, 2 H), 7.98
(s, 3 H).
13C NMR (100 MHz, CDCl3): d = 14.5, 30.1 (3 CH3), 56.3, 59.8,
91.3, 122.7, 123.1, 127.7 (2 CH), 129.3 (2 CH), 131.9, 133.5, 138.7,
144.0, 163.9.
MS (ESI): m/z = 361 (MH+).
Anal. Calcd for C18H21ClN4O2: C, 59.91; H, 5.87; N, 15.53. Found:
C, 59.75; H, 6.11; N, 15.66.
Synthesis 2009, No. 19, 3293–3300 © Thieme Stuttgart · New York

3298
S. K. Guchhait et al.
PAPER
N-Cyclohexyl-2-(3-methoxyphenyl)imidazo[1,2-a]pyridin-3-
4-(3-(tert-Butylamino)imidazo[1,2-a]pyridin-2-yl)phenylboron-
ic Acid (Table 2, Entry 1)
amine (Table 2, Entry 5)
Yellow solid; mp 188–190 °C.
Light yellow solid; mp 153–155 °C.
IR (KBr): 3567, 3442, 2961, 2868, 1772, 1609, 1017, 751 cm–1.
IR (KBr): 3317, 2928, 2853, 1454, 1260, 1046, 872, 751 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 1.00 (s, 9 H), 4.66 (br s, 1 H,
NH), 6.88 (t, J = 6.6 Hz, 1 H), 7.20 (t, J = 6.9 Hz, 1 H), 7.47 (d,
J = 9.0 Hz, 1 H), 7.82 (d, J = 7.8 Hz, 2 H), 8.01 (s, 2 H, 2 OH), 8.08
(d, J = 7.8 Hz, 2 H), 8.41 (d, J = 6.6 Hz, 1 H).
13C NMR (75 MHz, DMSO-d6): d = 30.4 (3 CH3), 56.1, 111.4,
116.9, 124.5 (2 CH, 1 C), 126.9 (2 CH), 134.1 (2 CH), 137.2, 138.2,
141.3.
1H NMR (400 MHz, CDCl3): d = 1.14–1.45 (m, 5 H), 1.58–1.93 (m,
5 H), 2.94–3.00 (m, 2 H), 3.89 (s, 3 H), 6.78 (t, J = 6.8 Hz, 1 H),
6.88 (d, J = 8.0 Hz, 1 H), 7.13 (t, J = 7.6 Hz, 1 H), 7.35 (t, J = 7.6
Hz, 1 H), 7.54 (d, J = 8.8 Hz, 1 H), 7.60 (d, J = 7.6 Hz, 1 H), 7.64
(s, 1 H), 8.11 (d, J = 6.8 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 24.7 (2 CH2), 25.7, 34.1 (2 CH2),
55.3, 56.9, 111.6, 112.1, 113.6, 117.2, 119.4, 122.7, 123.9, 125.1,
129.4, 135.7, 136.2, 141.4, 159.8.
MS (ESI): m/z = 310 (MH+).
MS (ESI): m/z = 322.2 (MH+).
Anal. Calcd for C17H20BN3O2: C, 66.04; H, 6.52; N, 13.59. Found:
C, 66.21; H, 6.72; N, 13.45.
Anal. Calcd for C20H23N3O: C, 74.74; H, 7.21; N, 13.07. Found: C,
74.89; H, 7.37; N, 12.86.
4-(3-(tert-Butylamino)imidazo[1,2-a]pyridin-2-yl)benzoic Acid
(Table 2, Entry 2)
Yellow solid; mp >300 °C.
N-Cyclohexyl-2-[4-(dimethylamino)phenyl]imidazo[1,2-a]pyri-
din-3-amine (Table 2, Entry 6)
Reddish brown solid; mp 170-171 °C.
IR (KBr): 3306, 2926, 2851, 1613, 1513, 1087, 822, 752, 626 cm–1.
IR (KBr): 3567, 2967, 2868, 1717, 1603, 1412, 1219, 771 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 0.75 (s, 9 H), 7.04 (t, J = 6.8
Hz, 1 H), 7.43 (t, J = 8.0 Hz, 1 H), 7.52 (d, J = 8.8 Hz, 1 H), 7.80 (d,
J = 8.4 Hz, 2 H), 8.01 (d, J = 8.0 Hz, 2 H), 8.48 (d, J = 7.2 Hz, 1 H).
13C NMR (100 MHz, DMSO-d6): d = 30.2 (3 CH3), 56.8, 114.2,
115.1, 125.9, 126.2, 128.4 (2 CH), 129.8 (2 CH), 130.0, 130.3,
130.9, 135.2, 139.2, 167.4.
1H NMR (400 MHz, CDCl3): d = 1.15–1.23 (m, 5 H), 1.58–1.59 (m,
1 H), 1.69–1.71 (m, 2 H), 1.81–1.84 (m, 2 H), 2.99–3.01 (m, 1 H),
3.01 (s, 6 H), 6.77–6.81 (m, 3 H), 7.13 (t, J = 8.0 Hz, 1 H), 7.60 (d,
J = 8.8 Hz, 1 H), 7.95 (d, J = 7.2 Hz, 2 H), 8.14 (d, J = 6.8 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 24.8 (2 CH2), 25.7, 34.1 (2 CH2),
40.4 (2 C), 56.8, 111.2, 112.3 (2 CH), 116.8, 122.5, 123.4, 123.5,
127.8 (2 CH), 134.0, 137.0, 141.3, 149.7.
MS (MALDI): m/z = 310 (MH+).
Anal. Calcd for C18H19N3O2: C, 69.88; H, 6.19; N, 13.58. Found: C,
69.52; H, 6.52; N, 13.79.
MS (ESI): m/z = 335 (MH+).
Anal. Calcd for C21H26N4: C, 75.41; H, 7.84; N, 16.75. Found: C,
75.53; H, 8.11; N, 16.36.
N-Cyclohexyl-2-(2,4,6-trimethylphenyl)imidazo[1,2-a]pyridin-
3-amine (Table 2, Entry 3)
Buff white solid; mp 166–168 °C.
IR (KBr): 3362, 2929, 2857, 1607, 1076, 746 cm–1.
N-Cyclohexyl-2-(2-bromophenyl)imidazo[1,2-a]pyridin-3-
amine (Table 2, Entry 7)
Dark brown solid; mp 140–142 °C.
IR (KBr): 3272, 2928, 2852, 1664, 1505, 1349, 1024, 751 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.98–1.14 (m, 5 H), 1.47–1.72 (m,
5 H), 2.63–2.74 (m, 1 H), 3.29 (br s, 1 H), 6.85 (t, J = 6.8 Hz, 1 H),
7.19 (t, J = 6.8 Hz, 1 H), 7.27 (t, J = 8.0 Hz, 1 H), 7.42 (t, J = 8.8
Hz, 1 H), 7.56–7.68 (m, 3 H), 8.17 (d, J = 6.8 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 24.5 (2 CH2), 25.6, 33.8 (2 CH2),
56.3, 111.8, 117.4, 122.9, 122.9, 124.1, 125.9, 127.4, 129.5, 132.6,
132.77, 135.6, 141.0.
1H NMR (400 MHz, CDCl3): d = 1.01–1.13 (m, 5 H), 1.48–1.53 (m,
1 H), 1.59–1.61 (m, 2 H), 1.68–1.71 (m, 2 H), 2.08 (s, 6 H), 2.33 (s,
3 H), 2.70–2.73 (m, 1 H), 6.79 (t, J = 6.8 Hz, 1 H), 6.92 (s, 2 H),
7.11 (t, J = 6.8 Hz, 1 H), 7.52 (d, J = 8.8 Hz, 1 H), 8.11 (d, J = 6.8
Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 20.1 (2 CH3), 21.2, 24.6 (2 CH2),
25.6, 33.9 (2 CH2), 56.4, 111.1, 117.4, 122.6, 122.7, 125.7, 128.0 (2
CH), 130.2, 136.2, 137.3, 137.5 (2 C), 141.3.
MS (ESI): m/z = 334 (MH+).
MS (MALDI): m/z = 370 (MH+).
Anal. Calcd for C22H27N3: C, 79.24; H, 8.16; N, 12.60. Found: C,
79.52; H, 8.02; N, 12.46.
Anal. Calcd for C19H20BrN3: C, 61.63; H, 5.44; N, 11.35. Found: C,
61.84; H, 5.36; N, 11.63.
N-Cyclohexyl-2-(3,4,5-trimethoxyphenyl)imidazo[1,2-a]pyri-
din-3-amine (Table 2, Entry 4)
Dark orange-brown solid; mp 162–164 °C.
N-Cyclohexyl-2-(naphthalen-2-yl)imidazo[1,2-a]pyridin-3-
amine (Table 2, Entry 8)
White solid; mp 138–140 °C.
IR (KBr): 3306, 2927, 2851, 1630, 1602, 1086, 752 cm–1.
IR (KBr): 3306, 2929, 2853, 1505, 1234, 1127, 1007, 751 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.14–1.29 (m, 5 H), 1.61–1.84 (m,
5 H), 3.03 (m, 2 H), 3.90 (s, 3 H), 3.95 (s, 6 H), 6.77 (t, J = 6.0 Hz,
1 H), 7.12 (t, J = 6.0 Hz, 1 H), 7.40 (s, 2 H), 7.52 (d, J = 9.0 Hz, 1
H), 8.07 (d, J = 6.0 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 25.3 (2 CH2), 26.2, 34.8 (2 CH2),
56.7 (2 CH3), 57.4, 61.4, 104.7 (2CH), 112.1, 117.8, 123.0, 124.4,
124.9, 130.7, 137.0, 137.9, 142.0, 153.8 (2 C).
1H NMR (400 MHz, CDCl3): d = 1.15–1.21 (m, 3 H), 1.25–1.36 (m,
2 H), 1.54–1.56 (m, 1 H), 1.66–1.73 (m, 2 H), 1.83–1.86 (m, 2 H),
2.96–3.03 (m, 1 H), 6.80 (t, J = 6.8 Hz, 1 H), 7.15 (t, J = 8.0 Hz, 1
H), 7.46–7.52 (m, 2 H), 7.62 (d, J = 8.8 Hz, 1 H), 7.83 (m, 1 H), 7.89
(d, J = 8.8 Hz, 1 H), 7.93–7.96 (m, 1 H), 8.15 (d, J = 5.6 Hz, 1 H),
8.23 (d, J = 8.8 Hz, 1 H), 8.57 (s, 1 H).
13C NMR (100 MHz, CDCl3): d = 24.8 (2 CH2), 25.6, 34.1 (2 CH2),
56.9, 112.0, 116.7, 122.8, 124.3, 124.7, 124.9, 125.4, 125.9 (1 CH,
1 C), 126.1, 127.6, 128.0, 128.4, 130.8, 131.0, 132.7, 133.5, 135.5,
141.1.
MS (ESI): m/z = 382 (MH+).
Anal. Calcd for C22H27N3O3: C, 69.27; H, 7.13; N, 11.02. Found: C,
69.41; H, 7.35; N, 11.36.
Synthesis 2009, No. 19, 3293–3300 © Thieme Stuttgart · New York

PAPER
Flexible and Efficient Synthesis of N-Fused Aminoimidazoles
3299
MS (ESI): m/z = 342 (MH+).
7.53 (d, J = 9.2 Hz, 1 H), 7.75 (t, J = 8 Hz, 1 H), 7.98 (d, J = 6.8 Hz,
1 H), 8.17 (d, J = 8 Hz, 1 H), 8.56 (d, J = 4.8 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 24.9 (2 CH2), 25.7, 34.0 (2 CH2),
55.4, 111.6, 117.8, 120.1, 121.0, 123.0, 123.2, 130.1, 131.1, 136.4,
140.7, 148.3, 155.0.
Anal. Calcd for C23H23N3: C, 80.90; H, 6.79; N, 12.31. Found: C,
81.01; H, 6.91; N, 12.08.
N-Cyclohexyl-2-(1H-pyrrol-2-yl)imidazo[1,2-a]pyridin-3-
amine (Table 2, Entry 9)
Greenish black solid; mp 166–167 °C.
IR (KBr): 3391, 2928, 2851, 1607, 1273, 750 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.16–1.39 (m, 5 H), 1.63–1.67 (m,
1 H), 1.73–1.76 (m, 2 H), 1.88–1.91 (m, 2 H), 3.06–3.15 (m, 2 H),
6.33 (q, J = 2.4 Hz, 1 H), 6.61–6.62 (m, 1 H), 6.78 (t, J = 6.8 Hz, 1
H), 6.87–6.88 (m, 1 H), 7.11 (t, J = 6.8 Hz, 1 H), 7.46 (d, J = 9.2 Hz,
1 H), 8.10 (d, J = 6.8 Hz, 1 H), 10.35 (br s, 1 H, NH).
13C NMR (100 MHz, CDCl3): d = 24.8 (2 CH2), 25.7, 34.3 (2 CH2),
56.7, 105.7, 109.5, 111.5, 116.3, 118.1, 122.5, 122.6, 123.8, 126.0,
131.4, 141.4.
MS (MALDI): m/z = 292 (M+).
Anal. Calcd for C18H20N4: C, 73.94; H, 6.89; N, 19.16. Found: C,
73.78; H, 7.21; N, 19.01.
N-Cyclohexyl-2-(ferrocenyl)imidazo[1,2-a]pyridin-3-amine
(Table 2, Entry 13)
Brownish black solid; mp 168–170 °C.
IR (KBr): 3400, 2923, 2857, 1621, 1384, 1259, 1049, 749 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.28–1.37 (m, 5 H), 1.66–1.68 (m,
1 H), 1.78–1.80 (m, 2 H), 1.89–1.92 (m, 2 H), 3.12–3.20 (m, 1 H),
4.10 (s, 5 H), 4.35 (s, 2 H), 4.93 (s, 2 H), 6.74 (t, J = 7.2 Hz, 1 H),
7.09 (t, J = 8.4 Hz, 1 H), 7.51 (d, J = 9.2 Hz, 1 H), 8.08 (d, J = 6.8
Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 25.0 (2 CH2), 25.8, 34.3 (2 CH2),
57.2, 66.8 (2 CH), 68.6 (2 CH), 69.2 (5 CH), 78.9, 111.1, 116.7,
122.3, 123.2, 123.7, 136.2, 141.5.
MS (ESI): m/z = 281 (MH+).
Anal. Calcd for C17H20N4: C, 72.83; H, 7.19; N, 19.98. Found: C,
72.95; H, 7.24; N, 19.81.
N-Cyclohexyl-2-(furan-2-yl)imidazo[1,2-a]pyridin-3-amine
(Table 2, Entry 10)
Creamish-yellow solid; mp 121–122 °C.
MS (ESI): m/z = 400 (MH+).
IR (KBr): 3286, 2930, 2854, 1667, 1536, 1349, 752, 737 cm–1.
N-tert-Butyl-2-pentylimidazo[1,2-a]pyridin-3-amine (Table 2,
Entry 14)
Dark yellow viscous liquid.
IR (neat): 3362, 2925, 2854, 1592, 1464, 751 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.80–0.88 (m, 3 H), 1.12 (s, 9 H),
1.18–1.30 (m, 4 H), 1.69–1.72 (m, 2 H), 2.64 (t, J = 8.1 Hz, 2 H),
6.63 (t, J = 6.6 Hz, 1 H), 6.99 (t, J = 7.8 Hz, 1 H), 7.37 (d, J = 9.0
Hz, 1 H), 8.07 (d, J = 6.9 Hz, 1 H).
1H NMR (400 MHz, CDCl3): d = 1.11–1.41 (m, 5 H), 1.59–1.75 (m,
3 H), 1.88–1.95 (m, 2 H), 2.95–2.99 (m, 1 H), 6.52–6.53 (m, 1 H),
6.78 (t, J = 6.8 Hz, 1 H), 6.88 (d, J = 3.2 Hz, 1 H), 7.12 (t, J = 8.0
Hz, 1 H), 7.48–7.50 (m, 2 H), 8.06 (d, J = 6.8 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 25.0 (2 CH2), 25.7, 34.1 (2 CH2),
57.0, 106.5, 111.5, 111.7, 117.1, 122.8, 124.1, 141.4, 141.7, 142.7,
150.2, 160.3.
MS (ESI): m/z = 282 (MH+).
13C NMR (75 MHz, CDCl3): d = 13.0, 21.5, 26.8, 28.2, 29.3 (3
CH3), 31.1, 54.4, 109.7, 115.5, 122.2, 122.3, 127.7, 129.8, 140.3.
Anal. Calcd for C17H19N3O: C, 72.57; H, 6.81; N, 14.94. Found: C,
72.41; H, 6.98; N, 14.81.
MS (ESI) m/z = 260 (MH+).
Anal. Calcd for C16H25N3: C, 74.09; H, 9.71; N, 16.20. Found: C,
74.01; H, 9.57; N, 16.42.
N-Cyclohexyl-2-(thiophen-2-yl)imidazo[1,2-a]pyridin-3-amine
(Table 2, Entry 11)
Greenish grey solid; mp 165–166 °C.
N-2-(2,4,4-Trimethylpentan-2-yl) 2-(4-chlorophenyl)imida-
zo[1,2-a]pyridin-3-amine (Table 2, Entry 15)
Light yellow solid; mp 200–201 °C.
IR (KBr): 3294, 2927, 2852, 1630, 1579, 1448, 1337, 1084, 751
cm–1.
1H NMR (400 MHz, CDCl3): d = 1.12–1.28 (m, 3 H), 1.30–1.43 (m,
2 H), 1.61–1.66 (m, 1 H), 1.73–1.76 (m, 2 H), 1.87–1.90 (m, 2 H),
3.08–3.14 (m, 2 H), 6.81 (t, J = 6.8 Hz, 1 H), 7.13–7.18 (m, 2 H),
7.34 (d, J = 5.2 Hz, 1 H), 7.57 (d, J = 8.8 Hz, 1 H), 7.67 (d, J = 3.6
Hz, 1 H), 8.12 (d, J = 6.8 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 24.7 (2 CH2), 25.7, 34.2 (2 CH2),
57.0, 111.7, 117.0, 122.7, 123.9, 124.3, 124.6, 127.6, 132.6, 137.0,
141.6 (2 C).
IR (KBr): 3401, 2952, 2873, 1384, 1245, 1050, 754 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.93 (s, 6 H), 0.98 (s, 9 H), 1.58
(s, 2 H), 7.15 (t, J = 6.8 Hz, 1 H), 7.25 (d, J = 8.4 Hz, 2 H), 7.47 (t,
J = 7.6 Hz, 1 H), 7.80 (d, J = 8.8 Hz, 1 H), 8.00 (d, J = 8.4 Hz, 2 H),
8.52 (d, J = 6.8 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 29.2 (2 CH3), 31.7, 31.8 (3 CH3),
57.1, 60.6, 111.5, 117.2, 123.3, 123.5, 124.3, 128.4 (2 CH), 129.6
(2 CH), 133.2, 133.8, 138.6, 142.0.
MS (ESI): m/z = 298 (MH+).
MS (ESI): m/z = 356 (MH+).
Anal. Calcd for C17H19N3S: C, 68.65; H, 6.44; N, 14.13; S; 10.78.
Found: C, 68.78; H, 6.67; N, 14.05; S, 10.50.
Anal. Calcd for C21H26ClN3: C, 70.87; H, 7.36; N, 11.81. Found: C,
71.16; H, 7.62; N, 11.65.
N-Cyclohexyl-2-(pyridin-2-yl)imidazo[1,2-a]pyridin-3-amine
(Table 2, Entry 12)
Greenish grey solid; mp 110–111 °C.
IR (KBr): 3292, 2928, 2852, 1593, 744 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.20–1.43 (m, 5 H), 1.54–1.66 (m,
1 H), 1.71–1.74 (m, 2 H), 1.88–1.96 (m, 2 H), 3.04–3.15 (m, 1 H),
6.27 (br s, 1 H, NH), 6.76 (t, J = 6.8 Hz, 1 H), 7.07–7.15 (m, 2 H),
N-(4-Methoxyphenyl) 2-(4-chlorophenyl)imidazo[1,2-a]pyri-
din-3-amine (Table 2, Entry 16)
Yellowish cream solid; mp 190–191 °C.
IR (KBr): 3233, 2829, 1508, 1235, 1092, 1036, 823, 754, 737 cm–1.
1H NMR (400 MHz, CDCl3): d = 3.75 (s, 3 H), 5.51 (br s, 1 H, NH),
6.54 (d, J = 8.8 Hz, 2 H), 6.78–6.81 (m, 3 H), 7.24 (t, J = 6.8 Hz, 1
H), 7.32 (d, J = 8.8 Hz, 2 H), 7.63 (d, J = 9.2 Hz, 1 H), 7.84 (d,
J = 6.8 Hz, 1 H), 7.96 (d, J = 8.4 Hz, 2 H).
Synthesis 2009, No. 19, 3293–3300 © Thieme Stuttgart · New York

3300
S. K. Guchhait et al.
PAPER
13C NMR (100 MHz, CDCl3): d = 112.4, 114.4 (2 CH), 115.3 (2
CH), 116.2, 117.5, 118.9, 122.8, 125.4, 128.4 (2 CH), 128.7 (2 CH),
131.7, 133.7, 138.0, 142.5, 153.7.
Cook, S. M.; Pike, A.; Brown, N.; Wafford, K. A.; Marshall,
G.; Castro, J. L.; Atack, J. R. J. Med. Chem. 2006, 49, 35.
(j) Abe, Y.; Kayakiri, H.; Satoh, S.; Inoue, T.; Sawada, Y.;
Imai, K.; Inamura, N.; Asano, M.; Hatori, C.; Katayama, A.;
Oku, T.; Tanaka, H. J. Med. Chem. 1998, 41, 564.
(k) Sanfilippo, P. J.; Urbanski, M.; Press, J. B.; Dubinsky,
B.; Moore, J. B. J. Med. Chem. 1988, 31, 2221.
(4) (a) Guchhait, S. K.; Madaan, C. Synlett 2009, 628.
(b) Krasavin, M.; Tsirulnikov, S.; Nikulnikov, M.;
Volodymyr, K.; Ivachtchenko, A. Tetrahedron Lett. 2008,
49, 5241. (c) Adib, M.; Sheibani, E.; Zhu, L.-G.; Mirzaei, P.
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Kennedy, J. M. J. Org. Chem. 2007, 72, 1013.
MS (ESI): m/z = 350 (MH+).
Anal. Calcd for C20H16ClN3O: C, 68.67; H, 4.61; N, 12.01. Found:
C, 68.83; H, 4.92; N, 11.78.
Acknowledgment
We gratefully acknowledge financial support from DST, New Delhi
for this investigation.
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Synthesis 2009, No. 19, 3293–3300 © Thieme Stuttgart · New York