A facile construction of 6-(arylmethyl)imidazo[1,2-a]pyrimidin-7-ylamines from allylamines derived from Baylis-Hillman adducts

Article abstract of DOI:10.1002/ejoc.200800448

A facile and convenient synthesis of substituted imidazo[1,2-a]pyrimidin-7- ylamines from the allylamine derivatives afforded by the Baylis-Hillman acetates of substituted benzaldehydes and heterocyclic aldehydes by treatment with cyanamide is described. Interestingly, the allylamines afforded by heterocyclic aldehydes, which undergo fast Baylis-Hillman reaction, were discovered to undergo a one-pot reaction, whereas allylamines derived from all other aldehydes reacted by a two-step procedure. Wiley-VCH Verlag GmbH & Co. KGaA, 2008.

Full text of DOI:10.1002/ejoc.200800448

FULL PAPER
DOI: 10.1002/ejoc.200800448
A Facile Construction of 6-(Arylmethyl)imidazo[1,2-a]pyrimidin-7-ylamines
from Allylamines Derived from Baylis–Hillman Adducts[‡]
Somnath Nag,[a] Amita Mishra,[a] and Sanjay Batra*[a]
Keywords: Baylis–Hillman reactions / Allylic compounds / Amines / Heterocycles
A facile and convenient synthesis of substituted imidazo[1,2-
a]pyrimidin-7-ylamines from the allylamine derivatives af-
forded by the Baylis–Hillman acetates of substituted benzal-
dehydes and heterocyclic aldehydes by treatment with cyan-
amide is described. Interestingly, the allylamines afforded by
heterocyclic aldehydes, which undergo fast Baylis–Hillman
reaction, were discovered to undergo a one-pot reaction,
whereas allylamines derived from all other aldehydes re-
acted by a two-step procedure.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
envisaged the synthesis of imidazo[1,2-a]pyrimidin-7-yl-
amines from appropriately substituted allylamines afforded
from the adducts of different aldehydes and acrylonitrile.
Indeed our approach was inspired by literature reports in
which the synthesis of imidazole was achieved from the re-
action between imidates and α-amino acetals.[11] The retro-
synthetic analysis delineated in Figure 2 explains our strat-
egy. Cleavage of the pyrimidine ring of imidazo[1,2-a]-
pyrimidin-7-ylamine IV gives the 1-substituted-2-amino-
imidazole III. This aminoimidazole in turn could be readily
generated from the allylamine I by reaction with cyanamide
by the initial formation of the intermediate II. The starting
secondary allylamine in turn could readily be synthesized
from the SN2Ј displacement reaction between 2,2-dimeth-
oxyethylamine (aminoacetaldehyde dimethyl acetal) and the
acetate afforded by the Baylis–Hillman adduct of acrylo-
nitrile.
Introduction
Pyrimidine-fused systems are of immense significance in
medicinal chemistry owing to their wide range of biological
activities.[1] From the broad spectrum of pyrimidine-annu-
lated heterocycles, imidazo[1,2-a]pyrimidine has been an at-
tractive target for synthetic chemists, because compounds
related to this scaffold are ligands for GABAA receptors,[2]
benzodiazepine receptor agonists,[3] COX-2 inhibitors[4] and
anticancer,[5] antimicrobial,[6] antibacterial[7] and antifun-
gal[8] agents. Imidazo[1,2-a]pyrimidine also forms the core
unit of the drug Divaplon (Figure 1).[9]
Figure 1. Structure of Divaplon.
The synthetic application of Baylis–Hillman derivatives
for achieving diverse molecular frameworks have been a
progressive feature of synthetic organic chemistry during
the past decade.[10] In particular, highly substituted allyl-
amines afforded by Baylis–Hillman chemistry are excellent
starting substrates for the construction of a variety of nitro-
gen-containing heterocyclic and fused heterocyclic sys-
tems.[10a] As a part of our continuing interest in the synthe-
sis of heterocycles employing Baylis–Hillman chemistry, we
Figure 2. Retrosynthetic analysis for the synthesis of imidazo[1,2-
a]pyrimidin-7-ylamine.
A study of the literature revealed that despite several ele-
gant strategies[12] being known for the synthesis of imid-
azo[1,2-a]pyrimidines bearing various substituents at dif-
ferent positions of the ring the procedure we envisioned was
a novel method. Notably, however, the CNS activity of
imidazo[1,2-a]pyrimidin-7-ylamines has been reported pre-
viously.[13] Nevertheless, we continued with our efforts in
[‡] CDRI Communication No. 7515.
[a] Medicinal and Process Chemistry Division, Central Drug
Research Institute,
P. O. Box 173, Lucknow 226001, India
Fax: +91-522-2623405, -2623938
E-mail: batra_san@yahoo.co.uk
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
4334
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 4334–4343

Imidazopyrimidinylamines from Allylamines
this field, and during the course of the study we discovered tified by the presence of a characteristic blue fluorescent
that the allylamines synthesized from the Baylis–Hillman spot during TLC analysis. Encouraged by this result we
adducts of simple benzaldehydes provided the final com- subjected amines 2b–k to a similar sequence to obtain 4b–
pounds in two steps, whereas the allylamines derived from k in good yields (Table 1). However, the product 3d gener-
the adducts of heterocyclic aldehydes undergoing fast ated from 1d failed to produce the corresponding imid-
Baylis–Hillman reaction afforded the title compounds in a azo[1,2-a]pyrimidin-7-ylamine 4d, instead giving a mixture
one-pot reaction. The successful results of this work are of inseparable products (Table 1, Entry 4). In order to con-
reported herein.
firm the presence of the free amino group in the product, a
representative compound, 4b, was treated with acetic anhy-
dride in the presence of pyridine. The reaction was complete
in 3 h, affording the anticipated acetylated derivative 5b.
Results and Discussion
In our initial investigations we found that the Baylis–
Hillman acetate 1a reacted with 3.0 equiv. of 2,2-dimethoxy-
ethylamine in methanol to yield the desired allylamine 2a
in 87% yield. The use of 3.0 equiv. of amine was actually
guided by our earlier observation that 1.0 equiv. of primary
amine during SN2Ј reactions generally leads to a mixture
of secondary and tertiary allylamines.[14] Under optimized
conditions, compound 2a was first treated with cyanamide
in aqueous acetic acid under heating at 90–100 °C for 2 h
followed by HCl and further heating for 5 min (Scheme 1).
The reaction mixture was cooled, diluted with water and
neutralized with sodium hydrogen carbonate. Workup and
subsequent purification of the crude mixture by column
chromatography led to the isolation of the product in good
yield. The isolated product was identified spectroscopically
as 3a instead of the anticipated product 4a. This implied
Table 1. Yields of compounds 2–4 synthesized from substituted
benzaldehydes.
Entry Compd. no.
R
Yield [%]
2
3
4
1
2
3
4
5
6
7
8
9
a
b
c
d
e
f
g
h
i
C6H5
2-Cl-C6H4
2-F-C6H4
2-O2N-C6H4
4-Cl-C6H4
4-F-C6H4
4-Me-C6H4
4-MeO-C6H4
2,4-Cl2-C6H3
2,6-Cl2-C6H3
3,4-(MeO)2-C6H3
87
95
89
93
92
89
87
94
86
91
92
65
69
67
60
67
68
74
69
66
70
71
72
78
70
–
69
76
83
73
71
74
68
10
11
j
k
With the objective of broadening the scope of our strat-
that the second nucleophilic attack of the amino group at egy, in the next stage of the study we investigated similar
the 2-position of the imidazole on the nitrile group of the reactions with substrates 1l–v generated from the Baylis–
intended cascade sequence did not take place under our ex- Hillman adducts of several heterocyclic aldehydes, includ-
perimental conditions. As a result we extended the time of ing 2-thiophenecarbaldehyde, 2-furancarbaldehyde, substi-
treatment with HCl beyond 5 min, monitoring the reaction tuted 5-, 4- and 3-isoxazolecarbaldehydes and substituted
for 24 h, but no change in the formation of the product was 3-pyrazolecarbaldehyde. Allylamines 2l and 2m derived
observed. With the knowledge that the desired cyclization from 2-thiophenecarbaldehyde and 2-furancarbaldehyde,
reaction between the amino and the nitrile group followed respectively, undergo a similar series of reactions to furnish
by isomerization of the benzylidene double bond from an 4l and 4m in good yields (Table 2). Intriguingly, however,
exocyclic to an endocyclic position can also be affected in when the allylamine 2n generated from the Baylis–Hillman
the presence of base,[15] we evaluated different bases to find acetate 1n derived from 3-phenyl-5-isoxazolecarbaldehyde
out if the desired cyclization was achievable. We were was treated with cyanamide in the presence of acetic acid
pleased to observe that the reaction of 3a with sodium followed by treatment with HCl for 5 min, it resulted in a
methoxide in methanol at reflux for 1 h smoothly furnished product that during TLC analysis was observed to be a mix-
the required product 6-benzylimidazo[1,2-a]pyrimidin-7-yl- ture of two compounds. One of the spots, corresponding to
amine (4a) in 76% yield. The formation of 4a was conclu- the more polar fraction, showed an intense blue fluorescent
sively confirmed from the IR spectrum, which displayed the colour on TLC similar to the ones observed for 4a–l. As a
loss of the signal arising from the nitrile group. Notably, it result of this observation the reaction mixture with HCl was
was discovered that the product 4a could be readily iden- heated further. It was gratifying to note that the reaction
Scheme 1. Reagents and conditions: (i) 2,2-dimethoxyethylamine, MeOH, room temp., 1 h; (ii) (1) NH2CN, AcOH/H2O, 90–100 °C, 2 h,
(2) HCl (conc.), 90–100 °C, 5 min; (iii) NaOMe, MeOH, room temp., 1 h; (iv) Ac2O, pyridine, room temp., 3 h; (v) (1) NH2CN, AcOH/
H2O (1:1, v/v), 90–100 °C, 2 h, (2) HCl (conc.), 90–100 °C, 30 min (one-pot).
Eur. J. Org. Chem. 2008, 4334–4343
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4335

S. Nag, A. Mishra, S. Batra
FULL PAPER
was complete in 30 min, furnishing a pure product in 79% the final product in one pot. Hence the reaction of allyl-
yield that showed an intense blue fluorescent spot. A care- amine 2v with cyanamide in the presence of acetic acid fol-
ful spectral analysis identified the isolated product as the lowed by treatment with HCl was performed. As antici-
required compound 4n.
pated, this reaction resulted in the formation of 4v in one
pot, albeit in only 48% yield (Table 2, Entry 11). Conse-
quently, we re-examined the reactions of 2l, 2m and 2u by
conducting the reactions for a longer period of time (ca.
24 h), but no change in the outcome was observed. The
product from 2m even decomposed upon prolonged heat-
ing.
Table 2. Yields of compounds 2–4 synthesized from heterocyclic
aldehydes.
Entry Compd. no.
R
Yield [%]
2
3
4
1
2
3
l
m
n
2-thienyl
2-furyl
89 61
90 68
71
67
79
76
3-phenylisoxazol-5-yl
88
87
–
–
4
5
6
7
o
p
3-(2-chlorophenyl)isoxazol-5-yl
3-(4-fluorophenyl)isoxazol-5-yl
3-(4-methylphenyl)isoxazol-5-yl
3-(4-benzyloxyphenyl)isoxazol-5-yl 91‘
3-(2,4-dichlorophenyl)isoxazol-5-yl 94
Conclusions
91 82[a] 80[b]
q
89 79[a] 73[b]
r[c]
s
–
–
–
62
72
68
73
48
We have disclosed a facile and general strategy for
accessing 6-arylmethylimidazo[1,2-a]pyrimidin-7-ylamines
from allylamines afforded by the Baylis–Hillman acetates.
The title compounds were formed by a one-pot procedure
from heterocyclic aldehydes, which undergo fast Baylis–
Hillman reactions, whereas all other aldehydes reacted by a
two-pot procedure. This synthetic methodology for ob-
taining the imidazo[1,2-a]pyrimidine scaffold is attractive as
it involves the use of common reagents and simple reaction
conditions.
8
9
10
11
t
u
v
5-phenylisoxazol-3-yl
5-methyl-3-phenylisoxazol-4-yl
1,5-diphenyl-1H-pyrazol-3-yl
88
87 69
83
–
[a] Yield of product obtained after stopping the reaction within
5 min. [b] Yield obtained by one-pot procedure. [c] The benzyloxy
group was debenzylated to the hydroxy group during the treatment
with acid.
This encouraged us to examine the versatility of the one-
pot reaction for other analogues (2o–s) obtained from
several 3-substituted phenyl-5-isoxazolecarbaldehydes. We
were pleased to observe that the reactions of these allyl-
amines (2o–s) with cyanamide furnished the final products
4o–s in 62–80% yields through a two-step operation in one
pot. It was observed that during the acid treatment of al-
lylamine 2r, debenzylation occurred to afford the product
4r (Table 2, Entry 7). At the same time, to ascertain that
the reaction proceeded by the initial formation of the 2-
aminoimidazole derivative, for two of the substrates 2p and
2q the reaction was terminated within 2 min of HCl treat-
ment. Suitable workup and isolation yielded the products
3p and 3q, respectively. This encouraged us to investigate
similar reactions of allylamines derived from the acetates of
the Baylis–Hillman adducts of substituted 3-isoxazolecar-
baldehyde and substituted 4-isoxazolecarbaldehyde. Hence,
as representative examples, the allylamines 2t and 2u were
prepared from the corresponding acetates 1t and 1u. Inter-
Experimental Section
General: Melting points are uncorrected and were determined in
capillary tubes with an apparatus containing silicon oil. IR spectra
were recorded by using a Perkin-Elmer Spectrum RX I FTIR spec-
trometer. 1H and 13C NMR spectra were recorded either with a
Bruker DPX-200 FT or Avance DRX-300 spectrometer by using
TMS as the internal standard (chemical shifts given in δ). ES-MS
and FAB-MS data were recorded with MICROMASS Quadro-II
LCMS and JEOL SX/102/DA 6000 spectrometers, respectively.
HRMS data were recorded as EI-HRMS data with a JEOL system
or as DART-HRMS data (recorded as ES+) with a JEOL-Accu-
TOF JMS-T100LC mass spectrometer having a DART (direct
analysis in real time) source. Elemental analyses were performed
with a Carlo Erba 108 or an Elementar Vario EL III microanalyzer.
General Procedure for the Synthesis of Allylamines 2 as Exemplified
for 2a: Acetate 1a (2.00 g, 9.95 mmol) dissolved in methanol
estingly, the allylamine 2t upon treatment with cyanamide (150 mL) was added dropwise to a solution of 2,2-dimethoxyethyl-
amine (aminoacetaldehyde dimethyl acetal) (3.25 mL, 30.02 mmol)
in methanol (20 mL), at room temperature with constant stirring.
The reaction was allowed to continue for 1 h, after which the sol-
vent was removed under reduced pressure. The crude product ob-
tained in this fashion was purified by column chromatography on
silica gel by using hexanes/ethyl acetate (5:1, v/v) to yield the pure
product 2a (2.13 g, 87%) as a yellow oil.
under acidic conditions furnished the product 4t in one pot
in 68% yield. In contrast, the allylamine 2u derived from
the acetate 1u exclusively yielded the corresponding 2-ami-
nopyrazole 3u. Reaction of 3u with sodium methoxide un-
der reflux, however, provided the desired product 4u in 73%
yield. This demonstrated that the allylamines generated
from the heterocyclic aldehydes,[16] which undergo fast
Baylis–Hillman reactions, produce the title compounds in
one pot. However, this unusual observation cannot be ex-
plained at the present time. We recently reported that 1,5-
diaryl-substituted 3-pyrazolecarbaldehyde is also a fast-re-
acting electrophile for the Baylis–Hillman reaction like 3-
and 5-isoxazolecarbaldehydes.[17] Therefore, it was expected
that the allylamine 2v derived from the acetate 1v would
2-{[(2,2-Dimethoxyethyl)amino]methyl}-3-phenylprop-2-enenitrile
(2a): IR (neat): ν
= 2214 (CN), 3355 (NH) cm–1 1H NMR
.
˜
max
(CDCl3, 300 MHz): δ = 2.80 (d, J = 5.4 Hz, 2 H, CH2), 3.42 (s, 6
H, 2ϫOCH3), 3.62 (d, J = 1.1 Hz, 2 H, CH2), 4.52 (t, J = 5.4 Hz,
1 H, CH), 7.12 (s, 1 H, =CH), 7.42–7.45 (m, 3 H, ArH), 7.76–7.79
(m, 2 H, ArH) ppm. 13C NMR (CDCl3, 75 MHz): δ = 49.7, 53.6,
54.1, 103.9, 110.2, 118.4, 128.7, 128.8, 128.9, 130.3, 144.1 ppm. MS
(ES+): m/z = 247.0 [M + 1]+. C14H18N2O2 (246.1368): calcd. C
also undergo the acid-mediated cascade cyclization to yield 68.27, H 7.37, N 11.37; found C 68.45, H 7.58, N 11.25.
4336 Eur. J. Org. Chem. 2008, 4334–4343
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Imidazopyrimidinylamines from Allylamines
3-(2-Chlorophenyl)-2-{[(2,2-dimethoxyethyl)amino]methyl}prop-2-
75 MHz): δ = 21.5, 49.7, 53.7, 54.1, 103.9, 108.9, 118.6, 128.9,
129.6, 130.6, 140.8, 144.1 ppm. MS (ES+): m/z = 260.9 [M + 1]+,
229.0 [M – 31]+. C15H20N2O2 (260.1525): calcd. C 69.20, H 7.74,
enenitrile (2b): Hexanes/ethyl acetate (5:1); yellow oil (2.27 g from
1
2.00 g). IR (neat): ν
= 2216 (CN), 3349 (NH) cm–1. H NMR
˜
max
(CDCl3, 300 MHz): δ = 2.81 (d, J = 5.3 Hz, 2 H, CH2), 3.42 (s, 6 N 10.76; found C 68.97, H 8.06, N 10.53.
H, 2ϫOCH3), 3.65 (d, J = 1.2 Hz, 2 H, CH2), 4.51 (t, J = 5.4 Hz,
2-{[(2,2-Dimethoxyethyl)amino]methyl}-3-(4-methoxyphenyl)prop-2-
1 H, CH), 7.33–7.36 (m, 2 H, ArH), 7.42–7.48 (m, 2 H, ArH and
=CH), 7.96–7.99 (m, 1 H, ArH) ppm. 13C NMR (CDCl3, 75 MHz):
δ = 49.6, 53.2, 54.1, 103.8, 113.8, 117.6, 127.1, 129.2, 129.7, 131.0,
131.8, 134.0, 140.5 ppm. MS (ES+): m/z = 280.9 [M + 1]+, 249.1
[M – 31]+. C14H17ClN2O2 (280.0979): calcd. C 59.89, H 6.10, N
9.98; found C 59.84, H 6.22, N 10.09.
enenitrile (2h): Hexanes/ethyl acetate (4:1); yellow oil (2.13 g from
1
1.90 g). IR (neat): ν
= 2209 (CN), 3434 (NH) cm–1. H NMR
˜
max
(CDCl3, 300 MHz): δ = 2.77 (d, J = 5.4 Hz, 2 H, CH2), 3.40 (s, 6
H, 2ϫOCH3), 3.56 (d, J = 0.7 Hz, 2 H, CH2), 3.84 (s, 3 H, OCH3),
4.49 (t, J = 5.4 Hz, 1 H, CH), 6.93 (d, J = 8.9 Hz, 2 H, ArH), 7.01
(s, 1 H, =CH), 7.74 (d, J = 8.8 Hz, 2 H, ArH) ppm. 13C NMR
(CDCl3, 75 MHz): δ = 49.6, 53.7, 54.0, 55.3, 103.8, 107.0, 114.2,
118.9, 126.0, 130.6, 143.7, 161.1 ppm. MS (ES+): m/z = 276.9 [M
+ 1]+, 245.0 [M – 31]+. C15H20N2O3 (276.1474): calcd. C 65.20, H
7.30, N 10.14; found C 65.01, H 7.67, N 10.25.
2-{[(2,2-Dimethoxyethyl)amino]methyl}-3-(2-fluorophenyl)prop-2-
enenitrile (2c): Hexanes/ethyl acetate (5:1); yellow oil (2.15 g from
1
2.00 g); IR (neat): ν
= 2215 (CN), 3346 (NH) cm–1. H NMR
˜
max
(CDCl3, 300 MHz): δ = 2.79 (d, J = 5.3 Hz, 2 H, CH2), 3.41 (s, 6
H, 2ϫOCH3), 3.63 (s, 2 H, CH2), 4.49 (t, J = 5.3 Hz, 1 H, CH),
7.10 (t, J = 9.3 Hz, 1 H, ArH), 7.22 (t, J = 7.6 Hz, 1 H, ArH),
7.36–7.43 (m, 2 H, ArH and =CH), 8.11 (t, J = 7.6 Hz, 1 H, ArH)
ppm. 13C NMR (CDCl3, 75 MHz): δ = 49.7, 53.5, 54.1, 103.9,
112.7, 115.5, 115.8, 117.9, 121.4, 121.6, 124.5, 128.4, 131.9, 132.0,
135.6, 135.7, 158.7, 162.1 ppm. MS (ES+): m/z = 264.9 [M + 1]+,
233.1 [M – 31]+. C14H17FN2O2 (264.1274): calcd. C 63.62, H 6.48,
N 10.60; found C 63.39, H 6.66, N 10.71.
3-(2,4-Dichlorophenyl)-2-{[(2,2-dimethoxyethyl)amino]methyl}prop-
2-enenitrile (2i): Hexanes/ethyl acetate (7:1); yellow oil (2.01 g from
1
2.00 g). IR (neat): ν
= 2217 (CN), 3432 (NH) cm–1. H NMR
˜
max
(CDCl3, 300 MHz): δ = 2.80 (d, J = 5.3 Hz, 2 H, CH2), 3.42 (s, 6
H, 2ϫOCH3), 3.64 (s, 2 H, CH2), 4.50 (t, J = 5.3 Hz, 1 H, CH),
7.29–7.35 (m, 1 H, ArH), 7.41 (s, 1 H, =CH), 7.46 (d, J = 1.7 Hz,
1 H, ArH), 7.93 (d, J = 8.4 Hz, 1 H, ArH) ppm. 13C NMR (CDCl3,
75 MHz): δ = 49.6, 53.1, 54.0, 54.1, 103.8, 114.4, 117.4, 127.5,
129.6, 129.8, 134.7, 136.3, 139.1, 141.5 ppm. MS (ES+): m/z =
314.9 [M + 1]+, 283.1 [M – 31]+. C14H16Cl2N2O2 (314.0589): calcd.
C 53.35, H 5.12, N 8.89; found C 53.26, H 5.38, N 8.68.
2-{[(2,2-Dimethoxyethyl)amino]methyl}-3-(2-nitrophenyl)prop-2-
enenitrile (2d): Hexanes/ethyl acetate (5:1); yellow oil (2.04 g from
1
1.85 g). IR (neat): ν
= 2221 (CN), 3434 (NH) cm–1. H NMR
˜
max
(CDCl3, 300 MHz): δ = 2.86 (d, J = 5.3 Hz, 2 H, CH2), 3.44 (s, 6
H, 2ϫOCH3), 3.68 (d, J = 1.4 Hz, 2 H, CH2), 4.51 (t, J = 5.3 Hz,
1 H, CH), 7.58–7.66 (m, 2 H, ArH and =CH), 7.72–7.83 (m, 2 H,
ArH), 8.19–8.21 (dd, J1 = 1.0, J2 = 8.2 Hz, 1 H, ArH) ppm. 13C
NMR (CDCl3, 75 MHz): δ = 49.8, 52.6, 54.2, 103.9, 115.6, 117.1,
125.1, 129.9, 130.5, 130.9, 134.1, 141.1, 147.2 ppm. MS (ES+): m/z
= 292.0 [M + 1]+. C14H17N3O4 (291.1219): calcd. C 57.72, H 5.88,
N 14.42; found C 57.91, H 6.03, N 14.31.
3-(2,6-Dichlorophenyl)-2-{[(2,2-dimethoxyethyl)amino]methyl}prop-
2-enenitrile (2j): Hexanes/ethyl acetate (7:1); yellow oil (2.23 g from
1
2.10 g). IR (neat): ν
= 2223 (CN), 3432 (NH) cm–1. H NMR
˜
max
(CDCl3, 300 MHz): δ = 2.84 (d, J = 5.3 Hz, 2 H, CH2), 3.41 (s, 6
H, 2ϫOCH3), 3.67 (d, J = 1.2 Hz, 2 H, CH2), 4.50 (t, J = 5.3 Hz,
1 H, CH), 7.11 (s, 1 H, =CH), 7.25–7.28 (m, 1 H, ArH), 7.38 (d, J
= 8.2 Hz, 2 H, ArH) ppm. 13C NMR (CDCl3, 75 MHz): δ = 49.4,
52.1, 54.0, 103.8, 116.3, 120.5, 128.2, 130.3, 132.1, 134.2,
139.0 ppm. MS (ES+): m/z = 314.9 [M + 1]+, 283.1 [M – 31]+.
C14H16Cl2N2O2 (314.0589): calcd. C 53.35, H 5.12, N 8.89; found
C 53.48, H 5.23, N 8.74.
3-(4-Chlorophenyl)-2-{[(2,2-dimethoxyethyl)amino]methyl}prop-2-
enenitrile (2e): Hexanes/ethyl acetate (5:1); yellow oil (2.30 g from
1
2.00 g). IR (neat): ν
= 2213 (CN), 3429 (NH) cm–1. H NMR
˜
max
(CDCl3, 300 MHz): δ = 2.78 (d, J = 5.3 Hz, 2 H, CH2), 3.41 (s, 6
H, 2ϫOCH3), 3.60 (d, J = 1.0 Hz, 2 H, CH2), 4.49 (t, J = 5.3 Hz,
1 H, CH), 7.07 (s, 1 H, =CH), 7.39 (d, J = 8.6 Hz, 2 H, ArH), 7.70
(d, J = 8.6 Hz, 2 H, ArH) ppm. 13C NMR (CDCl3, 75 MHz): δ
= 49.7, 53.5, 54.1, 103.8, 111.0, 118.1, 129.1, 130.0, 131.7, 136.1,
142.4 ppm. MS (ES+): m/z = 280.9 [M + 1]+, 249.1 [M – 31]+.
C14H17ClN2O2 (280.0979): calcd. C 59.89, H 6.10, N 9.98; found
C 59.62, H 6.41, N 9.76.
2-{[(2,2-Dimethoxyethyl)amino]methyl}-3-(3,4-dimethoxyphenyl)-
prop-2-enenitrile (2k): Hexanes/ethyl acetate (4:1); a white solid
(2.16 g from 2.00 g), m.p. 80–81 °C. IR (KBr): ν
= 2210 (CN),
˜
max
3370 (NH) cm–1. 1H NMR (CDCl3, 300 MHz): δ = 2.78 (d, J =
5.3 Hz, 2 H, CH2), 3.40 (s, 6 H, 2ϫOCH3), 3.58 (s, 2 H, CH2),
3.92 (s, 3 H, OCH3), 3.93 (s, 3 H, OCH3), 4.49 (t, J = 5.3 Hz, 1 H,
CH), 6.88 (d, J = 8.3 Hz, 1 H, ArH), 7.01 (s, 1 H, =CH), 7.21–
7.23 (dd, J1 = 1.8, J2 = 8.3 Hz, 1 H, ArH), 7.57 (d, J = 1.7 Hz, 1
H, ArH) ppm. 13C NMR (CDCl3, 75 MHz): δ = 49.6, 53.7, 54.1,
54.3, 55.9, 103.8, 107.1, 110.5, 110.8, 119.0, 123.5, 126.2, 144.0,
149.0, 150.9 ppm. MS (ES+): m/z = 306.9 [M + 1]+. C16H22N2O4
(306.1580): calcd. C 62.73, H 7.24, N 9.14; found C 62.59, H 7.48,
N 9.35.
2-{[(2,2-Dimethoxyethyl)amino]methyl}-3-(4-fluorophenyl)prop-2-
enenitrile (2f): Hexanes/ethyl acetate (5:1); yellow oil (2.15 g from
1
2.00 g). IR (neat): ν
= 2213 (CN), 3346 (NH) cm–1. H NMR
˜
max
(CDCl3, 300 MHz): δ = 2.78 (d, J = 5.4 Hz, 2 H, CH2), 3.41 (s, 6
H, 2ϫOCH3), 3.60 (s, 2 H, CH2), 4.49 (t, J = 5.3 Hz, 1 H, CH),
7.08–7.14 (m, 3 H, ArH and =CH), 7.75–7.79 (m, 2 H, ArH) ppm.
13C NMR (CDCl3, 75 MHz): δ = 49.7, 53.5, 54.1, 103.8, 110.0,
115.8, 116.1, 118.2, 129.5, 130.8, 130.9, 142.6, 161.9, 165.2 ppm.
MS (ES+): m/z = 264.9 [M + 1]+. C14H17FN2O2 (264.1274): calcd.
C 63.62, H 6.48, N 10.60; found C 63.56, H 6.75, N 10.46.
2-{[(2,2-Dimethoxyethyl)amino]methyl}-3-(2-thienyl)prop-2-ene-
nitrile (2l): Hexanes/ethyl acetate (5:1); yellow oil (2.34 g from
1
2.16 g); IR (neat): ν
= 2208 (CN), 3346 (NH) cm–1. H NMR
˜
max
(CDCl3, 300 MHz): δ = 2.77 (d, J = 5.3 Hz, 2 H, CH2), 3.40 (s, 6
H, 2ϫOCH3), 3.57 (d, J = 0.57 Hz, 2 H, CH2), 4.48 (t, J = 5.3 Hz,
1 H, CH), 7.08–7.11 (m, 1 H, ArH), 7.23 (s, 1 H, =CH), 7.47 (d, J
= 5.0 Hz, 1 H, ArH), 7.51 (d, J = 3.5 Hz, 1 H, ArH) ppm. 13C
2-{[(2,2-Dimethoxyethyl)amino]methyl}-3-(4-methylphenyl)prop-2-
enenitrile (2g): Hexanes/ethyl acetate (5:1); yellow oil (2.42 g from
1
2.30 g). IR (neat): ν
= 2212 (CN), 3432 (NH) cm–1. H NMR
˜
max
(CDCl3, 300 MHz): δ = 2.38 (s, 3 H, CH3), 2.77 (d, J = 5.3 Hz, 2 NMR (CDCl3, 75 MHz): δ = 49.7, 52.8, 54.1, 103.8, 107.1, 118.5,
H, CH2), 3.40 (s, 6 H, 2ϫOCH3), 3.58 (s, 2 H, CH2), 4.49 (t, J =
5.4 Hz, 1 H, CH), 7.05 (s, 1 H, =CH), 7.22 (d, J = 8.0 Hz, 2 H,
127.5, 129.2, 131.3, 136.4, 137.2 ppm. MS (ES+): m/z = 253.3 [M
+ 1]+. C12H16N2O2S (252.0932): calcd. C 57.12, H 6.39, N 11.10;
ArH), 7.66 (d, J = 8.1 Hz, 2 H, ArH) ppm. 13C NMR (CDCl3, found C 57.35, H 6.12, N 10.96.
Eur. J. Org. Chem. 2008, 4334–4343
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4337

S. Nag, A. Mishra, S. Batra
FULL PAPER
2-{[(2,2-Dimethoxyethyl)amino]methyl}-3-(2-furyl)prop-2-enenitrile
1628 (C=N), 2220 (CN), 3432 (NH) cm–1
.
1H NMR (CDCl3,
(2m): Hexanes/ethyl acetate (4:1); yellow oil (2.50 g from 2.25 g).
300 MHz): δ = 2.80 (d, J = 5.3 Hz, 2 H, CH2), 3.43 (s, 6 H,
1
IR (neat): ν
= 2212 (CN), 3404 (NH) cm–1. H NMR (CDCl3, 2ϫOCH3), 3.66 (d, J = 0.8 Hz, 2 H, CH2), 4.50 (t, J = 5.2 Hz, 1
˜
max
300 MHz): δ = 2.78 (d, J = 5.3 Hz, 2 H, CH2), 3.42 (s, 6 H,
H, CH), 5.13 (s, 2 H, CH2), 7.08 (d, J = 8.7 Hz, 2 H, ArH), 7.25
2ϫOCH3), 3.57 (d, J = 0.9 Hz, 2 H, CH2), 4.50 (t, J = 5.4 Hz, 1 (s, 1 H, =CH), 7.28 (s, 1 H, ArH), 7.36–7.48 (m, 5 H, ArH), 7.80
H, CH), 6.52–6.54 (m, 1 H, ArH), 6.97–7.04 (m, 2 H, ArH and (d, J = 8.7 Hz, 2 H, ArH) ppm. 13C NMR (CDCl3, 75 MHz): δ =
=CH), 7.55 (d, J = 1.4 Hz, 1 H, ArH) ppm. 13C NMR (CDCl3,
75 MHz): δ = 49.4, 52.4, 54.2, 103.6, 103.6, 105.9, 112.3, 114.4,
118.2, 131.3, 144.5, 149.4 ppm. MS (ES+): m/z = 237.0 [M + 1]+.
C12H16N2O3 (236.1161): calcd. C 61.00, H 6.83, N 11.86; found C
61.19, H 6.98, N 11.76.
49.9, 52.2, 54.2, 70.0, 102.7, 103.8, 113.9, 115.2, 116.0, 116.8, 121.0,
127.0, 127.4, 128.1, 128.3, 128.6, 136.4, 160.4, 162.6, 164.7 ppm.
MS (ES+): m/z = 420.0 [M + 1]+. C24H25N3O4 (419.1845): calcd.
C 68.72, H 6.01, N 10.02; found C 68.98, H 6.37, N 9.87.
3-[3-(2,4-Dichlorophenyl)isoxazol-5-yl]-2-{[(2,2-dimethoxyethyl)-
2-{[(2,2-Dimethoxyethyl)amino]methyl}-3-(3-phenylisoxazol-5-yl)-
amino]methyl}prop-2-enenitrile (2s): Hexanes/ethyl acetate (3:1);
prop-2-enenitrile (2n): Hexanes/ethyl acetate (3:1); a white solid
yellow oil (2.24 g from 2.10 g). IR (neat): νmax = 1649 (C=N), 2220
˜
1
(2.23 g from 2.16 g), m.p. 86–88 °C. IR (KBr): νmax = 1628 (C=N),
(CN), 3415 (NH) cm–1. H NMR (CDCl3, 300 MHz): δ = 2.79 (d,
˜
2220 (CN), 3432 (NH) cm–1. 1H NMR (CDCl3, 300 MHz): δ =
2.80 (d, J = 5.2 Hz, 2 H, CH2), 3.42 (s, 6 H, 2ϫOCH3), 3.66 (d, J
= 1.5 Hz, 2 H, CH2), 4.49 (t, J = 5.2 Hz, 1 H, CH), 7.27 (s, 1 H,
J = 5.2 Hz, 2 H, CH2), 3.42 (s, 6 H, 2ϫOCH3), 3.67 (d, J = 1.2 Hz,
2 H, CH2), 4.48 (t, J = 5.2 Hz, 1 H, CH), 7.29 (d, J = 1.9 Hz, 1 H,
ArH), 7.36–7.38 (dd, J1 = 2.0, J2 = 8.4 Hz, 1 H, ArH), 7.45 (s, 1
=CH), 7.33 (s, 1 H, ArH), 7.47–7.50 (m, 3 H, ArH), 7.84–7.88 (m, H, =CH), 7.54 (d, J = 2.0 Hz, 1 H, ArH), 7.71 (d, J = 8.4 Hz, 1
2 H, ArH) ppm. 13C NMR (CDCl3, 75 MHz): δ = 50.1, 52.4, 54.3,
103.0, 103.9, 116.4, 116.8, 126.9, 127.7, 128.4, 129.1, 130.4, 163.1,
165.1 ppm. MS (ES+): m/z = 314.0 [M + 1]+. C17H19N3O3
(313.1426): calcd. C 65.16, H 6.11, N 13.41; found C 65.37, H 6.44,
N 13.28.
H, ArH) ppm. 13C NMR (CDCl3, 75 MHz): δ = 50.0, 52.3, 54.3,
103.8, 106.1, 116.6, 116.8, 126.2, 127.3, 127.6, 130.4, 131.7, 133.7,
136.7, 160.8, 164.6 ppm. MS (ES+): m/z = 381.9 [M + 1]+, 350.4
[M – 31]+. C17H17Cl2N3O3 (381.0647): calcd. C 53.42, H 4.48, N
10.99; found C 53.53, H 4.80, N 11.06.
3-[3-(2-Chlorophenyl)isoxazol-5-yl]-2-{[(2,2-dimethoxyethyl)-
2-{[(2,2-Dimethoxyethyl)amino]methyl}-3-(5-phenylisoxazol-3-yl)-
amino]methyl}prop-2-enenitrile (2o): Hexanes/ethyl acetate (3:1);
prop-2-enenitrile (2t): Hexanes/ethyl acetate (3:1); a white solid
yellow oil (2.10 g from 2.10 g). IR (neat): νmax = 1645 (C=N), 2218 (2.06 g from 2.00 g), m.p. 85–87 °C. IR (KBr): νmax = 1616 (C=N),
˜
˜
1
(CN), 3349 (NH) cm–1. H NMR (CDCl3, 300 MHz): δ = 2.81 (d, 2211 (CN), 3416 (NH) cm–1. 1H NMR (CDCl3, 300 MHz): δ =
J = 5.3 Hz, 2 H, CH2), 3.43 (s, 6 H, 2ϫOCH3), 3.68 (d, J = 1.4 Hz, 2.80 (d, J = 5.3 Hz, 2 H, CH2), 3.42 (s, 6 H, 2ϫOCH3), 3.67 (d, J
2 H, CH2), 4.50 (t, J = 5.2 Hz, 1 H, CH), 7.30 (s, 1 H, =CH), 7.39– = 1.0 Hz, 2 H, CH2), 4.50 (t, J = 5.3 Hz, 1 H, CH), 7.34 (s, 1 H,
7.48 (m, 3 H, ArH), 7.52–7.55 (m, 1 H, ArH), 7.74–7.78 (m, 1 H,
ArH) ppm. 13C NMR (CDCl3, 50 MHz): δ = 50.4, 52.8, 54.6, 54.7,
104.3, 106.8, 116.9, 127.6, 127.9, 130.9, 131.4, 131.6, 133.4, 162.1,
=CH), 7.35 (s, 1 H, ArH), 7.48–7.51 (m, 3 H, ArH), 7.83–7.86 (m,
2 H, ArH) ppm. 13C NMR (CDCl3, 75 MHz): δ = 49.9, 52.8, 54.3,
97.6, 103.8, 117.1, 117.6, 126.0, 126.8, 129.1, 130.7, 131.5, 158.7,
164.8 ppm. MS (ES+): m/z = 347.8 [M + 1]+, 316.0 [M – 31]+. 171.1 ppm. MS (ES+): m/z = 313.8 [M + 1]+, 282.1 [M – 31]+.
C17H18ClN3O3 (347.1037): calcd. C 58.71, H 5.22, N 12.08; found
C 58.88, H 5.29, N 12.26.
C17H19N3O3 (313.1426): calcd. C 65.16, H 6.11, N 13.41; found C
65.29, H 6.01, N 13.58.
2-{[(2,2-Dimethoxyethyl)amino]methyl}-3-[3-(4-fluorophenyl)isox- 2-{[(2,2-Dimethoxyethyl)amino]methyl}-3-(5-methyl-3-phenylisox-
azol-5-yl]prop-2-enenitrile (2p): Hexanes/ethyl acetate (3:1); a white azol-4-yl)prop-2-enenitrile (2u): Hexanes/ethyl acetate (3:1); colour-
solid (2.05 g from 1.95 g), m.p. 101–103 °C. IR (KBr): νmax = 1609 less oil (2.22 g from 2.20 g). IR (neat): ν = 1638 (C=N), 2218
˜
˜
max
(C=N), 2219 (CN), 3385 (NH) cm–1. 1H NMR (CDCl3, 300 MHz): (CN), 3354 (NH) cm–1. H NMR (CDCl3, 300 MHz): δ = 2.57 (s,
δ = 2.79 (d, J = 5.3 Hz, 2 H, CH2), 3.42 (s, 6 H, 2ϫOCH3), 3.67 3 H, CH3), 2.78 (d, J = 5.3 Hz, 2 H, CH2), 3.40 (s, 6 H, 2ϫOCH3),
(d, J = 1.4 Hz, 2 H, CH2), 4.48 (t, J = 5.2 Hz, 1 H, CH), 7.14–7.20 3.62 (d, J = 0.9 Hz, 2 H, CH2), 4.47 (t, J = 5.3 Hz, 1 H, CH), 6.93
(m, 2 H, ArH), 7.28 (s, 1 H, =CH), 7.29 (s, 1 H, ArH), 7.82–7.86 (s, 1 H, =CH), 7.47–7.49 (m, 3 H, ArH), 7.58–7.62 (m, 2 H, ArH)
(m, 2 H, ArH) ppm. 13C NMR (CDCl3, 75 MHz): δ = 50.0, 52.3, ppm. 13C NMR (CDCl3, 75 MHz): δ = 13.8, 49.8, 52.4, 54.2, 103.8,
1
54.3, 102.7, 103.8, 116.0, 116.3, 116.5, 116.8, 124.5, 124.6, 127.6,
128.8, 128.9, 162.1, 165.2 ppm. MS (ES+): m/z = 331.8 [M + 1]+,
300.1 [M – 31]+. C17H18FN3O3 (331.1332): calcd. C 61.62, H 5.48,
N 12.68; found C 61.89, H 5.65, N 12.51.
110.1, 117.1, 117.4, 128.2, 128.5, 129.0, 130.1, 133.7, 161.3,
168.5 ppm. MS (ES+): m/z = 327.9 [M + 1]+, 296.0 [M – 31]+.
C18H21N3O3 (327.1583): calcd. C 66.04, H 6.47, N 12.84; found C
66.10, H 6.78, N 12.78.
2-{[(2,2-Dimethoxyethyl)amino]methyl}-3-[3-(4-methylphenyl)isox- 2-{[(2,2-Dimethoxyethyl)amino]methyl}-3-(1,5-diphenyl-1H-pyrazol-
azol-5-yl]prop-2-enenitrile (2q): Hexanes/ethyl acetate (5:2); yellow 3-yl)prop-2-enenitrile (2v): Hexanes/ethyl acetate (5:3); yellow oil
oil (2.04 g from 1.98 g). IR (neat): ν
= 1616 (C=N), 2220 (CN), (2.16 g from 2.30 g). IR (neat): ν
= 1636 (C=N), 2213 (CN),
˜
˜
max
max
3368 (NH) cm–1. H NMR (CDCl3, 300 MHz): δ = 2.43 (s, 3 H,
3425 (NH) cm–1. 1H NMR (CDCl3, 300 MHz): δ = 2.80 (d, J =
5.4 Hz, 2 H, CH2), 3.41 (s, 6 H, 2ϫOCH3), 3.64 (s, 2 H, CH2),
1
CH3), 2.81 (d, J = 5.2 Hz, 2 H, CH2), 3.43 (s, 6 H, 2ϫOCH3), 3.67
(d, J = 1.1 Hz, 2 H, CH2), 4.50 (t, J = 5.2 Hz, 1 H, CH), 7.28–7.33 4.51 (t, J = 5.4 Hz, 1 H, CH), 7.24–7.38 (m, 12 H, ArH and =CH)
(m, 4 H, ArH and =CH), 7.76 (d, J = 8.1 Hz, 2 H, ArH) ppm. 13
C
ppm. 13C NMR (CDCl3, 75 MHz): δ = 49.6, 53.0, 54.1, 103.8,
107.2, 110.8, 118.3, 125.2, 128.1, 128.6, 128.8, 129.1, 129.7, 136.7,
139.5, 144.7, 147.1 ppm. MS (ES+): m/z = 389.1 [M + 1]+, 357.2
[M – 31]+. C23H24N4O2 (388.1899): calcd. C 71.11, H 6.23, N 14.42;
found C 71.32, H 6.42, N 14.32.
NMR (CDCl3, 50 MHz): δ = 21.9, 50.4, 52.7, 54.7, 103.3, 104.2,
116.5, 117.3, 125.9, 127.2, 128.2, 130.2, 141.0, 163.4, 165.2 ppm.
MS (ES+): m/z = 328.1 [M + 1]+, 297.3 [M – 31]+. C18H21N3O3
(327.1583): calcd. C 66.04, H 6.47, N 12.84; found C 66.17, H 6.69,
N 12.96.
General Procedure for the Synthesis of Substituted 2-Aminoimid-
3-[3-(4-Benzyloxyphenyl)isoxazol-5-yl]-2-{[(2,2-dimethoxyethyl)- azoles 3 as Exemplified for 3a: Cyanamide (0.52 g, 12.38 mmol) was
amino]methyl}prop-2-enenitrile (2r): Hexanes/ethyl acetate (7:3); a
white solid (2.35 g from 2.31 g), m.p. 88–90 °C. IR (KBr): ν
added to the allylamine 2a (1.50 g, 6.10 mmol) dissolved in aqueous
acetic acid (0.36 mL in 1 mL of H2O), and the reaction mixture
=
˜
max
4338
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 4334–4343

Imidazopyrimidinylamines from Allylamines
was heated at 100 °C for 2 h. Thereafter, conc. HCl (5 mL) was
added to the reaction mixture, and it was further heated for 5 min.
Then the reaction mixture was diluted with water (50 mL), neutral-
ized with NaHCO3 and extracted with ethyl acetate (4ϫ20 mL).
2-[(2-Amino-1H-imidazol-1-yl)methyl]-3-(4-fluorophenyl)prop-2-
enenitrile (3f): Ethyl acetate/methanol (19:1); white solid (0.98 g
from 1.57 g), m.p. 234–236 °C. IR (KBr): νmax = 1663 (C=N), 2213
˜
(CN), 3452 (NH2) cm–1. 1H NMR ([D6]DMSO, 300 MHz): δ =
The organic layers were combined, dried with Na2SO4, concen- 5.10 (s, 2 H, CH2), 7.00 (d, J = 2.4 Hz, 1 H, ArH), 7.09 (d, J =
trated, and the residue thus obtained was purified by silica gel col-
umn chromatography. Elution with ethyl acetate/methanol (19:1,
v/v) gave the pure product 3a in 72% yield (0.98 g).
2.4 Hz, 1 H, ArH), 7.34–7.40 (m, 2 H, ArH), 7.78 (s, 1 H, =CH),
7.81–7.85 (m, 2 H, ArH), 8.14 (s, 2 H, NH2, exchangeable by D2O)
ppm. 13C NMR ([D6]DMSO, 75 MHz): δ = 47.7, 105.0, 113.9,
116.6, 116.8, 117.3, 129.6, 131.7, 131.9, 146.4, 147.1, 162.1,
165.4 ppm. MS (ES+): m/z = 243.4 [M + 1]+. HRMS (EI): calcd.
for C13H11FN4 242.0968; found 242.0955.
2-[(2-Amino-1H-imidazol-1-yl)methyl]-3-phenylprop-2-enenitrile
(3a): White solid, m.p. 163–165 °C. IR (KBr): ν
= 1639 (C=N),
˜
max
2214 (CN), 3407 (NH2) cm–1. 1H NMR (CDCl3, 300 MHz): δ =
4.25 (br. s, 2 H, NH2), 4.67 (s, 2 H, CH2), 6.64 (s, 1 H, ArH), 6.74
(s, 1 H, ArH), 6.92 (s, 1 H, =CH), 7.44–7.45 (m, 3 H, ArH), 7.73–
7.76 (m, 2 H, ArH) ppm. 13C NMR ([D6]DMSO, 75 MHz): δ =
47.7, 108.1, 115.1, 118.2, 124.8, 129.4, 129.8, 131.5, 133.6, 145.7,
150.0 ppm. MS (ES+): m/z = 225.1 [M + 1]+. HRMS (EI): calcd.
for C13H12N4 224.1062; found 224.1055.
2-[(2-Amino-1H-imidazol-1-yl)methyl]-3-(4-methylphenyl)prop-2-
enenitrile (3g): Ethyl acetate/methanol (20:1); white solid (0.99 g
from 1.47 g), m.p. 221–224 °C. IR (KBr): νmax = 1661 (C=N), 2207
˜
(CN), 3243 (NH2) cm–1. 1H NMR ([D6]DMSO, 300 MHz): δ =
2.35 (s, 3 H, CH3), 5.09 (s, 2 H, CH2), 6.99 (d, J = 2.3 Hz, 1 H,
ArH), 7.08 (d, J = 2.4 Hz, 1 H, ArH), 7.31 (d, J = 4.4 Hz, 2 H,
ArH), 7.67 (d, J = 8.1 Hz, 2 H, ArH), 7.72 (s, 1 H, =CH), 8.14 (s,
2 H, NH2) ppm. 13C NMR ([D6]DMSO, 75 MHz): δ = 21.7, 47.9,
104.1, 114.0, 116.7, 117.7, 129.4, 130.2, 130.4, 141.9, 147.2,
147.7 ppm. MS (ES+): m/z = 239.1 [M + 1]+. HRMS (EI): calcd.
for C14H14N4 238.1218; found 238.1207.
2-[(2-Amino-1H-imidazol-1-yl)methyl]-3-(2-chlorophenyl)prop-2-
enenitrile (3b): Ethyl acetate/methanol (20:1); white solid (1.02 g
from 1.60 g), m.p. 227–230 °C. IR (KBr): νmax = 1659 (C=N), 2215
˜
(CN), 3428 (NH2) cm–1. 1H NMR ([D6]DMSO, 300 MHz): δ =
5.04 (d, J = 2.2 Hz, 2 H, CH2), 6.67 (d, J = 1.1 Hz, 1 H, ArH),
6.89 (d, J = 1.1 Hz, 1 H, ArH), 7.45–7.48 (m, 3 H, ArH and =CH),
7.58–7.61 (m, 1 H, ArH), 7.84 (s, 1 H, ArH) ppm. 13C NMR ([D6]-
DMSO, 75 MHz): δ = 43.7, 116.3, 125.9, 126.4, 127.9, 130.0, 131.5,
132.6, 134.0, 134.4, 141.4, 164.8 ppm. MS (ES+): m/z = 259.2 [M +
1]+. HRMS (EI): calcd. for C13H11ClN4 258.0672; found 258.0679.
2-[(2-Amino-1H-imidazol-1-yl)methyl]-3-(4-methoxyphenyl)prop-2-
enenitrile (3h): Ethyl acetate/methanol (17:1); white solid (0.95 g
from 1.50 g), m.p. 205–207 °C. IR (KBr): νmax = 1663 (C=N), 2217
˜
(CN), 3245 (NH2) cm–1. 1H NMR ([D6]DMSO, 300 MHz): δ =
3.81 (s, 3 H, OCH3), 5.05 (s, 2 H, CH2), 6.99 (d, J = 2.4 Hz, 1 H,
ArH), 7.06–7.09 (m, 3 H, ArH and =CH), 7.69 (m, 1 H, ArH),
7.76 (d, J = 8.8 Hz, 2 H, ArH), 8.11 (s, 2 H, NH2) ppm. 13C NMR
([D6]DMSO, 75 MHz): δ = 47.9, 56.0, 101.8, 113.9, 115.1, 116.6,
118.0, 125.6, 131.3, 147.1, 147.4, 162.0 ppm. MS (ES+): m/z =
255.0 [M + 1]+. C14H14N4O (254.1168): calcd. C 66.13, H 5.55, N
22.03; found C 65.89, H 5.83, N 22.21.
2-[(2-Amino-1H-imidazol-1-yl)methyl]-3-(2-fluorophenyl)prop-2-
enenitrile (3c): Ethyl acetate/methanol (20:1); white solid (0.95 g
from 1.55 g), m.p. 158–160 °C. IR (KBr): νmax = 1620 (C=N), 2214
˜
(CN), 3415 (NH2) cm–1. 1H NMR ([D6]DMSO, 300 MHz): δ =
4.82 (s, 2 H, CH2), 5.57 (s, 2 H, NH2, replaceable by D2O), 6.45
(d, J = 1.4 Hz, 1 H, ArH), 6.65 (d, J = 1.4 Hz, 1 H, ArH), 7.30–
7.36 (m, 3 H, ArH and =CH), 7.52–7.55 (m, 1 H, ArH), 7.88–7.95
(m, 1 H, ArH) ppm. 13C NMR ([D6]DMSO, 75 MHz): δ = 47.3,
100.2, 111.4, 111.5, 114.9, 116.5, 116.8, 117.5, 121.4, 121.6, 124.9,
125.5, 125.6, 128.9, 128.9, 133.4, 133.5, 136.9, 137.0, 149.9, 158.7,
162.0 ppm. MS (ES+): m/z = 243.4 [M + 1]+. HRMS (EI): calcd.
for C13H11FN4 242.0968; found 242.0965.
2-[(2-Amino-1H-imidazol-1-yl)methyl]-3-(2,4-dichlorophenyl)prop-2-
enenitrile (3i): Ethyl acetate/methanol (22:1); white solid (1.01 g
from 1.65 g), m.p. 238–241 °C. IR (KBr): νmax = 1645 (C=N), 2219
˜
(CN), 3432 (NH2) cm–1. 1H NMR ([D6]DMSO, 300 MHz): δ =
5.15 (s, 2 H, CH2), 7.01 (d, J = 1.7 Hz, 1 H, ArH), 7.07 (d, J =
1.9 Hz, 1 H, ArH), 7.58–7.61 (dd, J1 = 1.6, J2 = 8.4 Hz, 1 H, ArH),
7.72 (s, 1 H, =CH), 7.79 (d, J = 1.7 Hz, 1 H, ArH), 7.85 (d, J =
8.4 Hz, 1 H, ArH), 8.12 (s, 2 H, NH2) ppm. 13C NMR ([D6]DMSO,
75 MHz): δ = 47.2, 110.7, 114.0, 116.4, 116.7, 128.5, 130.0, 130.7,
131.0, 134.6, 136.4, 142.7, 147.2 ppm. MS (ES+): m/z = 293.2 [M
+ 1]+. C13H10Cl2N4 (292.0283): calcd. C 53.26, H 3.44, N 19.11;
found C 53.12, H 24.38, N 18.98.
2-[(2-Amino-1H-imidazol-1-yl)methyl]-3-(2-nitrophenyl)prop-2-
enenitrile (3d): Ethyl acetate/methanol (20:1); white solid (0.95 g
from 1.72 g), m.p. 133–136 °C. IR (KBr): νmax = 1638 (C=N), 2224
˜
(CN), 3446 (NH2) cm–1. 1H NMR ([D6]DMSO, 300 MHz): δ =
4.83 (d, J = 1.0 Hz, 2 H, CH2), 5.63 (s, 2 H, NH2), 6.48 (d, J =
1.6 Hz, 1 H, ArH), 6.66 (d, J = 1.6 Hz, 1 H, ArH), 7.65 (s, 1 H,
=CH), 7.72–7.78 (m, 2 H, ArH), 7.87–7.93 (m, 1 H, ArH), 8.21–
8.23 (m, 1 H, ArH) ppm. 13C NMR ([D6]DMSO, 75 MHz): δ =
46.7, 112.6, 114.8, 116.9, 123.7, 125.7, 129.7, 131.4, 131.8, 135.2,
143.7, 147.6, 149.8 ppm. MS (ES+): m/z = 270.2 [M + 1]+. HRMS
(EI): calcd. for C13H11N5O2 269.0913; found 269.0936.
2-[(2-Amino-1H-imidazol-1-yl)methyl]-3-(2,6-dichlorophenyl)prop-2-
enenitrile (3j): Ethyl acetate/methanol (18:1); white solid (1.12 g
from 1.72 g), m.p. 268–270 °C. IR (KBr): νmax = 1663 (C=N), 2224
˜
(CN), 3246 (NH2) cm–1. 1H NMR ([D6]DMSO, 300 MHz): δ =
5.17 (s, 2 H, CH2), 6.80 (s, 1 H, ArH), 6.90 (s, 1 H, ArH), 7.32–
7.42 (m, 3 H, ArH and =CH), 7.63 (s, 1 H, ArH), 8.06 (s, 2 H,
NH2) ppm. 13C NMR ([D6]DMSO, 75 MHz): δ = 47.1, 114.8,
116.1, 116.2, 117.2, 129.9, 132.1, 133.1, 134.2, 144.6, 147.7 ppm.
MS (ES+): m/z = 293.2 [M + 1]+. HRMS (EI): calcd. for
C13H10Cl2N4 292.0283; found 292.0283.
2-[(2-Amino-1H-imidazol-1-yl)methyl]-3-(4-chlorophenyl)prop-2-
enenitrile (3e): Ethyl acetate/methanol (20:1); white solid (1.01 g
from 1.63 g), m.p. 120–122 °C. IR (KBr): νmax = 1635 (C=N), 2215
˜
(CN), 3431 (NH2) cm–1. 1H NMR ([D6]DMSO, 300 MHz): δ =
4.77 (s, 2 H, CH2), 5.65 (br. s, 2 H, NH2), 6.46 (s, 1 H, ArH), 6.65 2-[(2-Amino-1H-imidazol-1-yl)methyl]-3-(3,4-dimethoxyphenyl)-
(s, 1 H, ArH), 7.33 (s, 1 H, =CH), 7.54–7.59 (m, 2 H, ArH), 7.74
prop-2-enenitrile (3k): Ethyl acetate/methanol (17:1); white solid
(1.05 g from 1.60 g), m.p. 252–255 °C. IR (KBr): ν = 1663
(d, J = 6.5 Hz, 2 H, ArH) ppm. 13C NMR ([D6]DMSO, 75 MHz):
˜
max
δ = 47.4, 108.8, 114.9, 117.8, 124.4, 129.6, 129.8, 130.8, 131.0, (C=N), 2217 (CN), 3245 (NH2) cm–1 1H NMR ([D6]DMSO,
.
132.3, 135.8, 144.2, 149.2 ppm. MS (ES+): m/z = 259.1 [M + 1]+.
C13H11ClN4 (258.0672): calcd. C 60.35, H 4.29, N 21.66; found C
60.58, H 4.62, N 21.43.
300 MHz): δ = 3.83 (s, 6 H, 2ϫOCH3), 5.18 (d, J = 2.2 Hz, 2 H,
CH2), 6.67 (d, J = 1.2 Hz, 1 H, ArH), 6.94 (d, J = 1.3 Hz, 1 H,
ArH), 7.08 (s, 2 H, ArH), 7.11 (s, 1 H, =CH), 7.76 (s, 1 H, ArH)
Eur. J. Org. Chem. 2008, 4334–4343
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4339

S. Nag, A. Mishra, S. Batra
ppm. 13C NMR ([D6]DMSO, 50 MHz): δ = 47.9, 56.3, 56.5, 103.8, protocol to that described for the aforementioned synthesis of 3
FULL PAPER
112.0, 112.6, 115.7, 118.8, 120.2, 124.1, 126.2, 146.7, 149.5, 152.0,
167.2 ppm. MS (ES+): m/z = 285.1 [M + 1]+. HRMS (EI): calcd.
for C15H16N4O2 284.1273; found 284.1277.
was used, except the heating of the reaction mixture in the presence
of HCl was extended to 30 min.
General Procedure for the Synthesis of 6-(Arylmethyl)imidazo[1,2-
a]pyrimidin-7-ylamines 4a–m,u as Exemplified for 4a: Compound 3a
(0.50 g, 2.23 mmol) was added to a solution of NaOMe in meth-
anol [prepared by dissolving Na (0.11 g, 4.5 mmol) in methanol
(5 mL)], and the mixture was heated at reflux for 1 h. Upon com-
pletion, excess methanol was removed under vacuum, and water
(50 mL) was added to the residue. This mixture was extracted with
ethyl acetate (3ϫ15 mL), the organic layers were combined, dried
with Na2SO4 and concentrated to afford the crude product. Purifi-
cation of the crude material by silica gel column chromatography
employing ethyl acetate/methanol (19:1, v/v) as eluent furnished the
desired product 4a in 72% yield as a white solid (0.36 g).
2-[(2-Amino-1H-imidazol-1-yl)methyl]-3-(2-thienyl)prop-2-enenitrile
(3l): Ethyl acetate/methanol (19:1); white solid (0.92 g from 1.65 g),
m.p. 193–195 °C. IR (KBr): ν
= 1643 (C=N), 2212 (CN), 3406
˜
max
(NH2) cm–1. 1H NMR ([D6]DMSO, 300 MHz): δ = 5.13 (d, J =
2.3 Hz, 2 H, CH2), 6.71 (d, J = 1.4 Hz, 1 H, ArH), 7.02 (d, J =
1.4 Hz, 1 H, ArH), 7.29–7.32 (m, 1 H, ArH), 7.60 (d, J = 3.5 Hz,
1 H, =CH), 7.97–8.01 (m, 2 H, ArH) ppm. 13C NMR ([D6]DMSO,
75 MHz): δ = 43.4, 115.0, 118.2, 124.7, 127.8, 128.8, 131.2, 132.6,
136.3, 140.0, 160.0 ppm. MS (ES+): m/z = 231.3 [M + 1]+. HRMS
(EI): calcd. for C11H10N4S 230.0626; found 230.0625.
2-[(2-Amino-1H-imidazol-1-yl)methyl]-3-(2-furyl)prop-2-enenitrile
(3m): Ethyl acetate/methanol (19:1); white solid (0.94 g from
6-Benzylimidazo[1,2-a]pyrimidin-7-ylamine (4a): M.p. 225–227 °C.
1
IR (KBr): ν
= 1669 (C=N), 3427 (NH2) cm–1. H NMR ([D6]-
1.53 g), m.p. 159–160 °C. IR (KBr): ν
= 1643 (C=N), 2212
˜
max
˜
max
(CN), 3406 (NH2) cm–1. 1H NMR ([D6]DMSO, 300 MHz): δ =
4.70 (s, 2 H, CH2), 5.47 (s, 2 H, NH2), 6.42 (d, J = 1.4 Hz, 1 H,
ArH), 6.61 (d, J = 1.5 Hz, 1 H, ArH), 6.68–6.70 (m, 1 H, ArH),
7.02 (d, J = 3.5 Hz, 1 H, ArH), 7.05 (m, 1 H, =CH), 7.92 (d, J =
1.3 Hz, 1 H, ArH) ppm. 13C NMR ([D6]DMSO, 75 MHz): δ =
46.8, 103.9, 113.5, 114.9, 116.6, 118.05, 124.8, 131.8, 146.7, 149.2,
149.8 ppm. MS (ES+): m/z = 215.1 [M + 1]+. HRMS (EI): calcd.
for C11H10N4O 214.0855; found 214.0847.
DMSO, 300 MHz): δ = 3.79 (s, 2 H, CH2), 6.37 (s, 2 H, NH2), 7.11
(d, J = 1.4 Hz, 1 H, ArH), 7.17–7.30 (m, 6 H, ArH), 7.89 (s, 1 H,
ArH) ppm. 13C NMR (CDCl3 + [D6]DMSO, 75 MHz): δ = 32.5,
107.7, 110.0, 125.3, 127.3, 127.4, 129.5, 131.2, 135.9, 147.5,
155.9 ppm. MS (ES+): m/z = 225.3 [M + 1]+. HRMS (EI): calcd.
for C13H12N4 224.1062; found 224.1063.
6-(2-Chlorobenzyl)imidazo[1,2-a]pyrimidin-7-ylamine (4b): Ethyl
acetate/methanol (19:1); white solid (0.53 g from 0.68 g), m.p. 188–
2-[(2-Amino-1H-imidazol-1-yl)methyl]-3-[3-(4-fluorophenyl)-
isoxazol-5-yl]prop-2-enenitrile (3p): Ethyl acetate/methanol (18:1);
191 °C. IR (KBr): νmax = 1663 (C=N), 3402 (NH2) cm–1. 1H NMR
˜
([D6]DMSO, 300 MHz): δ = 3.88 (s, 2 H, CH2), 6.74 (br. s, 2 H,
NH2), 7.10 (d, J = 1.2 Hz, 1 H, ArH), 7.33–7.36 (m, 4 H, ArH),
7.50–7.53 (m, 1 H, ArH), 7.75 (s, 1 H, ArH) ppm. 13C NMR ([D6]-
DMSO, 75 MHz): δ = 31.9, 109.9, 110.1, 128.1, 129.3, 130.1, 131.1,
131.7, 132.7, 134.0, 135.7, 149.0, 157.5 ppm. MS (ES+): m/z =
259.4 [M + 1]+. HRMS (EI): calcd. for C13H11ClN4 258.0672;
found 258.0674.
white solid (1.16 g from 1.52 g), m.p. 242–243 °C. IR (KBr): ν
=
˜
max
1651 (C=N), 2219 (CN), 3433 (NH2) cm–1. 1H NMR ([D6]DMSO,
300 MHz): δ = 5.14 (s, 2 H, CH2), 7.04 (d, J = 2.2 Hz, 1 H, ArH),
7.11 (d, J = 2.2 Hz, 1 H, ArH), 7.37–7.43 (m, 2 H, ArH), 7.56 (s,
1 H, =CH), 7.65 (s, 1 H, ArH), 7.98–8.02 (m, 2 H, ArH), 8.10 (s,
2 H, NH2) ppm. 13C NMR ([D6]DMSO, 75 MHz): δ = 47.3, 106.8,
111.0, 114.2, 116.1, 116.8, 117.1, 124.8, 129.8, 129.9, 130.1, 147.4,
162.3, 162.4, 164.5, 165.7 ppm. MS (ES+): m/z = 310.1 [M + 1]+.
HRMS (EI): calcd. for C16H12FN5O 309.1026; found 309.1027.
6-(2-Fluorobenzyl)imidazo[1,2-a]pyrimidin-7-ylamine (4c): Ethyl
acetate/methanol (19:1); white solid (0.51 g from 0.73 g), m.p. 197–
200 °C. IR (KBr): νmax = 1669 (C=N), 3422 (NH2) cm–1. 1H NMR
˜
2-[(2-Amino-1H-imidazol-1-yl)methyl]-3-[3-(4-methylphenyl)-
isoxazol-5-yl]prop-2-enenitrile (3q): Ethyl acetate/methanol (18:1);
([D6]DMSO, 300 MHz): δ = 3.84 (s, 2 H, CH2), 6.73 (s, 2 H, NH2),
7.11–7.36 (m, 6 H, ArH), 7.97 (s, 1 H, ArH) ppm. 13C NMR ([D6]-
DMSO, 75 MHz): δ = 27.4, 110.0, 110.3, 115.9, 116.1, 125.2, 129.5,
131.2, 131.7, 133.1, 149.2, 157.6 ppm. MS (ES+): m/z = 243.4 [M +
1]+. HRMS (EI): calcd. for C13H11FN4 242.0968; found 242.0967.
white solid (1.20 g from 1.62 g), m.p. 215–217 °C. IR (KBr): ν
=
˜
max
1664 (C=N), 2225 (CN), 3288 (NH2) cm–1. H NMR ([D6]DMSO,
300 MHz): δ = 2.36 (s, 3 H, CH3), 5.24 (s, 2 H, CH2), 7.02 (s, 1 H,
ArH), 7.11 (s, 1 H, ArH), 7.34 (d, J = 7.7 Hz, 2 H, ArH), 7.50 (s,
1 H, =CH), 7.74 (s, 1 H, ArH), 7.80 (d, J = 7.7 Hz, 2 H, ArH),
8.23 (s, 2 H, NH2) ppm. 13C NMR ([D6]DMSO, 75 MHz): δ =
21.5, 47.1, 106.5, 110.7, 114.0, 116.0, 116.6, 125.2, 127.1, 130.1,
130.2, 141.0, 147.3, 162.9, 164.1 ppm. MS (ES+): m/z = 306.1 [M
+ 1]+. HRMS (DART, as ES+): calcd. for C17H16N5O 306.13548;
found 306.13556.
1
6-(4-Chlorobenzyl)imidazo[1,2-a]pyrimidin-7-ylamine (4e): Ethyl
acetate/methanol (19:1); a white solid (0.38 g from 0.55 g), m.p.
1
172–173 °C. IR (KBr): ν
= 1667 (C=N), 3471 (NH2) cm–1. H
˜
max
NMR ([D6]DMSO, 300 MHz): δ = 3.82 (s, 2 H, CH2), 6.63 (s, 2
H, NH2), 7.12 (s, 1 H, ArH), 7.31–7.36 (s, 5 H, ArH), 8.15 (s, 1 H,
ArH) ppm. 13C NMR ([D6]DMSO, 75 MHz): δ = 32.8, 109.8,
111.4, 128.9, 131.2, 131.6, 133.4, 137.8, 149.1, 157.4 ppm. MS
(ES+): m/z = 259.4 [M + 1]+. HRMS (EI): calcd. for C13H11ClN4
258.0672; found 258.0669.
2-[(2-Amino-1H-imidazol-1-yl)methyl]-3-(5-methyl-3-phenyl-
isoxazol-4-yl)prop-2-enenitrile (3u): Ethyl acetate/methanol (19:1);
white solid (1.03 g from 1.59 g), m.p. 131–133 °C. IR (KBr): ν
=
˜
max
1664 (C=N), 2217 (CN), 3367 (NH2) cm–1. 1H NMR ([D6]DMSO,
300 MHz): δ = 1.91 (s, 3 H, CH3), 4.84 (s, 2 H, CH2), 5.60 (br. s,
2 H, NH2), 6.49 (d, J = 1.4 Hz, 1 H, ArH), 6.70 (d, J = 1.4 Hz, 1
H, ArH), 7.02 (s, 1 H, =CH), 7.55 (d, J = 5.6 Hz, 3 H, ArH), 7.64–
7.67 (m, 2 H, ArH) ppm. 13C NMR ([D6]DMSO, 75 MHz): δ =
13.7, 46.7, 110.3, 115.3, 115.7, 122.1, 128.8, 130.0, 131.2, 135.6,
149.8, 169.5 ppm. MS (ES+): m/z = 306.1 [M + 1]+. HRMS
(DART, as ES+): calcd. for C17H16N5O 306.13548; found
306.13489.
6-(4-Fluorobenzyl)imidazo[1,2-a]pyrimidin-7-ylamine (4f): Ethyl ace-
tate/methanol (19:1); white solid (0.45 g from 0.59 g), m.p. 165–
168 °C. IR (KBr): νmax = 1663 (C=N), 3452 (NH2) cm–1. 1H NMR
˜
([D6]DMSO, 300 MHz): δ = 3.80 (s, 2 H, CH2), 6.66 (s, 2 H, NH2),
7.12–7.17 (m, 3 H, ArH), 7.31–7.36 (m, 3 H, ArH), 8.13 (s, 1 H,
ArH) ppm. 13C NMR ([D6]DMSO, 50 MHz): δ = 32.7, 109.8,
111.8, 115.6, 115.9, 131.1, 131.2, 133.3, 134.8, 149.1, 157.5, 159.9,
163.1 ppm. MS (ES+): m/z = 243.4 [M + 1]+. HRMS (EI): calcd.
for C13H11FN4 242.0968; found 242.0963.
General Procedure for the One-Pot Synthesis of 6-(Hetarylmethyl)-
imidazo[1,2-a]pyrimidin-7-ylamines 4n–t,v from 2n–t,v: A similar
6-(4-Methylbenzyl)imidazo[1,2-a]pyrimidin-7-ylamine (4g): Ethyl
acetate/methanol (19:1); white solid (0.51 g from 0.61 g), m.p. 263–
4340
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 4334–4343

Imidazopyrimidinylamines from Allylamines
265 °C. IR (KBr): νmax = 1676 (C=N), 3460 (NH2) cm–1. 1H NMR
([D6]DMSO, 300 MHz): δ = 2.25 (s, 3 H, CH3), 3.74 (s, 2 H, CH2),
J = 1.1 Hz, 1 H, ArH), 7.84 (d, J = 1.1 Hz, 1 H, ArH), 8.71 (s, 1
H, ArH) ppm. 13C NMR ([D6]DMSO, 75 MHz): δ = 27.8, 107.7,
˜
6.60 (s, 2 H, NH2), 7.09–7.18 (m, 5 H, ArH), 7.34 (s, 1 H, ArH), 111.3, 112.0, 115.7, 134.7, 135.6, 142.9, 147.1, 150.8, 152.3 ppm.
8.05 (s, 1 H, ArH) ppm. 13C NMR ([D6]DMSO, 75 MHz): δ =
21.3, 109.9, 112.2, 129.4, 129.7, 131.1, 133.2, 135.6, 136.1, 149.2,
157.7 ppm. MS (ES+): m/z = 239.4. [M + 1]+. HRMS (EI): calcd.
for C14H14N4 238.1218; found 238.1211.
MS (ES+): m/z = 215.4 [M + 1]+. HRMS (EI): calcd. for
C11H10N4S 214.0855; found 214.0863.
6-[(3-Phenylisoxazol-5-yl)methyl]imidazo[1,2-a]pyrimidin-7-ylamine
(4n): Ethyl acetate/methanol (15:1); white solid (1.12 g from 1.52 g),
6-(4-Methoxybenzyl)imidazo[1,2-a]pyrimidin-7-ylamine (4h): Ethyl
acetate/methanol (18:1); white solid (0.52 g from 0.71 g), m.p. 245–
m.p. 250–253 °C. IR (KBr): ν
= 1671 (C=N), 3432 (NH2) cm–1.
max
˜
1H NMR ([D6]DMSO, 200 MHz): δ = 4.11 (s, 2 H, CH2), 6.80 (s,
3 H, ArH and NH2), 7.15 (s, 1 H, ArH), 7.41 (s, 1 H, ArH), 7.44–
7.47 (m, 3 H, ArH), 7.82–7.85 (m, 2 H, ArH), 8.42 (s, 1 H, ArH)
247 °C. IR (KBr): νmax = 1667 (C=N), 3427 (NH2) cm–1. 1H NMR
˜
([D6]DMSO, 300 MHz): δ = 3.72 (s, 3 H, OCH3), 3.91 (s, 2 H,
CH2), 6.87 (d, J = 8.4 Hz, 2 H, ArH), 7.12 (d, J = 8.3 Hz, 2 H, ppm. 13C NMR ([D6]DMSO, 50 MHz): δ = 26.2, 101.5, 107.5,
ArH), 7.57 (s, 1 H, ArH), 7.80 (s, 1 H, ArH), 8.62 (s, 1 H, ArH)
110.3, 127.4, 129.5, 130.0, 131.0, 131.8, 134.8, 149.6, 157.6, 162.8,
ppm. 13C NMR ([D6]DMSO, 50 MHz): δ = 33.5, 55.5, 111.8, 114.5, 171.7 ppm. MS (ES+): m/z = 292.6 [M + 1]+. HRMS (EI): calcd.
118.7, 130.3, 130.8, 134.4, 135.2, 147.0, 150.9, 158.4 ppm. MS
(ES+): m/z = 255.2 [M + 1]+. HRMS (EI): calcd. for C14H14N4O
254.1168; found 254.1169.
for C16H13N5O 291.1120; found 291.1116.
6-{[3-(2-Chlorophenyl)isoxazol-5-yl]methyl}imidazo[1,2-a]pyrimidin-
7-ylamine (4o): Ethyl acetate/methanol (15:1); white solid (1.14 g
6-(2,4-Dichlorobenzyl)imidazo[1,2-a]pyrimidin-7-ylamine (4i): Ethyl
acetate/methanol (20:1); white solid (0.45 g from 0.63 g), m.p. 214–
from 1.60 g), 160 °C (decomp.). IR (KBr): ν
= 1673 (C=N),
˜
max
3434 (NH2) cm–1. H NMR ([D6]DMSO, 300 MHz): δ = 4.20 (s, 2
H, CH2), 6.78 (s, 1 H, ArH), 6.87 (s, 2 H, NH2), 7.15 (s, 1 H, ArH),
7.43–7.55 (m, 3 H, ArH), 7.60–7.68 (m, 2 H, ArH), 8.50 (s, 1 H,
ArH) ppm. 13C NMR ([D6]DMSO, 75 MHz): δ = 25.9, 104.3,
1
219 °C. IR (KBr): νmax = 1667 (C=N), 3374 (NH2) cm–1. 1H NMR
˜
([D6]DMSO, 300 MHz): δ = 3.85 (s, 2 H, CH2), 6.75 (s, 2 H, NH2),
7.09 (s, 1 H, ArH), 7.33–7.35 (m, 2 H, ArH), 7.43–7.45 (m, 1 H,
ArH), 7.69 (s, 1 H, ArH), 7.79 (s, 1 H, ArH) ppm. 13C NMR ([D6] 107.3, 110.1, 128.4, 128.5, 131.1, 131.5, 131.7, 132.2, 132.4, 134.7,
DMSO, 50 MHz): δ = 31.5, 109.8, 110.0, 128.3, 129.6, 131.1, 132.8,
132.9, 133.0, 134.9, 135.1, 149.1, 157.5 ppm. MS (ES+): m/z =
294.0 [M + 1]+. HRMS (EI): calcd. for C13H10Cl2N4 292.0283;
found 292.0281.
157.4, 161.2, 170.8 ppm. MS (ES+): m/z = 326.1 [M + 1]+. HRMS
(EI): calcd. for C16H12ClN5O 325.0730; found 325.0737.
6-{[3-(4-Fluorophenyl)isoxazol-5-yl]methyl}imidazo[1,2-a]pyrim-
idin-7-ylamine (4p): Ethyl acetate/methanol (15:1); white solid
6-(2,6-Dichlorobenzyl)imidazo[1,2-a]pyrimidin-7-ylamine (4j): Ethyl
acetate/methanol (20:1); white solid (0.39 g from 0.53 g), m.p. 255–
(0.84 g from 1.13 g), 200 °C (decomp.). IR (KBr): ν
= 1662
˜
max
(C=N), 3413 (NH2) cm–1. 1H NMR ([D6]DMSO, 300 MHz): δ =
4.15 (s, 2 H, CH2), 6.81 (s, 2 H, NH2), 6.84 (s, 1 H, ArH), 7.29–
257 °C. IR (KBr): νmax = 1640 (C=N), 3424 (NH2) cm–1. 1H NMR
˜
([D6]DMSO, 300 MHz): δ = 4.19 (s, 2 H, CH2), 7.39–7.45 (m, 1 H, 7.35 (m, 3 H, ArH), 7.87–7.92 (m, 3 H, ArH), 8.46 (s, 1 H, ArH)
ArH), 7.55–7.58 (m, 3 H, ArH), 7.77 (s, 1 H, ArH), 8.06 (s, 1 H, ppm. 13C NMR ([D6]DMSO, 75 MHz): δ = 25.8, 101.1, 107.2,
ArH) ppm. 13C NMR ([D6]DMSO, 75 MHz): δ = 30.5, 112.1, 116.4, 116.7, 129.3, 129.4, 131.2, 134.4, 157.2, 161.5, 165.2,
115.7, 129.4, 130.5, 133.0, 134.0, 135.9, 146.8, 150.9 ppm. MS
(ES+): m/z = 293.4 [M + 1]+. HRMS (EI): calcd. for C13H10Cl2N4
292.0283; found 292.0277.
171.5 ppm. MS (ES+): m/z = 310.1 [M + 1]+. C16H12FN5O
(309.1026): C 62.13, H 3.91, N 22.64; found C 62.33, H 4.12, N
22.53.
6-(3,4-Dimethoxybenzyl)imidazo[1,2-a]pyrimidin-7-ylamine (4k):
6-{[3-(4-Methylphenyl)isoxazol-5-yl]methyl}imidazo[1,2-a]-
pyrimidin-7-ylamine (4q): Ethyl acetate/methanol (15:1); white solid
Ethyl acetate/methanol (17:1); white solid (0.44 g from 0.65 g), m.p.
1
225–227 °C. IR (KBr): ν
= 1665 (C=N), 3448 (NH2) cm–1. H (0.83 g from 1.21 g), m.p. 220–222 °C. IR (KBr): ν
= 1668
˜
˜
max
max
NMR ([D6]DMSO, 300 MHz): δ = 3.72 (s, 6 H, 2ϫOCH3), 3.90
(s, 2 H, CH2), 6.72 (s, 1 H, ArH), 6.83–6.89 (m, 2 H, ArH), 7.58
(s, 1 H, ArH), 7.81 (s, 1 H, ArH), 8.59 (s, 1 H, ArH) ppm. 13C
(C=N), 3426 (NH2) cm–1. 1H NMR ([D6]DMSO, 300 MHz): δ =
2.33 (s, 3 H, CH3), 4.11 (s, 2 H, CH2), 6.77 (s, 1 H, ArH), 6.82 (s,
2 H, NH2), 7.17 (s, 1 H, ArH), 7.28 (d, J = 6.9 Hz, 2 H, ArH),
NMR ([D6]DMSO, 50 MHz): δ = 34.4, 56.3, 112.2, 112.8, 113.6, 7.42 (s, 1 H, ArH), 7.73 (d, J = 7.1 Hz, 2 H, ArH), 8.44 (s, 1 H,
119.1, 121.7, 131.6, 134.8, 135.6, 147.4, 148.3, 149.6, 151.3 ppm.
MS (ES+): m/z = 285.6 [M + 1]+. HRMS (EI): calcd. for
C15H16N4O2 284.1273; found 284.1274.
ArH) ppm. 13C NMR ([D6]DMSO, 75 MHz): δ = 21.4, 25.8, 101.0,
107.1, 109.9, 126.3, 126.9, 130.1, 134.4, 140.3, 149.1, 157.2, 162.3,
171.1 ppm. MS (ES+): m/z = 306.1 [M + 1]+. HRMS (DART, as
ES+): calcd. for C17H16N5O 306.1355; found 306.1339.
6-(2-Thienylmethyl)imidazo[1,2-a]pyrimidin-7-ylamine (4l): Ethyl
acetate/methanol (19:1); white solid (0.47 g from 0.66 g), m.p. 237–
4-{5-[(7-Aminoimidazo[1,2-a]pyrimidin-6-yl)methyl]isoxazol-3-
yl}phenol (4r): Ethyl acetate/methanol (15:1); white solid (0.50 g
240 °C. IR (KBr): νmax = 1655 (C=N), 3431 (NH2) cm–1. 1H NMR
˜
([D6]DMSO, 300 MHz): δ = 4.21 (s, 2 H, CH2), 6.90–6.91 (d, J = from 1.10 g), 225 °C (decomp.). IR (KBr): ν
= 1672 (C=N),
˜
max
1
2.5 Hz, 1 H, ArH), 6.95–6.98 (m, 1 H, ArH), 7.35–7.37 (m, 1 H,
ArH), 7.60 (d, J = 1.3 Hz, 1 H, ArH), 7.84 (d, J = 1.3 Hz, 1 H,
3431 (NH2) cm–1. H NMR ([D6]DMSO, 300 MHz): δ = 4.09 (s, 2
H, CH2), 6.70 (s, 1 H, ArH), 6.80 (s, 2 H, NH2), 6.87 (d, J = 7.8 Hz,
ArH), 8.79 (s, 1 H, ArH) ppm. 13C NMR ([D6]DMSO, 75 MHz): δ 2 H, ArH), 7.16 (s, 1 H, ArH), 7.42 (s, 1 H, ArH), 7.64 (d, J =
= 29.0, 112.0, 118.0, 125.4, 126.6, 127.7, 134.7, 135.4, 141.8, 147.0,
150.7 ppm. MS (ES+): m/z = 231.3 [M + 1]+. HRMS (EI): calcd.
for C11H10N4S 230.0626; found 230.0629.
6.9 Hz, 2 H, ArH), 8.42 (s, 1 H, ArH) ppm. 13C NMR ([D6]DMSO,
75 MHz): δ = 25.9, 101.0, 107.6, 110.1, 116.5, 119.9, 128.7, 131.1,
134.5, 149.2, 157.5, 160.0, 162.4, 170.7 ppm. MS (ES+): m/z =
308.5 [M + 1]+. C16H13N5O2 (307.1069): calcd. C 62.53, H 4.26, N
22.79; found C 62.72, H 4.49, N 22.81.
6-(2-Furylmethyl)imidazo[1,2-a]pyrimidin-7-ylamine (4m): Ethyl
acetate/methanol (19:1); white solid (0.39 g from 0.58 g), m.p. 234–
236 °C. IR (KBr): νmax = 1656 (C=N), 3431 (NH2) cm–1. 1H NMR
6-{[3-(2,4-Dichlorophenyl)isoxazol-5-yl]methyl}imidazo[1,2-a]-
pyrimidin-7-ylamine (4s): Ethyl acetate/methanol (15:1); white solid
˜
([D6]DMSO, 300 MHz): δ = 4.03 (s, 2 H, CH2), 6.18 (d, J = 2.7 Hz,
1 H, ArH), 6.38–6.40 (m, 1 H, ArH), 7.54 (s, 1 H, ArH), 7.60 (d,
(0.81 g from 1.20 g), m.p. 135–138 °C. IR (KBr): ν
= 1651
˜
max
Eur. J. Org. Chem. 2008, 4334–4343
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4341

S. Nag, A. Mishra, S. Batra
(C=N), 3424 (NH2) cm–1. 1H NMR ([D6]DMSO, 300 MHz): δ = tific and Industrial Research (CSIR), New Delhi in the form of
FULL PAPER
4.29 (s, 2 H, CH2), 6.89 (s, 2 H, NH2), 7.59–7.85 (m, 6 H, ArH),
8.67 (s, 1 H, ArH) ppm. 13C NMR ([D6]DMSO, 75 MHz): δ =
25.9, 104.9, 111.4, 112.8, 119.2, 127.6, 128.9, 130.8, 133.1, 133.6,
136.1, 136.3, 145.5, 160.7, 161.2, 170.1 ppm. MS (ES+): m/z =
360.1 [M + 1]+. HRMS (EI): calcd. for C16H11Cl2N5O 359.0341;
found 359.0344.
fellowships. This work was also supported by a grant from the De-
partment of Science and Technology (DST), New Delhi (SR/SI/
OC-16/2006).
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6-[(5-Phenylisoxazol-3-yl)methyl]imidazo[1,2-a]pyrimidin-7-yl-
amine (4t): Ethyl acetate/methanol (15:1); white solid (0.63 g from
1.00 g), m.p. 122–125 °C. IR (KBr): ν
= 1649 (C=N), 3411
˜
max
(NH2) cm–1. 1H NMR ([D6]DMSO, 300 MHz): δ = 4.08 (s, 2 H,
CH2), 7.02 (s, 1 H, ArH), 7.38–7.52 (m, 3 H, ArH), 7.63 (s, 1 H,
ArH), 7.73 (s, 1 H, ArH), 7.83 (br. s, 2 H, ArH), 8.56 (s, 1 H, ArH)
ppm. MS (ES+): m/z = 292.2 [M + 1]+. HRMS (EI): calcd. for
C16H13N5O 291.1120; found 291.1119.
6-[(5-Methyl-3-phenylisoxazol-4-yl)methyl]imidazo[1,2-a]pyrimidin-
7-ylamine (4u): Ethyl acetate/methanol (15:1); white solid (0.59 g
from 0.81 g), m.p. 136–138 °C. IR (KBr): νmax = 1666 (C=N), 3413
˜
(NH2) cm–1. 1H NMR ([D6]DMSO, 300 MHz): δ = 2.40 (s, 3 H,
CH3), 3.62 (s, 2 H, CH2), 6.87 (s, 2 H, NH2), 7.10 (s, 1 H, ArH),
7.33 (s, 1 H, ArH), 7.47 (s, 5 H, ArH), 7.89 (s, 1 H, ArH) ppm.
13C NMR ([D6]DMSO, 75 MHz): δ = 11.3, 21.7, 108.2, 110.0,
110.1, 127.9, 129.5, 130.2, 132.1, 148.7, 157.5, 162.4, 169.0 ppm.
MS (ES+): m/z = 306.2 [M + 1]+. HRMS (EI): calcd. for
C17H15N5O 305.1277; found 305.1281.
6-[(1,5-Diphenyl-1H-pyrazol-3-yl)methyl]imidazo[1,2-a]pyrimidin-
7-ylamine (4v): Ethyl acetate/methanol (17:1); white solid (0.67 g
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from 1.48 g), m.p. 191–193 °C. IR (KBr): νmax = 1664 (C=N), 3351
˜
(NH2) cm–1. 1H NMR ([D6]DMSO, 300 MHz): δ = 3.90 (s, 2 H,
CH2), 6.58 (s, 1 H, ArH), 6.86 (s, 2 H, NH2), 7.22–7.44 (m, 12 H,
ArH), 8.38 (s, 1 H, ArH) ppm. 13C NMR ([D6]DMSO, 75 MHz):
δ = 27.2, 108.2, 110.7, 111.7, 116.2, 125.7, 128.2, 128.9, 129.2,
129.6, 130.5, 133.7, 140.2, 144.1, 150.0, 158.8 ppm. MS (ES+): m/z
= 367.3 [M + 1]+. HRMS (EI): calcd. for C22H18N6 366.1593;
found 366.1601.
Typical Procedure for Acetylation of 4b: Ac2O (0.18 mL,
1.93 mmol) was added dropwise to a mixture of compound 4b
(0.25 g, 0.97 mmol) and pyridine (0.50 mL) at 0 °C, and the reac-
tion mixture was stirred at room temperature for 3 h. On comple-
tion (as monitored by TLC, ca. 3 h), the reaction mixture was di-
luted with ethyl acetate (15 mL) and washed with water (20 mL).
The organic layer was separated, whereas the aqueous layer was
extracted with ethyl acetate (2ϫ15 mL). The organic layers were
combined, dried with Na2SO4, concentrated and purified by col-
umn chromatography on silica gel using ethyl acetate/methanol
(40:1, v/v) as eluent to yield the pure product 5b (0.29 g, 81%) as
a white solid.
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N-[6-(2-Chlorobenzyl)imidazo[1,2-a]pyrimidin-7-yl]acetamide (5b):
M.p. 212–214 °C. IR (KBr): νmax = 1665 (C=N and NHCO), 3451
˜
(NH) cm–1. 1H NMR ([D6]DMSO, 300 MHz): δ = 2.10 (s, 3 H,
CH3), 4.07 (s, 2 H, CH2), 7.31–7.58 (m, 4 H, ArH), 7.82 (s, 1 H,
ArH), 8.33 (s, 1 H, ArH), 8.46 (s, 1 H, ArH) ppm. MS (ES+): m/z
= 301.2 [M + 1]+. C15H13ClN4O (300.0778): calcd. C 59.91, H 4.36,
N 18.63; found C 60.12, H 4.48, N 18.56.
Supporting Information (see footnote on the first page of this
1
article): Copies of the H and 13C NMR spectra of all new com-
pounds.
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S. N. and A. M. gratefully acknowledge financial support from the
University Grants Commission (UGC) and the Council of Scien-
4342
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Received: May 6, 2008
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Published Online: July 16, 2008
Eur. J. Org. Chem. 2008, 4334–4343
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4343