First example of the Groebke MCR using hydoxybenzaldehydes and substituted 2-aminopyrimidines

Article abstract of DOI:10.1002/jhet.5570450606

(Chemical Equation Presented) A three component condensation of 2-aminopyrimidines, isocyanides and 4-hydroxybenzaldehydes was studied. 3-Amino-2-(4-hydroxyphenyl)imidazo[1,2-a]pyrimidine derivatives were obtained in moderate yields. Using 4-hydroxy-3,5-dimethoxybenzaldehyde and 2-aminopyrimidine as starting materials in the condensation led to mixtures of isomeric 2- and 3-aminoimidazo[1,2-a]pyrimidines. It was demonstrated, that the regiospecificity of this reaction is mainly defined by the steric hindrance of substituents on the pyrimidine nucleus and the carbonyl activity of the corresponding aldehydes.

Full text of DOI:10.1002/jhet.5570450606

Nov-Dec 2008
1589
First example of the Groebke MCR using hydoxybenzaldehydes and
substituted 2-aminopyrimidines
Anatoliy I. Polyakova, Vera A. Eryominaa, Lidiya A. Medvedevaa, Nadezhda I.
Tihonovaa, Leonid. G. Voskressensky*b
aNew Chemistry Horizons Laboratories Ltd., P.O.B. 130, Moscow, Russia, 115522
bOrganic Chemistry Department of Russian Peoples FriendshipUniversity, 6, Miklukho-Maklaya St.,
Moscow, Russia, 117198
Received January 30, 2008
Ar
N
R3
N
N
N
NHR
Ar
R3
N
R2
C
NH2
N
N
NHR
N
20o C, H+
CH3OH
R2
R1
R1
R
O
R3
1
H
R1
N
R2
Ar
2
A three component condensation of 2-aminopyrimidines, isocyanides and 4-hydroxybenzaldehydes was
studied. 3-Amino-2-(4-hydroxyphenyl)imidazo[1,2-a]pyrimidine derivatives were obtained in moderate
yields. Using 4-hydroxy-3,5-dimethoxybenzaldehyde and 2-aminopyrimidine as starting materials in the
condensation led to mixtures of isomeric 2- and 3-aminoimidazo[1,2-a]pyrimidines. It was demonstrated,
that the regiospecificity of this reaction is mainly defined by the steric hindrance of substituents on the
pyrimidine nucleus and the carbonyl activity of the corresponding aldehydes.
J. Heterocyclic Chem., 45, 1589 (2008).
INTRODUCTION
and B. However we failed finding any information on the
reactivity of substituted 2-aminopyrimidines (2-amino-
pyrimidines derivatives) in this MCR. Moreover, the
usage of hydroxybenzaldehydes as carbonyl component in
this reaction has not yet been described.
In spite of the reported possibility [11] to preclude the
formation of isomer B by the use of NH4Cl as a catalyst
and aprotic solvent (toluene), more recent paper [12]
reports on the concurrent formation of isomers A and B
under the same reaction conditions . This information,
along with the data on high stereoselectivity of this MCR
in the case of 2-aminopyridine and 2-aminopyrazine [5,6]
let us suppose that the amine basicity and spatial
hindrance along with the reactivity of the carbonyl
compound are the key factors in determining the reaction
pathway.
Multi-component reactions (MCRs) are widely applied
in the synthesis of compounds with high molecular
diversity [1,2]. The three component, ‘one-pot’
condensation of 2-aminodiazines, aldehydes and
isocyanides suggested in 1998 by Groebke enabled to
obtain libraries of imidazo[1,2-a]azines [3-8]. Later the
preparative variants of this reaction were elaborated both
in solution and on solid support [9,10]. On further
studying the Groebke reaction [8,11] it was shown that
along
a]pyrimidines,
with
the
the
desired
isomeric
3-aminoimidazo[1,2-
2-aminoimidazo[1,2-
a]pyrimidines were formed as by-products (Scheme 1).
Scheme 1
In this context, we studied the reactions of 2-
aminopyrimidine, 4-methyl-2-aminopyrimidine and 4,6-
dimethyl-2-aminopyrimidine with various aromatic and
cycloaliphatic isocyanides and hydroxy-substituted
benzaldehydes.
O
N
R'
N C
NH2
R
H
N
20 oC, cat.
pathway b
CH3OH
pathway a
RESULTS AND DISCUSSION
H
N
N
N
N
Imidazo[1,2-a]pyrimidines obtained by this MCR are
representatives of 1,7-dideaza-5-azapurines, among which
compounds with different substantial bioactivity were
found [13]. The presence of a hydroxyl group in the target
compounds could not only add one more point of
diversity to the molecule core, but have a considerable
influence on their pharmaceutical properties (metabolism,
transportation, the influence on hypoxia and redox
N
R
R'
N
N
R
HN R'
A
B
The available literature data points out that according to
the Scheme 1, the Groebke reaction using 2-amino-
pyrimidine leads towards two main products A (“normal”)

1590
A. I. Polyakov, V. A. Eryomina, L. A. Medvedeva, N. I. Tihonova, L. G. Voskressensky
Vol 45
Scheme 2
Ar
N
N
R4NC
R3
Ar
R3
N
NHR4
N
N
R2
N
R3
R2
R1
pathway a
N
N
R1
R3
O
1-7, 9-21a, 22-30
CH3OH
R2
NH2
Ar
20 oC, cat.
H
R1
pathway b
N
N
R2
NH
C
NHR4
N
R4
N
N
R1
R3
N
Ar
Ar
R2
R1
8, 21b
processes in biomembranes and inside of cells). The
presence of hydroxyphenyl fragment is typical for many
synthetic and natural antioxidants [14-16]. Since the
pathogenetic role of active metabolites of oxygen and
organic free radicals was identified for more than 100
diseases, we can expect the synthesis and screening of
hydroxyl-containing aminoimidazo[1,2-a]azine deriva-
tives as antioxidants to be expedient.
Out of all the catalysts described in the literature
(HClO4, Sc(OTf)3, AcOH and NH4Cl) we used acetic acid
as catalyst of choice, since according to the previous data
[8] it does not favor the formation of B.
For unsubstituted 2-aminopyrimidine almost all the
reactions led to the formation of 2-alkyl(aryl)-3-
aminoimidazo[1,2-a]pyrimidine derivatives A as the only
isolated product of the reaction. The only exception was
the MCR, involving 2-aminopyrimidine and 4-hydroxy-
3,5-dimethoxybenzaldehyde, in this case the mixture of 2-
and 3-aminoimidazopyridines (Table 1, compounds 7, 8,
21a, 21b) was formed (Scheme 2). Compounds 7 and 8
were isolated by column chromatography of the reaction
mixture, whereas the attempts to separate compounds 21a
and 21b failed and they were characterized as a mixture,
4:1, according to NMR data.
The structures of 7 and 8 were unambiguously
elucidated on the base of the NOESY spectra. In the
NOESY spectrum of compound 8 the intense NOE
between 4-H and ꢀ-H was observed (Figure 1), whereas
its absence in the spectrum of 7 was consistent with the
offered structure. We refer the formation of two structural
Using acetic acid as a catalyst and carrying out the
reaction at 20 ºC provided a high regiospecifity although
it made the process longer (2-7 days). Moreover the mild
reaction conditions diminished the decomposition of
aromatic isocyanides. Yields of the recrystallized products
did not exceed 25-30% (Scheme 2, Table 1).
Table 1
Imidazo[1,2-a]pyrimidines 1-30 yields and MP.
ꢁꢁ
R1
H
R2
H
R3
R4
Ar
Yield, %
26
melting
point, °C
OMe
187-190
267-269
204-206
1
H
OH
OMe
CO2Me
39
35
2
3
H
H
H
H
H
H
OH
OMe
CO2Me
OH
CO2Me
OMe
29
17
33
230-232
224-225
232-233
4
CH3
CH3
CH3
H
H
H
CH3
CH3
CH3
OH
OMe
5
OH
OMe
617
CO2Me
OH

Nov-Dec 2008
First example of the Groebke MCR using hydoxybenzaldehydes
1591
Table 1 (continued)
ꢀꢀ
R1
H
R2
H
R3
H
R4
Ar
Yield, %
34
melting
point, °C
718
O
O
OMe
OH
250-252
OMe
819
O
O
OMe
H
H
H
15
128-130
OH
OMe
tert-Bu
920
10
260 (dec)
250-253
H
H
H
H
CH3
H
10
Me
OH
tert-Bu
O
O
OMe
31
OH
H
H
H
H
H
H
28
16
227-229
11
12
OH
Me
tert-Bu
211 (dec)
OH
tert-Bu
Et
Me
i-Pr
H
H
H
H
H
H
H
H
H
19
23
36
229 (dec)
263
13
14
15
OH
Et
i-Pr
i-Pr
i-Pr
i-Pr
OH
Me
257-259
OH
Me
tert-Bu
H
H
H
28
274-278
16
OMe
OH
tert-Bu
CO2Me
H
H
H
H
H
H
30
27
270-273
258-260
17
18
OH
OH
CO2Me
OMe
CH3
H
H
H
CH3
H
24
27
271-274
236-237
19
20
OMe
OH
tert-Bu
CO2Me
OH
tert-Bu
OMe
Me
H
H
H
H
H
H
according to
NMR a mixture
of 21a and 21b,
1:4
-
21a
21b
and
OH
OMe
OH
29
273-275
22
i-Pr
OH

1592
A. I. Polyakov, V. A. Eryomina, L. A. Medvedeva, N. I. Tihonova, L. G. Voskressensky
Vol 45
Table 1 (continued)
ꢀꢀ
R1
H
R2
H
R3
H
R4
Ar
Yield, %
46
melting
point, °C
OH
OH
23
24
254-256
CO2Me
tert-Bu
Me
H
H
H
H
H
H
H
H
H
25
27
49
247-249
280-284
266-268
OH
tert-Bu
tert-Bu
25
26
i-Pr
OH
tert-Bu
Me
Me
OMe
OH
OMe
OMe
27
CH3
H
CH3
31
145-146
i-Pr
OH
OMe
OMe
28
29
H
H
H
H
43
27
229-231
275-277
CO2Et
OH
OH
Me
Me
CH3
CH3
30
H
H
H
39
248-249
OH
isomers to the increased carbonyl activity of the starting
aldehyde, making the C=O attack to the cyclic pyrimidine
nitrogen possible.
presumably can be explained by the steric hindrance
caused by two Me groups, shielding the cyclic nitrogen
atom thus disfavoring pathway b. (Scheme 2)
The use of 4-methyl-2-aminopyrimidine in this MCR
always led to the formation of multi-component reaction
mixtures, which we were unable to separate. The only
exception was the condensation of 4-hydroxy-3,5-di-tert-
butylbenzaldehyde, 4-methyl-2-aminopyrimidine and 4-
methylphenylisocyanide where we were lucky to isolate
the corresponding “normal” product 9 (Figure 2).
O
O
HO
O
O
O
O
1
2
NH
N
N
ꢀ
2
7
3
NH
N
3
N
1
O
6
N
4
7
5
N
4
H
ꢀ
H
CH3
OH
5
6
O
H
NOE
N
N
5
1
N
7
8
N
4
H3C
N
H
N
2
Figure 1
3
H
H
N
N
tert-Bu
tert-Bu
H
When 2-amino-4,6-dimethylpyrimidine was used
instead of 2-aminopyrimidine in all the cases (including
the reaction of 3,5-dimethoxy-4-hydroxybenzaldehyde),
only the product A was isolated (Table 1, compounds 4-6,
19, 27, 29). Moreover, the NMR analysis of the reaction
mixture showed the absence of the isomer B. This fact
ꢀ
OH
tert-Bu
OH
tert-Bu
CH3
CH3
9
Figure 2

Nov-Dec 2008
First example of the Groebke MCR using hydoxybenzaldehydes
1593
= 7.0 Hz, 1H, CH-Ar), 6.78 (d, J = 8.4 Hz, 2H, CH-Ar), 3.92 (s,
3H, O-CH3), 3.58 (s, 3H, O-CH3) ppm. 13C NMR: ꢀ 166.2,
150.2, 147.9, 147.4, 146.9, 145.0, 139.3, 135.0, 131.5, 131.3,
124.2, 119.6, 118.1, 115.7, 114.8, 113.2, 112.1, 110.8, 108.7,
55.2, 51.9 ppm. IR (KBr) ꢁmax: 3506, 3332, 1711, 1673, 1509,
1466 cm-1. ESIMS. m/z: 352 (M+). Anal. Calcd for C21H18N4O4:
C, 64.61; H, 4.65; N, 14.38. Found: C, 64.77; H, 4.64; N, 14.27.
Methyl 2-{[2-(4-hydroxy-3-methoxyphenyl)imidazo[1,2-a]-
pyrimidin-3-yl]amino}benzoate (3). Yellow powder. 1H NMR:
ꢀ 9.25 (s, 1H, OH), 9.18 (s, 1H, NH), 8.57 (s, 1H, CH-Ar), 8.44
(d, J = 6.5 Hz, 1H, CH-Ar), 7.96 (d, J = 7.0 Hz, 1H, CH-Ar),
7.56 (s, 1H, CH-Ar), 7.45 (d, J = 6.8 Hz, 1H, CH-Ar), 7.26 (t, J
= 4.8 Hz, 1H, CH-Ar), 7.02 (t, J = 5.0 Hz, 1H, CH-Ar), 6.80 (m,
2H, CH-Ar), 6.18 (d, J = 6.0 Hz, 1H, CH-Ar), 3.92 (s, 3H, O-
CH3), 3.61 (s, 3H, O-CH3) ppm. 13C NMR: ꢀ 167.9, 150.1,
147.9, 147.4, 146.8, 144.9, 139.2, 135.0, 131.4, 131.2, 124.1,
119.7, 118.1, 115.6, 114.7, 113.1, 112.1, 110.5, 108.6, 55.0, 52.0
ppm. IR (KBr) ꢁmax: 3506, 3332, 1711, 1673, 1509, 1465 cm-1.
ESIMS. m/z: 391 (M+1)+. Anal. Calcd for C21H18N4O4: C,
64.61; H, 4.65; N, 14.35. Found: C, 64.81; H, 4.45; N, 14.25.
Methyl 3-{[2-(4-hydroxy-3-methoxyphenyl)-5,7-dimethyl-
imidazo[1,2-a]pyrimidin-3-yl]amino}benzoate (4). Pale
yellow powder. 1H NMR: ꢀ 9.09 (s, 1H, OH), 8.33 (s, 1H, NH),
7.58 (s, 1H, CH-Ar), 7.47 (d, J = 6.8 Hz, 1H, CH-Ar), 7.30 (s,
2H, CH-Ar), 7.11 (s, 1H, CH-Ar), 6.77 (d, J = 7.4 Hz, 2H, CH-
Ar), 6.72 (s, 1H, CH-Ar), 3.79 (s, 3H, O-CH3), 3.62 (s, 3H, O-
CH3), 2.62 (s, 3H, CH3), 2.48 (s, 3H, CH3) ppm. 13C NMR: ꢀ
166.2, 159.6, 148.1, 147.3, 146.6, 145.9, 144.3, 139.6, 130.9,
130.0, 124.3, 119.7, 119.0, 117.5, 115.7, 115.5, 113.0, 110.8,
110.5, 55.1, 52.0, 23.9, 17.5 ppm. IR (KBr) ꢁmax: 3294, 2359,
1722, 1520 cm-1. ESIMS. m/z: 419 (M+1)+. Anal. Calcd for
C23H22N4O4: C, 66.02; H, 5.30; N, 13.39. Found: C, 66.32; H,
5.10; N, 13.19.
According to TLC and 1H NMR analysis only one
isomer 9 is formed in the reaction. The structure of the
product is confirmed by selective 1D ROESY with
preirradiation saturation of 4-H. In the ROESY (standard
software for Bruker DRX-500, mixing time 200 ms) only
for compounds 9 spatial contacts between protons 4-H
and N-H, 5-H, ꢀ-H of N-(4-methylphenyl) fragment are
possible.
In conclusion we investigated the Groebke MCR of 4-
hydroxybenzaldehydes and substituted 2-amino-
pyrimidines. It was demonstrated, that the regiospecificity
of this reaction is mainly defined by the steric hindrance
of substituents on the pyrimidine nucleus and the carbonyl
activity of the corresponding aldehydes. The antioxidant
screening of the compounds synthesized is underway and
will be reported in due course.
EXPERIMENTAL
Melting points are uncorrected. All solvents were distilled and
dried before use. Column chromatography was performed with
1
aluminium oxide. H and 13C NMR spectra were recorded in
CDCl3 solutions, at 25 °C or in DMSO-d6 solutions at 40 °C,
using a 400 MHz NMR spectrometer operating at 400 and 100
MHz correspondingly, peak positions are given in parts per
million (ꢀ) with tetramethylsilane used as the internal standard.
Mass-spectra were registered using ESI or EI techniques.
General procedure. A solution of aminopyrimidine (2.0
mmol), aldehyde (2.0 mmol) and acetic acid (4.0 mmol) in 20
mL of methanol was stirred for 20 min at 20 ºC. The reaction
mixture was cooled and at 0 ºC and isocyanide (2.0 mmol) was
added in one portion. Stirring was continued at 20 ºC for
additional 5-6 hours (TCL monitoring). The products
crystallized from the reaction mixture or on adding several drops
of water. The product was collected by filterration, washed with
water (3ꢁ10 mL), dried and washed again with hexane (50 mL).
The crude product was crystallized (methanol) or purified by
column chromatography (CH2Cl2-CH3OH, 15:5) to give
crystalline compounds 1-30.
4-[3-(Cycloheptylamino)-5,7-dimethylimidazo[1,2-a]pyr-
1
imidine-2-yl]-2-methoxyphenol (5). White powder. H NMR:
ꢀ=8.98 (s, 1H, OH), 7.73 (s, 1H, CH-Ar), 7.56 (d, J = 6.5 Hz,
1H, CH-Ar), 6.82 (d, J = 7.0 Hz, 1H, CH-Ar), 6.60 (s, 1H, CH-
Ar), 4.40 (bs, 1H, NH-CH), 3.85 (s, 3H, O-CH3), 3.08 (m, 1H,
NH-CH), 2.92 (s, 3H, -CH3), 2.52 (s, 3H, CH3), 2.43 (s, 3H,
CH3), 1.40 (m, 12H, 6xCH2) ppm. 13C NMR: ꢀ 157.9, 147.2,
146.0, 145.1, 144.8, 138.7, 125.9, 123.7, 120.3, 115.2, 111.5,
110.0, 59.2, 55.5, 34.0, 27.7 (2C), 23.7 (2C), 23.6 (2C), 18.6
ppm. IR (KBr) ꢁmax: 3328, 2479, 1619, 1519 cm-1. ESIMS. m/z:
380 (M+). Anal. Calcd for C22H28N4O2: C, 69.45; H, 7.42; N,
14.72. Found C, 69.75; H, 7.22; N, 14.52.
4-[3-(Cycloheptylamino)imidazo[1,2-a]pyrimidin-2-yl]-2-
1
methoxyphenol (1). White powder. H NMR: ꢀ 9.14 (s, 1H,
OH), 8.67 (d, J = 6.5 Hz, 1H, CH-Ar), 8.41 (s, 1H, CH-Ar), 7.82
(s, 1H, CH-Ar), 7.68 (d, J = 8.2 Hz, CH-Ar), 6.99 (dd, J = 4.2,
9.9 Hz, 1H, CH-Ar), 6.85 (d, J = 8.2 Hz, 1H, CH-Ar), 4.76 (d, J
= 4.6 Hz, 1H, NH-CH), 3.86 (s, 3H, O-CH3), 3.14 (m, 1H, NH-
CH), 1.73 (m, 2H, CH2), 1.59 (m, 2H, CH2), 1.46 (m, 6H,
3xCH2), 1.23 (m, 2H, CH2) ppm. 13C NMR: ꢀ 148.5, 147.4,
146.2, 143.5, 136.6, 130.9, 125.4, 122.9, 119.9, 115.4, 110.9,
107.8, 57.9, 55.5, 34.7 (2C), 27.8 (2C), 23.3 (2C) ppm. IR (KBr)
ꢁmax: 3343, 2937, 1611, 1523, 1362 cm-1. EIMS. m/z (relative
intensity): 352 (28), 255 (57), 228 (100), 213 (8), 79 (64), 55
(45), 41 (31). Anal. Calcd for C20H24N4O2: C, 68.16; H, 6.86; N,
15.90. Found: C, 68.46; H, 6.76; N, 15.60.
Methyl 2-{[2-(4-hydroxy-3-methoxyphenyl)-5,7-dimethyl-
imidazo[1,2-a]pyrimidin-3-yl]amino}benzoate (6). Brown
1
powder. H NMR: ꢀ 9.21 (s, 1H, OH), 9.03 (bs, 1H, NH), 7.94
(d, J = 6.5 Hz, 1H, CH-Ar), 7.51 (s, 1H, CH-Ar), 7.42 (d, J = 6.3
Hz, 1H, CH-Ar), 7.31 (t, J = 4.7 Hz, 1H, CH-Ar), 6.78 (m, 2H,
CH-Ar), 6.70 (s, 1H, CH-Ar), 6.22 (d, J = 7.2 Hz, 1H, CH-Ar),
3.92 (s, 3H, O-CH3), 3.59 (s, 3H, O-CH3), 2.59 (s, 3H, CH3),
2.52 (s, 3H, CH3) ppm. 13C NMR: ꢀ 167.7, 159.3, 149.5, 147.2,
146.5, 146.0, 144.4, 139.1, 135.0, 131.3, 124.4, 119.6, 117.6,
115.4, 115.1, 114.1, 111.2, 110.5, 110.2, 54.9, 51.9, 23.9, 17.2
ppm. IR (KBr) ꢁmax: 3276, 1702, 1619, 1508 cm-1. ESIMS. m/z:
419 (M+1)+. Anal. Calcd for C23H22N4O4: C, 66.02; H, 5.30; N,
13.39. Found: C, 66.32; H, 5.10; N, 13.19.
Methyl 3-{[2-(4-hydroxy-3-methoxyphenyl)imidazo[1,2-a]-
pyrimidin-3-yl]amino}benzoate (2). Pale brown powder. 1H
NMR: ꢀ 9.62 (s, 1H, OH), 9.08 (s, 1H, NH), 8.53 (s, 1H, CH-
Ar), 8.41 (d, J = 6.8 Hz, 1H, CH-Ar), 7.93 (d, J = 7.0 Hz, 1H,
CH-Ar), 7.55 (s, 1H, CH-Ar), 7.41 (d, J = 6.8 Hz, 1H, CH-Ar),
7.25 (t, J = 7.7 Hz, 1H, CH-Ar), 7.16 (s, 1H, CH-Ar), 7.02 (d, J
4-[3-(2,3-Dihydro-1,4-benzodioxin-6-ylamino)imidazo[1,2-
a]pyrimidin-2-yl]-2,6-dimethoxyphenol (7). Pale brown
1
powder. H NMR: ꢀ 8.58 (s, 1H, OH), 8.55 (d, J = 6.8 Hz, 1H,
CH-Ar), 8.47 (d, J = 6.9 Hz, 1H, CH-Ar), 7.92 (s, 1H, NH),

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A. I. Polyakov, V. A. Eryomina, L. A. Medvedeva, N. I. Tihonova, L. G. Voskressensky
Vol 45
7.35 (s, 2H, CH-Ar), 7.04 (d, J = 6.4 Hz, 1H, CH-Ar), 6.67 (d, J
= 7.4 Hz, 1H, CH-Ar), 6.08 (d, J = 7.2 Hz, 1H, CH-Ar), 5.99 (s,
1H, CH-Ar), 4.13 (t, J = 5.2 Hz, 2H, CH2), 4.10 (t, J = 5.2 Hz,
2H, CH2), 3.70 (s, 6H, 2xO-CH3) ppm. 13C NMR: ꢀ 150.0, 147.9
(2C), 144.5, 143.9, 139.9, 138.5, 136.3, 135.8, 130.9, 123.1,
117.7, 117.2, 108.6, 106.2, 104.5 (2C), 101.5, 64.3, 63.7, 55.7
(2C) ppm. IR (KBr) ꢁmax: 3280, 2160, 1618, 1507 cm-1. ESIMS.
m/z: 421 (M+1)+. Anal. Calcd for C22H20N4O5: C, 62.85; H,
4.80; N, 13.33. Found: C, 62.55; H, 4.90; N, 13.43.
4-[2-(2,3-Dihydro-1,4-benzodioxin-6-ylamino)-imidazo[1,2-
a]pyrimidin-3-yl] (8). Dark green powder. 1H NMR: ꢀ 8.67 (s,
1H, OH), 8.65 (s, 1H, NH), 8.32 (d, J = 7.2 Hz, 1H, CH-Ar),
7.99 (s, 1H, CH-Ar), 7.37 (s, 1H, CH-Ar), 7.04 (dd, J = 2.3, 6.9
Hz, 1H, CH-Ar), 6.96 (dd, J = 4.4, 7.5 Hz, 1H, CH-Ar), 6.80 (s,
2H, CH-Ar), 6.68 (d, J = 6.8 Hz, 1H, CH-Ar), 4.21 (t, J = 4.7
Hz, 2H, CH2), 4.17 (t, J = 4.7 Hz, 2H, CH2), 3.80 (s, 6H, 2xO-
CH3) ppm. 13C NMR: ꢀ 148.5, 145.8, 144.7, 142.9, 137.0, 136.7,
135.8, 129.3, 117.0, 116.2 (2C), 110.4, 108.3, 106.9 (2C), 105.8,
105.5, 64.2, 63.7, 56.0 (2C) ppm. IR (KBr) ꢁmax: 3275, 2366,
1619, 1508 cm-1. ESIMS. m/z: 421 (M+1)+. Anal. Calcd for
C22H20N4O5: C, 62.85; H, 4.80; N, 13.33. Found: C, 62.55; H,
4.90; N, 13.43.
2,6-Di-tert-butyl-4-{7-methyl-3-[(4-methylphenyl)amino]-
imidazo[1,2-a]pyrimidin-2-yl}phenol (9). Brown powder. 1H
NMR: ꢀ 8.13 (d, J = 6.7 Hz, 1H, CH-Ar), 7.81 (s, 2H, OH, CH-
Ar), 7.75 (s, 1H, NH), 6.87 (d, J = 8.1 Hz, 2H, 2xCH-Ar), 6.78
(d, J = 6.7 Hz, 1H,CH-Ar), 6.55 (s, 1H, CH-Ar), 6.42 (d, J = 8.1
Hz, 2H, 2xCH-Ar), 2.59 (s, 3H, CH3), 2.21 (s, 3H, CH3), 1.34 (s,
18H, 2xCH-(CH3)3) ppm. 13C NMR: ꢀ=159.1, 153.7, 144.6,
143.3 (2C), 138.9, 138.7, 130.2, 129.6 (2C), 126.8, 124.7, 123.6
(2C), 116.1, 112.9 (2C), 109.0, 34.4, 30.2 (6C), 24.3, 20.0, 15.1
ppm. IR (KBr) ꢁmax: 3615, 3236, 2956, 2159, 1619, 1515 cm-1.
ESIMS. m/z: 441 (M+1)+. Anal. Calcd for C28H34N4O: C, 75.98;
H, 7.74; N, 12.66. Found: C, 75.68; H, 7.94; N, 12.86.
4-[3-(1,3-Benzodioxol-5-ylamino)imidazo[1,2-a]pyrimidin-
2-yl]-2-methoxyphenol (10). Pale brown powder. 1H NMR: ꢀ
9.14 (s, 1H, OH), 8.53 (s, 1H, CH-Ar), 8.39 (d, J = 6.3 Hz, 1H,
CH-Ar), 7.97 (s, 1H, NH), 7.64 (s, 1H, CH-Ar), 7.53 (d, J = 8.3
Hz, 1H, CH-Ar), 7,02 (dd, J = 4.2, 6.2 Hz, 1H, CH-Ar), 6.81 (d,
J = 8.3 Hz, 1H, CH-Ar), 6.68 (d, J = 8.3 Hz, 1H, CH-Ar), 6.23
(s, 1H, CH-Ar), 5.91 (d, J = 8.5 Hz, 1H, CH-Ar), 5.87 (s, 2H,
2xCH-Ar), 3.72 (s, 3H, CH3) ppm. 13C NMR: ꢀ 149.8, 148.1,
147.4, 146.7, 144.6, 140.8, 139.9, 138.8, 130.9, 124.4, 119.8,
116.7, 115.5, 110.9, 108.8, 108.5, 104.3, 100.4, 95.7, 55.3 ppm.
IR (KBr) ꢁmax: 3554, 3302, 1618, 1529, 1503 cm-1. EIMS. m/z
(relative intensity): 376 (19), 228 (18), 150 (12), 121 (6), 106
(10), 90 (6), 80 (100), 63 (23), 53 (47), 39 (18). Anal. Calcd for
C20H16N4O4: C, 63.83; H, 4.29; N, 14.89. Found: C, 63.53; H,
4.49; N, 15.09.
2,6-Di-tert-butyl-4-{3-[(2-ethyl-6-methylphenyl)amino]im-
idazo[1,2-a]pyrimidin-2-yl}phenol (12). Brown powder. 1H
NMR: ꢀ=8.47 (s, 1H, OH), 8.23 (d, J = 6.6 Hz, 1H, CH-Ar),
7.79 (s, 1H, NH), 7.14 (s, 2H, CH-Ar), 7.00 (m, 3H, CH-Ar),
6.84 (d, J = 7.0 Hz, 1H, CH-Ar), 6.72 (t, J = 7.4 Hz, 1H, CH-
Ar), 2,51 (m, 2H, CH2), 1,68 (s, 3H, CH3), 1.32 (s, 18H, 2x(C-
(CH3)3)), 1.02 (t, J = 7.3 Hz, 3H, CH2-CH3) ppm. 13C NMR: ꢀ
154.1, 149.2, 134.7, 140.6, 139.0, 135.3 (2C), 131.3, 131.1,
130.1, 127.6, 124.4, 124.8, 124.3 (2C), 120.4, 119.4, 108.6, 34.9
(2C), 30.6 (6C), 24.6, 18.8, 14.4 ppm. IR (KBr) ꢁmax: 3534,
2961, 1610, 1466 cm-1. ESIMS. m/z: 456 (M+). Anal. Calcd for
C29H36N4O: C, 76.28; H, 7.95; N, 12.27. Found: C, 76.48; H,
7.75; N, 12.37.
2,6-Diisopropyl-4-(3-(2-ethyl-6-methylphenyl)imidazo[1,2-
a]pyrimidin-2-yl)phenol (13). Brown powder. 1H NMR: ꢀ=8.48
(dd, J = 1.8, 4.0 Hz, 1H, CH-Ar), 8.44 (dd, J = 1.8, 6.7 Hz, 1H,
CH-Ar), 8.17 (s, 1H, OH), 7.54 (s, 2H, CH-Ar), 7,11 (s, 1H,
NH), 7.02 (dd, J = 4.1, 6.7 Hz, 1H, CH-Ar), 6.97 (d, J = 7.0 Hz,
1H, CH-Ar), 6.84 (d, J = 7.0 Hz, 1H, CH-Ar), 6.71 (t, J = 7.4
Hz, 1H, CH-Ar), 3.23 (m, 2H, 2xCH-(CH3)2), 2.48 (m, 2H, CH2-
CH3) 1.66 (s, 3H, CH3), 1.04 (m, 15H, 2xCH-(CH3)2+CH2-CH3)
ppm. 13C NMR: ꢀ 151.0, 149.3, 143.9, 140.9, 139.0, 135.2 (2C),
131.4, 131.1, 130.1, 127.5, 125.3, 124.7, 122.7 (2C), 120.2,
119.1, 108.6, 26.4 (2C), 24.4, 23.2 (4C), 18.8, 14.3 ppm. IR
(KBr) ꢁmax: 3534, 2960, 1612, 1498 cm-1. ESIMS. m/z: 428
(M+1)+. Anal. Calcd for C27H32N4O: C, 75.67; H, 7.53; N,
13.07. Found: C, 75.87; H, 7.33; N, 13.17.
2,6-Diisopropyl-4-{3-[(4-isopropylphenyl)amino]imidazo-
[1,2-a]pyrimidin-2-yl}phenol (14). Brown powder. 1H NMR: ꢀ
8.50 (m, 2H, CH-Ar), 8.12 (s, 1H, OH), 7.95 (s, 1H, NH), 7.66
(s, 2H, CH-Ar), 7.00 (m, 3H, CH-Ar), 6.45 (d, J = 8.4 Hz, 2H,
CH-Ar), 3.28 (m, 2H, 2xCH-(CH3)2), 2.74 (m, 1H, CH-(CH3)2),
1.12 (d, J = 6.8 Hz, 6H, CH-(CH3)2), 1.04 (d, J = 6.8 Hz, 12H,
2xCH-(CH3)2) ppm. 13C NMR: ꢀ 151.2, 150.0, 145.0, 144.0,
139.9, 138.9, 135.3 (2C), 131.3, 127.5 (2C), 124.9, 122.7 (2C),
117.0, 113.6 (2C), 108.8, 33.0, 26.3 (2C), 24.6 (2C), 23.2 (4C)
ppm. IR (KBr) ꢁmax: 3361, 3237, 2959, 1611, 1515 cm-1.
ESIMS. m/z: 429 (M+1)+. Anal. Calcd for C27H32N4O: C, 75.67;
H, 7.53; N, 13.07. Found: C, 75.67; H, 7.53; N, 13.07.
4-{3-[(2,6-Dimethylphenyl)amino]imidazo[1,2-a]pyrimid-
1
in-2-yl}phenol (15): Pale brown powder. H NMR: ꢀ 9.45 (s,
1H, OH), 8.46 (s, 1H, CH-Ar), 8.18 (d, J = 6.2 Hz, 1H, CH-Ar),
7.83 (d, J = 8.4 Hz, 2H, CH-Ar), 7.10 (s, 1H, NH), 6.97 (dd, J =
4.6, 9.9 Hz, 1H, CH-Ar), 6.90 (d, J = 7.3 Hz, 2H, CH-Ar), 6.74
(d, J = 8.5 Hz, 2H, CH-Ar), 6.69 (t, J = 7.4 Hz, 1H, CH-Ar),
1.88 (s, 6H, 2xCH3) ppm. 13C NMR: ꢀ 157.0, 148.7, 143.3,
140.6, 137.6, 130.4 (2C), 129.3 (2C), 128.4 (2C), 125.5, 124.2,
120.2, 118.9, 114.9 (2C), 108.2, 18.2 (2C) ppm. IR (KBr) ꢁmax
:
3553, 3310, 1610, 1496, 1473 cm-1. EIMS. m/z (relative
intensity): 330 (70), 236 (16), 223 (14), 211 (48), 198 (60), 132
(25), 120 (38), 103 (9), 91 (10), 79 (100), 65 (18), 53 (45), 44
(8), 39 (26). ESIMS. m/z: 330 (M+). Anal. Calcd for C20H18N4O:
C, 72.71; H, 5.49; N, 16.96. Found: C, 72.91; H, 5.29; N, 16.86.
2,6-Di-tert-butyl-4-{3-[(4-methoxyphenyl)amino]imidazo-
4-[3-(Cycloheptylamino)imidazo[1,2-a]pyrimidin-2-yl]-
1
phenol (11). White powder. H NMR: ꢀ 9.54 (s, 1H, OH), 8.64
(d, J = 6.5 Hz, 1H, CH-Ar), 8.41 (d, J = 1.7 Hz, 1H CH-Ar),
8.04 (d, J = 8.5 Hz, 2H, CH-Ar), 6.98 (dd, J = 4.6, 6.5 Hz, 1H,
CH-Ar), 6.82 (d, J = 8.3 Hz, 2H, CH-Ar), 4.71 (d, J = 5.1 Hz,
1H, NH), 3.15 (m, 1H, NH-CH), 1.72 (m, 2H, CH2), 1.58 (m,
2H, CH2), 1.41 (m, 6H, 3xCH2), 1.23 (m, 2H, CH2) ppm. 13C
NMR: ꢀ 156.9, 148.3, 143.5, 136.6, 130.8, 128.2 (2C), 125.0,
122.7, 115.1 (2C), 107.7, 57.7, 34.6 (2C), 27.9 (2C), 23.2 (2C)
ppm. IR (KBr) ꢁmax: 3300, 2934, 1609, 1503 cm-1. EIMS. m/z
(relative intensity): 322 (44), 225 (83), 198 (100), 119 (11), 79
(99), 65 (10), 55 (62), 41 (42). Anal. Calcd for C19H22N4O: C,
70.78; H, 6.88; N, 17.38. Found: C, 70.48; H, 6.98; N, 17.68.
1
[1,2-a]pyrimidin-2-yl}phenol (16): Brown powder. H NMR:
ꢀ=8.60 (d, J = 4.6 Hz, 1H, CH-Ar), 8.31 (dd, J = 1.5, 5.8 Hz,
1H, CH-Ar), 8.03 (s, 1H, OH), 7.42 (d, J = 8.4 Hz, 2H, CH-Ar),
7.26 (s, 2H, CH-Ar), 7.14 (s, 1H, NH), 6.95 (dd, J = 4.5, 6.32
Hz, 1H, CH-Ar), 6.76 (d, J = 8.8 Hz, 2H, CH-Ar), 3.69 (s, 3H,
O-CH3), 1.41 (s, 18H, 2xC-(CH3)3) ppm. 13C NMR: ꢀ 153.5,
152.9, 145.9, 145.7, 144.8, 139.6 (2C), 136.5, 128.7, 125.1 (2C),
118.9, 118.1 (2C), 113.6 (2C), 108.4, 106.0, 55.1, 34.5 (2C),

Nov-Dec 2008
First example of the Groebke MCR using hydoxybenzaldehydes
1595
30.1 (6C) ppm. IR (KBr) ꢀmax: 3554, 1620, 1571, 1511 cm-1.
EIMS. m/z (relative intensity): 444 (100), 429 (23), 222 (13), 79
(22), 57 (43), 41 (44). Anal. Calcd for C27H32N4O2: C, 72.95; H,
7.26; N, 12.60. Found: C, 72.75; H, 7.46; N, 12.70.
4-{3-[(4-Isopropylphenyl)amino]imidazo[1,2-a]pyrimidin-
2-yl}benzene-1,2-diol (22). Brown powder. H NMR: ꢁ 9.05 (s,
1
1H, OH), 8.94 (s, 1H, OH), 8.51 (dd, J = 1.6, 5.2 Hz, 1H, CH-
Ar), 8.29 (d, J = 6.6 Hz, 1H, CH-Ar), 7.99 (s, 1H, NH), 7.59 (s,
1H, CH-Ar), 7.39 (d, J = 8.2 Hz, 1H, CH-Ar), 6.99 (m, 3H, CH-
Ar), 6.73 (d, J = 8.2 Hz, 1H, CH-Ar), 6.43 (d, J = 8.2 Hz, 2H,
CH-Ar), 2.74 (m, 1H, CH-(CH3)2), 1.13 (d, J = 6.8 Hz, 6H, CH-
(CH3)2) ppm. IR (KBr) ꢀmax: 3221, 2959, 2361, 1607, 1535, 1514
cm-1. ESIMS. m/z: 360 (M+). Anal. Calcd for C21H20N4O2: C,
69.98; H, 5.59; N, 15.54. Found: C, 69.78; H, 5.79; N, 15.64.
Methyl 2-{[2-(3,4-dihydroxyphenyl)imidazo[1,2-a]pyrim-
Methyl 3-{[2-(4-hydroxyphenyl)imidazo[1,2-a]pyrimidin-
1
3-yl]amino}benzoate (17). Pale brown powder. H NMR: ꢁ 9.60
(s, 1H, OH), 8.55 (s, 1H, CH-Ar), 8.47 (s, 1H, NH), 8.39 (d, J =
6.4 Hz, 1H, CH-Ar), 7.89 (d, J = 8.4 Hz, 2H, CH-Ar), 7.34 (d, J =
7.5 Hz, 1H, CH-Ar), 7.27 (t, J = 7.7 Hz, 1H, CH-Ar), 7,16 (s, 1H,
CH-Ar), 7.02 (dd, J = 4.3, 6.3 Hz, 1H, CH-Ar), 6.79 (d, J = 8.4
Hz, 2H, CH-Ar), 6.73 (d, J = 7.2 Hz, 1H, CH-Ar), 3.77 (s, 3H,
CH3) ppm. IR (KBr) ꢀmax: 3559, 1727, 1609, 1529, 1480 cm-1.
EIMS. m/z (relative intensity): 360 (100), 198 (72), 120 (8), 102
(7), 79 (40), 53 (16), 38 (8). Anal. Calcd for C20H16N4O3: C,
66.66; H, 4.48; N, 15.55. Found: C, 66.86; H, 4.28; N, 15.65.
Methyl 2-{[2-(4-hydroxyphenyl)imidazo[1,2-a]pyrimidin-
1
idin-3-yl]amino}benzoate (23). Dark brown powder. H NMR:
ꢁ 9.24 (s, 1H, OH), 9.09 (s, 1H, NH), 9.01 (s, 1H, OH), 8.53 (dd,
J = 1.8, 3.9 Hz, 1H, CH-Ar), 8.36 (d, J = 6.6 Hz, 1H, CH-Ar),
7.97 (d, J = 6.9 Hz, 1H, CH-Ar), 7.52 (d, J = 1.66 Hz, 1H, CH-
Ar), 7.30 (dd, J = 1.7, 8.4 Hz, 1H, CH-Ar), 7.24 (d, J = 7.2 Hz,
1H, CH-Ar), 6.99 (dd, J = 4.2, 6.22 Hz, 1H, CH-Ar), 6.81 (t, J =
7.4 Hz, 1H, CH-Ar), 6.71 (d, J = 8.2 Hz, 1H, CH-Ar), 6.13 (d, J
1
3-yl]amino}benzoate (18). Pale brown powder. H NMR: ꢁ 9.61
(s, 1H, OH), 9.24 (s, 1H, NH), 8.54 (s, 1H, CH-Ar), 8.39 (d, J =
5.8 Hz, 1H, CH-Ar), 7.96 (d, J = 8.0 Hz, 1H, CH-Ar), 7.84 (d, J =
7.6 Hz, 2H, CH-Ar), 7.25 (t, J = 6.6 Hz, 1H, CH-Ar), 7.00 (s, 1H,
CH-Ar), 6.80 (m, 3H, CH-Ar), 6.14 (d, J = 8.5 Hz, 1H, CH-Ar),
3.93 (s, 3H, O-CH3) ppm. IR (KBr) ꢀmax: 3555, 3296, 1683, 1615,
1493 cm-1. EIMS. m/z (relative intensity): 360 (96), 328 (67), 299
(75), 198 (75), 164 (13), 130 (12), 119 (12), 102 (13), 92 (8), 79
(100), 65 (12), 53 (35), 39 (16). Anal. Calcd for C20H16N4O3: C,
66.66; H, 4.48; N, 15.55. Found: C, 66.86; H, 4.28; N, 15.65.
2-Methoxy-4-{3-[(4-methoxyphenyl)amino]-5,7-dimethyl-
imidazo[1,2-a]pyrimidin-2-yl}phenol (19): Brown powder. 1H
NMR: ꢁ 9.07 (s, 1H, OH), 7.71 (s, 1H, NH), 7.61 (s, 1H, CH-Ar),
7.49 (d, J = 8.2 Hz, 1H, CH-Ar), 6.76 (m, 3H, CH-Ar), 6.66 (s,
1H, CH-Ar), 6.40 (d, J = 8.5 Hz, 2H, CH-Ar), 3.63 (s, 6H, 2xO-
= 8.3 Hz, 1H, CH-Ar), 3.93 (s, 3H, CH3) ppm. IR (KBr) ꢀmax
:
3499, 3286, 2360, 1683, 1617, 1583, 1493 cm-1. ESIMS. m/z:
376 (M+). Anal. Calcd for C20H16N4O4: C, 63.83; H, 4.29; N,
14.89. Found: C, 63.63; H, 4.49; N, 14.79.
2,6-Di-tert-butyl-4-{3-[(2-methylphenyl)amino]imidazo-[1,2-
1
a]pyrimidin-2-yl}phenol (24). Brown powder. H NMR: ꢁ 8.70
(s, 1H, OH), 8.36 (s, 1H, NH), 7.42 (s, 1H, CH-Ar), 7.26 (s, 3H,
CH-Ar), 7.14 (s, 1H, CH-Ar), 7.07 (d, J = 6.8 Hz, 1H, CH-Ar),
7.00 (d, J = 4.9 Hz, 1H, CH-Ar), 6.95 (m, 1H, CH-Ar), 6.75 (t, J
= 7.2 Hz, 1H, CH-Ar), 2.22 (s, 3H, CH3), 1.38 (s, 18H, 2xC-
(CH3)3) ppm. IR (KBr) ꢀmax: 3410, 2959, 1619, 1502 cm-1.
ESIMS. m/z: 429 (M+). Anal. Calcd for C27H32N4O: C, 75.67; H,
7.53; N, 13.07. Found: C, 75.87; H, 7.33; N, 13.17.
CH3), 2.63 (s, 3H, CH3), 2.46 (s, 3H, CH3) ppm. IR (KBr) ꢀmax
:
2,6-Di-tert-butyl-4-{3-[(4-isopropylphenyl)amino]imidazo-
[1,2-a]pyrimidin-2-yl}phenol (25): Brown powder. H NMR: ꢁ
3522, 3396, 1620, 1509 cm-1. EIMS. m/z (relative intensity): 390
(25), 256 (32), 214 (10), 134 (14), 108 (100), 93 (13), 77 (15), 67
(93), 53 (12), 42 (23). Anal. Calcd for C22H22N4O3: C, 67.68; H,
5.68; N, 14.35. Found: C, 67.88; H, 5.48; N, 14.45.
1
8.53 (s, 1H, OH), 8.47 (d, J = 6.3 Hz, 1H, CH-Ar), 8.02 (s, 1H,
NH), 7.79 (s, 1H, CH-Ar), 7.02 (m, 4H, CH-Ar), 6.45 (d, J = 7.6
Hz, 2H, CH-Ar), 2.74 (m, 1H, CH-(CH3)2), 1.29 (s, 18H, 2xC-
(CH3)3), 1.12 (d, J = 6.0 Hz, 6H, CH-(CH3)2) ppm. IR (KBr)
ꢀmax: 3623, 3225, 2959, 1511, 1513 cm-1. ESIMS. m/z: 457 (M+).
Anal. Calcd for C29H36N4O: C, 76.28; H, 7.95; N, 12.27. Found:
C, 76.48; H, 7.75; N, 12.37.
Methyl 3-{[2-(3,5-di-tert-butyl-4-hydroxyphenyl)imidazo-
[1,2-a]pyrimidin-3-yl]amino}benzoate (20). Dark brown
1
powder. H NMR: ꢁ 8.56 (s, 1H, OH), 8.49 (m, 2H, NH+CH-
Ar), 7.82 (s, 2H, CH-Ar), 7.35 (d, J = 7.3 Hz, 1H, CH-Ar), 7.28
(t, J = 7.7 Hz, 1H, CH-Ar), 7.15 (s, 1H, CH-Ar), 7.08 (s, 1H,
CH-Ar), 7.04 (m, 1H, CH-Ar), 6.77 (d, J = 6.8 Hz, 1H, CH-Ar),
3.77 (s, 3H, O-CH3), 1.29 (s, 18H, 2xC-(CH3)3) ppm. 13C NMR:
ꢁ 166.2, 154.1, 149.9, 146.0, 144.8, 139.9, 138.8 (2C), 130.9,
130.6, 129.7, 124.2, 123.6 (2C), 119.2, 117.6, 115.4, 113.3,
108.6, 51.9, 34.4 (2C), 30.1 (6C) ppm. IR (KBr) ꢀmax: 3629,
2951, 2360, 1719, 1605 cm-1. ESIMS. m/z: 376 (M+). Anal.
Calcd for C28H32N4O3: C, 71.16; H, 6.83; N, 11.86. Found: C,
71.36; H, 6.93; N, 11.66.
Mixture of 4-[2-(o-tolylamino)imidazo[1,2-a]pyrimidin-3-
yl]- and 4-[2-(o-tolylamino)imidazo[1,2-a]pyrimidin-2-yl]-
2,6-dimethoxyphenols (21). Brown powder. Major compound
1H NMR: ꢁ 8.55 (m, 3H, OH+2CH-Ar), 7.54 (s, 1H, NH), 7.30
(s, 1H, CH-Ar), 7.12 (d, 1H, J = 7.3 Hz, CH-Ar), 7.04 (dd, 1H, J
= 4.7, 6.07 Hz, 1H, CH-Ar), 6.83 (d, J = 7.6 Hz, 1H, CH-Ar),
6.68 (t, J = 7.4 Hz, 1H, CH-Ar), 5.93 (d, J = 7.4 Hz, 1H, CH-
Ar), 3.66 (s, 6H, 2xO-CH3), 2.49 (s, 3H, CH3) ppm. Minor
compound: 1H NMR: ꢁ 8.78 (d, J = 7.4 Hz, 1H, CH-Ar), 8.62 (s,
1H, OH), 8.38 (s, 1H, NH), 7.25 (s, 2H, CH-Ar), 7.21 (m, 3H,
CH-Ar), 7.12 (d, J = 7.4 Hz, 1H, CH-Ar), 6.92 (t, J = 7.4 Hz,
1H, CH-Ar), 6.72 (t, J = 7.4 Hz, 1H, CH-Ar), 3.77 (s, 6H, 2xO-
CH3), 2.22 (s, 3H, CH3) ppm.
2,6-Dimethoxy-4-{3-[(2,6-dimethylphenyl)amino]imidazo-
[1,2-a]pyrimidin-2-yl}-phenol (26). Pale yellow powder. 1H
NMR: ꢁ 8.50 (m, 2H, CH-Ar+OH), 8.46 (s, 1H, NH), 7.14 (m,
3H, CH-Ar), 7.05 (dd, J = 4.7, 6.0 Hz, 1H, CH-Ar), 6.91 (d, J =
7.4 Hz, 2H, CH-Ar), 6.67 (t, J = 7.4 Hz, 1H, CH-Ar), 3.61 (s, 6H,
2xO-CH3), 1.87 (s, 6H, CH3) ppm. IR (KBr) ꢀmax: 3336, 1613,
1510 cm-1. ESIMS. m/z: 390 (M+). Anal. Calcd for C22H22N4O3: C,
67.68; H, 5.68; N, 14.35. Found: C, 67.48; H, 5.88; N, 14.45.
2,6-Dimethoxy-4-{3-[(4-isopropylphenyl)amino]-5,7-di-
methylimidazo[1,2-a]pyrimidin-2-yl}-phenol (27). Brown
powder. 1H NMR: ꢁ 8.44 (s, 1H, OH), 7.90 (s, 1H, NH), 7.27 (s,
2H, CH-Ar), 7.02 (d, J = 8.1 Hz, 2H, CH-Ar), 6.69 (s, 1H, CH-
Ar), 6.43 (d, J = 7.3 Hz, 2H, CH-Ar), 3.59 (s, 6H, 2xO-CH3),
2.74 (m, 1H, CH-(CH3)2), 2.66 (s, 3H, CH3), 2.47 (s, 3H, CH3),
1.12 (d, J = 6.8 Hz, 6H, CH-(CH3)2) ppm. IR (KBr) ꢀmax: 3598,
3304, 2359, 1617, 1515 cm-1. ESIMS. m/z: 432 (M+). Anal.
Calcd for C25H28N4O3: C, 69.42; H, 6.53; N, 12.95. Found: C,
69.22; H, 6.73; N, 12.75.
Ethyl 4-{[2-(4-hydroxy-3-methoxyphenyl)imidazo[1,2-a]-
pyrimidin-3-yl]amino}benzoate (28). Yellow powder. 1H
NMR: ꢁ 9.17(s, 1H, OH), 8.82 (s, 1H, NH), 8.56 (dd, J = 1.8,
4.0 Hz, 1H, CH-Ar), 8.43 (d, J = 6.6 Hz, 1H, CH-Ar), 7.77 (d, J

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A. I. Polyakov, V. A. Eryomina, L. A. Medvedeva, N. I. Tihonova, L. G. Voskressensky
Vol 45
REFERENCES
= 8.6 Hz, 2H, CH-Ar), 7.59 (s, 1H, CH-Ar), 7.48 (d, J = 8.2 Hz,
1H, CH-Ar), 7.04 (dd, J = 4.1, 6.6 Hz, 1H, CH-Ar), 6.80 (d, J =
8.2 Hz, 1H, CH-Ar), 6.62 (d, J = 8.1 Hz, 2H, CH-Ar), 4.23 (q, J
= 7.0, 7.0 Hz, 2H, CH2-CH3), 3.68 (s, 3H, O-CH3), 1.26 (t, J =
7.0 Hz, 3H, CH2-CH3) ppm. IR (KBr) ꢀmax: 3321, 1686, 1605,
1510 cm-1. ESIMS. m/z: 404 (M+). Anal. Calcd for C22H20N4O4:
C, 65.34; H, 4.98; N, 13.85. Found: C, 65.54; H, 4.78; N, 13.95.
4-{3-[(2,6-Dimethylphenyl)amino]-5,7-dimethylimidazo-
[1] Dömling, A. Chem. Rev. 2006, 106, 17-89.
[2] Zhu, J.; Bienayme, H. Multicomponent Reactions, Wiley-
VCH Verlag, Weinheim, 2005, pp 1-94.
[3] Groebke, K.; Weber, L.; Mehlin, F. Synlett. 1998, 661-663.
[4] Bienayme, H.; Bouzid, K. Angew.Chem. Int. Ed. 1998, 37,
2234-2237.
[5] Blackburn, C.; Guan, B.; Fleming, P.; Shiosaki, K.; Tsai, S.
Tetrahedron Lett. 1998, 39, 3635-3638.
[6] Blackburn, C. Tetrahedron Lett. 1998, 39, 5469-5472.
[7] Blackburn, C.; Guan, B. Tetrahedron Lett. 2000, 41, 1495-
1500.
[8] Mandair, G.; Light, M.; Russel, A.; Hursthouse, M.; Bradley,
M. Tetrahedron Lett. 2002, 43, 4267-4269.
[9] Chen, J. J.; Golebiowski, A.; Mc Clenaghan, J.; Klopfenstein,
S. R.; West, L. Tetrahedron Lett. 2001, 42, 2269-2271.
[10] Varma, R. S.; Kumar, D. Tetrahedron Lett. 1999, 40, 7665-
7669.
[11] Parchinsky, V. Z.; Shuvalova, O.; Ushakova, O. ;
Kravchenko, D. V.; Krasavin, M. Tetrahedron Lett. 2006, 47, 947-951.
[12] Nenaydenko, V. G.; Reznichenko, A. L.; Balenkova, E. S.
Isvestiya Academii Nauk RF 2007, 3, 539-541.
1
[1,2-a]pyrimidin-2-yl}phenol (29). Brown powder. H NMR: ꢁ
9.45 (s, 1H, OH), 7.71 (d, J = 8.6 Hz, 2H, CH-Ar), 7.02 (s, 1H,
NH), 6.84 (d, J = 7.4 Hz, 2H, CH-Ar), 6.69 (d, J = 8.3 Hz, 3H
,CH-Ar), 6.54 (t, J = 7.4 Hz, 1H, CH-Ar), 2.66 (s, 3H, CH3),
2.46 (s, 3H, CH3), 1.83 (s, 6H, 2xCH3) ppm. IR (KBr) ꢀmax
:
3587, 3358, 2361, 1618, 1520 cm-1. ESIMS. m/z: 358 (M+).
Anal. Calcd for C22H22N4O: C, 73.72; H, 6.19; N, 15.63. Found:
C, 73.82; H, 6.09; N, 15.83.
4-[3-(Cyclohexylamino)imidazo[1,2-a]pyrimidin-2-
1
yl]phenol (30): White powder. H NMR: ꢀ 9.56 (s, 1H,
OH), 8.84 (s, 1H, NH), 8.30 (d, J = 4.4 Hz, 1H, CH-Ar),
8.04 (d, J = 8.4 Hz, 2H, CH-Ar), 7.81 (d, J = 4.3 Hz, 1H,
CH-Ar), 6.84 (d, J = 8.3 Hz, 2H, CH-Ar), 4.88 (d, J = 6.3
Hz, 1H, CH-Ar), 1.37 (m, 10H, 5xCH2) ppm. IR (KBr)
[13] Legraverend, M.; Grierson, D. L. Bioorg. Med. Chem. 2006,
14, 3987-4006.
[14] Li, B.H.; Ma, X. F.; Wang, Y.; Tian, W. X. J. Biochem. 2005,
138, 679-685.
[15] Halliwell, B.; Gutteridge, J. M. C. Free Radicals in Biology
and medicine, Oxford University, Oxford, 1999 (3 Ed.), pp 200-245.
[16] Gilgun-Sherki, Y.; Rosenbaum, Z.; Melamed, E.; Offen, D.
Pharmacol. Rev. 2002, 54, 271-284.
ꢁ
max: 3299, 2922, 2852, 1611, 1496 cm-1. ESIMS. m/z:
308 (M+). Ana1. Calcd for C18H20N4O: C, 70.11; H, 6.54;
N, 18.17. Found: C, 70.31; H, 6.34; N, 18.27.
Acknowledgement. The authors thank Professor Alexander
S. Shashkov and Doctor Yuri A. Strelenko, N. D. Zelinsky
Institute of Organic Chemistry for providing NMR facilities.