2-(2-furyl)imidazo[1,2-a]pyrimidine synthesis and electrophilic substitution reactions

Article abstract of DOI:10.1007/s10593-006-0116-0

The synthesis of 2-(2-furyl)imidazo[1,2-a]pyrimidine has been carried out. Azocoupling, nitrosation, and bromination by 1 mole of bromine occur at position 3 of the bicycle. Reaction with 2 mol of bromine gives the 3,5′- disubstituted derivative. Brominat

Full text of DOI:10.1007/s10593-006-0116-0

Chemistry of Heterocyclic Compounds, Vol. 42, No. 4, 2006
2
-(2-FURYL)IMIDAZO[1,2-a]PYRIMIDINE
SYNTHESIS AND ELECTROPHILIC
SUBSTITUTION REACTIONS
N. Saldabol, J. Popelis, O. Lando, and V. Slavinska
The synthesis of 2-(2-furyl)imidazo[1,2-a]pyrimidine has been carried out. Azocoupling, nitrosation,
and bromination by 1 mole of bromine occur at position 3 of the bicycle. Reaction with 2 mol of bromine
gives the 3,5'-disubstituted derivative. Bromination using 1 mol of bromine in 40% hydrobromic acid
and sulfonation occur initially at the 5' position of the furyl group.
Keywords: 2-(2-furyl)imidazo[1,2-a]pyrimidine, azocoupling, bromination, nitrosation, sulfonation.
We have continued our study of the effect of the nature of heterocycles with a bridging nitrogen atom on
the reactivity of hetarylfurans. The reaction of an ether solution of freshly prepared 2-bromoacetylfuran (1) (an
unstable lachrymator) with 2-aminopyrimidine (2) gave 2-amino-1-(2-furoylmethyl)pyrimidinium bromide (3)
which was converted to 2-(2-furyl)imidazo[1,2-a]pyrimidine (4) by subsequent heating with NaHCO in water.
3
_
Br
N
+
+
O
COCH Br
2
O
COCH2
N
N
NH2
1
N
2
3
H N
2
N
O
N
N
4
A study of the electrophilic substitution of compound 4 has shown that the reactions with
p-nitrophenyldiazonium chloride and n-butylnitrite occur only at position 3 of the bicycle and give the
corresponding 3-(p-nitrophenylazo)- (5) and 3-nitroso- (6) substituted compounds. The structure of the latter was
1
proved by H NMR spectroscopy.
Analogously to previously reported formylation reaction of compound 4, which with 1 mol of reagent
occurs selectively at position 3 whereas an excess of reagent reacts at positions 3 and 5' [1], the action of 1 mol
of bromine on this compound in acetic acid gives the 3-bromo-substituted (7) and 2 mol of bromine the
3
,5'-disubstituted 8.
_
_________________________________________________________________________________________
Latvian Institute of Organic Synthesis, Riga LV-1006; e-mail: dzsile@osi.lv. Translated from Khimiya
Geterotsiklicheskikh Soedinenii, No. 4, pp. 565-570, April, 2006. Original article submitted May 25, 2004.
0
009-3122/06/4204-0495©2006 Springer Science+Business Media, Inc.
495

_
N=NC H NO -p
6
4
2
+
Cl
Br
O NC H N
N
2
6
4
2
Br2
N
N
4
Br
Br2
O
N
O
N
N
BuONO
N
5
8
Br
NO
N
N
O
N
N
O
N
N
6
7
Hence an electrophilic substitution reaction of 4 in neutral or weakly acidic media occurs in the same
way as in the case of its 8-desaza analog 2-(2-furyl)imidazo[1,2-a]pyrimidine [2, 3].
However, the action of 1 mole of bromine in acetic acid on the salt 4·HBr gives a mixture of 3-bromo-,
3
,5-'dibromo- and 5'-bromo-substituted 7-9 by contrast with 6-(2-furyl)imidazo[2,1-b]thiazole hydrobromide
which is completely converted to the 5'-bromofuryl derivative under the same conditions [4].
conc. H SO4
2
N
.
4
HBr
4
HO3S
O
12
H O
N
2
N
Br2
Br2
AcOH
40% HBr
COCH Br
2
Br
Br
O
2
1
0
7
8
N
2
+
–
Br
CO CH=N=N
O
N
N
O
11
9
From compound 4 it proved possible to obtain only the 5'-bromo derivative 9 by the action of 1 mol of
1
bromine in 40% hydrobromic acid medium. The H NMR spectrum of the reaction mixture after 1 h showed
signals for the bromo-substituted 8 and 9 but after 24 h only compound 9 and the starting material in the ratio
1
:1. This is likely to be the result of partial as well as complete debromination of compound 8. The occurrence of
debromination was previously reported when heating in DMF medium the furylimidazopyridine and
furylimidazothiazole hydrobromides which were bromo-substituted in the imidazole ring [5].
The mixture of the bromo-substituted 7-9 with the starting material was separated on a silica gel column.
A counter synthesis of the 5'-bromo-substituted 9 was carried out by the reaction of the 2-aminopyrimidine (2)
with the bromo ketone 10 and also with the precursor in the preparation of this bromo ketone, the diazo ketone
1
1.
The difference in reactivity of compound 4 and furylimidazopyridine was particularly clear in strongly
acidic medium. It has previously been shown [6] that the nitration of compound 4 with 1 mol of HNO in conc.
3
H SO occurs selectively to give the 5'-nitro derivative in 79% yield while the furylimidazopyridine these
2
4
conditions forms, in low yield, a mixture of the 5'-nitro- and 3,5'-dinitro-substituted compound with a
predominance of the latter [7]. Subsequent introduction of a nitro group in position 3 of compound 4 proves
strongly hindering [6]. If the furylimidazopyridine forms the 3,5'-disulfoacid in 68% yield with conc. H SO [7]
2
4
then compound 4 is sulfonated only in the furyl group and the reaction occurs with greater difficulty. The
1
H NMR spectrum of the reaction mixture showed the presence of only 40% of the 5'-sulfoacid 12 which could
not be separated.
4
96

TABLE 1. Characteristics of Compounds 3-9
Found, %
Com-
pound
Empirical
formula
——————
Calculated, %
Yield,%
(method)
mp, °С*
C
H
N
3
4
C
C
C
C
C
C
C
C
C
C
10
10
10
16
16
10
10
10
10
10
H
H
H
H
H
H
H
H
H
H
10BrN
3
O
2
2
42.41
3.64
3.80
3.78
3.81
3.61
3.54
2.51
2.43
2.84
3.02
2.76
2.87
2.21
2.29
1.94
2.02
14.48
14.79
22.73
22.69
14.53
14.79
20.09
20.28
24.89
25.14
25.98
26.10
16.14
15.91
11.97
12.18
220-222
212-214
258-260
238-239
>300
89
58
4
2.27
7
N
3
O
64.65
4.86
6
4
4
5
6
7
7
8
9
·HBr·H
2
O
10BrN
3
O
42.09
2.28
72
4
·picrate
10
10
N
N
4
6
O
8
3
46.09
6.39
—
4
6
O
57.11
7.22
99
5
6
6
7
5
6
N
O
2
55.83
6.07
223-225
184-186
268-270
281-283
252-254
81
5
BrN
3
O
45.23
5.48
81
4
·HBr
Br
2
2
N
3
3
O
35.05
4.81
84
3
Br
N
O
34.78
5.00
1.57
1.46
2.43
2.29
12.27
12.25
15.93
15.91
80
3
BrN
3
O
45.34
5.48
29 (A),
0 (B)
4
5
7
3 (C),
3
5 (D)
83
9
·HBr
C
10
H
7
Br
2
N
3
O
34.67
4.81
2.13
2.02
12.26
12.18
269-271
3
_
*
______
Compound 3 was purified by crystallization from a mixture of
EtOH–ether; 5 from DMF–EtOH; 6 from benzene; 4b, 4·HBr, 4·picrate, 7,
·HBr from aqueous EtOH; 8, 9 from aqueous DMF.
7
This observation additionally confirms the lowering of the susceptibility of the imidazole ring to
electrophilic substitution in acidic media with the increased π-deficiency of the heterocycle annelated via the
bridging nitrogen atom.
EXPERIMENTAL
1
6
H NMR spectra were recorded on a Bruker WH-90/DS (90 MHz) instrument using DMSO-d ,
CF COOH, 40% hydrobromic acid (internal standard HMDS, δ 0.055 ppm), or conc. H SO (internal standard
3
2
4
cyclohexane, δ 1.44 ppm). IR spectra were taken on a Perkin Elmer 580B instrument using vaseline oil (region
-
1
-1
2
000-600 cm ) and hexachlorobutadiene (regions 3600-2000 and 1500-1300 cm ). TLC was performed using
Silufol UV-254 plates in the systems benzene–dioxane–acetic acid (20:4:1) , benzene–ethyl acetate (1:3), or
acetone–chloroform (1:5) and were revealed using UV light. Mixture separation was carried out on a Woelm
silica gel column (2.5 × 40 cm) with chloroform eluent (compounds 4, 7-9). Melting points were measured on a
Boetius instrument. For the determination of the C and H content a combustion catalyst was used or the carbon
data obtained was too low.
2
-Amino-1-(2-furoylmethyl)pyrimidinium Bromide (3). 2-Aminopyrimidine 2 (38 g, 400 mmol) was
added to a solution of the bromo ketone 1 (75.6 g, 400 mmol) in ether (300 ml). The mixture was held for 5 days
at room temperature and the precipitate was filtered off and washed with ether. Yield 101 g. IR spectrum,
-
1
ν, cm : 3400 and 3320 (NH ), 2600-2500 (NHassoc.), 1668 (C=O), 1620 (C=N, δ NH), 1515 (COCH2).
2
4
97

1
TABLE 2. H NMR Spectra of 2-(2-Furyl)imidazo[1,2-a]pyrimidine and
Derivatives
Com-
pound
Chemical shifts, δ, ppm*
Solvent
H-3
H-5
H-6
H-7
H-3'
H-4'
H-5'
4
DMSO-d
CF COOH
DMSO-d
0% HBr
SO conc.
6
8.11
8.23
8.44
8.52
8.55
—
8.91
9.17
9.21
9.20
9.67
9.91
8.95
9.27
8.95
9.13
8.90
9.17
9.25
9.80
7.02
7.79
7.43
7.65
8.38
7.56
7.57
7.70
7.30
7.86
7.02
7.75
7.65
8.35
8.50
9.10
8.83
8.96
9.33
9.04
9.00
9.02
8.70
9.08
8.52
9.11
8.96
~9.5
6.88
7.26
7.15
7.30
7.52
7.75
7.79
7.62
7.87
7.48
6.91
7.48
7.30
6.87
6.68
6.72
6.74
6.73
6.87
6.86
6.90
6.72
7.38
6.72
6.69
6.72
6.73
~7.6
7.75
7.71
7.94
7.92
7.92
8.22
7.85
7.73
—
3
4
·HBr
·H SO
6
4
4
6
7
2
4
H
2
4
DMSO-d
DMSO-d
6
6
—
CF
DMSO-d
CF COOH
DMSO-d
CF COOH
·HBr* 40% HBr
3
COOH
—
8
9
6
—
3
—
—
6
8.15
8.25
8.56
8.76
—
3
—
2
9
1
—
2
2*
H
2
SO
4
conc.
—
_
*
______
Imidazopyrimidine signals: H-3 – s; H-5 – dd; H-6 – dd; H-7 – dd;
J5,6 = 6.4-6.7; J5,7 = 1.6-2.0; J6,7 = 4.1-4.4 Hz in DMSO-d and CF COOH;
6
3
J5,6 = 7.0 Hz in conc. H SO ; 2-substituted furan: H-3' – dd; H-4' – q;
2
4
H-5' – dd; J3,4 = 3.6-4.0; J3,5 = 0.8-0.9; J4,5 = 1.8 Hz; 2,5-disubstituted furan:
2
*
d, J = 3.6-4.0 Hz.
3,4
In a mixture with starting compound 4.
2
2
-(2-Furyl)imidazo[1,2-a]pyrimidine (4). The salt 3 (10 g, 35 mmol) in water (200 ml) with NaHCO3
(
10 g) was refluxed for 3 h. The precipitate formed on cooling was filtered off and washed with water.
Yield 3.78 g. It was purified by crystallization from aqueous ethanol or acetone, octane, or by vacuum
sublimation.
2
-(2-Furyl)-3-(p-nitrophenylazo)imidazo[1,2-a]pyrimidine (5). A solution of the diazonium salt
prepared from p-nitroaniline (1.52 g, 11 mmol), conc. HCl (3 ml), ice (50 g), and NaNO (1 g, 15 mmol) was
2
added at 0-5°C with stirring to a solution of compound 4 (1.85 g, 10 mmol) in pyridine (20 ml). The red-brown
precipitate was filtered off and washed with water and ethanol. Yield 3.33 g.
2
-(2-Furyl)-3-nitrosoimidazo[1,2-a]pyrimidine (6). Freshly distilled butylnitrite (1.55 g, 15 mmol)
was added with stirring to a solution of compound 4 (1.85 g, 10 mmol) in benzene (60 ml) cooled in ice. After
h the reaction mixture was diluted with petroleum ether (130 ml) and the green precipitate was filtered off and
washed with petroleum ether. Yield 1.73 g.
-Bromo-2-(2-furyl)imidazo[1,2-a]pyrimidine (7). A solution of bromine (0.51 ml, 10 mmol) in
2
3
glacial acetic acid (8 ml) was added to a solution of compound 4 (1.85 g, 10 mmol) in the same solvent (50 ml)
and stirred for 1 h. Ether (100 ml) was added and the precipitated 7·HBr salt was washed with ether.
Yield 2.90 g. Treatment of the salt (2.5 g) with a 20% aqueous NaOH solution gave compound 7 (1.55 g).
3
-Bromo-2-(5-bromo-2-furyl)imidazo[1,2-a]pyrimidine (8) was prepared similarly from compound 4
1.85 g, 10 mmol) and bromine (1.12 ml, 22 mmol). Yield of the base 2.74 g.
-(5-Bromo-2-furyl)imidazo[1,2-a]pyrimidine (9), 3-Bromo-2-(2-furyl)imidazo[1,2-a]pyrimidine
7), and 3-Bromo-2-(5-bromo-2-furyl)imidazo[1,2-a]pyrimidine (8). A. A solution of bromine (0.51 ml,
(
2
(
1
1
0 mmol) in AcOH (15 ml) was added over 30 min to a stirred suspension of compound 4·HBr·H O (2.84 g,
0 mmol) in AcOH (10 ml) and the temperature was held at 10-15°C. The product was stirred for 2 h, ether
2
4
98

(
150 ml) was added, and the precipitate formed was filtered off, washed with ether, triturated with 10% aqueous
NaOH solution, and then washed with water to give a mixture of compounds 4, 7-9 (2.04 g) in the ratio 2:2:1:4
1
(
3
H NMR spectrum in CF COOH). The mixture was separated on a column to give a first fraction of
compound 8 (0.065 g), second of 7 (0.12 g), and third of 9 (0.29 g).
-(5-Bromo-2-furyl)imidazo[1,2-a]pyrimidine (9). B. A solution of bromine (0.13 ml, 2.5 mmol) in
2
4
2
0% hydrobromic acid (2 ml) was added portionwise with stirring to a solution of compound 4 (0.462 g,
.5 mmol) in the same solvent (5 ml) and held for 24 h at room temperature. According to the H NMR spectrum
1
the mixture obtained was of 9 and 4 in the ratio 1:1.
C. A solution of 5-bromo-2-bromoacetylfuran 10 (2.68 g, 10 mmol) and the amine 2 (0.95 g, 10 mmol)
in ethanol (30 ml) was refluxed for 7 h, diluted with ether (60 ml), and the precipitated hydrobromide 9 was
filtered off. Yield 2.86 g.
This salt (2.0 g) was triturated with aqueous ammonia and the precipitate was filtered off and washed
with water to give the base 9 (1.35 g).
D. The diazo ketone 11 (2.15 g, 10 mmol) and amine 2 (0.95 g, 10 mmol) in absolute ethanol (30 ml)
were refluxed for 1 h and solvent was evaporated off. The residue was recrystallized from aqueous ethanol to
give compound 9 (0.92 g).
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1
2
.
.
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4
99