Investigations of imidazoles. 101. Synthesis of 2,3-dihydroimidazo-[1,2-a]pyrimidine from 2-aminopyrimidine

Article abstract of DOI:10.1023/A:1017571617287

Two novel preparative methods have been developed for the synthesis of 2,3-dihydroimidazo[1,2-a]-pyrimidine from 2-aminopyrimidine. These are the reaction with 1,2-dibromoethane and also the reaction with ethylene chloro(bromo)hydrin, subsequent treatment of 1-β-hydroxyethyl-2-imino-1,2-dihydropyrimidine with thionyl chloride, and cyclization of the intermediate 1-β-chloroethyl-2-imino-1,2-dihydropyrimidine in the presence of sodium hydroxide.

Full text of DOI:10.1023/A:1017571617287

Chemistry of Heterocyclic Compounds, Vol. 37, No. 2, 2001
INVESTIGATIONS OF
IMIDAZOLES. 101*. SYNTHESIS
OF 2,3-DIHYDROIMIDAZO-
[
1,2-a]PYRIMIDINE FROM
2-AMINOPYRIMIDINE
1
2
2
2
P. M. Kochergin , I. A. Mazur , G. K. Rogul'chenko , E. V. Aleksandrova ,
2
and B. E. Mandrichenko
Two novel preparative methods have been developed for the synthesis of 2,3-dihydroimidazo[1,2-a]-
pyrimidine from 2-aminopyrimidine. These are the reaction with 1,2-dibromoethane and also the
reaction with ethylene chloro(bromo)hydrin, subsequent treatment of 1-β-hydroxyethyl-2-imino-1,2-
dihydropyrimidine with thionyl chloride, and cyclization of the intermediate 1-β-chloroethyl-2-imino-
1
,2-dihydropyrimidine in the presence of sodium hydroxide.
Keywords: 2-aminopyrimidine, 1,2-dibromoethane, dihydroimidazopyrimidine, imidazole, ethylene
chloro(bromo)hydrin, cyclization.
The synthesis is known for 2,3-dihydroimidazo[1,2-a]pyrimidine [2] and certain of its derivatives
substituted in the pyrimidine part of the molecule [3, 4] from 2-methylmercaptopyrimidine [2] and from
2
-chloropyrimidine and its C-substituted derivatives. A drawback of these synthetic methods for
imidazolinopyrimidine and its derivatives is the difficulty in obtaining the starting materials and also the need
for carrying out the reaction at high temperature (180°C when using 2-methylmercaptopyrimidine) [2].
We have developed two simpler methods for preparing 2,3-dihydroimidazo[1,2-a]pyrimidine which is
based on the use of 2-aminopyrimidine (available as an intermediate in the production of the sulfanilamide
preparation sulfadiazine).
In the first of these methods 2-aminopyrimidine is heated with ethylene chlorohydrin or ethylene
bromohydrin in an organic solvent to give 1-β-hydroxyethyl-2-imino-1,2-dihydropyrimidine hydrochloride or
hydrobromide 1a,b.
_
*
_
______
For Communication 100 see [1].
___________________________________________________________________________________________
1
Center for the Chemistry of Medicinals. All Russian Chemical-Pharmaceutical Science Research
2
Institute, 119815 Moscow. Zaporozhe State Medicinal University, 330074 Zaporozhe, Ukraine. Translated
from Khimiya Geterotsiklicheskikh Soedinenii, No. 2, pp. 251-252, February, 2001. Original article submitted
April 13, 1999.
224
0009-3122/01/3702-0224$25.00©2001 Plenum Publishing Corporation

CH2
CH2
XCH CH OH
SOCl2
2
2
N
N
CH OH
CH Cl
2
2
N
NH.HX
N
NH.HX
N
1a,b
1
2
. NaOH
. HBr
N
CH2
NH2
N
CH Br
N
2
.HBr
N
NH.HBr
BrCH CH Br
2
2
N
N
2
X = Br, Cl
Upon treatment with thionyl chloride, compounds 1a,b are converted to 1-β-chloroethyl-2-imino-1,2-
dihydropyrimidine. Without separation of the pure material, the latter is heated with sodium hydroxide in
ethanol. Separation of a molecule of hydrogen chloride then occurs to form 2,3-dihydroimidazo[1,2-a]-
pyrimidine (2) which is isolated as the hydrobromide in 93% yield. Compound 2 has been reported previously
as the hydrochloride [2].
A still simpler, single stage method for the synthesis of the bicyclic compound 2 involves the reaction of
2
-aminopyrimidine with 1,2-dibromoethane by heating in a mixture of DMF and butanol. The yield of
compound 2 is 90%.
EXPERIMENTAL
The purity of the compounds obtained was determined using TLC on Silufol UV-254 plates and
visualization with iodine vapor or UV light.
1
-β-Hydroxyethyl-2-imino-1,2-dihydropyrimidine Hydrochloride (1a). A solution of 2-amino-
pyrimidine (1.9 g, 0.02 mol) and ethylene chlorohydrin (3.2 g, 0.04 mol) in anhydrous toluene (8 ml) was
refluxed for 8 h. The solvent was decanted and the residue was triturated with acetone, and the precipitate was
filtered, washed with acetone, and dried to give compound 1a (2.7 g, 77%) as colorless crystals; mp 178-180°C
(
decomp., from ethanol). Found, %: C 41.30; H 5.50; Cl 19.80; N 23.90. C
6
H
9
N O·HCl. Calculated, %: C 41.00;
3
H 5.70; Cl 20.20; N 23.90.
1
-β-Hydroxyethyl-2-imino-1,2-dihydropyrimidine Hydrobromide (1b). A solution of 2-amino-
pyrimidine (9.5 g, 0.1 mol) and ethylene bromohydrin (9.0 g, 0.11 mol) in a mixture of butanol (40 ml) and
DMF (10 ml) was refluxed for 9 h, cooled, and the precipitate was filtered off, washed with ether, and dried to
give compound 1b (17.6 g, 80%) as colorless crystals; mp 183-185°C (decomp., from propan-2-ol). Found, %:
C 35.20; H 5.10; Br 39.40; N 20.80. C
6
H
9
N O·HBr. Calculated, %: C 35.30; H 5.10; Br 39.20; N 20.60.
3
2
,3-Dihydroimidazo[1,2-a]pyrimidine Hydrobromide (2). A. Thionyl chloride (8-10 ml) was added
carefully to compound 1a or 1b (0.01 mol). The mixture was refluxed for 2 h, thionyl chloride distilled in vacuo
to dryness, a 10% alcoholic solution of sodium hydroxide (40 ml) was added, and the product was refluxed for
2
h. The solvent was distilled off in vacuo, the residue extracted with acetone with heating (2 × 20 ml), the
solution filtered, and 42-46% hydrobromic acid (1 ml) was added. The precipitate was filtered, washed with
ether, and dried to give compound 2 (2.0 g, 93%) as colorless prisms; mp 281-283°C (decomp., from butanol).
Found, %: C 38.90; H 3.80; Br 37.20; N 19.30. C
N 19.60.
H
6 7
3
N ·HBr. Calculated, %: C 39.30; H 3.80; Br 37.30;
B. A solution of 2-aminopyrimidine (2.9 g, 0.03 mol) and 1,2-dibromoethane (16.9 g, 0.09 mol) in a
mixture of DMF (5 ml) and butanol (15 ml) was refluxed for 6 h, cooled, and the precipitate was filtered off,
washed with ether, and dried to give compound 2 (5.8 g, 90%); mp 281-283°C (decomp., from butanol). A
sample mixed with a sample of compound 2 prepared by method A did not show a depression of melting point.
2
25

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1
.
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Geterotsikl. Soedin., 1674 (2000).
2
3
4
.
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.
W. L. F. Armarego, J. Chem. Soc., 2778 (1965).
J. Clark and T. Ramsden, J. Chem. Soc. (C), 675 (1971).
J. Clark and T. Ramsden, J. Chem. Soc. (C), 679 (1971).
226