Condensation of benzoxa(thia)zolyl-2-guanidines with dicarbonyl compounds

Article abstract of DOI:10.1007/s11176-005-0216-z

Heterocyclizations of benzoxa(thia)zolyl-2-guanidines with β-dicarbonyl compounds, such as diketones and derivatives of acetoacetic ether, were studied. 2005 Pleiades Publishing, Inc.

Full text of DOI:10.1007/s11176-005-0216-z

Russian Journal of General Chemistry, Vol. 75, No. 2, 2005, pp. 294 297. Translated from Zhurnal Obshchei Khimii, Vol. 75, No. 2, 2005,
pp. 322 325.
Original Russian Text Copyright
2005 by Shikhaliev, Kryl’skii, Kovygin, Verezhnikov.
Condensation of Benzoxa(thia)zolyl-2-guanidines
with Dicarbonyl Compounds
Kh. S. Shikhaliev, D. V. Kryl’skii, Yu. A. Kovygin, and V. N. Verezhnikov
Voronezh State University, Voronezh, Russia
Received June 25, 2003
Abstract Heterocyclizations of benzoxa(thia)zolyl-2-guanidines with -dicarbonyl compounds, such as
diketones and derivatives of acetoacetic ether, were studied.
The high reactivity of guanidine and its derivatives
allows them to be brought into a great number of
heterocyclizations, thereby preparing azaheterocycles
of various degree of complexity [1]. Much evidence is
available on the reactions of amidines and guanidines
with , -unsaturated carbonyl and -dicarbonyl com-
pounds, leading to pyrimidines and aminopyrimidines
[2 4]. Compounds of these classes exhibit bactericide
and antiviral activity, in particular, are anti-HIV
preparations [5 7].
activity of benzoxa(thia)zolyl-2-guanidines Ia
and Ib in heterocyclizations with -dicarbonyl com-
pounds: diketones IIa IIf and keto esters IVa IVh.
To effect condensation of compounds I with di-
ketones requires fairly rigid conditions: boiling for
3 10 h (depending on the reactivity of the diketone)
in xylene with azeotropic distillation of water. The
reaction products, 2-[benzoxa(thia)zol-2-ylamino]pyr-
imidines IIIa IIIi, are generally less soluble and preci-
pitate already from a hot reaction mixture or on its
cooling.
The aim of the present work was to study the re-
H
H
N
N
R3
O
O
N
N
NH
N
+
R1
R3
Q
Q
N
R2
NH2
R2
IIa IIf
R1
Ia, Ib
IIIa IIIi
I, Q = O (a), S (b); II, R1 = R3 = CH3, R2 = H (a); R1 = R2 = R3 = CH3 (b); R1 + R2 = (CH2)3, R3 = CH3 (c); R1 + R2 =
(CH2)4, R3 = C2H5 (d); R1 = CF3, R2 = H, R3 = CH3 (e); R1 = CF3, R2 = H, R3 = thienyl (f); III, Q = O, R1 = R3 = CH3,
R2 = H (a); Q = S, R1 = R3 = CH3, R2 = H (b); Q = O, R1 = R2 = R3 = CH3 (c); Q = O, R1 + R2 = (CH2)3, R3 = CH3 (d);
Q = S, R1 + R2 = (CH2)3, R3 = CH3 (e); Q = O, R1 + R2 = (CH2)4, R3 = C2H5 (f); Q = S, R1 + R2 = (CH2)4, R3 = C2H5
(g); Q = O, R1 = CF3, R2 = H, R3 = CH3 (h); Q = S, R1 = CF3, R2 = H, R3 = thienyl (i).
Benzoylacetone under prolonged heating in the
above conditions provides only traces of the reaction
product. As the reaction time is increased, stronger
tarring is observed. Dibenzoylmethane failed to react.
The reactivity of the diketones with respect to guani-
dine I decreases in the order CF3COCH2COCH3
CH3COCH2COCH3 > PhCOCH2COCH3 > PhCOCH2
COPh, which can be explained with the increase in
the same order of the fraction of the enol form that is
additionally stabilized by conjugation with the
benzene rings [8].
The yields and characteristics of 2-[benzoxa(thia)-
zol-2-ylamino]pyrimidines IIIa IIIi are listed in
the table.
The heterocyclization of guanidines I with keto es-
ters IV, too, occurs in boiling xylene, and azeotropic
distillation is most frequently not required. The reac-
tion products can be assigned the structure of 2-[benz-
oxa(thia)zol-2-ylamino]pyrimidin-4(3H)-ones (VB).
The 4-hydroxypyrimidine VI structure of the
heterocyclic fragment can be ruled out in view of the
1070-3632/05/7502-0294 2005 Pleiades Publishing, Inc.

CONDENSATION OF BENZOXA(THIA)ZOLYL-2-GUANIDINES
H
295
N
O
O
OH
R2
N
N
1
R3
+
I
R
Q
R2
N
R1
VI
IVa IVh
H
H
N
H
N
N
N
O
N
N
O
Q
Q
N
R2
HN
R2
R1
R1
Va Vj (A)
Va Vj (B)
IV, R1 = CH3, R2 = H (a); R1 = R2 = CH3 (b); R1 = Ph, R2 = H (c); R1 = CH3OCH2, R1 = H (d); R2 = CH3OCOCH2, R2 =
H (e); R1 = CH3, R2 = PhCH2 (f); R1 + R2 = (CH2)3 (g); R1 + R2 = (CH2)4 (h); V, Q = O, R1 = CH3, R2 = H (a); Q = O,
R1 = R2 = CH3 (b); Q = O, R1 = Ph, R2 = H (c); Q = S, R1 = CH3OCH2, R2 = H (d); Q = O, R1 = CH3OCH2, R2 = H (e);
Q = O, R1 = CH3OCOCH2, R2 = H (f); Q = S, R1 = CH3OCOCH2, R2 = H (g); Q = S, R1 = CH3, R2 = PhCH2 (h); Q = O,
R1 + R2 = (CH2)3 (i); Q = S, R1 + R2 = (CH2)4 (j).
1
presence in the H NMR spectrum of a singlet of the
olefin proton (R5 = H) at the pyrimidine C5 atom at
5.5 6.2 ppm. This signal is absent from in the spectra
of compounds III that have an aromatic ring and of
derivatives V in which the proton at C5 is replaced by
another group, say CH3 (compound Vb). The choice
between the quasi-p-quinoid (VA) and quasi-o-quinoid
(VB) structures is difficult to make on the basis of
1
the H NMR spectra, but, as shown in a detailed
study of the amide amide (N3H
N1H) tauto-
Yields, melting points, and elemental analyses of 2-[benzoxa(thia)zol-2-ylamino]pyrimidines IIIa IIIi and 2-[benzoxa-
(thia)zol-2-ylamino]pyrimidin-4(3H))-ones Va Vj
Found, %
H
Calculated, %
H
Comp.
no.
Yield, %
mp,
C
Formula
C
N
C
N
IIIa
IIIb
IIIc
IIId
IIIe
IIIf
IIIg
IIIh
IIIi
Va
Vb
Vc
Vd
Ve
Vf
Vg
58
46
42
64
48
53
60
62
54
42
61
39
52
54
47
68
65
38
41
202 203
245 247
240 241
233 235
273 275
203 205
230 231
205 207
291 292
>320
305 307
254 255
314 316
201 203
210 211
>320
65.05
61.07
66.01
67.44
63.57
69.71
65.44
53.24
50.89
59.36
61.12
67.33
54.01
57.15
56.21
53.02
65.55
62.54
60.25
5.14
4.45
5.67
5.45
5.12
6.28
5.57
2.95
2.26
4.21
4.58
4.06
4.44
4.60
3.88
3.95
4.51
4.67
4.78
23.21
21.90
21.88
20.85
20.03
18.85
18.14
19.22
14.64
23.01
21.77
18.28
19.25
20.65
18.85
17.54
16.21
20.92
18.65
C13H12N4O
C13H12N4S
C14H14N4O
C15H14N4O
C15H14N4S
64.99
60.92
66.13
67.65
63.81
69.37
65.78
53.07
50.79
59.50
60.93
67.10
54.15
57.35
56.00
53.16
65.50
62.68
60.38
5.03
4.72
5.55
5.30
5.00
6.16
5.84
3.08
2.40
4.16
4.72
3.97
4.20
4.44
4.03
3.82
4.63
4.51
4.73
23.32
21.86
22.03
21.04
19.84
19.03
18.05
19.04
14.81
23.13
21.86
18.41
19.43
20.58
18.66
17.71
16.08
20.88
18.78
C17H18N4O
C17H18N4S
C13H9F3N4O
C16H9F3N4S2
C12H10N4O2
C13H12N4O2
C17H12N4O2
C13H12N4O2S
C13H12N4O3
C14H12N4O4
C14H12N4O3S
C19H16N4OS
C14H12N4O2
C15H14N4OS
Vh
Vi
Vj
>320
302 304
>320
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 75 No. 2 2005

296
SHIKHALIEV et al.
merism of pyrimidin-4-ones [9], structure VB is
preferred.
N2-(4-Ethyl-5,6,7,8-tetrahydroquinazolin-2-yl]-
1,3-benzothiazol-2-amine (IIIg). H NMR spectrum,
1
, ppm: 1.49 t (3H, CH2CH3), 1.82 1.94 m (4H,
aliph.), 2.62 2.87 m (6H, aliph.), 7.18 t (1H, arom.),
7.33 t (1H, arom.), 7.64 d (1H, arom.), 7.77 d (1H,
arom.), 11.21 br.s (1H, NH).
The yields and characteristics of 2-[benzoxa(thia)-
zol-2-ylamino]pyrimidin-4(3H)-ones Va Vj are given
in the table.
N2-[4-Methyl-6-(trifluoromethyl)pyrimidin-2-yl)-
1,3-benzoxazol-2-amine (IIIh). H NMR spectrum,
EXPERIMENTAL
1
, ppm: 2.38 s (3H, CH3), 6.76 s (1H, pyrimidine),
7.13 7.27 m (2H, arom.), 7.51 t (2H, arom.),
11.21 br.s (1H, NH).
The reaction progress and product purity were
controlled by TLC on Merck UV-254 plates, eluent
ethyl acetate. The H NMR spectra were obtained on
a Bruker AC-300 instrument (300 MHz) in DMSO-d6
relative to TMS. The mass spectra were measured on
an LKB-9000 instrument, ionizing energy 70 eV.
1
N2-[4-(2-Thienyl)-6-(trifluoromethyl)pyrimidin-
1
2-yl]-1,3-benzothiazol-2-amine (IIIi). H NMR spec-
trum, , ppm: 6.88 s (1H, pyrimidine), 7.20 t (1H,
arom.), 7.33 t (1H, arom.), 7.42 7.58 m (3H, arom.),
7.68 d (1H, arom.), 7.89 d (1H, arom.), 11.26 br.s
(1H, NH).
Reaction of benzoxa(thia)zolyl-2-guanidines
with -diketones. A mixture of 0.015 mol of benz-
oxa(thia)zolyl-2-guanidine and 0.017 mol of diketone
was refluxed in xylene for 3 10 h with distillation of
water. The precipitate that formed was purified by
recrystallization from dioxane or dimethylformamide.
Reaction of benzoxa(thia)zolyl-2-guanidines
with -keto esters. A mixture of 0.015 mol of benz-
oxa(thia)zolylguanidine and 0.017 mol of keto ester
was refluxed in xylene for 3 10 h. The precipitate that
formed was purified by recrystallization from dioxane
or dimethylformamide.
N2-(4,6-Dimethylpyrimidin-2-yl)-1,3-benzoxazol-
1
2-amine (IIIa). H NMR spectrum, , ppm: 2.41 s
(6H, 2CH3), 6.79 s (1H, pyrimidine), 7.11 7.26 m
(2H, arom.), 7.46 t (2H, arom.), 10.91 br.s (1H, NH).
2-(1,3-Benzoxazol-2-ylamino)-6-methylpyrimi-
din-4(3H)-one (Va). 1H NMR spectrum, , ppm:
2.21 s (3H, CH3), 5.59 s (1H, pyrimidine C5), 7.13
7.27 m (2H, arom.), 7.43 d (1H, arom.), 7.51 d (1H,
arom.), 12.12 br.s (1H, NH), 12.32 br.s (1H, NH).
N2-(4,6-Dimethylpyrimidin-2-yl)-1,3-benzothia-
zol-2-amine (IIIb). 1H NMR spectrum, , ppm: 2.39 s
(6H, 2CH3), 6.86 s (1H, pyrimidine), 7.20 t (1H,
arom.), 7.38 t (1H, arom.), 7.66 d (1H, arom.), 7.91 d
(1H, arom.), 10.66 br.s (1H, NH).
2-(1,3-Benzoxazol-2-ylamino)-5,6-dimethylpyri-
1
N2-(4,5,6-Trimethylpyrimidin-2-yl)-1,3-benzoxa-
midin-4(3H)one (Vb). H NMR spectrum, , ppm:
1
1.87 s (3H, CH3), 2.22 s (3H, CH3), 7.09 7.26 m
(2H, arom.), 7.48 d (1H, arom.), 7.59 d (1H, arom.),
11.99 br.s (1H, NH), 12.36 br.s (1H, NH).
zol-2-amine (IIIc). H NMR spectrum, , ppm: 2.20 s
(3H, CH3), 2.43 s (6H, 2CH3), 7.11 7.25 m (2H,
arom.), 7.44 t (2H, arom.), 10.79 br.s (1H, NH).
N2-(4-Methyl-6,7-dihydro-5H-cyclopenta[d]pyr-
imidin-2-yl)-1,3-benzoxazol-2-amine (IIId). 1HNMR
spectrum, , ppm: 2.10 2.20 m (2H, aliph.), 2.39 s
(3H, CH3), 2.81 2.98 m (4H, aliph.), 7.07 7.22 m
(2H, arom.), 7.38 7.49 m (2H, arom.), 10.66 br.s (1H,
NH).
2-(1,3-Benzoxazol-2-ylamino)-6-phenylpyrimi-
din-4(3H)-one (Vc). 1H NMR spectrum, , ppm:
5.56 s (1H, pyrimidine C5), 7.13 7.27 m (4H, arom.),
7.43 d (1H, arom.), 7.51 d (1H, arom.), 7.63 7.72 m
(3H, arom.), 12.09 br.s (1H, NH), 12.27 br.s (1H,
NH).
N2-(4-Methyl-6,7-dihydro-5H-cyclopenta[d]-
pyrimidin-2-yl)-1,3-benzothiazol-2-amine (IIIe). H
2-(1,3-Benzothiazol-2-ylamino)-6-(methoxy-
methyl)pyrimidin-4(3H)-one (Vd). H NMR spec-
1
1
NMR spectrum, , ppm: 2.10 2.20 m (2H, aliph.),
2.44 s (3H, CH3), 2.78 3.01 m (4H, aliph.), 7.15 t
(1H, arom.), 7.31 t (1H, arom.), 7.64 d (1H, arom.),
7.75 d (1H, arom.), 11.01 br.s (1H, NH).
trum, , ppm: 3.47 s (3H, CH2OCH3), 4.31 s (2H,
CH2OCH3), 5.87 s (1H, pyrimidine C5), 7.22 t (1H,
arom.), 7.36 t (1H, arom.), 7.54 d (1H, arom.), 7.73 d
(1H, arom.), 12.04 br.s (1H, NH), 12.38 br.s (1H,
NH).
N2-(4-Ethyl-5,6,7,8-tetrahydroquinazolin-2-yl)-
1
1,3-benzoxazol-2-amine (IIIf). H NMR spectrum,
2-(1,3-Benzoxazol-2-ylamino)-6-(methoxyme-
thyl)pyrimidin-4(3H)-one (Ve). 1H NMR spectrum, ,
ppm: 3.44 s (3H, CH2OCH3), 4.29 s (2H, CH2OCH3),
5.70 s (1H, pyrimidine C5), 7.10 7.21 m (2H, arom.),
, ppm: 1.28 t (3H, CH2CH3), 1.77 1.92 m (4H,
aliph.), 2.60 2.82 m (6H, aliph.), 7.09 7.25 m (2H,
arom.), 7.52 t (2H, arom.), 10.72 br.s (1H, NH).
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 75 No. 2 2005

CONDENSATION OF BENZOXA(THIA)ZOLYL-2-GUANIDINES
7.35 d (1H, arom.), 7.47 d (1H, arom.), 12.30 br.s
297
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Methyl [[2-(1,3-benzoxazol-2-yl)amino)]-6-oxo-
1,6-dihydropyrimidin-4-yl]acetate (Vf). 1H NMR
spectrum, , ppm: 3.69 s (2H, CH2), 4.21 s (3H,
OCH3), 5.82 s (1H, pyrimidine C5), 7.16 7.32 m (2H,
arom.), 7.57 7.69 m (2H, arom.), 12.31 br.s (2H,
2NH).
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OCH3), 5.78 s (1H, pyrimidine C5) , 7.17 t (1H,
arom.), 7.28 t (1H, arom.), 7.51 d (1H, arom.), 7.70 d
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7.11 7.27 m (3H, arom.), 7.34 7.51 m (4H, arom.),
7.66 7.79 m (2H, arom.), 12.03 br.s (1H, NH),
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2.23 m (2H, aliph.), 7.23 7.34 m (2H, arom.), 7.56
7.78 m (2H, arom.), 12.02 br.s (2H, 2NH).
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1
hydroquinazolin-4-one (Vj). H NMR spectrum, ,
ppm: 1.61 1.82 m (4H, aliph.), 2.27 2.36 m (2H,
aliph.), 2.51 2.58 m (2H, aliph.), 7.23 t (1H, arom.),
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arom.), 11.89 br.s (2H, 2NH).
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RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 75 No. 2 2005