A convenient one-pot synthesis of benzopyrimido[1,8]naphthyridines by knoevenagel condensation

Article abstract of DOI:10.1007/s10593-005-0076-9

A series of 1-oxo-2,4-diphenyl-3-thioxobenzo[g]pyrimido[6,5-b]-1,8- naphthyridines has been synthesized by Knoevenagel condensation from 3-formyl-2-oxoquinolines and N,N-diphenyl-2-thiobarbituric acid on refluxing with liquid ammonia in absolute ethanol.

Full text of DOI:10.1007/s10593-005-0076-9

Chemistry of Heterocyclic Compounds, Vol. 40, No. 10, 2004
SYNTHESIS OF DERIVATIVES OF
7,8-DIHYDROTHIAZOLO[2,3-i]PURINE
BY HALOCYCLIZATION OF
6-ALLYLTHIOPURINE
D. G. Kim and Yu. R. Galina
7-Halomethyl-7,8-dihydrothiazolo[2,3-i]purines were synthesized by the reaction of bromine and iodine
with 6-allylthiopurine.
Keywords: 6-allylthiopurine, 7-bromomethyl-7,8-dihydrothiazolo[2,3-i]purine, 7-iodomethyl-7,8-
dihydrothiazolo[2,3-i]purine, halocyclization.
7,8-Dihydrothiazolo[2,3-i]purine and its derivatives were obtained by the reaction of 6-mercaptopurine
(1) and substituted 6-mercaptopurines with 1,2-dibromoethane [1, 2] and also by the interaction of
6-(2-hydroxyalkyl)thiopurines with SOCl2 [3], and by treatment of 6-(2-aminoethyl)thiopurines with
hydrochloric acid [4].
We have developed a new preparative synthesis of 7-substituted 7,8-dihydrothiazolo[2,3-i]purine by the
halocyclization of 6-allylthiopurine (2). The sulfide 2 was obtained by allylation of purine 1 with allyl bromide
in HMPA in the presence of alkali at room temperature. According to [5], alkylation of purine occurs primarily
at the sulfur atom.
SH
S
Br
N
N
N
N
N
N
KOH
N
N
H
H
1
2
1
The structure of sulfide 2 was confirmed by H NMR and chromato-mass spectroscopy. The molecular
ion M+ (m/z 192) and the maximum peak Φ2 with m/z 177, corresponding to the elimination of a methyl radical
are present in the mass spectrum. Apparently the molecular ion-radical cyclizes to give the ion radical Φ1, which
loses the methyl radical to form the aromatic thiazolo[2,3-i]purine cation Φ2 (Scheme 1).
When compound 2 reacted with bromine or iodine in chloroform compounds are formed containing
approximately 2 mol of halogen to 1 mol of substrate. Apparently they are trihalides of 7-halomethyl-7,8-
dihydrothiazolo[2,3-i]purine 3a,b. The tribromide 3a gave 7-bromomethyl-7,8-dihydrothiazolo[2,3-i]purine (4a)
on treatment with acetone, while the triiodide 3b gave 7-iodomethyl-7,8-dihydrothiazolo[2,3-i]purine (4b) on
treatment with sodium iodide in acetone (Scheme 2).
__________________________________________________________________________________________
Chelyabinsk State University, Chelyabinsk 454021, Russia; e-mail: kim@csu.ru. Translated from
Khimiya Geterotsiklicheskikh Soedinenii, No. 10, 1551-1553, October, 2004. Original article submitted
January 21, 2002.
0009-3122/04/4010-1339©2004 Springer Science+Business Media, Inc.
1339

Scheme 1
.
H2C
S
S
+
+
N
+
N
.
N
N
2
.
_
CH3
N
N
H
N
N
+
H
M
192
Ф2
Ф1
m/z 177
Scheme 2
_
X3
+
S
S
X
X
N
N
N
N
X2
+
2
_
X3
–HX, –X2
N
H
N
H
N
N
3a,b
9
8
S
S
1
N
7
X
X
N
N
N
6
+
2
5
N
_
N
3
N
N
4
4a,b (A)
4a,b (B)
3, 4 a X = Br; b X = I
It should be noted that in the 1H NMR spectra the signals of the protons of the purine ring (H-2 and H-5)
in the halocyclization products 4a,b resonate at weaker field than the corresponding protons (H-2 and H-8) in the
allylsulfide 2. This evidently indicates that these compounds exist in the bipolar form 4a,b (A).
EXPERIMENTAL
1H NMR spectra in (CD3)2SO were recorded with a Bruker WP-250 (250 MHz) spectrometer and 13C
NMR spectra in (CD3)2SO were recorded with a Bruker AM-300 (75 MHz) spectrometer with TMS as internal
standard. Mass spectra were recorded on a GC/MS instrument consisting of a HP-5890 chromatograph and a HP-
5972 mass selective detector.
6-Allylthiopurine (2). Allyl bromide (0.29 ml, 3.2 mmol) was added to a solution of KOH (0.180 g, 3.2
mmol) and 6-mercaptopurine (0.510 g, 3.0 mmol) in HMPA (2 ml). The reaction mixture was stirred at room
temperature for 1.5 h, after which it was diluted to 45 ml with water. Calcium chloride (3 g) was added to the
solution which was then kept for 6 h. The precipitate was filtered off and washed with water to give compound
1
3
2, 0.290 g (50%); mp 153°C. HNMR spectrum, δ, ppm (J, Hz): 4.03 (2H, d, J =6.9, SCH2); 5.11 (1H, dd,
CH=CH2); 5.34 (1H, dd, CH=CH2); 5.97 (1H, m, CH=CH2); 8.23 (1H, s, H-8); 8.58 (1H, s, H-2); 13.30 (1H, br.
s, NH). Found, %: C 49.45; H 4.43; S 16.35. C8H8N4S. Calculated, %: C 49.98; H 4.19; S 16.68.
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3-Bromomethyl-2,3-dihydrothiazolo[2,3-i]purine (4a). A solution of bromine (0.052 ml, 1 mmol) in
chloroform (4 ml) was added dropwise to a solution of 6-allylthiopurine (0.100 g, 0.5 mmol) in chloroform
(6 ml). A precipitate formed was separated, treated with acetone and filtered off to give 4a (0.120 g, 88%);
1
mp 191°C (dec.). H NMR spectrum, δ, ppm (J, Hz): 3.96 (1H, dd, SCH2); 4.19 (1H, dd, SCH2); 4.34 (2H, m,
13
CH2Br); 6.15 (1H, m, H-7); 8.89 (1H, s, H-2); 9.61 (1H, s, H-5). C NMR spectrum, δ, ppm: 33 (CH2Br), 133
(C-2), 108 (C-3a), 162 (C-5), 64 (C-7), 33 (C-8), 168 (C-9a). Found, %: Br 29.56; S 11.38. C8H7BrN4S.
Calculated, %: Br 29.47; S 11.83.
3-Iodomethyl-2,3-dihydrothiazolo[2,3-i]purine (4b). A solution of 6-allylthiopurine (0.100 g,
0.5 mmol) in chloroform (5 ml) was added to a solution of iodine (0.254 g, 1.0 mmol) in chloroform (3 ml). A
deep-red precipitate which separated over 48 h was treated with a saturated solution of NaI in acetone (6 ml).
The yellow precipitate was filtered off and washed with acetone to give compound 4b (0.154 g, 93%); mp 204°C
(dec.). 1H NMR spectrum, δ, ppm: 3.86 (1H, dd, SCH2); 3.97 (2H, m,CH2I); 4.25 (1H, dd, SCH2); 5.84 (1H, m,
H-7); 8.87 (1H, s, H-2); 9.47 (1H, s, H-5). 13C NMR spectrum, δ, ppm: 7 (CH2I), 146 (C-3a), 68 (C-7), 38 (C-8),
158 (C-9), 151 (C-9b). Found, %: I 39.01; S 9.86. C8H7IN4S. Calculated, %: I 39.89; S 10.08.
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