Ketene S,S-acetals in the synthesis of some new fused pyrimidine derivatives

Article abstract of DOI:10.1007/s10593-007-0056-3

Condensation of ketene dithioacetal derivatives with some aminoazoles (5-aminotetrazole monohydrate, 2-aminobenzimidazole, 2-aminobenzothiazole, and 2-aminothiazole) in the presence or absence of triethylamine gave the corresponding tetrazolopyrimidines,

Full text of DOI:10.1007/s10593-007-0056-3

Chemistry of Heterocyclic Compounds, Vol. 43, No. 3, 2007
KETENE S,S-ACETALS IN THE SYNTHESIS OF SOME
NEW FUSED PYRIMIDINE DERIVATIVES
M. A. Metwally, E. I. Desoky, R. Fawzy, and H. A. Etman
Condensation of ketene dithioacetal derivatives with some aminoazoles (5-aminotetrazole monohydrate,
2-aminobenzimidazole, 2-aminobenzothiazole, and 2-aminothiazole) in the presence or absence of
triethylamine gave the corresponding tetrazolopyrimidines, benzimidazopyrimidines, benzothiazolo-
pyrimidines, and thiazolopyrimidines.
Keywords: aminoazoles, ketene dithioacetals, pyrimidines.
Ketene S,S-acetals are attractive building blocks for the synthesis of heterocyclic compounds [1-21]. In
particular, pyrimidine derivatives have been the subject of chemical and biological studies due to their
interesting pharmacological activity, including antipyretic, analgesic, anti-inflammatory potential as well as
herbicide, fungicide, and leishmanicide properties [2, 22-24]. This work aimed to synthesize some pyrimidine
derivatives with the hope of obtaining interesting biological activities.
Scheme 1
O
CN
N
N
N
N
N
H
SMe
N
H
3
N
N
N
O
SMe
CN
NH2
N
NH2
N
H
HN
N
.
H2O
4
N
COOEt
SMe
NC
S
NH2
MeS
N
1
NH2
S
N
S
N
N
O
SMe
CN
O
CN
N
5
S
SMe
N
6
__________________________________________________________________________________________
Department of Chemistry, Faculty of Science, Mansoura University, Mansoura, Egypt; e-mail:
mamegs@mans.edu.eg. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 3, pp. 469-473, March,
2007. Original article submitted October 9, 2006.
382
0009-3122/07/4303-0382©2007 Springer Science+Business Media, Inc.

Due to the great interest in this class of pharmacologically active compounds, we report the preparation of
novel functionalized azolopyrimidine derivatives by the reaction of ketene S,S-acetal derivatives 1 (Scheme 1) and 2
(Scheme 2) with some aminoazoles in the presence (or absence) of triethylamine.
Scheme 2
NH2
N
CN
MeS
NH
EtOH
N
N
N
N
N
ТEА
CONH2
CN
N
N
H
SMe
N
8
9
EtOH
EtOH,
ТEА
S
NH2
N
S
N
SMe
CN
HN
N
NH2
.
H2O
N
N
N
HN
12
CONH2
NH2
NC
N
S
NH
MeS
SMe
2
CN
N
S
SMe
N
N
7
NH2
N
H
EtOH
EtOH,
ТEА
N
H
N
CN
N
H
CONH2
MeS
N
N
N
10
EtOH, TEA
SMe
CN
H2N
11
The treatment of ethyl 2-cyano-3,3-bis(methylthio)acrylate (1) [25] with 5-aminotetrazole monohydrate
in absolute ethanol allowed the isolation of a compound which possessed elemental analysis and spectral data
concordant with the formation of the tetrazolopyrimidine 3 (Scheme 1). The IR spectrum is characterized by the
presence of strong absorption bands of NH group at 3200, cyano group at 2207, and carbonyl group at 1669 cm-1.
The 1H NMR spectrum showed a singlet signal at δ 2.60 corresponding to the SCH3 protons and a singlet at δ 7.75
ppm due to NH proton.
Compound 1 was allowed to react with 2-aminobenzimidazole in absolute ethanol for 5 h to give
3-cyano-2-methylthio-4-oxo-1,4-dihydrobenzimidazo[1,2-a]pyrimidine (4) in 82% yield. Assignment of product
4 was based on its elemental analysis, IR, 1H NMR, and MS spectral data.
383

The reaction of 2-aminobenzothiazole with ethyl 2-cyano-3,3-bis(methylthio)acrylate (1) gave the
corresponding benzothiazolopyrimidine derivative 5. The structure of the latter was confirmed by its elemental
analysis and spectral data.
Thiazolo[3,2-a]pyrimidine derivatives 6 and 12 were synthesized by the treatment of 2-aminothiazole
with ketene S,S-acetals 1 and 2, respectively. The synthesis of 6 and 7 proceeded successfully in ethanol
containing a catalytic amount of triethylamine. The structures of thiazolo[3,2-a]pyrimidines 6 and 7 were
elucidated by their elemental analysis and spectral data.
Condensation of 2-cyano-3,3-bis(methylthio)acrylamide (2) [26] with 5-aminotetrazole monohydrate in
absolute ethanol afforded the enamine derivative 8 (Scheme 2). Compound 8 underwent cyclization upon boiling
in ethanol and triethylamine to give the tetrazolopyrimidine ring system 9. An alternative preparation of 9 was
carried out by the treatment of ketene S,S-acetal 2 with 5-aminotetrazole monohydrate in absolute ethanol and
triethylamine. The elemental analyses and spectral measurements are compatible with the assigned structures of
products 8 and 9.
Compound 2 reacts readily with 2-aminobenzimidazole in absolute ethanol to give the corresponding
enamine derivative 10. However, when the reaction mixture was refluxed in ethanol and triethylamine, the
pyrimidobenzimidazole derivative 11 was isolated directly. The structures of products 10 and 11 were
established by their elemental analyses and spectral data.
Compound 2 reacts readily with 2-aminobenzothiazole in absolute ethanol and triethylamine, the
pyrimidobenzothiazole derivative 12 was isolated directly. The structure of product 12 was established by its of
elemental analysis and spectral data. The IR spectrum of 12 revealed the absence of amide group and the
1
presence of imino function at 3109 in addition to the cyano function at 2208 cm-1. The H NMR spectrum
showed a singlet for SCH3 protons at δ 2.60, a multiplet for aromatic protons at δ 6.90-7.40, and a singlet
at δ 9.60 ppm for NH.
EXPERIMENTAL
All melting points (uncorrected) were determined on a Gallenkamp electric melting point apparatus.
Elemental analyses were carried out in the microanalytical center of Cairo University. IR spectra were recorded
1
(KBr pellets) on a Mattson 5000 FTIR spectrometer (not all frequencies are reported). H NMR spectra were
measured on a Brucker WP-300 (300 MHz) spectrometer using TMS as an internal standard. Mass spectra (EI,
70 eV) were recorded on a Finnigan MAT 212 instrument.
5-Methylsulfanyl-7-oxo-4,7-dihydrotetrazolo[1,5-a]pyrimidine-6-carbonitrile (3). A mixture of 1
(5 mmol) and 5-aminotetrazole monohydrate (5 mmol) in absolute ethanol (30 ml) was boiled under reflux for 10 h,
left to stand at room temperature overnight, poured into crushed ice, and neutralized with diluted hydrochloric
acid. The solid product separated was filtered off, dried, and crystallized from ethanol to give yellow crystals of
1
3. Yield 56%, mp 144-145°C. IR spectrum, ν, cm-1: 3200 (NH), 2207 (CN), 1669 (CO). H NMR spectrum
(CDCl3), δ, ppm: 2.60 (3H, s, SCH3); 7.25 (1H, s, NH). MS, m/z (Irel, %): 208 [M+] (70), 187 (5), 125 (8), 97
(15), 83 (23), 69 (40), 55 (100). Found, %: C 34.65; H 1.83; N 40.44. C6H4N6OS (M 208.20). Calculated, %:
C 34.61; H 1.94; N 40.37.
2-Methylsulfanyl-4-oxo-1,4-dihydropyrimido[1,2-a]benzimidazole-3-carbonitrile (4). A mixture of 1
(2 mmol) and 2-aminobenzimidazole (2 mmol) in absolute ethanol (20 ml) was refluxed for 10 h. The white
precipitate formed was filtered off and crystallized from EtOH−DMF, 2:1, to give compound 4. Yield 89%,
1
mp >300°C. IR spectrum, ν, cm-1: 3293 (NH), 2209 (CN), 1659 (CO). H NMR spectrum (DMSO-d6), δ, ppm:
2.60 (3H, s, SCH3); 7.15-7.60 (4H, m, Ar−H); 8.40 (1H, s, NH). MS, m/z (Irel, %): 256 [M+] (100), 201 (12), 195
(14), 181 (24), 160 (30), 133 (10), 102 (8), 90 (22). Found, %: C 56.33; H 3.27; N 21.80. C12H8N4OS
(M 256.28). Calculated, %: C 56.24; H 3.15; N 21.86.
384

2-Methylsulfanyl-4-oxo-4H-pyrimido[2,1-b]benzothiazole-3-carbonitrile (5).
A
mixture of 1
(2 mmol) and 2-aminobenzothiazole (2 mmol) in absolute ethanol (20 ml) was refluxed for 10 h. The yellow
precipitate formed was filtered off and recrystallized from EtOH−acetone mixture, 1:1, to give colorless crystals
1
of compound 5. Yield 64%, mp 200-201°C. IR spectrum, ν, cm-1: 2211 (CN), 1669 (CO). H NMR spectrum
(DMSO), δ, ppm: 2.60 (3H, s, CH3); 7.40-7.80 (4H, m, Ar−H). MS, m/z (Irel, %): 273 [M+] (100), 240 (30), 212
(25), 198 (65), 134 (25), 108 (16). Found, %: C 52.88; H 2.64; N 15.21. C12H7N3OS2 (M 273.33). Calculated, %:
C 52.73; H 2.58; N 15.37.
Thiazolo[3,2-a]pyrimidines 6 and 7 (General procedure). A mixture of 1 or 2 (3 mmol),
2-aminothiazole (3 mmol), and a few drops of triethylamine in absolute ethanol (20 ml) were refluxed for 5 h,
poured into crushed ice, and neutralized with diluted acetic acid. The solid product separated was filtered off,
dried, and crystallized from ethanol to give compound 6 or 7 as buff crystals.
7-Methylsulfanyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-6-carbonitrile (6). Yield 62%, mp 226-228°C.
1
IR spectrum, ν, cm-1: 2220 (CN), 1680 (CO). H NMR (DMSO) spectrum, δ, ppm (J, Hz): 2.60 (3H, s, SCH3);
7.60 (1H, d, J ~3, C-2); 8.10 (1H, d, J ~3, C-3). MS, m/z (Irel, %): 223 [M+] (100), 190 (25), 176 (28), 148 (43),
127 (23), 104 (15), 82 (19), 70 (26), 58 (80). Found, %: C 43.15; H 2.37; N 18.67. C8H5N3OS2 (M 223.27).
Calculated, %: C 43.03; H 2.26; N 18.82.
5-Imino-7-methylsulfanyl-5H-thiazolo[3,2-a]pyrimidine-6-carbonitrile (7). Yield 68%, mp 190-191°C.
IR spectrum, ν, cm-1: 3318 (NH), 2206 (CN), 1640 (C=N). Found, %: C 43.34; H 2.87; N 25.17. C8H6N4S2 (M
222.29). Calculated, %: C 43.23; H 2.72; N 25.20.
2-Cyano-3-methylsulfanyl-3-(1H-tetrazol-5-ylamino)acrylamide (8). A mixture of 2 (5 mmol) and
5-aminotetrazole monohydrate (5 mmol) in absolute ethanol (30 ml) was refluxed for 6 h and poured into
crushed ice. The solid product separated was filtered off and recrystallized from ethanol to give pale yellow
crystals of 8. Yield 80%, mp 135-136°C. IR spectrum, ν, cm-1: 3369, 3418 (NH and NH2), 2206 (CN), 1698
(CO). 1H NMR spectrum (DMSO), δ, ppm: 2.61 (3H, s, SCH3); 6.34 (1H, s, NH); 7.54 (1H, s, NH); 7.67 (2H, s,
NH2). MS, m/z (100%): 225 [M+] (5), 207 (5), 188 (20), 173 (68), 143 (22), 127 (37), 98 (75), 83 (60), 75 (32),
46 (100). Found, %: C 32.05; H 3.32; N 43.67. C6H7N7OS (M 225.23). Calculated, %: C 32.00; H 3.13; N 43.53.
7-Amino-5-methylsulfanyltetrazolo[1,5-a]pyrimidine-6-carbonitrile (9). A mixture of 2 (5 mmol)
and 5-aminotetrazole monohydrate (5 mmol) was refluxed for 10 h in 30 ml absolute ethanol containing 1 ml of
triethylamine. The yellow precipitate formed was filtered off and recrystallized from ethanol to give 9. Yield:
1
62%, mp 212-213°C. IR spectrum, ν, cm-1: 3402, 3200 (NH2), 2203 (CN), 1638 (C=N). H NMR spectrum
(DMSO), δ, ppm: 2.60 (3H, s, SCH3), 6.51 (2H, br. s, NH2). Found, %: C 34.91; H 2.52; N 47.35%. C8H10N6O2S
(M 207.22). Calculated, %: C 34.78; H 2.43; N 47.32.
3-(1H-Benzimidazol-2-ylamino)-2-cyano-3-methylsulfanylacrylamide (10). A mixture of 2 (2 mmol)
and 2-aminobenzimidazole (2 mmol) in absolute ethanol (20 ml) was refluxed for 10 h and poured into crushed
ice. The solid product separated was filtered off and recrystallized from ethanol to give compound 10 as yellow
crystals. Yield 66%, mp 178-179°C. IR spectrum, ν, cm-1: 3300, 3130 (NH, NH2), 2204 (CN), 1701 (CO), 1639
1
(C=N). H NMR spectrum (DMSO), δ, ppm: 2.55 (3H, s, SCH3); 6.40 (1H, s, NH); 7.05-7.60 (4H, m, Ar−H);
7.90 (2H, s, NH2); 8.40 (1H, s, NH). Found, %: C 52.82; H 4.22; N 25.7. C12H11N5OS (M 273.31). Calculated, %:
C 52.73; H 4.04; N 25.62.
4-Amino-2-methylsufanylpyrimido[1,2-a]benzimidazole-3-carbonitrile (11).
A
mixture of 2
(2 mmol), 2-aminobenzimidazole (2 mmol) and about 0.5 ml triethylamine in absolute ethanol (20 ml) was
refluxed for 10 h, poured into crushed ice, and neutralized with diluted acetic acid. The solid product separated
was filtered off, dried, and recrystallized from EtOH−DMF, 1:1, to give yellowish brown crystals of compound
1
11. Yield 72%, mp > 300°C. IR spectrum, ν, cm-1: 3412, 3111 (NH2), 2213 (CN), 1640 (C=N). H NMR
spectrum (DMSO), δ, ppm: 2.60 (3H, s, SCH3); 6.60 (1H, s, NH2), 7.10-7.70 (4H, m, Ar−H). Found, %: C 56.40;
H 3.45; N 27.34. C12H9N5S (M 255.30). Calculated, %: C 56.45; H 3.55; N 27.43.
385

4-Imino-2-methylsulfanyl-4H-pyrimido[2,1-b]benzothiazole-3-carbonitrile (12). Compound 12 was
prepared similarly to pyrimido[1,2-a]benzimidazole derivative 11 using 2-aminobenzo- thiazole instead of
1
2-aminobenzimidazole. Yield 55%, mp >300°C. IR spectrum, ν, cm-1: 3109, (NH), 2208 (CN). H NMR
(DMSO), δ, ppm: 2.60 (3H, s, SCH3); 6.90-7.40 (4H, m, Ar−H); 9.60 (1H, s, NH). MS, m/z (Irel., %): 273 [M+ + 1]
(15), 273 (M+ + 2, 27), 218 (17), 213 (15), 150 (100), 134 (23), 123 (18), 109 (22), 96 (32), 69 (29). Found, %:
C 52.98; H 2.87; N 20.66. C12H8N4S2. (M 272.35). Calculated. C 52.92; H 2.96; N 20.57.
REFERENCES
1.
2.
Y. Tominaga and Y. Mutsuda, J. Heterocycl. Chem., 22, 937 (1985).
R. K. Dieter, Tetrahedron, 42, 937 (1986).
3.
Y. Tominaga, J. Heterocycl. Chem., 26, 1167 (1989).
4.
5.
W. Reid and S. Aboul-Fetouh, Tetrahedron, 44, 7155 (1988).
R. Gompper and W. Topfi, Chem. Ber., 95, 2871 (1962).
6.
7.
8.
9.
10,
11.
12.
13.
14.
15.
16.
17.
W. D. Rudorf, A. Schierhorn, and M. Augustin, Tetrahedron, 35, 551 (1979).
S. M. S. Chauhan and H. Junjappa, Tetrahedron, 32, 1779 (1976).
S. M. S. Chauban and H. Junjappa, Tetrahedron, 32, 1911 (1976).
W. D. Rudorf and M. Augustin, J. Prakt. Chem., 320, 576 (1978).
K. T. Potts, M. J. Cipullo, P. Relli, and G. Theodorida, J. Org. Chem., 48, 4841 (1983).
H. Liu, G. Yang, K. Chen, and H. Yang, Synth. Commun., 29, 3143 (1999).
H. Kristen and M. Raddatz, Z. Chem., 21, 101 (1981).
R. Evers, Z. Chem., 19, 250 (1979).
S. Kohra, Y. Tominaga, Y. Matsuda, and G. Kobayashi, Heterocycles, 20, 1745 (1983).
S. Kohra, Y. Tominaga, and A. Hosomi, J. Heterocycl. Chem., 25, 959 (1988).
D. Briel, J. Sieler, G. Wagner, and W. Schade, Phosphorus, Sulfur, 35, 55 (1988).
Y. Tominaga, S. Sakai, S. Kohra, J. Tsuka, Y. Matsuda, and G. Kobayashi, Chem. Pharm. Bull., 33,
962 (1985).
18.
19.
V. J. Ram and M. Nath, Indian J. Chem., Sect. B: Org. Chem. Incl. Med. Chem., 34B, 416 (1995).
G. E. Elgemeie, H. A. Ali, and A. Mansour, Phosphorus, Sulfur, Silicon Relat. Elem., 90,
143 (1994).
20.
E. I. El-Desoky, S. Aboul-Fetouh, and M. A. Metwally, J. Chem. Technol. Biotechnol., 67,
153 (1996).
21.
22.
W. Ried and J. Laoutidis, Liebigs Ann. Chem., 207 (1990).
F. C. Tucci, Y. F. Zhu, Z. Guro, T. D. Gross, P. J. Connors, R. S. Stuthers, G. J. Reinhart, X. Wang;
J. Saunders, and C. A. Chen, Bioorg. Med. Chem. Lett., 12, 3491 (2002).
M. S. Planki, P. E. Erdman, A. M. Manning, A. Ow, L. J. Ransone, C. Spooner, and M. Suto, Bioorg.
Med. Chem. Lett., 10, 1645 (2000).
23.
24.
25.
26.
S. A. M. El-Hawash, E. A. M. Badaawey, and I. M. El-Ashwawey, Eur. J. Med. Chem., 41, 155 (2006).
R. Gompper and W. Topfi, Chem. Ber., 95, 2861 (1962).
Z. T. Huang and X. Shi, Synthesis, 162 (1990).
386