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Synlett 2002(11): 1831-1834
DOI: 10.1055/s-2002-34866
LETTER
© Georg Thieme Verlag Stuttgart · New York

Synthesis of Heterocyclic Systems by the Reaction of Zwitterionic Compounds with Isocyanates and Thiophosgene

Barbara Zaleska*, Marcin Karelus
Department of Organic Chemistry, Jagiellonian University, Ingardena 3, 30-060 Kraków, Poland
Fax: +48(12)6340515; e-Mail: zaleska@chemia.uj.edu.pl;
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Publication History

Received 13 September 2002
Publication Date:
21 October 2002 (online)

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Abstract

The reaction of various isocyanates or thiophosgene with zwitterionic pyrimidinylium and 1,3-diazepinylium derivatives has led to the formation of unusually substituted [1,3]oxazolo[3,4-a]pyrimidines and novel heterocyclic system such as [1,3]oxazolo[3,4-a][1,3]diazepine.

Key words

zwitterionic compounds - fused heterocycles - oxazolidine - pyrimidine - 1,3-diazepine

    References

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11

General procedure for the preparation of zwitterionic com-pounds 2 and 3: A solution of 0.5 g (1.52 mmol) 1 and 3.04 mmol of the corresponding diamine in toluene was heated for 5 min. Cooling the mixture yielded colorless crystals, which were purified by recrystallization from ethanol.

12

General procedure for the preparation of [1,3]oxazolo[3,4-a]pyrimidin-6-one derivatives 4 and [1,3]oxazolo[3,4-a][1,3]diazepin-7-one derivatives 5 using phenyl isocyanate:
The corresponding zwitterionic compound 2 or 3 (1 mmol) was dissolved in toluene at 100 °C and 2 mmol of phenyl isocyanate was added. The mixture was heated under reflux for 15 minutes. After cooling in an ice bath, the mixture was filtered to remove the N,N′-diphenylurea. Toluene was removed under reduced pressure and the crude product was purified by column chromatography (Al2O3, CCl4:acetone 5:1) and then crystallized from CCl4.

13

General procedure for the preparation of [1,3]oxazolo[3,4-a]pyrimidine-6-thione derivatives 6 and [1,3]oxazolo[3,4-a][1,3]diazepine-7-thione derivatives 7:
The corresponding zwitterionic compound 2 and 3 (1 mmol) was dissolved in 20 mL of chloroform at 0 °C, and 10 mL of water and 2 mmol of sodium bicarbonate were added. While stirring, 1 mmol of thiophosgene was added and the mixture was stirred vigorously for 40 minutes. The organic phase was then separated and evaporated under reduced pressure, at room temperature. The crude product was purified by column chromatography (Al2O3-CCl4: acetone 5:1) and then crystallized from CCl4.

14

Physical data: Melting points were determined on an electrothermal IA9000 digital melting point apparatus and are uncorrected. The IR spectra were obtained on a Bruker IFS 48 spectrometer at room temperature. 1H and 13C NMR spectra were recorded with a Bruker AMX 500 NMR spectrometer using TMS as internal standard. Chemical shifts are reported in ppm downfield from TMS.
Spectral data for compounds 2a and 3a are described in our recent work. [10]
2-Hydroxy-2-methyl-2-(1,3,4,5,6-pentahydropyrimidin-2-ylium)-1-( p -chlorophenylimino)thiolate (2b): C13H16ClN3OS; MW 297.8; mp 196-197 °C; (% C, H, N): calcd: 52.43, 5.42, 14.11; found: 52.43, 5.27, 14.07; IR (KBr): (cm-1) = 3323, 2885, 1661; 1H NMR (DMSO-d 6 ):
δ (ppm) = 7.75-10.00 broad (s, 2 H, 2 × NH), 7.38 (d, 2 H, p-chlorophenyl, J = 8.8 Hz), 7.22 (d, 2 H, p-chlorophenyl,
J = 8.8 Hz), 3.47 (t, 4 H, 2 × N-CH2, J = 5.8 Hz), 1.93 (quintet, 2 H, CH2, J = 5.8 Hz), 1.74 (s, 3 H, CH3); 13C NMR (DMSO-d 6 ): δ (ppm) = 186.4 (C-S), 166.2 (N-C-N), 151.7, 127.6, 125.3, 123.9 (p-chlorophenyl), 74.9 (C-O), 38.4 (N-CH2), 28.3 (CH3), 17.8 (CH2); MS (EI): m/z (%) = 298 (0.3) M+, 169 (2.8) Cl-C6H4-NCS+, 127 (100) M+ - Cl-C6H4-NCS, 111 (5.3) Cl-C6H4 +, 85 (4.5) M+ - Cl-C6H4-NCS - CH3COH.
2-Hydroxy-2-methyl-2-(1,3,4,5,6,7-hexahydro-1,3-diazepin-2-ylium)-1-( p -chlorophenylimino)thiolate (3b): C14H18ClN3OS; MW 311.8; mp 166-167 °C; (% C, H, N): calcd: 53.92, 5.82, 13.48; found: 53.80, 5.56, 13.49; IR (KBr): (cm-1) = 3278, 2929, 2862, 1680; 1H NMR (DMSO-d 6 ): δ (ppm) = 8.5-9.5 broad (s, 2 H, 2 × NH), 7.25 (d, 2 H, p-chlorophenyl, J = 8.8 Hz), 7.09 (d, 2 H, p-chlorophenyl, J = 8.8 Hz), 3.55-3.61 (m, 4 H, 2 × N-CH2-C), 1.84-1.93 (m, 4 H, C-CH2-CH2-C), 1.61 (s, 3 H, CH3); 13C NMR (DMSO-d 6 ): δ (ppm) = 186.8 (C-S), 171.2 (N-C-N), 151.6, 127.7, 125.5, 123.8 (p-chlorophenyl), 75.6 (C-O), 42.7 (N-CH2), 28.4 (CH3), 25.7 (CH2); MS (EI): m/z (%) = 311 (0.1) M+, 169 (3.1) Cl-C6H4-NCS+, 141(100) M+ - Cl-C6H4-NCS, 111 (6.9) Cl-C6H4 +, 99 (14.9) M+ - Cl-C6H4-NCS - CH3COH.
2,3,4,6-Tetrahydro-8-methyl-8-( N -phenylthio-carba-moyl)-8 H -[1,3]oxazolo[3,4- a ] pyrimidin-6-one (4a): C14H15N3O2S; MW 289.4; mp 130-131 °C; (% C, H, N): calcd: 58.11, 5.22, 14.52; found: 58.34, 5.05, 14.43; IR (KBr): (cm-1) = 3262, 3205, 1808, 1790, 1689, 1083; 1H NMR (CDCl3): δ (ppm) = 11.03 (s, 1 H, NH), 7.80 (d, 2 H, Ph, J = 8.4 Hz), 7.41 (t, 2 H, Ph, J = 8.4, Hz), 7.27 (t, 1 H, Ph, J = 8.4 Hz), 3.56-3.72 (m, 4 H, 2 × N-CH2), 1.96 (s, 3 H, CH3), 1.87-1.93 (m, 2 H, C-CH2-C); 13C NMR (CDCl3):
δ (ppm) = 193.1 (C=S), 154.9 (C=O), 152.6 (C=N), 138.1, 128.9, 126.9, 122.8 (Ph), 86.3 (C-O), 44.5 (N-CH2), 38.8 (N-CH2), 28.4 (CH3), 18.8 (CH2); MS (EI): m/z (%) = 289 (6.09) M+, 154(100) M+ - PhNCS, 135 (19.73) PhNCS+, 126 (15.41) M+ - PhNCS - CCH3, 109 (3.13) M+ - PhNCS - CO2, 84 (18.15) CH2CH2CH2NCO, 77 (14.64) Ph.
2,3,4,6-Tetrahydro-8-methyl-8-( N - p -chlorophenyl-thiocarbamoyl)-8 H -[1,3]oxazolo[3,4- a ]pyrimidin-6-one (4b): C14H14ClN3O2S; MW 323.8; mp 154-155 °C; (% C, H, N): calcd: 51.93, 4.36, 12.98; found: 52.08, 4.35, 12.98; IR (KBr): (cm-1) = 3183, 3111, 1800, 1694, 1081; 1H NMR (CDCl3): δ (ppm) = 11.03 (s, 1 H, NH), 7.76 (d, 2 H, p-chlorophenyl, J = 8.5 Hz), 7.36 (d, 2 H, p-chlorophenyl, J = 8.5 Hz), 3.56-3.72 (m, 4 H, 2 × N-CH2), 1.95 (s, 3 H, CH3), 1.88-1.93 (m, 2 H, C-CH2-C); 13C NMR (CDCl3): δ (ppm) = 193.4 (C=S), 154.9 (C=O), 152.5 (C=N), 136.7, 131.9, 129.0, 124.0 (p-chlorophenyl), 86.3 (C-O), 44.5 (N-CH2), 38.9 (N-CH2), 28.5 (CH3), 18.8 (CH2); MS (EI): m/z (%) = 323 (2.3) M+, 169 (24.5) Cl-C6H4-NCS+, 154(100) M+ - Cl-C6H4-NCS, 126 (16.4) M+ - Cl-C6H4-NCS - CCH3, 111 (14.1) Cl-C6H4 +, 84 (28.3) CH2CH2CH2NCO.
2,3,4,5,7,9-Hexahydro-9-methyl-9-( N -phenylthio-carbamoyl)-[1,3]oxazolo[3,4- a ][1,3]diazepin-7-one (5a): C15H17N3O2S; MW 303.4; mp 114-115 °C; (% C, H, N): calcd: 59.39, 5.65, 13.85; found: 59.16, 5.51, 13.71; IR (KBr): (cm-1) = 3179, 1798, 1694, 1087; 1H NMR (CDCl3): δ (ppm) = 11.61 (s, 1 H, NH), 7.82-7.23 (m, 5 H, Ph), 3.78-3.83 (m, 2 H, N-CH2), 3.66-3.77 (m, 2 H, N-CH2), 1.95-1.99 (m, 4 H, C-CH2CH2-C), 1.91 (s, 3 H, CH3); 13C NMR (CDCl3): δ (ppm) = 193.8 (C=S), 154.2 (C=O), 153.7 (C=N), 138.5, 128.9, 126.7, 122.4 (Ph), 85.1 (C-O), 50.9 (N-CH2), 46.4 (N-CH2), 29.7 (CH2), 29.2 (CH3), 26.2 (CH2); MS (EI): m/z (%) = 303(3) M+, 168 (100) M+ - PhNCS, 140 (8) M+ - PhNCS - CCH3, 135 (63) PhNCS+, 123 (23) M+ - PhNCS - CO2, 98 (18) CH2CH2CH2CH2NCO.
2,3,4,5,7,9-Hexahydro-9-methyl-9-( N - p -chlorophenyl-thiocarbamoyl)-[1,3]oxazolo[3,4- a ][1,3]diazepin-7-one (5b): C15H16ClN3O2S; MW 337.8; mp 128-129 °C; (% C, H, N): calcd: 53.33, 4.77, 12.44; found: 53.40, 4.88, 12.39; IR (KBr): (cm-1) = 3164, 3100, 1792, 1702, 1089; 1H NMR (CDCl3): δ (ppm) = 11.68 (s, 1 H, NH), 7.77 (d, 2 H, p-chlorophenyl, J = 8.5 Hz), 7.35 (d, 2 H, p-chlorophenyl, J = 8.5 Hz), 3.78-3.82 (m, 2 H, N-CH2), 3.67-3.73 (m, 2 H, N-CH2), 1.94-1.98 (m, 4 H, C-CH2CH2-C), 1.90 (s, 3 H, CH3); 13C NMR (CDCl3): δ (ppm) = 194.1 (C=S), 154.1 (C=O), 153.7 (C=N), 137.0, 131.6, 129.0, 123.6 (p-chlorophenyl), 85.1 (C-O), 50.9 (N-CH2), 46.4 (N-CH2), 29.7 (CH2), 29.3 (CH3), 26.2 (CH2); MS (EI): m/z (%) = 337 (15) M+, 169 (100) Cl-C6H4-NCS+, 168 (59.5) M+ - Cl-C6H4-NCS, 123 (41.3) M+ - Cl-C6H4-NCS - CO2, 111 (29.5) Cl-C6H4 +, 98 (6.2) CH2CH2CH2CH2NCO.
2,3,4,6-Tetrahydro-8-methyl-8-( N -phenylthio-carbamoyl)-8 H -[1,3]oxazolo[3,4- a ]pyrimidine-6-thione (6a): C14H15N3OS2; MW 305.4; mp 113-114 °C; (% C, H, N): calcd: 55.06, 4.95, 13.76; found: 54.96, 4.91, 13.77; IR (KBr): (cm-1) = 3271, 3206, 1697; 1H NMR (CDCl3):
δ (ppm) = 10.55 (s, 1 H, NH), 7.78 (d, 2 H, Ph, J = 8.5 Hz), 7.40 (t, 2 H, Ph, J = 8.5 Hz), 7.27 (t, 1 H, Ph, J = 8.5 Hz), 3.79-3.92 (m, 2 H, N-CH2), 3.58-3.69 (m, 2 H, N-CH2), 2.01 (s, 3 H, CH3), 1.93-1.97 (m, 2 H, C-CH2-C); 13C NMR (CDCl3): δ (ppm) = 192.2 (C=S), 185.0 (C=S, ester), 153.8 (C=N), 137.9, 128.9, 127.0, 122.9 (Ph), 89.9 (C-O), 44.7 (N-CH2), 42.2 (N-CH2), 27.9 (CH3), 19.0 (CH2); MS (EI): m/z (%) = 306 (58.00) M+, 170(100) M+ - PhNCS, 135 (85.79) PhNCS+, 110 (10.55) M+ - PhNCS - COS, 77 (14.64) Ph.
2,3,4,6-Tetrahydro-8-methyl-8-( N - p -chlorophenylthio-carbamoyl)-8 H -[1,3]oxazolo[3,4- a ]pyrimidine-6-thione (6b): C14H14ClN3OS2; MW 339.9; mp 126-127 °C; (% C, H, N): calcd: 49.48, 4.15, 12.36; found: 49.68, 3.87, 12.51; IR (KBr): (cm-1) = 3180, 3121, 1695; 1H NMR (CDCl3):
δ (ppm) = 10.61 (s, 1 H, NH), 7.75 (d, 2 H, p-chlorophenyl, J = 8.5 Hz), 7.36 (d, 2 H, p-chlorophenyl, J = 8.5 Hz), 3.79-3.92 (m, 2 H, N-CH2), 3.57-3.69 (m, 2 H, N-CH2), 1.99 (s, 3 H, CH3), 1.92-1.98 (m, 2 H, C-CH2-C); 13C NMR (CDCl3): δ (ppm) = 192.5 (C=S), 184.9 (C=S, ester), 153.9 (C=N), 136.4, 132.1, 129.0, 124.2 (p-chlorophenyl), 89.8 (C-O), 44.7 (N-CH2), 42.2 (N-CH2), 28.0 (CH3), 19.0 (CH2); MS (EI): m/z (%) = 169 (90.62) Cl-C6H4-NCS+, 170 (64.52) M+ - Cl-C6H4-NCS, 111 (23.06) Cl-C6H4 +.
2,3,4,5,7,9-Hexahydro-9-methyl-9-( N -phenylthio-carbamoyl)-[1,3]oxazolo[3,4- a ][1,3]diazepine-7-thione (7a): C15H17N3OS2; MW 319.5; mp 102-103 °C; (% C, H, N): calcd: 56.40, 5.36, 13.15; found: 56.32, 5.49, 13.21; IR (KBr): (cm-1) = 3193, 3137, 1704; 1H NMR (CDCl3):
δ (ppm) = 11.10 (s, 1 H, NH), 7.79 (d, 2 H, Ph, J = 8.5), 7.41 (t, 2 H, Ph, J = 8.5 Hz), 7.26 (t, 1 H, Ph, J = 8.5 Hz), 3.97-4.14 (m, 2 H, N-CH2), 3.86-3.87 (m, 2 H, N-CH2), 1.99-2.03 (m, 4 H, CH2CH2), 1.94 (s, 3 H, CH3); 13C NMR (CDCl3): δ (ppm) = 192.85 (C=S), 187.7 (C=S, ester), 152.6 (C=N), 138.2, 128.9, 126.8, 122.6 (Ph), 88.2 (C-O), 50.4 (N-CH2), 49.9 (N-CH2), 28.9 (CH2), 28.5 (CH3), 25.5 (CH2); MS (EI): m/z (%) = 184 (12.04) M+ - PhNCS, 135 (10.21) PhNCS+, 77 (17.87) Ph.
2,3,4,5,7,9-Hexahydro-9-methyl-9-( N - p -chlorophenyl-thiocarbamoyl)-[1,3]oxazolo[3,4- a ][1,3]diazepine-7-thione (7b): C15H16ClN3OS2; MW 353.9; mp 118-119 °C; (% C, H, N): calcd: 50.91, 4.56, 11.87; found: 50.88, 4.73, 11.86; IR (KBr): (cm-1) = 3171, 3119, 1694; 1H NMR (CDCl3): δ (ppm) = 11.16 (s, 1 H, NH), 7.75 (d, 2 H, p-chlorophenyl, J = 8.5 Hz), 7.35 (d, 2 H, p-chlorophenyl, J = 8.5 Hz), 3.98-4.20 (m, 2 H, N-CH2), 3.80-3.95 (m, 2 H, N-CH2), 1.98-2.05 (m, 4 H, C-CH2CH2-C), 1.93 (s, 3 H, CH3); 13C NMR (CDCl3): δ (ppm) = 193.1 (C=S), 187.6 (C=S, ester), 152.8 (C=N), 136.7, 131.8, 129.0, 123.8 (p-chlorophenyl), 88.2 (C-O), 50.4 (N-CH2), 49.9 (N-CH2), 29.0 (CH2), 28.7 (CH3), 25.5 (CH2); MS (EI): m/z (%) = 169 (44.73) Cl-C6H4-NCS+, 184 (16.54) M+ - Cl-C6H4-NCS.