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

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

• 1 Yukio H. Yoichi N. Keiji Y. Akihiro F. Tetsuya T. J. Chem. Soc., Chem. Commun.  1995,  1:  49 
• 2 Sahu RK. Magan A. Gupta B. Sondhi SM. Srimal RC. Patnaik GK. Phosphorus, Sulfur Silicon Relat. Elem.  1994,  88:  45 
• 3 Kappe CO. J. Org. Chem.  1997,  62:  3109 
• 4 Wehner W, and Friedrich HH. inventors; Ger. Offen. DE  19,915,388. 
• 5 Elliott RL. Pireh D. Griesgraber G. Nilius AM. Ewing PJ. J. Med. Chem.  1998,  41:  1651 
• 6 Agouridas C. Denis A. Auger JM. Benedetti Y. Bonnefoy A. J. Med. Chem.  1998,  41:  4080 
• 7 Elliott RL. Pireh D. Nilius AM. Johnson PM. Flamm RK. Bioorg. Med. Chem. Lett.  1997,  7:  641 
• 8 Keiichiro H. Yukihisa K. Tomonari K. Hiroshi T. J. Chem. Soc., Perkin Trans. 2  1992,  621 
• 9 Zaleska B. Socha R. Ciechanowicz-Rutkowska M. Pilati T. Monats. Chem.  2000,  131:  1151 
• 10 Zaleska B. Bazanek T. Socha R. Karelus M. Grochowski J. Serda P. J. Org. Chem.  2002,  67:  4526 

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-CCl_4: 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.