A New Strategy for Pyrrolo[1,2-a][1,4]diazepine Structure Formation

Abstract

A new method is elaborated for the synthesis of benzo- and thieno[2,3-b]pyrido-annelated pyrrolo[1,2-a][1,4]diazepine skeleton, as a result of recyclization of furfuryl amides of the corresponding aromatic and heteroaromatic acids with an amino group in the ortho position. A feature of the method is a simultaneous formation of pyrrole and diazepine rings in the reaction.

furan - ring opening - ring closure - pyrrolo[1,2-a][1,4]diazepinone

References and Notes

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15

General Procedure for the Preparation of Compounds 2a,b To a stirred solution of 5-methylfurfurylamine (12 mmol) in anhyd benzene (30 mL) a solution of 2-nitrobenzoyl or 2-nitroveratroyl chloride (10 mmol) in benzene (30 mL) was added dropwise over 30 min. The reaction mixture was agitated at r.t. for an additional 1 h and then cold sat. aq Na₂CO₃ (50 mL) was added. The organic layer was separated, washed with H₂O, dried over Na₂SO₄ and concentrated in vacuo. The residue was crystallized from PE-CH₂Cl₂.
Selected analytical data for 2b: mp 166-167 °C. IR: ν_max = 3260, 1642, 1580, 1519, 1339, 1289, 1267, 1226, 1052, 994, 872, 789 cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 2.28 (s, 3 H, CH₃), 3.96 (s, 3 H, OCH₃), 3.97 (s, 3 H, OCH₃), 4.58 (d, 2 H, J = 5.3 Hz, CH₂), 5.85 (d, 1 H, J = 3.0 Hz, H_Fur), 5.98 (br s, 1 H, NH), 6.22 (d, 1 H, J = 3.0 Hz, H_Fur), 6.91 (s, 1 H, H_Ar), 7.90 (s, 1 H, H_Ar). MS: m/z (%) = 302 (10) [M⁺ - 18], 215 (22), 194 (58), 181 (22), 164 (49), 150 (13), 136 (76), 110 (100), 95 (96). Anal. Calcd for C₁₅H₁₆N₂O₆: C, 56.25; H, 5.03; N, 8.75. Found: C, 56.12; H, 5.09; N, 8.80.

16

General Procedure for the Preparation of Compounds 3a,b A mixture of amide 2a,b (4.3 mmol), hydrazine hydrate (1.5 mL) and activated Raney nickel (1.0 g) in EtOH (60 mL) was refluxed for 10-20 min until complete conversion of 2a,b (TLC). The mixture was filtered, and the filtrate was evaporated to dryness under reduced pressure. The residue was decolorized with charcoal in EtOAc-PE solution. The solvent was removed in vacuo and the resulting product was recrystallized from PE-CH₂Cl₂ to afford amino amides 3a,b.
Selected analytical data for 3b: mp 125-126 °C. IR: ν_max = 3373, 3293, 1629, 1592, 1535, 1509, 1453, 1361, 1262, 1209, 1171, 1104, 1024, 887, 829, 780 cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 2.29 (s, 3 H, CH₃), 3.82 (s, 3 H, OCH₃), 3.86 (s, 3 H, OCH₃), 4.53 (d, 2 H, J = 5.3 Hz, CH₂), 5.42 (br s, 2 H, NH₂), 5.92 (d, 1 H, J = 3.0 Hz, H_Fur), 6.17 (d, 1 H, J = 3.0 Hz, H_Fur), 6.19 (br s, 2 H, NH + H_Ar), 6.82 (s, 1 H, H_Ar). MS: m/z (%) = 290 (9) [M⁺], 180 (22), 110 (89), 95 (100). Anal. Calcd for C₁₅H₁₈N₂O₄: C, 62.06; H, 6.25; N, 9.65. Found: C, 62.14; H, 6.19; N, 9.60.

17

General Procedure for the Preparation of Compounds 5a,b A mixture of amino amide 3a,b (2 mmol), glacial AcOH (10 mL) and concd HCl (1.5 mL) was kept at 60-70 °C until complete conversion of the initial compounds (TLC). The reaction mixture was poured into iced H₂O (100 mL) and neutralized with NaHCO₃ to approximately pH 7. The precipitate thus obtained was filtered off, washed with H₂O, air-dried and dissolved in EtOAc-PE. The solution was passed through a pad of silica gel and left for crystallization.
Selected analytical data for 5b: mp 195-196 °C. IR: ν_max = 3189, 1652, 1609, 1514, 1458, 1256, 1213, 1127, 1040, 1017, 926, 872, 799 cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 2.34 (s, 3 H, CH₃), 3.93 (s, 3 H, OCH₃), 3.96 (s, 3 H, OCH₃), 4.08-4.13 (m, 2 H, CH₂), 5.99 (d, 1 H, J = 3.2 Hz, H_Pyr), 6.02 (d, 1 H, J = 3.2 Hz, H_Pyr), 6.77 (s, 1 H, H_Ar), 7.01 (br s, 1 H, NH), 7.44 (s, 1 H, H_Ar). ¹³C NMR (50 MHz, CDCl₃): δ = 14.4, 38.2, 56.2, 104.6, 108.2, 109.5, 112.8, 121.4, 129.1, 130.1, 132.9, 147.2, 151.1, 170.3. MS: m/z (%) = 272 (100) [M⁺], 257 (30), 244 (16), 243 (57), 229 (24), 228 (66), 200(16), 198 (15), 185 (12), 172 (14), 170 (14), 165 (33), 122 (19). Anal. Calcd for C₁₅H₁₆N₂O₃: C, 66.16; H, 5.92; N, 10.29. Found: C, 66.10; H, 5.99; N, 10.23.

18

General Procedure for the Preparation of Compounds 7a-c To a suspension of pyridinethione 6 (10 mmol) in EtOH (75 mL) KOH (10 mmol, 10% aq soln) was added and the reaction mixture was heated until the complete dissolution of 6. Chloroacetamide was added and, after 15 min, the mixture was treated with a further portion of KOH (10 mmol, 10% aq soln). The solution thus obtained was allowed to stand for 2 h at r.t. The mixture was quenched with H₂O (25 mL) and the precipitate formed was separated by filtration. The crystals were dried and recrystallized from EtOH-DMF (10:3).
Selected analytical data for 7c: mp 77-78 °C. IR: ν_max = 3404, 3313, 3241, 1657, 1594, 1544, 1501, 1417, 1305, 1294, 1269, 1218, 1198, 1186, 1155, 1088, 1071, 1016, 918, 865, 799, 752, 705 cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 2.24 (s, 3 H, CH₃), 2.57 (s, 3 H, CH₃), 3.38 (s, 3 H, OCH₃), 4.34 (d, 2 H, J = 5.2 Hz, CH₂Fur), 4.83 (s, 2 H, CH ₂OCH₃), 5.98 (d, 1 H, J = 3.0 Hz, H_Fur), 6.10 (d, 1 H, J = 3.0 Hz, H_Fur), 6.91 (br s, 2 H, NH₂), 7.24 (s, 1 H, CH_Py), 8.13 (t, J = 5.2 Hz, NH). MS: m/z (%) = 345 (51) [M⁺], 235 (33), 219 (16), 208 (10), 204 (11), 175 (10), 110 (69), 96 (12), 95 (100). Anal. Calcd for C₁₇H₁₉N₃O₃S: C, 59.11; H, 5.54; N, 12.17. Found: C, 59.17; H, 5.49; N, 12.21.

19 Kaigorodova EA. Konyushkin LD. Mikhailichenko SN. Vasilin VK. Kul’nevich VG. Khim. Geterotsikl. Soedin.  1996,  1432 

20

Compounds 8a-c were prepared from 6a-c similarly to 5a,b (see ref. 17).
Selected analytical data for compound 8c: mp 240-241 °C. IR: ν_max = 3168, 1640, 1584, 1549, 1527, 1517, 1345, 1267, 1255, 1213, 1198, 1155, 1109, 942, 859, 804, 777, 752 cm^-1. ¹H NMR (300 MHz, DMSO-d ₆): δ = 1.93 (s, 3 H, CH₃), 2.65 (s, 3 H, CH₃), 3.23 (s, 3 H, OCH₃), 4.13 (d, J = 13.2 Hz, 1 H, CH₂), 4.15 (d, J = 5.2 Hz, 2 H, CH₂), 4.48 (d, J = 13.2 Hz, 1 H, CH₂), 6.10 (s, 2 H, H_Pyr), 7.45 (s, 1 H, H_Py), 8.72 (t, J = 5.2 Hz, NH). ¹³C NMR (50 MHz, CDCl₃): δ = 13.1, 24.0, 37.7, 58.2, 69.0, 105.7, 109.8, 120.0, 123.4, 128.3, 129.3, 129.6, 134.4, 144.1, 158.2, 158.7, 163.5. MS: m/z (%) = 327 (100) [M⁺], 312 (11), 284 (10), 283 (84), 280 (32), 268 (18), 267 (14), 266 (20), 253 (18), 240 (15), 239 (22), 238 (12), 225 (13), 218 (15), 217 (49), 190 (47), 189 (12), 149 (12), 133 (16). Anal. Calcd for C₁₇H₁₇N₃O₂S: C, 62.37; H, 5.23; N, 12.83. Found: C, 62.30; H, 5.29; N, 12.89.