Short and Simple Method of Synthesis of Some Pyrrolo[3,2-b]quinoline Derivatives from Easily Available Nitrobenzene Derivatives

Abstract

The Vilsmeier-Hack condensation of ortho-cyanomethylated nitroarenes with N-methylpyrrolidone, followed by cyclization promoted by O,N-bistrimethylsilylacetamide and DBU in DMF led directly to pyrrolo[3,2-b]quinoline derivatives.

Key words

indoles - cyclization - fused-ring systems - heterocycles - annulation

References and Notes

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• 1b Wróbel Z. Tetrahedron  1998,  54:  2607 
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• 7 Wróbel Z. Mąkosza M. Tetrahedron  1993,  49:  5315 
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17

General Procedure for the Synthesis of 5 from 2: The cyanomethylated nitroarene 2 (2 mmol) dissolved in anhyd N-methylpyrrolidone (10 mL) was cooled to 0 ˚C and Et₃N (3 mL) was added followed by slow addition of POCl₃ (0.5 mL). The cooling bath was then removed, and the reaction mixture was stirred for 30 min at r.t. The mixture was treated with diluted, cold, aq NaCl (200 mL) and extracted with EtOAc (3 × 50 mL). The combined extracts were washed with brine and dried with Na₂SO₄. The solvent was evaporated and the residue was chromatographed on SiO₂ using hexane-EtOAc mixture as an eluent. The obtained 3 (0.5 mmol) was dissolved in anhyd DMF (3 mL). BSA (2.5 mmol, 0.6 mL) and DBU (2.5 mmol, 0.38 mL) were added subsequently. The reaction mixture was stirred for the time, and at the temperature specified in Table  [¹] , then it was poured into diluted aq NaCl solution (50 mL), and extracted with EtOAc (3 × 30 mL). The extracts were combined, washed with brine, dried over Na₂SO₄, and the solvent was evaporated. The residue was chromatographed on SiO₂ using hexane-EtOAc mixture as an eluent.

18

Analytical data for the products: (2 E , Z )-(5-Chloro-2-nitrophenyl)(1-methylpyrrolidin-2-ylidene)acetonitrile (3a): red crystals; mp 112-115 ˚C. Two isomers, M (major)/N (minor) = 1.4. ^¹H NMR (500 MHz, CDCl₃): δ = 1.85-1.92 (m, 2 H, N), 2.00-2.10 (m, 2 H, M), 2.37 (t, J = 7.7 Hz, 2 H, N), 2.47 (s, 3 H, M), 3.06 (t, J = 7.7 Hz, 2 H, M), 3.38 (s, 3 H, N), 3.50-3.58 (m, 2 H, M + 2 H, N), 7.34-7.38 (m, 1 H, M + 1 H, N), 7.44 (d, J = 2.0 Hz, 1 H, M), 7.46 (d, J = 2.0 Hz, 1 H, N), 7.82 (d, J = 8.7 Hz, 1 H, N), 7.88 (d, J = 8.7 Hz, 1 H, M). MS (EI, 70 eV): m/z (%) = 277 (21), 137 (100). HRMS (EI): m/z calcd for C₁₃H₁₂N₃O₂ ^³5Cl: 277.0618; found: 277.0615. (2 E , Z )-(5-Bromo-2-nitrophenyl)(1-methyl-pyrrolidin-2-ylidene)acetonitrile (3b): red crystals; mp 105-107 ˚C (EtOH). Two isomers, M (major)/N (minor) = 1.3. ^¹H NMR (500 MHz, CDCl₃): δ = 1.85-1.92 (m, 2 H, N), 2.00-2.10 (m, 2 H, M), 2.37 (t, J = 7.6 Hz, 2 H, N), 2.47 (s, 3 H, M), 3.06 (t, J = 7.8 Hz, 2 H, M), 3.38 (s, 3 H, N), 3.50-3.58 (m, 2 H, M + 2 H, N), 7.34-7.38 (m, 1 H, M + 1 H, N), 7.44 (d, J = 2.0 Hz, 1 H, M), 7.46 (d, J = 2.0 Hz, 1 H, N), 7.82 (d, J = 8.7 Hz, 1 H, N), 7.88 (d, J = 8.7 Hz, 1 H, M). MS (EI, 70 eV): m/z (%) = 323 (10), 321 (10), 137 (100). HRMS (EI): m/z calcd for C₁₃H₁₂N₃O₂ ⁷⁹Br: 321.0113; found: 321.0118. (2 E , Z )-(5-Fluoro-2-nitrophenyl)(1-methylpyrrolidin-2-ylidene)acetonitrile (3c): orange crystals; mp 120-121 ˚C (hexane-EtOAc). Two isomers, M (major)/N (minor) = 1.4. ^¹H NMR (500 MHz, CDCl₃): δ = 1.84-1.92 (m, 2 H, N), 2.00-2.11 (m, 2 H, M), 2.38 (t, J = 7.7 Hz, 2 H, N), 2.47 (s, 3 H, M), 3.06 (t, J = 7.8 Hz, 2 H, M), 3.39 (s, 3 H, N), 3.50-3.58 (m, 2 H, M + 2 H, N), 7.05-7.10 (m, 1 H, M + 1 H, N), 7.12-7.17 (m, 1 H, M + 1 H, N), 7.92 (dd, J = 8.8, 5.3 Hz, 1 H, N), 7.99 (dd, J = 8.9, 5.3 Hz, 1 H, M). MS (EI, 70 eV): m/z (%) = 261 (11), 137 (100). HRMS (EI): m/z calcd for C₁₃H₁₂N₃O₂F: 261.0914; found: 261.0925. (2 E , Z )-(5-Methoxy-2-nitrophenyl)(1-methylpyrrolidin-2-ylidene)acetonitrile (3d):^¹6 red crystals; mp 89-92 ˚C. Two isomers, M (major)/N (minor) = 2. ^¹H NMR (500 MHz, CDCl₃): δ = 1.82-1.88 (m, 2 H, N), 2.00-2.09 (m, 2 H, M), 2.34 (t, J = 7.7 Hz, 2 H, N), 2.44 (s, 3 H, M), 3.06 (t, J = 7.7 Hz, 2 H, M), 3.44-3.65 (m, 2 H, M + 2 H, N), 3.88 (s, 3 H, N), 3.89 (s, 3 H, M), 3.99 (s, 3 H, N), 6.86-6.90 (m, 2 H, M + 2 H, N), 7.97 (d, J = 9.0 Hz, 1 H, N), 8.02 (d, J = 9.0 Hz, 1 H, M). MS (EI, 70 eV): m/z (%) = 274 (14), 137 (100). Anal. Calcd for C₁₄H₁₅N₃O₃: C, 61.53; H, 5.53; N, 15.38. Found: C, 61.59; H, 5.46; N, 15.22.
(2 E , Z )-(1-Methylpyrrolidin-2-ylidene)[2-nitro-5-(phenylthio)phenyl]acetonitrile (3e): red crystals; mp 147-151 ˚C (hexane-EtOAc). Two isomers, M (major)/N (minor) = 1.5. ^¹H NMR (500 MHz, CDCl₃): δ = 1.80-1.88 (m, 2 H, N), 1.95-2.10 (m, 2 H, M), 2.30 (t, J = 7.6 Hz, 2 H, N), 2.42 (s, 3 H, M), 3.00-3.05 (m, 2 H, M), 3.36 (s, 3 H, N), 3.46-3.56 (m, 2 H, M + 2 H, N), 6.99-7.06 (m, 1 H, M + 1 H, N), 7.15 (d, J = 2.0 Hz, 1 H, M), 7.17 (d, J = 1.9 Hz, 1 H, N), 7.42-7.47 (m, 3 H, M + 3 H, N), 7.50-7.55 (m, 2 H, M + 2 H, N), 7.76 (d, J = 8.6 Hz, 1 H, N), 7.82 (d, J = 8.6 Hz, 1 H, M). MS (EI, 70 eV): m/z (%) = 351 (38), 252 (76), 223 (54), 137 (100). HRMS (EI): m/z calcd for C₁₉H₁₇N₃SO₂: 351.1041; found: 351.1050. (2 E , Z )-(3,5-Dichloro-2-nitrophenyl)(1-methylpyrrolidin-2-ylidene)acetonitrile (3f): pale yellow crystals; mp 163-167 ˚C (hexane-EtOAc). Two isomers, M/N = 1. ^¹H NMR (500 MHz, CDCl₃): δ = 1.85-1.92 (m, 2 H, N), 1.98-2.06 (m, 2 H, M), 2.43 (t, J = 7.8 Hz, 2 H, M or N), 2.56 (s, 3 H, M or N), 2.96-3.02 (m, 2 H, M or N), 3.33 (s, 3 H, M or N), 3.48-3.55 (m, 2 H, M + 2 H, N), 7.33 (d, J = 2.1 Hz, 1 H, M or N), 7.33 (d, J = 2.0 Hz, 1 H, M or N), 7.45 (d, J = 2.0 Hz, 1 H, M or N), 7.46 (d, J = 2.1 Hz, 1 H, M or N). MS (EI, 70 eV): m/z (%) = 311 (9), 137 (100). HRMS (EI): m/z calcd for C₁₃H₁₁N₃O₂ ^³5Cl₂: 311.0228; found: 311.0222. (2 E , Z )-(5-Chloro-3-methoxy-2-nitrophenyl)(1-methylpyrrolidin-2-ylidene)- acetonitrile (3g): yellow crystals; mp 146-149 ˚C (EtOH). Two isomers, M (major)/ N (minor) = 1.2. ^¹H NMR (500 MHz, CDCl₃): δ = 1.82-1.90 (m, 2 H, N), 1.96-2.04 (m, 2 H, M), 2.44 (t, J = 7.8 Hz, 2 H, N), 2.57 (s, 3 H, M), 2.95-3.01 (m, 2 H, M), 3.32 (s, 3 H, N), 3.46-3.54 (m, 2 H, M + 2 H, N), 6.96-7.00 (m, 2 H, M + 2 H, N). MS (EI, 70 eV): m/z (%) = 307 (24), 137 (100). 7-Chloro-1-methyl-1 H -pyrrolo[3,2- b ]quinoline-9-carbonitrile (5a): yellow crystals; mp 198-201 ˚C. ^¹H NMR (500 MHz, THF-d ₈): δ = 4.19 (s, 3 H), 6.79 (d, J = 3.5 Hz, 1 H), 7.65 (dd, J = 9.1, 2.3 Hz, 1 H), 7.86 (d, J = 3.5 Hz, 1 H), 8.14 (d, J = 9.1 Hz, 1 H), 8.19 (d, J = 2.3 Hz, 1 H). ^¹³C NMR (125 MHz, THF-d ₈): δ = 34.8, 94.5, 103.4, 115.5, 123.4, 124.8, 128.8, 129.7, 132.8, 133.2, 142.4, 143.3, 152.6. MS (EI, 70 eV): m/z (%) = 241 (100), 240 (31), 179 (5). HRMS (EI): m/z calcd for C₁₃H₈N₃ ^³5Cl: 241.0407; found: 241.0410. 7-Bromo-1-methyl-1 H -pyrrolo[3,2- b ]quinoline-9-carbonitrile (5b): yellow crystals; mp 209-211 ˚C. ^¹H NMR (500 MHz, THF-d ₈): δ = 4.20 (s, 3 H), 6.80 (d, J = 3.5 Hz, 1 H), 7.78 (dd, J = 8.9, 2.2 Hz, 1 H), 7.88 (d, J = 3.5 Hz, 1 H), 8.07 (d, J = 8.9 Hz, 1 H), 8.36 (d, J = 2.2 Hz, 1 H). ^¹³C NMR (125 MHz, THF-d ₈): δ = 33.8, 93.4, 102.4, 114.5, 120.4, 124.3, 125.7, 128.6, 130.4, 131.8, 141.6, 142.4, 151.6. MS (EI, 70 eV):
m/z (%) = 287 (88), 285 (100), 205 (10), 179 (9). HRMS (EI): m/z calcd for C₁₃H₈N₃ ⁷⁹Br: 284.9902; found: 284.9911. 7-Fluoro-1-methyl-1 H -pyrrolo[3,2- b ]quinoline-9-carbonitrile (5c): pale green crystals; mp 182-185 ˚C (hexane-EtOAc). ^¹H NMR (500 MHz, THF-d ₈): δ = 4.18 (s, 3 H), 6.79 (d, J = 3.5 Hz, 1 H), 7.53 (ddd, J = 9.3, 8.1, 2.8 Hz, 1 H), 7.83 (d, J = 3.5 Hz, 1 H), 7.84 (ddd, J = 9.7, 2.8, 0.5 Hz, 1 H), 8.19 (ddd, J = 9.3, 5.7, 0.5 Hz, 1 H). ^¹³C NMR (125 MHz, THF-d ₈): δ = 34.8, 94.7 (d, J _C-F = 5.9 Hz), 103.4, 107.8 (d, J _C-F = 24.5 Hz), 115.7, 118.4 (d, J _C-F = 26.4 Hz), 125.1 (d, J _C-F = 10.2 Hz), 129.7, 133.8 (d, J _C-F = 9.3 Hz), 141.6 (d, J _C-F = 1.0 Hz), 142.1, 151.9 (d, J _C-F = 2.4 Hz), 161.8 (d, J _C-F = 247.8 Hz). MS (EI, 70 eV): m/z (%) = 225 (100), 197 (15), 183 (10), 171 (6). HRMS (EI): m/z calcd for C₁₃H₈N₃F: 225.0702; found: 225.0709. 7-Methoxy-1-methyl-1 H -pyrrolo[3,2- b ]quinoline-9-carbonitrile (5d): yellow crystals; mp 217-218 ˚C (EtOAc). ^¹H NMR (400 MHz, THF-d ₈): δ = 3.99 (s, 3 H), 4.16 (s, 3 H), 6.73 (d, J = 3.5 Hz, 1 H), 7.32 (dd, J = 9.3, 2.8 Hz, 1 H), 7.45 (d, J = 2.8 Hz, 1 H), 7.69 (d, J = 3.5 Hz, 1 H), 8.03 (dd, J = 9.3, 0.3 Hz, 1 H). ^¹³C NMR (100 MHz, THF-d ₈ ): δ = 34.7, 55.9, 93.8, 101.8, 103.3, 116.3, 121.5, 125.9, 129.5, 132.6, 139.8, 141.4, 150.0, 159.6. MS (EI, 70 eV): m/z (%) = 237 (100), 222 (39), 194 (69). HRMS (EI): m/z calcd for C₁₄H₁₁N₃O: 237.0902; found: 237.0896. 1-Methyl-7-(phenylthio)-1 H -pyrrolo[3,2- b ]quinoline-9-carbonitrile (5e): yellow crystals; mp 186-188 ˚C (EtOAc). ^¹H NMR (500 MHz, THF-d ₈): δ = 4.16 (s, 3 H), 6.76 (d, J = 3.5 Hz, 1 H), 7.30-7.40 (m, 3 H), 7.46-7.49 (m, 2 H), 7.50 (dd, J = 9.0, 2.0 Hz, 1 H), 7.81 (J = 3.5 Hz, 1 H), 8.05 (J = 9.0, 0.5 Hz, 1 H), 8.11 (J = 2.0, 0.5 Hz, 1 H). ^¹³C NMR (125 MHz, THF-d ₈): δ = 33.8, 93.5, 102.3, 114.6, 123.6, 123.7, 127.8, 128.6, 128.7, 129.4, 130.8, 132.1, 134.2, 135.7, 140.8, 142.9, 151.1. MS (EI, 70 eV): m/z (%) = 315 (100), 299 (12), 194 (8). HRMS (EI): m/z calcd for C₁₉H₁₃N₃S: 315.0830; found: 315.0837. 5,7-Dichloro-1-methyl-1 H -pyrrolo[3,2- b ]quinoline-9-carbonitrile (5f): pale brown crystals; mp 252 ˚C (dec.). ^¹H NMR (500 MHz, THF-d ₈): δ = 4.22 (s, 3 H), 6.91 (d, J = 3.5 Hz, 1 H), 7.90 (d, J = 2.2 Hz, 1 H), 7.96 (d, J = 3.5 Hz, 1 H), 8.17 (d, J = 2.2 Hz, 1 H). ^¹³C NMR (125 MHz, THF-d ₈): δ = 34.8, 95.3, 103.8, 115.3, 122.8, 125.6, 128.8, 130.0, 132.2, 136.4, 139.4, 143.5, 152.7. MS (EI, 70 eV): m/z (%) = 277 (70), 275 (100). HRMS (EI): m/z calcd for C₁₃H₇N₃ ^³5Cl₂: 275.0017; found: 275.0025. 7-Chloro-5-methoxy-1-methyl-1 H -pyrrolo[3,2- b ]quinoline-9-carbonitrile (5g): pale brown crystals; mp >250 ˚C. ^¹H NMR (500 MHz, THF-d ₈): δ = 4.06 (s, 3 H), 4.19 (s, 3 H), 6.82 (d, J = 3.5 Hz, 1 H), 7.08 (d, J = 2.0 Hz, 1 H), 7.75 (d, J = 2.0 Hz, 1 H), 7.83 (d, J = 3.5 Hz, 1 H). ^¹³C NMR (125 MHz, THF-d ₈): δ = 34.7, 56.6, 94.2, 103.9, 107.8, 114.9, 115.8, 125.7, 129.7, 133.7, 136.0, 141.6, 150.9, 158.4. MS (EI, 70 eV): m/z (%) = 271 (95), 242 (100), 236 (35), 206 (11). HRMS (EI): m/z calcd for C₁₄H₁₀N₃O^³5Cl: 271.0512; found: 271.0519.