Synthesis of Substituted 3-Cyano- and 3-(Arenesulfonyl)indoles from o-Nitrobenzyl Cyanides and Sulfones

Abstract

Formation of enamines, in the reaction of o-nitrophenyl­acetonitriles with Vilsmeier reagents, followed by reductive cyclization using Zn in acetic acid, leads to variously substituted 3-cyanoindoles, possessing aryl, alkyl, and aminoalkyl substituents at C-2. The method, when starting from the appropriate o-nitrobenzylsulfones, allows the synthesis of substituted 3-(arenesulfonyl)-­indoles.

indoles - amides - cyclization - nitriles - sulfones

References and Notes

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General Procedure for the Synthesis of Enamines 3a,e,k The amide 2 (3 mmol) dissolved in dry MeCN (10 mL) was cooled to -40 ˚C and treated with oxalyl chloride (3 mmol). The cooling bath was removed, and the reaction mixture allowed to reach r.t. After evolution of gas ceased (ca. 30 min) the reaction mixture was cooled to -40 ˚C and treated with a solution of substrate 1 (1 mmol) and Et₃N (5 mmol) in dry MeCN (10 mL). (In the case of less soluble sulfones they were added in powdered form to the cooled Vilsmeier reagent followed by the addition of Et₃N). After stirring for 1 h the reaction mixture was poured into sat. NH₄Cl solution (20 mL), extracted with EtOAc (3 × 20 mL), the extract was dried (Na₂SO₄), filtered, evaporated and purified by chromatography.
Enamines 3b-d and 3f-i were synthesized according to the procedure described previously.^¹7
General Procedure for the Synthesis of 3-Cyanoindoles 4 Enamine 3 (1 mmol) in glacial AcOH (20 mL) was treated with Zn powder (10 mmol) (Note: a slight exotherm was observed). After stirring for 1 h at r.t. the mixture was heated to reflux for 1 h. After cooling the solvent was evaporated to dryness, the residue was dissolved in EtOAc (20 mL), and treated cautiously with sat. NaHCO₃ (3 mL). After filtering through Celite^® the solution was evaporated, and the residue purified by chromatography.
Representative Analytical Data(2 E , Z )-2-(5-Chloro-2-nitrophenyl)-3-(dimethylamino)-3-phenylacrylonitrile (3a) White solid, mp 103-106 ˚C. ^¹H NMR (600 MHz, DMSO-d ₆): two isomers, M (major)/N (minor) = 1.2. δ = 2.65 (s, 6 H, M), 3.18 (s, 6 H, N), 7.07 (dd, J = 8.7, 2.2 Hz, 1 H, M), 7.10-7.12 (m, 2 H, M), 7.20-7.24 (m, 2 H, M), 7.29-7.32 (m, 1 H, M), 7.33 (dd, J = 8.7, 2.2 Hz, 1 H, N), 7.43 (d, J = 2.2 Hz, 1 H, M), 7.48-7.55 (m, 5 H, N), 7.51 (d, J = 8.7 Hz, 1 H, M), 7.58 (d, J = 2.2 Hz, 1 H, N), 7.79 (d, J = 8.7 Hz, 1 H, N). MS (EI, 70 eV): m/z (%) = 327 (36), 283 (9), 187 (55), 148 (20), 118 (100), 105 (40). HRMS (EI): m/z calcd for C₁₇H₁₄N₃O₂ ^³5Cl: 327.0774; found: 327. 0771.
2-{1-[(4-Methoxyphenyl)methyl]-2-methyl-5-nitro-1 H -indol-4-yl}-2-[(2 E , Z )-1-methylpyrrolidin-2-ylidene]-acetonitrile (3d) Yellow crystals, mp 165-166 ˚C (hexane-EtOAc). ^¹H NMR (500 MHz, DMSO-d ₆): two isomers, M (major)/N (minor) = 2.5. δ = 7.74 (d, J = 8.9 Hz, 1 H, M), 7.70 (d, J = 8.9 Hz, 1 H, N), 7.57 (d, J = 8.9 Hz, 1 H, M), 7.56 (d, J = 8.9 Hz, 1 H, N), 6.97-7.01 (m, 2 H, N), 6.93-6.97 (m, 2 H, M), 6.85-6.89 (m, 2 H, M + 2 H, N), 6.45-6.46 (m, 1 H, N), 6.39-6.40 (m, 1 H, M), 5.37-5.47 (m, 2 H, M + 2 H, N), 3.70 (s, 3 H, N), 3.69 (s, 3 H, M), 3.42-3.55 (m, 2 H, M + 2 H, N), 3.34 (s, 3 H, N), 2.92-3.08 (m, 2 H, M), 2.41 (d, J = 0.9 Hz, 3 H, N), 2.41 (d, J = 0.9 Hz, 3 H, M), 2.18 (s, 3 H, M), 2.08-2.22 (m, 2 H, N), 1.96-2.05 (m, 2 H, M), 1.70-1.76 (m, 2 H, N). MS (EI, 70 eV): m/z (%) = 416 (11), 121 (100). HRMS (EI): m/z calcd for C₂₄H₂₄N₄O₃: 416.1848; found: 416.1860.
(2 E , Z )-2-(5-Chloro-2-nitrophenyl)-3-pyrrolidin-1-ylpent-2-enenitrile (3e) Brown oil. ^¹H NMR (500 MHz, DMSO-d ₆): two inseparable isomers, δ = 1.14-1.24 (m, 3 H), 1.68-1.82 (m, 5 H), 2.50-2.70 (m, 2 H), 2.90-3.15 (m, 3 H), 7.45 (br s, 1 H), 7.53-7.59 (m, 1 H), 7.94 (d, J = 8.4 Hz, 1 H). MS (EI, 70 eV): m/z (%) = 305 (31), 235 (12), 165 (100), 110 (15). HRMS (EI): m/z calcd for C₁₅H₁₆N₃ ^³5ClO₂: 305.0931; found: 305.0933.
5-Chloro-2-phenyl-1 H -indole-3-carbonitrile ( 4a) Pale yellow solid, mp >260 ˚C. ^¹H NMR (500 MHz, DMSO-d ₆): δ = 7.33 (dd, J = 8.6, 1.9 Hz, 1 H), 7.56-7.60 (m, 2 H), 7.62-7.68 (m, 3 H), 7.96-7.99 (m, 2 H), 12.80 (br s, 1 H). ^¹³C NMR (125 MHz, DMSO-d):^²5 δ = 81.7, 114.8, 116.8, 118.0, 124.5, 127.2, 127.6, 129.4, 129.8, 130.8, 134.6, 146.6. MS (EI, 70 eV): m/z (%) = 252 (100), 217 (11), 190 (14). HRMS (EI): m/z calcd for C₁₅H₉N₂ ^³5Cl: 252.0454; found: 252.0449.
6-[(4-Methoxyphenyl)methyl]-7-methyl-2-[3-(methyl-amino)propyl]-3 H ,6 H -pyrrolo[3,2- e ]indole-1-carbonitrile ( 4d) Pale yellow crystals, mp 177 ˚C (dec., EtOH). ^¹H NMR (500 MHz, DMSO-d ₆):^²6 δ = 1.87-1.94 (m, 2 H), 2.32 (s, 3 H), 2.41 (s, 3 H), 2.58 (t, J = 7.0 Hz, 2 H), 2.93 (t, J = 7.4 Hz, 2 H), 3.67 (s, 3 H), 5.36 (s, 2 H), 6.55 (s, 1 H), 6.82-6.85 (m, 2 H), 6.89-6.93 (m, 2 H), 7.10 (d, J = 8.7 Hz, 1 H), 7.23 (d, J = 8.7 Hz, 1 H). ^¹³C NMR (125 MHz, DMSO-d): δ = 13.0, 25.1, 28.6, 35.7, 45.9, 50.5, 55.5, 81.6, 97.7, 106.0, 106.9, 114.4, 118.3, 118.5, 119.1, 127.8, 129.6, 130.8, 132.4, 136.1, 147.1, 158.7. MS (EI, 70 eV): m/z (%) = 386 (39), 355 (12), 121 (100). HRMS (EI): m/z calcd for C₂₄H₂₆N₄O: 386.2107; found: 386.2098.
5-Chloro-2-ethyl-1 H -indole-3-carbonitrile ( 4e) White crystals, mp 176-182 ˚C. ^¹H NMR (500 MHz, DMSO-d ₆): δ = 1.33 (t, J = 7.6 Hz, 3 H), 2.91 (t, J = 7.6 Hz, 2 H), 7.23 (dd, J = 8.6, 2.0 Hz, 1 H), 7.47 (d, J = 8.6 Hz, 1 H), 7.54 (d, J = 2.0 Hz, 1 H), 12.28 (br s, 1 H). ^¹³C NMR (125 MHz, DMSO-d): δ = 13.1, 20.4, 81.7, 113.7, 115.7, 117.1, 122.8, 126.1, 128.3, 133.3, 152.8. MS (EI, 70 eV): m/z (%) = 204 (46), 189 (100). HRMS (EI): m/z calcd for C₁₁H₉N₂ ^³5Cl: 204.0454; found: 204.0463
2-(Dimethylamino)-1 H -benzo[ g ]indole-3-carbonitrile (5) ^²7 Yellow solid. MS (EI, 70 eV): m/z (%) = 235 (100), 220 (54), 192 (24), 164 (8). HRMS (EI): m/z calcd for C₁₅H₁₃N₃: 235.1110; found: 325.1103.
5-Chloro-2-ethyl-1-hydroxy-1 H -indole-3-carbonitrile ( 7e) Colorless crystals, mp 177-183 ˚C (hexane-EtOAc). ^¹H NMR (500 MHz, DMSO-d ₆): δ = 1.32 (t, J = 7.6 Hz, 3 H), 2.93 (q, J = 7.6 Hz, 2 H),7.31 (dd, J = 8.7, 2.0 Hz, 1 H), 7.55 (dd, J = 8.7, 0.6 Hz, 1 H), 7.60 (dd, J = 2.0, 0.6 Hz, 1 H), 12.07 (s, 1 H). ^¹³C NMR (125 MHz, DMSO-d): δ = 13.1, 18.6, 77.4, 111.7, 115.7, 117.8, 123.7, 124.2, 127.2, 131.7, 149.5. MS (EI, 70 eV): m/z (%) = 220 (100), 205 (46), 189 (46). HRMS (EI): m/z calcd for C₁₁H₉N₂ ^³5ClO: 220.0403; found: 220.0405.

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<A NAME="RD15411ST-25">25</A>

One carbon resonance was not observed.

<A NAME="RD15411ST-26">26</A>

N-H signals not visible.

<A NAME="RD15411ST-27">27</A>

Compound 5 was isolated in insufficient quantities to obtain full analytical data.