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Synlett 2011(17): 2567-2571  
DOI: 10.1055/s-0030-1289515
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

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

Zbigniew Wróbel, Krzysztof Wojciechowski*
Institute of Organic Chemistry, Polish Academy of Sciences, ul. Kasprzaka 44, POB 58, 01-224 Warszawa 42, Poland
Fax: +48(22)6326681; e-Mail: krzysztof.wojciechowski@icho.edu.pl;
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Publication History

Received 19 May 2011
Publication Date:
06 October 2011 (online)

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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.

Key words

indoles - amides - cyclization - nitriles - sulfones

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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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One carbon resonance was not observed.

26

N-H signals not visible.

27

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