A New Approach to 3-Substituted Indoles through Palladium-Catalyzed C-H Activation Followed by Intramolecular Amination Reaction of Enamines

Abstract

Palladium-catalyzed C-H activation followed by intramolecular amination reaction of enamine compounds was achieved using a Pd(OAc)₂ (10 mol%)/Cu(OAc)₂ (100 mol%) catalyst system in DMSO. This work introduces an entirely new approach to 3-substituted indoles.

palladium - catalysis - C-H activation - indoles - aminations

References and Notes

For selected recent reviews, see:

1a Higuchi K. Kawasaki T. Nat. Prod. Rep.  2007,  24:  843 

1b Brancale A. Silvestri R. Med. Res. Rev.  2007,  27:  209 

1c O’Connor SE. Maresh J. Nat. Prod. Rep.  2006,  23:  532 

For selected recent examples, see:

2a Peifer C. Selig R. Kinkel K. Ott D. Totzke F. Schächtele C. Heidenreich R. Röcken M. Schollmeyer D. Laufer S. J. Med. Chem.  2008,  51:  3814 

2b Romagnoli R. Baraldi PG. Sarkar T. Carrion MD. Cara CL. Cruz-Lopez O. Preti D. Tabrizi MA. Tolomeo M. Grimaudo S. Cristina AD. Zonta N. Balzarini J. Brancale A. Hsieh H.-P. Hamel E. J. Med. Chem.  2008,  51:  1464 

2c McKew JC. Lee KL. Shen MWH. Thakker P. Foley MA. Behnke ML. Hu B. Sum F.-W. Tam S. Hu Y. Chen L. Kirincich SJ. Michalak R. Thomason J. Ipek M. Wu K. Wooder L. Ramarao MK. Murphy EA. Goodwin DG. Albert L. Xu X. Donahue F. Ku MS. Keith J. Nickerson-Nutter CL. Abraham WM. Williams C. Hegen M. Clark JD. J. Med. Chem.  2008,  51:  3388 

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3a Patil NT. Yamamoto Y. Chem. Rev.  2008,  108:  3395 

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3c Humphrey GR. Kuethe JT. Chem. Rev.  2006,  106:  2875 

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5a Cacchi S. Fabrizi G. Pace P. J. Org. Chem.  1998,  63:  1001 

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6a Sakamoto T. Nagano T. Kondo Y. Yamanaka H. Synthesis  1990,  215 

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7 Takeda A. Kamijo S. Yamamoto Y. J. Am. Chem. Soc.  2000,  122:  5662 

8a Watanabe M. Yamamoto T. Nishiyama M. Angew. Chem. Int. Ed.  2000,  39:  2501 

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8c Peat AJ. Buchwald SL. J. Am. Chem. Soc.  1996,  118:  1028 

9 Jensen T. Pedersen H. Bang-Andersen B. Madsen R. Jørgensen M. Angew. Chem. Int. Ed.  2008,  47:  888 

10 Ackermann L. Althammer A. Angew. Chem. Int. Ed.  2007,  46:  1627 

11 Ackermann L. Org. Lett.  2005,  7:  439 

12 Willis MC. Brace GN. Findlay TJK. Holmes IP. Adv. Synth. Catal.  2006,  348:  851 

Similar Pd-mediated synthesis of indoles in the presence of 0.5 equiv Pd(OAc)₂ and 3.0 equiv Cu(OAc)₂ was previously reported, see:

13a Queiroz M.-JRP. Abreu AS. Castanheira EMS. Ferreira PMT. Tetrahedron  2007,  63:  2215 

13b Abreu AS. Ferreira PMT. Queiroz M.-JRP. Ferreira ICFR. Calhelha RC. Estevinho LM. Eur. J. Org. Chem.  2005,  2951 

13c Abreu AS. Silva NO. Ferreira PMT. Queiroz M.-JRP. Venanzi M. Eur. J. Org. Chem.  2003,  4792 

13d Abreu AS. Silva NO. Ferreira PMT. Queiroz M.-JRP. Tetrahedron Lett.  2003,  44:  3377 

Only a few examples of Pd-catalyzed C-H amination have been reported to date, see:

14a Tsang WCP. Zheng N. Buchwald SL. J. Am. Chem. Soc.  2005,  127:  14560 

14b Thu H.-Y. Yu W.-Y. Che C.-M. J. Am. Chem. Soc.  2006,  128:  9048 

15 We have already reported the synthesis of indazoles using a Pd-catalyzed intramolecular C-H amination process, see: Inamoto K. Saito T. Katsuno M. Sakamoto T. Hiroya K. Org. Lett.  2007,  9:  2931 

16 Lee KY. Lee CG. Kim JN. Tetrahedron Lett.  2003,  44:  1231 

17

Use of solvents such as DMF, NMP, MeCN, dioxane, toluene, and DCE resulted in decreased yields.

18

We also examined the effect of a variety of additives such as phosphines, N-heterocyclic carbenes, tetraalkylammonium salts, inorganic bases, lithium and silver salts, and so on, all of which led to unsatisfactory results.

19

Typical Procedure for the Pd-Catalyzed C-H Amination of Enamines (Table 1, entry 9)
A mixture of 1 (50.0 mg, 0.14 mmol), Pd(OAc)₂ (3.2 mg, 0.014 mmol), and Cu(OAc)₂ (26.0 mg, 0.14 mmol) in DMSO (2.9 mL) was stirred at 80 ˚C for 24 h. The reaction mixture was extracted with EtOAc (3 × 5 mL) and the combined organic layer was washed with brine (10 mL), and dried over MgSO₄. The solvent was evaporated and the residue was purified by silica gel column chromatography (hexane-EtOAc, 9:1) to give indole 2 (26.2 mg, 53%) as a colorless solid.
1-(4-Methylphenylsulfonyl)-3-phenylindole (2)
Mp 151-152 ˚C (colorless needles from hexane-EtOAc). IR (film): 2924, 1597, 1447, 1371, 1175, 669 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 2.34 (3 H, s), 7.22 (2 H, d, J = 8.2 Hz), 7.26-7.30 (1 H, m), 7.34-7.38 (2 H, m), 7.46 (2 H, t, J = 7.8 Hz), 7.59-7.61 (2 H, m), 7.69 (1 H, s), 7.77 (1 H, d, J = 7.8 Hz), 7.80 (2 H, d, J = 8.4 Hz), 8.05 (1 H, d, J = 8.4 Hz). ^¹³C NMR (100 MHz, CDCl₃): δ = 21.5, 113.7, 120.3, 122.8, 123.4, 123.8, 124.8, 126.7, 127.4, 127.8, 128.8, 129.1, 129.8, 132.9, 135.0, 135.4, 144.9. MS: m/z = 347 (50.2) [M⁺], 192 (100). HRMS: m/z calcd for C₂₁H₁₇NO₂S: 347.0980; found: 347.0967. Anal. Calcd for C₂₁H₁₇NO₂S: C, 72.60; H, 4.93; N, 4.03. Found C, 72.63; H, 5.08; N, 3.99.

20

Typical Procedure for the Synthesis of Enol Ether (4a, Table 2, entry 1)
To a solution of(methoxymethyl)triphenylphosphinium chloride (1.1 g, 3.1 mmol) in anhyd dioxane (5 mL) was slowly added BuLi (1.53 M solution in hexane, 2.3 mL, 3.1 mmol) at 0 ˚C and stirred for 30 min at the same temperature. A solution of 3a (0.50 g, 2.1 mmol) in anhyd dioxane (10 mL) was then slowly added at 0 ˚C, and the mixture was heated under reflux for 10 h. The reaction mixture was treated with sat. aq NH₄Cl soln (5 mL), and the aqueous phase was extracted with EtOAc (3 × 10 mL). The combined organic layer was washed with brine (5 mL) and dried over MgSO₄. The solvent was evaporated, and the residue was purified by silica gel column chromatography (hexane-EtOAc, 9:1) to give 4a (0.4 g, 67%) as a colorless oil.
1,1-Bis(4-methoxyphenyl)-2-methoxyethene (4a)
IR (film): 2359, 1341, 1508, 1244 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 3.73 (3 H, s), 3.80 (6 H, s), 6.32 (1 H, s), 6.82 (2 H, d, J = 8.8 Hz), 6.85 (2 H, d, J = 8.8 Hz), 7.13 (2 H, d, J = 8.8 Hz), 7.31 (2 H, d, J = 8.8 Hz). ^¹³C NMR (100 MHz, CDCl₃). δ = 55.1, 55.2, 60.3, 113.2, 113.5, 119.5, 129.2, 130.2, 130.7, 133.0, 133.6, 157.9, 158.2. MS: m/z = 270 (100) [M⁺]. 1,1-Bis(4-fluorophenyl)-2-methoxyethene (4b)
IR (film): 2934, 2361, 1636, 1508, 1229, 1109, 835 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 3.76 (3 H, s), 6.37 (1 H, s), 6.95-7.02 (4 H, m), 7.14 (2 H, dd, J = 8.8, 5.6 Hz), 7.32 (2 H, dd, J = 8.8, 5.6 Hz). MS: m/z = 246 (100) [M⁺]. HRMS: m/z calcd for C₁₅H₁₂F₂O: 246.0856; found: 246.0841.
1,1-Bis(4-ethoxycarbonylphenyl)-2-methoxyethene (4c)
IR (film): 3477, 2981, 1717, 1277 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 1.39 (6 H, t, J = 7.2 Hz), 3.82 (3 H, s), 4.37 (4 H, q, J = 7.2 Hz), 6.61 (1 H, s), 7.24 (2 H, d, J = 8.0 Hz), 7.42 (2 H, d, J = 8.4 Hz), 7.96 (2 H, d, J = 8.4 Hz), 8.00 (2 H, d, J = 8.0 Hz). MS: m/z = 355 (4.58) [M⁺ + 1], 177 (100). HRMS: m/z calcd for C₂₁H₂₂O₅: 354.1467; found: 354.1438.
1,1-Bis(4-cyanophenyl)-2-methoxyethene (4d)
IR (film): 2922, 2849, 2226, 1628, 1601, 1240, 1103 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 3.86 (3 H, s), 6.64 (1 H, s), 7.26 (2 H, d, J = 8.2 Hz), 7.44 (2 H, d, J = 8.4 Hz), 7.58 (2 H, d, J = 8.2 Hz), 7.61 (2 H, d, J = 8.4 Hz). ^¹³C NMR (100 MHz, CDCl₃): δ = 61.3, 110.2, 110.3, 117.7, 118.7, 118.8, 128.3, 130.2, 131.8, 132.2, 141.1, 143.9, 149.7. MS: m/z (%) = 260 (100) [M⁺]. HRMS: m/z calcd for C₁₇H₁₂N₂O: 260.0950; found: 260.0965.
1,1-Bis(3-methoxyphenyl)-2-methoxyethene (4e)
IR (film): 2999, 2936, 2833, 1597, 1576, 1485, 1285, 1252, 1229, 1105, 1049 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 3.75 (3 H, s), 3.761 (3 H, s), 3.764 (3 H, s), 6.46 (1 H, s), 6.76-6.81 (4 H, m), 6.93-6.97 (2 H, m), 7.17 (1 H, d, J = 8.0 Hz), 7.21 (1 H, d, J = 8.0 Hz). ^¹³C NMR (100 MHz, CDCl₃): d = 55.17, 55.21, 111.7, 112.0, 113.9, 115.5, 120.2, 120.7, 122.3, 128.7, 129.0, 138.7, 141.6, 146.5, 146.5, 159.1, 159.4. MS: m/z = 270 (100) [M⁺], 135 (17.5). HRMS: m/z calcd for C₁₇H₁₈O₃: 270.1256; found: 270.1248.
1-Phenyl-1-(3-methoxyphenyl)-2-methoxyethene (4f)
Obtained as a mixture of E- and Z-isomers (1.2:1). IR (film): 2932, 2835, 1634, 1597, 1236, 1107, 696 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 3.75-3.76 (6 H, m), 6.44 (0.55 H, s), 6.47 (0.45 H, s), 6.76-6.81 (2 H, m), 6.93-6.96 (1 H, m), 7.19-7.38 (6 H, m). MS: m/z (%) = 240 (100) [M⁺], 197 (26.2). HRMS: m/z calcd for C₁₆H₁₆O₂: 240.1150; found: 240.1134.
Typical Procedure for the Synthesis of Enamines (5a, Table 2, Entry 1)
A solution of 4a (48.9 mg, 0.18 mmol) in CH₂Cl₂ (2 mL) was added to a solution of 4-toluenesulfonamide (34.1 mg, 0.20 mmol) in CH₂Cl₂ (2 mL). Then, TFAA (42.0 mg, 0.20 mmol) and TFA (22.8 mg, 0.20 mmol) were added to the reaction mixture at r.t., and the mixture was heated under reflux for 13.5 h. The mixture was poured into cold H₂O and extracted with CH₂Cl₂ (3 × 5 mL), and dried over MgSO₄. The solvent was evaporated, and the residue was purified by silica gel column chromatography (hexane-EtOAc, 9:1) to give 5a (58.5 mg, 79%) as a colorless amorphous solid.
N -[2,2-Bis(4-methoxyphenyl)vinyl] 4-Methylphenyl-sulfonamide (5a)
IR (film): 3273, 1607, 1512, 1352, 1246, 1165 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 2.44 (3 H, s), 3.77 (3 H, s), 3.82 (3 H, s), 6.22 (1 H, d, J = 11.4 Hz), 6.65 (1 H, d, J = 11.4 Hz), 6.76-6.86 (6 H, m), 7.02 (2 H, d, J = 8.8 Hz), 7.33 (2 H, d, J = 8.4 Hz), 7.71 (2 H, d, J = 8.4 Hz). ^¹³C NMR (100 MHz, CDCl₃): δ = 21.6, 55.28, 55.30, 113.7, 114.6, 118.5, 125.8, 126.7, 127.6, 128.5, 129.8, 130.6, 132.2, 136.6, 143.7, 158.7, 159.1. MS: m/z (%) = 409 (33.4) [M⁺], 254 (100). HRMS: m/z calcd for C₂₃H₂₃NO₄S: 409.1348; found: 409.1341.
N -[2,2-Bis(4-fluorophenyl)vinyl] 4-Methylphenyl-sulfonamide (5b)
Mp 144-145 ˚C (colorless plates from hexane-EtOAc). IR (film): 3267, 2361, 1638, 1601, 1510, 1167 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): d = 2.46 (3 H, s), 6.25 (1 H, d, J = 11.4 Hz), 6.71 (1 H, d, J = 11.4 Hz), 6.87-6.95 (4 H, m), 7.01-7.06 (4 H, m), 7.35 (2 H, d, J = 8.4 Hz), 7.72 (2 H, d, J = 8.4 Hz). MS m/z (%) = 385 (41.0), 230 (100). HRMS: m/z calcd for C₂₁H₁₇F₂NO₂S: 385.0948; found: 385.0930. Anal. Calcd for C₂₁H₁₇F₂NO₂S: C, 65.44; H, 4.45; N, 3.63. Found: C, 65.38; H, 4.50; N, 3.62.
N -[2,2-Bis(4-ethoxycarbonylphenyl)vinyl] 4-Methyl-phenylsulfonamide (5c)
Compound 4c (0.91 g, 2.6 mmol) was dissolved in a solution of 10% H₂SO₄ in AcOH (20 mL) and stirred for 18 h at r.t. The reaction mixture was extracted with EtOAc (3 × 10 mL) and the combined organic layer was washed with brine (5 mL) and dried over MgSO₄. The solvent was evaporated to give 2,2-bis(4-ethoxycarbonylphenyl)acetaldehyde, which was used to the next reaction without further purification. A solution of the above aldehyde (0.87 g, 2.6 mmol) and TFAA (0.54 g, 2.6 mmol) in CH₂Cl₂ (20 mL) was added to a solution of 4-toluenesulfonamide (0.20 g, 1.2 mmol) in CH₂Cl₂ (10 mL) and heated under reflux for 20.5 h. The reaction mixture was extracted with CH₂Cl₂ (3 × 10 mL) and the combined organic layer was washed with brine (10 mL) and dried over MgSO₄. The solvent was evaporated and the residue was purified by silica gel column chromatography (hexane-EtOAc, 9:1) to give 5c (0.47 g, 37%) as a colorless amorphous solid. IR (film): 3238, 2361, 1717, 1601, 1275, 1167, 1103 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 1.36-1.43 (6 H, m), 2.47 (3 H, s), 4.33-4.44 (4 H, m), 6.34 (1 H, d, J = 12.2 Hz), 6.94 (1 H, d, J = 12.2 Hz), 7.03 (2 H, d, J = 8.4 Hz), 7.12 (2 H, d, J = 8.0 Hz), 7.36 (2 H, d, J = 8.4 Hz), 7.73 (2 H, d, J = 8.4 Hz), 7.91 (2 H, d, J = 8.0 Hz), 8.04 (2 H, d, J = 8.4 Hz). ^¹³C NMR (100 MHz, CDCl₃): δ = 14.2, 21.5, 60.8, 61.1, 122.8, 123.1, 126.1, 126.5, 127.0, 128.7, 129.5, 129.6, 129.8, 129.9, 130.4, 136.6, 140.6, 143.4, 144.0, 165.6, 165.9. MS: m/z (%) = 493 (100) [M⁺], 292 (48.5). HRMS: m/z calcd for C₂₇H₂₇NO₆S: 493.1559; found: 493.1549.
N -[2,2-Bis(4-cyanophenyl)vinyl] 4-Methylphenyl-sulfonamide (5d)
Mp 232-233 ˚C (colorless plates from hexane-CHCl₃). IR (film): 3261, 2226, 1634, 1599, 1339, 1165 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 2.47 (3 H, s), 6.82 (1 H, d, J = 11.8 Hz), 6.96 (1 H, d, J = 11.8 Hz), 7.12 (2 H, d, J = 8.0 Hz), 7.13 (2 H, d, J = 8.4 Hz), 7.37 (2 H, d, J = 8.4 Hz), 7.53 (2 H, d, J = 8.0 Hz), 7.65 (2 H, d, J = 8.0 Hz), 7.72 (2 H, d, J = 8.0 Hz). ^¹³C NMR (100 MHz, CDCl₃): δ = 21.7, 110.5, 112.3, 117.9, 118.5, 121.2, 124.3, 126.6, 126.8, 130.1, 130.6, 132.3, 133.3, 136.3, 140.3, 143.1, 144.6. MS: m/z (%) = 399 (45.0) [M⁺], 244 (100). HRMS: m/z calcd for C₂₃H₁₇N₃O₂S: 399.1042; found: 399.1025.
N -[2,2-Bis(3-methoxyphenyl)vinyl] 4-Methylphenyl-sulfonamide (5e)
IR (film): 3265, 2937, 2835, 1597, 1578, 1350, 1286, 1161, 1090 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 2.44 (3 H, s), 3.71 (3 H, s), 3.74 (3 H, s), 6.30 (1 H, d, J = 12.0 Hz), 6.46 (1 H, s), 6.49 (1 H, d, J = 8.1 Hz), 6.63-6.64 (1 H, m), 6.72 (1 H, dt, J = 8.1, 0.8 Hz), 6.75 (1 H, dd, J = 8.1, 2.8 Hz), 6.79 (1 H, d, J = 12.0 Hz), 6.86 (1 H, dd, J = 8.1, 2.8 Hz), 7.16 (1 H, t, J = 8.1 Hz), 7.25 (1 H, t, J = 8.1 Hz), 7.32 (2 H, d, J = 8.2 Hz), 7.71 (2 H, d, J = 8.2 Hz). ^¹³C NMR (100 MHz, CDCl₃): δ = 21.7, 55.21, 55.24, 112.1, 112.5, 113.8, 114.8, 119.0, 120.4, 121.6, 125.7, 126.7, 129.2, 129.8, 130.4, 136.6, 137.4, 140.6, 143.9, 159.5, 160.2. MS: m/z (%) = 409 (49.0) [M⁺], 254 (100). HRMS: m/z calcd for C₂₃H₂₃NO₄S: 409.1348; found: 409.1331. Anal. Calcd for C₂₃H₂₃NO₄S: C, 67.46; H, 5.66; N, 3.42. Found: C, 67.51; H, 5.69; N, 3.44.
N -[2-(3-Methoxyphenyl)-2-phenylvinyl] 4-Methyl-phenylsulfonamide (5f)
Obtained as a mixture of E- and Z-isomers (1.1:1). Recrystallization gave the single isomer. Mp 150-151 ˚C (colorless needles from hexane-EtOAc). ^¹H NMR (400 MHz, CDCl₃): δ = 2.44 (3 H, s), 3.72 (3 H, s), 6.33 (1 H, d, J = 11.6 Hz), 6.47 (1 H, s), 6.50 (1 H, d, J = 7.7 Hz), 6.78 (1 H, d, J = 11.6 Hz), 6.86 (1 H, dd, J = 7.7, 2.6 Hz), 7.12 (2 H, d, J = 8.2 Hz), 7.20-7.28 (4 H, m), 7.33 (2 H, d, J = 8.2 Hz), 7.71 (2 H, d, J = 8.2 Hz). ^¹³C NMR (100 MHz, CDCl₃): δ = 21.5, 55.2, 113.8, 115.0, 120.3, 121.7, 125.9, 126.5, 126.8, 127.1, 128.4, 129.9, 130.5, 136.9, 137.7, 139.2, 144.0, 160.4. MS: m/z (%) = 379 (55.3) [M⁺], 224 (100). HRMS: m/z calcd for C₂₂H₂₁NO₃S: 379.1242; found: 379.1230. Anal. Calcd for C₂₂H₂₁NO₃S: C, 69.63; H, 5.58; N, 3.69. Found: C, 69.37; H, 5.65; N, 3.71.
6-Methoxy-3-(4-methoxyphenyl)-1-(4-methylphenyl-sulfonyl) indole (6a)
IR (film): 2934, 2837, 1597, 1508, 1369, 1252, 1173, 1115, 1032 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 2.35 (3 H, s), 2.86 (3 H, s), 2.90 (3 H, s), 6.89 (1 H, dd, J = 8.8, 2.6 Hz), 6.96 (1 H, d, J = 8.8 Hz), 6.98 (1 H, d, J = 8.8 Hz), 7.22 (1 H, d, J = 7.6 Hz), 7.49-7.51 (3 H, m), 7.585 (1 H, s), 7.593 (1 H, d, J = 7.6 Hz), 7.78-7.80 (3 H, m). ^¹³C NMR (100 MHz, CDCl₃): δ = 21.6, 55.3, 55.8, 98.1, 112.5, 114.2, 120.8, 123.2, 123.6, 125.5, 126.7, 128.8, 129.8, 135.1, 136.5, 144.8, 157.9, 159.0. MS: m/z (%) = 407 (31.0) [M⁺], 252 (100). HRMS: m/z calcd for C₂₃H₂₁NO₄S: 407.1191; found: 407.1184.
6-Fluoro-3-(4-fluorophenyl)-1-(4-methylphenylsulfonyl) indole (6b)
IR (film): 3111, 2926, 1504, 1375, 1188, 1175, 1107, 679 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 2.36 (3 H, s), 7.00-7.06 (1 H, m), 7.12-7.16 (2 H, m), 7.26 (2 H, d, J = 8.0 Hz), 7.49-7.53 (2 H, m), 7.59-7.63 (1 H, m), 7.61 (1 H, s), 7.76-7.81 (3 H, m). MS: m/z = 383 (40.0) [M⁺], 319 (9.0), 228 (100). HRMS: m/z calcd for C₂₁H₁₅F₂NO₂S: 383.0781; found: 383.0782.
6-Ethoxycarbonyl-3-(4-ethoxycarbonylphenyl)-1-(4-methylphenylsulfonyl) indole (6c)
IR (film): 2982, 1715, 1375, 1279, 1177, 1163 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 1.41-1.47 (6 H, m), 2.36 (3 H, s), 4.39-4.47 (4 H, m), 7.27 (2 H, d, J = 8.6 Hz), 7.66 (2 H, d, J = 8.0 Hz), 7.80 (2 H, d, J = 8.6 Hz), 7.85 (1 H, d, J = 8.6 Hz), 7.90 (1 H, s), 7.99 (1 H, d, J = 8.6 Hz), 8.14 (2 H, d, J = 8.0 Hz), 8.74 (1 H, s). ^¹³C NMR (100 MHz, CDCl₃): δ = 14.4, 14.5, 21.7, 61.1, 61.2, 115.5, 119.9, 122.6, 124.7, 126.3, 127.0, 127.3, 127.5, 129.6, 130.1, 130.2, 132.1, 134.7, 134.8, 137.0, 145.5, 166.1, 166.4. MS: m/z (%) = 491 (81.9) [M⁺], 336 (100). HRMS: m/z calcd for C₂₇H₂₅NO₆S: 491.1403; found: 491.1409.
6-Cyano-3-(4-cyanophenyl)-1-(4-methylphenylsulfonyl)-indole (6d)
Mp 238-239 ˚C (colorless prisms from hexane-EtOAc). IR (film): 2922, 2228, 1611, 1431, 1379, 1175 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 2.40 (3 H, s), 7.32 (2 H, d, J = 8.4 Hz), 7.56 (1 H, dd, J = 8.4, 1.2 Hz), 7.67 (2 H, d, J = 8.0 Hz), 7.77 (2 H, d, J = 8.0 Hz), 7.82 (1 H, d, J = 8.4 Hz), 7.84 (2 H, d, J = 8.4 Hz), 7.95 (1 H, s), 8.38 (1 H, s). ^¹³C NMR (100 MHz, CDCl₃): δ = 21.8, 108.4, 109.7, 111.6, 118.2, 118.4, 119.0, 120.9, 121.7, 126.8, 127.0, 127.1, 128.3, 130.4, 131.3, 132.8, 134.3, 136.6, 146.2. MS: m/z (%) = 397 (100) [M⁺]. HRMS: m/z calcd for C₂₃H₁₅N₃O₂S: 397.0885; found: 397.0873.
5-Methoxy-3-(3-methoxyphenyl)-1-(4-methylphenyl-sulfonyl) indole (6e) IR (film): 2934, 2835, 1597, 1472, 1371, 1219, 1173, 1132, 667 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 2.33 (3 H, s), 3.81 (3 H, s), 3.86 (3 H, s), 6.91 (1 H, dd, J = 8.1, 2.4 Hz), 6.97 (1 H, dd, J = 9.2, 2.4 Hz), 7.10 (1 H, s), 7.16 (1 H, d, J = 8.1 Hz), 7.19-7.22 (3 H, m), 7.37 (1 H, t, J = 8.1 Hz), 7.64 (1 H, s), 7.76 (2 H, d, J = 8.1 Hz), 7.93 (1 H, d, J = 9.2 Hz). ^¹³C NMR (100 MHz, CDCl₃): δ = 21.6, 55.3, 55.7, 102.9, 113.0, 113.3, 113.8, 114.7, 120.1, 123.83, 123.85, 126.7, 129.8, 129.9, 130.1, 130.2, 134.4, 135.0, 144.8, 156.6, 159.9. MS: m/z (%) = 407 (59.9) [M⁺], 252 (100). HRMS: m/z calcd for C₂₃H₂₁NO₄S: 407.1191; found: 407.1178. Anal. Calcd for C₂₃H₂₁NO₄S: C, 67.79; H, 5.19; N, 3.44. Found C, 67.86; H, 5.33; N, 3.44.
5-Methoxy-1-(4-methylphenylsulfonyl)-3-phenylindole (6f-A) and 3-(3-Methoxyphenyl)-1-(4-methylphenyl-sulfonyl) indole (6f-B)
IR (film): 2926, 2361, 1597, 1470, 1371, 1173, 1134, 669 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 2.33 (3 H, s), 3.80 (2.49 H, s), 3.86 (0.51 H, s), 6.91 (0.17 H, ddd, J = 8.2, 2.5, 1.3 Hz), 6.97 (0.83 H, dd, J = 9.2, 2.4 Hz), 7.13 (0.17 H, dd, J = 2.5, 1.3 Hz), 7.18-7.25 (3 H, m), 7.28 (0.17 H, d, J = 7.6 Hz), 7.34-7.38 (1.17 H, m), 7.45 (1.66 H, dd, J = 8.0, 7.2 Hz), 7.56 (1.66 H, dd, J = 8.2, 1.4 Hz), 7.63 (0.83 H, s), 7.69 (0.17 H, s), 7.76 (1.66 H, d, J = 8.4 Hz), 7.78-7.80 (0.51 H, m), 7.94 (0.83 H, d, J = 8.8 Hz), 8.04 (0.17 H, d, J = 8.4 Hz). ^¹³C NMR (100 MHz, CDCl₃): δ = 21.5, 55.7, 103.0, 113.8, 114.8, 123.8, 124.1, 126.8, 127.5, 127.8, 128.9, 129.87, 129.92, 130.3, 133.2, 135.2, 144.9, 156.8. MS: m/z (%) = 377 (60.4) [M⁺], 222 (100). HRMS: m/z calcd for C₂₂H₁₉NO₃S: 377.1086; found: 377.1068.

21

Geometry of enamine 5f was determined by NOESY.

22

Regioisomeric products 6f-A and 6f-B could not be separated from one another; their ratio was determined by ^¹H NMR spectroscopy.