Diels-Alder Reactions of 4-Alkoxy-4-alkylcyclohexa-2,5-dienimines: Synthesis of 5-Alkylindoles

Abstract

N-arylsulfonyl 4-alkoxy-4-alkylcyclohexadienimines undergo thermal Diels-Alder reactions with 1,3-butadienes to yield the expected cycloadducts. The crude adducts when treated with anhydrous acid yield dihydronaphthalenes which when subjected to a series of simple transformations produce 5-alkyl indoles in good overall yields.

indoles - Diels-Alder - quinones - heterocycles

References

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6 Kraus and co-workers cleaved a 1,4-tosylamido dihydronaphthalene in an elegant synthesis of the pyrroloindole subunit of CC-1065. See: Kraus GA. Yue S. Sy J. J. Org. Chem.  1985,  50:  284 

7

The Diels-Alder reactions of N-arylsulfonyl QIK’s at ambient pressures and conversion to indoles have been studied by us will be reported in due course.

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Typical experimental procedure: Diels-Alder reaction. Preparation of N -(4,8-dimethyl-5,8-dihydronaphthalen-1-yl)-4-methylbenzenesulfonamide ( 13a): The reaction mixture was prepared by combining N-(4-methoxy-4-methylcyclohexa-2,5-dien-1-ylidene)-4methylbenzene-sulfonamide 15 (1.00g, 3.4 mmol), piperylene (0.82 g, 12.0 mmol, 1.2 mL), and a few crystals of BHT, with 5 mL dry toluene in a sealed tube. The reaction mixture was then heated to 140 °C for 5 days, after which time, the reaction was complete as determined by TLC. The solvent was evaporated and the crude product was dissolved in 50 mL THF and 3 drops of concentrated HCl were added. Once aromatization was complete (1 h), solid NaHCO₃ was added. The reaction mixture was then dried using solid MgSO₄ filtered and concentrated. Compound 8a was then purified via flash column chromatography to afford a white solid, (0.800 g, 2.40 mmol, 72%). Mp = 142-144 °C; ¹H NMR (400 MHz, CDCl₃) δ = 7.62 (d, J = 8.2 Hz, 2 H), 7.19 (d, J = 7.0 Hz, 2 H), 6.96 (d, J = 8.2 Hz, 1 H), 6.90 (d, J = 8.2 Hz, 1 H), 6.31 (s, 1 H), 5.81 (m, 2 H), 3.34 (m, 1 H), 3.14 (m, 2 H), 2.38 (s, 3 H), 2.18 (s, 3 H), 1.06 (d, J = 6.8 Hz, 3 H); ¹³C NMR (100 MHz, CDCl₃) 144.4, 137.5, 135.0, 134.9, 134.8, 131.7, 131.3, 130.3, 128.5, 128.0, 123.9, 122.9, 30.9, 29.0, 23.7, 22.8, 20.8; IR (thin film) = 3278, 1480, 1323, 1180
cm^-1; MS m/z (relative intensity) 328.3 (13, M + 1), 327.3 (54, M⁺), 172.1 (100), 155.2 (96); EIHRMS for C₁₉H₂₁NO₂S: found 327.1297, requires 327.1293.

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Indole formation: Preparation of {3,5-dimethyl-1-[(4-methylphenyl)sulfonyl]-1 H -indol-4-yl}acetaldehyde ( 9a). Compound 8a (0.428g, 1.30 mmol) was taken up in 6 mL THF and 2 mL water. To this mixture a single crystal (<1 mg) of osmium tetroxide is added. Once the reaction mixture turned brown, NMO (0.211g, 1.80 mmol) was added. When the reaction was complete as determined by TLC (˜3 hours), Na₂SO₃ (2.3, 18 mmol) was added and the reaction mixture was allowed to stir for hour, after which the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water, brine, dried over anhydrous MgSO₄ and concentrated. The crude unpurified diol was then taken up in 25 mL CH₂Cl_2, and added drop wise to a suspension of NaIO₄/SiO₂ (3.54 g in 50 mL in CH₂Cl₂). Upon consumption of starting material as evidenced by TLC (ca 5 hours), the mixture was filtered and concentrated. The crude unpurified dialdehyde was then taken up in 20 mL THF and 3 drops of concentrated sulfuric acid were added. Upon complete disappearance of starting material as determined by TLC (ca 7 hours) solid NaHCO₃ and MgSO₄ were added, and the mixture was allowed to stir for 10 minutes. The mixture was then filtered and concentrated. Flash Column chromatography gave compound 9a (0.345g, 1 mmol, 77%) as an off white solid. mp 143-144 °C; ¹H NMR (400 MHz, CDCl₃) δ = 9.71 (t,
J = 2.0, 1 H), 7.83 (d, J = 8.6 Hz, 1 H), 7.73 (d, J = 8.2 Hz, 2 H), 7.29 (d, J = 1.2 Hz, 1 H), 7.20 (d, J = 8.2, Hz, 2 H), 7.14 (d, J = 8.2 Hz 1 H), 4.06 (d, J = 2 Hz, 2 H), 2.36 (s, 3 H), 2.33 (s, 3 H), 2.32 (s, 3 H); ¹³C NMR (100 MHz, CDCl₃) 199.0, 145.0, 135.3, 134.8, 132.4, 130.6, 130.0, 127.6, 127.0, 125.0, 123.8, 118.1, 113.0, 44.6, 22.0, 20.1, 14.3; IR (thin film) = 1723, 1364, 1175 cm^-1; MS m/z (relative intensity) 342.1 (21, M + 1), 341.1 (91, M⁺), 312.1 (100), 158.1 (76), 142 (24), 91 (47), 49 (26); EIHRMS for C₁₉H₁₉NO₃S: found 341.1089, requires 341.1086.

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Direct oxidative scission was unsuccessful.

13 Zhong Y.-L. Shing TKM. J. Org. Chem.  1997,  62:  2622