Four-Component Reaction of Substituted β-Nitrostyrenes, Cyclohexanones, Activated Methylene Compounds, and Ammonium Acetate: Efficient Strategy for Construction of Tetrahydroindole Skeletons

Abstract

An efficient one-pot four-component reaction was developed for the synthesis of two different stereochemical classes of substituted 2-aminotetrahydroindoles from substituted β-nitrostyrenes, cyclohexanones, ammonium acetate, and activated methylene compounds, such as Meldrum’s acid, 4-hydroxycoumarin, cyclohexanediones, cyclopentane-1,3-dione, or alkyl cyanoacetates. Both electron-donating and electron-withdrawing groups are tolerated in the aryl ring of the β-nitrostyrene. The reaction utilizes the triethylamine-promoted formation of new C–C and C–N bonds, and simultaneous aromatization in a domino fashion.

Key words

indoles - multicomponent reactions - domino reactions - cyclizations

• References

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• 16 C7a-Substituted 3-Aryl-5,6,7,7a-tetrahydro-4H-indol-2-amines 4a–r and C7-Substituted 3-Aryl-5,6-dihydro-1H-indol-2-amines 5a–x; General Procedure Et₃N (7.5 mmol, 0.757 g) was added to a mixture of the appropriate substituted β-nitrostyrene (3 mmol), cycloalkanone (3 mmol), and NH₄OAc (3 mmol, 0.231 g) in EtOH (15 mL), and the mixture was stirred at 65 °C for 2 h. The appropriate activated methylene compound (Meldrum’s acid, 4-hydroxy-2H-chromen-2-one, cyclohexane-1,3-dione, cyclopentane-1,3-dione, or cyanoacetate) (3 mmol) was added, and the mixture was stirred for about 24 h until the reaction was complete (TLC; hexanes–EtOAc, 1:1). The mixture was then filtered, and the residue was washed with cold EtOAc (10 mL) to give a white solid product 4a–r. Subsequently, the filtrate was concentrated under reduced pressure, and the residue was mixed with H₂O (10 mL) and extracted with CH₂Cl₂ (2 × 10 mL). The organic phase was washed successively with H₂O (10 mL) and brine (5 mL) then dried (Na₂SO₄) and concentrated. The crude product was purified by flash chromatography [silica gel, EtOAc–hexanes (1:1)] to give the desired product 5a–x. 5-[2-Amino-3-(4-methoxyphenyl)-4,5,6,7-tetrahydro-7aH-indol-7a-yl]-2,2-dimethyl-1,3-dioxane-4,6-dione (4a) White solid; yield: 0.541g (65%); mp 225.3–225.6 °C (MeOH–CH₂Cl₂). IR (KBr): 3209, 3143, 2939, 2852, 1677, 1610, 1551, 1519, 1479, 1206, 1077, 830, 747 cm^–1. ¹H NMR (600 MHz, DMSO-d₆ ): δ = 9.57 (s, 1 H), 7.83 (s, 1 H), 7.61 (s, 1 H), 7.22 (d, J = 8.4 Hz, 2 H), 7.07 (d, J = 8.4 Hz, 2 H), 3.80 (s, 3 H), 3.46 (d, J = 12.0 Hz, 1 H), 2.62 (d, J = 11.4 Hz, 1 H), 2.35 (td, J = 13.2, 6.0 Hz, 1 H), 1.80 (d, J = 11.4 Hz, 1 H), 1.58 (d, J = 13.2 Hz, 1 H), 1.54 (s, 6 H), 1.47–1.41 (m, 1 H), 1.05–0.98 (m, 1 H), 0.89 (t, J = 11.4 Hz, 1 H). ¹³C NMR (150 MHz, DMSO-d₆ ): δ = 171.70, 163.61, 159.24, 130.69, 121.50, 120.15, 114.35, 99.14, 86.89, 71.02, 70.97, 55.19, 27.51, 27.26, 22.27. HRMS (ESI): m/z [M + Na]⁺ calcd for C₂₁H₂₄N₂NaO₅: 407.1583; found: 407.1578. 5-[2-Amino-3-(4-methoxyphenyl)-1,4,5,6-tetrahydro-7H-indol-7-ylidene]-2,2-dimethyl-1,3-dioxane-4,6-dione (5a) White solid; yield: 0.091 g (11%); mp 189.4–189.5 °C (MeOH–CH₂Cl₂). IR (KBr): 3380, 3234, 2932, 1677, 1605, 1556, 1481, 1450, 1256, 1076, 938, 786 cm^–1. ¹H NMR (600 MHz, DMSO-d₆ ): δ = 11.35 (s, 1 H), 7.79 (s, 2 H), 7.27 (d, J = 8.4 Hz, 2 H), 7.03 (d, J = 7.8 Hz, 2 H), 3.80 (s, 3 H), 2.90 (t, J = 6.0 Hz, 2 H), 2.60 (t, J = 6.6 Hz, 2 H), 1.76 (t, J = 6.6 Hz, 2 H), 1.59 (s, 6 H). ¹³C NMR (150 MHz, DMSO-d₆ ): δ = 163.82, 158.62, 154.73, 144.64, 130.13, 126.50, 122.78, 116.25, 114.29, 100.24, 83.89, 55.17, 31.59, 25.83, 24.43, 23.37. HRMS (ESI): m/z [M + Na]⁺ calcd for C₂₁H₂₂N₂NaO₅: 405.1426; found: 405.1418
• 17 CCDC 930559 (4d), 933723 (5a), 979509 (5c), 992839 (5s), 990834 (5t) contain the supplementary crystallographic data for this paper. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/getstructures.