Regioselective and Versatile Synthesis of Indoles via Intramolecular Friedel-Crafts Heteroannulation of Enaminones

María del Carmen Cruz; Fabiola Jiménez; Francisco Delgado; Joaquín Tamariz

doi:10.1055/s-2006-933135

LETTER

Regioselective and Versatile Synthesis of Indoles via Intramolecular Friedel-Crafts Heteroannulation of Enaminones

María del Carmen Cruz^a,b, Fabiola Jiménez^a, Francisco Delgado^a, Joaquín Tamariz*^a
^a Departamento de Química Orgánica, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional. Prol. Carpio y Plan de Ayala, 11340 México, D.F., Mexico
^b Centro de Investigación en Biotecnología Aplicada, Instituto Politécnico Nacional. Km 15 Carretera Sta. Inés Tecuexcomac, Tepetitla, 90700 Tlaxcala, Mexico
Fax: +52(55)53963503; e-Mail: jtamariz@woodward.encb.ipn.mx;

Abstract

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Abstract

A new approach is described for the synthesis of substituted indoles 5, through an intramolecular and regioselective Friedel-Crafts cyclization of enaminones 6a-h catalyzed by Lewis acids. Compounds 6 were prepared from the 2-anilinocarbonyl compounds 7, by treatment with DMFDMA under thermal or microwave (MW) irradiation conditions. An alternative and shorter one-pot two-step synthesis of indoles 5 was achieved starting from compounds 7 and promoted by MW radiation, including the elusive 2-acetylindoles 5i-m.

Key words

indoles - enaminones - Friedel-Crafts annulations - Lewis acid catalysis - microwaves

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References

References and Notes

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Typical Procedure for Preparation of 7b.
Under an N₂ atmosphere, a mixture of 8b (1.0 g, 9.33 mmol) and anhyd K₂CO₃ (1.93 g, 14.0 mmol) in dry acetone (10 mL) was heated to 60 °C for 1 h. Methyl bromoacetate (9, 1.57 g, 10.26 mmol) was added dropwise and the mixture was stirred at 60 °C for 12 h. The mixture was filtered and the solvent was removed under vacuum. The residue was purified by column chromatography over silica gel (20 g/g of sample, hexane-EtOAc, 95:5), to give 1.44 g (86%) of 7b as a brownish solid.
R _f = 0.45 (hexane-EtOAc, 8:2); mp 44-45 °C (hexane-EtOAc, 8:2) [lit. [16] 40 °C]. IR (KBr): 3393, 1741, 1608, 1513, 1439, 1213, 1180, 772 cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 2.33 (s, 3 H, CH₃Ar), 3.81 (s, 3 H, CO₂Me), 3.93 (s, 2 H, CH₂N), 4.24 (br s, 1 H, NH), 6.43-6.49 (m, 2 H, H-2, H-6), 6.63 (br d, J = 7.5 Hz, 1 H, H-4), 7.13 (t, J = 7.5 Hz, 1 H, H-5). ¹³C NMR (75.4 MHz, CDCl₃): δ = 21.4 (CH₃Ar), 45.4 (CH₂N), 51.9 (CO₂ CH₃), 109.8 (C-6), 113.6 (C-2), 118.9 (C-4), 129.0 (C-5), 138.8 (C-3), 146.8 (C-1), 171.5 (CO₂Me). MS (70 eV): m/z (%) = 179 (65) [M⁺], 136 (7), 122 (34), 121 (100), 93 (3), 63 (5).

Typical Procedure for Preparation of 6b.
A mixture of 7b (0.20 g, 1.12 mmol) and DMFDMA (0.20 g, 1.68 mmol) was heated to 90 °C for 5 h, under an N₂ atmosphere. The crude mixture was evaporated under vacuum and the residue was purified by column chromatography over silica gel (20 g/g of sample, hexane-EtOAc, 8:2), to give 0.21 g (79%) of 6b as an orange solid.
R _f = 0.25 (hexane-EtOAc, 8:2); mp 65-72 °C (decomp., hexane-EtOAc, 8:2). IR (KBr): 3318, 3025, 1735, 1645, 1607, 1488, 1435, 1227, 777 cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 2.26 (s, 3 H, CH₃Ar), 3.02 [s, 6 H, N(CH₃)₂], 3.61 (s, 3 H, CO₂CH₃), 4.62 (br s, 1 H, NH), 6.40-6.47 (m, 2 H, ArH), 6.54 (br d, J = 7.8 Hz, 1 H, H-4), 7.04 (dd, J = 7.8, 7.2 Hz, 1 H, H-5), 7.39 (s, 1 H, HC=). ¹³C NMR (75.4 MHz, CDCl₃): δ = 21.5 (CH₃Ar), 41.6 [N(CH₃)₂], 51.1 (CO₂ CH₃), 98.6 (NC=), 110.4 (C-6), 114.1 (C-2), 118.9 (C-4), 128.8 (C-5), 138.7 (C-3), 146.3 (HC=), 149.1 (C-1), 169.6 (CO₂CH₃). MS (70 eV): m/z (%) = 234 (4) [M⁺], 203 (3), 132 (6), 118 (14), 91 (36), 83 (18), 65 (16), 57 (66), 42 (100). Anal. Calcd for C₁₃H₁₈N₂O₂: C, 66.64; H, 7.74; N, 11.96. Found: C, 66.47; H, 7.64; N, 11.74.
NMR spectral data of representative examples. Compound 6a: ¹H NMR (300 MHz, CDCl₃): δ = 3.01 [s, 6 H, N(CH₃)₂], 3.62 (s, 3 H, CO₂CH₃), 4.66 (br s, 1 H, NH), 6.62 (br d, J = 7.5 Hz, 2 H, H-2), 6.72 (t, J = 7.5 Hz, 1 H, H-4), 7.15 (br t, J = 7.5 Hz, 1 H, H-3), 7.40 (s, 1 H, HC=). ¹³C NMR (75.4 MHz, CDCl₃): δ = 41.6 [N(CH₃)₂], 51.1 (CO₂ CH₃), 98.6 (NC=), 113.4 (C-2), 117.9 (C-4), 129.0 (C-3), 146.3 (HC=), 149.1 (C-1), 169.6 (CO₂CH₃).
Compound 6c: ¹H NMR (300 MHz, CDCl₃): δ = 2.22 (s, 3 H, CH₃Ar), 3.01 [s, 6 H, N(CH₃)₂], 3.60 (s, 3 H, CO₂CH₃), 4.52 (br s, 1 H, NH), 6.51-6.57 (m, 2 H, H-2), 6.93-7.00 (m, 2 H, H-3), 7.36 (s, 1 H, HC=). ¹³C NMR (75.4 MHz, CDCl₃): δ = 20.3 (CH₃Ar), 41.6 [N(CH₃)₂], 51.1 (CO₂ CH₃), 99.1 (NC=), 113.4 (C-2), 127.1 (C-4), 129.5 (C-3), 146.1 (HC=), 146.8 (C-1), 169.6 (CO₂CH₃).
Compound 6h: ¹H NMR (300 MHz, CDCl₃): δ = 1.20 (t, J = 7.2 Hz, 3 H, CH ₃CH₂O), 3.03 [s, 6 H, N(CH₃)₂], 3.73 (s, 6 H, OMe), 4.10 (q, J = 7.2 Hz, 2 H, CH₃CH ₂O), 4.70 (br s, 1 H, NH), 5.84 (d, J = 2.1 Hz, 2 H, H-2, H-6), 5.89 (t, J = 2.1 Hz, 1 H, H-4), 7.36 (s, 1 H, HC=). ¹³C NMR (75.4 MHz, CDCl₃): δ = 14.6 (CH₃CH₂O), 41.8 [N(CH₃)₂], 55.05 (OMe), 55.08 (OMe), 59.7 (CO₂ CH₂CH₃), 90.3 (C-4), 92.4 (C-2, C-6), 98.8 (NC=), 146.0 (HC=), 151.5 (C-1), 161.5 (C-3, C-5), 169.0 (CO₂Et).

Typical Procedure for Preparation of 5b.
Anhyd AlCl₃ (0.057 g, 0.43 mmol) was added to a solution of 6b (0.10 g, 0.43 mmol) in dry CH₂Cl₂ (100 mL) at r.t. The mixture was stirred at r.t. for 24 h and filtered. The filtrate was washed with H₂O (3 × 25 mL), the organic layer was dried (Na₂SO₄), and the solvent was removed under vacuum. The residue was purified by column chromatography over silica gel (10 g, hexane-EtOAc, 95:5), to give 0.061 g (76%) of 5b as a white solid.
R _f = 0.33 (hexane-EtOAc, 8:2); mp 97-98 °C (hexane-EtOAc, 7:3) [lit. [17] 128-129 °C]. IR (KBr): 3324, 1697, 1527, 1441, 1333, 1262, 1211, 764 cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 2.47 (s, 3 H, CH₃Ar), 3.94 (s, 3 H, CO₂Me), 6.99 (dd, J = 8.1, 0.9 Hz, 1 H, H-5), 7.18 (dd, J = 2.1, 0.9 Hz, 1 H, H-3), 7.20 (br s, 1 H, H-7), 7.56 (d, J = 8.1 Hz, 1 H, H-4), 8.85 (br s, 1 H, NH). ¹³C NMR (75.4 MHz, CDCl₃): δ = 22.0 (CH₃Ar), 51.9 (CO₂ CH₃), 108.8 (C-3), 111.5 (C-7), 122.2 (C-4), 123.0 (C-5), 125.3 (ArC), 126.5 (ArC), 135.7 (ArC), 157.3 (C-7a), 162.5 (CO₂CH₃). MS (70 eV): m/z (%) = 189 (24) [M⁺], 175 (17), 157 (87), 129 (91), 103 (80), 102 (100), 77 (69), 51 (69).
NMR spectral data of representative examples.
Compound 5a: ¹H NMR (300 MHz, CDCl₃): δ = 3.95 (s, 3 H, CO₂CH₃), 7.16 (ddd, J = 8.1, 6.8, 1.0 Hz, 2 H, H-5), 7.23 (dd, J = 2.3, 1.0 Hz, 1 H, H-3), 7.33 (ddd, J = 8.4, 6.8, 1.0 Hz, 1 H, H-6), 7.58 (ddd, J = 8.4, 1.0, 0.9 Hz, 1 H, H-7), 7.70 (dd, J = 8.1, 0.9 Hz, 1 H, H-4), 8.98 (br s, 1 H, NH). ¹³C NMR (75.4 MHz, CDCl₃): δ = 52.0 (CO₂ CH₃), 108.8 (C-3), 111.9 (C-7), 120.8 (C-5), 122.6 (C-4), 125.4 (C-6), 127.1 (C-2), 127.4 (C-3a), 136.8 (C-7a), 162.4 (CO₂CH₃).
Compound 5c: ¹H NMR (300 MHz, CDCl₃): δ = 2.43 (s, 3 H, CH₃Ar), 3.94 (s, 3 H, CO₂CH₃), 7.14 (br s, 1 H, H-3), 7.15 (dd, J = 8.4, 1.5 Hz, 1 H, H-6), 7.31 (br d, J = 8.4 Hz, 1 H, H-7), 7.45 (br s, 1 H, H-4), 9.11 (br s, 1 H, NH). ¹³C NMR (75.4 MHz, CDCl₃): δ = 21.4 (CH₃Ar), 51.9 (CO₂ CH₃), 108.2 (C-3), 111.6 (C-7), 121.8 (C-4), 127.0 (C-2), 127.4 (C-6), 127.7 (C-5), 130.1 (C-3a), 135.3 (C-7a), 162.6 (CO₂CH₃).
Compound 5h: ¹H NMR (300 MHz, CDCl₃): δ = 1.39 (t, J = 7.0 Hz, 3 H, CH ₃CH₂O), 3.83 (s, 3 H, OMe), 3.90 (s, 3 H, OMe), 4.38 (q, J = 7.0 Hz, 2 H, CH₃CH ₂O), 6.18 (d, J = 1.5 Hz, 2 H, H-2, H-5), 6.43 (dd, J = 1.5, 0.9 Hz, 1 H, H-7), 7.27 (dd, J = 2.3, 0.9 Hz, 1 H, H-3), 9.10 (br s, 1 H, NH). ¹³C NMR (75.4 MHz, CDCl₃): δ = 14.4 (CH₃CH₂O), 55.3 (OMe), 55.5 (OMe), 60.7 (CO₂ CH₂CH₃), 86.1 (C-7), 92.6 (C-5), 106.7 (C-3), 113.7 (C-3a), 124.8 (C-2), 138.6 (C-7a), 155.0 (C-4), 160.1 (C-6), 162.1 (CO₂Et).

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