A Non-Classical Route to 2,3-Diiodoindoles from Indole-2-carboxylic Acids

Abstract

A non-classical route to prepare 2,3-diiodoindole derivatives is described, starting from the readily available indole-2-carboxylic acids. A single step of iodinative decarboxylation is applied for the first time to substituted indoles.

Key words

2,3-diiodoindole - iodination - decarboxylation

References and Notes

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13

Typical Procedure for Iodinative Decarboxylation: To a stirred solution of NaHCO₃ (34 mg, 0.40 mmol) in H₂O (1.5 mL) was added 1-(ethoxymethyl)-6-methoxy-1H-indole-2-carboxylic acid (1a; 50 mg, 0.20 mmol). The suspension was stirred until a homogenous solution was obtained. CHCl₃ (1.5 mL) and iodine (102 mg, 0.40 mmol) were added and the dark purple mixture was stirred at 70 °C for 4 h. The reaction mixture was diluted with H₂O (10 mL) and CHCl₃ (10 mL) and the organic layer was separated. The aqueous layer was extracted with CHCl₃ (2 × 10 mL). The combined organic extracts were washed with a sat. aq solution of Na₂S₂O₃, dried over Na₂SO₄ and evaporated in vacuo. The crude residue was purified by flash chromatography (PE-EtOAc, 95:5) to afford 2a (87 mg, 95%) as an oil which crystallized at r.t.; mp 81-82 °C (EtOAc-PE). IR (KBr): 3027, 2974, 2824, 1617, 1573, 1492, 1441, 1214, 1095 cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 1.17 (t, J = 7.2 Hz, 3 H, CH₃), 3.50 (q, J = 7.2 Hz, 2 H, CH₂), 3.87 (s, 3 H, OCH₃), 5.60 (s, 2 H, CH₂), 6.83 (dd, J = 2.1, 8.8 Hz, 1 H, H-5), 6.95 (d, J = 2.1 Hz, 1 H, H-7), 7.28 (d, J = 8.8 Hz, 1 H, H-4). ¹³C NMR (75 MHz, CDCl₃): δ = 15.1 (CH₃), 55.9 (OCH₃), 64.0 (CH₂), 74.9 (C), 77.6 (CH₂), 92.2 (C), 94.1 (CH), 111.5 (CH), 122.2 (CH), 126.6 (C), 138.5 (C), 157.4 (C). MS (ESI): m/z = 458 [M + H]⁺. Anal. Calcd for C₁₂H₁₃I₂NO₂: C, 31.54; H, 2.87; N, 3.06. Found: C, 31.88; H, 3.00; N, 3.12.

15

Analytical Data of Compound 2b: oil. IR (film): 3058, 2975, 1436, 1389, 1215, 1094 cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 1.16 (t, J = 7.2 Hz, 3 H, CH₃), 3.49 (q, J = 7.2 Hz, 2 H, CH₂), 5.66 (s, 2 H, CH₂), 7.19-7.24 (m, 2 H, H-5, H-6), 7.41-7.48 (m, 2 H, H-4, H-7). ¹³C NMR (75 MHz, CDCl₃): δ = 15.1 (CH₃), 64.2 (CH₂), 75.3 (C), 77.7 (CH₂), 95.3 (C), 110.4 (CH), 121.6 (CH), 121.8 (CH), 123.5 (CH), 132.2 (C), 138.2 (C). MS (ESI): m/z = 428 [M + H]⁺. Anal. Calcd for C₁₁H₁₁I₂NO: C, 30.94; H, 2.60; N, 3.28. Found: C, 31.22; H, 2.65; N, 3.33.

16

Analytical Data of Compound 2c: mp 93-94 °C (EtOAc-PE). IR (KBr): 3020, 2973, 2837, 1602, 1575, 1500, 1459, 1426, 1388, 1251, 1176, 1086 cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 1.15 (t, J = 7.2 Hz, 3 H, CH₃), 3.48 (q, J = 7.2 Hz, 2 H, CH₂), 3.94 (s, 3 H, OCH₃), 5.62 (s, 2 H, CH₂), 6.53-6.59 (m, 1 H, H-5), 7.12-7.14 (m, 2 H, H-6, H-7). ¹³C NMR (75 MHz, CDCl₃): δ = 15.1 (CH₃), 55.5 (OCH₃), 64.1 (CH₂), 68.5 (C), 78.2 (CH₂), 95.6 (C), 101.5 (CH), 103.7 (CH), 120.8 (C), 124.2 (CH), 139.9 (C), 152.2 (C). MS (ESI): m/z = 458 [M + H]⁺. Anal. Calcd for C₁₂H₁₃I₂NO₂: C, 31.53; H, 2.87; N, 3.06. Found: C, 31.75; H, 2.71; N, 2.90.

17

Analytical Data of Compound 2d: mp 89-91 °C (EtOAc-PE). IR (KBr): 3063, 2978, 2836, 1613, 1489, 1445, 1429, 1208, 1101, 1085 cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 1.15 (t, J = 7.2 Hz, 3 H, CH₃), 3.47 (q, J = 7.2 Hz, 2 H, CH₂), 3.89 (s, 3 H, OCH₃), 5.61 (s, 2 H, CH₂), 6.83-6.86 (m, 2 H, H-4, H-6), 7.36 (d, J = 9.4 Hz, 1 H, H-7). ¹³C NMR (75 MHz, CDCl₃): δ = 15.1 (CH₃), 55.9 (OCH₃), 64.1 (CH₂), 74.5 (C), 77.8 (CH₂), 95.0 (C), 103.0 (CH), 111.4 (CH), 113.8 (CH), 132.5 (C), 133.2 (C), 155.7 (C). MS (ESI): m/z = 458 [M + H]⁺. Anal. Calcd for C₁₂H₁₃I₂NO₂: C, 31.53; H, 2.87; N, 3.06. Found: C, 31.40; H, 2.77; N, 3.11.

19

Analytical Data of Compound 2o: mp 93-95 °C (EtOAc-PE). IR (KBr): 3056, 2985, 2827, 1619, 1569, 1488, 1445, 1431, 1169, 1093 cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 3.85 (s, 3 H, OCH₃), 4.85 (d, J = 4.7 Hz, 2 H, CH₂), 4.94 (d, J = 17.1 Hz, 1 H, =CH₂), 5.19 (d, J = 10.2 Hz, 1 H, =CH₂), 5.82-5.94 (m, 1 H, =CH), 6.72 (d, J = 1.9 Hz, 1 H, H-7), 6.80 (dd, J = 1.9, 8.9 Hz, 1 H, H-5), 7.28 (d, J = 8.9 Hz, 1 H, H-4). ¹³C NMR (75 MHz, CDCl₃): δ = 51.3 (CH₂), 55.9 (OCH₃), 72.2 (C), 92.6 (C), 93.9 (CH), 110.8 (CH), 117.4 (=CH₂), 122.1 (CH), 126.4 (C), 132.2 (CH), 138.0 (C), 157.2 (C). MS (ESI): m/z = 440 [M + H]⁺. Anal. Calcd for C₁₂H₁₁I₂NO: C, 32.83; H, 2.53; N, 3.19. Found: C, 32.86; H, 2.44; N, 3.08.

20

Analytical Data of Compound 3o: mp 165-167 °C (CHCl₃-Et₂O). IR (KBr): 3014, 2957, 1730, 1620, 1405, 1090 cm^-1. ¹H NMR (300 MHz, DMSO-d ₆): δ = 3.55-3.66 (m, 2 H, CH₂I), 3.86 (s, 3 H, OCH₃), 4.14 (dd, J = 10.2, 12.8 Hz, 1 H, NCH₂), 4.81 (dd, J = 3.3, 12.8 Hz, 1 H, NCH₂), 4.86-4.94 (m, 1 H, CH), 6.90 (dd, J = 1.9, 8.9 Hz, 1 H, H-5), 7.14 (d, J = 1.9 Hz, 1 H, H-7), 7.36 (d, J = 8.9 Hz, 1 H, H-4). ¹³C NMR (75 MHz, DMSO-d ₆): δ = 4.2 (CH₂I), 44.9 (NCH₂), 55.7 (OCH₃), 68.4 (C), 75.4 (CH), 92.8 (CH), 114.1 (CH), 121.1 (C), 123.7 (CH), 124.6 (C), 137.4 (C), 157.6 (C), 159.7 (C). MS (ESI): m/z = 484 [M + H]⁺. Anal. Calcd for C₁₃H₁₁I₂NO₃: C, 32.32; H, 2.30; N, 2.90. Found: C, 32.63; H, 2.27; N, 3.02.