Hypervalent Iodine(III) Mediated
Decarboxylative Halogenation of Indolecarboxylic Acids
for the Synthesis of Haloindole Derivatives

Hiromi Hamamoto; Hideaki Umemoto; Misako Umemoto; Chiaki Ohta; Masashi Dohshita; Yasuyoshi Miki

doi:10.1055/s-0030-1258585

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Synlett 2010(17): 2593-2596
DOI: 10.1055/s-0030-1258585

LETTER

Hypervalent Iodine(III) Mediated Decarboxylative Halogenation of Indolecarboxylic Acids for the Synthesis of Haloindole Derivatives

Hiromi Hamamoto, Hideaki Umemoto, Misako Umemoto, Chiaki Ohta, Masashi Dohshita, Yasuyoshi Miki*
School of Pharmaceutical Sciences, Kinki University, 3-4-1 Kowakae, Higashi-Osaka 577-8502, Japan
Fax: +81(6)67212505; e-Mail: y_miki@phar.kindai.ac.jp;

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Publication History

Received 2 July 2010
Publication Date:
23 September 2010 (online)

Abstract
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Abstract

The treatment of 1-methylindole-2,3-dicarboxylic acid with hypervalent iodine(III) reagent, phenyliodine diacetate (PIDA), in the presence of lithium bromide gave 1-methyl-3,3-dibromooxindole. However, the reaction of 1-(phenylsulfonyl)indole-2,3-dicarboxylic acid with PIDA in the presence of lithium bromide afforded 2,3-dibromo-1-(phenylsulfonyl)indole. In a similar manner, the 2,3-dichloro- and 2,3-diiodo-indole derivatives were obtained by the reaction of the indole-2,3-dicarboxylic acids with PIDA in the presence of lithium chloride and iodide.

Key words

indolecarboxylic acid - decarboxylation - bromination - chlorination - iodation

References and Notes

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22

Typical Procedure for the Decarboxylative Halogenation of Indole-2,3-dicarboxylic Acid(1) with PIDA in the Presence of Lithium Halide
To a mixture of PIDA and lithium halide in THF (10 mL) was added indolecarboxylic acids 1, 6, 7 (1 mmol) at r.t., and then the reaction mixture was stirred. H₂O was added to the reaction mixture, and the mixture was extracted with CH₂Cl₂. The combined extracts were washed with 2-3% Na₂S₂O₃ solution, then H₂O, and dried over Na₂SO₄. The extracts were concentrated under reduced pressure to give a solid, which was purified by column chromatography on silica gel to afford the 3-halogenoindole-2-carboxylic acids(2), 2,3-dihalogenoindoles 3, 8, and 3,3-dihalogeno-oxindoles 4, 9.
1-Phenylsulfonyl-3-bromoindole-2-carboxylic Acid (2a)
Mp 124-125 ˚C. IR (mull): ν = 2856, 2585, 1697 cm^-¹. ^¹H NMR (400 MHz, DMSO-d ₆): δ = 7.24-7.36 (3 H, m), 7.50-7.68 (3 H, m), 7.91 (1 H, dd, J = 8.0, 1.5 Hz), 8.25-8.32 (2 H, m). HRMS (EI): m/z calcd for C₁₅H₁₁NSO₄Br₂S: 379.9592; found: 379.9602.
1-Phenylsulfonyl-2,3-dibromoindole (3a)
Mp 143 ˚C (lit.^¹5 mp 141-143 ˚C). ^¹H NMR (400 MHz, CDCl₃): δ = 7.22-7.40 (5 H, m), 7.46-7.54 (1 H, m), 7.78-7.84 (2 H, m), 8.19-8.25 (1 H, m).
3-Bromo-1-methylindole-2-carboxylic Acid (2b)
Mp 184-186 ˚C [lit.^¹7 mp 180 ˚C (dec)]. IR (KBr): ν = 1671 cm^-¹. ^¹H NMR (400 MHz, DMSO-d ₆): δ = 3.99 (3 H, s, CH₃), 7.22 (1 H, t, J = 8.0 Hz, H-5 or H-6), 7.40 (1 H, t, J = 8.0 Hz, H-6 or H-5), 7.54 (1 H, d, J = 8.0 Hz, H-4 or H-7), 7.62 (1 H, d, J = 8.0 Hz, H-7 or H-4).
3,3-Dibromo-1-methyloxindole (4b)
Mp 202-204 ˚C (lit.^¹8 mp 204-205 ˚C). IR (CHCl₃): ν = 1737 cm^-¹. ^¹H NMR (400 MHz, DMSO-d ₆): δ = 3.26 (3 H, s, CH₃), 6.86 (1 H, d, J = 8.0 Hz, H-4 or H-7), 7.17 (1 H, dt, J = 8.0, 1.5 Hz, H-5 or H-6), 7.34 (1 H, dt, J = 8.0, 1.5 Hz, H-6 or H-5), 7.62 (1 H, dd, J = 8.0, 1.5 Hz, H-7 or H-4). ^¹³C NMR (100 MHz, DMSO-d ₆): δ = 169.16, 139.64, 131.87, 130.37, 125.38, 124.05, 110.08, 45.28, 27.03. HRMS (EI): m/z calcd for C₉H₇NOBr₂: 302.8895; found: 302.8883.
1-Phenylsulfonyl-2,3-dichloroindole (8a)
Mp 122 ˚C. ^¹H NMR (400 MHz, CDCl₃): δ = 7.30-7.63 (6 H, m), 7.84-7.92 (2 H, m), 8.28 (1 H, br d, J = 8.0 Hz, H-7 or H-4). ^¹³C NMR (100 MHz, DMSO-d ₆): δ = 137.59, 134.70, 134.40, 129.30, 126.94, 126.54, 126.14, 124.57, 121.24, 118.15, 114.98, 113.78. HRMS (EI): m/z calcd for C₁₄H₉NO₂Cl₂S: 324.9677; found: 324.9737.

1-Phenylsulfonyl-2,3-diiodoindole (8b)
Mp 165-167 ˚C (lit.^¹9 mp 166-167 ˚C). ^¹H NMR (400 MHz, CDCl₃): δ = 7.25-7.60 (6 H, m), 7.90 (2 H, br d, J = 8.0 Hz), 8.28 (1 H, br d, J = 8.0 Hz, H-7).
2,3-Diiodo-1-methylindole (8c)
Mp 76-77 ˚C (lit.^²0 mp 76-78 ˚C). ^¹H NMR (400 MHz, CDCl₃): δ = 3.89 (3 H, s, CH₃), 7.10-7.42 (4 H, m). ^¹³C NMR (100 MHz, DMSO-d ₆): δ = 138.11, 131.15, 122.71, 120.80, 120.50, 111.06, 99.78, 71.72, 36.09. HRMS (EI): m/z calcd for C₉H₇NI₂: 382.8668; found: 382.8671.
3,3-Dichloro-1-methyloxindole (9)
Mp 144-147 ˚C (lit.^²¹ 143 ˚C). IR (KBr): ν = 1740 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 3.25 (3 H, s, CH₃), 6.85 (1 H, d, J = 8.0 Hz, H-4 or H-7), 7.17 (1 H, t, J = 8.0 Hz, H-5 or H-6), 7.39 (1 H, t, J = 8.0, 1.5 Hz, H-6 or H-5), 7.61 (1 H, d, J = 8.0 Hz, H-7 or H-4). ^¹³C NMR (100 MHz, CDCl₃): δ = 168.80, 140.58, 131.85, 129.16, 125.13, 124.70, 124.14, 109.08, 26.98.