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Synlett 2007(18): 2792-2796  
DOI: 10.1055/s-2007-990955
LETTER
© Georg Thieme Verlag Stuttgart · New York

One-Pot Synthesis of Highly Functionalized Oxindoles under Swern Oxidation Conditions

Pilar López-Alvarado, Judith Steinhoff, Sonia Miranda, Carmen Avendaño, J. Carlos Menéndez*
Departamento de Química Orgánica y Farmacéutica, Facultad de Farmacia, Universidad Complutense, 28040 Madrid, Spain
Fax: +34(91)3941822; e-Mail: josecm@farm.ucm.es;
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Publication History

Received 1 March 2007
Publication Date:
19 October 2007 (online)

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Abstract

The reaction of indole derivatives bearing a 3- or 4-hydroxyalkyl chain with dimethyl sulfoxide and oxalyl chloride under Swern conditions led to a one-pot process involving three different synthetic transformations, namely oxidation of indole to oxindole, introduction of a chlorine substituent at the oxindole C-3 position, and substitution of the hydroxyl group in the side chain by chlorine. In spite of its mechanistic complexity, this synthetically useful process proceeded in good to excellent overall yield.

Key words

indoles - Swern reaction - oxindole synthesis - halogenation - oxidation

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Representative Experimental Procedure
To a solution of oxalyl chloride (5 equiv) in anhyd CH2Cl2 (10 mL), at -78 °C under an argon atmophere, was added DMSO (7 equiv). The solution was stirred for ca. 10 min, until effervescence ceased. A solution of alcohol 6b (350 mg, 0.77 mmol) in anhyd CH2Cl2 (3 mL) was added dropwise via cannula, and the red solution was stirred for 10 min at -78 °C. Then, Et3N (10 equiv) was added and the solution was left to warm to r.t. for 20 min, while stirred. The reaction mixture was diluted with CH2Cl2 (20 mL) and washed with sat. aq NH4Cl (3 × 20 mL). The organic layer was dried (Na2SO4) and evaporated, and the residue was purified by rapid chromatography on silica gel, eluting with PE-EtOAc mixtures (gradient from 20:1 to 5:1), to yield compound 8b (357 mg, 90%). Slower chromatographic separation may lead to considerable amounts of decomposition products, specially from hydrolysis of the terminal chloromethylene moiety.

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Data for Representative Compounds 8
Compound 8b: IR (film on NaCl): 1731.6 (C=O), 1112.9 (C-O) cm-1. 1H NMR (250 MHz, CDCl3): δ = 7.73-7.67 (m, 4 H, H-2′′,6′′), 7.50-7.35 (m, 8 H, H-5,6,3′′,4′′,5′′), 6.77 (d, 1 H, J = 7.6 Hz, H-7), 5.07 (d, 1 H, J = 14.2 Hz, CH2O), 4.90 (d, 1 H, J = 14.2 Hz, CH2O), 3.31-3.13 (m, 2 H, H-3′), 3.21 (s, 3 H, NCH3), 2.40-2.17 (m, 2 H, H-1′), 1.43-1.28 (m, 2 H, H-2′), 1.12 [s, 9 H, C(CH3)3]. 13C NMR (62.9 MHz, CDCl3): δ = 173.2 (C-2), 142.4 (C-7a), 139.1 (C-4), 135.5 (C-2′′,6′′), 133.0 (C-1′′), 130.5 (C-6), 129.9 (C-4′′), 127.8 (C-3′′,5′′), 123.2 (C-3a), 121.6 (C-5), 107.4 (C-7), 64.4 (C-3), 60.9 (CH2O), 43.6 (C-3′), 35.6 (C-1′), 27.7 (C-2′), 26.85 (NCH3), 26.75 [C(CH3)3], 19.3 [C(CH3)3]. Anal. Calcd for C29H33Cl2NO2Si: C, 66.15; H, 6.32; N, 2.66. Found: C, 65.97; H, 6.02; N, 2.36.
Compound 8d (major diastereomer, 8da; minor diastereomer, 8db): IR (film on NaCl): 1729.0 (C=O) cm-1. 1H NMR (250 MHz, CDCl3): δ = 7.35-7.25 (m, 2 H, H-4,6), 7.07 (t, 1 H, J = 7.6 Hz, H-5), 6.80 (d, 1 H, J = 7.8 Hz, H-7), 3.75-3.60 (m, 1 H, H-3′), 3.18 (m, 3 H, NCH3), 2.70-2.10 (m, 2 H, H-1′), 1.80-1.35 (m, 4 H, H-2′, CH2CH3), 0.95-0.80 (m, 3 H, CH2CH3). 13C NMR (62.9 MHz, CDCl3): δ = 174.1 (CO), 143.0 (C-7a, 8da), 142.9 (C-7a, 8db), 130.7 (C-4), 129.7 (C-3a, 8da), 129.5 (C-3a, 8db), 124.6 (C-6), 124.0 (C-5, 8db), 123.9 (C-5, 8da), 109.1 (C-7), 65.1 (C-3′, 8db), 64.9 (C-3′, 8da), 64.7 (C-3), 36.8 (C-1′, 8db), 36.3 (C-1′, 8da), 33.1 (C-2′, 8db), 32.7 (C-2′, 8da), 31.8 (CH2, 8da), 31.5 (CH2, 8db), 27.1 (NCH3), 11.3 (CH2CH3). Anal. Calcd for C14H17Cl2NO: C, 58.75; H, 5.99; N, 4.89. Found: C, 58.80; H, 5.91; N, 4.99.
Compound 8g (major diastereomer, 8ga; minor diastereomer, 8gb): IR (film on NaCl): 3296.0 (NH), 1718.7 (C=O) cm-1. 1H NMR (250 MHz, CDCl3): δ = 8.96 (s, 1 H, NH, 8ga), 8.90 (s, 1 H, NH, 8gb), 6.96 (d, 1 H, J = 2.4 Hz, H-4), 6.88 (d, 1 H, J = 8.5 Hz, H-6), 6.82 (dd, 1 H, J = 8.5, 2.4 Hz, H-7), 4.05-3.85 (m, 1 H, H-3′), 3.81 (s, 3 H, OCH3), 2.60-2.40 (m, 2 H, H-1′), 2.40-2.20 (m, 2 H, H-2′), 1.48 (d, 3 H, J = 6.5 Hz, CH3, 8ga), 1.46 (d, 3 H, J = 6.3 Hz, CH3, 8gb). 13C NMR (62.9 MHz, CDCl3): δ = 177.1 (CO), 156.3 (C-5), 141.1 (C-7a), 134.1 (C-3a, 8gb), 133.8 (C-3a, 8ga), 115.7 (C-7, 8gb), 115.5 (C-7, 8ga), 111.8 (C-4, 8ga), 111.5 (C-4, 8gb), 111.3 (C-6), 68.0 (C-3), 58.2 (C-3′, 8gb), 58.0 (C-3′, 8ga), 56.2 (OCH3), 36.9 (C-1′, 8gb), 36.5 (C-1′, 8ga), 35.1 (C-2′, 8gb), 34.8 (C-2′, 8ga), 25.7 (CH3, 8gb), 25.5 (CH3, 8ga). Anal. Calcd for C13H15Cl2NO2: C, 54.18; H, 5.25; N, 4.86. Found: C, 53.95; H, 5.12; N, 4.75.

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Data for 3-Chloro-1-methyl-3-(3-oxobutyl)oxindole
IR (film on NaCl): 1728.2, 1717.0 (C=O) cm-1. 1H NMR (250 MHz, CDCl3): δ = 7.39 (d, 1 H, J = 7.6 Hz, H-4), 7.37 (t, 1 H, J = 7.6 Hz, H-6), 7.15 (t, 1 H, J = 7.6 Hz, H-5), 6.87 (d, 1 H, J = 7.6 Hz, H-7), 3.25 (s, 3 H, NCH3), 2.65-2.40 (m, 4 H, H-1′,2′), 2.11 (s, 3 H, COCH3). 13C NMR (62.9 MHz, CDCl3): δ = 206.9 (C-3′), 173.9 (C-2), 142.7 (C-7a), 130.8 (C-4), 129.8 (C-3a), 124.5 (C-6), 123.9 (C-5), 109.2 (C-7), 64.4 (C-3), 38.4 (C-2′), 33.2 (C-1′), 30.4 (COCH3), 27.0 (NCH3). MS: m/z = 251 [M+]. Anal. Calcd for C13H14ClNO2: C, 62.03; H, 5.61; N, 5.56. Found: C, 62.35; H, 5.81; N, 5.62.

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Indeed, compounds 8 were not obtained when oxalyl chloride was replaced by TFAA.