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Synlett 2008(7): 975-978  
DOI: 10.1055/s-2008-1072584
LETTER
© Georg Thieme Verlag Stuttgart · New York

Brønsted Acid Catalyzed C3-Selective Propargylation and Benzylation of Indoles with Tertiary Alcohols

Roberto Sanz*a, Delia Miguela, Julia M. Álvarez-Gutiérreza, Félix Rodríguezb
a Departamento de Química, Área de Química Orgánica, Facultad de Ciencias, Universidad de Burgos, Pza. Misael Bañuelos s/n, 09001 Burgos, Spain
Fax: +34(947)258831; e-Mail: rsd@ubu.es;
b Instituto Universitario de Química Organometálica ‘Enrique Moles’, Universidad de Oviedo, C/Julián Clavería 8, 33006 Oviedo, Spain
Further Information

Publication History

Received 16 January 2008
Publication Date:
31 March 2008 (online)

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Abstract

A Brønsted acid catalyzed C3-selective tert-alkylation of indoles using tertiary propargylic and benzylic alcohols has been developed. New C3-propargylated indole derivatives with a quaternary carbon at the propargylic position have been efficiently synthesized. Reactions were performed in air with undried solvents, and water was the only side product of the process.

Key words

catalysis - indoles - alcohols - nucleophiles - alkylations

13

The absence of examples where tertiary alcohols are used is probably due to their high tendency to undergo elimination processes under the acidic conditions. Only the alkylation of N-methylindole with 2-phenylpropan-2-ol has been reported. See ref. 10c and 11a.

16

Typical Procedure for the Synthesis of 3-Alkylated Indole Derivatives 3, 5, and 7; Synthesis of 3-(1,3-Diphenylpent-1-yn-3-yl)-1-methyl-1 H -indole (3aa; Table 2, Entry 1): To a mixture of alcohol 2a (0.567 g, 2.4 mmol) and N-methylindole (1a; 0.262 g, 2.0 mmol) in analytical grade MeCN (2 mL), PTSA (0.019 g, 0.1 mmol) was added. The reaction was stirred at r.t. for 2 h (the completion of the reaction was monitored by GC-MS and TLC). The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (eluent: hexane-Et2O, 10:1) to afford 3aa (0.545 g, 78%) as a white solid, which was recrystallized in hexane-Et2O (2:1); mp 124-126 ºC. 1H NMR (400 MHz, CDCl3): δ = 1.32 (t, J = 7.3 Hz, 3 H), 2.56 (dq, J = 7.2, 14.3 Hz, 1 H), 2.83 (dq, J = 7.2, 14.3 Hz, 1 H), 3.82 (s, 3 H), 7.16-7.24 (m, 2 H), 7.35-7.54 (m, 2 H), 7.66-7.74 (m, 2 H), 7.81 (d, J = 8.0 Hz, 1 H), 7.86 (d, J = 7.2 Hz, 2 H). 13C NMR (100.6 MHz, CDCl3): δ = 10.1 (Me), 32.7 (Me), 34.8 (CH2), 45.4 (C), 84.9 (C), 93.7 (C), 109.3 (CH), 118.8 (CH), 119.5 (C), 121.3 (CH), 121.6 (CH), 124.0 (C), 126.3 (C), 126.4 (CH), 126.5 (CH), 127.3 (2 × CH), 127.8 (CH), 128.1 (2 × CH), 128.3 (2 × CH), 131.7 (2 × CH), 137.7 (C), 144.6 (C). IR (KBr): 2962, 2930, 1488, 1463, 1326, 758, 741, 701 cm-1. LRMS (EI): m/z = 349 (9) [M+], 320 (100). HRMS: m/z calcd for C26H23N: 349.1830; found: 349.1836.

17

A dialkyl-substituted alkynol, such as 2-methyl-4-phenyl-3-butyn-2-ol, gave a low yield (28%) of the corresponding propargylated indole when reacted with 1a.

18

Alkynols 4 were prepared by addition of phenylethynyl-lithium to the corresponding 2-cycloalken-1-one at low temperature in THF.

19

Trace amounts of the corresponding product coming from a direct attack of the indole on the propargylic position were observed in the crude of the reactions when alcohols 4b and 4c were used.

20

Alcohols 6a and 6c are commercially available. Alcohol 6b was synthesized by addition of n-BuLi to acetophenone at low temperature in THF.