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

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.

catalysis - indoles - alcohols - nucleophiles - alkylations

References and Notes

1 Sundberg RJ. Indoles   Academic Press; San Diego: 1996. 

2 Lakhdar S. Westermaier M. Terrier F. Goumont R. Boubaker T. Ofial AR. Mayr H. J. Org. Chem.  2006,  71:  9088 

3 For a review, see: Bandini M. Melloni A. Tommasi S. Umani-Ronchi A. Synlett  2005,  1199 

4 For a recent example, see: Kang Q. Zhao Z.-A. You S.-L. J. Am. Chem. Soc.  2007,  129:  1484 

5 For a review, see: Saracoglu N. Top. Heterocycl. Chem.  2007,  11:  1 

6 See, for instance: Bandini M. Cozzi PG. Melchiorre P. Umani-Ronchi A. J. Org. Chem.  2002,  67:  5386 

7 Bandini M. Melloni A. Umani-Ronchi A. Org. Lett.  2004,  6:  3199 

See, for instance:

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12a While preparing this manuscript some works about this reaction using different Lewis acids as catalysts appeared (see ref. 10b-e). We have also reported a single example about the Brønsted acid catalyzed alkylation of indoles with propargylic alcohols: Sanz R. Martínez A. Álvarez-Gutiérrez JM. Rodríguez F. Eur. J. Org. Chem.  2006,  1383 

12b

Remarkably, in all these reactions only secondary propargylic alcohols are used.

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.

See ref. 12 and also:

14a Sanz R. Martínez A. Miguel D. Álvarez-Gutiérrez JM. Rodríguez F. Adv. Synth. Catal.  2006,  348:  1841 

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14d Sanz R. Martínez A. Álvarez-Gutiérrez JM. Rodríguez F. Synthesis  2007,  3252 

14e Sanz R. Martínez A. Guilarte V. Álvarez-Gutiérrez JM. Rodríguez F. Eur. J. Org. Chem.  2007,  4642 

15 Alkynols 2 were synthesized by nucleophilic addition of the alkynylcerium reagents to the corresponding aryl alkyl ketones as previously described: Imamoto T. Sugiura Y. Takiyama N. Tetrahedron Lett.  1984,  25:  4233 

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.