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

<A NAME="RD01308ST-1">1</A> Sundberg RJ. Indoles   Academic Press; San Diego: 1996. 

<A NAME="RD01308ST-2">2</A> Lakhdar S. Westermaier M. Terrier F. Goumont R. Boubaker T. Ofial AR. Mayr H. J. Org. Chem.  2006,  71:  9088 

<A NAME="RD01308ST-3">3</A> For a review, see: Bandini M. Melloni A. Tommasi S. Umani-Ronchi A. Synlett  2005,  1199 

<A NAME="RD01308ST-4">4</A> For a recent example, see: Kang Q. Zhao Z.-A. You S.-L. J. Am. Chem. Soc.  2007,  129:  1484 

<A NAME="RD01308ST-5">5</A> For a review, see: Saracoglu N. Top. Heterocycl. Chem.  2007,  11:  1 

<A NAME="RD01308ST-6">6</A> See, for instance: Bandini M. Cozzi PG. Melchiorre P. Umani-Ronchi A. J. Org. Chem.  2002,  67:  5386 

<A NAME="RD01308ST-7">7</A> Bandini M. Melloni A. Umani-Ronchi A. Org. Lett.  2004,  6:  3199 

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<A NAME="RD01308ST-10A">10a</A> Yasuda M. Somyo T. Baba A. Angew. Chem. Int. Ed.  2006,  45:  793 

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<A NAME="RD01308ST-11A">11a</A> Shirakawa S. Kobayashi S. Org. Lett.  2007,  9:  311 

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<A NAME="RD01308ST-12A">12a</A> 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 

<A NAME="RD01308ST-12B">12b</A>

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

<A NAME="RD01308ST-13">13</A>

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:

<A NAME="RD01308ST-14A">14a</A> Sanz R. Martínez A. Miguel D. Álvarez-Gutiérrez JM. Rodríguez F. Adv. Synth. Catal.  2006,  348:  1841 

<A NAME="RD01308ST-14B">14b</A> Sanz R. Miguel D. Martínez A. Álvarez-Gutiérrez JM. Rodríguez F. Org. Lett.  2007,  9:  727 

<A NAME="RD01308ST-14C">14c</A> Sanz R. Miguel D. Martínez A. Álvarez-Gutiérrez JM. Rodríguez F. Org. Lett.  2007,  9:  2027 

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<A NAME="RD01308ST-15">15</A> 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 

<A NAME="RD01308ST-16">16</A>

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.

<A NAME="RD01308ST-17">17</A>

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.

<A NAME="RD01308ST-18">18</A>

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

<A NAME="RD01308ST-19">19</A>

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.

<A NAME="RD01308ST-20">20</A>

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