Search tips
Search criteria 


Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
J Am Chem Soc. Author manuscript; available in PMC 2013 January 11.
Published in final edited form as:
PMCID: PMC3383063

Palladium-Catalyzed C3-Benzylation of Indoles


A general method for regioselective C3-benzylation of indoles has been developed. Various 3-substituted indoles and benzyl methyl carbonates of different electronic properties react under mild conditions to afford a diverse range of 3-benzylindolenine products in good yields.

The prevalence of the indole nucleus in natural products, pharmaceutical ingredients, and organic materials has spurred considerable effort on the development of efficient and selective functionalizations of this primary heterocycle.1 In the past few decades, Pd-catalyzed reactions of indoles have become powerful tools in the arsenal of synthetic chemists.1a While much attention has been focused on Pd-catalyzed indole allylation reactions,2 the corresponding benzylation reaction of 3-substituted indoles3 has not been reported. Such a fundamental transformation would allow access to 3-benzylindolenines bearing a newly formed quaternary center,4 which constitute the core structures of many biologically active natural products and synthetic compounds.5 Given the centrality of the benzyl unit, there have been several recent reports on synthetic methods6-8 involving π-benzyl-Pd intermediates,9 although the Pd-catalyzed benzylation of non-stabilized nucleophiles using simple benzyl alcohol derivatives remains undeveloped. We report here a general, mild method for the Pd-catalyzed C3-benzylation of 3-substituted and 2,3-disubstituted indoles using benzyl carbonates (Scheme 1).

Scheme 1
Pd-catalyzed Indole Benzylation

As anticipated, the benzylation of indoles proved more challenging than the corresponding allylation. Reaction conditions that are effective for allylation of 2,3-dimethylindole 1a, gave little or none of the benzylation product when using benzyl methyl carbonate 2a, even at 80 °C (Table 1, entries 1–5). It was observed that ligands bearing large bite angles10 such as DPPF, Xantphos, and, in particular DPEphos, are quite effective for the benzylation reaction (entries 6–8). Importantly, the reaction is completely C3-selective with none of the N-benzyl product being present. Evidently, the highly polarizable π-benzyl-Pd intermediate preferentially reacts on the carbon of the ambident indole. Evaluation of a series of synthetic DPEphos-type ligands revealed that the yield diminished when ligands bearing either electron-rich (entries 9 and 10) or electron-deficient phosphorus ligands (entries 11 and 12) were utilized. DPEphos was found to be optimal in providing the right balance between the rates of different steps in the catalytic cycle, resulting in highest overall reaction rate.

Table 1
Ligand screening a

Further optimization of the reaction conditions was aimed at lowering the catalyst loading and the reaction temperature (Table 2). Benzyl acetate and benzyl alcohol afford the product in low yields (entries 1 and 2), and lowering the catalyst loading to 5 mol% slows down the reaction considerably (entry 3). Examination of additives led to the observation that triethylborane (BEt3) significantly promotes the reaction (entries 4 and 5).2b Indeed, in the presence of BEt3, a 2.5 mmol scale reaction proceeds at 40 °C, giving the product in 83% yield (entry 6). To the best of our knowledge, this result represents the first example of a Pd-catalyzed benzylation reaction using a benzyl carbonate carried out below 60 °C. The benzylation reaction also proceeds with substoichiometric BEt3, albeit in lower yield (entry 7).11

Table 2
Reaction optimization a

The optimized conditions (1.2 equivalents of 2, 5 mol% catalyst, 1.2 equivalents of BSA, 1.1 equivalents of BEt3, 50 °C) were found to be applicable to a diverse range of 2,3-disubstituted indoles and substituted benzyl methyl carbonates (Table 3). Both electron-rich and electron-deficient substituted benzyl carbonates are well tolerated (entries 1–4). Substitutions on the indole modulate the reactivity such that the indole nucleophilicity is enhanced by a methoxy group and diminished by a chloro-substituent (entries 5 and 6). Moreover, both carba- and heterocycle-fused indoles proved to be excellent substrates. The reactions between 1,2,3,4-tetrahydrocarbazole and various benzyl carbonates of different electronic properties afford high yields (entries 7–11), with naphthylmethyl carbonate reacting faster than 2a (entry 12). Notably, both tetrahydro-β-carboline and tetrahydro-γ-carboline derivatives are transformed to the respective heterocycle fused indolenines (entries 13 and 14).

Table 3
Benzylation of 2,3-disubstituted indoles a

The benzylation reactions of 3-substituted indoles are more challenging because the 3-alkyl-3-benzylindolenine products are prone to rearrangement to 3-alkyl-2-benzylindoles, owing to the high migratory aptitude of the benzyl group. Jackson synthesized 3o in only 4% yield via 3-methylindolyl magnesium iodide, and preparation of 3-(p-methoxybenzyl)-3-methylindolenine failed completely.12 By contrast, 3-methylindole 1b nicely undergoes the Pd-catalyzed benzylation reaction and furnishes the desired product 3o in 88% yield. The unwanted rearrangement is completely avoided under these reaction conditions (Table 4, entry 1). In addition, 1b reacts smoothly with substituted benzyl carbonates 2b and 2c. Although the 3-benzyl-3-methylindolenine products are in equilibrium with the corresponding cyclic trimers (1,3,5-triazinanes),13 they can be transformed cleanly either to indoline derivative 3p by reduction or to 2-benzylindole derivative 3q via acid catalyzed rearrangement (entries 2 and 3). The intramolecular trapping of the indolenine C=N bond by a pendant nucleophile is of particular interest since the resulting heterocycle-fused indoline is found as a core structure of many natural products. N-tosyltryptamine 1c and tryptophol 1d participate nicely in the reaction and give the cis-fused pyrrolo- and furano-indolines in high yields (entries 4 and 5). The fact that a sulfonamide and an alcohol are tolerated reflects the high chemoselectivity of the reaction. The reaction between indole 1e and 1.0 equivalent of 2a affords 3-benzylindole 3t in 69% yield, along with a small amount of 3,3-dibenzyl indolenine 3u (entry 6). The use of excess 2a affords 3u as the sole product in high yield (entry 7). Finally, in contrast to 1-phenylethyl carbonate 2d (entry 8), 1-(naphthalen-2-yl)ethyl carbonate 2e shows excellent reactivity (entries 9 and 10).

Table 4
Benzylation of indole and 3-substituted indolesa

In order to probe the reactivity differences between allyl, naphthylmethyl and benzyl carbonates, a series of competition studies were carried out (Scheme 2). The Pd-catalyzed reactions of 1f with mixtures of 4 and 2a or 4 and 2f produce allylation product 5 exclusively (equations 1 and 2). When 1f is subjected to a mixture of equal amounts of 2a and 2f, product 3l is isolated predominantly, together with less than 2% of 3g (equation 3). The dramatic decrease in reactivity for Pd-catalyzed indole alkylation reactions when going from 4 to 2f to 2a correlates with the increased aromaticity disruption in the formation of corresponding η3-palladium complexes. Compared with many reports of Pd-catalyzed benzylation reactions employing extended π-systems, the indole benzylation reaction described above represents a rare example of Pd-catalyzed benzylation of non-stabilized nucleophiles using simple benzyl alcohol derivatives.

Scheme 2
Competition studies a

A plausible mechanism for the benzylation reaction is shown in Scheme 3.14 It is likely that BEt3 facilitates the formation of π-benzyl-Pd (A) by binding to the carbonyl group of benzyl carbonate 2.15, 16 BSA is proposed to play dual roles: it silylates the methoxide, thereby removing it from the π-benzyl-Pd cation, and the resulting amide anion (B) subsequently deprotonates indole 1 to generate the indolyl anion (C).

Scheme 3
Proposed reaction mechanism a

In conclusion, we have developed the first general method for the regioselective C3-benzylation of 3-substituted indoles. This Pd-catalyzed transformation is effective for indoles and benzyl carbonates possessing sterically and electronically diverse substituents, affording the C3-benzyl indolenine products in high yields. The mild reaction conditions provide future opportunities for applying this methodology to complex molecules and for developing an enantioselective variant of this reaction.6g, 17

Supplementary Material



This work was funded by the National Institutes of Health (P50-GM086145).


Supporting Information. Experimental procedures and characterization data for new compounds. This material is available free of charge via the Internet at


(1)(a) Cacchi S, Fabrizi G. Chem. Rev. 2005;105:2873. [PubMed]Chem. Rev. 2011;111:PR215. Update 1: [PubMed](b) Joucla L, Djakovitch L. Adv. Synth. Catal. 2009;351:673.(c) Bandini M, Eichholzer A. Angew. Chem. Int. Ed. 2009;48:9608. [PubMed](d) Bartoli G, Bencivenni G, Dalpozzo R. Chem. Soc. Rev. 2010;39:4449. [PubMed]
(2) For selected examples of Pd-catalyzed allylation reaction of 3-unsubstituted indoles: Bandini M, Melloni A, Umani-Ronchi A. Org. Lett. 2004;6:3199. [PubMed] Kimura M, Futamata M, Mukai R, Tamaru Y. J. Am. Chem. Soc. 2005;127:4592. [PubMed] Bandini M, Melloni A, Piccinelli F, Sinisi R, Tommasi S, Umani-Ronchi A. J. Am. Chem. Soc. 2006;128:1424. [PubMed] 3-Substituted indoles: Trost BM, Quancard J. J. Am. Chem. Soc. 2006;128:6314. [PubMed] Kagawa N, Malerich JP, Rawal VH. Org. Lett. 2008;10:2381. [PubMed]
(3) For examples of alkylation of indolyl anion using alkyl halide: Hoshino T. Liebigs Ann. Chem. 1933;500:35. Nakazaki M. Bull. Chem. Soc. Jpn. 1959;32:838. Reactions between indoles and o-halomethyl phenol/aniline: Spande TF, Wilchek M, Witkop B. J. Am. Chem. Soc. 1968;90:3256. [PubMed] May JA, Zeidan RK, Stoltz BM. Tetrahedron Lett. 2003;44:1203.
(4) For selected examples using indolenines as intermediates in syntheses: Robinson R, Suginome H. J. Chem. Soc. 1932:298. Woodward RB, Cava MP, Ollis WD, Hunger A, Daeniker HU, Schenker K. J. Am. Chem. Soc. 1954;76:4749. Stork G, Dolfini JE. J. Am. Chem. Soc. 1963;85:2872. He F, Bo Y, Altom JD, Corey EJ. J. Am. Chem. Soc. 1999;121:6771. Kozmin SA, Iwama T, Huang Y, Rawal VH. J. Am. Chem. Soc. 2002;124:4628. [PubMed]
(5)(a) Numata A, Takahashi C, Ito Y, Takada T, Kawai K, Usami Y, Matsumura E, Imachi M, Ito T, Hasegawa T. Tetrahedron Lett. 1993;34:2355.(b) Verbitski SM, Mayne CL, Davis RA, Concepcion GP, Ireland CM. J. Org. Chem. 2002;67:7124. [PubMed](c) Yu S, Qin D, Shangary S, Chen J, Wang G, Ding K, McEachern D, Qiu S, Nikolovska-Coleska Z, Miller R, Kang S, Yang D, Wang S. J. Med. Chem. 2009;52:7970. [PubMed]
(6) For selected examples of catalytic reactions involving π-benzyl-Pd intermediates: Legros J-Y, Fiaud J-C. Tetrahedron Lett. 1992;33:2509. Nettekoven U, Hartwig JF. J. Am. Chem. Soc. 2002;124:1166. [PubMed] Kuwano R, Kondo Y, Matsuyama Y. J. Am. Chem. Soc. 2003;125:12104. [PubMed] Lapointe D, Fagnou K. Org. Lett. 2009;11:4160. [PubMed] Mukai T, Hirano K, Satoh T, Miura M. Org. Lett. 2010;12:1360. [PubMed] Toyoshima T, Mikano Y, Miura T, Murakami M. Org. Lett. 2010;12:4584. [PubMed] Trost BM, Czabaniuk LC. J. Am. Chem. Soc. 2010;132:15534. [PubMed] Liao L, Jana R, Urkalan KB, Sigman MS. J. Am. Chem. Soc. 2011;133:5784. [PubMed]
(7) For examples of decarboxylative benzylation: Wendy HF, Chruma JJ. Org. Lett. 2010;12:316. [PubMed] Torregrosa RRP, Ariyarathna Y, Chattopadhyay K, Tunge JA. J. Am. Chem. Soc. 2010;132:9280. [PubMed]
(8) For reviews: Liegault B, Renaud J, Bruneau C. Chem. Soc. Rev. 2008;37:290. [PubMed] Kuwano R. Synthesis. 2009:1049. Messaoudi S, Brion J, Alami M. Eur. J. Org. Chem. 2010:6495. Weaver JD, Recio A, III, Grenning AJ, Tunge JA. Chem. Rev. 2011;111:1846. [PubMed]
(9)(a) Roberts JS, Klabunde KJ. J. Am. Chem. Soc. 1977;99:2509.(b) Becker Y, Stille JK. J. Am. Chem. Soc. 1978;100:845.
(10) For effect of bite angle on the reaction rate between π-benzyl-Pd and amines: Johns AM, Utsunomiya M, Incarvito CD, Hartwig JF. J. Am. Chem. Soc. 2006;128:1828. [PubMed]
(11) Control experiments show that no reaction occurs in the absence of the palladium catalyst, the ligand, or BSA. Benzyl acetate and benzyl alcohol show low or no reactivity under the optimized reaction conditions. See Supporting Information for details.
(12) Jackson AH, Lynch PP. J. Chem. Soc., Perkin Trans. 2. 1987:1215.
(13) Indolenines are known to form cyclic trimers (1,3,5-triazinanes), see: Fritz H, Pfaender P. Chem. Ber. 1965;98:989.
(14) In order to rule out the possibility of an initial N1-benzylation followed by benzyl transfer to C3, 1-benzyl-2,3-dimethylindole was subjected to the optimized conditions. Formation of 3a was not observed. See Supporting Information for details.
(15) For a discussion of the Lewis acidity of BEt3, see: Jiang Y, Hess J, Fox T, Berke H. J. Am. Chem. Soc. 2010;132:18233. [PubMed]
(16) The binding of BEt3 to the indolyl anion nitrogen may also play a role. See reference 2d for this role of borane in enantioselective indole allylation reactions.
(17) A reaction with (R)-Binap as ligand gave 3g in 37% e.e. See Supporting Information for details.