Ruthenium(II)-Catalyzed Regio- and Stereoselective C–H Allylation of

Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX

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Ruthenium(II)-Catalyzed Regio- and Stereoselective C−H Allylation of Indoles with Allyl Alcohols Xiaowei Wu† and Haitao Ji*,†,‡ †

Drug Discovery Department, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, Florida 33612-9416, United States ‡ Department of Oncologic Sciences, University of South Florida, Tampa, Florida 33612, United States S Supporting Information *

ABSTRACT: A ruthenium-catalyzed C−H allylation of indoles with allyl alcohols via β-hydroxide elimination is reported. Without external oxidants and expensive additives, this reaction features mild reaction conditions, compatibility with various functional groups, and good to excellent regioselectivity and stereoselectivity.

O

overcome these drawbacks is highly desirable. In addition, as for the allylation reagents, preactivated allyl alcohol derivatives are necessary for transition metal-catalyzed C−H allylation of arenes. By contrast, the examples of utilizing unactivated allyl alcohols as the allylation reagents are limited with few reported.7,8 We aim to functionalize position 2 of the indole ring through C−H activation reactions to design and synthesize potent inhibitors for the β-catenin/T-cell factor (Tcf) protein− protein interaction.10 Herein, we report a ruthenium(II)catalyzed C−H allylation at the C-2 position of N-ethoxycarbamoyl indoles with allyl alcohols via β-hydroxide elimination, wherein the N-ethoxycarbamoyl directing group is crucial for this reaction. Further, this method does not require high temperature, external oxidants, and expensive additives. As a starting point, we chose the coupling reaction between Nethoxycarbamoyl indole (1a) and 1-phenylprop-2-en-1-ol (2a) in the presence of inexpensive [{RuCl2(p-cymene)}2] and NaOAc in MeOH at 45 °C as the catalytic condition. This reaction afforded the desired C2-allylated product 3a in only 8% yield (Table 1, entry 1). After screening various solvents, we found that the yield was increased to 77% with E/Z > 25:1 when the reaction was conducted in 1,2-dichloroethane (entry 6). In contrast, other polar solvents, such as CH3CN, dioxane, and THF hardly provided the desired product (entries 2−4). Further investigation of different bases demonstrated that NaOH and Na2CO3 led to no reaction (entries 8 and 10). The yield of product was decreased when CsOAc was used as the additive (entry 9). When 0.3 equiv of NaOAc was employed, the yield of product was only 32% (entry 11). We also investigated the consequence of the use of different directing groups in the reaction. The results indicated that all of the other directing groups (entries 12−16) did not work under the optimized reaction conditions. Further, the reaction cannot afford the

ver the past decades, the direct functionalization of C−H bonds via transition metal-catalyzed reactions represents an efficient approach for the construction and rapid modification of heterocyclic compounds.1 The allylation of arenes is important in organic synthesis due to the versatility of olefin transformations to generate many useful functional groups. Classic methods for the introduction of the allyl moiety rely on nucleophilic substitutions, Lewis acid-mediated Friedel−Crafts type allylation, and cross-coupling reactions.2 These methods usually suffer from limited reaction scope, harsh reaction conditions, and prefunctionalized substrates. In this context, the direct C−H allylation reactions of the aromatic rings with various allylation reagents under transition metals have attracted much attention.3 Recently, Ma and Cramer reported an efficient Rh(III)catalyzed ortho allylation of N-methoxybenzamides with polysubstituted allenes, independently.4 Subsequently, Rh(III)catalyzed direct C−H allylation reactions utilizing preactivated allyl alcohol derivatives, such as allyl acetates, allyl carbonates, or allyl halides, were documented by Glorius, Loh, Li, Wang, and other groups.5 As a cost-effective transition metal catalyst, Glorius and Ackermann reported Cp*Co(III) catalyzed C−H allylation reactions of indoles, pyrroles, 2-phenylpyridines, and benzamides using preactivated allyl alcohol derivatives under mild reaction conditions.6 In 2015, Kanai and Matsunaga pioneered that unactivated allyl alcohols could be used as the allylation reagents for C−H allylation under Cp*Co(III) catalysis.7 Subsequently, Ru(II)-catalyzed C−H allylation using allyl alcohols was reported by Kupar.8 This reaction requires external oxidants and high temperature. Kim disclosed Ru(II)catalyzed oxidative allylation of (hetero)aromatics with allylic carbonates.9a Although notable advances were made in this particular context, most of these reactions require high reaction temperatures and stoichiometric amounts of external oxidants and expensive additives (such as copper salts and silver salts).5−9 Therefore, the development of new approaches that can © XXXX American Chemical Society

Received: February 15, 2018

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DOI: 10.1021/acs.orglett.8b00567 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters Table 1. Optimization of Reaction Conditionsa

No.

solvent

base

3a yield (%)b

1 2 3 4 5 6 7 8 9 10 11d 12e 13f 14g 15h 16i 17j 18k 19l

MeOH CH3CN dioxane THF toluene DCE DCM DCE DCE DCE DCE DCE DCE DCE DCE DCE DCE DCE DCE

NaOAc NaOAc NaOAc NaOAc NaOAc NaOAc NaOAc Na2CO3 CsOAc NaOH NaOAc NaOAc NaOAc NaOAc NaOAc NaOAc NaOAc

8 trace 6 trace 43 77(72) 56 trace 64 0 32 0 0 trace 0 0 0 trace 0

NaOAc

Scheme 1. Scope of Indolesa,b

E/Z ratioc

>25:1 >25:1 >25:1 >25:1 >25:1

a

Reaction conditions: 1 (0.2 mmol), 2a (0.3 mmol), [{RuCl2(pcymene)}2] (5 mol %), NaOAc (1 equiv) in DCE at 45 °C, Ar atmosphere, 6−12 h. Unless otherwise noted, the E/Z ratios of all products are >25:1. bIsolated yields are reported. cMethyl(1phenylallyl)carbonate 2a′ was used.

yield with excellent stereoselectivity (3i), while the chlorine substituted substrate afforded the product in moderate yield (3j). Additionally, the methyl and phenyl substituents were introduced to the C-3 position to explore the effect of steric hindrance. The desired products were obtained in good yields when the standard conditions were applied (3k and 3l). We next explored the scope of the reaction with respect to allyl alcohols as the coupling partners (Scheme 2). In general, the coupling reaction of substrate 1a and various substituted allyl alcohols afforded the corresponding products in good yields (3m−3v). The desired products were obtained in good yields with either electron-withdrawing groups (F, Cl, and Br) or electron-donating groups (Me and MeO−) attaching to the para-position of the benzene ring of allyl alcohols (3m−3q). The substrates in which the phenyl moiety of allyl alcohols was replaced with the thiophenyl and naphthyl groups also underwent the coupling reaction smoothly with good yields (3r and 3s). When the alkyl substituted allyl alcohols were explored, the reaction afforded the desired products in good yields with satisfactory stereoselectivity (3t−3v). The higher stereoselectivity of 3a−3l, when compared with 3t−3v, was probably triggered by the bulky aryl group of 2a. Unfortunately, the reaction did not proceed to produce 3w when prop-2-en-1-ol was used as the coupling partner. However, the product 3w can be obtained in good yield using allyl methyl carbonate as the coupling partner under the standard reaction conditions. It should be noted that the use of nonterminal crotyl alcohol 2m (or its methyl carbonate 2m′) and cinnamyl alcohol 2n, and tertiary alcohol 2o (or its methyl carbonate 2o′) did not offer the products. To shed light on the mechanism of this catalytic reaction, a series of deuterium-labeling experiments were conducted. The reversibility of the step of the C−H bond cleavage was

a Reaction conditions: 1a (0.2 mmol), 2a (0.3 mmol), catalyst (5 mol %), base (1 equiv) in 2 mL of solvent at 45 °C, Ar atmosphere. bNMR yields using CH2Br2 as an internal standard, and isolated yields in parentheses. cDetermined by 1H NMR analysis of the crude reaction mixtures. d0.3 equiv of NaOAc was employed. e1a-1 instead of 1a. f1a2 instead of 1a. g1a-3 instead of 1a. h1a-4 instead of 1a. i1a-5 instead of 1a. jNo [{RuCl2(p-cymene)}2]. kNo NaOAc. l5 mol % Pd(OAc)2 was used.

desired product without NaOAc or the catalyst [{RuCl2(pcymene)}2] (entries 17 and 18). The reaction did not proceed when Pd(OAc)2 was used as the catalyst (entry 19). With the optimized reaction conditions in hand, the scope of the reaction was investigated. In general, the reaction was compatible with a variety of indoles bearing electron-donating and electron-withdrawing substituents to produce the desired allylation products in moderate to good yields with excellent regioselectivity and stereoselectivity (Scheme 1). It afforded the desired product 3a in moderate yield with E/Z > 25/1 when methyl(1-phenylallyl)carbonate was used as the coupling partner. The introduction of halogen groups, such as bromine and chlorine to the C-5 position of indoles offered the corresponding products in good yields (3b and 3c), while the substrates bearing the fluorine group resulted in decreased yield (3d). When other electron-donating groups (−Me and −OMe) and electron-withdrawing groups (such as −CO2Me) were introduced to the C-5 position of the indole ring, the reaction afforded the corresponding products smoothly (3e−3g). It also afforded the product in moderate yield when a fluorine group was attached to the C-6 position (3h). The methyl group at the C-4 position of the indole ring provided the desired product in good B

DOI: 10.1021/acs.orglett.8b00567 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters Scheme 2. Scope of Allyl Alcoholsa,b

Scheme 3. Preliminary Mechanism Studies

a

Scheme 4. Proposed Mechanism

Reaction conditions: 1a (0.2 mmol), 2 (0.3 mmol), [{RuCl2(pcymene)}2] (5 mol %), NaOAc (1 equiv) in DCE at 45 °C, Ar atmosphere, 6−12 h. Unless otherwise noted, the E/Z ratios of all products are >25:1. bIsolated yields are reported. cAllyl methyl carbonate was used.

determined by removing allyl alcohol 2a and performing the reaction with an excess amount of methanol-d4 (Scheme 3a). The results revealed that about 52% deuteration and 32% deuteration were incorporated at the C-2 and C-3 positions of the indole ring, respectively (see the Supporting Information for the experimental details). Carrying out the same reaction in the absence of NaOAc led to no deuterium incorporation at the C-2 and C-3 positions of the indole ring. Further, performing the reaction in the presence of 2a resulted in 40% deuteration at the C-3 position. These results suggest that the step of C−H activation might be reversible, the base NaOAc is critical for the step of C−H activation, and the cycloruthenation can proceed by the concerted metalation−deprotonation (CMD) with the aid of acetate ion.11 Further, the kinetic isotope effect (KIE) experiments were conducted. An intermolecular KIE kH/kD = 0.81 was observed for the competition reaction of 1a and deuteriumlabeled 1a-D with 2a (Scheme 3b). Two independent reactions using 1a and 1a-D gave a KIE value of 0.79. The results suggested that the step of the C−H bond cleavage was unlikely involved in the rate-limiting step.12 Based on the preliminary mechanistic experiments and the previous literatures,7,8 a possible reaction pathway was proposed (Scheme 4). Initial ionization in the presence of sodium acetate led to the active catalyst. Coordination of substrate 1a to the active ruthenium catalyst is followed by the C−H bond activation

to give the ruthenacycle I. Insertion of the allyl alcohol results in intermediate II. Subsequently, the β-hydroxide elimination of II affords the product 3, and regenerates the active catalyst by AcOH to complete the catalytic cycle. In summary, we have reported a ruthenium-catalyzed C−H allylation at the C-2 position of N-ethoxycarbamoyl indoles by using allyl alcohols as allylating reagents, wherein the Nethoxycarbamoyl directing group proves to be crucial for this reaction. This method provides access to C2-allylated indoles in moderate to good yields with good to excellent regioselectivity and stereoselectivity. In addition, this reaction features mild C

DOI: 10.1021/acs.orglett.8b00567 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters

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reaction conditions, compatibility with various functional groups, and broad substrate scope.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b00567. Experimental procedures, characterization data, and copies of NMR (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: haitao.ji@moffitt.org. ORCID

Haitao Ji: 0000-0001-5526-4503 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by the Susan G. Komen Career Catalyst Research Grant CCR16380693. The H. Lee Moffitt Cancer Center & Research Institute is an NCI-designated Comprehensive Cancer Center, supported under NIH grant P30-CA76292.

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DOI: 10.1021/acs.orglett.8b00567 Org. Lett. XXXX, XXX, XXX−XXX