Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Ruthenium(II)-Catalyzed Direct C−H Arylation of Indoles with Arylsilanes in Water Pradeep Nareddy, Frank Jordan, and Michal Szostak* Department of Chemistry, Rutgers University, 73 Warren Street, Newark, New Jersey 07102, United States S Supporting Information *
ABSTRACT: The ruthenium(II)-catalyzed, heteroatom-directed C−H arylation of indoles with arylsilanes in water has been developed. The method represents the first example of a ruthenium(II)-catalyzed oxidative C−H arylation in water/aqueous media as a sustainable solvent for C−H functionalization. The reaction enables the synthesis of a wide range of indoles with exquisite selectivity for arylation at the C-2 position. Preliminary mechanistic studies indicate reversibility of the C−H ruthenation step under the developed reaction conditions.
I
n the last 15 years, tremendous advances have been made in the development of C−H functionalization methods as an enabling tool for organic synthesis.1,2 While the majority of studies have centered on palladium, ruthenium(II)-catalyzed direct C−H arylation has received growing interest, 3,4 undoubtedly fueled by (1) the low price of ruthenium,5 (2) broad functional group tolerance,6 (3) operational simplicity, and (4) orthogonal selectivity.4 Principally, two reaction pathways for ruthenium(II)-catalyzed direct C−H arylation of Csp2 bonds have been developed: (1) Ru(II)/Ru(IV) catalytic cycle with haloarenes as cross-coupling partners7 and (2) Ru(II)/Ru(0) catalytic cycle with organometallics as attractive alternative transmetalating reagents under mild, functional group tolerant, oxidative conditions.8 The inherent advantages of such Ru(II)-catalyzed C−H functionalizations show a profound impact on chemical synthesis.3,4 In this context, direct C−H arylation of indoles at the C-2 position is important because of the prevalence of 2-arylindoles in a variety of biologically active compounds, complex natural products, and synthetic materials (Figure 1).9,10 While
Figure 2. Ru- and Rh-catalyzed C−H arylation of indoles: (a) previous studies; (b) this work. Pym = 2-pyrimidyl.
Ru(II)/Ru(IV) catalytic cycle.11 More recently, Pilarski et al.12 and Kapur et al.13 independently developed direct C-2 C−H arylations of N-pyrimidyl indoles with aryl boronic acids via a Ru(II)/Ru(0) catalytic cycle. In a related development, Loh et al.14 demonstrated direct C-2 C−H arylation of N-pyrimidyl indoles with arylsilanes via a Rh(III)/Rh(I) catalytic manifold in aqueous media.15,16 As a part of our program in ruthenium catalysis17 and C−H functionalization,18 herein we advance the concept of Ru(II)catalyzed direct Hiyama arylations19 and describe the successful development of the Ru(II)-catalyzed, heteroatom-directed C−H arylation of indoles with arylsilanes in water (Figure 2B). The following features of our findings are notable: (1) cost-effective, functional group tolerant Ru(II) catalysis; (2) arylsilanes as attractive, benign organometallic coupling partners;20 (3) the first Ru(II)-catalyzed oxidative C−H arylation in water/aqueous media as a sustainable solvent for C−H functionalization.15,16 The method provides a general approach to 2-arylindoles under sustainable conditions. The combined features of our protocol could enable the development of a wide range of Ru(II)/(0)catalyzed direct C−H arylations in aqueous media.
Figure 1. Selected examples of biologically active 2-arylindoles.
remarkable progress has been made in Pd-catalyzed direct C− H arylation, including regioselective C2/C3/C7 arylations, heteroatom-directed arylations, and arylations of unprotected NH indoles,10 Ru-catalyzed C−H arylation of indoles has been scarcely studied (Figure 2A). The pioneering work by Ackermann et al. established the facility of a direct C-2 C−H arylation of indoles using N-pyrimidyl directing group via a © XXXX American Chemical Society
Received: November 16, 2017
A
DOI: 10.1021/acs.orglett.7b03567 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters
activator and Ag2O as a Ru(0) reoxidant furnished the desired product in promising 40% yield (entry 4). The reaction efficiency could be improved by using i-PrOH as a solvent (entry 5). Of note, the use of i-PrOH as an inexpensive and environmentally friendly solvent is desirable in C−H activation protocols.21 While evaluation of other silane activators together with Ag2O was unproductive (entries 6−8), a combination of CuF2 and Ag2O efficiently promoted the coupling (entry 9). Interestingly, the yield could be further improved by removing Ag2O from the reaction system (entry 10), presumably due to incompatibility of the Ru(0) oxidation with silane activation step. At this point, the influence of solvent on the reaction was examined (entries 11− 20). Importantly, various solvents were compatible with this C− H arylation, including THF, DCE, dioxane, DMF and toluene (entries 11−17). In an effort to render the process more environmentally friendly, we examined the reaction in a 1:1 mixture of i-PrOH/water (entry 18). Pleasingly, the reaction cleanly delivered the C−H arylation product. Moreover, we were surprised to f ind that water can be used as a sole reaction medium without decrease in the reaction eff iciency (entry 19). Seventy percent conversion is observed at the boiling point of water. AgSbF6 is required for efficient arylation; in its absence approximately 50% conversion is observed. Finally, we determined that stoichiometry of both the silane and CuF2 could be decreased to 1.2 and 1.5 equiv, respectively (entry 20). To our knowledge, the process represents the first example of both (1) direct Ru(II)-catalyzed oxidative C−H arylation in water3,4 and (2) direct Hiyama cross-coupling in water as a sole reaction medium.14,19,20 Moreover, the employed stoichiometry of silane/CuF2 (1.2:1.5 equiv) compares very favorably with the previous examples of Ru(II)-catalyzed direct Hiyama crosscoupling.17b,c With the optimized conditions in hand, the scope of indoles and arylsilanes that could participate in this reaction was examined (Scheme 1 and Table 2). Typically, water was used as a sole reaction medium, while i-PrOH/water (1:1 v/vol) was used for insoluble substrates. As shown in Scheme 1, a wide range of indoles underwent C−H arylation under the developed conditions. In all cases examined, exclusive C2 C−H arylation site-selectivity was observed. Notably, electron-donating and electron-withdrawing substituents at the C5 position were readily accommodated (3b−d). Steric substitution at both C3 and C7 was also well-tolerated (3e−f). Importantly, indoles bearing a wide range of electrophilic functional handles at different positions around the indole ring, such as bromides (3g− i), esters (3j,k), and a nitro group (3l), were also competent electrophiles in this C−H arylation. At present, free indole is not compatible with the reaction conditions. Of note, aryl bromide functional handles are not readily accessible by a Ru(II)/(IV) catalytic cycle,3,4 showing a subtle advantage of the oxidative coupling manifold. We next turned our attention to the scope of the arylsilane coupling partner (Table 2). Triethoxyphenylsilane showed similar efficiency to trimethoxyphenylsilane without modification of the reaction conditions (entries 1 and 2).19c Arylsilanes bearing various substituents, including electron-donating (entries 3 and 4) and electron-withdrawing (entries 5 and 6), performed well in the reaction. A noteworthy aspect is high tolerance for halides on the arylsilane component (entries 7 and 8). To our knowledge, the results provide the first example of a bromo substituent on arylsilane in the Hiyama C−H arylation of indoles.14,19 Meta-substitution was well accommodated (entry 9). Finally, it is noteworthy that a sterically demanding ortho-
Recently, our laboratory introduced a new method for the direct Ru(II)-catalyzed C−H arylation with arylsilanes.17b,c A critical feature is the in situ generation of a cationic Ru(II) catalyst3a to enable C−H arylation by both weakly and strongly coordinating directing groups.1,2 We hypothesized that indoles could serve as suitable and general precursors for the direct C−H arylation under Ru(II)-catalyzed Hiyama conditions. Despite unique advantages of organosilicon coupling partners in organic synthesis, including low toxicity, high stability, safe handling, accessibility, and functional group compatibility,20 the use of organosilanes as viable cross-coupling partners in C−H arylation represents a major challenge due to (1) low nucleophilicity of organosilanes and (2) incompatibility of silane activation and metal re-oxidation steps. To test the reaction feasibility, we examined the direct C−H arylation of N-pyrimidylindole with trimethoxyphenylsilane under a variety of conditions. Selected optimization results are summarized in Table 1. The central challenge was to identify a Table 1. Optimization of Reaction Conditionsa
entry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20d
fluoride
oxidant
AgF (2.0 equiv) Cu(OTf)2 CuF2 (2.0 equiv) Cu(OTf)2 CsF (2.0 equiv) Cu(OTf)2 AgF (2.0 equiv) Ag2O AgF (2.0 equiv) Ag2O AgF (2.0 equiv) Cu(OTf)2 KF (2.0 equiv) Ag2O CsF (2.0 equiv) Ag2O CuF2 (2.0 equiv) Ag2O CuF2 (3.0 equiv) CuF2 (3.0 equiv) CuF2 (3.0 equiv) CuF2 (3.0 equiv) CuF2 (3.0 equiv) CuF2(3.0 equiv) CuF2 (3.0 equiv) CuF2 (3.0 equiv) CuF2 (2.0 equiv) CuF2 (2.0 equiv) CuF2 (1.5 equiv)
solvent
yieldb (%)
DCE DCE DCE DCE i-PrOH i-PrOH i-PrOH i-PrOH i-PrOH i-PrOH THF DCE dioxane DMF CHCl3 CH3CN toluene i-PrOH/H2Oc H2O H2O
