Communication pubs.acs.org/Organometallics
Iridium-Promoted, Palladium-Catalyzed Direct Arylation of Unactivated Arenes Landon J. Durak and Jared C. Lewis* Department of Chemistry, The University of Chicago, Chicago, Illinois 60637, United States S Supporting Information *
ABSTRACT: A Pd-catalyzed cross-coupling reaction between Cp*(PMe3)IrBn2 and aryl halides was developed. Examining the scope of this reaction led to the discovery that Cp*(PMe3)IrMeCl activates C−H bonds on arene substrates that undergo subsequent Pd-catalyzed cross-coupling with aryl iodides. This Ir-promoted, Pd-catalyzed direct arylation is notable for its distal selectivity on substituted arenes lacking directing groups or a particular electronic bias.
C
a fundamental advance toward our ultimate goal of dual catalytic C−H functionalization. Studies on the transmetalation of hydrocarbyl ligands from Cp*(PMe3)Ir(R1)2 complexes to electrophilic d8 Pt(II) and Pd(II) complexes led to the discovery that Pd(II) catalyzes oxidative homocoupling of benzyl ligands from 1a in the presence of Ag2O.16 We hypothesized that changing the stoichiometric oxidant from Ag(I) to an aryl halide would enable catalytic cross-coupling reactions of Cp*(PMe3)IrIII hydrocarbyl complexes.11,17 1a was therefore reacted with PhI in the presence of different Pd catalysts and additives intended to increase Pd electrophilicity via anion metathesis or abstraction (Table 1).16 Initial trials using Pd(OAc)2 showed that the addition of a noncoordinating anion led to formation of the desired product, diphenylmethane, in up to 16% yield (entries 1−3). Exploring Pd catalysts revealed that Pd(0) with a
atalytic C−H functionalization has the potential to streamline chemical synthesis, enable the use of inexpensive chemical feedstocks, and eliminate substrate prefunctionalization (e.g., halogenation or metalation) and waste associated with analogous cross-coupling processes.1−3 Most methods for metal-catalyzed C−H functionalization require chelate assistance by a proximal directing group or a strong electronic bias to enable C−H activation, which provides a mechanism for selective functionalization.4,5 Relatively few catalysts have been developed for selective functionalization of C−H bonds distal to arene substituents,6 but such steric control is exhibited by a number of metal complexes (M1) that promote stoichiometric C−H bond activation.7−9 This stoichiometric reactivity could be exploited for catalysis if the activated organic fragment (R1) underwent transmetalation to a second metal (M2) for functionalization (Scheme 1).10−15 We previously established that trans-
Table 1. Optimizing Pd-Catalyzed 1a/PhI Cross-Couplinga
Scheme 1. Dual Catalytic Cycle for C−H Functionalization
metalation of hydrocarbyl (R1) and trifluoroacetate (X) ligands between Cp*(PMe3)Ir(R1)2 and (COD)Pt(Me)(X) complexes was possible.16 Here, similar transmetalation chemistry is exploited for Pd-catalyzed cross-coupling of Cp*(PMe3)Ir(Bn)2 (1a) with aryl halides (R2-X). Ir-promoted, Pd-catalyzed direct arylation of unactivated arenes (R1-H) using aryl halides (R2-X) can also be achieved. This reaction affords biaryl products in good yields with regioselectivity for the sterically most accessible distal position of the arene substrates and constitutes © 2014 American Chemical Society
entry
Pd source
additive
A, %b
B, %b
1 2 3 4 5 6 7c
Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd2(dba)3 Pd[P(t-Bu)3]2 Pd[P(t-Bu)3]2 Pd[P(t-Bu)3]2
NaOAc NaBF4 LiN(Tf)2 LiN(Tf)2 LiN(Tf)2 KBAr4F KBAr4F
0 8 16 70 90 125 124
17 21 27 3 0 0 0
Reactions were conducted at 0.01 M at 23 °C for 16 h. bYields were calculated by GC analysis of crude reaction mixtures relative to 1,3,5trimethoxybenzene internal standard added after completion of the reaction. cReaction was conducted in 1/1 PhMe/H2O. a
Received: December 23, 2013 Published: January 30, 2014 620
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Organometallics
Communication
Different Cp*(PMe3)IrIII complexes were also explored. When Cp*(PMe3)IrMeCl (1b) was reacted with 2-iodonaphthalene in 1/1 benzene/water, the expected cross-coupling product was not observed. Instead, the major product resulted from direct arylation of benzene using 2-iodonaphthalene (Scheme 2). This reaction, though stoichiometric in Ir complex 1b, constitutes an unusual example of direct arylation18,19 without the need for a directing group6 on an unactivated substrate.
bulky phosphine ligand (Pd[P(t-Bu)3]2) increased the yield of diphenylmethane to 90% (entries 3−5). Finally, combining Pd[P(t-Bu)3]2 and the weakly coordinating BAr4F anion (BAr4F− = tetrakis(pentafluorophenyl)borate) led to yields in excess of 100% relative to 1a due to the reaction of both benzyl ligands (entry 6). Similar efficiency was observed using biphasic water/toluene mixtures, which were intended to improve the solubility of the salt additives investigated (entry 7). Reactions conducted with Cp*(PMe3)IrBnX (X = Cl/I), the presumed Ir product from transmetalation,16 provided significantly lower yields than 1a; therefore, the reported yields reflect the transmetalation of one benzyl ligand of 1a. The optimized reaction conditions (2 mol % Pd, 1.3 equiv of ArX, 1 equiv of KBAr4F, toluene solvent) were then used to explore the substrate scope of the cross-coupling process (Table 2). Both aryl iodides and aryl bromides were competent coupling partners (entries 1−9), but aryl chlorides were unreactive (entry 10). Electron-rich and electron-deficient aryl halides, including examples with ortho substitution and ester, pyridine, and ether functional groups, underwent crosscoupling.
Scheme 2. Unexpected Ir-Mediated C−H Activation/PdCatalyzed Cross-Coupling of Benzene with 2Iodonaphthalene
While this reaction proved highly sensitive to residual oxygen and the method used to agitate the biphasic mixture, conditions for reliable direct arylation were identified. The scope of this process was explored using p-iodoanisole and various arene substrates (Table 3, entries 1−8). Both electron-rich and electron-deficient arenes are competent substrates, and the regioselectivities observed in the biaryl products appear to result primarily from steric, rather than electronic, effects. For both ortho- and meta-disubstituted arenes, the meta C−H bond is arylated, and monosubstituted substrates provide a statistical mixture of meta- and para-functionalized products (Table 3, entries 3 and 7). Para-disubstituted and 1,3,5trisubstituted arenes were unreactive. Our survey of the substrates revealed that the regioselectivity is neither consistent with that expected for electrophilic aromatic substitution (Table 3, entry 1) nor reflective of a preference toward cleavage of the most acidic C−H bond (Table 3, entry 7). Several additional aryl halides were subjected to the reaction conditions (entries 8−10). Unlike the aforementioned crosscoupling reactions, the direct arylation does not tolerate aryl bromides or functional groups, including esters, alcohols, or amines, on either the arene or the aryl halide. However, the examples in Table 3 show regioselectivity trends similar to those observed for Ir-catalyzed C−H borylation,6b,21 Pdcatalyzed C−H amination,22 and several dehydrogenative cross-coupling reactions.6a,c,d The lack of a strong electronic effect on the regioselectivity of this reaction differs significantly from that observed for reported examples of Pd-catalyzed direct arylation;4,18,19 however, a Pt-catalyzed direct arylation exhibiting both steric and electronic control of regioselectivity has recently been reported.23 The differences in reactivity between these reported systems and the bimetallic system described herein suggest that distinct modes of C−H activation will provide a means to functionalize a broad range of substrates with unique selectivities. Currently, the selectivity of this system for cross-coupling over homocoupling is generally modest (ca. (2−3):1), but some substrates do provide good levels of cross-coupling products (entries 7 and 8). Further studies, including a broader survey of Pd catalysts, ligands, and additives, are underway to clarify these effects and improve reaction selectivity. Key to these efforts will be a detailed understanding of the reaction mechanism. Both metals were required for efficient direct arylation; omitting Pd[P(t-Bu)3]2 led to trace product
Table 2. Scope of Pd-Catalyzed 1a/Aryl Halide CrossCoupling
a Yield determined by 1H NMR analysis of crude reaction mixtures relative to one benzyl ligand of 1a (1,3,5-trimethoxybenzene internal standard).
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Table 3. Scope of Bimetallic Direct Arylation of Arenes Using Aryl Iodides
Scheme 3. Mechanistic Hypothesis for C−H Activation/ Cross-Coupling of Arenes and Aryl Iodides
reaction conditions. Control experiments showed that no C−H activation occurred in the presence of either KBAr4F or water alone, even at elevated temperatures. Complex 5 could then undergo transmetalation with Pd complex 6 directly (as shown in Scheme 3) or as a neutral species following reaction with halide generated during the reaction. Reductive elimination of Pd complex 7 would afford the biaryl product and regenerate Pd(0) in analogy to conventional cross-coupling reactions.27 Specific details regarding the elementary steps of this proposed mechanism, particularly those involving the fate of Ir, remain unclear and are the focus of ongoing studies in our laboratory. In conclusion, we have developed conditions for Pd-catalyzed cross-coupling of Cp*(PMe3)Ir(Bn)2 and aryl halides as well as Ir-promoted, Pd-catalyzed direct arylation of arenes using aryl iodides. In both cases including the weakly coordinating BAr4F− anion was crucial to achieving good to high yields. The bimetallic direct arylation is notable for its distal regioselectivity on unactivated arenes. Future work will focus on developing a mechanistic understanding of the C−H activation/crosscoupling that will hopefully lead to a more selective process and ultimately one that is catalytic in both metals, as shown in Scheme 1.
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ASSOCIATED CONTENT
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AUTHOR INFORMATION
S Supporting Information *
Text and figures giving experimental procedures and characterization data for new compounds. This material is available free of charge via the Internet at http://pubs.acs.org. Corresponding Author
*E-mail for J.C.L.:
[email protected]. Notes
The authors declare no competing financial interest.
a
Yields determined by 1H NMR analysis of crude reaction mixtures using 1,3,5-trimethoxybenzene as an internal standard relative to 1b. b Product ratios determined by GC analysis of reaction mixtures.20
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ACKNOWLEDGMENTS This work was supported by The University of Chicago Louis Block Fund for Basic Research and Advanced Study.
formation, while only aryl iodide homocoupling resulted in the absence of 1b. Our current working hypothesis is therefore based on the transmetalation pathway outlined in Scheme 1. Within this context, the initial C−H activation step can be rationalized in analogy to the known reactivity of Cp*(PMe3)IrCl224 and Cp*(PMe3)IrMeOTf25 toward hydrocarbons. It has been suggested that D2O promotes ionization of Cp*(PMe3)IrCl2 to form [Cp*(PMe3)IrCl]+Cl−, which catalyzes H/D exchange in organic substrates.24 Similarly, Cp*(PMe3)IrMeOTf ionizes via loss of OTf− to generate Cp*(PMe3)IrMe+, which reacts with arenes (ArH) to form Cp*(PMe3)IrAr+ and CH4.25 On the basis of this precedent, we propose that water ionizes 1b in the presence of BAr4F− to generate cationic complex 4,26 which reacts with arene solvent to form CH4 and iridium aryl complex 5 (Scheme 3). Indeed, the Ir cation of 5 was observed by mass spectrometry under the
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