Protecting group-free, selective cross-coupling of alkyltrifluoroborates with borylated aryl bromides via photoredox/nickel dual catalysis Yohei Yamashitaa,b,1, John C. Tellisa,1, and Gary A. Molandera,2 a Roy and Diana Vagelos Laboratories, Department of Chemistry, University of Pennsylvania, Philadelphia, PA 19104-6323; and bProcess Chemistry Laboratories, Astellas Pharma Inc., Ibaraki 318-0001, Japan

Edited by John F. Hartwig, University of California, Berkeley, CA, and approved August 19, 2015 (received for review May 18, 2015)

Orthogonal reactivity modes offer substantial opportunities for rapid construction of complex small molecules. However, most strategies for imparting orthogonality to cross-coupling reactions rely on differential protection of reactive sites, greatly reducing both atom and step economies. Reported here is a strategy for orthogonal cross-coupling wherein a mechanistically distinct activation mode for transmetalation of sp3-hybridized organoboron reagents enables C-C bond formation in the presence of various protected and unprotected sp2-hybridized organoborons. This manifold has the potential for broad application, because orthogonality is inherent to the activation mode itself. The diversification potential of this platform is shown in the rapid elaboration of a trifunctional lynchpin through various transition metal-catalyzed processes without nonproductive deprotection or functional group manipulation steps.


orthogonal cross-coupling photoredox/nickel dual catalysis single-electron transmetalation organotrifluoroborate




he development of strategies for rapid generation of molecular complexity from simple building blocks is central to the advancement of organic synthesis. A general platform for achievement of this ideal would have a profound impact on those disciplines whose progress is reliant on the efficient production of complex small molecules. Transition metal-catalyzed cross-coupling reactions have been instrumental to advancement in this realm, because these mild and functional group-tolerant methods are naturally amenable to the late-stage union of fully elaborated and minimally protected molecular fragments (1). Within this context, a variety of methods have been developed for iterative assembly of small-molecule scaffolds through orthogonal crosscoupling enabled by judicious attenuation of reactivity at either the organometallic or organic (pseudo-)halide site (2–5). Among these various approaches, the greatest advancements have been realized in Suzuki cross-coupling, because organoboron reagents are chemically robust and can be rendered inactive through topological and/or electronic differentiation or appropriate selection of heteroatomic substituents (5, 6). In an example of the former, Morken and coworkers (7–10) have reported the selective cross-coupling of geminal and vicinal diboronates through Pd catalysis. However, the requirement for proximal boryl substitution severely restricts the utility of these methods as a result of reduced substrate availability and reaction scope. More general approaches to orthogonal cross-coupling have been developed through the use of various boronic acid masking groups as a means to control site selectivity. These strategies rely on the protection of one organoboron reagent in a latent form unable to engage the Pd catalyst in transmetalation, whereas another, existing in a reactive form, participates in the initial C-C bond formation. Continuation of the iterative process is then enabled by subsequent deprotection of the masked boronic acid. A variety of protecting groups have been explored for these purposes, most notably N-methyliminodiacetic acid (MIDA) (6, 11–13) and 1,8-diaminonaphthalene (BDAN) (14–18). In

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addition to these reagents, isolated reports have used organotrifluoroborates (RBF3K) (19) and catecholboronates (20) as protected boronic acid equivalents in specific settings. Although effective, these protecting group strategies are inherently suboptimal in terms of atom and step economy (21). Nevertheless, this manifold of orthogonal protection is the only possible recourse when the desired iterative cross-coupling makes use of the same fundamental activation mode [i.e., transmetalation of an organoboron reagent to a Pd(II) intermediate]. In view of this paradigmatic limitation, we sought to develop an unprecedented class of orthogonal cross-coupling in which organoboron sites are mechanistically differentiated, thus allowing orthogonal reactivity without artificial attenuation of reactivity. This strategy would be enabled by our recently developed single-electron transmetalation manifold, wherein sp3-hybridized organoboron reagents participate in Ni-catalyzed cross-coupling through oxidative fragmentation to an alkyl radical promoted by an Ir photoredox catalyst (22–24). Our previous observation (22) that an sp3-hybridized organotrifluoroborate participates in photoredox/nickel dualcatalytic cross-coupling selectively in the presence of an sp2hybridized organotrifluoroborate confirmed that the single-electron transmetalation activation mode is, indeed, orthogonal to the traditional two-electron regime under relevant reaction conditions. Furthermore, we were confident that the trivalent sp2-hybridized organoborons [pinacolboronate (BPin), neopentylglycolboronate (BNeop), and B(OH)2] used in conventional cross-coupling reactions would be left intact during the course of the photoredox cross-coupling, because decomposition pathways, such as Significance Efficient assembly of small-molecule scaffolds is among the most fundamental goals of organic synthesis. Iterative synthesis, wherein predefined building blocks are unified in an “assembly line” fashion using only a small number of reaction types, is an attractive means for achieving this ideal. These methods are particularly well-suited for applications in drug discovery, agrochemistry, and materials science, where rapid generation of structural diversity is a central objective. A strategy is described in which two reactive sites are differentiated by their preferred mode of reactivity (single vs. two electron). This unique platform allows discrimination between the two sites without artificial blocking of reactivity, streamlining the iterative process by removing the need for deprotection or interconversion of functional groups. Author contributions: J.C.T. and G.A.M. designed research; Y.Y. and J.C.T. performed research; Y.Y. and J.C.T. analyzed data; and J.C.T. and G.A.M. wrote the paper. The authors declare no conflict of interest. This article is a PNAS Direct Submission. 1

Y.Y. and J.C.T. contributed equally to this work.


To whom correspondence should be addressed. Email: [email protected]

This article contains supporting information online at 1073/pnas.1509715112/-/DCSupplemental.


confirmed that the boronate was intact after cross-coupling, and subsequent studies involving transition metal-catalyzed sequential functionalization unequivocally confirm the survival of the boronate functional group (vide infra). Nearly all commonly used boronic acid derivatives smoothly underwent orthogonal cross-coupling, including those of neopentylglycol, MIDA, and 1,8-diaminonaphthalene. Particularly remarkable is the successful cross-coupling of unprotected 4-bromophenylboronic acid, albeit in moderate yield. This example is especially notable given the high reactivity and reduced stability of free boronic acids in cross-coupling relative to the related boronate esters (25). To our knowledge, this transformation is the first reported Csp3-Csp2 cross-coupling that is tolerant of boronic acids as latent functional groups, effectively highlighting the mildness and functional group tolerance of this photoredox/nickel dual-catalysis platform (Fig. 2).



Fig. 1. Strategies for orthogonal cross-coupling. (A) Conventional orthogonal protection approach requiring three discrete steps. (B) Photoredox cross-coupling approach relying on single-electron transmetalation of sp3-hybridized organoboron reagents to establish orthogonal reactivity patterns, allowing formation of two bonds in a single two-stage process. 9-BBN, 9-borabicyclo[3.3.1]nonane; BMIDA, N-methyliminodiacetic acid boronate.

protodeboronation and oxidation, are unlikely to occur under the exceptionally mild conditions used therein (Fig. 1). Our studies were initiated with analysis of the reaction of potassium benzyltrifluoroborate with 4-bromophenylboronic acid pinacol ester. Slight modification of the reaction conditions previously reported for the photoredox/Ni dual-catalytic cross-coupling of primary benzyltrifluoroborates allowed the efficient C-C bond formation between these partners to form the borylated diarylmethane product selectively. [No evidence of biaryl formation arising from competitive cross-coupling of the BPin moiety was observed by GC-MS analysis.] Specifically, use of ethereal solvents, such as THF and dioxane, and 2,2,6,6-tetramethylpiperidine in place of 2,6-lutidine suppressed formation of undesired side products and improved conversion. [The major side product observed by GC-MS was benzylBPin (PhCH2BPin). We suggest that this may be formed by fluoride abstraction from RBF3K by BF3 (generated during the course of the reaction by oxidative fragmentation of RBF3K) followed by transesterification with the aryl boronate.] Increased catalyst loading [3 mol % Ir [dFCF3ppy]2(bpy)PF6 Ir (dFCF3ppy, 2-(2,4-difluorophenyl)-5(trifluoromethyl)pyridine; bpy, 2,2′-bipyridine) and 5 mol % Ni (COD)2 (COD, 1,5-cyclooctadiene)] was necessary to induce complete conversion within 24 h, although reduced loadings were effective at prolonged reaction times. Under these conditions, the orthogonal cross-coupling could be achieved in 76% yield after oxidation to the corresponding alcohol. We next sought to explore the scope of the reaction with regard to the substituents about the sp2-hybridized organoboron reagent. Trivalent boronate reagents were oxidized before isolation, because these compounds are prone to decomposition via hydrolysis and/or protodeboronation during column chromatography, thereby artificially suppressing the observed yields. This cross-coupling/oxidation procedure proved more consistent and reliable for assessment of reaction efficiency compared with direct isolation of the boronate esters or boronic acids themselves. 11 B NMR analysis of crude reaction mixtures before oxidation Yamashita et al.

Fig. 2. Substrate scope for orthogonal cross-coupling of benzylic trifluoroborates with borylated aryl bromides. BMIDA, N-methyliminodiacetic acid boronate; CFL, compact fluorescent lamp; dtbbpy, 4,4′-di-tert-butylbipyridyl; HTMP, 2,2,6,6-tetramethylpiperidine.

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Fig. 3. Modular functionalization of lynchpin 6 through photoredox/Ni dual-catalytic orthogonal cross-coupling. Reaction conditions: (A) shown in Fig. 2; (B) 3-bromopyridine (1.2 eq), Pd(PPh3)4 (5 mol %), K3PO4 (3 eq), and THF:H2O (5:1) at 80 °C for 20 h; (C ) morpholine (1.5 eq), Pd2(dba)3 (10 mol %), RuPhos (10 mol %), NaOt-Bu (3 eq), and dioxane at 100 °C for 14 h; (D) methyl vinyl ketone (1.2 eq), [Rh(OH)(COD)]2 (5 mol %), and THF:H2O (5:1) at 60 °C for 20 h; and (E) potassium 3-(trifluoroborato)-2,6-dimethoxypyridine (1.2 eq), Pd(OAc)2 (10 mol %), XPhos (20 mol %), K3PO4 (3 eq), and dioxane:H2O (4:1) at 90 °C for 22 h. dba, dibenzylideneacetone; RuPhos, 2-Dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl; XPhos, 2-Dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl.

Additional exploration of the reaction scope revealed tolerance of 3-boryl substitution of the aryl bromide as well as trifluoromethyl and cyano substituents. Although 2-bromophenylpinacol boronate proved a reluctant partner, the cross-coupled product was formed in 25% yield with the sterically demanding ortho-pinacolboronate substituent. A variety of substituted potassium benzyltrifluoroborates also proved competent partners (4f–4i). Product 4f is particularly striking, because the reaction manifold was shown to be selective for cross-coupling of aryl bromides in preference to aryl chlorides, offering yet another level of orthogonality and diversification. In general, functional group tolerance was found to be comparable with that reported for the related coupling with nonborylated aryl bromides (22) (Fig. 3). In an effort to showcase the potential that this orthogonal cross-coupling paradigm has in the rapid diversification of simple building blocks, a protocol was developed for the modular functionalization of bromochloroborylarene 6. In one pathway, photoredox/Ni sp3-sp2 cross-coupling was followed directly by Pd-catalyzed Suzuki coupling of the arylBPin with 3-bromopyridine without intermediate purification. The product thus generated was subjected to Buchwald–Hartwig amination with morpholine to afford 9 in 53% overall yield in a sequence involving three bond-forming processes and only two purification steps without need for nonproductive functional group manipulations (Fig. 4). In a second transformation, the arylBPin intermediate was diverted into a Rh(I)-catalyzed conjugate addition with methyl vinyl ketone to afford 10 in 70% yield. Subsequent Pd-catalyzed Suzuki coupling proceeded in good yield, generating 11 in 60% overall yield. These representative examples attest to the diversification potential of this platform, because it is easy to envision library development by simple alteration of the modular building blocks used in each step or using any of the myriad methods for functionalization of arylboronates and/or aryl halides through transition metal-catalyzed protocols. Furthermore, nontransition metal-catalyzed transformations of boronic acids and esters could be used for scaffold elaboration, including Matteson homologation, diazo insertion, amination, and halogenation (25–28). Indeed, the rich chemistry of boronic acids and related derivatives allows them to serve effectively as a “universal functional group” from which nearly any structural element can be readily accessed. Although the benzylic cross-coupling reported herein is meant primarily as a proof of concept that the single-electron transmetalation manifold can be exploited for orthogonal cross-coupling, it is clear that the impact of this concept is dependent on the diversity of sp3-hybridized organotrifluoroborates that can participate in the photoredox/Ni dual-catalytic C-C bond-forming process. 12028 |

Our laboratory is actively expanding the palette of competent partners, the results of which will be disclosed in due course. It is reasonable to suggest that orthogonal cross-coupling should be achievable with each new class of substrates, because the success of the platform is not dependent on the nature of substrates but rather the unique mechanistic features of the single-electron transmetalation manifold, features that will be shared by all newly reported methods. In an effort to support this perceived generality, secondary α-alkoxyalkyltrifluoroborate 12 was engaged in orthogonal cross-coupling with 2a under the conditions optimized for use with primary benzylic trifluoroborates. Thus, sp3-sp2



Fig. 4. Photoredox orthogonal cross-coupling of secondary alkyltrifluoroborates. (A) Cross-coupling of 1-benzyloxy-3-phenylpropyltrifluoroborate with 13. (B) Cross-coupling of various unactivated secondary alkyltrifluoroborates.

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acid derivatives, including MIDA boronates, presents an opportunity for greatly expanding the capabilities of this potentially important technology. The ability of the orthogonal cross-couplings to be performed without intermediate purification bodes favorably for application in an automated fashion, and the compatibility of photoredox chemistry with continuous flow reactors has been previously established (32). In conclusion, we have delineated a conceptually unique strategy for orthogonal cross-coupling that makes use of a mechanistically distinct manifold for the activation of sp3-hybridized reagents for transmetalation. The described mechanistic differentiation of organoboron sites represents a fundamental departure from conventional protocols for orthogonal cross-coupling, which most often rely on inefficient, differential protection strategies. This reaction platform provides unprecedented opportunities for rapid diversification of polyfunctional building blocks in a straightforward manner and without intermediate purification, deprotection, or functional group manipulation procedures. Evidence has been provided with regard to the broader utility of this protocol for the crosscoupling of a variety of sp3-hybridized organotrifluoroborates, and potential applications in automated, iterative small-molecule production have been discussed. We anticipate that the proof of concept provided herein will serve as a powerful tool to practitioners in the field and that future developments and advances will greatly expand the power of the described methods (SI Appendix).

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ACKNOWLEDGMENTS. Dr. Rakesh Kohli is acknowledged for collection of mass spectrometric data used for characterization purposes. David Primer is acknowledged for helpful discussions. Frontier Scientific is acknowledged for donation of the organoboron compounds used in this study. Sigma-Aldrich and Johnson-Matthey are thanked for donations of IrCl3. Funding for this research was provided by the National Institute of General Medical Sciences Grant R0I-GM113878.

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cross-coupling product 14 was afforded in 54% yield under these unoptimized conditions, with no detectable cross-coupling occurring at the trivalent sp2 organoboron site. Furthermore, various unactivated secondary alkyltrifluoroborates were shown to cross-couple with 2a under conditions previously developed in our laboratory (23). These examples effectively validate photoredox orthogonal cross-coupling as a general manifold for achieving sp3-sp2 C-C bond formation in the presence of sp2-hybridized organoborons that can be directly used in subsequent conventional cross-coupling reactions. The results reported herein assume even greater significance in light of Burke and coworkers’ (29) recent report of automated iterative cross-coupling of brominated MIDA boronates. Here, a vast array of natural products, pharmaceutical agents, and druglike compounds were synthesized through cross-coupling procedures strictly limited to sp2- and primary sp3-hybridized organoborons. Despite the tremendous power shown in this report, this limitation handicaps the potential impact of the technology, because no general protocol exists for the Suzuki cross-coupling of secondary alkylboron compounds (30, 31). Thus, although simple hydrocarbon substructures often provide satisfactory yields, organoboron compounds displaying α-branching [e.g., 17b; the methods of Biscoe (31) and Molander (30) for Suzuki cross-coupling of secondary alkylboron reagents generate isomerized side products with branched substrates] and a variety of functional groups and/or heteroatoms (e.g., 17c and 17d) cannot be crosscoupled using conventional technologies. [Suzuki cross-coupling of the piperidine- and tetrahydropyran-based alkylboron compounds leading to 18c and 18d has never been reported.] To our knowledge, photoredox/Ni dual-catalytic cross-coupling offers for the first time a general family of protocols for use with this subclass of reagents. This strategy, combined with the ability for orthogonal cross-coupling in the presence of a variety of sp2-hybridized boronic

nickel dual catalysis.

Orthogonal reactivity modes offer substantial opportunities for rapid construction of complex small molecules. However, most strategies for imparting ...
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