Site-Selective Ni-Catalyzed Reductive Coupling of α-Haloboranes

scenarios via catalytic sp3 C–C bond-forming reactions. Table 1. ... n=0. BPin. Cl δ– δ+. I. I. H. Page 1 of 6. ACS Paragon Plus Environment. Jo...
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Site-Selective Ni-Catalyzed Reductive Coupling of a-Haloboranes with Unactivated Olefins Shang-Zheng Sun, Marino Börjesson, Raul Martin, and Ruben Martin J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b09425 • Publication Date (Web): 23 Sep 2018 Downloaded from http://pubs.acs.org on September 23, 2018

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Site-Selective Ni-Catalyzed Reductive Coupling of α-Haloboranes with Unactivated Olefins Shang-Zheng Sun,† Marino Börjesson,† Raul Martin-Montero† and Ruben Martin†§* †Institute of Chemical Research of Catalonia (ICIQ), The Barcelona Institute of Science and Technology, Av. Països Catalans 16, 43007 Tarragona, Spain § ICREA, Passeig Lluís Companys, 23, 08010, Barcelona, Spain Supporting Information Placeholder ABSTRACT: A mild, chemo- and site-selective catalytic

protocol that allows for incorporating an alkylboron fragment into unactivated olefins is described. The use of internal olefins enables C–C bond-formation at remote sp3 C–H sites, constituting a complementary and conceptually different approach to existing borylation techniques that are currently available at sp3 centers. The versatility of organoboranes as synthons in organic synthesis makes the hydroboration of alkenes one of the most fundamental reactions in our synthetic repertoire.1 Although the use of α-olefins has become routine (Scheme 1, path a),1,2 site-selectivity issues come into play with unactivated internal olefins lacking directing groups in the vicinity (Scheme 1, path b).3 Indeed, the ability to effectively discriminate the incorporation of a boron fragment across an internal and unbiased olefin still remains an elusive goal in synthetic endeavours.4 Scheme 1. Coupling of Boron Fragments into Olefins. “classical” hydroboration of unactivated olefins R2B

R2BH

R2BH H n

site-selectivity issues

path b n≠0

H n

unactivated alkene

path a n=0

of ambiphilic α-haloboranes I with olefin feedstocks (Scheme 1, bottom).7,8 If successful, we recognized that this platform might complement existing 1,2-metallate shifts9 or conjunctive couplings10 via tetracoordinated boron atoms, C–B bond-formations of organic (pseudo)halides11 or techniques based on well-defined organometallic reagents,12 while offering new strategic approaches for preparing useful building blocks from simple olefins as raw materials. Although anti-Markovnikov selectivity was expected with α-olefins (path c),5 it was unclear whether regioselectivity could be controlled with internal, yet unbiased, olefins. However, we hypothesized that a chain-walking event13 might offer a solution to such synthetic challenge, and enable C–C bondformations at remote and unfunctionalized sp3 C–H sites (path d).14 Herein, we report the successful realization of this goal. Our method is distinguished by its mild conditions, as well as by its exquisite chemo- and siteselectivity, even by using isomeric mixtures of internal olefins, thus allowing the implementation of iterative scenarios via catalytic sp3 C–C bond-forming reactions. Table 1. Optimization of the Reaction Conditions.a

BR2 widely known & general

site-selective coupling of α-haloboranes & unactivated olefins (this work) Cl I δ+ δ– BPin Ni H-source path d

n≠0 H n

BPin

Cl I δ+ δ– BPin Ni

H n

remote sp3 C–H site

H-source path c

exquisite site-selectivity mild conditions & general iterative sp3 C–C events

n=0

H BPin

At the current level of development, the catalytic regioselective incorporation of an alkylboron fragment into unactivated olefins still constitutes an uncharted territory within the hydrofunctionalization arena.5 In our continuing interest in Ni catalysis,6 we questioned whether we could enable a site-selective catalytic reductive coupling ACS Paragon Plus Environment

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1a (0.20 mmol), 2a (0.34 mmol), NiI2 (5 mol%), L2 (6 mol%), (EtO)2MeSiH (0.30 mmol), Na2CO3 (0.15 mmol), DMA/THF (3:1, 0.4 mL) at rt. b GC yields using 1-decane as internal standard. c Isolated yield. d NiI2 (1 mol%), 24 h.

Our study began by evaluating the reaction of 1a with 2a (Table 1). After careful optimization of the reaction conditions,15 a combination of NiI2 (5 mol%), L2 (6 mol%), (EtO)2MeSiH, Na2CO3 and DMA/THF at rt afforded 3a in 83% isolated yield as a single regioisomer. As shown in entries 2-3, lower yields were found when using NiBr2 or even Ni(COD)2 as precatalysts, with the latter likely suggesting that COD might compete with substrate binding. The intriguing dichotomy exerted by the nature and position of the substituents on the ligand backbone is evident from the results shown in entries 48 vs entry 1, with 2,2’-bipyridines possessing a 6-methyl group and substituents at 4,4’-positions providing the best results, thus showing the subtleties of our system. As shown in entries 9-11, solvents or hydride sources other than DMA/THF or (EtO)2MeSiH resulted in markedly lower yields of 3a. As anticipated, control experiments revealed that all of the reaction parameters were critical for yielding 3a (entry 12).15-17

affording the targeted products as single regioisomers.18 The chemoselectivity profile of our method is illustrated by the fact that ketones (3c, 3j), nitriles (3d, 3r), esters (3h, 3i), amides (3f) or silyl ethers (3q), among others, could all be well accommodated. Equally interesting was the possibility to conduct this reaction in the presence of aryl halides (3h, 3i), alkyl halides (3e, 3l, 3s) or even boronic esters (3g), leaving ample room for further derivatization via classical cross-coupling technologies.19 As expected, the nature of the α-haloboronate was largely inconsequential to the reactivity profile (3k-3v), even with α-branched derivatives (3u, 3v) or unsubstituted motifs (3t), the latter on a gram scale. Table 3. Scope of Internal Olefins. a,b

Table 2. Scope of Terminal Olefins.a,b

a

As Table 2, with NiI2 (10 mol%), L6 (12 mol%), Na2CO3 (1.0 equiv) in DMA. b Isolated yields, average of two independent runs (regioisomeric ratios are indicated in parenthesis). c 10 ºC. d dr = 1:1. e α-haloborane (2.0 equiv), NiBr2·diglyme (10 mol%). f >99:1 ratio.

a

As Table 1 (entry 1). b Isolated yields, average of two independent runs. c NiBr2·diglyme (10 mol%). d NiI2 (10 mol%). e NiBr2·diglyme (10 mol%), olefin (0.5 mmol). f dr = 1:1. g NiI2 (10 mol%), L6 (12 mol%). h 6.0 mmol scale. i NiBr2·diglyme (10 mol%) at 40 ºC, with a bromoborane.

Encouraged by our results, we turned our attention to exploring the generality of our reaction with terminal, unactivated olefins. As shown from the results compiled in Table 2, a host of α-olefins or 1,1-disubstituted analogues (3n) could be equally employed as substrates,

The lower binding affinity of internal olefins20 and the propensity of nickel catalysts to enable C–C bondformation at the initial reaction site21 left a reasonable doubt as to whether the site-selectivity could be either tuned or controlled with internal alkenes. Indeed, the reaction of 2-heptene with α-chloro heptylboronic acid pinacol ester under the optimized conditions of Table 2 based on the Ni/L2 couple resulted in 11% yield of 4a (8.5:1 ratio).22 Gratifyingly, a cocktail consisting of NiI2 (10 mol%) and L6 (12 mol%) furnished 4a from 2heptene in 66% yield (Table 3) and with excellent siteselectivity (44:1),22 favoring the functionalization at the primary sp3 C–H site. Importantly, isomeric 3-heptene or

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4-octene gave rise to 4a and 4b in good yields and excellent site-selectivities. As shown, cyclic (4h) or acyclic olefins (4a-g, 4i-s), regardless of the double bond geometry,23 posed no problems. Although one might argue that an erosion in site-selectivity might arise with sidechains containing weak, benzylic sp3 C–H bonds, C–C bond-formation occurred preferentially at the primary sp3 C–H site (4c).24 Likewise, the inclusion of esters (4i), carbamates (4f), acetals (4k), nitriles (4r), silyl ethers (4p), alkyl halides (4q) or nitrogen-containing heterocycles (4f, 4j, 4l) did not interfere with productive chainwalking. Of particular relevance was the functionalization of polyunsaturated backbones (4g) or substrates containing branched methyl groups (4e, 4g); while the less-sterically hindered olefin was selectively functionalized in the former, reaction took place at the most accessible primary sp3 C–H site in the latter.

Scheme 3. Mechanistic Experiments.

Scheme 2. Iterative Platform for C–C Bond-Formations.

The data compiled in Tables 2-3 advocated the notion that our protocol might serve as a platform to build up C(sp3)–C(sp3) bonds in an iterative manner by using simple olefin feedstocks as starting materials. As shown in Scheme 2, this turned out to be the case. Specifically, Ni/L2-catalyzed reductive coupling of commerciallyavailable 5 with 3-butenylbenzene followed by Matteson homologation25 cleanly furnished 6 in 51% yield on a gram scale. As expected, exposure of 6 under a Ni/L6 protocol in the presence of statistical mixtures (1:1:1) of isomeric heptenes gave rise to 7 (44:1 ratio). Likewise, 8 could be easily prepared by using a terminal olefin with the Ni/L2 couple whereas C(sp3)–C(sp2) bond-formation en route to 9 could be enabled by a catalytic umpolung arylation with Ni/L1 and Zn dust.26 Particularly noteworthy is the orthogonality observed with pending alkenes in the latter, suggesting that subsequent homologations at the alkene terminus might be easily within reach. Taken together, the results shown in Tables 2-3 and Scheme 2 highlights the versatility, modularity and the prospective synthetic impact of our protocol.

In principle, two different mechanistic interpretations are conceivable for our results: (a) initial single-electron transfer (SET) from Ni(0)Ln to I, leading to boronstabilized alkyl radicals II prior to addition across the olefin partner (Scheme 3, top left)27 or (b) hydrofunctionalization of an olefin via nickel hydride species en route to III,5,28 ultimately enabling C–C bond-formation by reaction with I (top right). Although our experimental data does not allow to rigorously distinguish between these two manifolds, we decided to gather indirect evidence about the mechanism by studying the reaction of 10 and 11 with 1a. C3-selectivity was anticipated for a mechanism consisting of the intermediacy of II;29 on the contrary, C–C bond-formation at C2 would suggest the involvement of a nickel hydride that might generate III prior to addition to 1a. As shown in Scheme 3 (bottom), 12 and 13 were exclusively obtained using either a Ni/L2 or a Ni/L6 protocol; under the limits of detection, not even traces of 12’ or 13’ were detected in the crude mixtures, suggesting that a nickel hydride scenario seems more likely.30 Whether these results suggest the involvement of Ni(I) entities31 or other mechanistic interpretations32 is subject of ongoing studies. In summary, we have discovered a mild, chemo- and site-selective reductive coupling of α-haloboranes with simple olefin feedstocks, thus giving access to αbranched boranes from simple and available precursors. The utilization of internal, unactivated olefins results in a C–C bond-formation at remote unfunctionalized sp3 C–H sites. Further investigations into related processes, including the design of an asymmetric variant,33 are currently ongoing in our laboratories.

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ASSOCIATED CONTENT Supporting Information. Experimental procedures, crystallographic data and spectral data. This material is available free of charge via the Internet at http://pubs.acs.org.

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AUTHOR INFORMATION Corresponding Author

* [email protected] Funding Sources

No competing financial interests have been declared.

ACKNOWLEDGMENT We thank ICIQ, MINECO (CTQ2015-65496-R & Severo Ochoa Accreditation SEV-2013-0319) for support. S.–Z. Sun, M. Börjesson and R. Martin thank MINECO and La Caixa for predoctoral fellowships. This paper is dedicated to professor Ernesto Carmona on his 70th birthday.

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tions: Lu, X.; Xiao, B.; Zhang, Z.; Gong, T.; Su, W.; Yi, J.; Fu, Y.; Liu, L. Nat. Commun. 2016, 7, 11129. The mass balance of the reactions compiled in Tables 2-3 accounts for hydrogenolysis of the C–Cl bond and traces of β-hydride elimination and homocoupling of α-haloboranes. De Meijere, A.; Brase, S.; Oestreich, M. Metal-Catalyzed Cross-Coupling Reactions. Wiley-VCH, Weinheim, Germany, 2004. (a) Vasseur, A.; Bruffaerts, J.; Marek, I., Remote functionalization through alkene isomerization. Nat. Chem. 2016, 8, 209. (b) Larionov, E.; Li, H.; Mazet, C. Well-Defined Transition Metal Hydrides in Catalytic Isomerizations. Chem. Commun. 2014, 50, 9816. a) Ananikov V. P. Nickel: The "Spirited Horse" of Transition Metal Catalysis. ACS Catal. 2015, 5, 1964. (b) Tasker, S. Z.; Standley, E. A.; Jamison, T. F. Recent Advances in Homogeneous Nickel Catalysis. Nature 2014, 509, 299. (c) Koga, N.; Obara, S.; Kitaura, K.; Morokuma, K. Role of Agostic Interaction in β-Elimination of Palladium and Nickel Complexes. An ab Initio MO Study. J. Am. Chem. Soc. 1985, 107, 7109. For the identity of the minor regioisomers, see ref. 15. (E)– or (Z)–configured olefins provided identical results (a) Peng, L.; Li, Z.; Yin, G. Photochemical NickelCatalyzed Reductive Migratory Cross-Coupling of Alkyl Bromides with Aryl Bromides. Org. Lett. 2018, 20, 1880. (b) Refs 15a, 15 c-d. (a) Matteson, D. S. α-Halo Boronic Esters: Intermediates for Stereodirected Synthesis. Chem. Rev. 1989, 89, 1535. (b) Matteson, D. S.; Ray, R. α-Chloro Boronic Esters from Homologation of Boronic Esters. J. Am. Chem. Soc. 1980, 102, 7590. Sun, S.-Z.; Martin, R. Nickel-Catalyzed Umpolung Arylation of Ambiphilic α-Bromoalkyl Boronic Esters. Angew. Chem. Int. Ed. 2018, 57, 3622. This stabilization is due to the effective delocalization of the radical through the vacant p orbital of the boron atom, suggesting substantial stabilization by C–B π-bonding. The utilization of internal olefins would also generate III via chain-walking. C3 selectivity would also be expected if olefin isomerization occurs at early stages (see ref. 15 for control experiments in the absence of 1a), as stabilized α-amino or α-oxygen radicals should be generated upon addition of II across the olefin. As expected, an identical reactivity profile was observed with the 2,3-dihydroheterocycle analogues. See ref. 15. This interpretation gains credence by the observation that aryl and alkyl halides are tolerated under our conditions (Tables 2 & 3), as these motifs might undergo facile oxidative addition or SET with Ni(0)Ln species. Additionally, we found that olefins decorated with an adjacent cyclopropyl motif do not undergo substantial ring-opening. See ref. 15. At present, it is unclear whether hydrofunctionalization occurs via Ni(II)- or Ni(I)-hydrides. For the generation of Ni(I)-hydrides by reaction of Ni(0)Ln with R3SiH, see: Cornella, J.; Gómez-Bengoa, E.; Martin, R. Combined Experimental and Theoretical Study On the Reductive Cleavage of Inert C–O Bonds with Silanes: Ruling Out a Classical Ni(0)/Ni(II) Catalytic Couple and Evidence for Ni(I) Intermediates. J. Am. Chem. Soc. 2013, 135, 1997. Unfortunately, the preparation of Ni(0)(L2)2 or Ni(0)(L6)2 in analytically pure form proved to be particularly elusive. Preliminary results on the enantioselective version using an enantiopure Pyr-Ox ligand showed 30% ee. For details see ref. 15.

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