Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Copper-Catalyzed Synthesis of Tetrasubstituted Enynylboronates via Chemo‑, Regio‑, and Stereoselective Borylalkynylation Jung Tae Han and Jaesook Yun* Department of Chemistry and Institute of Basic Science, Sungkyunkwan University, Suwon 16419, Korea S Supporting Information *
ABSTRACT: An efficient, catalytic method for accessing tetrasubstituted enynylboronates has been established via copper-catalyzed chemo-, regio-, and stereoselective borylalkynylation of internal alkynes. In this protocol, a range of symmetrical and unsymmetrical internal alkynes with aryl, heteroaryl, and alkyl substituents afforded fully substituted enynylboron compounds in good yields and with high levels of regio- and stereoselectivity, up to a ratio of >20:1. The enynylboron products could be further utilized in transforming the C−B bond into C−C bonds by coupling reactions.
C
Scheme 1. Approaches To Synthesize Tetrasubstituted Enynylbornates
onjugated enynes are useful compounds in modern synthetic chemistry. These materials are found in a variety of bioactive compounds and are widely used in material science, polymer chemistry, and natural product synthesis.1 Moreover, enyne derivatives are key intermediates for the synthesis of multisubstituted benzene rings.2 Enynylboronates containing an extra boron functional group are especially versatile building blocks for the synthesis of complex molecules that could be used in further applications. In this regard, the development of their efficient preparation is considered highly valuable.3−5 However, approaches to synthesizing such molecules are scarce and represent a challenge, especially in the case of fully substituted compounds. Only a few examples to access tetrasubstituted enynylboronates have been reported to date in the literature. In 2006, Suginome and co-workers reported the nickel-catalyzed borylalkynylation of internal alkynes to furnish the tetrasubstituted enynylboronates (Scheme 1a).3b Although this method was a pioneering example of borylalkynylation of alkynes, control of both regioselectivity and stereoselectivity was not perfect, forming mixtures of regio- (∼9:1) and stereoisomers (cis/trans = ∼9:1). More recently, transition-metal-free borylalkynylations of internal alkynes have been disclosed by the Uchiyama group (Scheme 1b).5 In this protocol, propargylic alcohols were essential as the starting materials for coupling with alkynylboronates. Consequently, the general and practical methods for the synthesis of tetrasubstituted enynylboronates in a regio- and stereoselective manner are in high demand. Transition-metal-catalyzed carboborations of alkynes have opened up possibilities for facile access to tetrasubstituted alkenylboronates.6 In particular, copper-catalyzed carboborations of alkynes have proven to be reliable processes for preparing such multisubstituted alkenylboronates in recent years.7 Since the pioneering work of Tortosa on coppercatalyzed borylalkylation of alkynes,7a other three-component protocols have been developed with electrophiles, including the alkyl,7a−e aryl,7f allyl,7g,h and carboxyl group.7i © XXXX American Chemical Society
An alkynyl group is significantly important due to the synthetic utility of the triple bond;8 however, to the best of our knowledge, borylalkynylation of alkynes with an alkyne electrophile has not been reported yet. Furthermore, examples of C−C bond formation between an sp2C−Cu species and an sp-hybridized carbon of electrophilic alkynyl reagents such as haloalkynes are scarce, and successful examples have been only reported with heterocyclic-copper intermediates derived from triazoles, oxazoles, and indolizines.9 The bond formation between benzylic copper (Csp3−Cu) species and alkyne electrophiles was only recently reported.10 Based on our previous work on the capture of organocopper intermediates by using a proton and an allyl group as electrophiles,11 we envisioned that the vinylcopper species generated in situ from Received: February 25, 2018
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DOI: 10.1021/acs.orglett.8b00665 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters borylcupration of alkyne substrates might be trapped by alkynyl electrophiles (Scheme 1c). For successful establishment of the tandem borylalkynylation of alkynes, the following challenges should be overcome: (1) chemoselective reaction of a Cu−B catalytic species in the presence of two different internal alkynes; (2) regioselective addition of the Cu−B species to unsymmetrical internal alkynes; (3) efficient C−C bond coupling between ligand (NHC)-bound vinylcopper species and Csp-based-electrophiles under multicomponent reaction conditions, which has not been reported yet. Herein, we report a chemo-, regio-, and stereoselective borylalkynylation of internal alkynes, which provides a facile route to tetrasubstituted enynylboronates. We initially examined the reaction of diphenylacetylene (1a) with bis(pinacolato)diboron (B 2 pin 2 ) and triisopropylsilylethynyl bromide (2) under a range of reaction conditions in the presence of a copper precatalyst and base (Table 1). A
combination of an electron-rich ICy·HCl salt and CuCl showed slightly diminished reactivity, compared to IMes−CuCl (entry 3). Neither bulky IPr−CuCl nor π-accepting NQIMes− CuCl7e,13 were effective for this transformation (entries 4 and 5). While the use of DMA (= N,N-dimethylacetamide) solvent resulted in poor reactivity, toluene significantly increased the product yield (entries 6 and 7). Other alkoxide bases led to slightly reduced yields, while cesium carbonate was less effective (entries 8−10). With the optimized reaction conditions in hand, we investigated the substrate scope of alkynes (1) in our catalytic process. A variety of internal alkyne substrates containing aryl, heteroaryl, and alkyl groups were generally reactive, providing the corresponding tetrasubstituted enynylboronate products in good yields with high regio- and stereoselectivities (Scheme 2).14 Reactions of symmetrical diaryl alkynes with electron-
Table 1. Optimization of Reaction Conditions
Scheme 2. Copper-Catalyzed Chemo-, Regio-, and Stereoselective Borylalkynylation of 1a
entry
precatalyst
base
solvent
yield (%)a
1 2 3 4 5 6 7 8 9 10
IMes−CuCl SIMes−CuCl ICy·HCl/CuCl IPr−CuCl NQ IMes−CuCl IMes−CuCl IMes−CuCl IMes−CuCl IMes−CuCl IMes−CuCl
LiOt-Bu LiOt-Bu LiOt-Bu LiOt-Bu LiOt-Bu LiOt-Bu LiOt-Bu NaOt-Bu KOt-Bu Cs2CO3
THF THF THF THF THF DMA toluene toluene toluene toluene
58 21 44
