Nickel-catalysed migratory hydroalkynylation and enantioselective hydroalkynylation of olefins with bromoalkynes

Abstract

Abstractα-Chiral alkyne is a key structural element of many bioactive compounds, chemical probes, and functional materials, and is a valuable synthon in organic synthesis. Here we report a NiH-catalysed reductive migratory hydroalkynylation of olefins with bromoalkynes that delivers the corresponding benzylic alkynylation products in high yields with excellent regioselectivities. Catalytic enantioselective hydroalkynylation of styrenes has also been realized using a simple chiral PyrOx ligand. The obtained enantioenriched benzylic alkynes are versatile synthetic intermediates and can be readily transformed into synthetically useful chiral synthons.

Catalytic Asymmetric Hydroalkylation of α,β-Unsaturated Amides Enabled by Regio-Reversed and Enantiodifferentiating syn-Hydronickellation

“…It also circumvents another issue encountered in conventional cross-coupling, that the basic and nucleophilic nature of pregenerated organometallic reagents can often lead to limited functional-group compatibility, rendering it unable to handle sensitive functionality. Recently, nickel hydride − has proved to be an efficient catalyst for enantioselective reductive hydrofunctionalization, especially in hydroalkylation reactions (Figure a). In this process, chiral induction could occur in one of two possible steps: (i) enantioconvergent alkylation with racemic 2° or 3° alkyl halide to form enantioenriched Ni­(III) intermediates, constructing stereocenter at the carbon originating from racemic electrophile; − or (ii) enantioselective syn -hydrometalation of NiH with an alkene to form enantioenriched alkylnickel species, constructing a stereocenter at the carbon originating from achiral olefin. − …”

Modular Ni(0)/Silane Catalytic System for the Isomerization of Alkenes

“…Nickel catalysts are particularly attractive not only because Ni is an Earth-abundant, first-row transition metal but also because they are mechanistically versatile (i.e., able to proceed through 1-electron and 2-electron pathways). ,− Ni has been proposed to isomerize alkenes through insertion/elimination, − radical, and π-allyl-type ,,, mechanisms. The insertion/elimination pathway using a Ni–H catalyst is particularly attractive because it is the proposed mechanism for many chain walking applications. ,,,− Elucidation of the active species structure and the effect of ancillary ligands has been specifically identified as the major challenge in Ni-catalyzed remote functionalization reactions . This task is difficult because multiple steps and processes are occurring in remote functionalization (namely, the chain walking and functionalization processes), which convolute analysis.…”

Enantioselective Hydroalkenylation and Hydroalkynylation of Alkenes Enabled by a Transient Directing Group

“…[11] In parallel to these advances, various catalytic asymmetric hydroalkynylation methods have been described. [12][13][14][15] Notably, in an elegant series of studies Li has applied a monodentate directing group strategy to achieve rhodium-and iridiumcatalyzed enantioselective hydroalkynation of activated and unactivated alkenes with terminal alkynes. [14] Our group's continued interest in developing a chiral transient directing group approach for regio-and stereoselective alkene functionalization [16][17][18] led us to question whether a complementary approach for asymmetric hydroalkenylation and hydroalkynylation could be developed by employing alkenyl and alkynyl halides in a reductive Heck reaction paradigm (Scheme 1B).…”

“…To reduce this general idea to practice, we selected (Z)-2-(prop-1-en-1-yl)benzaldehyde (1a) as a model substrate (Table 1). In the envisioned design, TDG-mediated migratory insertion would form a new C(sp 3 )-C stereocenter at the homobenzylic position of the arylalkene (the b position using styrene labeling conventions), thereby complementing existing hydroalkenylation [6][7][8]10] and hydroalkynylation [15] methods of arylalkenes (or their derivates) that form the new C(sp 3 )-C bond at the benzylic (α) position due to their distinct mechanisms. Optimization was performed using a combination of one-factor-ata-time and Design of Experiment (DoE).…”

“…Based on the tolerance of this hydroalkenylation protocol for different substitution patterns on the alkenyl bromide coupling partner, we questioned whether an alkynyl bromide would also participate in an analogous reductive coupling. While at first glance this would seem to be a straightforward extension, hydroalkynylation via a Pd-catalyzed reductive Heck process remains unknown to our knowledge, [15] underscoring the challenges of suppressing secondary reactions of the alkyne products among other complicating factors. To our delight, we found that after minor optimization of the conditions, we were able to identify effective conditions in which TIPS-protected alkynyl bromide 4 [27] participated in this TDG/Pd-catalyzed reductive Heck process, enabling access to products 5a, 5c, and 5f in good yield and excellent er.…”