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11 Nickel in Photocatalysis

DOI: 10.1055/sos-SD-229-00192

Kelly, C. B.; Matsui, J. K.; Phelan, J. P.; Gutiérrez Bonet, Á.; Lang, S. B.; Molander, G. A.Science of Synthesis: Photocatalysis in Organic Synthesis, (20181339.

General Introduction

The tremendous contribution of metal-catalyzed cross coupling [C(sp2)–C(sp2), C(sp)–C(sp2), etc.] to charting new chemistry territory is virtually unparalleled. Such processes have granted access to a multitude of novel compounds and enabled construction of several “blockbuster” pharmacons. However, notable gaps exist in current cross-coupling protocols for accessing the three-dimensional space often required for successful drug candidates.[‌1‌] The stark difference in the structure of medicinal compounds is striking when comparing synthetic versus naturally occurring compounds. Scheme 1 shows the structures of the synthetic anti-cancer agent imatinib (Gleevec; Novartis) and antibiotic ciprofloxacin (Ciprobay; Bayer) along with the naturally occurring anti-cancer agent taxol (Paclitaxel; Bristol-Myers Squibb) and antibiotic erythromycin (Ilosone; Eli Lilly).

Scheme 1 Representative Comparison of Synthetic (top) and Natural (bottom) Medicinal Compounds

Rationalizations for the enhanced success of compounds with a higher fraction of sp3-hybridized centers range from greater bioavailability via better solubility to improved enzyme–substrate selectivity.[‌2‌] Unfortunately, process and medicinal chemists have limited options when trying to access the chemistry terrain with a higher fraction of sp3-hybridized centers and greater chiral carbon counts.[‌3‌] The underlying challenge in C(sp2)–C(sp3) cross coupling from stable, storable, functional-group-tolerant organometallic precursors is to overcome the often enthalpically demanding transmetalation step.[‌4‌] Hence, processes involving Suzuki- or Hiyama-like sp3-hybridized organometallics are predisposed to difficulty, if not complete failure. Alternatively, Negishi or Kumada-type couplings can be employed, but at the expense of safety and broad functional-group tolerance because of the reactive nature of the organometallic nucleophile.[‌5‌]

As a general resolution to this mechanistic impediment, an odd-electron activation mode was considered (Scheme 2, route b), wherein a net oxidation of a radical precursor would generate an alkyl radical to engage a transition-metal cross-coupling catalyst complex in what amounts to a “single-electron transmetalation”.[‌6‌] Reduction of this complex furnishes the same intermediate as in a traditional two-electron transmetalation (route a), but with a much lower energy of activation.

Scheme 2 Comparisons of Transmetalation Paradigms[‌6‌]

This single-electron transmetalation paradigm was realized via the concerted action of a nickel complex and a visible-light-activated photocatalyst. By engaging C(sp3)-hybridized radicals generated by photoredox-mediated single-electron-transfer (SET) events with transition-metal catalysts via facile radical metalation, C(sp3)C(sp2) bonds can be forged under mild reaction conditions.[‌7‌,‌8‌] Utilization of nickel/photoredox dual catalysis has resulted in numerous methods for the installation of various fragments onto aryl electrophiles (aryl and alkenyl halides and trifluoromethanesulfonates) and has been extended to C(sp2)Y bond construction (Y = N, O, S, and P).[‌9‌] To date, several classes of C(sp3) radical precursors have been incorporated into this reaction class, including potassium alkyltrifluoroborates (R1BF3K), carboxylic acids, ammonium alkylbis(catecholato)silicates, 4-alkyl-1,4-dihydropyridines (DHPs), and even activated CH bonds.[‌10‌]

Scheme 3 General Mechanism of Nickel/Photoredox Dual Catalysis

The current working hypothesis for the mechanism of nickel/photoredox catalysis is presented in Scheme 3 and is largely based on computationally derived data as well as electrochemical measurements.[‌11‌] The process begins by oxidation of an appropriate radical precursor 1 by the excited state of a photocatalyst (PC) [SET oxidation propensity C(sp3) > C(sp2) > C(sp); transmetalation propensity (organoboron) C(sp) > C(sp2) > C(sp3); E1/2 range for radical precursors 0.4–1.6 V vs SCE]. The resulting radical can either be funneled directly into the nickel cycle or undergo hydrogen-atom transfer (HAT) with a reactive CH bond, furnishing a new radical. Subsequent metalation of the radical generated by either process with a nickel(0) complex generates an alkylnickel(I) species 2. Next, this alkylnickel(I) species reacts with organic electrophiles (aryl/alkenyl halides and pseudohalides, or even alkyl halides) via oxidative addition, giving a high-valent nickel(III) species 3. From here, reductive elimination forges a CY bond and generates a nickel(I)X species 4. Reduction of this nickel(I) species by the reduced state of the photocatalyst returns the nickel catalyst back to its initial nickel(0) oxidation state, turning over both catalytic cycles simultaneously.

The aim of this section within Photocatalysis in Organic Synthesis is to detail the state of the art of nickel/photoredox dual catalysis. Specifically, the subject matter will be broken down by the structure of the radical precursor. Within those sections, the use of various electrophiles will be discussed as applicable. Additionally, processes for forging CY bonds will be discussed. The preparation and use of silicates in photocatalysis is discussed in further detail in Section 15 of this volume.

SAFETY: Virtually all the reagents described herein do not require any special handling techniques. However, direct eye contact should be avoided with the LEDs used for visible-light irradiation. In many cases, blue LEDs are used and can be efficiently filtered using commercially available orange-tinted safety glasses.