Metallaphotoredox-catalysed sp(3)-sp(3) cross-coupling of carboxylic acids with alkyl halides

Abstract

In the past 50 years, cross-coupling reactions mediated by transition metals have changed the way in which complex organic molecules are synthesized. The predictable and chemoselective nature of these transformations has led to their widespread adoption across many areas of chemical research. However, the construction of a bond between two sp(3)-hybridized carbon atoms, a fundamental unit of organic chemistry, remains an important yet elusive objective for engineering cross-coupling reactions. In comparison to related procedures with sp(2)-hybridized species, the development of methods for sp(3)-sp(3) bond formation via transition metal catalysis has been hampered historically by deleterious side-reactions, such as β-hydride elimination with palladium catalysis or the reluctance of alkyl halides to undergo oxidative addition. To address this issue, nickel-catalysed cross-coupling processes can be used to form sp(3)-sp(3) bonds that utilize organometallic nucleophiles and alkyl electrophiles. In particular, the coupling of alkyl halides with pre-generated organozinc, Grignard and organoborane species has been used to furnish diverse molecular structures. However, the manipulations required to produce these activated structures is inefficient, leading to poor step- and atom-economies. Moreover, the operational difficulties associated with making and using these reactive coupling partners, and preserving them through a synthetic sequence, has hindered their widespread adoption. A generically useful sp(3)-sp(3) coupling technology that uses bench-stable, native organic functional groups, without the need for pre-functionalization or substrate derivatization, would therefore be valuable. Here we demonstrate that the synergistic merger of photoredox and nickel catalysis enables the direct formation of sp(3)-sp(3) bonds using only simple carboxylic acids and alkyl halides as the nucleophilic and electrophilic coupling partners, respectively. This metallaphotoredox protocol is suitable for many primary and secondary carboxylic acids. The merit of this coupling strategy is illustrated by the synthesis of the pharmaceutical tirofiban in four steps from commercially available starting materials.

Figure 1. Carboxylic acids as coupling partners in a metallaphotoredox-mediated process to form sp³–sp³ bonds

The majority of transition metal-catalyzed cross-couplings generally employ at least one sp^2-hydridized coupling partner. The direct utilization of robust, widely available, native functional groups such as carboxylic acids should encourage greater adoption of sp³–sp³ bond forming methods.

Figure 2. Proposed mechanism for the metallaphotoredox-mediated cross-coupling of carboxylic acids to generate sp³–sp³ bonds

The photoredox catalytic cycle commences with excitation of Ir^III 1 to give the excited state 2. Single electron oxidation of the carboxylate anion derived from acid 3 produces the alkyl radical 4 after CO₂-extrusion along with Ir^II 5. Ni⁰ catalyst 6 captures the alkyl radical 4 to form the Ni^I species 7. Ensuing oxidative addition with alkyl halide 8 leads to nickel(III) intermediate 9. Reductive elimination would then liberate the desired product 10 and Ni^I 11. Both catalytic cycles converge to complete a single turnover via a SET event that regenerates the photoredox and nickel catalysts

Figure 3. Carboxylic acid and alkyl halide scope in the dual nickel-photoredox catalyzed sp³–sp³ coupling reaction

A broad array of alkyl halides and carboxylic acids are amenable coupling partners in this transformation. Top, generalized reaction; bottom, substrate scope. Primary and secondary electrophiles were coupled efficiently with proline derivatives. Alternative α-heteroatom substituted carboxylic acids could also be employed to form functionalized amines and ethers. Challenging substrates lacking apparent radical stabilization could also be employed successfully. Isolated yields are reported below each entry. See Supplementary Information for full experimental details. *Reaction run in flow (GC yield), see S.I. ^†Cyclopropylacetic acid was used.

Figure 4. Application of two metallaphotoredox strategies to the synthesis of tirofiban

The cross-coupling of acid 42 and alkyl halide 43 generates a new sp³–sp³ bond and subsequent TBAF deprotection provides alcohol 44. Tirofiban 45 is then synthesized in two further steps in good yield via a Ni-photoredox-mediated etherification reaction and acidic deprotection. ^†34% of bromide starting material recovered.