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. 2021 Oct;598(7881):451-456.
doi: 10.1038/s41586-021-03920-6. Epub 2021 Aug 31.

Metallaphotoredox-enabled deoxygenative arylation of alcohols

Zhe Dong  1 , David W C MacMillan  2
Affiliations

Metallaphotoredox-enabled deoxygenative arylation of alcohols

Zhe Dong et al. Nature. 2021 Oct.

Abstract

Metal-catalysed cross-couplings are a mainstay of organic synthesis and are widely used for the formation of C-C bonds, particularly in the production of unsaturated scaffolds1. However, alkyl cross-couplings using native sp3-hybridized functional groups such as alcohols remain relatively underdeveloped2. In particular, a robust and general method for the direct deoxygenative coupling of alcohols would have major implications for the field of organic synthesis. A general method for the direct deoxygenative cross-coupling of free alcohols must overcome several challenges, most notably the in situ cleavage of strong C-O bonds3, but would allow access to the vast collection of commercially available, structurally diverse alcohols as coupling partners4. We report herein a metallaphotoredox-based cross-coupling platform in which free alcohols are activated in situ by N-heterocyclic carbene salts for carbon-carbon bond formation with aryl halide coupling partners. This method is mild, robust, selective and most importantly, capable of accommodating a wide range of primary, secondary and tertiary alcohols as well as pharmaceutically relevant aryl and heteroaryl bromides and chlorides. The power of the transformation has been demonstrated in a number of complex settings, including the late-stage functionalization of Taxol and a modular synthesis of Januvia, an antidiabetic medication. This technology represents a general strategy for the merger of in situ alcohol activation with transition metal catalysis.

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Conflict of interest statement

Competing interests The authors declare no competing interests.

Figures

Extended Data Fig. 1 |
Extended Data Fig. 1 |. Aryl halide scope for deoxygenative arylation.
Both (hetero)aryl bromides and chlorides can be utilized under same reaction conditions. All yields are isolated. Experiments typically run with 1.0 equivalent of aryl halide, 1.7 equivalent of alcohol and 1.6 equivalent of NHC on 0.5 mmol scale. *See Supplementary Information for experimental details.
Fig. 1 |
Fig. 1 |. Direct deoxygenative arylation of alcohols.
a, Alcohols are the most widely available alkyl fragment; however, there is no general strategy for the use of alcohols as C(sp3) fragments in cross-coupling reactions. b, A general strategy for the cross-coupling of alcohols is enabled by the merger of NHC-mediated alcohol activation, photoredox catalysis, and nickel catalysis. c, The success of alcohol deoxygenative cross-coupling relies on the facile NHC-mediated C–O bond homolytic cleavage. This method is amenable to a wide range of primary, secondary and tertiary alcohols. This activation mode can be used for the late-stage deoxygenative arylation of drugs, such as Taxol. NHC, nitrogen-heterocyclic carbene; Ac, acetyl; Bz, benzoyl; Me, methyl; Ph, phenyl; t-Bu, tert-butyl; TBS, tert-butyldimethylsilyl.
Fig. 2 |
Fig. 2 |. Proposed mechanism and nitrogen-heterocyclic carbene evaluation for deoxygenative arylation.
a, The starting alcohol 1 is converted to adduct 3 in the presence of NHC salt 2 and base. The deoxygenative radical 10 is generated from 3 upon sequential electron–proton transfer and followed by facile β-scission, which can be captured by Ni-aryl species 14 to yield the arylated product 16. b, Evaluation of N-heterocyclic carbene salts for deoxygenative arylation. For detailed optimization, see Supplementary Information. c, Stern–Volmer quenching comparison of NHC adduct 3 and other readily oxidizable functional groups. Py•HBF4, pyridinium tetrafluoroborate; Q, quinuclidine; t-BuOMe, methyl tert-butyl ether; DMA, dimethylacetamide; R, 3-tetrahydrofuranyl.
Fig. 3 |
Fig. 3 |. Alcohol scope for deoxygenative arylation.
Primary, secondary and tertiary alcohols can be used as alkyl coupling partners in the arylation. All yields are isolated unless otherwise noted. Experiments typically run with 1.0 equivalent of aryl halide, 1.7 equivalent of alcohol and 1.6 equivalent of NHC salts on 0.5 mmol scale. *See Supplementary Information for experimental details. §Ni(TMHD)2 and methyl 4-bromobenzoate are used as the catalyst and aryl halide coupling partner, respectively. Boc, tert-butyloxycarbonyl; Bn, benzyl; Et, ethyl; PMB, 4-methoxybenzyl; Piv, pivaloyl; Ts, 4-toluenesulfonyl; Ni(TMHD)2, nickel(ii) bis(2,2,6,6-tetramethyl-3,5-heptanedionate).
Fig. 4 |
Fig. 4 |. Chirality transfer from chiral diol and late-stage drug molecule functionalization.
a, Double deoxygenative functionalization of commercially available C2-symmetric diols permits transfer of chirality to bis-arylated products via diastereocontrol. *Benzyl arylate was used instead of nickel catalyst. b, This protocol can also be applied to a modular synthesis of Januvia and its variants, as well as to the late-stage functionalization of pharmaceutical variants, such as Taxol and Simvastatin. All yields are isolated; see Supplementary Information for exact conditions. c, To demonstrate the generality of the deoxygenative arylation, primary and secondary alcohols were evaluated with 18 different complex halides. Among 36 distinct combinations of coupling partners, 32 reactions successfully gave the desired product. Yields were obtained by UPLC analysis; see Supplementary Information for details.
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