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. 2022 Apr 13;144(14):6185-6192.
doi: 10.1021/jacs.2c02062. Epub 2022 Mar 30.

Nontraditional Fragment Couplings of Alcohols and Carboxylic Acids: C(sp3)-C(sp3) Cross-Coupling via Radical Sorting

Holt A Sakai  1 , David W C MacMillan  1
Affiliations

Nontraditional Fragment Couplings of Alcohols and Carboxylic Acids: C(sp3)-C(sp3) Cross-Coupling via Radical Sorting

Holt A Sakai et al. J Am Chem Soc. .

Abstract

Alcohols and carboxylic acids are among the most commercially abundant, synthetically versatile, and operationally convenient functional groups in organic chemistry. Under visible light photoredox catalysis, these native synthetic handles readily undergo radical activation, and the resulting open-shell intermediates can subsequently participate in transition metal catalysis. In this report, we describe the C(sp3)-C(sp3) cross-coupling of alcohols and carboxylic acids through the dual combination of N-heterocyclic carbene (NHC)-mediated deoxygenation and hypervalent iodine-mediated decarboxylation. This mild and practical Ni-catalyzed radical-coupling protocol was employed to prepare a wide array of alkyl-alkyl cross-coupled products, including highly congested quaternary carbon centers from the corresponding tertiary alcohols or tertiary carboxylic acids. We demonstrate the synthetic applications of this methodology to alcohol C1-alkylation and formal homologation, as well as to the late-stage functionalization of drugs, natural products, and biomolecules.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1.
Figure 1.
Cross-coupling of alcohols and carboxylic acids.
Figure 2.
Figure 2.
Proposed reaction design.
See this image and copyright information in PMC

References

    1. Ertl P An Algorithm to Identify Functional Groups in Organic Molecules. J. Cheminform 2017, 9, 1–7. - PMC - PubMed
    2. Ertl P; S T A Systematic Cheminformatics Analysis of Functional Groups Occurring in Natural Products. J. Nat. Prod 2019, 82, 1258–1263. - PubMed
    3. Henkel T; Brunne RM; Müller H; Reichel F Statistical Investigation into the Structural Complementarity of Natural Products and Synthetic Compounds. Angew. Chem., Int. Ed 1999, 38, 643–647. - PubMed
    1. Reaxys search from January 2022 of commercially available alkyl fragments: alcohols (177,700), carboxylic acids (98,451), alkyl chlorides (54,009), alkyl bromides (26,966), alkyl iodides (3,232), alkyl boronates/zincates/Grignards/lithiums (1,297).
    1. Esterification is estimated to account for ~10% of all reactions in medicinal chemistry.
    2. Brown DG; Boström J Analysis of Past and Present Synthetic Methodologies on Medicinal Chemistry: Where Have All the New Reactions Gone? J. Med. Chem 2016, 59, 4443–4458. - PubMed
    3. Fischer E; Speier A Darstellung der Ester. Chem. Ber 1895, 28, 3252–3258.
    1. Choi J; Fu GC Transition Metal–Catalyzed Alkyl-Alkyl Bond Formation: Another Dimension in Cross-Coupling Chemistry. Science 2017, 356, eaaf7230. - PMC - PubMed
    1. Zuo Z; Ahneman DT; Chu L; Terrett JA; Doyle AG; MacMillan DWC Merging Photoredox with Nickel Catalysis: Coupling of α-Carboxyl sp3-Carbons with Aryl Halides. Science 2014, 345, 437–440. - PMC - PubMed
    2. Dong Z; MacMillan DWC Metallaphotoredox-Enabled Deoxygenative Arylation of Alcohols. Nature 2021, 598, 451–456. - PMC - PubMed

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