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. 2021 Aug 9;60(33):17925-17931.
doi: 10.1002/anie.202105354. Epub 2021 Jul 14.

Light-Driven Carbene Catalysis for the Synthesis of Aliphatic and α-Amino Ketones

Anna V Bay  1 , Keegan P Fitzpatrick  1 , Gisela A González-Montiel  2 , Abdikani Omar Farah  2 , Paul Ha-Yeon Cheong  2 , Karl A Scheidt  1
Affiliations

Light-Driven Carbene Catalysis for the Synthesis of Aliphatic and α-Amino Ketones

Anna V Bay et al. Angew Chem Int Ed Engl. .

Abstract

Single-electron N-heterocyclic carbene (NHC) catalysis has gained attention recently for the synthesis of C-C bonds. Guided by density functional theory and mechanistic analyses, we report the light-driven synthesis of aliphatic and α-amino ketones using single-electron NHC operators. Computational and experimental results reveal that the reactivity of the key radical intermediate is substrate-dependent and can be modulated through steric and electronic parameters of the NHC. Catalyst potential is harnessed in the visible-light driven generation of an acyl azolium radical species that undergoes selective coupling with various radical partners to afford diverse ketone products. This methodology is showcased in the direct late-stage functionalization of amino acids and pharmaceutical compounds, highlighting the utility of single-electron NHC operators.

Keywords: carbene; catalysis; density functional theory; late-stage functionalization; photochemistry.

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Figures

Figure 1.
Figure 1.
(A) Selected examples of ketones in pharmaceutically relevant compounds. (B) Standard approaches for ketone synthesis. (C) Acyl azolium radicals for the construction of aryl, alkyl, and α-amino ketones; ORP = oxidatively generated radical precursor, CDI = carbonyldiimidazole.
Figure 2.
Figure 2.
(A) Radical coupling accessibility model for aliphatic acyl azoliums with spin density distributions of optimized aliphatic acyl azolium structures (R = CH2Ph). (B) Proposed mechanism for the combined NHC/photoredox-catalyzed construction of aliphatic and α-amino ketones. Reported energies are for Az-B in kcal/mol.
Figure 3.
Figure 3.
Computed potential energy surfaces for benzyl radical coordination to C1 or C2 of the aliphatic acyl azolium radical (III) with Az-A or Az-B.
See this image and copyright information in PMC

References

    1. Chen KK, Ann. N.Y. Acad. Sci 1948, 51, 83–97; - PubMed
    2. Boyle EA, Freemanm PC, Mangan FR, Thomson MJ, J. Pharm. Pharmacol 1982, 34, 562–569; - PubMed
    3. Tanaka T, Kawase M, Tani S, Biorg. Med. Chem. 2004, 12, 501–505; - PubMed
    4. Redelinghuys P, Nchinda AT, Chibale K, Sturrock ED, Biol. Chem 2006, 387, 461–466; - PubMed
    5. Riley AB, Tafreshi MJ, Haber SL, Am. J. Health-Syst. Pharm 2008, 65, 1019–1028; - PubMed
    6. Hoyos P, Sinisterra J-V, Molinari F, Alcántara AR, Domínguez de María P, Acc. Chem. Res 2010, 43, 288–299; - PubMed
    7. Liu Y, Han S-J, Liu W-B, Stoltz BM, Acc. Chem. Res 2015, 48, 740–751; - PMC - PubMed
    8. Allen LAT, Raclea R-C, Natho P, Parsons PJ, Org. Biomol. Chem 2021, 19, 498–513. - PubMed
    1. Milstein D, Stille JK, J. Am. Chem. Soc 1978, 100, 3636–3638;
    2. Richardson SK, in General and Synthetic Methods: Volume 14, Vol. 14 (Ed.: Pattenden G), The Royal Society of Chemistry, 1992, pp. 26–62;
    3. Dieter RK, Tetrahedron 1999, 55, 4177–4236;
    4. Zhou F, Li C-J, Nat. Commun 2014, 5, 4254; - PubMed
    5. Miles DH, Guasch J, Toste FD, J. Am. Chem. Soc 2015, 137, 7632–7635; - PMC - PubMed
    6. Zhang M, Xie J, Zhu C, Nat. Commun 2018, 9, 3517; - PMC - PubMed
    7. Ruzi R, Liu K, Zhu C, Xie J, Nat. Commun 2020, 11, 3312. - PMC - PubMed
    1. Grignard V, Hebd CR. Séances. Acad. Sci 1900, 130, 1322– 1325;
    2. Nahm S, Weinreb SM, Tetrahedron Lett. 1981, 22, 3815–3818;
    3. Alonso F, Lorenzo E, Yus M, J. Org. Chem 1996, 61, 6058–6059;
    4. Knochel P, Dohle W, Gommermann N, Kneisel FF, Kopp F, Korn T, Sapountzis I, Vu VA, Angew. Chem. Int. Ed 2003, 42, 4302–4320; - PubMed
    5. Kagan HB, Angew. Chem. Int. Ed 2012, 51, 7376–7382; - PubMed
    6. Colas K, dos Santos ACVD, Mendoza A, Org. Lett 2019, 21, 7908–7913. - PubMed
    1. Rueping M, Nachtsheim BJ, Beilstein J Org. Chem 2010, 6, 6; - PMC - PubMed
    2. Heravi MM, Zadsirjan V, Saedi P, Momeni T, RSC Adv. 2018, 8, 40061–40163. - PMC - PubMed
    1. Yin H, Zhao C, You H, Lin K, Gong H, Chem. Commun 2012, 48, 7034–7036; - PubMed
    2. Cherney AH, Kadunce NT, Reisman SE, J. Am. Chem. Soc 2013, 135, 7442–7445; - PubMed
    3. Buchspies J, Szostak M, Catalysts 2019, 9, 53.

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