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. 2023 May 24;145(20):10930-10937.
doi: 10.1021/jacs.2c11563. Epub 2023 May 15.

Formal Cross-Coupling of Amines and Carboxylic Acids to Form sp3-sp2 Carbon-Carbon Bonds

James L Douthwaite  1 , Ruheng Zhao  1 , Eunjae Shim  2 , Babak Mahjour  1 , Paul M Zimmerman  2 , Tim Cernak  1   2
Affiliations

Formal Cross-Coupling of Amines and Carboxylic Acids to Form sp3-sp2 Carbon-Carbon Bonds

James L Douthwaite et al. J Am Chem Soc. .

Abstract

Amines and carboxylic acids are abundant synthetic building blocks that are classically united to form an amide bond. To access new pockets of chemical space, we are interested in the development of amine-acid coupling reactions that complement the amide coupling. In particular, the formation of carbon-carbon bonds by formal deamination and decarboxylation would be an impactful addition to the synthesis toolbox. Here, we report a formal cross-coupling of alkyl amines and aryl carboxylic acids to form C(sp3)-C(sp2) bonds following preactivation of the amine-acid building blocks as a pyridinium salt and N-acyl-glutarimide, respectively. Under nickel-catalyzed reductive cross-coupling conditions, a diversity of simple and complex substrates are united in good to excellent yield, and numerous pharmaceuticals are successfully diversified. High-throughput experimentation was leveraged in the development of the reaction and the discovery of performance-enhancing additives such as phthalimide, RuCl3, and GaCl3. Mechanistic investigations suggest phthalimide may play a role in stabilizing productive Ni complexes rather than being involved in oxidative addition of the N-acyl-imide and that RuCl3 supports the decarbonylation event, thereby improving reaction selectivity.

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Conflict of interest statement

The authors declare the following competing financial interest(s): The Cernak Lab has received research funding or in-kind donations from MilliporeSigma, Relay Therapeutics, Janssen Therapeutics, SPT Labtech, Entos, Inc. and Merck & Co., Inc. T.C. holds equity in Scorpion Therapeutics and is a co-Founder and equity holder of Entos, Inc.

Figures

Figure 1
Figure 1
(A) Cross-coupling of amines and carboxylic acids to form C(sp3)–C(sp2) bonds as a complement to amide coupling. (B) Substructure search of 320 possible products from amine–acid coupling in the DrugBank database. (C) Analysis of building block availability from MilliporeSigma. Unions represent exact substructures differing only by the indicated functionality.
Figure 2
Figure 2
(A) HTE optimization on 10 μmol scale in 24- and 96-reaction arrays. Assay yields were determined by UPLC-MS. Selected conditions were repeated on the 0.25 mmol scale and analyzed by 1H NMR with an internal standard. Isolated yield in parentheses. (B) Key compounds.
Figure 3
Figure 3
Substrate scope of C(sp3)–C(sp2) coupling of N-acyl-glutarimides with primary alkylpyridinium salts on 0.10–0.25 mmol scale. Isolated yields are shown.
Figure 4
Figure 4
(A) Effect of RuCl3 on selectivity. Isolated yield on 0.25 mmol shown. Pie charts determined from 1H NMR analysis of crude reaction with reference to an internal standard. (B) Effect of RuCl3 in the absence of NiBr2·DME. TPP = triphenylpyridinium. (C) Coupling of 1 and 2 in the presence of ketone 37 and RuCl3. aNot detected by UPLC-MS. bYield from 1H NMR.
Figure 5
Figure 5
Substrate scope of C(sp3)–C(sp2) coupling of N-acyl-glutarimides with secondary and benzyl alkylpyridinium salts on 0.25 mmol scale. Isolated yields are shown.
Figure 6
Figure 6
(A) Replacement of 1 with N-acyl phthalimide 45, 1H NMR yields shown. (B) DFT comparison of oxidative addition of 1 and 45. (C) Proposed catalytic cycle.
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References

    1. Haas D.; Hammann J. M.; Greiner R.; Knochel P. Recent Developments in Negishi Cross-Coupling Reactions. ACS Catal. 2016, 6 (3), 1540–1552. 10.1021/acscatal.5b02718. - DOI
    1. Frisch A. C.; Shaikh N.; Zapf A.; Beller M. Palladium-Catalyzed Coupling of Alkyl Chlorides and Grignard Reagents. Angew. Chem., Int. Ed. 2002, 41 (21), 4056–4059. 10.1002/1521-3773(20021104)41:21<4056::AID-ANIE4056>3.0.CO;2-8. - DOI - PubMed
    1. Cordovilla C.; Bartolomé C.; Martínez-Ilarduya J. M.; Espinet P. The Stille Reaction, 38 Years Later. ACS Catalysis. 2015, 5, 3040–3053. 10.1021/acscatal.5b00448. - DOI
    1. Han C.; Zhang Z.; Xu S.; Wang K.; Chen K.; Zhao J. Palladium-Catalyzed Hiyama Coupling of Benzylic Ammonium Salts via C-N Bond Cleavage. J. Org. Chem. 2019, 84 (24), 16308–16313. 10.1021/acs.joc.9b02554. - DOI - PubMed
    1. Shimazumi R.; Tanimoto R.; Kodama T.; Tobisu M. Palladium-Catalyzed Unimolecular Fragment Coupling of N-Allylamides via Elimination of Isocyanate. J. Am. Chem. Soc. 2022, 144 (24), 11033–11043. 10.1021/jacs.2c04527. - DOI - PubMed