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. 2022 Jan 27:9:822625.
doi: 10.3389/fchem.2021.822625. eCollection 2021.

Synthesis of N-Heteroarenemethyl Esters via C-C Bond Cleavage of Acyl Cyanides Under Transition Metal-Free Conditions

Miao Lai  1 , Fangyao Su  1 , Jingyi Hu  1 , Mengzhuo Wang  1 , Mingqin Zhao  1 , Ganlin Zhang  1
Affiliations

Synthesis of N-Heteroarenemethyl Esters via C-C Bond Cleavage of Acyl Cyanides Under Transition Metal-Free Conditions

Miao Lai et al. Front Chem. .

Abstract

A practical method to synthesize N-heteroaryl esters from N-heteroaryl methanols with acyl cyanides via C-C bond cleavage without using any transition metal is demonstrated here. The use of Na2CO3/15-crown-5 couple enables access to a series of N-heteroaryl esters in high efficiency. This protocol is operationally simple and highly environmentally benign producing only cyanides as byproducts.

Keywords: C-C bond cleavage; N-heteroaryl esters; N-heteroaryl methanols; acyl cyanides; transition-metal free synthesis.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

SCHEME 1
SCHEME 1
Strategies toward the synthesis of esterification products.
SCHEME 2
SCHEME 2
Substrate scope of heteroaryl methanols for the acylation reactions. a,b Reaction conditions: a heteroaryl methanols 1 (0.5 mmol), benzoylacetonitrile 2 (0.2 mmol), Na2CO3 (0.2 mmol), 15-crown-5 (0.2 mmol), and toluene (1 ml) at 140°C for 24 h, under N2 atmosphere. b Isolated yields.
SCHEME 3
SCHEME 3
Substrate scope of benzoylacetonitriles for the acylation reactions. a,bReaction conditions: a heteroaryl methanols 1 (0.5 mmol), benzoylacetonitrile derivatives 2 (0.2 mmol), Na2CO3 (0.2 mmol), 15-crown-5 (0.2 mmol), and toluene (1 ml) at 140°C for 24 h, under N2 atmosphere. b Isolated yields.
SCHEME 4
SCHEME 4
Substrate scope of benzoyl cyanides for the acylation reactions. a,b Reaction conditions: a heteroaryl methanols 1 (0.5 mmol), benzoyl cyanides 2 (0.2 mmol), Na2CO3 (0.2 mmol), 15-crown-5 (0.2 mmol), and toluene (1 ml) at 140°C for 24 h, under N2 atmosphere. b Isolated yields.
SCHEME 5
SCHEME 5
Gram-scale reaction of 1a and 2k.
SCHEME 6
SCHEME 6
Mechanistic experiments.
SCHEME 7
SCHEME 7
Plausible reaction mechanism.
See this image and copyright information in PMC

References

    1. Akhlaghinia B., Safaei E., Larki P. (2010). Chemoselective Protocol for O-Acylation with a New Catalyst. Trends Org. Chem. 14, 93–106. 10.1039/toc100814a - DOI
    1. Armani E., Amari G., Rizzi A., Fanti R. D., Ghidini E., Capaldi C., et al. (2014). Novel Class of Benzoic Acid Ester Derivatives as Potent PDE4 Inhibitors for Inhaled Administration in the Treatment of Respiratory Diseases. J. Med. Chem. 57, 793–816. 10.1021/jm401549m - DOI - PubMed
    1. Arzumanyan A. V. (2017). Iron-catalyzed C C Bond Activation/C O Bond Formation: Direct Conversion of Ketones to Esters. Tetrahedron Lett. 58, 4667–4671. 10.1016/j.tetlet.2017.10.068 - DOI
    1. Balalaie S., Mahdidoust M., Eshaghi-Najafabadi R. (2008). ChemInform Abstract: 2-1h-Benzotriazole-1-Yl-1,1,3,3-Tetramethyluronium Tetrafluoro Borate (TBTU) as an Efficient Coupling Reagent for the Esterification of Carboxylic Acids with Alcohols and Phenols at Room Temperature. ChemInform 39, 1141–1144. 10.1002/chin.200839075 - DOI
    1. Bayout I., Bouzemi N., Guo N., Mao X., Serra S., Riva S., et al. (2020). Natural Flavor Ester Synthesis Catalyzed by Lipases. Flavour Fragr J. 35, 209–218. 10.1002/ffj.3554 - DOI

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