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Phototriggered Ketone Formation from an Aminocyclopropenone and a Carboxylic Acid Kenji Mishiro, Yuki Yushima, and Munetaka Kunishima J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b02250 • Publication Date (Web): 27 Sep 2018 Downloaded from http://pubs.acs.org on September 27, 2018
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The Journal of Organic Chemistry
Phototriggered Ketone Formation from an Aminocyclopropenone and a Carboxylic Acid Kenji Mishiro*†, Yuki Yushima‡ and Munetaka Kunishima*‡ †
Institute for Frontier Science Initiative, Kanazawa University, Kakuma-machi, Kanazawa 920-1192 Japan Faculty of Pharmaceutical Sciences, Institute of Medical, Pharmaceutical, and Health Sciences, Kanazawa University, Kakuma-machi, Kanazawa 920-1192 Japan Supporting Information Placeholder ‡
ABSTRACT: A novel phototriggered functionalization reaction of a carboxylic acid using an aminocyclopropenone has been developed. Irradiation of an aminocyclopropenone and carboxylic acid mixture generated ketones that possessed substituents from both the carboxylic acid and the aminocyclopropenone. This reaction occurred through two distinct phototriggered processes. Using this reaction, substituents in an aminocyclopropenone can be connected with a carboxylic acid containing molecule.
Phototriggered bond formation reactions have attracted considerable attention, especially in the fields of polymer science and biological research. 1 , 2 This technique has been used to selectively construct stable bonds at the precise location where a photoreactive group and the target molecule coexist. To date, various photoreactive groups, such as benzophenone,3 diazirine,4 and azide,5 have been used for the phototriggered conjugations. These reaction precursors are photoexited and generate biradical, carbene, or nitrene as active species, respectively. These species are so reactive that they can react with inert C-H bonds, leading to effective bond formation with poorly reactive targets, while undesired bond formation or quenching of the active species could be occasionally problematic. Recently a photoaffinity labeling method of a carboxylic acid using a tetrazole derivative was reported by Yao et al.6 In this method, the tetrazole was used as a photolabile precursor of a nitrile imine, which selectively reacts with a carboxylic acid to form a stable acyl hydrazide. Because of the relatively high population of carboxylic acids on the surface area of proteins, a carboxylic acid is a promising target for a ligand directed specific functionalization method 7 . In fact, the phototriggered functionalization of a carboxylic acid using a tetrazole derivative could yield superior results compared to classical photoaffinity labeling methods.6b, 6c In addition to biological studies, the tetrazole-based phototriggered conjugation reaction has been applied to the modification of polymers.8 As demonstrated in these examples, phototriggered functionalization methods targeting carboxylic acids could be useful tools for advancing biology and polymer science. Photodecarbonylation of a cyclopropenone is a useful reaction for generating a reactive alkyne derivative in situ, as demonstrated by Popik et al.9 Recently, we reported a phototriggered dehydration condensation of a carboxylic acid and an amine using an aminocyclopropenone (Scheme 1). 10 In this reaction, photodecarbonylation of aminocyclopropenone 1 forms highly reactive ynamine 611 followed by a formation of acyloxyenamine 7 from ynamine 6 and carboxylic acid 2. Consequent aminolysis of 7 with 3 yields amide 4 and hydrated ynamine 5.12 In our original publication, unidentified side products were found when irradiation was performed under
intense light conditions; thus, they were likely produced via a photochemically induced side reaction. Here, we report the detailed study of the side reaction and a potential application of it toward the functionalization of carboxylic acids.
Scheme 1. Mechanism of the phototriggered dehydration condensation using an aminocyclopropenone. In order to identify the structures of the side products from the phototriggered dehydration condensation, the reaction conditions were optimized to increase the side product yield. Aminocyclopropenone 1a, carboxylic acid 2a, and amine 3a were used as model substrates. A mixture of 1a, 2a, and 3a were irradiated with UV light until 1a was completely consumed; thereafter, the products were analyzed after an aqueous work up (Table 1). Under the optimal conditions for the phototriggered dehydration condensation (condition A: 6W handheld UVB lamp), 1a was completely consumed after 3 h, and amide 4aa was obtained in 88% yield with a small amount of the side products (entry 1). In contrast, under intense light condition (condition B: 80 W medium pressure Hg lamp with
