Photofluorination of Aliphatic C-H Bonds Promoted by the Phthalimide Group Hiromichi Egami,* Shuya Masuda, Yuji Kawato, and Yoshitaka Hamashima* School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan * S Supporting Information ABSTRACT: Aliphatic C-H fluorination of phthalimide derivatives with Selectfluor was investigated under photo- irradiation conditions. The reaction did not require any additive or catalyst and afforded C-H fluorinated products in moderate to good yields. It is likely that the reaction site depends on the C-H bond energy, and this may be the reason for the good to high regioselectivity. T he amino group is found in many molecules, including naturally occurring bioactive compounds, pharmaceutical drugs, and functional materials. A substitution reaction with phthalimide is one of the methods available for the introduction of amino equivalents, as exemplified by the Gabriel reaction 1 and Mitsunobu 2 reaction. Consequently, the phthalimide unit can be found in various synthetic intermediates. Normally it is used as a protecting group, and a deprotection step is necessary at a later stage to provide the corresponding primary amine. In contrast, the function of phthalimide as a photosensitizer has been less well studied. In 1972, Kanaoka reported a photocyclization reaction via C-H abstraction by a photo- excited phthalimide (Scheme 1a). 3 Later, Mariano and Yoon applied the photoexcitation of phthalimide to the generation of azomethine ylides from phthalimide derivatives with a silicon- containing electron donor. 4 These studies led to the develop- ment of various transformations that are initiated by photo- excited phthalimide-mediated C-H abstraction or single electron transfer. 5 The incorporation of fluorine atom(s) is widely used to modify the activity or properties of the parent compounds in pharmaceutical, agrochemical, and materials sciences. 6 There- fore, various fluorination methodologies have been developed. 7 Among them, C-H fluorination is of great interest from the viewpoint of atom and step economy. 8 The classical method- ology is to use molecular fluorine or CF 3 OF under photo- irradiation, 9 and perfluorinated compounds are generally the major products. Recent progress in this area has enabled more selective C-H fluorination of simple benzylic and aliphatic compounds with safer electrophilic fluorine sources in the presence of metal catalysts or organocatalysts. 10,11 Also, a remarkable Norrish-Yang-type fluorination of polycyclic terpenoid derivatives was recently reported by Lectka. 12 We have been working on fluorination and trifluoromethy- lation reactions of C-C multiple bonds, 13 and we have recently focused on direct C-H fluoro-functionalizations. 14 For example, we reported C-H trifluoromethylation via the formation of a photoenol as an active nucleophilic species generated from a 2-methylbenzophenone derivative under photoirradiation conditions. 14b These results prompted us to examine the feasibility of using phthalimide derivatives in photofluorination. In this report, we describe aliphatic C-H photofluorination of phthalimide derivatives, in which the phthalimide group plays a key role as an activating group (Scheme 1b). Although there are several C-H fluorination reactions that are applicable to phthalimide derivatives, they normally need a catalyst 10d,f,i,j Tan reported a C-H fluorination of aliphatic compounds, in which anthraquinone was required as a photosensitizer. 10h In order to optimize the reaction conditions, the reaction was carried out with N-butylphthalimide 1a as a test substrate (Table 1). According to the literature, a suitable wavelength for excitation of phthalimide (n-π*) was expected to be 320-340 nm. 15 To our delight, the reaction in MeCN proceeded Received: January 12, 2018 Scheme 1. Photoexcitation of Phthalimide Letter pubs.acs.org/OrgLett Cite This: Org. Lett. XXXX, XXX, XXX-XXX © XXXX American Chemical Society A DOI: 10.1021/acs.orglett.8b00133 Org. Lett. XXXX, XXX, XXX-XXX