Article Cite This: J. Org. Chem. 2018, 83, 578−587
pubs.acs.org/joc
Hydrophosphonodifluoromethylation of Alkenes via Thiyl-Radical/ Photoredox Catalysis Wenhao Huang,† Jingzhi Chen,† Daocheng Hong,‡ Wenxin Chen,† Xu Cheng,*,†,§ Yuxi Tian,*,‡ and Guigen Li† †
Institute of Chemistry and Biomedical Science and ‡Key Laboratory of Mesoscopic Chemistry of MOE, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, China § State Key Laboratory of Elemento-organic Chemistry, Nankai University, Tianjin, China S Supporting Information *
ABSTRACT: Visible-light-induced catalytic hydrophosphonodifluoromethylation of mono- and disubstituted alkenes using bromodifluoromethanephosphonate with a Hantzsch ester as the terminal reductant is reported. The combination of thiyl-radical catalysis with photoredox catalysis is important for achieving good chemoselectivity and high yields.
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INTRODUCTION Hantzsch esters (HEs) have been shown to act as efficient terminal reductants in a number of visible-light-induced reactions. Owing to their unique dihydropyridine structure, HEs can donate an electron in several ways. For example, in photoredox catalysis,1 an HE can transfer an electron to the photocatalyst and become a cationic radical.2 Alternatively, in the absence of a photocatalyst, an HE can absorb visible light, and the resulting excited-state species can then transfer an electron directly to a substrate via a so-called encounter complex.3 In 2016, we reported a thiyl-radical-catalyzed photoreductive reaction employing an HE as a terminal reductant.4 In this reaction, the HE reacts with the thiyl radical by means of a hydrogen atom transfer process and forms a neutral radical, a key intermediate that is reductive enough to initiate an electron transfer process. On the basis of these results, we hypothesized that thiyl-radical catalysis could be linked to transition-metal catalysis via an HE to achieve novel transformation.5 To test this hypothesis, we explored a hydrophosphonodifluoromethylation reaction of alkenes. Although there are several well-documented methods for introducing a difluorophosphonomethyl group at an sp3 carbonincluding nucleophilic addition, transition-metal catalysis, photoredox catalysis, and radical addition (Scheme 1)none of these methods have successfully been used to accomplish hydrophosphonodifluoromethylation. For example, anionic nucleophilic addition requires a strong base or a stoichiometric amount of metal to generate a difluorophosphonomethyl anion, and an electrophilic reagent is necessary.6 For transition-metal catalysis, the transition-metal species must undergo further functionalization after insertion of the M− CF2PO(OEt)2 group into the alkene double bond.7 Use of © 2017 American Chemical Society
the radical-addition procedure usually results in halogen atom transfer radical addition, and therefore, an additional step is necessary to remove the halogen atom.8 In photoredox catalysis, a PC*/PC+ (PC = photocatalyst) pathway (oxidative quenching) frequently leads to oxidation of the radical intermediate.9 In comparison with the many successful examples of hydrotrifluoromethylation reactions,10 there have been only a few reports of hydrophosphonodifluoromethylation reactions; these reactions require a Se/Sn reagent or UV irradiation and are applicable only to pure alkene or enol ether substrates.11 Because many pharmaceutical molecules bear a difluoromethane phosphate group, an efficient catalytic hydrophosphonodifluoromethylation protocol that is compatible with a variety of functionalities is highly desirable.12 Herein, we report that combining a thiyl-radical-catalyzed hydrogen atom transfer of an HE with a PC−/PC* catalytic cycle provides a chemoselective method for the direct hydrophosphonodifluoromethylation of alkenes. The method does not require strongly basic conditions, and direct installation of the hydrogen atom avoids the innate halogen atom transfer radical addition pathway. In addition, the substrate scope of the method shows good potential for use in pharmaceutical contexts.
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RESULTS AND DISCUSSION We chose monosubstituted alkene 1a and diethyl bromodifluoromethanephosphonate 2a as model substrates for the hydrophosphonodifluoromethylation reaction in the presence of HSAcOMe, fac-Ir(ppy)3, Et-HE, and K2CO3 (Table 1). After irradiation with blue LEDs for 48 h at room Received: September 17, 2017 Published: December 20, 2017 578
DOI: 10.1021/acs.joc.7b02354 J. Org. Chem. 2018, 83, 578−587
Article
The Journal of Organic Chemistry Scheme 1. Strategies for Constructing sp3 C−CF2PO(OEt)2 Bonds
temperature, we obtained a 99% relative GC-MS yield (64% isolated yield) of desired product 3a (entry 1). When the catalyst loading was increased from 0.2 to 1 mol %, the yield increased only marginally (entry 2). If fac-Ir(ppy)3 was not present, no product was detected (entry 3). Furthermore, in the absence of HSAcOMe, the relative GC-MS yield of 3a dropped to
