Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Visible-Light-Promoted Redox Neutral γ,γ-Difluoroallylation of Cycloketone Oxime Ethers with Trifluoromethyl Alkenes via C−C and C−F Bond Cleavage Yuwei He,†,‡ Devireddy Anand,† Zhengchang Sun,† and Lei Zhou*,† †
School of Chemistry, Sun Yat-Sen University, 135 Xingang West Road, Guangzhou, 510275, China Key Lab of Functional Molecular Engineering of Guangdong Province, Guangzhou, China
‡
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ABSTRACT: A visible-light-promoted redox neutral γ,γdifluoroallylation of cycloketone oxime ethers with trifluoromethyl alkenes through C−C and C−F bond cleavage has been achieved, which affords various cyano-substituted gemdifluoroalkenes in generally good yields. The reaction provides a facile protocol for forming gem-difluoroalkene functionality and a cyano group while incorporating them into one molecule. The conversion of the resulting cyano-substituted gem-difluoroalkenes to cyclic monofluoroalkenes via a second C−F bond cleavage was also described.
gem-Difluoroalkenes belong to those structurally unique organic compounds which are known as not only a stable bioisostere for the metabolically susceptible carbonyl group in drug research1 but also versatile building blocks for the synthesis of fluorine-containing molecules.2 For instance, they can be readily converted into monofluoroalkenes upon reduction3 or addition of nucleophiles.4 They can undergo hydrogenation to give difluoromethyl groups.5 The electrophilic fluorination of gem-difluoroalkenes with Selectfluor can generate functionalized 2,2,2-trifluoroethyl groups.6 The growing interest in the applications of gem-difluoroalkenes has led to two main strategies for their preparation. The conventional approach relies on the functional group conversion, which consists of difluoroolefination of carbonyl groups2b,c or diazo compounds.7 In a convergent approach, the addition of nucleophiles to trifluoromethyl alkenes followed by β-fluoride elimination in an SN2′ manner allows the formation of gem-difluoroalkenes concomitant by introducing an additional substituent.8 However, the nucleophiles in this strategy are limited to reactive organometallics or carbanions generated from strong basic conditions, and thus suffer from poor functional group tolerance. Recently, Molander9 and our research group10 disclosed a photocatalytic protocol for the synthesis of gem-difluoroalkenes via defluorinative crosscoupling of trifluoromethyl alkenes with various radical precursors. Ni-catalyzed reductive coupling of trifluoromethyl alkenes with electrophiles was developed by Wang11 and Fu.12 One of the key features of photocatalysis or Ni-catalysis is its ability to crossover from a radical to a polar pathway during the overall catalytic process. Since the pioneering work of Zard,13 iminyl radical-triggered C−C bond cleavage of cycloketone oxime derivatives has been established as a straightforward method to access diverse valuable distally functionalized nitriles. Transition metal © XXXX American Chemical Society
catalysis (Ir, Fe, Cu, Ni) and/or heating at high temperature were frequently employed for the generation of cyclic iminyl radicals and their fragmentations.14 Recently, we15a and Xiao15b have independently developed visible-light-induced SET reduction of cycloketone oxime esters to deliver the distal cyano-substituted alkyl radicals.15 However, the exclusive use of reductive conditions limited the types of bond formations. In this context, a new approach for the generation of iminyl radicals based on SET oxidation of carboxylic acid derived oxime ethers has been disclosed by the groups of Studer16 and Leonori,17 respectively. Using this activation mode, remote fluorination, chlorination, azidation, and alkynylation of cycloketone oxime ethers were achieved.18 Herein, we report a visible-light-promoted redox neutral γ,γdifluoroallylation of cycloketone oxime ethers through C−C and C−F bond cleavage, which provides various cyanosubstituted gem-difluoroalkenes under mild conditions (Scheme 1). Although gem-difluoroalkenes and nitriles are two of the most ubiquitous chemical feedstocks in organic synthesis,19 no concise method is available for generating both of them in a single catalytic cycle.20 In addition, the proton Scheme 1. Synthesis of Cyano-Substituted gemDifluoroalkenes and Their Subsequent Conversion to Cyclic Monofluoroalkenes
Received: April 5, 2019
A
DOI: 10.1021/acs.orglett.9b01210 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters adjacent to the cyano group has weak acidity [pKa(MeCN) ≈ 31.3 in DMSO].21 To our knowledge, there is only one report on the reaction of gem-difluoroalkene and α-proton of nitriles, mainly due to the high pKa of simple alkylnitriles.22 As a continuation of our interest in dual C−F bond cleavage of trifluoromethyl alkenes,23a−c the conversion of resulting cyanosubstituted gem-difluoroalkenes to cyclic monofluoroalkenes via a base-mediated intramolecular SNV reaction was also described.24 Initially, the reaction was optimized using α-CF3-p-phenylstyrene 1a and oxime ether 2a as the model substrates with Ir[dF(CF3)ppy]2(dtbbpy)PF6 (Ir-1) as the photocatalyst under the irradiation of a 5 W blue LED. As shown in Table 1, the reaction gave the desired product 3a in 31−72% yields
With the optimized conditions in hand, we next examined the scope of this photocatalytic reaction using cyclobutanone oxime ether 2a and a variety of trifluoromethyl alkenes (Scheme 2). The reaction was found to be not significantly Scheme 2. Reaction Scope of Trifluoromethyl Alkenes 1a
Table 1. Optimization of Reaction Conditionsa,b
entry
photocatalyst
base
yield (%)b
1 2 3 4 5 6 7 8 9c 10c 11c 12c 13 14d
Ir-1 Ir-1 Ir-1 Ir-1 Ir-1 Ir-1 Ir-2 Ir-3 4CzIPN 4DPAIPN TPPBF4 MesAcrClO4 − Ir-1
Li2CO3 Na2CO3 K2CO3 Cs2CO3 LiOH 2,6-lutidine LiOH LiOH LiOH LiOH LiOH LiOH LiOH LiOH
31 72 62 61 76 0 75 3 64 34
