Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Regioselective and Stereoselective Difluoromethylation of Enamides with Difluoromethyltriphenylphosphonium Bromide via Photoredox Catalysis Tong-Hao Zhu,†,§ Ze-Yu Zhang,† Ji-Yu Tao,† Kai Zhao,*,† and Teck-Peng Loh*,†,‡
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†
Institute of Advanced Synthesis, School of Chemistry and Molecular Engineering, Jiangsu National Synergetic Innovation Center for Advanced Materials, Nanjing Tech University, Nanjing 211816, China ‡ Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University, Singapore 637371, Singapore § Institute of Advanced Studies, Taizhou University, 1139 Shifu Avenue, Taizhou 318000, China S Supporting Information *
ABSTRACT: A regioselective and stereoselective difluoromethylation of enamides with bench-stable and easily accessible difluoromethyltriphenylphosphonium bromide is described. A broad array of synthetically important and geometrically defined β-difluoromethylated enamides bearing various functional groups are obtained with up to 91% yield.
O
efficacious and attractive tools for difluoromethylation reactions. Enamides are particularly attractive scaffolds being endowed with a delicate balance of reactivity and stability, allowing them to serve as essential synthons for dozens of biologically and pharmaceutically important molecules.14 Consequently, we have witnessed a blooming progress on the stereo- and regioselective functionalization of enamides, especially on their C(sp2)−H bond at C-3 position, giving rise to a diverse range of β-functionalized enamides bearing aryl,15 alkene,16 alkyne,17 alkyl,18 carbonyl,19 arylsulfonyl,20 and many other useful functional groups.21 In particular, the deployment of fluorine-containing functionalities into enamides proved to be a topic of interest during the pursuit of new active drug candidates. In this aspect, our group previously demonstrated a copper-catalyzed trifluoromethylation of enamides, delivering β-trifluoromethylated enamides stereoselectively (Scheme 1a).22a A similar iron-catalyzed version was elegantly disclosed by Gillaizeau and co-workers (Scheme 1b).22b However, to the best of our knowledge, the regioselective and stereoselective difluoromethylation reactions of enamides has remained an unexplored area. Herein, we demonstrate a practical and efficient difluoromethylation of enamides with bromodifluoromethylphosphonium bromide, affording a broad range of synthetically and pharmaceutically important β-difluoromethy-
rganofluorine compounds play a crucial and prominent role as privileged scaffolds in the development of manifold agrochemicals and pharmaceuticals, because of their unique biological, physical, and chemical properties, with regard to enhancing the metabolic stability and lipophilicity.1 Particularly, a difluoromethyl (CF2H) moiety proved to be an essential donor in lipophilic hydrogen bonding, allowing it to serve as a bioisosteres of thiol and alcohols.2 Therefore, a plethora of novel synthetic methods and reagents for the incorporation of a difluoromethyl group into organic molecules via nucleophilic,3 electrophilic,4 and radical pathways5 were developed. In the past few decades, myriad efforts have been focused on the difluoromethylation of arenes and heteroarenes, as evidenced by the pioneering work established by research groups led by Hartwig,3a Baran,5a,b Mikami,6 Zhang,7 and Shen.3d,e Until recently, the regioselective and stereoselective difluoromethylation of alkenes has been attracting increased attention in the chemical community with significant breakthroughs attained by the groups led by Hu,8 Dolbier,5e−i Koike and Akita,9 and Tan.10 Nevertheless, the difluoromethylating agents used in the above cases, such as HCF2SO2Cl, Zn(SO2CF2H)2, HCF2SO2Na, and N-tosyl-S-difluoromethylS-phenylsulfoximine, required nonreadily available starting materials and multiple preparation steps. Thus, the exploration of practical, inexpensive, and simply handled difluoromethylating agents is of particular interest. In this context, with several seminal achievements by the Qing,11 Studer,12 and Xiao13 groups, the bench-stable and easily accessible difluoromethyltriphenylphosphonium bromide or triflate have emerged as © XXXX American Chemical Society
Received: July 8, 2019
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DOI: 10.1021/acs.orglett.9b02361 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters
1−3). The optimal loading of fac-Ir(ppy)3 was 2.5 mol %, in view of the cost and efficiency (Table 1, entries 4−6). By judicious screening of various solvent, N,N-dimethylformamide (DMF) stood out as the solvent of choice to forge 3a in 81% yield (Table 1, entry 14). Notably, the control experiments in the absence of fac-Ir(ppy)3 or illumination failed to furnish 3a, implying their essential roles in this reaction. With the optimal reaction conditions in hand, we commenced to explore the substrate generality, with respect to a broad range of enamides. As shown in Scheme 2, substrate
Scheme 1. Trifluoromethylation and Difluoromethylation of Enamides
Scheme 2. Substrate Scope of Enamidesa
lated enamides in a regioselective and stereoselective manner (Scheme 1c). At the outset of our investigation, the model reaction of enamide 1a with difluoromethyltriphenylphosphonium bromide 2 was performed for the screening of optimal conditions. Gratifyingly, the β-difluoromethylated enamide 3a was attained in 53% yield by using 5 mol % of fac-Ir(ppy)3 as a photocatalyst and tetrahydrofuran (THF) as the solvent (Table 1, entry 4). Other photocatalyst including Ru(bpy)3Cl2·6H2O, Eosin Y, Mes-AcrClO4 proved to be noneffective to promote the transformation (Table 1, entries Table 1. Optimization of Reaction Conditionsa
entry
photocatalyst (mol %)
solvent
yieldb (%)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18c
Ru(bpy)3Cl2·6H2O (5) Eosin Y (5) Mes-AcrClO4 (5) fac-Ir(ppy)3 (5) fac-Ir(ppy)3 (2.5) fac-Ir(ppy)3 (1) fac-Ir(ppy)3 (2.5) fac-Ir(ppy)3 (2.5) fac-Ir(ppy)3 (2.5) fac-Ir(ppy)3 (2.5) fac-Ir(ppy)3 (2.5) fac-Ir(ppy)3 (2.5) fac-Ir(ppy)3 (2.5) fac-Ir(ppy)3 (2.5) fac-Ir(ppy)3 (2.5) fac-Ir(ppy)3 (2.5) − fac-Ir(ppy)3 (2.5)
THF THF THF THF THF THF 1,4-dioxane DCE toluene MeCN EtOAc DMSO HMPA DMF DMA NMP DMF DMF
