Electroreductive Cross‐Coupling of Trifluoromethyl Alkenes and Redox Active Esters for the Synthesis of Gem‐Difluoroalkenes

Abstract

An electroreductive access to gem-difluoroalkenes has been developed through the decarboxylative/defluorinative coupling of N-hydroxyphtalimides esters and αtrifluoromethyl alkenes. The electrolysis is performed under very simple reaction conditions in an undivided cell using cheap carbon graphite electrodes. This metal-free transformation features broad scope with good to excellent yields. Tertiary, secondary as well as primary alkyl radicals could be easily introduced. α-aminoacids L-aspartic and Lglutamic acid-derived redox active esters were good reactive partners furnishing potentially relevant gemdifluoroalkenes. In addition, it has been demonstrated that our electrosynthetic approach toward the synthesis of gemdifluoroalkenes could use an easily prepared Kratitsky salt as alkyl radical precursor via a deaminative/defluorinative carbofunctionalization of trifluoromethylstyrene.

Electrosynthetic C–F bond cleavage

“…64 Masson, Claraz and co-workers demonstrated coupling of Katritzky salts as well as NHP esters in yields up to 94%, including amino acid derived alkyl NHP esters (Figure 18, Method B). 65 Similarly, Xia, Guo and co-workers demonstrated that αtrifluoromethyl styrene substrates react with NHP esters and Katritzky salts, as well as alkyl halides, in yields up to 76% (Figure 18, Method C). 66 In the cases where a Fe sacrificial 60 Qi, Huang and Lei and co-workers reported yields up to 99% with alkyl halides as coupling partners, using a direct electrolysis method for alkyl iodides (Figure 18, Method D) or an indirect electrolysis method with a Ni(bpy)-complex in catalytic amounts for alkyl bromides.…”

“…The resulting radical carboxylate would thereafter undergo a second electron transfer to the corresponding enolate that decomposes to the gem-difluoroalkene product with release of fluoride (Figure Electroreductive C-F bond cleavage and concomitant functionalization of α-trifluoromethyl styrenes to gem-difluoroalkenes have recently been reported using radical precursors such as alkyl halides, redox active esters and Katritzky salts, as well as aryl halides (Figure 18). 64,65,66,67,68 Ni, Guo and Wang and co-workers demonstrated that Katritzky salts could be successfully used as coupling partners in DMSO under galvanostatic conditions with a sacrificial Zn anode and a Ni foam cathode, furnishing products in up to 85% yield (Figure 18, Method A). 64 Masson, Claraz and co-workers demonstrated coupling of Katritzky salts as well as NHP esters in yields up to 94%, including amino acid derived alkyl NHP esters (Figure 18, Method B).…”

“…18). [64][65][66][67][68] Ni, Guo and Wang and coworkers demonstrated that Katritzky salts could be successfully used as coupling partners in DMSO under galvanostatic conditions with a sacrificial Zn anode and a Ni foam cathode, furnishing products in up to 85% yield (Fig. 18, Method A).…”

Defluorinative Alkylation of Trifluoromethyl Alkenes with Soft Carbon Nucleophiles Enabled by a Catalytic Amount of Base

“…Meanwhile, catalytic variants by virtue of transition metals, [6] photoredox, [7] and electrochemical [8] technique were also described to enable the incorporation of diversified functional groups attached to gem ‐difluoroalkenes through β‐F elimination of TAs. In the historical context of synthesizing alkyl substituted gem ‐difluoroalkenes, existing protocols usually relied on the pre‐functionalized alkyl group progenitors as the coupling partners, such as halides, [6c,i,j,7f–i,8a,b] acetals, [6d] oxime ethers, [6e,7e] carboxylates, [6h,7b–d,8c] trifluoroborates, [7a] etc (Figure 1a). Notwithstanding these achievements, the exploration of efficient and operationally mild strategies that avoid the use of organometallic reagents, strong bases, and transition metals, and install a densely functionalized alkyl group to gem ‐difluoroalkenes that permits further elaborations is highly sought‐after.…”

Regio- and Stereoselective Electrochemical Alkylation of Morita–Baylis–Hillman Adducts

“… 13 Among others, C–H functionalizations and cross-coupling processes were primary targeted, 14 whereas the use of RAEs on eChem derivatizations of olefins have faced less attention. 15 In particular, the condensation of RAEs 2 and MBH acetates 1 is unprecedented ( Scheme 1 b), posing some important questions toward the overall chemo- and regioselectivity of the process. In this report, we disclose a highly stereoselective (the E -isomers were exclusively isolated), electroreductive strategy for the regioselective S N 2′ radical alkylation of MBH adducts 1 with RAEs 2 .…”