Nickel-Catalyzed Defluorinative Coupling of Aliphatic Aldehydes with Trifluoromethyl Alkenes

Abstract: A simple procedure is reported for the nickel-catalyzed defluorinative alkylation of unactivated aliphatic aldehydes. The process involves the catalytic reductive union of trifluoromethyl alkenes with aldehydes using a nickel complex of a 6,6’-disubstituted bipyridine ligand with zinc metal as the terminal reductant. The protocol is distinguished by its broad substrate scope, mild conditions, and simple catalytic setup. Reaction outcomes are consistent with the intermediacy of an a-silyloxy(alkyl)nickel intermediate generated by a low-valent nickel catalyst, silyl electrophile, and the aldehyde substrate.

Transition metal-catalyzed reductive coupling reactions that avoid the need for pre-generation of air-and moisture-sensitive organometallic reagents provide an attractive route to highly functionalized synthetic intermediates. [1] Notably, reductive couplings of unsaturated compounds with aldehydes have demonstrated high efficiency for the construction of carbon-carbon bonds in a number of contexts using alkynes, [2] 1,3-dienes, [3] or allenes (Scheme 1A). [4] Couplings of alkenes with aldehydes, however, are more difficult, and methods are often restricted to intramolecular versions, [5] highly activated alkenes such as norbornene [6] and methylenecyclopropane, [7] or hydroacylations of styrenes. [8] Advances using triethylsilyl triflate as promoter enabled considerable improvements in olefin scope to include alkenes with aromatic aldehydes and tertiary aliphatic aldehydes (Scheme 1B). [9] More recently, cobalt-and chromium cocatalyzed branch-selective coupling of alkenes with aldehydes through an alkyl chromium intermediate further broadened the scope of substrate combinations tolerated. [10] Additionally, iron-catalyzed transfer hydrogenative coupling of alkenes with aromatic and aliphatic aldehydes [11] and Bronsted acid enabled nickel-catalyzed hydroalkenylation of styrene derivatives with unactivated aldehydes provided further advances. [12] Despite these developments, the majority of current methods for aldehyde-alkene reductive coupling are restricted to aromatic aldehydes, [13] and the direct coupling reaction of abundantly available alkenes with unactivated aliphatic aldehydes still presents challenges in many cases.
An alternative approach for functionalization α to oxygen involves the generation and capture of α-oxy radical intermediates, which have been developed as highly useful cross-coupling partners using nickel catalysis. [14] Among these approaches, ketyl radicals offer a versatile platform of reactivity for reversing the traditional electrophilic character of carbonyls and play a pivotal role in numerous bond-forming and bond-breaking processes including ketyl-olefin couplings. [15] The requirement for strong, stoichiometric reductants, however, places practical limits on the synthetic utility of ketyl intermediates generated by classical approaches. [16] Several innovative strategies to generate ketyl radical were recently reported through processes such as concerted proton-coupled electron transfer, [17] Lewis acid-facilitated photocatalytic reduction, [18] redox-neutral photochemical promotion through transient a-acetoxy vinyl iodides intermediate, [19] and electrocatalytic reduction. [20] Recent efforts in our laboratory have identified the addition of Ni(0) to aliphatic aldehydes through the activation by silyl halides as an alternative strategy for promoting reductive cross couplings of aldehydes either involving cyclization of an ynal with alkylation by an alkyl bromide or through direct coupling of the aldehyde with an alkyl bromide. [21] By analogy, we envisioned that trifluoromethylsubstituted alkenes [22] might serves as competent electrophiles in cross couplings with aldehydes under reductive conditions. This outcome would enable reactivity that serves as a functional synthetic equivalent of ketyl radicals through activation of the aldehyde by a low-valent nickel species in the presence of a silyl chloride. The 1,1-difluoroalkenes obtained through reductive couplings of aldehydes with trifluoromethyl-substituted alkenes with extrusion of a single fluorine atom are intriguing motifs owing to their presence in a number of biologically active compounds. [23] Due to their resistance to in vivo metabolism, gem-difluoroalkenes are a promising carbonyl bioisostere owing to their steric and electronic similarity to aldehydes, ketones, and esters. [24] Herein, we describe efficient nickelcatalyzed defluorinative couplings of trifluoromethyl-substituted alkenes with aliphatic aldehydes to provide homoallylic alcohols possessing the gem-difluoroalkenes structural motif.
We next turned our attention to define the substrate scope using the optimized conditions from the above studies. First, we explored an array of aliphatic aldehydes 1 to examine the generality of the coupling with trifluoromethyl alkenes (2a) (Table 2).
We next demonstrated the generality of this protocol with respect to the trifluoromethyl alkenes 2a−t (Table 3). Under these mild and base-free conditions, various 1,1-trifluoromethylstyrenes featuring either electron-rich (4a-4e) or electron-deficient (4g-4k) substituents underwent the transformation smoothly, affording the corresponding products in good yields (71-93%). Notably, this reductive protocol is tolerant of a wide range of functionality on the alkene coupling partner, such as esters (4i), amides (4j), sulfonyl groups (4k), nitriles (4l), and sulfides (4m). Furthermore, heterocycles including quinolone (4o), benzofuran (4p), benzothiophene (4q), dibenzofuran (4r), and carbazole (4s), are also readily compatible. It is noteworthy that beyond the aryl and heteroaryl system, monosubstituted alkenes, such as 2-nonafluorobutyl-1alkene (2t), smoothly proceeded to afford the desired product 4t in moderate yield. NiCl 2 •DME (10 mol %) L1 (15 mol %) TESCl (3.0 equiv) 1,5-hexadiene (1. To showcase the robustness and practicality of our method, a 5-mmol-scale experiment was conducted under an inert atmosphere using a benchtop setup without glovebox manipulations to provide 1.5 g of the desired product 3a in 73% yield using only 2 mol% catalyst loading (Scheme 2A). Additionally, the protocol was also expanded to include b-trifluoromethyl enoates. As shown in Scheme 2B, subjecting methyl 4,4,4-trifluorocrotonate (5) to this catalytic system exclusively provided the defluorinative alkylation product 6 in high yield, illustrating that the trifluoromethyl group directs regiochemistry of the addition in analogy to the examples provided in Tables 2 and 3. Alkyl-substituted trifluoromethyl alkene (7), however, did not participate in the process, and competitive formation of enol ether 9 and reduced silyl ether 10 was observed, with most of trifluoromethyl alkene 7 recovered intact with only 6% yield of the desired product 8 observed by GCMS analysis.
While this manuscript was in preparation, a related chromium-catalyzed method for the addition of ketyl radicals to trifluoroalkene intermediates was described. [25] Notably, the use of nickel catalysis was described in that study as ineffective in promoting the reaction, illustrating the unique effectiveness of the ligand/additive/reductant combination developed herein. Control experiments illustrated that CrCl3, used in the method of Wang, has little effect on rates or outcomes of our optimal nickel-catalyzed conditions, suggesting that co-catalysis with trace chromium is not involved in the method describe herein.    In conclusion, an efficient method for defluorinative cross-couplings of aliphatic aldehydes with trifluoromethyl alkenes has been developed. The facile installation of the difluoromethylene unit to an array of aldehyde structures provides an effective entry to this desirable functional group class. The substrate scope enables wide variation of the aldehyde reaction partner, and the protocol is amenable to gram-scale syntheses. The combination of a hindered 6,6'-disubstituted bipyridine ligand, 1,5-hexadiene as an additive, triethylsilyl chloride, and nanopowder zinc were key components of the optimized procedure. This work expands the use of simple alkenes in nickel-catalyzed reductive couplings of aldehydes and illustrates that bipyridine ligand frameworks enable unique reactivity in processes of this type when used in combination with simple diene additives.