Mingyou Hu

Copper‐Catalyzed Di‐ and Trifluoromethylation of α,β‐Unsaturated Carboxylic Acids: A Protocol for Vinylic Fluoroalkylations

Dual action: the Lewis acid CuF(2) ⋅2 H(2)O efficiently catalyzes the reaction between electrophilic fluoroalkylating agents and α,β-unsaturated carboxylic acids by dually activating both reactants, thus affording di- and trifluoromethyl alkenes in high yields with excellent E/Z selectivity.

Copper-catalyzed gem-difluoroolefination of diazo compounds with TMSCF3 via C-F bond cleavage.

A novel Cu-catalyzed gem-difluoroolefination of diazo compounds is described. This transformation starts from readily available TMSCF3 and diazo compounds, via trifluoromethylation followed by C-F bond cleavage, to afford the desired 1,1-difluoroalkene products.

Copper-Mediated Trifluoromethylthiolation of α-Diazoesters

A novel Cu-mediated trifluoromethylthiolation of diazo compounds has been developed that provides a convenient synthetic route for the efficient α-trifluoromethylthiolation of simple esters under mild reaction conditions. The reaction is typically carried out at room temperature, and water could be used to promote the reaction.

gem-Difluoroolefination of Diazo Compounds with TMSCF3 or TMSCF2Br: Transition-Metal-Free Cross-Coupling of Two Carbene Precursors

A new olefination protocol for transition-metal-free cross-coupling of two carbene fragments arising from two different sources, namely, a nonfluorinated carbene fragment resulting from a diazo compound and a difluorocarbene fragment derived from Ruppert-Prakash reagent (TMSCF3) or TMSCF2Br, has been developed. This gem-difluoroolefination proceeds through the direct nucleophilic addition of diazo compounds to difluorocarbene followed by elimination of N2. Compared to previously reported Cu-catalyzed gem-difluoroolefination of diazo compounds with TMSCF3, which possesses a narrow substrate scope due to a demanding requirement on the reactivity of diazo compounds and in-situ-generated CuCF3, this transition-metal-free protocol affords a general and efficient approach to various disubstituted 1,1-difluoroalkenes, including difluoroacrylates, diaryldifluoroolefins, as well as arylalkyldifluoroolefins. In view of the ready availability of diazo compounds and difluorocarbene reagents and versatile transformations of 1,1-difluoroalkenes, this new gem-difluoroolefination method is expected to find wide applications in organic synthesis.

Copper‐Catalyzed Difluoromethylation of β,γ‐Unsaturated Carboxylic Acids: An Efficient Allylic Difluoromethylation

The difluoromethyl group (CF2H) is an intriguing structural motif, which has great potential for many applications in lifescience-related fields. It has been realized that the CF2H group can act as lipophilic hydrogen-bond donors and as a bioisostere of alcohols and thiols. In this context, the development of efficient methods for the incorporation of the CF2H group into organic molecules has attracted much attention. 2,6–9] Recently, transition-metal-mediated or transition-metal-catalyzed difluoromethylation (or difluoroalkylation) of aryl halides and aryl boronic acids to construct Csp2 CF2H (or Csp2 CF2R) bonds have been intensively studied. Baran and co-workers also reported an elegant process for the direct difluoromethylation of arenes by a free radical process. However, the transition-metal-mediated or transition-metal-catalyzed difluoromethylation and difluoroalkylation for the construction of allylic Csp3 CF2H (or allylic Csp3 CF2R) bonds are scarce. Previously, Burton and Hartgraves reported the difluoromethylations of allyl halides using either a difluoromethyl cadmium or copper reagent. However, the regioselectivity of these reactions was not well controlled, and in many cases, both a-attack and g-attack products were obtained [Scheme 1, Eq. (1)]. Herein, we disclose a new catalytic protocol for the regiospecific construction of allylic Csp3 CF2H (or allylic Csp3 CF2R) bonds by copper-catalyzed decarboxylative difluoromethylation of b,g-unsaturated carboxylic acids [Scheme 1, Eq. (2)]. Recently, we discovered the copper-catalyzed decarboxylative fluoroalkylation of a,b-unsaturated carboxylic acids, a method which provides a powerful tool for vinylic diand trifluoromethylations. We envisaged that this decarboxylative fluoroalkylation strategy might be also used to tackle the challenging allylic difluoromethylation problem when the b,gunsaturated carboxylic acids are used as substrates. With this consideration in mind, we chose the reaction between the I(III)-CF2SO2Ph reagent 1 [14] and 3-(p-tolyl)-3-butenoic acid (2a) as a model reaction to survey the reaction conditions. As shown in Table 1, selection of the proper Lewis acid catalyst, solvent, and temperature was found to be crucial for the reaction. In the absence of a Lewis acid, the desired decarboxylative fluoroalkylation reaction could hardly proceed (entry 21). While Ni(OAc)2·4 H2O and Pd(OAc)2 were

Copper-mediated trifluoromethylation of propiolic acids: facile synthesis of α-trifluoromethyl ketones

Copper-mediated decarboxylative trifluoromethylation provides a new protocol for the efficient preparation of α-trifluoromethyl ketones from propiolic acids. It was found that water is involved as a reactant in the reaction, which is significantly different from the previously reported decarboxylative fluoroalkylation reactions.

gem‐Difluoroolefination of Diaryl Ketones and Enolizable Aldehydes with Difluoromethyl 2‐Pyridyl Sulfone: New Insights into the Julia–Kocienski Reaction

The direct conversion of diaryl ketones and enolizable aliphatic aldehydes into gem-difluoroalkenes has been a long-standing challenge in organofluorine chemistry. Herein, we report efficient strategies to tackle this problem by using difluoromethyl 2-pyridyl sulfone as a general gem-difluoroolefination reagent. The gem-difluoroolefination of diaryl ketones proceeds by acid-promoted Smiles rearrangement of the carbinol intermediate; the gem-difluoroolefination is otherwise difficult to achieve through a conventional Julia-Kocienski olefination protocol under basic conditions due to the retro-aldol type decomposition of the key intermediate. Efficient gem-difluoroolefination of aliphatic aldehydes was achieved by the use of an amide base generated in situ (from CsF and tris(trimethylsilyl)amine), which diminishes the undesired enolization of aliphatic aldehydes and provides a powerful synthetic method for chemoselective gem-difluoroolefination of multi-carbonyl compounds. Our results provide new insights into the mechanistic understanding of the classical Julia-Kocienski reaction.

TMSCF3 as a Convenient Source of CF2=CF2 for Pentafluoroethylation, (Aryloxy)tetrafluoroethylation, and Tetrafluoroethylation

A new method for the on-site preparation of tetrafluoroethylene (TFE) and a procedure for its efficient use in pentafluoroethylation by fluoride addition were developed by using a simple two-chamber system. The on-site preparation of TFE was accomplished by dimerization of difluorocarbene derived from (trifluoromethyl)trimethylsilane (TMSCF3 ) under mild conditions. Other fluoroalkylation reactions, such as (aryloxy)tetrafluoroethylation and tetrafluoroethylation processes, were also achieved using a similar approach. This work not only demonstrates a convenient and safe approach for the generation and use of TFE in academic laboratories, but also provides a new strategy for pentafluoroethylation.