ngchun Li

Synthesis of gem‐Difluorocyclopropa(e)nes and O‐, S‐, N‐, and P‐Difluoromethylated Compounds with TMSCF2Br

Two-in-one: Me3 SiCF2 Br is an efficient difluorocarbene source and is compatible with both neutral and aqueous basic conditions. Bromide-ion-initiated [2+1] cycloaddition with alkenes/alkynes and hydroxide ion promoted α-addition with (thio)phenols, (thio)alcohols, sulfinates, heterocyclic amines, and H-phosphine oxides give the corresponding gem-difluorinated compounds with broad functional-group tolerance.

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.

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.

Deoxygenative gem-difluoroolefination of carbonyl compounds with (chlorodifluoromethyl)trimethylsilane and triphenylphosphine

Summary Background: 1,1-Difluoroalkenes cannot only be used as valuable precursors for organic synthesis, but also act as bioisosteres for enzyme inhibitors. Among various methods for their preparation, the carbonyl olefination with difluoromethylene phosphonium ylide represents one of the most straightforward methods. Results: The combination of (chlorodifluoromethyl)trimethylsilane (TMSCF2Cl) and triphenylphosphine (PPh3) can be used for the synthesis of gem-difluoroolefins from carbonyl compounds. Comparative experiments demonstrate that TMSCF2Cl is superior to (bromodifluoromethyl)trimethylsilane (TMSCF2Br) and (trifluoromethyl)trimethylsilane (TMSCF3) in this reaction. Conclusion: Similar to many other Wittig-type gem-difluoroolefination reactions in the presence of PPh3, the reaction of TMSCF2Cl with aldehydes and activated ketones is effective.

Efficient Difluoromethylation of Alcohols Using TMSCF2Br as a Unique and Practical Difluorocarbene Reagent under Mild Conditions

A general method for the efficient difluoromethylation of alcohols using commercially available TMSCF2 Br (TMS=trimethylsilyl) as a unique and practical difluorocarbene source is developed. This method allows primary, secondary, and even tertiary alkyl difluoromethyl ethers to be synthesized under weakly basic or acidic conditions. The reaction mainly proceeds through the direct interaction between a neutral alcohol and difluorocarbene, which is different from the difluoromethylation of phenols. Moreover, alcohols containing other moieties that are also reactive toward difluorocarbene can be transformed divergently by using TMSCF2 Br. This research not only solves the synthetic problem of difluorocarbene-mediated difluoromethylation of alcohols, it also provides new insights into the different reaction mechanisms of alcohol difluoromethylation and phenol difluoromethylation with difluorocarbene species.

Palladium-Catalyzed Monofluoromethylation of Arylboronic Esters with Fluoromethyl Iodide

The first palladium-catalyzed direct monofluoromethylation of arylboronic esters to produce monofluoromethyl arenes is reported. The reaction is typically carried out at room temperature within 4 h and has a good functional group tolerance. The monofluoromethylating agent, CH2FI, was readily prepared via a halogen-exchange process.

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.

Deoxyfluorination of alcohols with 3,3-difluoro-1,2-diarylcyclopropenes

Aromatic cation activation is a useful strategy to promote deoxyfunctionalization; however, the deoxyfluorination of alcohols with cyclopropenium cation remains an unsolved problem due to the weak nucleophilicity of fluoride ion. Here we report the use of 3,3-difluoro-1,2-diarylcyclopropenes (CpFluors) as easily accessible and reactivity-tunable deoxyfluorination reagents. The electronic nature of CpFluors is critical for fluorination of monoalcohols via alkoxycyclopropenium cations, and CpFluors with electron-rich aryl substituents facilitate the transformation with high efficiency; however, selective monofluorination of 1,2- and 1,3-diols, which proceeds via cyclopropenone acetals, is less dependent on the electronic nature of CpFluors. Moreover, CpFluors are more sensitive to the electronic nature of alcohols than many other deoxyfluorination reagents, thus fluorination of longer diols can be achieved selectively at the relatively electron-rich position. This research not only unveils the first example of deoxyfluorination reagents that contain an all-carbon scaffold, but also sheds light on the divergent reactivity of cyclopropenium cation in deoxyfunctionalization of alcohols.