Palladium Difluorocarbene Involved Catalytic Coupling with Terminal Alkynes

Abstract

Cite this: CCS Chem. 2020, 2, 293-304Difluoromethylated alkynes are a versatile synthon for the diversity-oriented synthesis of difluoromethyl compounds that are of great interest in life and materials sciences. However, the catalytic cross-coupling for the synthesis of difluoromethylated alkynes remains challenging, despite impressive achievements made in the cross-coupling reactions for alkynes, including the Sonogashira reaction. Here, we report a palladium difluorocarbene involvement in catalytic coupling with terminal alkynes, representing a new mode of conjugation reaction, which circumvents the radical pathway usually encountered during the coupling of alkynes with fluoroalkyl electrophiles. The reaction uses inexpensive and abundant industrial raw material chlorodifluoromethane (ClCF 2 H) as the difluorocarbene precursor, and features cost-effectiveness, excellent functional group tolerance, and broad substrate scope, including synthesis of drug-like complex molecules. Our mechanistic studies showed a unique catalytic pathway of this process, in which additive hydroquinone plays a pivotal role in promoting the reaction. + [Pd] (2.5 mol %) Xantphos (2.5 or 7.5 mol %) Hydroquinone, K 2 CO 3 dioxane/DMA (w/wo), 80 o C CF 2 H R Het R Het [Pd 0 ]=CF 2 via cat. [Pd] nucleophilic 32 examples, yield up to 95% alkyne hydroquinone hydroquinone F F Cl H RESEARCH ARTICLE

Late-stage difluoromethylation: concepts, developments and perspective

“…In 2020, Zhang and co-workers extended the palladium difluorocarbene ([Pd = CF 2 ]) chemistry (described in Section 2.1.c) to the difluoromethylation of alkynes (Scheme 63). 206 The protocol employed chlorodifluoromethane as the difluorocarbene precursor, and featured good functional group tolerance, broad substrate scope, and was applied to the synthesis of complex drug molecules. One limitation of this method is the use of chlorodifluoromethane, an ODS.…”

Atom Recombination of Difluorocarbene Enables 3-Fluorinated Oxindoles from 2-Aminoarylketones

“…The transformation of difluorocarbene (:CF 2 ) has emerged as a powerful difluorination platform, which can be widely used to introduce fluorine into organic molecules. [1][2][3][4] Typical conversion of difluorocarbene, including attachment with a nucleophile and an electrophile, [5][6][7][8][9][10][11][12][13][14][15][16] Wittig reaction with carbonyls, [17][18][19][20] [2+1] cycloaddition with alkenes or alkynes 21 , metal-difluorocarbene involved catalytic coupling [22][23][24] and combining with other carbene, [25][26][27][28][29] can quickly construct different organofluorine compounds, such as gemdifluoroalkenes and gem-difluorocyclopropanes and other gem-difluorinated compounds (Fig. 1A).…”

Deconstrutive Difunctionalizations of Cyclic Ethers Enabled by Difluorocarbene to Access Difluoromethyl Ethers

“…Subsequently, Ngai et al reported a distinct radical approach for catalytic C-H difluoromethoxylation of (hetero)arenes using difluoromethoxylative reagents [11][12] (Figure 1B, left). Of note, as an important and special fluorine-containing intermediate in organic synthesis [13][14][15][16][17][18][19][20][21][22][23][24] , difluorocarbene has been combined with various alcohols or thiolsto synthesize difluoromethyl ethers [25][26][27][28] or thioethers [29][30] (Figure 1B, right). Despite the progress achieved in recent years on the synthesis of difluoromethyl ethers, their efficient synthetic methods are still rare and the development of a general and practical strategy for their construction is still highly appealing, especially in terms of complexity and versatility of difluoromethoxy compounds.…”