A Journey of the Development of Privileged Difluorocarbene Reagents TMSCF2X (X = Br, F, Cl) for Organic Synthesis.

ConspectusAs fluorine has played an increasingly important role in modulating the physical, chemical, and biological properties of organic molecules, the selective introduction of fluorine atom(s) or fluorinated moieties into target molecules has become a powerful tool in the development of new pharmaceuticals, agrochemicals, and functional materials. In this context, the difluoromethylene (CF2) and difluoromethyl (CF2H) groups are of special interest because of their ability to serve as bioisosteres of ethereal oxygen atoms and hydroxyl (OH) and thiol (SH) groups, respectively. Difluorocarbene is one of the most versatile reactive intermediates to incorporate CF2 and CF2H groups; however, before 2006, most of the previously known difluorocarbene reagents suffered from several drawbacks such as using ozone-depleting substances (ODSs), difficult-to-handle reagents, or harsh reaction conditions or having narrow substrate scope and/or low yields. Moreover, the reactivity of difluorocarbene generated from different precursors (reagents) was often unpredictable, since the difluorocarbene generation conditions (activation modes) of various difluorocarbene precursors are different, and these conditions may mismatch those required for subsequent difluorocarbene-involved transformations. Therefore, the development of new environmentally friendly and versatile difluorocarbene reagents, as well as the investigation of the mechanistic insights into difluorocarbene-involved reactions, has been highly desirable.In this Account, we summarize our contributions to the development of new difluorocarbene reagents and their applications in organic synthesis since 2006. We have developed seven new difluorocarbene reagents, including 2-chloro-2,2-difluoroacetophenone (1), chlorodifluoromethyl phenyl sulfone (2), S-difluoromethyl-S-phenyl-N-tosylsulfoximine (3), difluoromethyltri(n-butyl)ammonium chloride (4), (chlorodifluoromethyl)trimethylsilane (TMSCF2Cl, 5), (bromodifluoromethyl)trimethylsilane (TMSCF2Br, 6), and (trifluoromethyl)trimethylsilane (TMSCF3, 7). In this journey, we realized the key factor for an ideal difluorocarbene reagent that can be used for a broad range of reactions, that is, the reagent should allow various activation modes for the generation of difluorocarbene species, such as under basic/acidic/neutral conditions, at wide range of temperatures, and in different solvents, which are compatible with a wide range of difluorocarbene-involved transformations. Among all known difluorocarbene reagents, silanes TMSCF2X (X = Br, F, Cl) have stood out as privileged ones, which paves a new avenue for further developing difluorocarbene chemistry. In particular, TMSCF2Br was recognized as an "all-rounder": TMSCF2Br can be applied in almost all common difluorocarbene-involved reactions, and more importantly, TMSCF2Br also enables many other novel transformations that other difluorocarbene reagents cannot achieve, thanks to its unique structure and rich activation modes of releasing difluorocarbene under different reaction conditions. It can be expected that with the commercial availability of TMSCF2X reagents (X = Br, F, Cl) now, the development of difluorocarbene chemistry will be accelerated in the years to come.

Controllable Double Difluoromethylene Insertions into S-Cu Bonds: (Arylthio)tetrafluoroethylation of Aryl Iodides with TMSCF2Br.

A new method of constructing "ArSCF2CF2Cu" from ArSCu and TMSCF2Br (TMS=trimethylsilyl) has been developed. The cross-coupling reactions of the obtained "ArSCF2CF2Cu" with diverse aryl iodides (Ar'I) provide an efficient access to Ar'CF2CF2SAr. Mechanistic studies demonstrate that the "ArSCF2CF2Cu" species were generated through controllable double difluoromethylene insertions into ArS-Cu bonds rather than the 1,2-addition of ArSCu to tetrafluoroethylene.

Programmable Amine Synthesis via Iterative Boron Homologation.

The value of Matteson-type reactions has been increasingly recognized for developing automated organic synthesis. However, the typical Matteson reactions almost exclusively focus on homologation of carbon units. Here, we report the detailed development of sequential insertion of nitrogen and carbon atoms into boronate C-B bonds, which provides a modular and iterative approach to access functionalized tertiary amines. A new class of nitrenoid reagents is uncovered to allow direct formation of aminoboranes from aryl or alkyl boronates via N-insertion. The one-pot N-insertion followed by controlled mono- or double-carbenoid insertion has been realized with widely available aryl boronates. The resulting aminoalkyl boronate products can undergo further homologation and various other transformations. Preliminary success on homologation of N,N-dialkylaminoboranes and sequential N- and C-insertions with alkyl boronates have also been achieved. To broaden the synthetic utility, selective removal of a benzyl or aryl substituent permits access to secondary or primary amine products. The application of this method has been demonstrated in the modular synthesis of bioactive compounds and the programmable construction of diamines and aminoethers. A plausible reaction mechanism, supported by preliminary NMR (nuclear magnetic resonance) and computational studies, is also proposed.

Transition-Metal-Free Controllable Single and Double Difluoromethylene Formal Insertions into C-H Bonds of Aldehydes with TMSCF2 Br.

We have developed a new strategy for controllable single and double difluoromethylene (CF2 ) formal insertions into C-H bonds of aldehydes with nearly full selectivity under transition-metal-free conditions. The key to the success of controllable CF2 insertions lies in the well-defined formation of 2,2-difluoroenolsilyl ether and 2,2,3,3-tetrafluorocyclopropanolsilyl ether intermediates using difluorocarbene reagent TMSCF2 Br (TMS=trimethylsilyl). These two intermediates can react with various electrophiles including proton sources and various halogenation reagents, allowing for the access to diverse arrays of ketones containing difluoromethylene (CF2 ) and tetrafluoroethylene (CF2 CF2 ) units. The first synthesis of relatively stable 2,2,3,3-tetrafluorocyclopropanolsilyl ethers has been achieved, which offers a new platform to explore other unknown chemical space.

Programmable Ether Synthesis Enabled by Oxa-Matteson Reaction.

The Matteson-type reactions have received increasing interest in constructing complex organic molecules via iterative synthetic strategies; however, the current tactics are almost exclusively based on homologation of pure carbon chains. Here, we report the development of the oxa-Matteson reaction that enables sequential oxygen and carbenoid insertions into diverse alkyl- and arylboronates. It offers a distinct entry to a wide range of boron-substituted ethers. The utilities of this method are demonstrated in the preparation of various functional ethers, the asymmetric synthesis of an acetyl-CoA-carboxylase inhibitor, and the programmable construction of polyethers.

Copper-mediated pentafluoroethylation of organoboronates and terminal alkynes with TMSCF3.

The TMSCF3-derived CuCF2CF3 species has been successfully applied in pentafluoroethylation of organoboronates and terminal alkynes. By using 1,10-phenanthroline as a ligand, a broad range of (hetero)arylboronates and alkenylboronates were smoothly pentafluoroethylated under aerobic conditions. Furthermore, terminal alkynes can undergo aerobic cross-coupling with the TMSCF3-derived CuCF2CF3 species in the absence of additional ligands.

TMSCF2 Br-Enabled Fluorination-Aminocarbonylation of Aldehydes: Modular Access to α-Fluoroamides.

A protocol for the modular assembly of the α-fluoroamide motif has been developed, which provides a practical method for the efficient synthesis of structurally diverse α-fluoroamides from easily available aldehydes and tertiary amines through a three-component fluorination-aminocarbonylation process. The key to the success of this process is taking advantage of the multiple roles of the unique difluorocarbene reagent TMSCF2 Br (TMS=trimethylsilyl). The mechanism of the process involves the 1,2-fluorine and oxygen migrations of the in situ formed TMS-protected α-aminodifluoromethyl carbinol intermediates, which represents a new type of deoxyfluorination reaction.

Difluorocarbene-Induced Ring-Opening Difluoromethylation-Halogenation of Cyclic (Thio)Ethers with TMSCF2 X (X=Br, Cl).

The ring-opening difluoromethylation-halogenation of cyclic (thio)ethers is reported through a simple strategy relying on carbon-chalcogen bond activation with difluorocarbene. The reaction proceeds through in situ protonation of the previously little-known difluoromethylene oxonium or sulfonium ylide intermediate followed by ring-opening with halide ion to afford halogenated acyclic difluoromethyl (thio)ethers that can then be employed for further elaboration. TMSCF2 X (X=Br, Cl) are unique reagents to achieve this synthetic purpose, which serve as both the difluorocarbene source and the halide ion source.

Aza-Matteson Reactions via Controlled Mono- and Double-Methylene Insertions into Nitrogen-Boron Bonds.

Boron-homologation reactions represent an efficient and programmable approach to prepare alkylboronates, which are valuable and versatile synthetic intermediates. The typical boron-homologation reaction, also known as the Matteson reaction, involves formal carbenoid insertions into C-B bonds. Here we report the development of aza-Matteson reactions via carbenoid insertions into the N-B bonds of aminoboranes. By changing the leaving groups of the carbenoids and altering Lewis acid activators, selective mono- and double-methylene insertions can be realized to access various α- and ß-boron-substituted tertiary amines, respectively, from common secondary amines. The derivatization of complex amine-containing bioactive molecules, diverse functionalization of the boronate products, and sequential insertions of different carbenoids have also been achieved.

Generation of Carbocations under Photoredox Catalysis: Electrophilic Aromatic Substitution with 1-Fluoroalkylbenzyl Bromides.

A novel Friedel-Crafts-type alkylation of arenes to access valuable 1-fluoroalkyl-1,1-biaryl compounds is established under mild conditions. The key to success is the efficient generation of a destabilized benzylic carbocation intermediate via two consecutive single-electron transfer processes by virtue of visible-light photoredox catalysis. This unique activation pattern avoids using strong Lewis acids and high temperatures that are required for generation of destabilized carbocations in traditional Friedel-Crafts reactions. This protocol demonstrates the first example of photoredox-catalyzed heterolysis of electronically deactivated benzylic C-Br bonds for the formation of destabilized carbocation intermediates.

From C1 to C3 : Copper-Catalyzed gem-Bis(trifluoromethyl)olefination of α-Diazo Esters with TMSCF3.

A Cu-catalyzed gem-bis(trifluoromethyl)olefination of α-diazo esters, using TMSCF3 as the only fluorocarbon source, has been developed and provides an exquisite method to access gem-bis(trifluoromethyl)alkenes. This unprecedented olefination process involves a carbene migratory insertion into "CuCF3 " to generate the α-CF3 -substituted organocopper species, which then undergoes ß-fluoride elimination and two consecutive addition-elimination processes to give the desired products. The key to this efficient one-pot C1 -to-C3 synthetic protocol lies in the controllable double (over single and triple) trifluoromethylations of the gem-difluoroalkene intermediates.

Nucleophilic (Phenylsulfonyl/arylthio)difluoromethylation of Aldehydes with TMSCF2Br: A Three-Component Strategy.

An efficient method for nucleophilic (phenylsulfonyl/arylthio)difluoromethylation of aldehydes with TMSCF2Br was developed. The reaction proceeds through in situ generation of difluorocarbene, which is captured by PhSO2Na or ArSNa to form the corresponding PhSO2CF2- or PhSCF2- anions, followed by nucleophilic addition to aldehydes to give the desired difluoromethylated products.

A General Protocol for C-H Difluoromethylation of Carbon Acids with TMSCF2 Br.

An efficient method for the selective C-difluoromethylation of carbon acids with the reagent TMSCF2 Br has been developed. A variety of structurally diverse sp3 - and sp-hybridized carbon nucleophiles, including esters, amides, fluorenes, terminal alkynes, ß-ketoesters, malonates, and other activated C-H nucleophiles, could be efficiently and selectively transformed into the corresponding C-difluoromethylated products under mild conditions. This protocol is also effective for the late-stage difluoromethylation of pharmaceutically relevant molecules and can be readily scaled up. Moreover, ambident substrates with more than one reactive site towards difluorocarbene can be difluoromethylated orthogonally using TMSCF2 Br.

Controllable double CF2-insertion into sp2 C-Cu bond using TMSCF3: a facile access to tetrafluoroethylene-bridged structures.

A highly efficient method for controllable double CF2-insertion into pentafluorophenylcopper species using TMSCF3 as difluoromethylene source has been developed. The newly generated fluoroalkylcopper(i) species, C6F5CF2CF2Cu, shows good reactivity towards a myriad of structurally diverse aryl, heteroaryl and alkenyl iodides. This protocol is easy to handle, ready to scale up and applicable for the synthesis of relative complex molecules, thus providing a convenient method for facile access to tetrafluoroethylene-bridged structures.

From C1 to C2 : TMSCF3 as a Precursor for Pentafluoroethylation.

A highly efficient copper-mediated aromatic pentafluoroethylation method using TMSCF3 as the sole fluoroalkyl source is described. The reaction proceeds by a key C1 to C2 process, that is, the generation of CuCF3 from TMSCF3 , followed by a subsequent spontaneous transformation into CuC2 F5 . Various aryl iodides were pentafluoroethylated with the TMSCF3 -derived CuC2 F5 . This method represents the first practical and efficient method for pentafluoroethylation of aryl iodides using commercially available TMSCF3 as a pentafluoroethyl precursor.

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.

Efficient Difluoromethylation of Alcohols Using TMSCF2 Br 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.