Difluorocarbene-induced [1,2]- and [2,3]-Stevens rearrangement of tertiary amines.

The [1,2]- and [2,3]-Stevens rearrangements are one of the most fascinating chemical bond reorganization strategies in organic chemistry, and they have been demonstrated in a wide range of applications, representing a fundamental reaction tactic for the synthesis of nitrogen compounds in chemical community. However, their applicabilities are limited by the scarcity of efficient, general, and straightforward methods for generating ammonium ylides. Herein, we report a general difluorocarbene-induced tertiary amine-involved [1,2]- and [2,3]-Stevens rearrangements stemmed from in situ generated difluoromethyl ammonium ylides, which allows for the rearrangements of versatile tertiary amines bearing either allyl, benzyl, or propargyl groups, resulting in the corresponding products in one reaction under the same reaction conditions with a general way. Broad substrate scope, simple operation, mild reaction conditions and late-stage modification of natural products highlight the advantages of this strategy, meanwhile, this general rearrangement reaction is believed to bring opportunities for the transformations of nitrogen ylides and the assembly of valuable tertiary amines and amino acids. This will further enrich the reaction repertoire of difluorocarbene species, facilitate the development of reactions involving difluoromethyl ammonium salts, and provide an avenue for the development of this type of rearrangement reactions.

Decarboxylation of ß-boryl NHPI esters enables radical 1,2-boron shift for the assembly of versatile organoborons.

In recent years, numerous 1,2-R shift (R = aliphatic or aryl) based on tetracoordinate boron species have been well investigated. In the contrary, the corresponding radical migrations, especially 1,2-boryl radical shift for the construction of organoborons is still in its infancy. Given the paucity and significance of such strategies in boron chemistry, it is urgent to develop other efficient and alternative synthetic protocols to enrich these underdeveloped radical 1,2-boron migrations, before their fundamental potential applications could be fully explored at will. Herein, we have demonstrated a visible-light-induced photoredox neutral decarboxylative radical cross-coupling reaction, which undergoes a radical 1,2-boron shift to give a translocated C-radical for further capture of versatile radical acceptors. The mild reaction conditions, good functional-group tolerance, and broad ß-boryl NHPI esters scope as well as versatile radical acceptors make this protocol applicable in modification of bioactive molecules. It can be expected that this methodology will be a very useful tool and an alternative strategy for the construction of primary organoborons via a novel radical 1,2-boron shift mode.

Synthesis of Phosphachromones by Cyclized Coupling of Ethyl Hydrogen (Phenylethynyl)phosphonate with Arynes.

A straightforward and efficient strategy for the synthesis of phosphachromones has been reported via the insertion of arynes into P-O bonds. This operationally simple reaction is compatible with different functional groups, affording various phosphachromones by the simultaneous formation of C-P and C-O bonds in one step with moderate to good yields, and the Fries rearrangement involving phosphorus atoms is a key step in the reaction.

Difluorocarbene-Enabled Synthesis of 3-Alkenyl-2-oxindoles from ortho-Aminophenylacetylenes.

Herein, we report a transition-metal-free [4 + 1] cyclization pathway from difluorocarbene and ortho-amino aryl alkynone, rendering an effective and universal strategy for the construction of 3-alkenyl-2-oxindoles. Our strategy starts from cheap and accessible ortho-amino aryl alkynone instead of the direct indole skeleton; moreover, in situ generated difluorocarbene from commercially available halogenated difluoroalkylative reagents enables the cleavage of a C-N bond and formation of new C-N bonds and C-C bonds.

Unconventional Transformations of Difluorocarbene with Amines and Ethers.

ConspectusFluorine-containing compounds are extensively involved in various fields originating from intriguing and unique characteristics of fluorine atom; notably, in pharmaceuticals, the involvement of a fluorine atom or a fluorine-containing group is a chief technique for improving the pesticide effect and developing new drugs. Difluorocarbene, one of the most important and powerful fluorine-containing reagents, is widely employed and studied in many areas mainly to assemble gem-difluoromethyl molecules, including but not limited to the abundant reactions between difluorocarbene with nucleophilic substrates, Wittig reaction with ketones or aldehydes, cascade reaction with both a nucleophile and an electrophile, or [2+1] cycloaddition with alkenes or alkynes. However, its unconventional and intriguing protocols beyond as a difluoromethyl synthon have rarely been studied, and thus, it is highly desired given its abundance, inexpensiveness and peculiar properties. In this Account, we mainly discuss our discovery with unconventional transformations of difluorocarbene, instead of as a sole difluoromethyl source (different from other dihalocarbene), actually can serve as an electron acceptor to activate C-X bonds (X = N and O) and thus promote a myriad of fascinating transformations for the assembly of versatile valuable products with various aza-compounds (primary/secondary/tertiary amines as well as NH3 and NaNH2 and so on) and aliphatic ethers in the absence of transition metals and expensive ligands. Inspired by the electron-deficient characteristics of difluorocarbene, we first found that the isocyanides could be readily formed in situ when the unoccupied orbital of difluorocarbene meets the lone-pair of primary amines; in basic condition, a cascade defluorination and cyclizations could afford plethora of valuable N-containing heterocycles. Meanwhile, we disclosed that cyano anion could be accessible in situ as well when difluorocarbene and NaNH2 or NH3 were mixed up in suitable basic conditions, and thus a series of aryl nitrile compounds were obtained in the presence of Pd catalysis and ArI. Interestingly, when difluorocarbene encountered secondary amines, formamides were rendered under mild reactions. Of note, concomitant functionalizations of C and N moieties via cleavage of the unstrained C(sp3)-N bond in the absence of metal and oxidant are sparce, which indeed significantly add versatility and diversity to products. Gratifyingly, by uitilizing difluorocarbene and cyclic tertiary amines, we achieved difluorocarbene-mediated deconstructive functionalizations for the first time, showing successive C(sp3)-N bond scission of amines and simultaneous functionalization of C and N atoms which would be introduced into the products in the absence of transition metals and oxidants. This method provides a brand-new while very universal synthetic pathway to selectively cleave inert unactivated Csp3-N bonds, in which halodifluoromethyl reagents act as both C1 synthon and halo (Cl, Br, I) sources. Fascinatingly, nitrogen ylides are generated in situ from difluorocarbene and tertiary amines, and an intriguing and universal approach for deaminative arylation or alkenylation of tertiary amines was disclosed for the first time in appropriate basic conditions, which represents an intriguing reaction mode to lead to a formal transition-metal free Suzuki cross coupling. Besides, we also disclosed that difluorocarbene could proceed novel atom recombination to render meaningful 2-fluoroindoles or 3-(2,2-difluoroethyl)-2-fluoroindoles from ortho-vinylanilines, 3-fluorined oxindoles from 2-aminoarylketones, in which difluorocarbene acts as a C1 synthon and F1 source simultaneously. Last but not the least, we recently found that the lone-pair-electron of oxygen could trap difluorocarbene as well to form oxonium ylide, which eventually leads to C-O bond cleavage with the formation of difluoromethyl ethers.

Cu-Catalyzed Three-Component Cascade Synthesis of 1,3-Benzothiazines from ortho-Aminohydrazones and Bromodifluoroacetamides.

An efficient and convenient synthesis of benzo[d][1,3]thiazine has been developed by employing a copper-catalyzed transformation of readily available ketone-derived hydrazones with elemental sulfur and bromodifluoroalkylative reagents. The strategy involves an S8-catalyzed selective triple-cleavage of bromodifluoroacetamides, which acts as a C1 synthon at the 2-position of benzo[d][1,3]thiazine. A mechanism proceeding through a Cu-carbene intermediate is proposed for the C-S bond formation.

Deaminative Arylation and Alkenyaltion of Aliphatic Tertiary Amines with Aryl and Alkenylboronic Acids via Nitrogen Ylides.

Transition-metal-catalyzed Suzuki-Miyaura coupling has significantly advanced C-C bond formation and has been well recognized in organic synthesis, pharmaceuticals, materials science and other fields. In this rapid development, cross coupling without transition metal catalyst is a big challenge in this field, and using widely existing tertiary amines as electrophiles to directly couple with boronic acids has great hurdles yet significant application prospects. Herein, we report an efficient and general deaminative arylation and alkenylation of tertiary amines (propargyl amines, allyl amines and 1H-indol-3-yl methane amines) with ary and alkenylboronic acids enabled by difluorocarbene under transition-metal-free conditions. Preliminary mechanism experiments suggest that in situ formed difluoromethyl quaternary amine salt, nitrogen ylide and tetracoordinate boron species are the key intermediates, the subsequent 1,2-metallate shift and protodeboronation complete the new coupling reaction.

Double Capture of Difluorocarbene by 2-Aminostyrenes Enables the Construction of 3-(2,2-Difluoroethyl)-2-fluoroindoles.

We report herein an efficient strategy to construct 3-(2,2-difluoroethyl)-2-fluoroindoles from activated o-aminostyrenes with ethyl bromodi-fluoroacetate as a difluorocarbene source. Through double capture of a difluorocarbene, two different types of fluorine motifs are incorporated into the products with simultaneous construction of one C-N and two C-C bonds, without the need for transition metals. This reaction features high efficiency and excellent functional group compatibility and has great potential in the late-stage modifications of pharmaceutical molecules and natural products.

Difluorocarbene enables to access 2-fluoroindoles from ortho-vinylanilines.

2-Fluoroindoles as an important structural scaffold are widely existing in many bioactive or therapeutic agents. Despite their potential usefulness, efficient constructions of 2-fluoroindole derivatives are very sparce. The development of straightforward synthetic approaches to access 2-fluoroindoles is highly desirable for studying their fundamental properties and applications. Herein, we report an efficient and general strategy for the construction of 2-fluoroindoles in which a wide variety of 2-fluoroindoles were accessed with high efficiency and chemoselectivity. Instead of starting from indole skeletons, our strategy constructs indole scaffolds alongside the incorporation of fluorine atom on C2 position in a formal [4+1] cyclization from readily accessible ortho-vinylanilines and difluorocarbene. In our protocol, commercially accessible halodifluoroalkylative reagents provide one carbon and one fluorine atom by cleaving one C-N tertiary bond and forming one C-N bond and one C-C double bond with ortho-vinylanilines. Downstream transformations on 2-fluoroindoles lead to various valuable bioactive molecules which demonstrated significant synthetic advantages over previous reports. And mechanistic studies suggest that the reaction undergoes a cascade difluorocarbene-trapping and intramolecular Michael addition reaction followed by Csp3-F bond cleavage.

Elemental-Sulfur-Enabled Divergent Synthesis of Disulfides, Diselenides, and Polythiophenes from ß-CF3 -1,3-Enynes.

Divergent synthesis for precise constructions of cyclic unsymmetrical diaryl disulfides or diselenides and polythiophenes from CF3 -containing 1,3-enynes and S8 was developed when the ortho group is F, Cl, Br, and NO2 on aromatic rings. Meanwhile, disulfides (diselenides) were also quickly constructed when the ortho group is H. These transformations undergo cascade thiophene construction/selective C3-position thiolation process, featuring simple operations, divergent synthesis, broad substrate scope, readily available starting materials, and valuable products. A novel plausible radical annulation process was proposed and validated by DFT calculations for the first time. A series of derivatizations about the thiophene (TBT) and disulfides were also well-represented.

Deconstructive Functionalizations of Unstrained Carbon-Nitrogen Cleavage Enabled by Difluorocarbene.

Transition-metal- or oxidant-promoted deconstructive functionalizations of noncyclic carbon-nitrogen bonds are well established, usually only leaving one moiety functionalized toward the final product. In contrast, concomitant C- and N-functionalizations via the unstrained C(sp3)-N bond under metal- and oxidant-free conditions are very rare, which would favorably confer versatility and product diversity. Disclosed herein is the first difluorocarbene-induced deconstructive functionalizations embodying successive C(sp3)-N bond cleavage of cyclic amines and synchronous functionalization of both constituent atoms which would be preserved in the eventual molecular outputs under transition-metal-free and oxidant-free conditions. Correspondent access to deuterated formamides with ample isotopic incorporation was demonstrated by a switch to heavy water which is conceivably useful in pharmaceutical sciences. The current strategy remarkably administers a very convenient, operationally simple and novel method toward molecular diversity from readily available starting materials. Therefore, we project that these findings would be of broad interest to research endeavors encompassing fluorine chemistry, carbene chemistry, C-N bond activation, as well as medicinal chemistry.

Chlorodifluoromethane as a C1 Synthon in the Assembly of N-Containing Compounds.

The development of C1 synthons to afford the products that add one extra carbon has become an important research theme in the past decade, and significant progress has been achieved with CO2, CO, HCOOH, and others as C1 units. Despite the great advance, the search for new C1 synthons that display unique reactivity, complement to the current C1 sources, and add more value to C1 chemistry is still desirable. Herein, we report a quadruple cleavage of chlorodifluoromethane to yield a C1 source, which was successfully employed in the construction of various N-containing compounds especially with pharmaceutical molecules under mild conditions. This strategy provides a useful method for late-stage modification of pharmaceutical compounds. Four bonds in ClCF2H were orderly cleaved under basic conditions in the absence of transition metals. Preliminary mechanistic studies revealed that (E)-N-phenylformimidoyl fluoride intermediate is involved in this process by in situ1H NMR studies and control experiments.