Unconventional Transformations of Difluorocarbene with Amines and Ethers

Abstract

Metrics & MoreArticle Recommendations CONSPECTUS: Fluorine-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 NH 3 and NaNH 2 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 NaNH 2 or NH 3 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(sp 3 )−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(sp 3 )−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 Csp 3 −N bonds, in which halodifluoromethyl reagents act as both C1 synthon and...

Photochemically Mediated Ring Expansion of Indoles and Pyrroles with Chlorodiazirines: Synthetic Methodology and Thermal Hazard Assessment

“…A further assessment of functional group compatibility was made using a Glorius-type robustness screen (Scheme 3). [41,42] Consistent with the known reactivity of (halo)carbenes, [43][44][45][46][47] basic nitrogen both suppressed the desired transformation and was itself decomposed under the reaction conditions (Scheme 3, compare entry a to entries be). In contrast, nitrogen protected as a sulfonamide (f), carbamate (g), or secondary/tertiary amide (m-o) was tolerated, consistent with the results presented in Scheme 2.…”

“…[23] Photolytically-generated chlorocarbenes can also be used to effect C-atom insertion into the NÀ N bond of Nalkyl pyrazoles (Scheme 2D). The corresponding pyrimidinium salts are formed in high yield for a range of (poly)substituted substrates (43)(44)(45)(46)(47), and are again isolated by simple filtration. Although superficially similar to the reactions of indoles and pyrroles, this ring expansion-first reported for NÀ H diazoles under thermolytic conditions [40] is proposed to proceed via a mechanistically distinct pathway that involves initial N 2 quaternization of the pyrazole.…”

Photoinduced regioselective difluorination of secondary inert C(sp3)–H bonds in sulfonamides via 1,5-hydrogen-atom transfer

“…15 Therefore, developing efficient methods for synthesizing compounds containing this group has attracted increasing interest. Among various methods, [16][17][18][19][20][21][22][23][24][25][26] direct C(sp 3 )-H difluorination that can introduce two fluorine atoms at once is especially desirable for forming diverse molecules and functionalizing complex substrates at a late stage, which can avoid pre-functionalization and reduce the generation of harmful waste. 27,28 Previous studies have mainly focused on substrates with active C(sp 3 )-H bonds adjacent to iminyl, 29 carbonyl, [30][31][32][33] aryl 31,[33][34][35][36][37][38] or hetero-aryl 39 groups (Fig.…”

C–F bond functionalizations via fluorinated carbenes

“…11 Thus, fluorinated carbenes, even though they have been known for a long time, have started to attract increasing interest from the organic community due to the high electronegativity, low polarizability, and small atomic radius of fluorine atoms. 12 A carbene center directly installing fluorines will stabilize the reactive center thermodynamically, while fluorine groups on the carbon atom next to the carbene carbon will kinetically stabilize the carbene through inhibiting the 1,2-fluorine shift (Scheme 1b). 13 In addition, it was discovered that the fluorinated group might function as a unique kind of π-electron-donating group rather than a conventional σ-electron-withdrawing substituent.…”