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

Sheng, Heyun; Su, Jianke; Li, Xin; Li, Xue; Song, Qiuling

doi:10.1021/acs.orglett.1c02816

Cited by 32 publications

(18 citation statements)

References 60 publications

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“…To our delight, we indeed disclosed an efficient approach to assemble 3-(2,2-difluoroethyl)-2-fluoroindoles from o -aminostyrenes with two difluorocarbene species (Scheme ). In this protocol, there are two different types of fluorine sources are introduced into the final target products via double capture of difluorocarbene with synchronous formation of one C–N and two C–C bonds under transition-metals-free conditions. This reaction has great potential in the late-stage modifications of complex molecules, and features high efficiency, excellent functional group compatibility as well.…”

Section: Difluorocarbene-enabled Unusual Activation Modes For the Sel...mentioning

confidence: 99%

Unconventional Transformations of Difluorocarbene with Amines and Ethers

Song

2023

Acc. Chem. Res.

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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...

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Section: Difluorocarbene-enabled Unusual Activation Modes For the Sel...mentioning

confidence: 99%

Unconventional Transformations of Difluorocarbene with Amines and Ethers

Song

2023

Acc. Chem. Res.

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“…Later on, this strategy was extended to the synthesis of difluorinated dihydrobenzothiophenes from thiosalicylic aldehydes 117 and 2-acylthiophenols, 118 as well as to the synthesis of fluorinated indoles from vinyl-anilines. 119 A remarkable case of [4 + 1]-annulations of difluorocarbene is its interception by frustrated Lewis pairs (FLP) having a 1,4dipole structure. This type of annulation was recently demonstrated by Dilman et al 120 Thus, the interaction of o-diphenylphosphine-substituted phenylboronic acid esters 183 with potassium bromodifluoroacetate affords zwitter-ionic adducts 184 (Scheme 63).…”

Section: [4 + 1]-annulations With Difluorocarbenementioning

confidence: 99%

Section: [4 + 1]-annulations With Diazo Compounds and Other Carbene P...mentioning

confidence: 99%

Recent advances in the application of ylide-like species in [4 + 1]-annulation reactions: an updated review

2022

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“…In this context, difluoromethylative functionalization, where a difluoromethyl anion 17 – 26 , carbene 27 – 32 or radical precursor 33 – 50 is engaged in the direct transfer of the CF 2 H unit, has been vigorously pursued as a strategy with great promise in organic synthesis. Particularly, radical hydrodifluoromethylation in which CF 2 H • and H • equivalents add across to unsaturated C−C π bonds has become a central strategy to access a relatively limited class of aliphatic hydrocarbons that contain difluoromethyl group 51 – 57 .…”

Section: Introductionmentioning

confidence: 99%

Radical hydrodifluoromethylation of unsaturated C−C bonds via an electroreductively triggered two-pronged approach

et al. 2022

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Due to its superior ability in controlling pharmaceutical activity, the installation of difluoromethyl (CF2H) functionality into organic molecules has been an area of intensive research. In this context, difluoromethylation of C−C π bonds mediated by a CF2H radical have been pursued as a central strategy to grant access to difluoromethylated hydrocarbons. However, early precedents necessitate the generation of oxidative chemical species that can limit the generality and utility of the reaction. We report here the successful implementation of radical hydrodifluoromethylation of unsaturated C−C bonds via an electroreductively triggered two-pronged approach. Preliminary mechanistic investigations suggest that the key distinction of the present strategy originates from the reconciliation of multiple redox processes under highly reducing electrochemical conditions. The reaction conditions can be chosen based on the electronic properties of the alkenes of interest, highlighting the hydrodifluoromethylation of both unactivated and activated alkenes. Notably, the reaction delivers geminal (bis)difluoromethylated products from alkynes in a single step by consecutive hydrodifluoromethylation, granting access to an underutilized 1,1,3,3-tetrafluoropropan-2-yl functional group. The late-stage hydrodifluoromethylation of densely functionalized pharmaceutical agents is also presented.

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

Cited by 32 publications

References 60 publications

Unconventional Transformations of Difluorocarbene with Amines and Ethers

Unconventional Transformations of Difluorocarbene with Amines and Ethers

Recent advances in the application of ylide-like species in [4 + 1]-annulation reactions: an updated review

Radical hydrodifluoromethylation of unsaturated C−C bonds via an electroreductively triggered two-pronged approach

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