Search

The applicability of allenylboronates as novel all-carbon formal 1,3-dipoles in the silver-catalysed annulation reaction with aryldiazonium salts for the synthesis of N-aryl pyrazoles is disclosed.

A cesium carbonate (Cs2CO3)-catalyzed [3+3] cycloaddition reaction of coumarin-diazo reagents with glycine imino esters is established to produce tetrahydro-1,2,4-triazines in good yields with excellent regioselectivity. One-pot cycloaddition/oxidation protocol could further provide practical access to a series of new coumarin-decorated 1,2,4-triazines.

A N-iodosuccinimide (NIS)-promoted [3 + 2] annulation reaction of aryldiazonium salts with guanidines has been developed for the construction of previously elusive 2-aryl-5-amino-2H-tetrazoles. This transformation takes advantage of readily available starting materials, proceeds under metal-free, mild, and robust conditions, and holds broad functional group compatibility. The utility of this protocol is further manifested via coupling, annulation, deamination, and denitrogenation derivatizations.

A diethylzinc-promoted unconventional annulation reaction of 2,2,2-trifluorodiazoethane with 2H-azirines is described. This transformation involves two [3 + 2] cycloaddition steps and one dinitrogen extrusion process in one pot, thus giving a broad array of 3-trifluoromethyl pyrazolines in good yields with excellent diastereoselectivities. Further transformations provide facile access to 3-trifluoromethyl pyrazoles and 3,5-ditrifluoromethyl pyridazines with good efficiency.

Here we present a quadruple functionalization approach for the modular construction of fully substituted N

A poly trifluoromethylated chiral spirocyclic phosphoric acid was developed and employed with hexafluoroisoproyl alcohol (HFIP) to render the catalytic asymmetric Mukaiyama-Mannich reaction of difluoroenoxysilanes with in situ formed ketimines. This unique multiple-fluorine system provides rapid access to difluoromethylated tetrasubstituted stereocenters in isoindolones with wide substrate scope under mild conditions. Further synthetic transformations to enantioenriched CF2H-isoindolones and CF2-decorated fused isoindolones were also implemented with good efficiency.

A general and practical cross-dehydrogenative coupling protocol between readily available trisubstituted α,β-dehydro α-amino carboxylic esters and H-phosphites is described. This C(sp2)–H phosphory...

The general synthesis of fully substituted N2-aryl-1,2,3-triazoles is hitherto challenging compared with that of the N1-aryl counterparts. Herein, we describe a Cu-catalyzed annulation reaction of azirines and aryldiazonium salts. This regiospecific method allows access to a broad spectrum of tri-carbo N2-aryl-1,2,3-triazoles substituted with diverse aryl and alkyl moieties. Its utility is highlighted by the synthesis of several triazole precursors applicable in drug discovery, as well as novel chiral binaphthyl ligands bearing triazole moieties.

Herein we report a novel and straightforward protocol for the construction of valuable gem-BPs by means of proton-coupled electron-transfer (PCET)-triggered enamido C(sp2 )-H diphosphorylation. This reaction represents a rare example of realizing the challenging double C-P bond formation at a single carbon atom, thus providing facile access to a broad variety of structurally diverse bisphosphonates from simple enamides under silver-mediated conditions. Initial mechanistic studies demonstrated that the diphosphorylation involves two rounds of PCET-initiated radical relay process.

Here we describe an enantioselective Mannich reaction of cyclic iminoglyoxylates with enamides by virtue of chiral phosphoric acid catalysis in a one-pot manner. The wide substrate scope, mild reaction conditions, and constantly excellent enantioselectivities (>95% ee in most cases) render this protocol highly practical for the rapid construction of valuable noncanonical chiral α-amino-acid building blocks.

Here we report a Ag-catalyzed [3 + 2] cycloaddition reaction between aryl diazonium salts and Seyferth-Gilbert reagent in a regioselective manner. This operationally simple transformation proceeds in an atom-economical way under mild reaction conditions, providing facile access to a broad set of phosphonylated tetrazoles. The synthetic utility of this method is further showcased by a straightforward procedure from upstream aromatic amines, denitrogenation transformations, and preparation of a phosphonylated drug scaffold.

We report a general and efficient approach to construct achiral and chiral gem-difluoroallylic amines from a masked difluorodiazo reagent (PhSO2CF2CHN2) and readily available imines. This facile protocol takes advantage of the phenylsulfonyl and diazo moieties as efficient activating and directing groups to assist difluoroalkyl incorporation and facilitate the chemodivergent and stereoselective formation of gem-difluoroallylic amines.

A silver-catalyzed regioselective [3 + 2] cycloaddition reaction of PhSO2CF2CHN2 with aryl diazonium salts is described. This protocol enables the straightforward construction of a novel class of difluoromethylated tetrazoles under mild conditions, tolerates a broad spectrum of functionalities, and is applicable to one-pot operation from commercially available aniline derivatives. The synthetic merit of this method is further demonstrated by the facile preparation of versatile difluoromethylated azoles, including a valuable HCF2-analogue of P2X3 receptor antagonist.

A one-pot transformation of α,β-unsaturated trifluoromethyl ketones with 2-(phenylsulfinyl)acetamide to give trifluoromethylated 2-pyridones is realized. The reaction proceeds under mild conditions and involves multiple steps in an expeditious and controlled sequence to provide efficient access to a broad range of trifluoromethylated 2-pyridones in moderate to high yields. Moreover, further synthetic manipulations permit the routine synthesis of a diverse array of trifluoromethylated pyridines with good efficiency.

A Et3N-triggered regioselective [3 + 2] cycloaddition reaction of 3-alkynoates with Seyferth-Gilbert reagent has been developed to furnish a series of trisubstituted pyrazole-3-phosphonates. A one-pot cycloaddition/alkylation sequence further offered access to the corresponding fully substituted pyrazoles.

The development of new synthetic strategies for the efficient construction of versatile pyrrole pharmacores, especially in an operationally simple and environmentally benign fashion, still remains a momentous yet challenging goal. Here, we report a KOAc-catalyzed double decarboxylative transannulation between readily accessible oxazolones and isoxazolidinediones. This transformation represents a new way for skeletal remodeling by utilizing CO2 moiety as traceless activating and directing groups in both reaction partners. The synthetic value is evidenced by the rapid preparation of a broad spectrum of highly functionalized 3-carbamoyl-4-aryl pyrroles in good to excellent yields with exclusive regio-control, including the important Atorvastatin core.

Cyano-tetrazole is the first reported compound that bears four nitrogen atoms in a single five-membered ring. This unique molecular scaffold has long been ignored after its discovery in 1885, mainly attributed to the scarcity of available synthetic methods. Indeed, the most popular approach to tetrazoles (that is the cycloaddition reaction between nitriles and azides) has inevitably excluded the possibility of introducing valuable cyano groups to decorate the final heterocyclic cores. Here, we describe a completely different disconnection strategy to the long time-pursued cyano-tetrazoles via a simple, direct, and practical cycloaddition transformation between readily accessible aryl diazonium salts and diazoacetonitrile. This method provides both regioisomers of disubstituted tetrazoles from the same set of starting materials in a metal cation controlled fashion.

Remote functionalization reactions have the power to transform a C-H (or C-C) bond at a distant position from a functional group. This Review summarizes recent advances and key breakthroughs in remote fluorination, trifluoromethylation, difluoromethylation, trifluoromethylthiolation, and fluoroalkenylation reactions. Several powerful strategies have emerged to control the reactivity and distal selectivity such as the undirected radical approach, the 1,5-hydrogen atom transfer, the metal migration, the use of distant directing groups, and the ring-opening reactions. These unconventional and predictable C-H (and C-C) functionalization transformations should allow for the preparation of a wide range of otherwise-difficult-to-access alkyl, aromatic, heteroaromatic, and structurally complex fluorides.

A diastereo- and enantioselective approach to access chiral CF2-functionalized aziridines from difluorodiazoethyl phenyl sulfone (PhSO2CF2CHN2) and in situ-formed aldimines is described. This multicomponent reaction is enabled by a combined strong Brønsted acid catalytic platform consisting of a chiral disulfonimide and 2-carboxyphenylboronic acid. The optical purity of the obtained CF2-substituted aziridines could be further improved by a practical dissolution–filtration procedure.

A zinc-mediated Mannich-type transformation of 2,2,2-trifluorodiazoethane with a series of imines has been described. This method provides facile access to a wide range of trifluorodiazoethyl-substituted amines in moderate to high yields under mild conditions. The synthetic utility of the afforded adducts is demonstrated by further transformations to valuable β-CF3-amines.

Phenylsulfone difluorodiazoethane (PhSO2CF2CHN2), an easy-to-prepare and bench-stable masked CF2-building block, has been developed. The synthetic utility of this reagent is demonstrated by a direct regioselective [3 + 2] cycloaddition with electron-deficient alkynes and alkenes. This protocol enables facile construction of an array of difluoromethyl-substituted pyrazoles in good to high yields under mild reaction conditions.

A Et3N-mediated Neber reaction of aryl/alkyl-2,2,2-trifluoroethylketoximes has been developed. This one-pot metal-free protocol enables the facile construction of an array of trifluoromethyl-substituted azirines in moderate to high yields under mild reaction conditions. Further transformations of azirines to CF3-containing pyrrole and amino-alcohol derivatives are also demonstrated.

International audience; A telescoping process involving the consecutive addition of four reagents (trifluorodiazoethane, phosphine, allenyl ester, and acetic acid) into a single reactor was developed for the novel functionalization of allenyl esters. First, new phosphazenes derived from trifluorodiazoethane and phosphines were generated and reacted with allenyl esters to give unexpected α‐iminophosphoranes through the creation of C=P, C=N, and C−H bonds at the α‐, β‐, and γ‐carbon atoms, respectively, of the allenyl esters. The α‐iminophosphoranes did not react with aldehydes in a classic Wittig reaction, but instead β‐enamino esters were obtained. The overall sequence of reactions offered a formal hydrohydrazonation of allenyl esters. The method was extended to other related diazo compounds and applied to the preparation of novel 5‐pyrazolone derivatives. Not only is the telescoping process described herein an effective approach for truncating the multistep synthesis, but also each step has been dissected to understand and support the reaction mechanisms.

A facile enantioselective addition of terminal 3-en-1-ynes to cyclic N-acyl trifluoromethyl ketimines is reported. In the presence of Zinc/BINOL complexes, a series of enynylated tertiary carbinamines were readily obtained in 90–97% yield with 70–97% enantiomeric excess in a single chemical operation under mild reaction conditions.

One-pot cascade transformations are developed that involve [3 + 2] cycloaddition/Michael/aldol and [3 + 2] cycloaddition/double 1,2-addition reactions of zinc trifluorodiazoethylide with various α,β-unsaturated enones. The protocol provides straightforward access to trifluoromethyl-substituted polycyclic pyrazolines with high chemo-, regio-, and diastereoselectivity.

Herein, we present a facile approach to a diverse collection of 1,4-disubstituted 3-di- or mono-fluoromethylpyrazoles utilizing our previously developed cyanopyrazoles as key building blocks. This method features several merits, such as easily accessible starting materials, broad substrate scope, mild reaction conditions, and simple operation. This protocol further deserves to be highlighted by the successful translation into the synthesis of commercialized fungicide fluxapyroxad and its analogues.

A Et3N-catalyzed [3 + 2] cycloaddition reaction of allenoates with acceptor diazo compounds that include diazoesters, diazoketones, and diazoamides, has been developed. This transformation allows direct and regioselective synthetic route to a variety of pyrazoles from allenoates. 3-Alkynoates also participate in the cycloaddition reaction by isomerizing to the corresponding allenoates in situ.

The diastereoselective carbometalation reaction of cyclopropenyl esters followed by reaction with acylsilanes provides γ-silylated lactones that undergo a ‘sila-Grob’ fragmentation to give pyrone enolates as a new source of acyclic δ-diketones, δ-keto acid, and δ-keto ester derivatives possessing a quaternary stereocenter.

Here we present a dipolar [3 + 2] cycloaddition transformation of diazoacetates with arenediazonium salts under silver catalysis, thus offering a straightforward approach for the regioselective construction of carboxylic tetrazoles. Several merits are accompanied with this reaction including readily available starting reagents, broad coupling scope, high yields, and friendly reaction conditions. The synthetic value is further showcased by one-pot conversion of commercially available primary arylamines to tetrazoles and successful transformations of the cycloadducts into valuable 5-fluoromethyltetrazoles and an analogue of P2X3 receptor antagonist.

From a single α-silylated carbinol intermediate, easily accessible by carbometallation of cyclopropenes, various scaffolds featuring a quaternary carbon stereocenter could be obtained selectively. The selectivity towards these different products was achieved by either changing the experimental conditions or the nature of the organometallic species involved.

A series of pyrrole- and indole-fused trifluoromethyl-functionalized piperazine derivatives were constructed in moderate to good yields with excellent chemoselectivities via a Pictet-Spengler reaction under mild and operationally simple conditions. The synthetic utility of this protocol was further extended by the facile preparation of indole-fused CF3-1,4-diazocane and enantioenriched CF3-piperazines via a vinylogous Pictet-Spengler reaction and an asymmetric Pictet-Spengler reaction, respectively.

A facile and effective enantioselective addition of terminal 1,3-diynes to acyclic α-CF 3 ketimine esters has been developed by using zinc/Binol complexes. The reaction works well with a variety of aromatic-, aliphatic- and silyl-substituted diynes, providing the desired products in up to 97% yield and 97% enantiomeric excess.

A novel enantioselective diynylation of cyclic N-acyl trifluoromethylketimines with chloramphenicol-amine derivatives as chiral additives has been successfully developed. A series of diynylated tertiary trifluoromethylcarbinamines were obtained in high yields with good to excellent enantioselectivities (with up to 99% ee).

In the presence of saccharide-derived bifunctional amine-thiourea catalysts, the direct aldol condensation of trifluoroacetaldehyde methyl hemiacetal with aromatic ketones proceeds to produce ( R )-β-hydroxy β-trifluoroalkyl ketones in low to moderate yields with good enantioselectivities.

The catalytic activity of the novel title catalyst (I) is demonstrated in the highly enantioselective amination of benzofuranones with diester (III).

A highly regioselective cycloaddition procedure of electron-deficient allenes with trifluorodiazoethane (CF3CHN2) is described. In absence of bases, the reaction proceeded smoothly to give 5-(trifluoromethyl)pyrazolines, whereas the utility of Et3N led to the formation of 3-(trifluoromethyl)pyrazoles.

This work describes the design, synthesis, and application of de novo chiral fluorinating agents as analogues of popular N-fluorodibenzenesulfonimide (NFSI). The fluorination step by means of elemental fluorine is presented. Enantioselective fluorination is demonstrated in cyclic β-keto esters and in the synthesis of BMS-204352 (up to 86 % ee). Oxidative aminofluorination is also examined.

A highly efficient, organocatalytic, enantioselective Strecker reaction of cyclic N-acyl ketimines was developed for the preparation of enantioenriched cyclic α-amino nitriles with a quaternary carbon stereocentre and anti-HIV drug DPC 083.

A novel enantioselective diynylation of cyclic N-acyl trifluoromethylketimines with chloramphenicol-amine derivatives as chiral additives has been successfully developed. A series of diynylated tertiary trifluoromethylcarbinamines were obtained in high yields with good to excellent enantioselectivities (with up to 99% ee).