Asymmetric Diels–Alder Reaction of α‐Substituted and β,β‐Disubstituted α,β‐Enals via Diarylprolinol Silyl Ether for the Construction of All‐Carbon Quaternary Stereocenters

The asymmetric Diels–Alder reaction of α‐substituted acrolein proceeds in the presence of the trifluoroacetic acid salt of trifluoromethyl‐substituted diarylprolinol silyl ether to afford the exo‐isomer with both excellent diastereoselectivity and high enantioselectivity. In the Diels–Alder reaction of a β,β‐disubstituted α,β‐unsaturated aldehyde, good exo‐selectivity and excellent enantioselectivity was obtained when the perchloric acid salt of the bulky triisopropyl silyl ether of trifluoromethyl substituted diarylprolinol was employed as an organocatalyst in the presence of water. In both cases, all‐carbon quaternary stereocenters are constructed enantioselectively.     

Efficient Synthesis of 9H‐Pyrrolo[1,2‐α]Indoles via Michael Addition–Condensation of 3‐Substituted Indoles with α,β‐Unsaturated Ketimines

By employing copper dibromide as a catalyst, Michael addition–condensation of 3‐substituted indoles with α,β‐unsaturated ketimines was realized. The reactions afforded a large variety of 9H‐pyrrolo[1,2‐α ]indoles with good yields (up to 99 %). In addition, a plausible reaction mechanism was proposed.     

Enantioselective Organocatalytic Reduction of β‐Trifluoromethyl Nitroalkenes: An Efficient Strategy for the Synthesis of Chiral β‐Trifluoromethyl Amines

An efficient organocatalytic stereoselective reduction of β‐trifluoromethyl‐substituted nitroalkenes, mediated by 3,5‐dicarboxylic ester‐dihydropyridines (Hantzsch ester type), has been successfully developed. A multifunctional thiourea‐based (S)‐valine derivative was found to be the catalyst of choice, promoting the reaction in up to 97 % ee. The methodology has been applied to a wide variety of substrates, leading to the formation of differently substituted precursors of enantiomerically enriched β‐trifluoromethyl amines. The mechanism of the reaction and the mode of action of the metal‐free catalytic species were computationally investigated; on the basis of DFT transition‐state (TS) analysis, a model of stereoselection was also proposed.     

Divergent Reactivity in Palladium‐Catalyzed Annulation with Diarylamines and α,β‐Unsaturated Acids: Direct Access to Substituted 2‐Quinolinones and Indoles

A palladium‐catalyzed C?H activation strategy has been successfully employed for exclusive synthesis of a variety of 3‐substituted indoles. A [3+3] annulation for synthesizing substituted 2‐quinolinones was recently developed by reaction of α,β‐unsaturated carboxylic acids with diarylamines under acidic conditions. In the present work, an analogous [3+2] annulation is achieved from the same set of starting materials under basic conditions to generate 1,3‐disubstituted indoles exclusively. Mechanistic studies revealed an ortho‐palladation–π‐coordination–β‐migratory insertion–β‐hydride elimination reaction sequence to be operative under the reaction conditions.     

A Cinchona Alkaloid‐Functionalized Mesostructured Silica for Construction of Enriched Chiral β‐Trifluoromethyl‐β‐Hydroxy Ketones over An Epoxidation‐Relay Reduction Process

A cinchona alkaloid‐functionalized heterogeneous catalyst is prepared through a thiol‐ene click reaction of chiral N‐(3,5‐ditrifluoromethylbenzyl)quininium bromide and a mesostructured silica, which is obtained by co‐condensation of 1,2‐bis(triethoxysilyl)ethane and 3‐(triethoxysilyl)propane‐1‐thiol. Structural analyses and characterizations disclose its well‐defined chiral single‐site active center, and electron microscopy images reveal its monodisperse property. As a heterogenous catalyst, it enables an efficient asymmetric epoxidation of achiral β‐trifluoromethyl‐β,β‐disubstituted enones, the obtained chiral products can then be converted easily into enriched chiral β‐trifluoromethyl‐β‐hydroxy ketones through a sequential epoxidation‐relay reduction process. Furthermore, such a heterogeneous catalyst can be recovered conveniently and reused in asymmetric epoxidation of 4,4,4‐trifluoro‐1,3‐diphenylbut‐2‐enone, showing an attractive feature in a practical construction of enriched chiral β‐CF₃‐substituted molecules.     

Copper(I)‐Catalyzed Asymmetric [3+2]‐Cycloaddition of α‐Substituted Iminoesters with α‐Trifluoromethyl α,β‐Unsaturated Esters

Reported herein is an example of highly regio‐, diastereo‐ and enantioselective Cu(I)‐catalyzed intermolecular [3+2] cycloaddition reaction of α‐substituted iminoesters with α‐trifluoromethyl α,β‐unsaturated esters. This novel strategy provided a facile access to pyrrolidines with two skipped (aza)quaternary stereocenters including a CF₃ all‐carbon quaternary stereocenter. A broad substrate scope was observed and high yields (up to 94%) with excellent diastereoselectivity (up to >20 : 1 d.r.) and enantioselectivity (up to 98% ee) were obtained.     

Diastereo‐ and Enantioselective Copper(I)‐Catalyzed Intermolecular [3+2] Cycloaddition of Azomethine Ylides with β‐Trifluoromethyl β,β‐Disubstituted Enones

Reported herein is an asymmetric [3+2] cycloaddition reaction of azomethine ylides with β‐trifluoromethyl β,β‐disubstituted enones, a reaction which is enabled by a Ming‐Phos‐derived copper(I) catalyst (Ming‐Phos=chiral sulfinamide monophosphines, Figure 2 ). This method provides scalable and efficient access to the highly substituted pyrrolidines with a trifluoromethylated, all‐carbon quaternary stereocenter in good yields with up to greater than 20:1 d.r. and 98 % ee. The reaction has a broad substrate scope and tolerates a wide range of functional groups.     

Double CF Bond Activation through β‐Fluorine Elimination: Nickel‐Mediated [3+2] Cycloaddition of 2‐Trifluoromethyl‐1‐alkenes with Alkynes

The nickel‐mediated [3+2] cycloaddition of 2‐trifluoromethyl‐1‐alkenes with alkynes afforded fluorine‐containing multi‐substituted cyclopentadienes in a regioselective manner. This reaction involves the consecutive two C? F bond cleavage of a trifluoromethyl or a pentafluoroethyl group through β‐fluorine elimination.     

Pd‐Catalyzed Cyclocarbonylation of 2‐(2‐Bromoaryl)indoles with CO as a C1 Source: Selective Access to 6 H‐Isoindolo[2,1‐a]indol‐6‐ones and Indeno[1,2‐b]indol‐10(5 H)‐ones

A highly efficient and regioselective synthetic route to 6 H‐isoindolo[2,1‐a]indol‐6‐ones and indeno[1,2‐b]indol‐10(5 H)‐ones through the Pd‐catalyzed cyclocarbonylation of 2‐(2‐bromoaryl)indoles under atmospheric CO pressure has been achieved. Notably, the regioselectivity of the reaction was exclusively dependent on the structural characteristics of the indole substrates. With N‐unsubstituted indoles as the starting materials, the reaction afforded 6H‐isoindolo[2,1‐a]indol‐6‐ones in good‐to‐excellent yields. On the other hand, with N‐substituted indoles as the substrates, the reaction gave indeno[1,2‐b]indol‐10(5 H)‐ones in a highly regioselective manner.     

Synthesis of Three‐, Five‐, and Six‐Membered Heterocycles Derived from New β‐Amino‐α‐(trifluoromethyl) Alcohols

Nucleophilic trifluoromethylation of α‐imino ketones 2 , derived from arylglyoxal, with Ruppert–Prakash reagent (CF₃SiMe₃) offers a convenient access to the corresponding O‐silylated β‐imino‐α‐(trifluoromethyl) alcohols. In a ‘one‐pot’ procedure, by treatment with NaBH₄, these products smoothly undergo reduction and desilylation yielding the expected β‐amino‐α‐(trifluoromethyl) alcohols 4 . The latter were used as starting materials for the synthesis of diverse trifluoromethylated heterocycles, including aziridines 5 , 1,3‐oxazolidines 8 , 1,3‐oxazolidin‐2‐ones 9 , 1,3,2‐oxazaphospholidine 2‐oxides 10 , 1,2,3‐oxathiazolidine 2‐oxides 11 , and morpholine‐2,3‐diones 12 . An optically active 5‐(trifluoromethyl)‐substituted 1,3‐oxazolidin‐2‐one 9g was also obtained.     

Copper‐Catalysed Decarboxylative Trifluoromethylation of β‐Ketoacids

An efficient method for Cu‐catalyzed decarboxylative trifluoromethylation of β ‐ketoacids to achieve α ‐trifluoromethyl ketones was developed. A wide variety of synthetically useful α ‐trifluoromethyl ketones were obtained in modest to good yields under mild reaction conditions. The present method also exhibits good functional‐group compatibility.     

Regio‐ and Enantioselective Synthesis of Trifluoromethyl‐Substituted Homoallylic α‐Tertiary NH2‐Amines by Reactions Facilitated by a Threonine‐Based Boron‐Containing Catalyst

A method for catalytic regio‐ and enantioselective synthesis of trifluoromethyl‐substituted and aryl‐, heteroaryl‐, alkenyl‐, and alkynyl‐substituted homoallylic α‐tertiary NH₂‐amines is introduced. Easy‐to‐synthesize and robust N‐silyl ketimines are converted to NH‐ketimines in situ, which then react with a Z‐allyl boronate. Transformations are promoted by a readily accessible l ‐threonine‐derived aminophenol‐based boryl catalyst, affording the desired products in up to 91 % yield, >98:2 α:γ selectivity, >98:2 Z:E selectivity, and >99:1 enantiomeric ratio. A commercially available aminophenol may be used, and allyl boronates, which may contain an alkyl‐, a chloro‐, or a bromo‐substituted Z‐alkene, can either be purchased or prepared by catalytic stereoretentive cross‐metathesis. What is more, Z‐trisubstituted allyl boronates may be used. Various chemo‐, regio‐, and diastereoselective transformations of the α‐tertiary homoallylic NH₂‐amine products highlight the utility of the approach; this includes diastereo‐ and regioselective epoxide formation/trichloroacetic acid cleavage to generate differentiated diol derivatives.     

Designing New α,β‐Unsaturated Thioesters for the Catalytic,Enantioselective Friedel?Crafts Alkylation of Indoles

A new class of α,β‐unsaturated S‐(1,3‐benzoxazol‐2‐yl) thioesters of type 2 have been synthesized and effectively employed as electrophiles in the stereoselective alkylation of indoles. The combination of electronic as well as steric properties of such Michael acceptors allowed us to carry out Friedel? Crafts alkylations of various substituted indoles in the presence of a catalytic amount (20 mol‐%) of chiral cationic [Pd^II(Tol‐binap)] complexes. With the optimized catalytic system (PdCl₂(MeCN)₂/Tol‐binap/AgSbF₆), the desired β‐indolyl‐substituted thioderivatives 4 were obtained in good yield, with an enantiomeric excess (ee) of up to 86%. The remarkable versatility of the enantiomerically enriched thioesters 4 was demonstrated by quantitatively transforming them into optically active β‐indolyl esters and amides under mild conditions. With this stereoselective, catalytic Friedel? Crafts reaction, we open up the way towards new α,β‐unsaturated compounds that could be suitable candidates for the preparation of a number of optically active β‐substituted carboxylic compounds.     

TiO2‐Nanoparticles Catalyzed Synthesis of New Trifluoromethyl‐4,5‐dihydro‐1,2,4‐oxadiazoles and Trifluoromethyl‐1,2,4‐oxadiazoles

Synthesis of a new series of trifluoromethyl‐4,5‐dihydro‐1,2,4‐oxadiazoles and trifluoromethyl‐1,2,4‐oxadiazoles have been described by utilizing the reactions between amidoximes and trifluoroacetimidoyl chlorides. Trifluoromethyl‐4,5‐dihydro‐1,2,4‐oxadiazoles have been synthesized under mild conditions such as Na₂CO₃, THF‐H₂O, and titanium dioxide nanoparticles as catalyst in good to excellent yields. Also, trifluoromethyl‐1,2,4‐oxadiazoles have been synthesized directly from reaction of amidoximes and trifluoroacetimidoyl chlorides in a one‐pot manner in present of NaH, THF, and titanium dioxide nanoparticle as catalyst.     

Titelbild: Double C?F Bond Activation through β‐Fluorine Elimination: Nickel‐Mediated [3+2] Cycloaddition of 2‐Trifluoromethyl‐1‐alkenes with Alkynes (Angew. Chem. 29/2014)

The nickel‐mediated [3+2] cycloaddition of 2‐trifluoromethyl‐1‐alkenes with alkynes afforded fluorine‐containing multi‐substituted cyclopentadienes in a regioselective manner. This reaction involves the consecutive two C F bond cleavage of a trifluoromethyl or a pentafluoroethyl group through β‐fluorine elimination.     

Synthesis of tetracyclic system of 2,4‐di(tert‐butyl)‐6,7‐dihydrofuro[2′,3′:3,4]cyclohepta[1,2‐b]indole

For the first time, tetracyclic compounds, namely, furo[2′,3′:3,4]cyclohepta[1,2‐b]indoles were synthesized by recyclization of ortho‐substituted aryldifurylmethanes containing tert‐butyl groups at C5 positions of the furan rings. It was shown that [2‐(benzoylamino)phenyl]bis(5‐tert‐butyl‐2‐furyl)methanes 12 are transformed into tetracycles 15 at room temperature under treatment with POCl₃ in benzene solution containing some drops of water. The reaction proceeds via the intermediate formation of 1‐benzoylamino‐3‐(5‐tert‐butyl‐2‐furyl)‐2‐(4,4‐dimethyl‐3‐oxopentyl)indoles 14 which can be isolated from the reaction mixture. The method is very simple but its application is restricted due to side reactions if electron‐releasing groups are present in 12 . On the other hand, the decrease of electron density on furan ring in the starting compounds (for example, the use of [2‐X‐phenyl]difurylmethanes (where X = tosylamino or hydroxy group) prevents cyclization under the studied reaction conditions. As a result, corresponding ketones are formed as products of recyclization. J. Heterocyclic Chem., (2011).     

Rapid Access to β‐Trifluoromethyl‐Substituted Ketones: Harnessing Inductive Effects in Wacker‐Type Oxidations of Internal Alkenes

We present a practical trifluoromethyl‐directed Wacker‐type oxidation of internal alkenes that enables rapid access to β‐trifluoromethyl‐substituted ketones. Allylic trifluoromethyl‐substituted alkenes bearing a wide range of functional groups can be oxidized in high yield and regioselectivity. The distance dependence of the regioselectivity was established by systematic variation of the number of methylene units between the double bond and the trifluoromethyl group. The regioselectivity enforced by traditional directing groups could even be reversed by introduction of a competing trifluoromethyl group. Besides being a new powerful synthetic method to prepare fluorinated molecules, this work directly probes the role of inductive effects on nucleopalladation events.     

A Copper(I)‐Catalyzed Enantioselective γ‐Boryl Substitution of Trifluoromethyl‐Substituted Alkenes: Synthesis of Enantioenriched γ,γ‐gem‐Difluoroallylboronates

The first catalytic enantioselective γ‐boryl substitution of CF₃‐substituted alkenes is reported. A series of CF₃‐substituted alkenes was treated with a diboron reagent in the presence of a copper(I)/Josiphos catalyst to afford the corresponding optically active γ,γ‐gem‐difluoroallylboronates in high enantioselectivity. The thus obtained products could be readily converted into the corresponding difluoromethylene‐containing homoallylic alcohols using highly stereospecific allylation reactions.     

Reaction of β‐Bromo‐β,γ‐unsaturated Pyrroline Nitroxide Aldehydes and Nitriles with Aromatic N,S‐Binucleophiles

Reactions of β‐bromo‐β,γ‐unsaturated pyrroline nitroxide aldehyde ( 1 ) or nitrile ( 4 ) or their diamagnetic forms ( 5, 6 ) with 2‐aminothiophenol or 2‐mercaptobenzimidazole were evaluated. The reaction could be reproduced more easily with the application of O‐acetyl derivatives of nitroxides to generate 2‐substituted‐benzothiazole, pyrrolo[3,4‐b ]benzo[1,5]tiazepine scaffolds with 2‐aminothiophenol and benzimidazo[2,1‐b ]pyrrolo[3,4‐e ]‐[1,3]thiazine scaffold with 2‐mercaptobenzimidazole.     

Efficient Synthesis of α‐Benzylidene‐γ‐methyl‐γ‐butyrolactones

A concise synthesis of α‐benzylidene‐γ‐methyl‐γ‐butyrolactones 5a – g from substituted benzaldehydes is described. Compounds 1a – g on reaction with phosphorane 2 , provide the pentenoates 3a – g , which can be hydrolyzed to the acids 4a – g . The latter are cyclized to the corresponding butyrolactones 5a – g in excellent yields. The pentenoates 3a – g , on acid catalyzed cyclization, also provide 5a – g in very high yields.