Synthesis of Functionalized Indoles with a Trifluoromethyl‐Substituted Stereogenic Tertiary Carbon Atom Through an Enantioselective Friedel–Crafts Alkylation with β‐Trifluoromethyl‐α,β‐enones

Chiral complexes of BINOL‐based ligands with zirconium tert‐butoxide catalyze the Friedel–Crafts alkylation reaction of indoles with β‐trifluoromethyl‐α,β‐unsaturated ketones to give functionalized indoles with an asymmetric tertiary carbon center attached to a trifluoromethyl group. The reaction can be applied to a large number of substituted α‐trifluoromethyl enones and substituted indoles. The expected products were obtained with good yields and ees of up to 99 %.     

Platinum‐Catalyzed Multi‐Step Reaction of Propargyl Alcohols with N‐Heteroaromatics

N‐Methyl indole reacts with but‐2‐yn‐1‐ol in the presence of PtCl₂ in MeOH giving indole derivatives having a substituted 3‐oxobutyl group at the 3‐position in good yield. Under the reaction conditions, various substituted indoles and substituted propargyl alcohols are successfully involved in the reaction giving the corresponding addition products in good to moderate yields. The catalytic reaction can be further extended to N‐phenyl pyrrole. In the present multi‐step reaction, PtCl₂ likely plays dual roles: as the catalyst for the rearrangement of propargyl alcohols to the corresponding alkenyl ketones and as the catalyst for the addition of indoles to the alkenyl ketones. Experimental evidence is provided to support the proposed mechanism.     

Preparation of 3-arylmethylindoles as selective COX-2 inhibitors

The 3-arylmethylation of indoles using TMSOTf/Et₃SiH with a wide variety of substituted benzaldehydes has been accomplished. Under these mild Lewis acid mediated reductive conditions, it was demonstrated that indoles bearing both 6-MeSO₂ and 2-methyl substituents could be 3-arylmethylated in good to excellent yields to afford the corresponding 3-arylmethyl indoles, effective as selective COX-2 inhibitors. In addition, the viability of this method for the reductive alkylation of indoles by ketones was demonstrated and shown to be C-3 regioselective. For indoles bearing both a 6-MeSO₂ and 2-cyano substituent where this indole reductive alkylation methodology was unsuccessful, an unprecedented Pd(0) mediated arylorganozinc coupling with the requisite substituted 3-methylcarbonatomethylindole proved successful in affording the desired 2-cyano-6-MeSO₂-3-arylmethylindoles effective as selective COX-2 inhibitors.     

Dy(OTf)3/Pybox-catalyzed enantioselective Friedel-Crafts alkylation of indoles with α,β-unsaturated trifluoromethyl ketones

The first catalytic enantioselective Friedel-Crafts alkylation of indoles with α,β-unsaturated trifluoromethyl ketones has been accomplished. The reaction was achieved in the presence of the Dy(OTf)₃/Pybox complex, producing the desired products in high yields (up to 99%) with good enantioselectivities (up to 86% ee). The absolute stereochemistry of the resulting adducts was determined by X-ray analysis.     

Silver salts and DBU cooperatively catalyzed domino reaction of propargylic alcohols with trifluoromethyl ketones: direct method to trifluoromethyl‐substituted 5‐alkylidene‐1,3‐dioxolane derivatives

A general and efficient synthesis of trifluoromethyl‐substituted 5‐alkylidene‐1,3‐dioxolanes using AgNO₃ and DBU cooperatively catalyzed domino reaction of propargylic alcohols and trifluoromethyl ketones is described. The reaction tolerates a broad range of functional groups, and the desired products are obtained in good to excellent yields (62–99%) with acceptable diastereoselectivities. Copyright © 2016 John Wiley & Sons, Ltd.     

Csp-Csp bond formation via Lewis acid/ammonium salt cocatalyzed tandem addition and oxidative dehydrogenation strategy: alkenylation of indoles with α,β-unsaturated ketones

The alkenylation of indoles with α,β-unsaturated ketones through a tandem addition and oxidative dehydrogenation strategy has been developed. This method provides an alternative approach for C3 alkenylation of indoles with α,β-unsaturated ketones. Using inexpensive and readily available BF₃·Et₂O and an ammonium salt as the efficient cocatalyst constitutes the attractive advantage of this reaction.     

Selenium heterocycles. XXXIII. Synthesis of thieno[3,4-b]furan,seleno[3,4-b]furan,thieno[3,4-b]indole and seleno[3,4-b]indole. four novel heterocycles

Starting from the readily available 2-methyl-3-benzoylfuran, 1-phenylthieno[3,4-b]furan and 1-phenyl-seleno[3,4-b]furan were prepared. Also, starting from phenyl 3-methylindol-2-yl ketone and aryl 2-methyl-indole-3-yl ketones a series of substituted thieno[3,4-b]indoles and substituted seleno[3,4-b]indoles were prepared.     

Efficient Access to Multifunctional Trifluoromethyl Alcohols through Base‐Free Catalytic Asymmetric C−C Bond Formation with Terminal Ynamides

The asymmetric addition of terminal ynamides to trifluoromethyl ketones with a readily available chiral zinc catalyst gives CF₃‐substituted tertiary propargylic alcohols in up to 99 % yield and 96 % ee. The exclusion of organozinc additives and base as well as the general synthetic utility of the products are key features of this reaction. The value of the β‐hydroxy‐β‐trifluoromethyl ynamides is exemplified by selective transformations to chiral Z‐ and E‐enamides, an amide, and N,O‐ketene acetals. The highly regioselective hydration, stereoselective reduction, and hydroacyloxylation reactions proceed with high yields and without erosion of the ee value of the parent β‐hydroxy ynamides.     

L-脯氨酸催化下甲基酮和1-芳基-2,2,2-三氟乙酮的不对称Aldol反应

Direct asymmetric aldol addition of methyl ketones to 2,2,2-trifluoro-1-phenylethanone and its ring-substituted derivatives was achieved using L-proline as a chiral promoter. Various optically active β-trifluoromethyl-β-hydroxy ketones were obtained in almost quantitative yields with moderate enantioselectivities up to 64 % ee.     

Synthesis of new 3‐(trifluoromethyl)‐1H‐indoles by reduction of trifluoromethyloxoindoles

This work describes the synthesis of new 3‐trifluoromethylindoles. Different isatins were trifluoromethylated using (trifluoromethyl) trimethylsilane (Me₃SiCF₃) as a nucleophilic agent giving new 3‐hydroxy‐3‐(trifluoromethyl)indolin‐2‐one. Different “one‐step” procedures to transform the latter compounds into the reduced indoles were attempted, but failed. For the synthesis of the new trifluoromethylindoles the corresponding 2‐oxo‐3‐(trifluoromethyl)indoles were reduced using borane/THF complex to furnish 3‐(trifluoromethyl)indolin‐3‐ol that additionally were dehydrated using thionyl chloride in pyridine to give excellent yields of the desired products.     

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.     

PhI(OAc)2‐Mediated Radical Trifluoromethylation of Vinyl Azides with Me3SiCF3

The fluorine‐containing organic motif is becoming privileged in pharmaceuticals, agrochemicals, and functional materials, owing to its unique properties such as electron‐withdrawing character, metabolic stability, and lipophilicity. Described herein is the PhI(OAc)₂‐mediated radical trifluoromethylation of vinyl azides with Me₃SiCF₃ to efficiently generate α‐trifluoromethyl azines. The resulting α‐trifluoromethyl azines were successfully transformed to valuable fluorine‐containing molecules such as α‐trifluoromethyl ketones, β‐trifluoromethyl amines, 5‐fluoropyrazoles, and trifluoroethyl isoquinolines.     

Catalyst-Free Site Selective Hydroxyalkylation of 5-Phenylthiophen-2-amine with α-Trifluoromethyl Ketones through Electrophilic Aromatic Substitution

An original and effective approach for achieving trifluoromethyl hydroxyalkylation of 5-phenylthiophen-2-amine using α-trifluoromethyl ketones is described. In the last few years, reaction of Friedel-Crafts had been widely used to realize hydroxyalkylation on heterocycles such as indoles or thiophenes by means of Lewis acid as catalyst. Additionally, amine functions are rarely free when carbonyl reagents are used because of their tendency to form imines. This is the first time that a site-selective electrophilic aromatic substitution on C₃ atom of an unprotected 5-phenylthiophen-2-amine moiety is reported. The liberty to allow reaction in neutral conditions between free amine is valuable in a synthesis pathway. The reaction proceeds smoothly using an atom-economical metal-and catalyst-free methodology in good to excellent yields. A mechanism similar to an electrophilic aromatic substitution has been proposed.     

Synthesis of some trifluoromethyl substituted 1‐methylpyrazoles

The major products from the reaction of β‐alkoxyvinyl trifluoromethyl ketones 1a‐c with methylhydrazine ( 2 ) in absolute ethanol are the 3‐(trifluoromethyl)‐substituted‐1‐methylpyrazoles 3a‐3c with lesser amounts of the 5‐(trifluoromethyl)‐substituted products 4a‐4c and 5a‐5c. Carrying out the reaction in non‐polar, aprotic solvents can further enhance the regioselectivity favoring the 3‐ (trifluoromethyl) ‐substituted isomers.     

Palladium‐Catalyzed Direct C2 Arylation of N‐Substituted Indoles with 1‐Aryltriazenes

A novel and efficient palladium‐catalyzed C2 arylation of N‐substituted indoles with 1‐aryltriazenes for the synthesis of 2‐arylindoles was developed. In the presence of BF₃ ? OEt₂ and palladium(II) acetate (Pd(OAc)₂), N‐substituted indoles reacted with 1‐aryltriazenes in N,N‐dimethylacetamide (DMAC) to afford the corresponding aryl–indole‐type products in good to excellent yields.     

NHC–Copper(I) Halide‐Catalyzed Direct Alkynylation of Trifluoromethyl Ketones on Water

An efficient and easily scalable NHC–copper(I) halide‐catalyzed addition of terminal alkynes to 1,1,1‐trifluoromethyl ketones, carried out on water for the first time, is reported. A series of addition reactions were performed with as little as 0.1–2.0 mol % of [(NHC)CuX] (X=Cl, Br, I, OAc, OTf) complexes, providing tertiary propargylic trifluoromethyl alcohols in high yields and with excellent chemoselectivity from a broad range of aryl‐ and more challenging alkyl‐substituted trifluoromethyl ketones (TFMKs). DFT calculations were performed to rationalize the correlation between the yield of catalytic alkynylation and the sterics of N‐heterocyclic carbenes (NHCs), expressed as buried volume (%VBur), indicating that steric effects dominate the yield of the reaction. Additional DFT calculations shed some light on the differential reactivity of [(NHC)CuX] complexes in the alkynylation of TFMKs. The first enantioselective version of a direct alkynylation in the presence of C₁‐symmetric NHC–copper(I) complexes is also presented.     

First heterogeneously palladium-catalysed fully selective C3-arylation of free NH-indoles

A simple heterogeneously palladium-catalysed procedure for the selective C3-arylation of indoles is reported. Under relatively standard reaction conditions (Pd-catalyst, K₂CO₃, dioxane, reflux), using only 1 mol % [Pd(NH₃)₄]/NaY as the catalyst, indoles substituted or not at position 2 gave up to 92% conversion (i.e., 85% isolated yield) towards the expected C3-arylated indole.     

Combining Photoredox‐Catalyzed Trifluoromethylation and Oxidation with DMSO: Facile Synthesis of α‐Trifluoromethylated Ketones from Aromatic Alkenes

Trifluoromethylated ketones are useful building blocks for organic compounds with a trifluoromethyl group. A new and facile synthesis of ketones with a trifluoromethyl substituent in the α‐position proceeds through a one‐pot photoredox‐catalyzed trifluoromethylation–oxidation sequence of aromatic alkenes. Dimethyl sulfoxide (DMSO) serves as a key and mild oxidant under these photocatalytic conditions. Furthermore, an iridium photocatalyst, fac[Ir(ppy)₃] (ppy=2‐phenylpyridine), turned out to be crucial for the present photoredox process.     

Highly Efficient InBr3 Catalyzed Michael Addition of Indoles to α, β-Unsaturated Esters

A highly efficient synthetic strategy toward Michael addition of indoles to α,β‐unsaturated esters has been developed using Lewis acid InBr₃ as catalyst. The reactions generated 3‐substituted indoles in high yields with excellent regio‐selectivity in the presence of catalytic amount of InBr₃ under mild reaction conditions. The method is simple, efficient and practical.     

Chiral Primary‐Amine‐Catalyzed Conjugate Addition to α‐Substituted Vinyl Ketones/Aldehydes: Divergent Stereocontrol Modes on Enamine Protonation

Enantioselective protonation with a catalytic enamine intermediate represents a challenging, yet fundamentally important process for the synthesis of α‐chiral carbonyls. We describe herein chiral primary‐amine‐catalyzed conjugate additions of indoles to both α‐substituted acroleins and vinyl ketones. These reactions feature enamine protonation as the stereogenic step. A simple primary–tertiary vicinal diamine 1 with trifluoromethanesulfonic acid (TfOH) was found to enable both of the reactions of acroleins and vinyl ketones with good activity and high enantioselectivity. Detailed mechanistic studies reveal that these reactions are rate‐limiting in iminium formation and they all involve a uniform H₂O/acid‐bridged proton transfer in the stereogenic steps but divergent stereocontrol modes for the protonation stereoselectivity. For the reactions of α‐branched acroleins, facial selections on H₂O‐bridged protonation determine the enantioselectivity, which is enhanced by an OH???π interaction with indole as uncovered by DFT calculations. On the other hand, the stereoselectivity of the reactions with vinyl ketones is controlled according to the Curtin–Hammett principle in the C? C bond‐formation step, which precedes a highly stereospecific enamine protonation.