Xiu-Hua Xu

Synthesis of Indole and Biindolyl Triflones: Trifluoromethanesulfonylation of Indoles with Tf2O/TTBP (2,4,6-tri-tert-butylpyridine) System

A convenient synthesis of indole triflones is reported. N-Alkyl, aryl and N-H indole triflones were obtained in 82-96% yields by the Tf(2)O/TTBP System. Biindolyl triflones were accessed in 51-81% yields for the first time by simple treatment of the resulting indole triflones with a base and without any use of organometallic chemistry. An environmentally friendly solvent, Solkane 365/227, can be substituted for this process without any loss of efficiency.

Regioselective synthesis of heteroaryl triflones by LDA (lithium diisopropylamide)-mediated anionic thia-Fries rearrangement.

Novel heteroaryl triflones including oxindole, pyrazolone, pyridine, and quinoline derivatives have been regioselectively synthesized by LDA-mediated thia-Fries rearrangement for the first time. These reactions are also the first examples of the application of anionic thia-Fries rearrangement in heteroaromatic compounds.

S-((phenylsulfonyl)difluoromethyl)thiophenium salts: carbon-selective electrophilic difluoromethylation of β-ketoesters, β-diketones, and dicyanoalkylidenes.

S-((Phenylsulfonyl)difluoromethyl)thiophenium salts were designed and prepared by a triflic acid catalyzed intramolecular cyclization of ortho-ethynyl aryldifluoromethyl sulfanes. The thiophenium salts were found to be efficient as electrophilic difluoromehtylating reagents for introduction of a CF2 H group to sp(3) -hybridized carbon nucleophiles such as of β-ketoesters and dicyanoalkylidenes. The (phenylsulfonyl)difluoromethyl group can be readily transformed into CF2 H under mild reaction conditions. Enantioselective electrophilic difluoromethylation was also achieved in the presence of bis(cinchona) alkaloids.

Selective O-Difluoromethylation of 1,3-Diones by Bromodifluoromethylating Reagents

The regioselective O-difluoromethylation of 1,3-diones was achieved via in situ generation of difluorocarbene from bromodifluoromethylating reagents in the presence of an organic base. A wide variety of difluormethyl enol ethers were obtained in good to excellent yields. The reaction mechanism is discussed based on ab initio calculations (kcal/mol).

Organic reaction in Solkane® 365 mfc: homocoupling reaction of terminal alkynes

Solkane® 365 mfc is proven to be an environmentally benign alternative solvent for the homocoupling reaction of terminal alkynes catalyzed by CuCl/TMEDA under air at room temperature. A variety of terminal alkynes, including aromatic, heteroaromatic and aliphatic alkynes, were cleanly transformed into 1,3-diynes within a short period in high to excellent yields up to 98%.

Remote Anionic Fries Rearrangement of Sulfonates: Regioselective Synthesis of Indole Triflones

An unusual NaH-mediated remote anionic 1,5-thia-Fries rearrangement reaction was developed. This method provides an efficient approach for the regioselective synthesis of not only 2-(2-hydroxyphenyl)-3-indole triflones but also related 3-sulfonylindoles.

Efficient Difluoromethylation of sp3 Carbon Nucleophiles by Bromodifluoromethylation Reagents with Organic Bases

Introduction of a difluoromethyl (CF2H) unit into organic molecules is of specific interest in medicinal chemistry and chemical biology, as compounds with a CF2H moiety can act as an isostere to molecules having a methanol (CH2OH) unit with improved lipophilicity.[1–6] Among several strategies for the synthesis of CF2H compounds available, a late-stage difluoromethylation using easy-to-handle reagents under mild conditions is principally advantageous for the synthesis of complex molecules.[7, 9f] Transferring a CF2H group from a reagent to a target molecule is key for the reaction, and the reagents are classified according to their nucleophilic, radical, or electrophilic character.[8–10] Electrophilic difluoromethylation through difluorocarbene species has attracted considerable attention, and several methods have been reported.8a–h, j, l Although the difluoromethylation of heteroatom-centered nucleophiles such as oxygen, sulfur and nitrogen nucleophiles is well studied,[11], 8g, j, l mild and efficient difluoromethylation methods for carbon-centered nucleophiles are relatively scarce.8i, k–m, 12d In 2007, Prakash and co-workers developed a new electrophilic difluoromethylating reagent, S-(difluoromethyl)diarylsulfonium tetrafluoroborate.8i This reagent is effective for the introduction of a CF2H group into a wide range of heteroatom-centered nucleophiles, but it failed to transfer to carbon nucleophiles. Besides, they point out the drawback of S-(difluoromethyl)diarylsulfonium tetrafluoroborate being its slow decomposition over time even at low temperatures.8m Lately, Prakash group designed a novel electrophilic difluoromethylating protocol employing in situ prepared N,N-dimethyl-S-difluoromethyl-S-phenylsulfoximinium salt as a robust electrophilic difluoromethylating reagent.8m The reagent has exhibited good reactivity toward a broad scope of nucleophiles (N, P, S, and O nucleophiles), but no example was shown for carbon nucleophiles. N-Tosyl-S-difluoromethyl-S-phenylsulfoximine, which was developed as a difluorocarbene precursor by Hu and co-workers in 2009, is effective for transferring a CF2H group to both heteroatom and carbon nucleophiles.8l However, for carbon nucleophiles, only a limited number of phenylacetylene derivatives was examined as substrates for difluoromethylation. As part of our research program towards the enantioselective synthesis of biologically attractive fluoro-organic compounds,[12, 13] we required electrophilic difluoromethylation reagents reactive enough for sp3 carbon nucleophiles, which provide the CF2H compounds with an asymmetric carbon center. In 2010, Xiao et al. for the first time reported symmetrical S-(bromodifluoromethyl)diphenylsulfonium salts.8q Recently, we reported the efficient synthesis of a series of unsymmetrical S-(bromodifluoromethyl)diarylsulfonium salts 1 which are effective for electrophilic bromodifluoromethylation (+CF2Br) of terminal alkynes in response to nBuLi.8p We disclose herein that the same regents 1 can be used as electrophilic difluoromethylation reagents for sp3 carbon nucleophiles mediated by organic bases (Scheme 1). Allylic difluoromethylation of dicyanoalkylidenes proceeds nicely by 1 in the presence of a P1 base to give CF2H products with a quaternary carbon center in high to excellent yields. A wide range of β-ketoesters are also efficiently reacted with 1, mediated by 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU )to provide carbon—CF2H compounds as major products with a small amount of oxygen—CF2H products in high to excellent yields. In addition to the high yields of the carbon—CF2H products, the use of reagents 1 having CF2Br moieties as a CF2H source is of further advantage, as the CF2Br-reagents 1 are quite stable due to the lack of an acidic hydrogen atom.8i, l, m

Catalyst -free and catalytic Friedel–Crafts alkylations of indoles in Solkane® 365mfc, an environmentally benign alternative solvent

Solkane® 365mfc is a proven environmentally benign alternative solvent for catalyst-free Friedel–Crafts (F–C) alkylations of indoles with trifluoropyruvate and glyoxylate. Their enantioselective variants are also achieved by virtue of the high-affinity of fluorous cinchona alkaloids catalysts to Solkane® 365mfc to provide F–C adducts in excellent yields with good to excellent ees (up to 96% ee).

Stereoselective Synthesis of Vinyl Triflones and Heteroaryl Triflones through Anionic O→Cvinyl and N→Cvinyl Trifluoromethanesulfonyl Migration Reactions

Vinyl triflone (trifluoromethanesulfone) is a simple, unique, and useful structural unit which takes advantage of the strong electron-withdrawing power and the manifold reactivity of the triflyl (trifluoromethanesulfonyl; SO2CF3) group. Research on vinyl triflone began about two decades ago. Although vinyl triflones have some potential with applications in medicinal chemistry and material science, they are not widely available. There are mainly two methods to synthesize vinyl triflones: direct condensation of triflyl-containing building blocks with aldehydes 5] and indirect transformation from alkynyl triflones or alkyl triflones. 4d, 7] Although these methods are efficient, they suffer from either comparably narrow substrate scope or multiple reaction steps. Critically, they require precursors which already contain a carbon–triflyl moiety, that is, C SO2CF3. To meet the increasing demand of organofluorine compounds in agrochemicals, pharmaceuticals, and materials, it is highly desirable to develop straightforward methods for the synthesis of vinyl triflones by direct Cvinyl Striflyl bond formation (Figure 1). The anionic Fries rearrangement, developed in the 1980s, has become a common concept in the synthesis of polysubstituted aromatics. The anionic thia-Fries rearrangement, uncovered by Lloyd-Jones in 2003, has been widely applied in the synthesis of various aryl triflones. Recently, our group reported the regioselective synthesis of various heteroaryl triflones by anionic thia-Fries rearrangement. Next we were wondering if we could extend its application to the synthesis of vinyl triflones. However, the Oaryl!Cvinyl sulfonyl migration reaction is still a challenge. As in these remote anionic Fries-type rearrangement reactions, the chemo-, regio-, and stereoselectivity must be simultaneously considered. Thus, to date, only few examples have been reported, and the substrates were limited to a special structure. In continuation of our recent research interest in triflone chemistry, 15] we report herein our original results about stereoselective synthesis of substituted vinyl triflones from easily accessible gem-bromovinyl substrates through an anionic thia-Fries-type rearrangement. A Cvinyl Striflyl bond formation was realized with the help of an intramolecular migration reaction. The reaction of gem-dibromovinyl substrates with nBuLi (2.0 equiv) is well known as the general method for preparing alkynes [Eq. (1), Scheme 1]. We were pleased to find that

Efficient direct ester condensation between equimolar amounts of carboxylic acids and alcohols catalyzed by trifluoromethanesulfonic acid (TfOH) in Solkane365mfc

A simple, practical, and environmentally benign esterification protocol has been devised on the basis of TfOH as the catalyst and Solkane365mfc as the reaction medium. The direct condensation of equimolar amounts of various carboxylic acids and alcohols was conveniently carried out without recourse to any additional water removal technique, giving the desired carboxylic esters in excellent yields.