Visible light irradiation of N‐bromosuccinimide serves as an effective means to convert methyl 2‐(azidomethyl)‐3‐arylpropenoates and 2‐(azidomethyl)‐3‐arylacrylonitriles to the corresponding iminyl radicals via α‐hydrogen abstraction and subsequent extrusion of dinitrogen. Thus formed iminyl radicals then undergo intramolecular ortho attack on the aryl ring, affording methyl quinoline‐3‐carboxylates and quinoline‐3‐carbonitriles respectively.
α‐Substituted β‐acetyl amides could undergo C C bond cleavage to form α‐keto amides when treated with copper(II) chloride (CuCl2) and boron trifluoride diethyl etherate (BF3⋅OEt2) under an oxygen atmosphere. The yield can be increased by the addition of tert‐butyl hydroperoxide which alone can also effect the reaction. The reaction provides a new protocol for the synthesis of α‐keto amides.
The iron(III) chloride‐multicatalyzed dioxygenation of enamides with TEMPO in the presence of alcohols has been developed. This multicomponent domino process affords efficient new strategies for the synthesis of α‐oxy‐N‐acylhemiaminals or α‐oxyimides in good to excellent yields under mild conditions.
A straightforward approach for the chemodivergent synthesis of quinolines is described through site‐selective coupling of ortho‐aminoaryl ketones with α‐enolic dithioesters (DTEs) under solvent‐free conditions. The operationally and user‐simple one‐pot methodology is based on the trifunctional nature of DTEs. Both the carbonyl and the thiocarbonyl moiety in α‐enolic dithioesters were employed for the efficient construction of three differently substituted quinolines in a chemoselective manner simply by variation of an easy to handle acid catalyst.
A highly effective aldol cyclization of α‐isothiocyanato imide to both β,γ‐unsaturated α‐keto esters and aryl‐substituted α‐keto esters has been developed. A chiral N,N′‐dioxide–yttrium triflate complex was used as the catalyst. A series of cyclic thiocarbamates bearing chiral quaternary stereocenters was synthesized in good to high yields, excellent diastereo‐ (up to 25:1 dr) and enantioselectivities (up to 99 % ee). In addition, the reaction could be carried out on a gram‐scale, and other functionalized derivatives are also conveniently transformed. Interestingly, a discrepancy of diastereoselection was observed between the reactions of β,γ‐unsaturated α‐keto esters and aryl‐substituted α‐keto esters. Moreover, a substrate dependency of non‐linear effects was observed in this reaction. On the basis of the experimental results and the absolute configuration of the products, possible catalytic models have been proposed to explain the origin of the asymmetric process.
A new enantioselective synthetic method for the synthesis of α,α‐dialkylmalonates with a quaternary carbon center was developed via α‐alkylation of prochiral malonates by phase‐transfer catalysis (PTC). Asymmetric α‐alkylation of benzylideneamino tert‐butyl α‐methylmalonates under phase‐transfer catalytic conditions in the presence of (S,S)‐3,4,5‐trifluorophenyl‐NAS bromide afforded the corresponding α,α‐dialkylmalonates in high yields (up to 97%) with excellent enantioselectivities (up to 98% ee). The products were then selectively hydrolyzed to chiral malonic monoacids under basic, acidic, or catalytic hydrogenation conditions.
We have developed a new strategy for palladium‐catalyzed arylation reactions with triazolopyridines, wherein two different chemical transformations (C‐3 vs. C‐7) are observed by differentiating the substrates using different bases. The reactive palladium carbenoids were directly generated from triazolopyridines and underwent denitrogenative arylations with aryl bromides. Intriguingly, when potassium carbonate was replaced with potassium tert‐butoxide, direct C H arylation occurred at the most acidic position (C‐7). Moreover, two different catalytic arylation events were successfully performed in a one‐pot sequence, providing a convenient access to 6‐aryl‐2‐α‐styrylpyridines.
The dynamic kinetic resolution of α‐substituted racemic β‐lactams by alcoholytic ring‐opening, catalyzed by immobilized lipase B from Candida antarctica is described. With this process, a variety of racemic α‐substituted N‐Cbz‐azetidinones (Cbz=benzyloxycarbonyl) was transformed to the corresponding N‐Cbz‐protected β2‐amino acid allyl esters with high enantioselectivity (up to 99%) and high yields (up to quantitative) at room temperature.
Copper chloride‐catalyzed aerobic oxidative annulation of N‐furfuryl‐β‐enaminones provides access to polysubstituted pyrroles and indoles. This protocol involves an unprecedented copper chloride‐catalyzed oxidative chlorination of furan and pyrrole rings with oxygen as the terminal oxidant.
A practical and novel process for the decarboxylative fluorination of β‐ketoacids in water in the presence of phase transfer catalyst has been developed, affording a series of α‐fluoroketones in good to excellent yields. Furthermore, a preliminary investigation for the catalytic asymmetric transformation was performed and a proposed mechanistic pathway for this catalytic process was proposed.
An efficient system for the direct catalytic intermolecular α‐arylation of acetamide derivatives with aryl bromides and chlorides is presented. The palladium catalyst is supported by Kwong’s indole‐based phosphine ligand and provides monoarylated amides in up to 95% yield. Excellent chemoselectivities (>10:1) in the mono‐ and diarylation with aryl bromides were achieved by careful selection of bases, solvents, and stoichiometry. Under the coupling conditions, the weakly acidic α‐protons of amides (pKa up to 35) were reversibly depotonated by lithium tert‐butoxide (LiO‐t‐Bu), sodium tert‐butoxide (NaO‐t‐Bu) or sodium bis(trimethylsilyl)amide [NaN(SiMe3)2].
The highly catalytic asymmetric α‐hydroxylation of β‐indanone esters and β‐indanone amides using peroxide as the oxidant was realized with a new C‐2′ substituted Cinchona alkaloid derivatives. The two enantiomers of α‐hydroxy‐β‐indanone esters could be obtained by simply changing the oxidant. This protocol allows a convenient access to the corresponding α‐hydroxy‐β‐indanone esters and α‐hydroxy‐β‐indanone amides with up to 99% yield and 98% ee.
A new copper‐mediated synthesis of α‐sulfonylethanone oximes from styrenes, sodium arylsulfinates and tert‐butyl nitrite (t‐BuONO; TBN) is presented. This intermolecular three‐component method enables the one‐step formation of C N and C S bonds under mild conditions, and represents a new, straightforward approach to α‐sulfonylethanone oximes.
Highly regio‐ and diastereoselective 1,2‐addition of organolithium reagents to chiral fluoroalkyl α,β‐unsaturated N‐tert‐butanesulfinyl ketimines was developed, providing a general and efficient method for the asymmetric synthesis of structurally diverse α‐tertiary fluoroalkyl allylic amines in high yields and with excellent diastereoselectivities (dr up to>99:1). The synthetic application of the method was demonstrated by the rapid and convenient preparation of challenging α‐fluoroalkyl α‐amino acids with α‐tetrasubstituted carbon.
A metal‐free vinylic carbon‐hydrogen bond thiolation has been developed. Under the catalysis of iodine (10 mol%), the cyclization of α‐alkenoyl ketene dithioacetals afforded a broad range of polyfunctionalized 2‐methylene‐3‐thiophenones in good selectivity with moderate to excellent yields via tandem iodocyclization and dehydroiodination. The synthetic strategy can also be extended to the cyclization of ortho‐methylthiophenyl vinyl ketones leading to 2‐methylene‐3‐benzothiophenones.
We describe a practical (time‐efficient, with commercially available building blocks, user friendly reaction conditions, high purity of products) synthesis of pharmacologically relevant quinoxalinones with three points of diversification that takes advantage of solid‐phase synthesis and cyclative cleavage. Resin‐bound (S)‐2‐(N‐alkyl‐2‐nitrophenyl)sulfonamide‐3‐alkyl‐N‐(2‐hydroxyethyl)propanamides, which are accessible from Fmoc‐protected α‐amino acids, 2‐nitrobenzenesulfonyl chloride and alcohols, underwent base‐mediated N‐arylation. The reduction of the nitro group produced acyclic intermediates that were subjected to acid‐mediated cyclative cleavage to yield 3,4‐dihydroquinoxalin‐2(1H)‐ones.
In the presence of sodium carbonate, the [4+3] cycloadditions of α‐halogeno hydrazones with nitrones were performed efficiently, and affording 2,3,4,7‐tetrahydro‐1,2,4,5‐oxatriazepines in moderate to high yields.
A chemoselective reduction of α‐keto amides to biologically important α‐hydroxy amides (mandelamides) by polymethylhydrosiloxane (PMHS) using 5 mol% potassium phosphate (K3PO4) as catalyst has been developed. This transition metal‐free protocol discloses excellent chemoselectivity for the ketone reduction of α‐keto amides in the presence of other reducible functionalities like ketone, nitro, halides, nitrile and amide. Also, the chemoselectively reduced α‐hydroxy amide has been derivatized to isocyanide‐free Passerini adducts. The N‐alkyl‐α‐hydroxy amides have been successfully converted to 3‐phenyloxindole derivatives by treatment with methanesulfonyl cholride and triethylamine.
A three‐component reaction of a 1,2‐amino alcohol or 1,3‐amino alcohol with a formaldehyde solution and a propiolic acid was developed and studied. This new strategy provided an efficient access to biologically and synthetically important N‐propargyl oxazolidines, 1,3‐oxazinanes and thiazolidine bearing a diverse range of substituents in good yields. The transformation involves a cascade process that begins with an annulation and is followed by the metal‐free decarboxylative coupling.
The asymmetric synthesis of a set of hydroxyphenyl γ‐valerolactones was achieved starting from 2‐silyloxyfuran and alkoxy‐substituted benzaldehydes as common precursors. Key synthesis steps included an enantioselective vinylogous Mukaiyama aldol reaction and a Barton–McCombie deoxygenation. Five enantioenriched γ‐valerolactone targets were obtained in 5–6 steps, 18–63% overall yields and 82–98 % ee, paving the way for the straightforward entry to this class of biologically effective and poorly available flavan‐3‐ol metabolites. In parallel, an unprecedented one‐pot reductive ring expansion process was fortuitously discovered, yielding racemic δ‐lactone analogues from phenolic butanolide precursors.
