Efficient synthesis of tri- and difluoroacetyl hydrazides as useful building blocks for non-symmetrically substituted, fluoroalkylated 1,3,4-oxadiazoles

A convenient and efficient approach to 2-arylamino-5-fluoroalkyl-1,3,4-oxadiazoles has been established via heterocyclization of tri- and difluoroacetylated thiosemicarbazides using dicyclohexylcarbodiimide. A heterocyclization performed with selected thiosemicarbazides under basic conditions led to 4-aryl-5-fluoroalkyl-2,4-dihydro-3H-1,2,4-triazole-3-thiones in moderate yields. The starting fluoroacetylated thiosemicarbazides were prepared by fluoroacetylation of benzyloxycarbonyl-protected hydrazine with a corresponding anhydride, followed by hydrogenolytic deprotection and reaction with arylisothiocyanates. Fluoroacetylated semicarbazides were prepared similarly, but all attempts to achieve their heterocyclization were unsuccessful

Application of diethyl ethynylphosphonate to the synthesis of 3‐phosphonylated β‐lactams via the Kinugasa reaction

Dedicated to Prof. Jacek Młochowski on the occasion of his 80th birthday.The easily available diethyl ethynylphosphonate reacts with diverse aldonitrones under Kinugasa reaction conditions at room temperature, providing 3‐phosphonylated β‐lactams in good yields. In all cases, the reaction led to the trans‐isomer exclusively. The trans‐configuration was assigned based on 1H‐NMR spectroscopic analysis.Authors acknowledge the National Science Center (PL-Cracow) for financial support (Grant OPUS–7 (UMO– 2014/13/B/ST5/04004))

Generation and reactions of thiocarbonyl S-(2,2,2-trifluoroethanides). Synthesis of trifluoromethylated 1,3-dithiolanes, thiiranes and alkenes

The ‘in situ’ generated 1,1,1-trifluorodiazoethane reacts with thioketones as C=S dipolarophiles in a two-phase system (DCM/H$_2$O) at room temperature to yield trifluoromethylated 2,5-dihydro-1,3,4-thiadiazoles. Whereas stable crystalline products were obtained with cyclobutanethiones, the reaction with aromatic and heteroaromatic thioketones occured with spontaneous elimination of nitrogen. The formation of sterically crowded 4,4,5,5-tetrahetaryl-1,3-dithiolanes indicates that thiocarbonyl S-methanides are formed immediately and entered formal [3+2]-cycloaddition as diradical species with the starting thioketone. A protocol for the preparation of 3,3,3-trifluoropropene derivatives starting from corresponding thioketones and 1,1,1-trifluorodiazoethane is also presented

A novel access to 4-trifluoromethyl-1,3-thiazole derivatives via an intermediate thiocarbonyl ylide

A Lewis acid catalyzed reaction of trifluoroacetyldiazomethane (CF3COCHN2) with thiourea occurs in boiling THF solution in the presence of BF3·OEt2 yielding 2-amino-4-trifluoromethyl-1,3-thiazole in a fair yield. Analogous reactions with aromatic thioamides, performed in the presence of a mesylchloride/triethylamine mixture as a dehydrating agent led to the corresponding 2-aryl-4-trifluoromethyl-1,3-thiazoles. Aromatic thioamides also react with CF3COCHN2 under MW irradiation, and after 2 min, the corresponding 1,3-thiazoles were obtained in fair yields. The obtained fluorinated 2-amino-1,3-thiazole was used for the reactions with selected N-alkylating and N-acylating reagents to give trifluoromethylated analogues of commonly known pharmaceuticals with 1,3-thiazole structures (Fanetizole and Lotifazole)

Efficient synthesis of fluoroalkylated 1,4,2-oxathiazoles via regioselective [3 + 2]-cycloaddition of fluorinated nitrile oxides with thioketones

Fluorinated acetonitrile oxides, generated from the corresponding hydroximoyl bromides in the presence of aryl, hetaryl, ferrocenyl, and cycloaliphatic thioketones, undergo efficient [3 + 2]-cycloadditions to give 3- fluoroalkylated 1,4,2-oxathiazoles in good to excellent yields. The reactions proceed regioselectively with no competitive formation of furoxans as dimers of the intermediate 1,3-dipoles

Cyclization of substitued 2-(2-fluorophenylazo)azines to azino[1,2-c]benzo[d][1,2,4]triazinium derivatives

Light-induced cyclization of several substituted 2-(2-fluorophenylazo)azines in the presence of Ca2+ ions to the corresponding triazinium derivatives is investigated experimentally and computationally. The azo derivatives of 4-methylpyridine 4 undergo facile cyclization to the corresponding triazinium 1, and the rate of cyclization increases with increasing number of fluorine atoms at the benzene ring. No triazinium ions were obtained from azo derivatives of 4-cyanopyridine, pyrazine and pyrimidine, presumably due to their instability under the reaction conditions. The experimental results and mechanism are discussed with the aid of DFT computational results

Efficient synthesis of fluoroalkylated 1,4,2-oxathiazoles via regioselective [3 + 2]-cycloaddition of fluorinated nitrile oxides with thioketones

Fluorinated acetonitrile oxides, generated from the corresponding hydroximoyl bromides in the presence of aryl, hetaryl, ferrocenyl, and cycloaliphatic thioketones, undergo efficient [3 + 2]-cycloadditions to give 3- fluoroalkylated 1,4,2-oxathiazoles in good to excellent yields. The reactions proceed regioselectively with no competitive formation of furoxans as dimers of the intermediate 1,3-dipoles

A Remarkable Influence of a Trifluoromethyl Group on the Reactions of β‐Mercaptoalcohols with Fluorinated α‐Bromoenones

Isomeric fluorinated α‐bromoenones react with dinucleophilic β‐mercaptoalcohols in CH2Cl2 at room temperature in the presence of Et3N in a multistep process. Depending on the position of the CF3 group, different O,S‐heterocycles or non‐cyclic products were obtained. With 3‐bromo‐1,1,1‐trifluorobut‐3‐en‐2‐ones derivatives of 1,4‐oxathianes were formed, but isomeric 2‐bromo‐4,4,4‐trifluorobut‐2‐en‐1‐ones yielded 1,3‐oxathiolanes or non‐cyclic sulfides. The thia‐Michael addition is proposed as the initial step of the reaction, and the final heterocyclization is governed by the location of the CF3 group

First application of fluorinated nitrones for the synthesis of fluoroalkylated β-lactams via the Kinugasa reaction

The regioselective reactions of fluorinated nitrones with selected terminal alkynes (Kinugasa reaction) was studied in the presence of Cu(I) iodide and TEA as a base. After chromatographic purification the desired β-lactams were obtained in high yields (up to 93%) and high diastereoselectivities (up to 9:1). The reactions performed in the presence of chiral, enantiomerically pure ligands led to enantiomerically enriched products (ee values up to 26%) obtained as one of the possible diastereoisomers depending on the type of chiral ligand used