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Silylformamidine 1 exists in equilibrium with its carbenic form 1' due to an easy migration of the silyl group. The reaction of 1 with variously substituted fluorobenzenes proceeds as an insertion of the nucleophilic carbene 1' into the most acidic C-H bond upon mixing the reagents and does not require any catalyst. According to DFT calculations, the classical interpretation of the insertion reaction proceeding via a three-membered transition state structure requires high activation energy. Instead, low activation barriers are predicted for a transfer of the most acidic proton in the aromatic substrate to the carbene carbon. As the next step, a barrierless rearrangement of the formed ion pair toward the product completes the process. The reactivity of substituted benzenes in the reaction with silylformamidine can be roughly assessed by calculated pKa (DMSO) values for the C-H hydrogens. Benzene derivatives having pKa approx. less than 31 can undergo C-H insertion. The reaction provides aminals as the first products, which can easily be transformed into the corresponding aldehydes via acidic hydrolysis. As silylformamidine 1 is tolerant to many functional groups, the reaction can be applied to numerous benzene derivatives, making it a reliable strategy for application in organic synthesis.

The reaction of trimethyl(trifluoromethyl)silane-tetrabutylammonium difluorotriphenylsilicate (CF

A Cu-catalyzed, easily scalable one-pot synthesis of fused pyridines by the reaction of cyclic ketones with propargylamine is described. The protocol was optimized based on the results of more than 30 experiments. The highest product yields were achieved in i-PrOH as a solvent in the presence of 5.0 mol % CuCl2 in air. In contrast to the well-known Au-catalyzed protocol, our procedure is "laboratory friendly", cost-effective, and suitable for preparing dozens of grams of fused pyridine-based building blocks and does not require a high-pressure autoclave technique. Decreasing the catalyst amount in the reaction to 1.25 mol % CuCl2 provided a yield comparable to that achieved with 5 mol % catalyst, though a longer reaction time was required. A plausible reaction mechanism was proposed. The scope and limitation of the reaction were studied using 24 different cyclic ketones as starting materials. The fused pyridine yield decreased among cyclic ketones in the following order: six-membered ≫ eight-membered > five-membered ∼ seven-membered. The elaborated reaction conditions demonstrated tolerance to a number of protective functional groups in ketone such as ester, tert-butoxycarbonyl (Boc)-protected amine, and acetal moieties.

Using DFT and ab initio calculations, we demonstrate that noncyclic formamidines can undergo thermal rearrangement into their isomeric aminocarbenes under rather mild conditions. We synthesized the silylformamidine, for which the lowest activation energy in this process was predicted. Experimental studies proved it to serve as a very reactive nucleophilic carbene. The reactions with acetylenes, benzenes, and trifluoromethane proceeded via insertion into sp, sp

A comprehensive study on the synthesis of 5-fluoroalkyl-substituted isoxazoles starting from functionalized halogenoximes is reported. One-pot metal-free [3 + 2] cycloaddition of CF3-substituted alkenes and halogenoximes bearing ester, bromo, chloromethyl, and protected amino groups was developed for the preparation of 5-trifluoromethylisoxazoles. The target 3,5-disubstituted derivatives were obtained in a regioselective manner in good to excellent yield on up to 130 g scale. 5-Fluoromethyl- and 5-difluoromethylisoxazoles were synthesized by late-stage deoxofluorination of the corresponding 5-hydroxymethyl or 5-formyl derivatives, respectively, in turn prepared via metal-free cycloaddition of halogenoximes and propargylic alcohol. An alternative approach based on nucleophilic substitution in 5-bromomethyl derivatives was found to be more convenient for the preparation of 5-fluoromethylisoxazoles. Reaction of isoxazole-5-carbaldehydes with the Ruppert-Prakash reagent was used for the preparation of (β,β,β-trifluoro-α-hydroxyethyl)isoxazoles. Utility of described approaches was shown by multigram preparation of side-chain functionalized mono-, di-, and trifluoromethylisoxazoles, for example, fluorinated analogues of ABT-418 and ESI-09.

Structural restriction of the sulfonamide bond was used to design sultams with abnormal geometric parameters. Based on analysis of tertiary aliphatic sulfonamides published in the Cambridge crystallographic database, Paquette's sultams (i.e., bridged bicyclic sultams with a bridgehead nitrogen atom) were outlined, and a number of these compounds (including the novel smallest representative, 2-thia-1-azabicyclo[2.1.1]hexane 2,2-dioxide) were synthesized by cyclization of the corresponding amino sulfonyl fluorides. A series of tertiary aliphatic sulfonamides was studied by crystallographic and quantum chemical methods. It was found that the s-character of the nitrogen lone pair is the most important factor defining properties of the S-N bond. Thus, going from the sp3-hybrid lone pair in common sulfonamides to the sp-like lone pair in the smallest Paquette's sultam resulted in an increase in S-N bond length by ca. 0.06 A. The strain energy of ca. 30 kcal/mol was predicted for the latter compound, which was higher than for any existing sulfonamides studied.

Several possible reaction pathways are analyzed for the recently studied experimental reaction of diaminocarbenes with aroylimines, where the carbene acted as an oxygen-abstracting agent. A number of structures corresponding to local minima and transition states are located by geometry optimization. In contrast to the more recent interpretation of the mechanism of this process, the reaction does not proceed via the direct formation of the corresponding carbonyl ylide resulted from the electrophilic addition of diaminocarbene to the carbonyl oxygen atom. Two other, more favorable pathways were predicted instead: the nucleophilic attack of the carbene lone pair on the imino nitrogen (pathway "a") or on the carbon atom in the C═N moiety of aroylimine (pathway "b"), in agreement with predictions of the frontier molecular orbital (FMO) theory. Both intermediate adducts undergo a subsequent decomposition onto nitrile ylide and urea. Which of the two pathways becomes preferential depends on the nature of the substituents: pathway "a" is more favored for the experimentally studied species, whereas pathway "b" is thermodynamically preferable for the small-sized model structures.