Synthesis of Fluorinated and Fluoroalkylated Heterocycles Containing at Least One Sulfur Atom via Cycloaddition Reactions

Fluorinated heterocycles constitute an important group of organic compounds with a rap- idly growing number of applications in such areas as medicinal chemistry, agrochemicals produc- tion, polymer chemistry, as well as chemistry of advanced materials. In the latter case, fluorinated thiophenes are considered as a lead class of compounds with numerous spectacular applications. On the other hand, cycloaddition reactions offer a superior methodology for stereo-chemically con- trolled synthesis of heterocycles with a diverse ring size and a variable number of heteroatoms. A comprehensive review of methods based on cycloaddition reactions and applied for construction of fluorinated and/or fluoroalkylated S-heterocycles has not yet been published. For this reason, the main goal of the presented review was to fill the existing gap and to summarize the results pub- lished over last six decades. In this context, the [3+2]- and [4+2]-cycloadditions (Huisgen reactions, and Diels–Alder reactions, respectively) are of special importance. Some questions related to the discussed mechanisms of cycloaddition processes observed in reactions with electron deficient, fluorinated substrates (dipolarophiles and dienophiles), and electron-rich sulfur containing counter partners, are of fundamental importance for the development of interpretations of organic reaction mechanisms

Unexpected course of the attempted conversions of ferrocenyl(hetaryl)methanols into thiols using Lawesson’s reagent

A series of secondary methanols bearing ferrocenyl and a hetaryl substituent was tested in reactions with Lawesson’s reagent (LR) aimed at the preparation of respective methanethiols. The study showed that in boiling toluene after only few minutes the starting alcohols were consumed and unexpectedly, depending on the type of hetaryl substituent, tetra-substituted ethane or disubstituted methane derivatives were obtained in good to excellent yields. The presence of the ferrocene moiety is crucial for the observed reaction courses

Strong influence of the trifluoromethyl group on the chemoselectivity of [3+2]-cycloadditions of thiocarbonyl S-methanides with α,β-unsaturated ketones

The in situ-generated reactive thiocarbonyl S-methanides were reacted with fluorinated enones. The type of the obtained [3+2]-cycloadduct depends strongly on the location of the activating CF3 group. In the case of enones containing the CF3CH=CH moiety, the [3+2]- cycloaddition occurs chemo- and regioselectively onto the C=C bond to give trifluoromethylated tetrahydrothiophene derivatives. On the other hand, enones containing the CF3–C=O unit react as carbonyl dipolarophiles leading to trifluoromethylated 1,3- oxathiolanes also in a chemo- and regioselective manner. These are the first reported reactions of thiocarbonyl S-methanides with α,β-unsaturated ketones

Thermal [2+2]-cycloadditions of diphenylketene with aryl- and hetaryl-substituted thioketones

The reaction of diphenylketene (1) with aryl- and hetaryl-substituted thioketones (2) gave the corresponding 3,3,4,4-tetraarylthietan-2-ones (3) in good yields. Remarkably, the reactions with bis-hetaryl-substituted thioketones occurred significantly faster compared with those involving the bis-aryl-substituted thioketones. The structure of compound 3c has been established by X-ray crystallography

Synthesis of optically active polycyclic N-heterocycles derived from L-prolinamine

The N-Boc-protected (S)-prolinamine reacts readily with formaldehyde and diverse alpha-hydroxyimino ketones to give imidazole N-oxides with an enantiomerically pure N-protected (pyrrolidin-2-yl)methyl substituent. Subsequent deprotection yields the corresponding NH derivatives. Upon treatment of these products with Ac2O at room temperature, a cascade of reactions leads to optically active tricyclic products. In all these processes, the stereogenic center is preserved. In one case, the bis-heterocyclic imidazole N-oxide was transformed into the corresponding optically active imidazole-2-thione via a sulfur-transfer reaction with 2,2,4,4-tetramethylcyclobutane-1,3-dithione

First thia-Diels–Alder reactions of thiochalcones with 1,4-quinones

Aryl and hetaryl thiochalcones react smoothly with 1,4-quinones in THF solution at 60 °C yielding the corresponding fused 4H-thiopyrans after spontaneous dehydrogenation of the initially formed [4 + 2] cycloadducts. In general, the yields of the isolated products were high. With 5-chloro-10-hydroxy-1,4-anthraquinone, the thia-Diels–Alder reaction occurred with complete regioselectivity. In the case of the reaction of vitamin K3 (menadione) with diphenylthiochalcone, the initial cycloadduct was isolated in 37% yield

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

Ferrocenyl-substituted tetrahydrothiophenes via formal [3 + 2]-cycloaddition reactions of ferrocenyl thioketones with donor-acceptor cyclopropanes

Ferrocenyl thioketones reacted with donor-acceptor cyclopropanes in dichloromethane at room temperature in the presence of catalytic amounts of Sc(OTf)3 yielding tetrahydrothiophene derivatives, products of formal [3 + 2]-cycloaddition reactions, in moderate to high yields. In all studied cases, dimethyl 2-arylcyclopropane dicarboxylates reacted with the corresponding aryl ferrocenyl thioketones in a completely diastereoselective manner to form single products in which (C-2)-Ar and (C-5)-ferrocenyl groups were oriented in a cis-fashion. In contrast, the same cyclopropanes underwent reaction with alkyl ferrocenyl thioketones to form nearly equal amounts of both diastereoisomeric tetrahydrothiophenes. A low selectivity was also observed in the reaction of a 2-phthalimide-derived cyclopropane with ferrocenyl phenyl thioketone