Preparation of Trifluoromethylpyridine Libraries

Abstract

S-Alkylation followed by heterocyclization of trifluoromethyl-3-cyano-2(1H)-pyridinethiones was used for preparation of libraries of S-alkyl trifluoromethylpyridines and thieno[2,3-b]pyridines. The S-alkylation (in water--DMF mixtures) was successful for all 18 alkylating agents employed (yields typically > 50%). S-Alkyl derivatives were further converted to corresponding thieno[2,3-b]pyridines via heterocyclization in base conditions (yields > 65%). Structures of new compounds were elucidated by a combination of IR and 1H NMR spectroscopy and elemental analysis and were confirmed by means of single-crystal X-ray diffraction analysis.

Synthesis and domino reactions of polymethylene‐3‐cyanopyridine‐2(1Н)‐thiones

“…Guareschi-Thorpe reaction. We have described this type of domino reactions relatively recently, [28] and this reaction only supplements the knowledge of domino reactions. [29] We used this method for the synthesis of substituted thienodipyridines 14 (Scheme 4, Table 2).…”

Synthesis of 3-cyano-2-fluoropyridines

“…We also investigated the utility of readily available 3-cyanopyridine-2(1H)-thiones [25][26][27] as starting materials for the synthesis of Biologically active 3-cyano-2-fluoropyridines. These compounds were first converted into 3-cyano-2-methanesulphonylpyridines 4 by a previously published protocol [28].…”

One-Pot Synthesis of Diverse 4-Di(tri)fluoromethyl-3-cyanopyridine-2(1H)-thiones and Their Utilities in the Cascade Synthesis of Annulated Heterocycles

“…The introduction of the di(tri)fluoromethyl group into a structure of an organic molecule often causes significant changes in its chemical, physical, and physiological properties; , consequently, many fluoromethyl-substituted compounds attract significant attention as possible agrochemicals and drug candidates. – Likewise, 3-cyanopyridine-2(1 H )-thiones have been shown to exhibit several potent biological activities such as selective binding to the 5-HT1A, the dopamine D4, and the adenosine receptors, as well as inhibition of nitric oxide synthase. – Fluoromethylpyridines themselves were identified as potential herbicides ,– and medically important compounds. ,,,, Apart from the useful biological properties, 6-methyl-4-trifluoromethyl-3-cyanopyridine-2(1 H )-thiones and 4-methyl-6-trifluoromethyl-3-cyanopyridine-(1 H )-thiones have been effectively utilized in the past as versatile building blocks suitable for preparation of diverse libraries of annulated and nonannulated heterocycles . These reasons motivated us to develop a new efficient method to synthesize diverse 3-cyanopyridine-2(1 H )-thiones, containing the di(tri)fluoromethyl group, and to demonstrate these compounds as effective building blocks suitable for fast derivatization.…”

“…In most cases, fluoromethylated 3-cyanopyridine-2(1 H )-thiones are obtained by the reaction of fluoromethylated 1,3-diketones with cyanothioacetamide. ,,– Unfortunately, synthesis, isolation, and purification of the fluoromethylated 1,3-diketone starting materials often involve laborious multistep procedures, resulting in poor yields. – , Hence, the diversity of the accessible fluoromethylated 3-cyanopyridine-2(1 H )-thiones was usually determined by the commercial availability of the corresponding fluoromethylated 1,3-diketones, ,– the majority of which stem from aroyltrifluoroacetones. Here, we report a new regioselective method to synthesize 4-difluoro(trifluoro)methyl-3-cyanopyridine-2(1 H )-thiones, which excludes the isolation and the purification of the fluoromethylated 1,3-diketone intermediates and allows facile preparation of fluoromethylated 3-canopyridine-2(1 H )-thione products containing both aromatic and aliphatic substituents in the fifth and sixth positions.…”