Intramolecular electrophilic cyclization of functional derivatives of unsaturated Compounds: I. Synthesis of 5-arylsulfanyl-6-phenylpiperidin-2-ones from cinnamylacetamides and arylsulfenyl chlorides

Abstract

Sterically nonhindered N-alkyl(aryl)amides of cinnamylacetic acid in the reaction with phenyl(4-tolyl)sulfenyl chlorides in acetic acid in the presence of lithium perchlorate undergo a selective cyclization into 5-arylsulfanyl-6-phenylpiperidin-2-ones. Under similar conditions the reaction with arylsulfenyl chlorides of amides containing bulky substituents at the nitrogen atom resulted in 5-arylsulfanyl-6-phenyltetrahydropyran-2-iminium perchlorates, which by treatment with aqueous ethanol were converted into the corresponding derivatives of pyran-2-ones.Piperidin-2-ones are compounds with unique biological characteristics [1][2][3]. They underlie the preparation of piperidine systems included into the composition of many alkaloids and physiologically active substances [4][5][6]. Therefore nowadays new substituted piperidones are synthesized [7][8][9][10][11].The introduction of sulfanyl groups in the piperidone ring can essentially modify the chemical and biological characteristics. In particular, among the sulfanyl derivatives of piperidin-2-oneов (δ-lactams) compounds were found capable to inhibit the activation of p38MAP-kinase [12], a very important quality both for prophylactic and treatment of infl ammation and autoimmune diseases, rheumatoid arthritis, infectious diseases, atherosclerosis, and pancreatitis.Although there are well developed approaches to nonfunctional piperidones, the methods of the synthesis of 5-alkyl(aryl)sulfanyl-substituted piperidones [12][13][14] are multistage and apply diffi cultly accessible and toxic reagents.Considering the synthetic potential of the reaction of electrophilic cyclization of unsaturated amides [15] and aiming at the development of the synthesis of 5-arylsulfanylpiperidin-2-ones we examined in detail the arylsulfenylation of cinnamylacetamides Iа-Ig. These compounds react with arylsulfenyl chlorides IIа-IIc at room temperature in acetic acid in the presence of an equimolar amount of LiClO 4 as "dopping-additive" [16,17] forming cyclization products whose structure is controlled mainly by the steric parameters of the substituent at the nitrogen atom of the nucleophilic substrate and the electronic characteristics of the electrophilic reagent.Amide with sterically nonhindered aliphatic (Ib, Ic) or aromatic (If, Ig) substituents react with phenyl-or 4-tolylsulfenyl chlorides (IIа, IIb) giving 5-arylsulfanyl-6-phenylpiperidones IIIb-IIIg, IIIi, IIIj (path а) in 81-95% yield (Scheme 1). In event of 4-nitrophenylsulfenyl chloride a decreased selectivity of reaction is observed due to the nucleophilic involvement of the oxygen atom of the iniial amides (path b), and as a result forms a mixture of compounds III and IV in the ratio 5 : 1 from amide If and 4 : 1 from amide Ig.In the reaction of unsubstituted amide Ia with 4-tolylsulfenyl chloride (IIb) lactam IIIa was isolated.

Dimeric Manganese‐Catalyzed Hydroarylation and Hydroalkenylation of Unsaturated Amides

“…With Mn(I)‐catalyzed hydroalkenylation of unsaturated amides, we can readily assemble a rich library of structurally diverse β‐alkenylated amides. As shown in Scheme , several multisubstituted five‐ and six‐membered lactams can be prepared in one step and in moderate to good yields, further stressing the synthetic value of the reaction in organic synthesis and drug discovery …”

Dimeric Manganese‐Catalyzed Hydroarylation and Hydroalkenylation of Unsaturated Amides

“…As shown in Scheme 6, several multisubstituted five-and six-membered lactams can be prepared in one step and in moderate to good yields, further stressing the synthetic value of the reaction in organic synthesis and drug discovery. [41][42][43] We found that the addition of 3 equivalents of EtOH can improve the yield of this reaction, and we postulated that it may play a special role as a proton source in the protodemetalation. As shown in Scheme 7 a, deuterium-labeling control experiments indicated that the hydrogen atom at the a- 8) at 120 8C, and these will immediately undergo transmetallation with aryl boronic acids in the presence of external base to generate an intermediate (9).…”

Selective reduction and oxidation of 1-aryl-5-aryl-sulfanyl-6-phenylpiperidine-2-ones

“…Не-щодавно [4] на основі реакції електрофільної внут-рішньомолекулярної циклізації N-алкіл(арил)амі-дів цинамілоцтової кислоти з арилсульфенілхло-ридами ми розробили ефективний стереоселек-тивний метод синтезу раніше невідомих 5-арил-сульфаніл-6-фенілпіперидин-2-онів. Ці сполуки містять чутливі до дії відновників карбонільну та сульфанільну групи (остання також схильна до окиснення) і є зручними моделями для дослі-дження селективності перебігу таких перетво-рень.…”