Synthesis of an Enantiomerically Pure 1,3-Thiazole-5(4H)-thione and Its Stereoselective 1,3-Dipolar Cycloaddition with an Azomethine Ylide

Abstract

Starting from the enantiomerically pure 2H-azirin-3-amines (R,S)-4 and (S,S)-4, the enantiomeric, optically active 4-benzyl-4-methyl-2-phenyl-1,3-thiazole-5(4H)-thiones (R)-1 and (S)-1, respectively, have been prepared (Schemes 2 and 3). In each case, the reaction of 1 with N-(benzylidene)[(trimethylsilyl)methyl]amine (2) in HMPA in the presence of CsF and trimethylsilyl triflate gave a mixture of four optically active spirocyclic cycloadducts (Scheme 4). Separation by preparative HPLC yielded two pure diastereoisomers, e.g., (4R,5R,9S)-10 and (4R,5R,9R)-10. The regioisomeric compounds 11 were obtained as a mixture of diastereoisomers. The products were formed by a 1,3-dipolar cycloaddition of 1 with in situ generated azomethine ylide 3, which attacks 1 stereoselectively from the sterically less-hindered side, i.e., with (R)-1 the attack occurs from the reside and in the case of (S)-1 from the si-side.1. Introduction. ± Since the first [2 3] cycloadditions, described by Huisgen and coworkers [1 ± 5], azomethine ylides became a well-known class of 1,3-dipoles, and they found many applications in the synthesis of five-membered heterocycles [6 ± 17]. The 1,3-cycloaddition with olefins and acetylenes has frequently been used for the preparation of pyrrolidines and pyrroles with a large range of substitution [3] [7] [18 ± 24], and DeShong et al. described an intramolecular variation for the synthesis of bicyclic pyrrolidines and pyrroles [25]. Azomethine ylides were also used in the synthesis of indolizines [26] and other natural products [12] [27 ± 29], recent examples being those of epibatidine and epiboxidine, which were found to have potential analgesic activity [30] [31]. On the other hand, analogous reactions with thiocarbonyl compounds leading to 1,3-thiazolidines are rarely described [32 ± 37], but recently, Gallagher and co-workers published an elegant synthesis of penam and penem skeletons by 1,3-dipolar cycloadditions of azomethine ylides with thioketones [38]. Convenient methods to generate nonstabilized azomethine ylides are the desilylation of a-silyliminium salts [11] [12] [39] [40] and a-cyano-a'-silylamines, [32] or the treatment of a-silylated imines with trimethylsilyl triflate [41] (for other methods see [42 ± 50]).For many years, our research interest has been focused on the reactivity of the thiocarbonyl group in 1,3-dipolar cycloaddition reactions [51 ± 56]. In the last few years, we reported on the cycloadditions of azomethine ylides with aromatic thioketones [57] [58] and 1,3-thiazole-5(4H)-thiones [59] [60]. Recently, we reported on a stereoselective cycloaddition of an azomethine ylide, generated via thermal ring opening of cis-1-methyl-2,3-diphenylaziridine, with a chiral 1,3-thiazole-5(4H)-thione [61].

2-Azaallyl Anions, 2-Azaallyl Cations, 2-Azaallyl Radicals, and Azomethine Ylides

“…67a ). It is worth noting that N -alkyl azomethine ylides (section ) tend to react with ketone and aldehyde carbonyls via 1,3-dipolar cycloaddition instead of the direct nucleophilic attack observed for semistabilized 2 -azaallyl anions. − Hydrolysis of the imine functionality in the products 67 was readily achieved in high yield by treatment with aqueous HCl.…”

Reactions of Acid Chlorides/Ketenes with 2‐Substituted 4,5‐Dihydro‐4,4‐dimethyl‐1,3‐thiazoles: Formation of Penam Derivatives

“…13 C-NMR: 167.9 (s, C (7) -3-dichloroacetyl-4,4-dimethyl-5-methylsulfanyl-1,3-thiazolidine (7a) and 2, 3,6, [1,3] 4.73,Cl 19.57,N 3.87,S 17.70;found: C 49.50,H 4.48,Cl 19.77,N 3.99,S 17.40.…”

“…-A convenient synthesis of 4,4-disubstituted 1,3-thiazole-5(4H)-thiones 1, the less well-known di-sulfur analogs of 1,3-oxazol-5(4H)-ones (azlactones), was developed in the eighties [2]. The method also allowed the preparation of enantiomerically pure examples [3]. In a large series of experiments, it has been shown that the C=S group of 1 is the most reactive part of the molecule [4].…”

NMR study, theoretical calculations for assignment of theZ‐ andE‐isomers, and kinetics investigation of stable phosphorus ylides involving a 2‐mercapto‐4,6‐dimethyl pyrimidine

“…The synthesis of phosphorus ylides is an important reaction in organic chemistry because of the application of these compounds in the synthesis of organic products 1–29. Several methods have been developed for the preparation of phosphorus ylides 10,11.…”

“…Michael addition of phosphorus(III) compounds such as triphenylphosphine to acetylenic esters leads to reactive 1,3‐dipolar intermediate betaines, which are not detected even at low temperatures 14. These unstable species can be trapped by a protic reagent, ZH, such as methanol, amide, or imide, to produce various compounds, for example, ylides 4–29.…”