T3P-promoted synthesis of a series of novel 2-aryl-3-phenyl-2,3,5,6-tetrahydro-4H-1,3-thiazin-4-ones

T3P-Promoted Synthesis of a Series of 2-Aryl-3-phenyl-2,3-dihydro-4H-pyrido[3,2-e][1,3]thiazin-4-ones and Their Activity against the Kinetoplastid Parasite Trypanosoma brucei

“…Thus, it would appear that the reaction may have an equilibrium between the aromatic 3 and the nonaromatic 3T (Scheme 3) which could account for the yields being between those of aromatic thiosalicylic acid and nonaromatic 3-mercaptopropionic acid. Based on these results and mechanisms previously proposed by us [12,14] and Un sworth et al [17], one possible pathway for the reaction is shown in Scheme 4. In the pro posed mechanism, the carboxylate of 3T attacks a phosphorus of T3P, opening the ring and forming a phosphate ester 4.…”

“…In cases where the imine was a liquid (2g, 2l, and 2n), the reactions were performed as three-component couplings, forming the imine in situ from an aldehyde and aniline rather than preparing it separately. As we have reported previously in the similar reaction of 3-mercaptopropionic acid [12], yields were expected to be a little lower for the three-component reaction than for the two-component reaction. Equimolar amounts of imine 2 (or aldehyde and aniline) and thionicotinic acid 3 were used, with excesses of T3P and pyridine.…”

“…Reaction of the same meta-and para-substituted imines 2a, 2b, 2d-2n with thiosali cylic acid (2-mercaptobenzoic acid), an aromatic thioacid, had ranged from 12-43% with an average yield of 30% [14]. The more reactive aliphatic 3-mercaptopropionic acid gav yields of 33-75%, averaging 58% [12]. The yields for 3 (35-63%, average 48%) thus fall in between these two-better than thiosalicylic acid but not as good as 3-mercaptopropioni acid.…”

“…A common method used for preparation of a variety of 2,3-dihydro-4H-1,3-thiazin-4-ones is the cyclization of an imine with a 3-thiocarboxylic acid [11]. However, it is known that N-aryl imines are less reactive in the preparation of similar 2,3-dihydro-4H-1,3-thiazin-4-ones than N-alkyl imines [12][13][14]. Furthermore, Dandia et al reported in 2004 that reaction of N-aryl imines with thionicotinic acid (2-mercaptopyridine-3-carboxylic acid) 3 by thermal methods with various catalysts and solvents failed, which they attributed to the "low reactivity" of 3 [9].…”

“…Where both of these methods involved specialized equipment (microwave oven, ultrasonic processor) and high temperature, we have previously reported simple, room temperature synthesis of various 2,3-diaryl-2,3-dihydro-4H-1,3-thiazin-4-ones [5,[12][13][14], including a few 2-aryl-3-phenyl-2,3-dihydro-4H-pyrido[3,2-e][1,3]thiazin-4-ones [4,5,15], using amide coupling agent 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide (T3P). T3P has several advantages over other amide-forming reagents, including that the reagent is safe, the by-products are water soluble and easily removed, and in combination with pyridine epimerization at the carbon alpha to the carboxylic acid is minimized [16].…”