Diphenyl Open-Chain Compound

From the reaction of 6-p-chlorostyryl-3-thioxo-3,4-dihydro-l,2,4-triazin-5(2F/)-one (271) with phenylmagnesium bromide a mixture of seven products was isolated. These were separated and identified as 6-/ -chlorostyryl-5-phenyl-l,2,4-triazine-3(2/f)-thione (272), 6-p-chlorostyryl-5,5-diphenyl-4,5-dihydro-l,2,4-triazine-3(2//)-thione (273), the open-chain compounds (274)- 276), thiosemicarbazide and sulfur (Scheme 49). Mechanisms for the formation of these products were suggested <84JHC905>... 

It was found (616) that the course of the heterogeneous reaction of 1-hydroxy-5,5- dimethyl-2,4- diphenyl-3-imidazoline-3-oxide with PhLi depends on the crystalline phase of the starting compound, which can be obtained, predominantly, in cyclic or open chain tautomeric forms. 

Oxazoles with a free 2-position are metallated thereat by n-butyllithium, while 2,4,5-trimethyloxazole forms the anion (142) (81JOC1410). In the presence of a carboxyl or methoxycarbonyl group at C(4) the metallation is directed to the 5-position, even in the absence of a 2-substituent, to give, for example, the lithio compounds (143) and (144) (81TL3163). 2-Lithiooxazoles can equilibrate with open-chain isocyanides and the diphenyl compound has been trapped as a mixture of cis- and /rans-trimethylsilyl ethers (equation 9). 

Reactions.— The nucleophilic reactivity of the thiocarbonyl sulphur atom in thioureas has been further exemplified in a series of papers reporting on S-alkylation reactions of open-chain " as well as cyclic thioureas using alkyl halides. Ried and his co-workers have reported that (4-quinazolyl)thioureas (315) react smoothly with methylene iodide in the presence of triethylamine to yield the 1,3-thiazetidines (316). The ready formation of (316) was attributed to the special effect of the intramolecular hydrogen bonding in (315), as common thioureas usually did not enter into this reaction in a well-defined and profitable way. 5,5-Diphenyl-2-thio-hydantoin reacted with symmetrical ao>-dibromo-alkanes to yield the cyclization products (317). The action of excess of methyl iodide on N -substituted N-(o-aminophenyl)thioureas afforded the benzimidazoles (318), alternatively obtainable by treatment of the same thioureas with mercuric chloride." " In a similar manner, l-amino-6,7-dimethoxy-3,4-di-hydroisoquinolines were formed by the action of mercuric chloride on the thioureas (319)" or their S-methyl derivatives (320). " A recent paper by Klayman and his co-workers deals with the reactivity of S-methiodide derivatives of thioureas that are activated by electron-withdrawing groups towards hydroxylic compounds. "... 

The X-ray structure of BACE-1 in complex with compound 11 (Fig. 4e) revealed a relatively open flap conformation, with the aliphatic chain of the inhibitor projecting towards S2 in close proximity to a pocket that we termed F. In X-ray structures of peptidomimetic inhibitors bound to BACE-1 [99], the F pocket is occupied by flap Tyr71 but is vacated in X-ray crystal structures of iminohydantoin 11 and related compounds. Incorporation of 5-phenyl substitution to exploit occupancy of F was a key design concept that resulted in identification of 5,5 -diphenyl-iminohydantoin 12, in which one of the C5 phenyl substituents now... 

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