The Synthesis of 3,5‐Diamino‐1,2,4‐oxadiazoles. 2^nd Communication

Abstract

SummaryThe 5-amino-3-arylamino-1,2,4-oxadiazoles 2 are conveniently prepared by oxidative cyclization of the arylamidinoureas 10. The process is also capable of producing a variety of the 5-substituted-amino analogs 32 when the appropriately substituted guanidine 31 is employed as the substrate. Two different types of rearrangement leading to triazol-3-ones accompany cyclization depending on the choice of starting material. The structures of the rearranged products were established by X-ray crystallographic analysis and the reaction mechanisms leading to these unexpected products are discussed.Introduction. -In the accompanying paper [I], we have described two methods for the preparation of the 5-amino-3-substituted-amino-1,2,4-oxadiazoles 1. Although these procedures proved useful for the preparation of numerous analogs, continuing pharmacological interest in this class of compounds prompted the search for an improved approach capable of providing the 5-amino-3-anilino-l,2,4-oxadiazoles 2 on a large scale without the need for chromatographic purification.

Total Synthesis of the Anti Methicillin-ResistantStaphylococcus aureusPeptide Antibiotics TAN-1057A-D

“…Only one report in the literature has described this unusual ring system, and recently, a related five-membered cyclic amidinourea was found in an antitumor antibiotic NA22598 . All of the published methods, which includes the reaction of guanidines with isocyanates, hydrogenation of 5,3-diamino-1,2,4-oxadiazoles, or the hydrolysis of cyanoguanidines under strongly acidic conditions, are either inefficient, involve harsh reaction conditions, or require numerous steps . We have examined and subsequently determined that none of these methods were suitable for accessing the labile TAN-1057 amidinourea substructure.…”

Chlorination and Subsequent Cyclization to 1,3,4-Oxadiazoles of N1-Acyl-N3-cyanoguanidines and Related Compounds

“…5 Shortly later, Tilley et al 4 reinvestigated that N 2 -chloro-N 1 -methoxycarbonyl-N 3 -phenylguanidine (2a) gave corresponding 1,2,4-oxadiazole as reported by Goetz et al 3 and they suggested that N 1 -alkoxycarbonyl-N 2 -chloro-N 3 -substituted guanidines in which the N 3 -alkyl derivative underwent rearrangement, whereas the corresponding N 3 -aryl derivative cyclized with essentially no rearrangement. They also suggested that electron-withdrawing groups on the aromatic ring of the N 3 -aryl-N 1 -carbamoylguanidines (3) seemed to favor 1,2,4-oxadiazole formation.…”

Synthetic accesses to biguanide compounds

“…The N-substituted cyanoguanidines formed (typically in refluxing ethanol), are able to further react with another amine, as described above in the dedicated section. However, there are a few counter examples where the addition of the amine took place on the cyano group first: by using trimethylsilylamines [74], activation of the thiomethyl group by Cu(I) [75], or in case of consequent steric hindrance in the vicinity of the isothiourea carbon atom [76] (Scheme 36).…”