Synthesis and Selected Transformations of 1H‐Imidazole 3‐Oxides Derived from Amino Acid Esters

Abstract

A series of new optically active 1H-imidazole 3-oxides 5 with a substituted acetate group at N(1) as the chiral unit were prepared by the reaction of a-(hydroxyimino) ketones, a-amino acid methyl esters, and formaldehyde. In an analogous reaction, ethyl 2-(hydroxyimino)-3-oxobutyrate and 1,3,5-trialkylhexahydro-1,3,5-triazines gave 3-oxido-1H-imidazole-4-carboxylates 14, which easily rearranged into the 2-oxo derivatives 15. Selected examples of N-oxides 5 could be transformed into the corresponding 2,3dihydro-1H-imidazole-2-thione derivatives 10 via a sulfur-transfer reaction, and the reduction of the histidine derivative 5i with Raney-Ni yielded the optically active 2,3-bis(imidazolyl)propanoate 12. Furthermore, reaction of the (1H-imidazol-1-yl)acetates with primary amines yielded the corresponding acetamides.

Temperature-dependent polymorphism of N-(4-fluorophenyl)-1,5-dimethyl-1H-imidazole-4-carboxamide 3-oxide: experimental and theoretical studies on intermolecular interactions in the crystal state

“…A large number of key 2-unsubstituted N-oxides exhibit limited stability either under high temperature, UV irradiation or in the presence of acylating agents, and can undergo isomerization to the corresponding imidazol-2-ones. Therefore, we turned our attention to derivatives bearing hydrogen donor groups at the vicinal C(4) position, namely amide [10,11] and hydrazide [12,13] moieties. The presence of such groups and stable N-oxide function offers an opportunity for their application in more complex structures including biologically active compounds and enables carrying out the reactions under harsh conditions.…”

2-Unsubstituted Imidazole N-Oxides as Novel Precursors of Chiral 3-Alkoxyimidazol-2-ylidenes Derived from trans-1,2-Diaminocyclohexane and Other Chiral Amino Compounds

“…Thus, the corresponding formaldimines 4f – h (Scheme 4) were converted into imidazole N -oxides 10a – c by reaction with the α-hydroxyiminoketone 5a under standard conditions (see Experimental Section). In addition, enantiopure 10d , readily available by aminolysis of the corresponding ester with ( R )-α-MBA [22] was used. The obtained imidazole N -oxides 10 were used for the preparation of imidazolium salts 11a – d , which upon treatment with triethylamine in pyridine in the presence of elemental sulfur gave the optically active imidazole-2-thiones 13a – d in good yields (Scheme 7).…”

“…α-Methylbenzyloxyamine (α-MBOA) [27] and benzyloxyamine (BOA) [40] were prepared based on modified literature procedures. Formaldimines 4e [20], 4f [21], 4g [21], and 4h [22] were synthetized from corresponding amino compounds and formaldehyde based on the published procedures.…”

“…In our earlier publications, we described an efficient method for the synthesis of enantiomerically pure bis- and mono-imidazole N -oxides derived either from trans -1,2-diaminocyclohexane [18,19], α-methylbenzylamine [20], β-amino alcohols [21], and amino acid esters [22]. In another study, we demonstrated that 2-unsubstituted imidazole N -oxides including some chiral derivatives can be O-alkylated by treatment with alkyl bromides [23].…”

New β-amino-α-trifluoromethyl alcohols and their exploration in the synthesis of trifluoromethylated imidazole derivatives

“…In general, 2-unsubstituted imidazole N-oxides bearing an electron withdrawing substituent at C(4) tend to undergo spontaneous isomerization to the corresponding imidazolones already at room temperature [10]. Otherwise, the isomerization requires …”