Imidazole ring synthesis

Oximes can be also used for the imidazole ring synthesis. Thus, reaction of a-amino-oximes 122 and orthoesters leads to imidazole Af-oxides 123 (equation 53) . Interaction of a-ketooxime 124 with triazinanes also afforded imidazole Af-oxides 125 in good yields (equation 54) . Similarly, a-ketooximes in the system NH3/H20/aromatic aldehyde afforded trisubstituted 1-hydroxyimidazoles . ... 

Insertion of a triazole ring in place of an imidazole ring is consistent in some cases with retention of antifungal activity. The synthesis of one such agent, azoconazole (64), proceeds simply by displacement of halide with 1,2,4-triazole. The route to terconazole (65) is rather like that to ketoconazole (34). ... 

An imidazole derivative which is also a hypotensive agent by virtue of adrenergic a-2-receptor blockade is imiloxan (75). Its synthe.sis begins by conversion of 2-cyanomethyl-1,4-benzodioxane (72) to its iminosMhylether with anhydrous HC in clhanol (73). Reaction of the latter with aminoacetaldehyde diethylacetal and subsequent acid treatment produces the imidazole ring (74). Alkylation of 74 with ethyl iodide mediated by sodium hydride completes the synthesis [251. 

Construction of the imidazole ring onto a triazine has been also used for the synthesis of this group of compounds. The reaction of 3-aminobenzofl, 2,4]triazine with a-bromoacetaldehyde acetal gave the [1,2-b] linear isomer. On the other hand, the similar reaction on 1-oxide 461... 

Scheme 24.—Correspondence between the carbon atoms of AIR and those of pyramine, and the mode of opening of the imidazole ring in the ring expansion in the synthesis of pyramine.

Scheme 26, which recalls the classic reactions involved in the synthesis of 50 from small, common molecules, will help in following the methods used for labeling the imidazole ring of AIRs. Nitrosation with (l5N)NaN02 allowed the preparation of AIRs labeled on N-3. When methyl cyanoacetate was prepared with (i5N)KCN, AIRs labeled on the amino nitrogen were obtained. 

A modification of this method, related to the Beckmann rearrangement, entails treatment of a ketoxime with one equivalent of CDI, then four to five equivalents of a reactive halide such as allyl bromide or methyl iodide (R3X) under reflux in acetonitrile for 0.5-1.5 h. Quatemization of the imidazole ring effectively promotes the reaction by increasing the electron-withdrawing effect. The target amides then are obtained by hydrolysis. High yields, neutral conditions, and a very simple procedure make this modification of the synthesis of amides by azolides a very useful alternative. 1243... 

Recognizing the distinct difference in reactivity for each site of N-protected 2,4,5-triiodoimidazole 23, Ohta s group successfully arylated 23 regioselectively [32, 33], In the total synthesis of nortopsentin C, they coupled 23 with one equivalent of 3-indolylboronic acid 24 to elaborate imidazolylindole 25. The Suzuki reaction occurred regioselectively at C(2) of the imidazole ring. 

An intramolecular heteroaryl Heck was the pivotal step in the synthesis of 5-butyl-1-methyl-l//-imidazo[4,5-c]quinolin-4(5//)-one (63), a potent antiasthmatic agent [46], The optimum yield was obtained under Jeffery s ligand-free conditions, echoing Ohta s observation for the intermolecular version. Once again, the Caryi—Caryi bond was constructed at the C(5) position of the imidazole ring. Another intramolecular heteroaryl Heck cyclization of pyrrole and imidazole derivatives was also reported to assemble annulated isoindoles [47]. 

Further divergence from classical benzamide structure is represented by the synthesis of ondansetron (GRF 38032F, (33)), a potent 5-HT3 receptor antagonist where the basic nitrogen atom is part of an imidazole ring and the aromatic ring is part of tetrahydrocarbazolone ring system [27],... 

The synthesis of this ring system by condensation of 3,4,5-triamino-l,2,6-thiadiazine-l,1-dioxide with formic acid equivalents to give the fused imidazole ring dates back to the review by Montgomery and Secrist <1984GHEC(5)607>. This methodology was extended to cyclocondensation reactions of 3,4,5-triamino-l,2,6-thiadia-zine-1,1-dioxide with electrophiles such as methyl chloroformate and carbon disulfide to yield 6-oxo 98 and 6-thioxo 99 derivatives of 4-aminoimidazo[4,5-d-l,2,6-thiadiazine-2,2-dioxide respectively (Scheme 72) <1999BMC1617>. 

Biotin (6.24) consists of an imidazole ring fused to a tetrahydrothiophene ring with a valeric acid side chain. Biotin acts as a co-enzyme for carboxylases involved in the synthesis and catabolism of fatty acids and for branched-chain amino acids and gluconeogenesis. 

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