Imidazole ring formation

Omeprazole 5 -Methoxy-2- [(4 -methoxy-3,5-dimethyl-2-pyridinyl) methyl] sulfinylj -17/-benzimidazol O-methylation, imidazole ring formation using thiourea, A-oxidation, nucleophilic displacement, A-methylation, S -oxidation... 

Access to 10 allowed the Yamanouchi process group to turn their attention to two shortcomings of the discovery synthesis (1) capricious imidazole ring formation (14—>1), which led to the formation of oxazolobenzazepine byproduct 15 and necessitated the chromatographic purification of 1, and (2) the installation biphenyl-2-carbonyl chloride (derived from costly biphenyl-2-carboxylic acid) early in the synthetic sequence, which led to considerable waste of this costly material through losses over the subsequent steps of the synthesis. 

Imidazole ring formation of acyclo C-nucleoside 543 was made by reaction of 6-chloro-l,3-dimethyl-5-nitrouracil with o-glucopyranosylamine (541), followed by catalytic hydrogenation and concomitant cyclization of 542 (67CB492). The same C-nucleoside (543) was obtained by reacting 1-amino-l-deoxy-D-glucitol (544) with 6-chloro-l,3-dimethyluracil and subsequent nitrosation and cyclization (96S459) (Scheme 145). 

The first syntheses of IcP, also including unsubstituted 2, 86, 61 and 62 were carried out with 3,4-DAPs 29 and 48 and aliphatic or aromatic aldehydes. A specific feature of a procedure described by Weidenhagen et al. was the application of an oxidant, copper(II) acetate (38CB2347), to complete imidazole ring formation. This reaction was later extended to the synthesis of other IPs derivatives (42CB1936). 

Another example of imidazole ring formation in aqueous medium is reported by Proenca and Costa [65]. A one-pot condensation/cyclization reaction involving l-(cyanomethyl)pyridinimn chloride 94 and salicylaldehyde 95 in aqueous sodimn carbonate solution leads to the formation of chromeno-imidazo[l,2-a]pyridine scaffold 96 with 47-71% yield. The reaction is general to electron-donating groups (EDG) and electron-withdrawing groups (EWG). A representative example is shown in Scheme 31. 

Molina, P., Almendros, P., and Fresneda, P.M. (1994) Iminophosphorane-mediated imidazole ring formation A new and general entry to aplysinopsin-type alkaloids of marine origin. Tetrahedron, 50,2241-2254. 

A -Bridgehead compounds have been obtained from the photochemical cyclization of cfi-1-styrylimidazoles. For example, irradiation of the imidazole (532) in methanol in the presence of I2 resulted in cyclization at the 2-position of the imidazole ring with the formation of an imidazo[2,l-a]isoquinoline (533) (76JCS(Pl)75). Isomerization of the trans-to the c/i-styrylimidazole was followed by photodehydrocyclization, trans- 1-Styrylbenzimidazole (534) was isomerized under Pyrex-filtered light in the presence of one molar equivalent of I2. The resulting cis isomer on irradiation through quartz gave the benzimidazo[2,l-a]isoquinoline (535) in 53% yield. 

The 5H-imidazole ring (37) possesses two nitrogen atoms with lone pairs e,vailable for quaternary salt formation, but unlike those in the... 

MO studies (AMI and AMI-SMI) on the tautomerism and protonation of 2-thiopurine have been reported [95THE(334)223]. Heats of formation and relative energies have been calculated for the nine tautomeric forms in the gas phase. Tire proton affinities were determined for the most stable tautomers 8a-8d. Tire pyrimidine ring in the thiones 8a and 8b has shown a greater proton affinity in comparison with the imidazole ring, or with the other tautomers. In solution, the thione tautomers are claimed to be more stabilized by solvent effects than the thiol forms, and the 3H,1H tautomer 8b is the most stable. So far, no additional experimental data or ab initio calculations have been reported to confirm these conclusions. 

Formation of a 2 1 L-histidine Au(III) complex is suggested on the basis of multiinstrumental techniques the N1 of the imidazole ring and the nitrogen of the a-amino group are likely involved in the coordination [66]. 

The formation of the five-membered ring of the linear 5 6 5 system can also be achieved via cyclodehydration of 208 to synthesize the second imidazole ring of 209 (Equation 56) <2001JME4284> as well as the related sulfur-containing variant <2005PS(180)1629>. 

Hunter and Nelson (41 Mil) attempted the preparation of 4(5)-aminoimidazole (25 R = H) from its acetyl derivative (28 R = H, R1 = Me), which they obtained by reduction of 4(5)-nitroimidazole (27 R = H) with tin(II) chloride in acetic anhydride. The authors noted that hydrolysis of compound (28 R = H, R = Me) with aqueous acids resulted in fission of the imidazole ring and formation of acetic acid, formic acid, ammonia, and glycine. Base hydrolysis gave similar results (41 Mil), although a trace of 4(5)-aminoimidazole (25 R = H) was detected. 

This alkylation reaction can be applied to intramolecular alkylation affording cyclic products, as shown in Equations (19)-(21). The reaction of 2-vinylpyridines with 1,5- or 1,6-dienes results in the formation of five- or six-membered carbocycles with good efficiency.20,20a,20b In addition to pyridine functionality, oxozole and imidazole rings can be applied to this intramolecular cyclization. When the reaction is conducted in the presence of a monodentate chiral ferrocenylphosphine and [RhCl(coe)2]2, enantiomerically enriched carbocycles are obtained. A similar type of intramolecular cyclization is applied to TV-heterocycles. The microwave irradiation strongly... 

The mechanism of hydrolysis of cysteine peptidases, in particular cysteine endopeptidases (EC 3.4.22), shows similarities and differences with that of serine peptidases [2] [3a] [55 - 59]. Cysteine peptidases also form a covalent, ac-ylated intermediate, but here the attacking nucleophile is the SH group of a cysteine residue, or, rather, the deprotonated thiolate group. Like in serine hydrolases, the imidazole ring of a histidine residue activates the nucleophile, but there is a major difference, since here proton abstraction does not appear to be concerted with nucleophilic substitution but with formation of the stable thiolate-imidazolium ion pair. Presumably as a result of this specific activation of the nucleophile, a H-bond acceptor group like Glu or Asp as found in serine hydrolases is seldom present to complete a catalytic triad. For this reason, cysteine endopeptidases are considered to possess a catalytic dyad (i.e., Cys-S plus H-His+). The active site also contains an oxyanion hole where the terminal NH2 group of a glutamine residue plays a major role. 

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