Imidazoles N-acylation

Imidazole, 4-acetyl-5-methyl-2-phenyl-synthesis, 5, 475 Imidazole, 1-acyl-reactions, 5, 452 rearrangement, 5, 379 Imidazole, 2-acyl-synthesis, 5, 392, 402, 408 Imidazole, 4-acyl-synthesis, 5, 468 Imidazole, C-acyl-UV spectra, 5, 356 Imidazole, N-acyl-hydrolysis rate constant, 5, 350 reactions, 5, 451-453 synthesis, 5, 54, 390-393 Imidazole, alkenyl-oxidation, 5, 437 polymerization, 5, 437 Imidazole, 1-alkoxycarbonyl-decarboxylation, 5, 453 Imidazole, 2-alkoxy-l-methyl-reactions, 5, 102 thermal rearrangement, 5, 443 Imidazole, 4-alkoxymethyl-synthesis, 5, 480 Imidazole, alkyl-oxidation, 5, 430 synthesis, 5, 484 UV spectra, 5, 355 Imidazole, 1-alkyl-alkylation, 5, 73 bromination, 5, 398, 399 HNMR, 5, 353 synthesis, 5, 383 thermal rearrangement, 5, 363 Imidazole, 2-alkyl-reactions, 5, 88 synthesis, 5, 469... 

Azoles containing a free NH group react comparatively readily with acyl halides. N-Acyl-pyrazoles, -imidazoles, etc. can be prepared by reaction sequences of either type (66) -> (67) or type (70)->(71) or (72). Such reactions have been carried out with benzoyl halides, sulfonyl halides, isocyanates, isothiocyanates and chloroformates. Reactions occur under Schotten-Baumann conditions or in inert solvents. When two isomeric products could result, only the thermodynamically stable one is usually obtained because the acylation reactions are reversible and the products interconvert readily. Thus benzotriazole forms 1-acyl derivatives (99) which preserve the Kekule resonance of the benzene ring and are therefore more stable than the isomeric 2-acyl derivatives. Acylation of pyrazoles also usually gives the more stable isomer as the sole product (66AHCi6)347). The imidazole-catalyzed hydrolysis of esters can be classified as an electrophilic attack on the multiply bonded imidazole nitrogen. 

Imidazole, 1 -hydroxy-2,4,5-triphenyl-3-oxides reactions, S, 455 Imidazole, iodo-nitrodehalogenation, 5, 396-397 Imidazole, 1-iodo-reactions, S, 454 stability, S, 110 Imidazole, 2-iodo-synthesis, S, 401 Imidazole, N-iodo-, S, 393 reactions, 5, 454 Imidazole, 4-iodo-5-methyl-iodination, 5, 400 Imidazole, 2-isopropyl-4-nitro-N-nitration, 5, 351 Imidazole, 2-lithio-reactions, S, 106, 448 Imidazole, 2-mercapto-l-methyl-as antithyroid drug, 1, 171 mass spectra, 5, 358 Imidazole, 1-methoxymethyl-acylation, S, 402 Imidazole, 5-methoxy-l-methyl-reactions... 

Ochiai, who reported in 1936 the first synthesis of the imidazo[2,l-h]thia-zole system (36CB1650), transformed ethyl 2-mercapto-5-methyl-imidaz-oIe-4-carboxylate with monochloroacetone into 2-(acylalkylthio)-imidazole 36. Refluxing 36 in phosphorus oxychloride yields ethyl 3,5-dimethylim-idazo[2,l-h]thiazole-6-carboxylate. No cyclization could be achieved by heating 36 in acetic anhydride because N-acylation (to 37) inhibited further reaction to the bicyclic system. 

Statt der N-Acyl-Verbindungen konnen auch die entsprechenden a-Chlor-immonium-chloride cyclisiert werden. So erhalt man durch Einleiten von Ammoniak in Losungen von N-Aryl-N-(aryl-chlor-methylen)-N-(l,2-diaryl-2-oxo-ethyl)-ammonium-chloriden in Dichlormethan 1,2,4,5-Tetraaryl-imidazole in sehr guten Ausbeuten von 85-97% (insgesamt 10 Deriva-te)240... 

Data taken from (71PMH(3)297), which contains references to the original literature. bSimple alkyl- and aryl-imidazoles. A-Unsubstituted compounds are N-acylated prior to injection. ... 

Acid chlorides convert l-methylbenzimidazol-2-yl-silanes and -stannanes into 2-acylbenzimida-zoles. The reaction also works with imidazoles, with the stannanes being more reactive than the silanes. The mechanism is believed to involve initial N-acylation, then loss of the silicon or tin substituent to give a zwitterion, and finally N — C-migration of the acyl group (83JHC1011). 

Heterocycles containing an NH group, such as pyrroles, indoles, imidazoles, triazoles, etc., can be linked to insoluble supports as N-alkyl, N-aryl, or N-acyl derivatives (Table 3.29). The optimal choice depends mainly on the NH acidity of the heterocycle in question. Increasing acidity will facilitate the acidolytic cleavage of N-benzyl groups and the nucleophilic cleavage of /V-acyl groups from these heterocycles. 

Page et al. (see [298] and references therein) have shown that generally excellent stereocontrol in organic reactions can be obtained by using DITOX (1,3-dithiane-l-oxide) derivatives as chiral auxiliaries. The one-pot stereo-controlled cycloalkanone synthesis given here outlines some aspects of the chemistry worked out for efficient acylation-alkylations steps. Of note are the use of N-acyl imidazoles under mixed base (sodium hexamethyldisilazide/n-butyllithium) conditions to yield the lithium enolates of 2-acyl-l,3-dithiane-l-oxides) and the sequential alkylation-cyclization of the latter (steps (iv) and (v)). 

Since N-acylation is a reversible process, it has allowed the regiospecific alkylation of, for example, imidazoles to give the sterically less favored derivative. This principle is illustrated in Scheme 24 (see also Scheme 15). 

Substituted imidazoles can be acylated at the 2-position by acid chlorides in the presence of triethylamine, e.g., <2005JME2154>. This reaction proceeds by proton loss from the N-acylated intermediate 347. An analogous reaction with phenyl isocyanate gives 348, probably via a similar mechanism. Benzimidazoles react similarly, but most pyrazoles do not (cf. Section 3.4.1.4.6). 

In general, methyl groups at the 4- and 5-positions of imidazole, oxazole, and thiazole do not undergo such deprotonation-mediated reactions, even when the ring is cationic. A quaternary form can be generated in situ by N-acylation (Scheme 127) <2005TL4789>. 

Reference has been made to 1,3,5-tribromotriazoIe and 1,3-dichlorotriazole which act as halogenating agents (Section 4.12.3.2.2). Transfer of N-acyl functions to 1,2,4-triazole has been illustrated in Scheme 28 but AT-acyltriazole and especially carbonylditriazole (83) may be used similarly to the analogous imidazole compounds (79LA1756) except that the latter are more economical. 

Direct acylation of AT-protected imidazole involves formation of an AT-acyl azolium salt, which is then deprotonated at C-2 followed by rearrangement of the acylazolium ylide to the 2-acylated imidazole (for mechanism and a number of applications, see CHEC-II(1996)). An example is shown in Scheme 82 N-acylation of imidazole 350 followed by 2-deprotonation of the azolium cation, then migration of the acyl group to C-2 gives product 351 <2005JME2154>. 

Treatment of N-acylated a-aminonitriles 1077 with PPh3 and a carbon tetrahalide affords 2,4-disubstituted 5-halo-17/-imidazoles 1078 in good yields. A variety of alkyl and aryl substituents (R and R ) are tolerated. A possible mechanism involves the formation of a novel seven-membered ring intermediate and then elimination of triphenyl-phosphine oxide, as illustrated in Scheme 261 <20040L929>. 

Replacing the carbonyl group in the ketoamides with a cyano group leads to N-acylated a-aminonitriles (see Section 4.02.9.1(i)). These compounds, such as 1219, react with ammonium acetate at high temperature to give cyclized products, imidazoline 1220 and li7-imidazol-5(4//)-imine 1221 (Scheme 298) <1996H(43)937, 1997T5359>. 

Imidazoles have been N-acylated by isocyanates (at elevated tempera-tures) " (Scheme 21), acid halides, and alkyl chlorocarbonates, but 2-methylimidazole would not react with formamide and phosphoryl chloride. Trifluoromethylsulfonation forms the imidazolide which is a convenient reagent for the introduction of the triflate group. ° With highly basic I-substituted imidazoles, acetyl halides form the 1-acetyl-... 

Since N-acylation is a reversible process, it has allowed the regiospecific alkylation of imidazoles to give the sterically less-favored derivative, i.e., the 1,5-disubstituted derivative (e.g., 109 Scheme 22). ° The sequence followed is (1) acylation (2) alkylation (often with oxonium reagents) and (3) deacylation with alcohol, water, or base. The N-acylation of 2-substituted imidazoles using ethyl chloroformate, triethylamine, and acetonitrile gives JV-alkoxycarbonylimidazoles ° which can lose carbon dioxide to give the JV-alkyl derivatives. The reaction is of limited use in the synthesis of asymmetrically substituted imidazoles since, whereas 2-ethyl-4-methylimidazole gave >95% of l-carbethoxy-2-ethyl-4-methylimidazole, the subsequent decarboxylation afforded a 3 1 mixture of 1,2-diethyl-4-methyl and l,2-diethyl-5-methyl compounds. 

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