Imidazole 4- alkyl-2-carboxylates

Cobalt, Co " (d ) 6, octahedral O-Carboxylate, N-imidazole Alkyl group transfer in vitamin B12 (cyanocobalamin)... 

Trisubstituted 4-mercaptoimjdazoles can be made by the exothermic reaction of A -unsubstituted a-oxothionamides (9) with aldimines (Scheme 4.1.6). Yields vary between 9 and 81%, but many lie in the 50-60% region [46, 47]. Alkylation of the sulfur atom of ethyl 2-thioxamate (9) (R = OEt) followed by treatment with aminoacetone gives ethyl 4-methylimidazole-2-carboxylate (10) in a reaction which provides a useful, general synthetic approach to imidazole-2-carboxylates (Scheme 4.1.6) [32]. 

Imidazole-4-carboxylates have been made from amidines derived from or-ainino acids (see Section 2.2.1 and Table 2.2.1), by Claisen rearrangement of the adduct formed when an arylamidoxime reacts with a propiolate ester (see Section 2.2.1 and Scheme 2.2.6), from a-aminocarbonyls with cyanates or thiocyanates (see Section 4.1 and Table 4.1.1), from a-oximino- 6-dicarbonyl compounds heated with an aUcylamine (see Section 4.1 and Scheme 4.1.7), and by anionic cycloaddition of an alkyl isocyanoacetate to diethoxyacetonitrile (see Section 4.2 and Scheme 4.2.11 see also Scheme 4.2.12). A further useful approach is to use an appropriate tricarbonyl compound with an aldehyde and a source of ammonia (see Chapter and Scheme 5.1.1). Irradiation of 1-alkenyltetrazoles bearing an ester substituent may have applications (see Section 6.1.2.3). 

Regiochemical synthesis of 1-substituted imidazole-4-carboxylates can be achieved by treatment of a (Z)-)3-dimethylamino-of-isocyanoacrylate with an alkyl or acyl halide (see Section 2.1.1 and Scheme 2.1.8), by cyclization of 3-alkylamino-2-aminopropanoic acids with triethyl orthoformate followed by dehydrogenation of the initially formed imidazoline (see Section 3.1.1 and Scheme 3.1.2), by condensation of 3-arylamino-2-nitro-2-enones with ortho esters in the presence of reducing agents (see Section 3.1.1 and Scheme 3.1.4), by reaction of an alkyl A -cyanoalkylimidate with a primary amine (see Section 3.2 and Scheme 3.2.1), the poor-yielding acid-catalysed cyclization of a 2-azabutadiene with a primary amine (see Section 3.2 and Scheme 3.2.3), the cyclocondensation of an isothiourea with the enolate form of ethyl isocyanoacetate (see Section 4.2 and Scheme 4.2.5), and from the interaction of of-aminonitrile, primary tunine and triethyl orthoformate (see Chapter 5, Scheme 5.1.5, and Tables 5.1.1 and 5.1.2). 

Alkyl radicals produced by oxidative decarboxylation of carboxylic acids are nucleophilic and attack protonated azoles at the most electron-deficient sites. Thus imidazole and 1-alkylimidazoles are alkylated exclusively at the 2-position (80AHC(27)241). Similarly, thiazoles are attacked in acidic media by methyl and propyl radicals to give 2-substituted derivatives in moderate yields, with smaller amounts of 5-substitution. These reactions have been reviewed (74AHC(i6)123) the mechanism involves an intermediate cr-complex. 

Reactions of Phosphonic and Phosphinic Acid Derivatives.—The reactions of phos-phonic and thiophosphonic amides and chlorides with carboxylic acid chlorides and amides have been discussed.101 Dialkyl alkylphosphonates and alkyl dialkylphos-phinates may be used for the iV-alkylation of imidazoles, triazoles, and pyrroles.105... 

Reaction of the imidazole (7-4) with the benzofuran derivative (6-7) leads to the displacement of the benzylic halogen and the formation of the alkylation product (8-1). Treatment of that intermediate with trifluoroacetic acid breaks open the urethane to afford the corresponding free amine. This is allowed to react with ttiflic anhydride to afford the trifluoromethyl sulfonamide (8-2). The ester group on the imdidazole is then saponified, and the newly formed acid is reacted with carbonyl diimidazole. Reaction with ammonia converts the activated carboxyl group to the amide. There is thus obtained the angiotensin antagonist saprisartan (8-3) [6]. 

Considerable work has been devoted to the search for agents devoid of the sedative effect that accompanied some of the earlier antihistamines. One stratagem for achieving that comprises adding a function that will diminish the likelihood that the dmg will cross the blood-brain barrier. The antistamine emedastine (41-3), for example, incorporates a terminal ether that can be potentially metabolized to a carboxylic acid. Alkylation of the imidazole (41-1), available from imidazol-2-one by reaction with phosphoms oxychloride, with the chloroether (41-2) leads to a reaction on nitrogen to afford (41-3). Displacement of the enol chloride in that intermediate with A-methyl-l-4-diazepine (41-4) leads to emedastine (41- 5) [43]. 

A benzisoxazole moiety provides the nucleus of an anticonvulsant agent whose structure differs markedly from the traditional agents in this class. The synthesis starts with a compound (61-1) that incorporates a preformed benzisoxazole. Bromination proceeds on the position adjacent to the carboxylic acid (61-2). This intermediate loses carbon dioxide on heating, leaving behind the bromomethyl derivative (61-3). Displacement of the halogen with the ion from the reaction of imidazole with sodium hydride yields the alkylation product (61-4). The short side chain is then methylated by successive treatment with a base and methyl idodide to afford zoniclezole (61-5) [64]. 

Entries 6 and 7 in Table 3.3 are additional linkers based on intramolecular nucleophilic cleavage. In Entry 6, it is an imidazole that efficiently catalyzes the saponification of the ester linkage, whereas in Entry 7 a hydroquinone is O-alkylated intramole-cularly, with the carboxylate acting as a leaving group. Esters of resin-bound (2-hydro-xyethyl)silanes have also been used as linkers, which can be cleaved by treatment with either TFA or fluoride ions (TBAF in THF [76]). 

---