4,5-disubstituted imidazoles syntheses

The imidazole nucleus is often found in biologically active molecules,3 and a large variety of methods have been employed for their synthesis.4 We recently needed to develop a more viable process for the preparation of kilogram quantities of 2,4-disubstituted imidazoles. The condensation of amidines, which are readily accessible from nitriles,5 with a-halo ketones has become a widely used method for the synthesis of 2,4-disubstituted imidazoles. A literature survey indicated that chloroform was the most commonly used solvent for this reaction.6 In addition to the use of a toxic solvent, yields of the reaction varied from poor to moderate, and column chromatography was often required for product isolation. Use of other solvents such as alcohols,7 DMF,8 and acetonitrile9 have also been utilized in this reaction, but yields are also frequently been reported as poor. 

Fresneda, P.M., Molina, P. and Sanz, M.A., Microwave-assisted regioselective synthesis of 2,4-disubstituted imidazoles nortopsentin D synthesized by minimal effort, Synlett, 2001, 218-221. 

The reaction of these anions with electrophiles presents a general synthesis route to 2-, 5-monosubstituted or 2,5-disubstituted imidazoles (figure 10). 

Palladium(0)-mediated couplings continue to show utility for iodoimidazole functionalizations, as illustrated in several reports of synthesis of (lR,2S,3R)-acetyl-4(5)-[(l,2,3,4)-tetrahydroxybutyl]imidazole (58) [95TL5969], and the trihydroxybutyl analogs [95JOC2378]. In contrast, 1,2-disubstituted imidazoles undergo palladium-mediated carbonylation, in the presence of alkenes, to afford 4-alkenoylimidazoles (59) [96JACS493]. 

A reaction restricted to the synthesis of 2,4-disubstituted imidazoles is that between a-aminonitriles and aldehydes.110 The same bonds... 

The specific synthesis of 1,4- and 1,5-disubstituted imidazoles in 70% yields has been achieved by cyclizing 2-amino-3-methylaminopropionic acid with triethyl orthoformate. The products are isolated after dehydrogenation with active manganese dioxide of the 2-imidazoline (69 Scheme 37) (70AHC(12)103). 

Whereas a-amino ketones readily form imidazoles with formamide, they are often not easy to prepare. Accordingly, they can be replaced by precursors, a-oximino ketones, which can be reduced either by dithionite or using catalytic mehods in formamide at 70-100 °C. Ring closure can then be achieved by raising the temperature (Scheme 80). When a-ketol esters are used it appears that the imidazole formation may in this instance proceed by way of the oxazole. A further special case is the formation of 4,5-disubstituted imidazoles from 1-chloro-l,2-epoxides and formamide. One recent example of an application of Bredereck s method is the synthesis of the imidazolepropanol (144) from 3-bromo-2-methoxytetra-hydropyran (Scheme 81) (80AHC(27)241). 

A specific synthesis of 1,4- and 1,5-disubstituted imidazoles has been accomplished in about 70% yields by cyclization of 2-amino-3-methylaminopropanoic acid and 3-amino-2-methylaminopropanoic acid, respectively, with tricthyl orthoformate (Scheme 3.1.2). The initial product is the 2-imidazoline, which needs to be aromatized by treatment with active manganese dioxide [10]. 

A two-step synthesis of 1,4-disubstituted imidazoles (8) from TOSMIC (1) plus an aldehyde, followed by reaction with ammonia or a primary amine, proceeds via a 4-tosyloxazoline (11). The reaction sequence could be classified as 1,2 and 1,5 bond formation, 1,5 bond formation, or transformation of another heterocycle. There are, however, analogies to the aldimine reactions, and so the process is detailed at this stage. Certainly the synthesis is carried out in two steps often with isolation of the oxazoline (see also Chapter 6). Heating (11) with a saturated solution of methanolic ammonia gives a 4-substituted imidazole with methanolic methylamine a 1,4-disubstituted product is isolated as a single regioisomer (Scheme 4.2.4). Some of the oxazolines cannot be isolated as they are unstable oils which have to be heated immediately with the amino compound [12]. Related is the synthesis of 2-carbamoyl-4-(2 -deoxy- 0-D-ribofuranosyl)imidazole [13]. 

This classification is illustrated in Scheme 291. By definition, imidazole synthesis under this classification requires an amine or its derivatives as one of the starting materials. Enamines, imines, and isonitriles have been used as the other reactants. Thus, reaction of primary amines with methyl 3-bromo-2-isocyanoacrylates 1189 leads to methyl 1,5-disubstituted imidazole-4-carboxylates 1190, which can undergo decarboxylation to give 1,5-disubstituted imidazoles 1191 (Scheme 292) <1996JME596>. 

A CuzO-catalyzed synthesis of 1,4-disubstituted imidazoles 1331 via cross-cycloaddition between two different isocyanides (i.e., 1329, 1330) has been reported. The reaction is proposed to start with the activation of a C-H bond of the isocyanide by the influence of CU2O catalyst, as depicted in Scheme 340 <2006JA10662>. 

Scheme 359 illustrates this classification. Bredereck s formamide cyclization continues to be one of the choices for the synthesis of 4,5-disubstituted or 4(5)-monosubstituted imidazoles <2005JME6632, 2005H(65)2783, 1997S347>. Typically, the reaction proceeds at high temperature with formamides and a-haloketones as the starting materials. For instance, monosubstituted imidazole 1389 is prepared from compound 1388 in 25% yield. 4,5-Disubstituted imidazole 1391 with a hindered side-chain is obtained from 1390 in 48% yield (Scheme 360) <2000JOC8402>. 

Some 1,5-disubstituted imidazoles have been found to exhibit potent inhibitory activity against platelet aggregation and as thromboxane synthetase inhibitors. Hence synthesis of imidazole analogues of prostaglandin require 1,5-orientation. Good yields of these desired isomers are obtained when 4-/-butyldimethylsilyloxymethylimidazole is treated in succession with butyllithium and an... 

Ring cleavage of iV-acyl- and A-(arylsulfonyl)histamines with di-(-butyl carbonate presumably involves quaternizing iV-acylation prior to ring cleavage <84JCS(Pl)59,89S825> (Equation (21)). The use of l-acyl-4-substituted imidazoles as intermediates in the synthesis of sterically hindered 1,5-disubstituted imidazoles has been known for some years (see CHEC-I), and in 1993 was rediscovered <93H(35)433>. 

A facile synthesis of various methyl 1,5-disubstituted imidazole-4-carboxylates can be realized by the reaction of methyl 3-bromo-2-isocyanoacrylates with a variety of primary amines [1194]. Dehydration of formamide 1581 with phosphoryl chloride at —20 °C for 2 h affords the isocyanide 1582 in 90-94% yield. 

Scheme 8.43 CujO-catalyzed synthesis of 1,4-disubstituted imidazoles from alkylisocyanides and arylisocyanidesa.

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