4- Amino-1 -substituted imidazoles reaction with formates

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]. 

Several syntheses of l,3-dioxoperhydropyrrolo[l,2-c]imidazoles have been developed using different strategies. a-Substituted bicyclic proline hydantoins were prepared by alkylation of aldimines 135 of resin-bound amino acids with a,tu-dihaloalkanes and intramolecular displacement of the halide to generate cr-substituted prolines 136 and homologs (Scheme 18). After formation of resin-bound ureas 137 by reaction of these sterically hindered secondary amines with isocyanates, base-catalyzed cyclization/cleavage yielded the desired hydantoin products <2005TL3131>. 

A new method of synthesis162 of the imidazole ring by the use of A-cyaniminodithiocarbonic esters (41) involves formation of the 4 5-bond. Reaction of (42) with KNCO in acetic acid yielded the corresponding amide (43) which was cyclized by sodium hydroxide to the substituted purine (44). Treatment of (42) with Raney nickel and hydrogen produced 4-amino-5-carbethoxy-l-methyl-4-imidazo-line (45), which could also be cyclized to a purine (46).162... 

An interesting corollary of these reactions is the formation of 2-aminoimidazoles from guanidines and suitably substituted ketones. At -10 °C in methanol, l-phenylpropane-1,2-dione reacts with 1,1-disubstituted guanidines to give 2-(disubstituted amino)-4-hydroxy-4-methyl-4H-imidazoles (121) which, on catalytic hydrogenation, give excellent yields of... 

These reactions which lead to homocysteine formation in some creatures and its utilization in others are undoubtedly representative of a general thiol group transfer mechanism. The initial condensation of the donor thiol, most commonly cysteine, with some suitably reactive receptor generates a thioether. The differences in the requirement for O-acylation when starting from serine and homoserine may refiect two completely different mechanisms for this thiol substitution reaction. In the case of serine, the removal of the hydroxyl as hydroxide and the stabilization of an electrophilic centre on the side-chain carbon can be achieved through the pyridoxal phosphate-amino acid adduct. A similar example is in the carbon-carbon condensation between serine and imidazole in tryptophan... 

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