A short synthesis of 4‐imidazolidinone

Abstract

A gram-scale. convcnient, and simple synthesis or Cimidazoiidinone (1 a) is described. Starting from the readily available glycinamide. 1 a is obtained for the first time in a pure. solid form.In the course of a synthetic programme') substantial amounts of 4-imidazolidinone (1 a), as a key intermediate, were required. Previously, compound 1 a had been obtained in small quantities by reductive desulfurization of 1-benzyloxycarbonyl-2-thiohydantoin in an attempt to prepare the labile 3,5-dihydro-4H-imidazol-4-one (2), as described by Witkop and coworkers'). This reaction requires large amounts of the expensive and pyrophoric Raney nickel catalyst. Moreover, in our hands it appeared low-yielding, scarcely reproducible, and therefore not suitable for medium-scale preparations. Based on the above and on other literature data3), we thought that the reduction of imidazolone 2 could represent a straightforward and easy entry to 1 a. Therefore, the described*) cyclization of N-(iminomethy1)glycine 2-phenylethyl ester was repeated. 'H-NMR analysis of the obtained solution confirmed the presence of 2 and, for the first time, allowed its direct and unequivocal spectroscopic characterization. However, 2 appeared to be an elusive and unstable compound. In the meantime, an apparently cffcient, one-step synthesis of the imidazolone 2 starting from aminoacetonitrile hydrochloride and trimethyl orthoformate was reported4). After careful examination we reached the conclusion, indepcndently supported by other authors ' I, that such a reaction yields actually N-formylaminoacetonitrile as the main product. A by-product identical to that described from the same reaction when catalyzed by formic acid was also isolated. For this product the bicyclic structure 3 was proposed4). However, owing to a very weak stretching IR absorption at 2240 cm-', and to a signal at 116 ppm in the l3C-NMR spectrum due to the presence of a nitrile group, the monocyclic isomeric structure 4 must be considered more appropriate6). Compounds 5a, b were easily cyclized in excellent yields by treatment with formaldehyde to give the imidazolidinones 6a, b, respectively7! Hydrogenolysis of 6 b at 2.5 atm over Pd afforded the monobenzyl derivative 1 b, whereas removal of the amidic benzyl group required, as expectedXJ, conditions not compatible with our preparative purposes. The N-hydroxymethyl substituent could be eliminated from amides by high-pressure hydrogenolysis'~, by mild hydrolysis after oxidation to N-formyl derivatives lo), or by direct hydrolysis "I. However, hydrolytic treatment of the present compound 6 a was completely ineffective or led to concomitant destruction of the ring.We found a very efficient and simple method consisting in the thermal removal of formaldehyde in vacuo from 6a, which afforded in very good yields I-benzyl-4-imida~olidinone (6c). This compound was easily alkylated to give, for instance, 6d, e, thus becoming the precursor of a series of substituted imidazolidinones of potential pharmacological interest 12). Hydrogenolysis of the ...

Synthesis and pharmacological activity of a series of dihydro-1H-pyrrolo[1,2-a]imidazole-2,5(3H,6H)-diones, a novel class of potent cognition enhancers

“…A mixture of 14 (2 g, 9.89 mmol), hexa-Pinza et al methyldisilazane (20 mL), and trimethylchlorosilane (10 mL) in dry acetonitrile (50 mL) was refluxed under nitrogen for 4 h. After cooling, the precipitate was filtered off and the filtrate was evaporated under vacuum. The residue was dissolved in methanol (20 mL) containing a few drops of concentrated hydrochloric acid and stirred for 10 min. The insoluble material was filtered off and the filtrate was evaporated to dryness.…”

Preparation of Lactams from Cyclic Anhydrides via N‐Carboxyanhydride Intermediates

“…The efficient lactamisation heteroatom‐decorated related anhydrides 15 , 17 and 19 to generate 16 , 18 and 20 was also facile (entries 2–4). Notably, these compounds are not accessible via existing amidation protocols, most likely due to the required generation of a hydrolytically unstable hemi(thio)acetal or hemiaminal motif prior to cyclisation [9] . While substitution at the 2‐position did little to aid discrimination between two different aliphatic carbonyl units associated with anhydride 21 in the synthesis of 22 (entry 5), good regioselectivity for ring‐opening at the aliphatic carbonyl was observed utilising the benzo‐fused homophthalic anhydride ( i. e .…”

“…Notably, these compounds are not accessible via existing amidation protocols, most likely due to the required generation of a hydrolytically unstable hemi(thio)acetal or hemiaminal motif prior to cyclisation. [9] While substitution at the 2-position did little to aid discrimination between two different aliphatic carbonyl units associated with anhydride 21 in the synthesis of 22 (entry 5), good regioselectivity for ring-opening at the aliphatic carbonyl was observed utilising the benzo-fused homophthalic anhydride (i. e. formation of 24 from 23, 9 : 1 r.r., entry 6). In stark contrast, no nucleophilic ring opening with azide was observed in the case of naphthalic anhydride even on warming to room temperature (25, entry 7).…”

5,5‐diaryl and 5‐alkyl‐3‐phenyl‐4‐imidazolidones: A novel synthesis

“…4-imidazolidones can be prepared by multistep synthesis involving reagents which are difficult to handle [6]. Although sodium and amyl alcohol [7], sodium amalgam [8], H 2 pressure on Pd-charcoal catalyst [9], and Raney nickel [10] have been reported as dethiating agents for 2-thiohydantoins, the yields range from low to moderate. However, the synthesis of 4-imidazolidones by reductive desulfurization of 2-thiohydantoins has not received attention.…”