Acylureas acids

Allenic acylureas 152, prepared in situ from the corresponding allenic acid 151 and carbodiimides, afforded lactams in good yields [126]. 

O-acylisourea generates peptide, the theoretical yield of peptide is one equivalent and one equivalent of A,/V -dialkylurea is liberated. However, a fourth and undesirable course of action is possible because of the nature the (9-acylisourea. The latter contains a basic nitrogen atom (C=NR3) in proximity to the activated carbonyl. This atom can act as a nucleophile, giving rise to a rearrangement (path J) that produces the. V-acylurea (see Section 1.12) that is a stable inert form of the acid. This reaction is irreversible and consumes starting acid without generating peptide. The exact fate of the O-acylisourea in any synthesis depends on a multitude of factors this is addressed in Section 2.3. 

NL Benoiton, FMF Chen. Reaction of A-t-butoxycarbonylamino acid anhydrides with tertiary amines and carbodiimides. New precursors for 2-f-butoxyoxazol-5(4//)-one and IV-acylureas. J Chem Soc Chem Commun 1225, 1981. 

FIGURE 7.1 A carbodiimide reacts with a carboxylic acid (A) to give the O-acylisourea, which may rearrange (B) to the A-acylurea. It also reacts with amino groups (C) to produce guanidines if no carboxyl group is available. 

The discovery of the sedative/hynoptic activity of derivatives of barbituric acid has led to very extensive dissections of that molecule. One outcome of this work is the realization that acylurea and acylamide derivatives often exhibit CNS depressant activity. A fair number of such molecules have been prepared that contain a succinimide or glutarimide pharmacophore. For example, Michael addition of cyanide to the stereochemically xmdefined cinnamate... 

A-Acylthioureas (149) treated with Bt2 or H2O2 in a perchloric acid medium give 1,2,4-dithi-azolium salts (150 X = C104 ) <8575371 >. Oxidation of (149) to the 1,2,4-dithiazolium salts was also carried out electrochemically, the A-acylurea having been isolated as a by-product <91JPR537>. When disulfides (151), obtained by Bt2 oxidation of (149 R = = H), are heated in AcOH 1,2,4-... 

Evidence for this mechanism was the preparation of O-acylureas similar to 98 and the finding that when catalyzed by acids they react with alcohols to give esters.647... 

The importance of solvent choice with regard to limiting the extent of /V-acylureas formation has long been appreciated Sheehan, J. C. Goodman, M. Hess, G. P. Peptide Derivatives Containing Hydroxyamino Acids, J. Am. Chem. Soc. 1956, 78, 1367. 

The carbodiimide method has been employed in several syntheses of depsipeptides. However, direct application of DCC for the formation of the ester bond between the amino acid and hydroxy acid components under the usual conditions of amide coupling affords the desired depsipeptides in acceptable yields only in the case of unhindered co-hydroxy units [54] or an active hydroxy group, such as in TV-benzoyl-u-hydroxyglycine benzyl ester. For example, Ravdel et al.[55 have performed the esterification of various benzyloxycarbonyl- and phthalylamino acids with /V-benzoyl-a-hydroxyglycine benzyl ester with DCC in 50-65% yield. On the other hand, Shemyakin et all21 failed to obtain the expected depsipeptide products on condensation of bulky benzyloxycarbonyl- or phthalylvaline with a-hydroxy-isovaleric acid benzyl ester. The main product was acylurea in the first case and phthalylvaline anhydride in the second. Thus, the classical carbodiimide procedure could not be applied in practical depsipeptide preparation. 

The esterification of support-bound carboxylic acids has not been investigated as thoroughly as the esterification of support-bound alcohols. Resin-bound activated acid derivatives that are well suited to the preparation of esters include O-acylisoureas (formed from acids and carbodiimides), acyl halides [23,226-228], and mixed anhydrides (Table 13.15). A-Acylurea formation does not compete with esterifications as efficiently as it does with the formation of amides from support-bound acids. Esters can also be prepared from carboxylic acids on insoluble supports by acid-catalyzed esterification [152,229]. Alternatively, support-bound carboxylic acids can be esteri-fied by O-alkylation, either with primary or secondary aliphatic alcohols under Mitsu-nobu conditions or with reactive alkyl halides or sulfonates (Table 13.15). 

Carboxylic acids react under Pfitzner-Moffatt conditions, resulting in the formation of methylthiomethyl esters and /V-acylureas.41 Nevertheless, although the authors are not aware of any report involving the selective oxidation of alcohols in the presence of a carboxylic acid, such outcome would be likely with carboxylic acids with little nucleophilicity, as standard Pfitzner-Moffatt oxidations are performed in the presence of trifluoroacetate that is known for not to interfere. 

The reaction of /V-cyclohexyl-/V-(2-pyridyl)carbodiimide and the allenic acid 83 in dry tetrahydrofuran at ambient temperature for 3 days afforded a 2 1 mixture of isomeric 2-oxo-2H- and 4-oxo-4/7-pyrido[l,2-a]pyrimid-ines 88 and 87 instead of the expected Diels-Alder adduct (92HCA1262). The formation of an activated ester 84 was suggested in the first step, which underwent a 1,5- or 1,3-acyl migration, giving rise to the isomeric pyrido(l,2-a]pyrimidines 87 and 88 via acylureas 85 and 86, respectively (Scheme 6). 

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