4- -oxazolones amines

Difficulties are often encountered in the formation of peptides from a-amino acids which lack an a-hydrogen atom, e.g. a-methylalanine, presumably because of steric hindrance. This problem is obviated by use of the oxazolone 35, an excellent reagent for the addition of a single a-methylalanyl residue to an amine or amino acid [Eq. (22)]... 

Several approaches to the 1,2,3-triazole core have been published in 2000. Iodobenzene diacetate-mediated oxidation of hydrazones 152 led to fused 1,2,3-triazoloheterocycles 153 <00SC417>. Treatment of oxazolone 154 with iso-pentyl nitrite in the presence of acetic acid gave 1,2,3-triazole 155, a precursor to 3-(W-l,2,3-triazolyl)-substituted a,P-unsaturated a amino acid derivatives <00SC2863>. Aroyl-substituted ketene aminals 156 reacted with aryl azides to provide polysubstituted 1,23-triazoles 157 <00HC387>. 2-Aryl-2T/,4/f-imidazo[43-d][l,2,3]triazoles 159 were prepared from the reaction of triethyl AM-ethyl-2-methyl-4-nitro-l//-imidazol-5-yl phosphoramidate (158) with aryl isocyanates <00TL9889>. 

Unfortunately, in many cases the reaction is not so straightforward it becomes complicated because of the nature of the activated component. There is another nucleophile in the vicinity that can react with the electrophile namely, the oxygen atom of the carbonyl adjacent to the substituted amino group. This nucleophile competes with the amine nucleophile for the electrophilic center, and when successful, it generates a cyclic compound — the oxazolone. The intermolecular reaction (path A) produces the desired peptide, and the intramolecular reaction (path B) generates the oxazolone. The course of events that follows is dictated by the nature of the atom adjacent to the carbonyl that is implicated in the side reaction. 

V-alkoxycarbonylamino add (Figure 1.10, path B) did not occur without immediate expulsion of the alkyl group, giving the amino-acid Af-carboxyanhydride (see Section 7.13). 2-Alkoxy-5(47/)-oxazolones are now recognized as intermediates in coupling reactions and are products that are generated by the action of tertiary amines on activated A-alkoxy carbonyl amino adds (see Section 4.16).20 22... 

More /V-acylurea is generated if tertiary amine is present because the latter removes any protons that might prevent the rearrangement (see Section 2.12). The two intramolecular reactions also occur to a greater extent when interaction between the O-acylisourea and the /V-nucleophile is impeded by the side chain of the activated residue. This means that more 2-alkoxy-5(4//)-oxazolone and /V-acylurea are generated when the activated residues are hindered (see Section 1.4). A corollary of the above is that the best way to prepare an /V-acylurea, should it be needed, is to heat... 

That being said, it must be recognized that the evidence that the (V-acy I isourea is the precursor of the 2-alkoxy-5(4//)-oxazolone is only circumstantial because experiments starting from the former have yet to be achieved. The oxazolone could theoretically come from the symmetrical anhydride. The latter generates 2-alkoxy-5(4//)-oxazolone in the presence of tertiary amines (see Section 4.16) even dicy-clohexylcarbodiimide (DCC) was basic enough to generate 2-t< rt-butoxy-5(4 )-oxazolone from Boc-valine anhydride. However the weight of evidence points to O-acylisourea as the precursor of the 2-alkoxy-5(4//)-oxazolone. In the absence of. V-nucleophile, such as in the preparation of esters, the major precursor of product is the symmetrical anhydride.7,8... 

FIGURE 2.14 Peptide-bond formation from chlorides of A-alkoxycarbonylamino acids. N-9-Fluorenylmethoxycarbonylamino-acid chlorides.41 The base is NaHCO, Na2C03, or a tertiary amine. The reaction is carried out in a one- or two-phase system. The latter is used to try to suppress formation of the 2-alkoxy-5(4//)-oxazolone that is generated by the action of the base on the acid chloride. The method is applicable primarily to Fmoc-amino-acid derivatives that do not have acid-sensitive protecting groups on their side chains. 

FIGURE 4.14 Reactions of activated A-alkoxycarbonylamino acids in the presence of tertiary amine. Acyl halides and mixed and symmetrical anhydrides generate 2-alkoxy-5(4/7)-oxazolone in the presence of tertiary amine. Aminolysis of 2-alkoxy-5(47f)-oxazolone in the presence of E N led to partially epimerized products. OAct = activating group. 

IMPLICATIONS OF OXAZOLONE FORMATION IN THE COUPLINGS OF N-ALKOXYCARBONLYAMINO ACIDS IN THE PRESENCE OF TERTIARY AMINE... 

The addition of hydrazine to diphenylvinylene carbonate 92 quantitatively affords a 1 1 mixture of perhydro-l,3,4-oxadiazin-2-one 93 and 2-oxazolidinone 94 derivatives, both of which are smoothly dehydrated with P2O5 to afford 1,3,4-oxadiazin-2-one 95 and 3-amino-2(3//)-oxazolone 96 (Fig. 5.24), respectively. Addition of primary amines to diphenylvinylene carbonate results in exclusive formation of 3-aIkyl-2(3//)-oxazolones, previously investigated as amino protecting groups in peptide synthesis. 

The 2(3//)-oxazolones may be synthesized by the direct condensation of three components. Thus, a mixmre of a-halo ketones 123, carbon dioxide, and primary amines can be heated at 80-100 °C under gas pressure of 50 kg/cm to result in the direct formation of 3-substituted 2-oxazolones 124 in 4-25% yield (Fig. 5.30). " ... 

The 2(3/T)-oxazolone homopolymer 217 and the 2(37f)-oxazolone copolymer 219 with a carbon-carbon bond backbone structure are readily obtained by heating a 3-acyl-2(3/7)-oxazolone alone or with styrene, respectively, at 70 °C in the presence of BPO with the exclusion of air." " ° The A -acetyl polymers serve as regioselective and chemoselective acylating reagents for amines and alcohols (Fig. 5.53). ° ... 

Dimethyl-2-vmyl-5(4/i/)-oxazolone (VDMO) 140 and 4,4-dimethyl-2-isopro-penyl-5(4//)-oxazolone 328 have been extensively investigated as monomers (Fig. 7.32). Copolymeiization of 140 or 328 with other monomers, for example, acrylates or acrylamides produces reactive polymers that are conveniently further modified by nucleophilic reaction with alcohols, amines, or other nucleophiles. ""... 

Ethoxymethylene)-2-phenyl-5(47/)-oxazolone 404, readily available from hippuric acid and triethyl orthoformate, has also been used as a starting material for other unsaturated oxazolones via addition-elimination reactions. Nitrogen nucleophiles are most commonly used and amines give rise to 4-(aminomethyl-ene)-2-phenyl-5(4//)-oxazolones 405 (Scheme 7.130 Table 7.37, Fig. 7.48) which, in many cases have been evaluated as antihypertensives. 

Heterocyclic amines also react as nucleophiles and, in this context, indole reacts with 404 to yield the unsaturated oxazolone 406, an intermediate in the synthesis of tryptophan (Scheme 7.13It is noteworthy that 406 is the product of carbon-carbon bond formation. Imidazole also reacts with 404 but in this case the product is 396, identical with that obtained from the 4-(chloromethylene) derivative 395. ... 

In general, the reaction of unsaturated 5(4//)-oxazolones 497 with nitrogen nucleophiles effects ring opening to give the corresponding unsaturated acylamino amides 498 (Scheme 7.158). Depending on the nucleophile, for example, amines, hydrazines, oximes, and so on, the products obtained can be cyclized and this process allows the synthesis of a wide variety of new heterocyclic compounds. 

There are a number of comprehensive studies reported of the reactions of a particular unsaturated oxazolone with nitrogen nucleophiles. On the other hand, unsaturated 5(4/f)-oxazolones react with a variety of amines to yield acylamino amides with interesting agrochemical properties. ... 

The mechanism of the aminolysis and the electronic effects of substituents at C-2 or C-4 on the kinetics of amide bond formation have been studied. In some cases, ring opening with amines occurs with partial isomerization of the exocyclic double bond. However, with more hindered compounds, such as unsaturated oxazolones derived from ketones, ring opening is stereospecific.Ring opening using diamines has also been described. Selected examples of dehydroamino acid amides prepared by aminolysis of unsaturated 5(4//)-oxazolones are shown in Table 7.40 (Fig. 7.51). 

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