Oxazole basicity

The standard, acidic Mannich conditions do not allow simple substitutions of the imidazole and thiazole systems with the much less basic oxazole an intramolecular Mannich cyclisation has been described. ... 

NMR data for 4-methyloxazole have been compared with those of 4-methylthiazole the data clearly show that the ring protons in each are shielded. In a comprehensive study of a range of oxazoles. Brown and Ghosh also reported NMR data but based a discussion of resonance stabilization on pK and UV spectral data (69JCS(B)270). The weak basicity of oxazole (pX a 0.8) relative to 1-methylimidazole (pK 7.44) and thiazole (pK 2.44) demonstrates that delocalization of the oxygen lone pair, which would have a base-strengthening effect on the nitrogen atom, is not extensive. It must be concluded that not only the experimental measurement but also the very definition of aromaticity in the azole series is as yet poorly quantified. Nevertheless, its importance in the interpretation of reactivity is enormous. 

The pKa values of a number of isoxazoles have been reported and again the weakly basic nature of the ring, being less than oxazole, is demonstrated (see Table 3) (7iPMH(3)i. p. 23). 

Oxazole is a five-membered aromatic heterocycle. Would you expect oxazoie to be more basic or less basic than pyrrole Explain. 

The diazotization of heteroaromatic amines is basically analogous to that of aromatic amines. Among the five-membered systems the amino-azoles (pyrroles, diazoles, triazoles, tetrazoles, oxazoles, isooxazoles, thia-, selena-, and dithiazoles) have all been diazotized. In general, diazotization in dilute mineral acid is possible, but diazotization in concentrated sulfuric acid (nitrosylsulfuric acid, see Sec. 2.2) or in organic solvents using an ester of nitrous acid (ethyl or isopentyl nitrite) is often preferable. Amino derivatives of aromatic heterocycles without ring nitrogen (furan and thiophene) can also be diazotized. 

The basic hydrolysis of the 3-oxoperhydropyrrolo[l,2-c]oxazole 302 with KOH in ethanol followed by reaction with propargyl bromide 303 in presence of Hilnig s base in THF produced the derivative 304. This compound was further converted in a few steps to the natural product allopumiliotoxin 267A, 305 (Scheme 43) <1999JA6098, 2000JA6950>. 

Natural product o-methylhalfordinol 117 is a basic principle of the oxa-zole alkaloids of Halfordia scleroxyla and Aegle marmelos. Annuloline 119, a blue fluorescent pigment, has been isolated from the roots of rye stalk Lolium multifiorum. The total synthesis of 2,5-disubstituted oxazole alkaloids o-methylhalfordinol and annuloline is based on the aza-Wittig reaction (Scheme 48). Thus 4-methoxyphenacylazide 115, triphenylphos-... 

Oxazole (pATa 0.8) and thiazole (pATa 2.5) are weak bases. The basicity of the nitrogen is reduced by the presence of the other heteroatom. Oxygen and sulfur provide a stronger electron-withdrawing inductive... 

Meso-ionic l,3-oxazol-4-imines (87) have not been isolated by basic treatment of the corresponding salts (88). These salts (88) are formed by acid-catalyzed cyclization of the nitriles (89). ... 

Attempts to prepare meso-ionic l,2-oxazol-4-ones (367) have not been successful, although the corresponding salts (368) have been isolated. Treatment of the salts (368) with basic reagents may have yielded l,2-oxazol-4-ones (367), but these could not be isolated. 

Cyclic peptides have been synthesized not only for the purpose of improving biological activities and selectivity, but also to explore basic features of secondary structures in peptides and to investigate with such mimetic compounds the conformational behavior of proteins. For this purpose artificial building blocks have been frequently used or amide bonds have been modified isosterically. Nature also offers a variety of modifications in cyclic peptides that are critically involved in their bioactivity. Some of the most common natural and synthetic modifications including unusual structural elements such as thiazoles (and dihy-drothiazoles) and oxazoles (and dihydrooxazoles) with broad synthetic applications will be presented in the following section. 

Hydrogen bond basicity is of much relevance to the problem of drug design. Hydrogen bond basicity was shown to correlate with the location of the electrostatic potential local minimum along the axis of the nitrogen lone pair in a series of heterocycles (94JCS(P2)199). The experimental and calculated basicities for oxazole, 2,4,5-trimethyloxazole, and pyridine are shown in Table 2. 

Imidazoles, because of their high basicity, are very unreactive unless electron-withdrawing substituents are present. The deuteration of oxazole using CF3C02D/D20 was reported to occur exclusively at the 2 position (90IJC(B)562). 

Few solid-phase syntheses of oxazoles have been reported (Table 15.17). The most general strategy is the dehydration of a-(acylamino) ketones (Entry 2, Table 15.17) or 2-(acylamino)phenols (Entry 1, Table 15.17). Oxazolidin-2-ones have been prepared by intramolecular nucleophilic cleavage of carbamates from insoluble supports (Entries 5 and 6, Table 15.17). Resin-bound 2-aminoethanols, which are accessible by nucleophilic ring-opening of oxiranes with amines, undergo cyclocondensation with aldehydes to yield oxazolidines [220,221]. These compounds are unstable towards acids, and can be released from the support only under neutral or basic reaction conditions. 

The azoles (oxazole, imidazole, and thiazole) are five-membered aromatic heterocycles that have two heteroatoms in the ring. One of the heteroatoms in each of these heterocycles is an sp2-hybridized nitrogen that contributes one electron to the 6n aromatic system and has a basic nonbonded lone pair. The other heteroatom (oxygen, nitrogen, or sulfur) contributes two electrons to the 6n system. The imidazole skeleton is present in the amino acid histidine. The thiazole ring occurs in thiamin (vitamin B. ... 

Imidazole (pjfa=7.0) is more basic than oxazole (pA a=0.8) or thiazole (p/fa=2.5). This increased basicity arises from the greater electron-releasing capacity of two nitrogen atoms relative to a combination of nitrogen and a heteroatom of higher electronegativity. Also note that a symmetrical resonance-stabilised cation 3.7a,b is formed. 

Virtually no taxonomic utility has been ascribed to the Rutaceae oxazoles by Waterman (22), and certainly their incidence (although confined to two of the three major subfamilies, Table II) seems too infrequent—perhaps as a consequence of their photolability—for any valid taxonomic conclusions to be drawn. Formation of the oxazole nucleus in the Rutaceae therefore seems to be an elaboration (oxidation, cyclodehydration) of the basic p-phenylethylamide skeleton, which at present has no far-reaching implications for the phylogeny of this well-studied family. 

Oxazoles are extremely weak bases, oxazole itself being approximately 10,000 times weaker in basicity than pyridine (3, 123). Virtually all of the natural compounds have been isolated under neutral conditions using standard or reversed-phase chromatography, depending on the complexity of the mixture. The weak... 

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