Oxazole ring aldehydes

The structural diversity (and complexity) of the products obtained by the MCR between tertiary isocyano amides, aldehydes, and amines could be increased to various heterocyclic scaffolds by combining the initial 2,4,5-tiisubstituted oxazole MCR with in situ intramolecular tandem processes (Fig. 17). Most tandem processes reported are based on the reactivity of the oxazole ring toward C=C or C=C bonds in hetero Diels-Alder reactions followed by ring opening reactions generating the rather complex heterocyclic products with high degrees of variation. 

The oxazole ring of benzoxazoles, in which the 4,5-bond is masked by incorporation in a benzene ring, survives many oxidation reactions. 2-Methylbenzoxazole (100), for example, can be oxidized to benzoxazole-2-carboxylic acid, and 2-methylnaphth[2,1 -d ]oxazole (101) forms the corresponding aldehyde by the action of selenium dioxide. 

The presence of electron-withdrawing substituents at C(4) facilitates reactions with nucleophiles, which may well be initiated by attack at C(5). Thus oxazole-4-aldehydes undergo ring-fission on treatment with aqueous alkali to form (acylamino)malondialdehydes (equation 3), and 2-pentyloxazole-4-carboxylic acid yields 2-pentylimidazole, with concomitant decarboxylation, when heated with ammonia at 150 °C. An example of a more complex ring transformation is the formation of 3-aminopyridines (131) by the action of malononitrile on 4-acetyloxazoles under alkaline conditions (equation 4). 

Carbon atom 2 of the oxazole ring is also supplied by aldehydes in their reaction with a- (hydroxylamino) ketones, which proceeds in the presence of sulfuric acid and acetic anhydride (equation 109). Three further oxazole syntheses involving incorporation of a C(2) fragment are the condensation of triethyl orthoformate with the hydrochlorides of a-aminoacetophenones (equation 110), the reaction of acyl chlorides with a-azido ketones or a-azido esters in the presence of triphenylphosphine (equation 111), and the preparation of 2-aminobenzoxazole and benzoxazoleimines from o-aminophenols and cyanogen bromide (equation 112). 

A truncated Passerini reaction between various aldehydes or ketones and a-alkyl-a-isocyanoacetamides in toluene at 70 °C in the presence of LiBr afforded 2,4,5-trisubstituted oxazoles in satisfactory yields (38-98%). For instance, stereoselective nucleophilic addition of 110 to A,A-dibenzylphenylalanal 111 led predominantly to the awfi-adduct 112 (dr = 9 1) which was smoothly converted after acidic hydrolysis of the oxazole ring into the dipeptide 113, containing an a-hydroxy-P-amino acid (norstatine) component <04T4879>. 

Several oxazole-4-aldehydes have been described, while only one oxazole-2-aldehyde is known so far 2 4 they are fairly stable to oxidation by air. Since the oxazoles are not known to undergo Friedel-Crafts acylation, ketone substituents are introduced indirectly into the nucleus, either before the ring is formed40 332 391 or by modification of substituents already present.147 4-Acetyloxazoles are oxidized to the corresponding acids with sodium hypobromite.147 Both oxazolyl aldehydes and ketones form derivatives with hydroxylamine, phenylhydrazine, etc., as expected. 

Konopelski and co-workers also used an a-diazo-p-ketoester to prepare a 2-chloroindole C-D-E fragment 1467 in a model study for 1192 (Scheme 1.375). They converted commercially available isatin to Al-Boc-2-chloro-3-indolecarbox-aldehyde 1464 in three steps. The p-ketoester 1465 was prepared in high yield and then converted to the a-diazo-p-ketoester 1466. The authors found that standard reaction conditions failed to convert 1465 to 1466. In this case, substitution of DBU for TEA was critical for success. The oxazole ring was then constmcted using Doyle s protocol. ... 

Radspieler and Liebscher prepared several 4-chloro-2,5-disubstituted oxazoles 1520 from aromatic acyl cyanides 1519. These oxazoles are the first examples in which the 2-substitutent was not derived from an aromatic aldehyde. They extended this methodology to prepare suitably functionalized dichloro indole bis-oxazole C-D-E fragments. Their approach is noteworthy as the first synthesis of such fragments that does not involve chlorination of an intact oxazole ring. 

Addition to Aldehydes. The Vedejs oxazole metalation has often been applied in the addition of oxazoles to aldehydes. In order to avoid ring opening to the isonitrile, the oxazole is first complexed with borane, then reacted with BuLi to generate the 2-metalo nucleophile (eq 15). This has been applied in the synthesis of a-ketooxazole inhibitors, and angiotensin II (AT2)... 

The aldehyde functionality present in 3-phenyl-2H-azirine-2-carbox-aldehyde reacts selectively with amines and with Qrignard and Wittig reagents to give a variety of substituted azirines. These azirines have been used, in turn, to prepare a wide assortment of heterocyclic rings such as oxazoles, imidazoles, pyrazoles, pyrroles, and benzazepins. ... 

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. 

Aryl-5,6-dihydrobenzo[4,5]imidazo[l,2-C]-quinazolines Isatoic anhydride could also be reacted with amino-, hydroxyl- or thiolanilines to form 2-(2-aminophenyl)benz-imidazoles, oxazoles or thiazoles, Scheme 5.38. In the case of 2-(2-aminophenyl)benzimidazoles (X=N), the product was formed after 3 min at 150°C in acetic acid. The products could subsequently be further elaborated 6-aryl-5,6-dihydrobenzo[4,5]imidazo[l,2-C]quinazolines, a four ring system, was formed by treatment of the 2-(2-aminophenyl) benzimidazole (X=N) with different aldehydes in acetic acid at 150°C for 5 min (J. Westman, and K. Orrling, Personal Chemistry, Uppsala, Sweden, unpublished results). Fifteen compounds were synthesised in 20-75% overall yield. This 3 + 5 min procedure should be compared to the conventional heating protocol developed by Devi and co-workers57, where each reaction step was run overnight to eventually afford the products in only 30-50% yield. 

Allenes may take the place of alkenes in this process, leading to ero-methylenesuccinimides as products. With unsymmetrically substituted allenes, the less-substituted double bond is chemoselectively in-coiporated into the heterocyclic ring. The alkene may also be replaced by an aldehyde in this cycloaddition, leading to l,3-oxazole-2,4-diones (Scheme 20). ... 

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