Oxazoles intramolecular

The mechanism of the condensation in Part D probably involves thioformylation of the metallated isocyanoacetate followed by intramolecular 1,1-addition of the tautomeric enethiol to the isonitrile. This thi2izole synthesis is analogous to the formation of oxazoles from acylation of metallated isonitriles with acid chlorides or anhydrides. " Interestingly, ethyl formate does not react with isocyanoacetate under the conditions of this procedure. Ethyl and methyl isocyanoacetate have been prepared in a similar manner by dehydration of the corresponding N-formylglycine esters with phosgene and trichloromethyl chloroformate, respectively. The phosphoryl chloride method described here was provided to the submitters by Professor U. Schollkopf and is based on the procedure of Bohme and Fuchs. The preparation of O-ethyl thioformate in Part C was developed from a report by Ohno, Koi/.uma, and Tsuchihaski. " ... 

The preparation of 3-vinylpyrroles was investigated utilizing the Horner-Wads worth-Emmons reaction with 3-formyl-lV-tosylpyrrole <06S1494>. The intramolecular acylation of pyrrole-2-Weinreb amides provided access to novel indolizinone derivatives <06T6182>. The amidation of pyrrole-2-carbonyl chloride was utilized as a key step in the preparation of pyrrole-oxazole analogue 90 of the insecticide Pirate <06S1975>. 

Palladium chemistry involving heterocycles has its unique characteristics stemming from the heterocycles inherently different structural and electronic properties in comparison to the corresponding carbocyclic aryl compounds. One example illustrating the striking difference in reactivity between a heteroarene and a carbocyclic arene is the heteroaryl Heck reaction (vide infra, see Section 1.4). We define a heteroaryl Heck reaction as an intermolecular or an intramolecular Heck reaction occurring onto a heteroaryl recipient. Intermolecular Heck reactions of carbocyclic arenes as the recipients are rare [12a-d], whereas heterocycles including thiophenes, furans, thiazoles, oxazoles, imidazoles, pyrroles and indoles, etc. are excellent substrates. For instance, the heteroaryl Heck reaction of 2-chloro-3,6-diethylpyrazine (1) and benzoxazole occurred at the C(2) position of benzoxazole to elaborate pyrazinylbenzoxazole 2 [12e]. 

The rhodium acetate complex catalyzed the intramolecular C-H insertion of (/ )-diazo-fR)-(phenylsulfonyl)acet-amides 359 derived from (f )-amino acids to afford in high yield the 6-benzenesulfonyl-3,3-dimethyl-7-phenyl-tetrahydro-pyrrolo[l,2-c]oxazol-5-one 360 (Equation 63) <2002JOC6582, 2005TL143>. 

The electron impact mass spectra of 3-methyl-4-nitro-5-styryl-isoxazoles exhibit, on the contrary, only negligible loss of OH"80. This has been interpreted in terms of an isoxazole-to-azirine rearrangement80. The latter fragments directly to an abundant cinnamoyl ion as well as rearranges to oxazole and an epoxide through an intramolecular oxidation of the ethylenic bond by the nitro group80 see Scheme 10. 

Corey s retrosynthetic concept (Scheme 9) is based on two key transformations a cationic cyclization and an intramolecular Diels-Alder (IMDA) reaction. Thus, cationic cychzation of diene 50 would give a precursor 49 for epf-pseudo-pteroxazole (48), which could be converted into 49 via nitration and oxazole formation. Compound 50 would be obtained by deamination of compound 51 and subsequent Wittig chain elongation. A stereocontroUed IMDA reaction of quinone imide 52 would dehver the decaline core of 51. IMDA precursor 52 should be accessible by amide couphng of diene acid 54 and aminophenol 53 followed by oxidative generation of the quinone imide 52 [28]. 

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. 

Fig. 17 Selected examples for scaffold diversity obtained by the trisubstituted oxazole MCR followed by intramolecular tandem processes...

Dihydroimidazo[2,l-b]oxazoles were prepared fi om an intramolecular nucleophilic ipso-substitution of 2-alkylsulfonylimidazoles <99S1613>. The synthesis of hitherto unknown 2-(2,4,6-triarylphenyl)substituted 4,5-dihydro-1/f-imidazolium perchlorates from 2-methyl imidazolium perchlorates and 2,4,6-triarylpyrylium perchlorate salts was published <99JC813>. Substituted aromatic heterocycles from reactions of 2,3-dihydrospiro[l/f-4-and... 

Mesoionic oxazolium-5-oxides 49 react with aminomalonic ester to give pyrrolidinones 50 as the major or exclusive products <99H(50)71> and the oxazolamine 51 is converted by sodium acetate in acetic acid into the hydantoin 52 <99JHC283>. The intramolecular Diels-Alder cycloaddition of the oxazole 53 and related compounds has been used as a route to substituted isoquinolines <99JOC3595>. ... 

Proposed mechanism for intramolecular catalysis of oxazole formation by pyrrole NH. 

A synthesis of the antitumor agent elliptidne has utilized the indolyl-substituted oxazole (351) as a key intermediate (77JOC2039). Diels-Alder reaction of (351) with acrylonitrile in acetic acid afforded a pyridinecarbonitrile (352) which was reacted with methyllithium, and the ketimine salt was hydrolyzed and cyclized to ellipticine (353 Scheme 76). Other Diels-Alder reactions of this type, particularly intramolecular cycloadditions of oxazoles with alkenic dienophiles should provide rapid access to a variety of alkaloid systems. 

A synthesis of the furanoeremophilane ( )-ligularone has been accomplished via the intramolecular Diels-Alder reaction of an oxazole with an alkynic dienophile (81JA4611). The lactone (359) was treated with lithium methylisocyanide to yield the oxazole (360). Oxidation of alcohol to aldehyde and reaction of this unstable aldehyde with lithiopropyne gave a 55 45 mixture of diastereomeric alcohols (361). Oxidation of the mixture gave a single alkynic ketone (362) which when refluxed in ethylbenzene afforded the desired furanosesquiterpene (363 Scheme 78). 

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 intramolecular coupling of the terminal amine with the oxazol-idine ring attached to the other end of the polymeric chain involves the C-5 carbonylic group since the C-2 CO group appears to be much less reactive (see, e. g. p. 6). However, for steric reasons such a reaction is prevented in the initiating dimer, hence the amine of the dimer may react only with the 2-carbonyl group, viz. 

Reactions of mercury salts on penams result in S( 1)—C(5) bond cleavage, thus generating an iminium intermediate that reacts subsequently in an intramolecular way with the C-6 amide side chain (Scheme 8). Afterward, the bicyclic heterocycle decomposes to the oxazole 12 <20000L103>. 

Annulated pyridines are reported to be synthesized via a [4+2] cycloaddition involving oxazoles (Scheme 121 Table 10) <20010L877>. The reaction mechanism is classified as a domino process with an intramolecular Diels-Alder cycloaddition followed by a retro-Michael reaction. 

Intramolecular cyclization of 4,5-dihydro-3-(2-thienyl)-oxazol-2-ones 39 gave 1 -hydroxyethylthieno[2,3-d]pyrimidine-2,4(3// )-diones 40... 

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