Dienes 4- oxazole

Four-Component Synthesis of Pyrrolopyridines If a primary amine were used as an input, the three-component reaction shown in Scheme 15.10 would produce an oxazole bearing a secondary amine. In other words, the so-produced adduct 24 would contain both a diene (oxazole) and a nucleophilic site (amine). Therefore, a dienophile bearing an electrophihc center would pair perfectly with the dual reactivity of 24. In practice, if an activated a,P-unsaturated carboxylic acid derivative were introduced after the three-component reaction, a sequence of N-acylation/intramolecular Diels-Alder reaction (IMDA) might occur to produce the four-component adducts. 

In this one-pot transformation, seven functional groups reacted with each other in a highly ordered manner, leading to the creation of seven chemical bonds and a polyheterocyclic scaffold with a hexasubstituted benzene core. Not less than nine elementary reactions were involved in this experimentally simple MCR. Two dienes (oxazole and furan, both are isolable) were generated in the course of the reaction, which subsequently reacted with two different dienophiles. A catalytic amount of CSA (0.1 equiv) was the only reagent required to catalyze the entire reaction sequence. 

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 oxazoles and their derivatives have played a variety of fascinating roles in the preparation of new molecular systems. Much of this chemistry stems from their ability to serve as diene components (azabutadiene equivalents) in reactions with a variety of dienophilic agents, to undergo nuclear metallation, to activate attached aryl or alkyl groups to deprotonation (thus functioning as masked aldehydes, ketones or carboxylic acid groups), and to serve as useful electrophiles on conversion to AT-alkylated salts. 

The expected adduct (430) from the Diels-Alder reaction of the oxazole (429) with diphenylcyclopropenone could not be isolated (Scheme 145) (70JCS(C)552). Instead the pyran-4-one (431) is obtained, resulting from elimination of acetonitrile. This process is essentially irreversible because the pyranone lacks diene properties and nitriles are poor dienophiles. 

Oxazaborolidine, in reduction reactions, 9, 226-227 Oxazoles, in C-H bond alkylation, 10, 218 Oxazolidinone, via ring-closing diene metathesis, 11, 235 Oxazolines... 

Alkyl-substituted oxazoles have been found to react with maleic acid or its anhydride in a diene synthesis to yield substituted pyridine readily converted to pyridoxine (39). In this route, ethyl d, 1-alaninate hydrochloride is treated with formic-acetic anhydride to yield ethyl N-formyl d,1-alaninate (78%). This compound is refluxed in chloroform with phosphorous pentoxide (40), quenched with aqueous potassium hydroxide, and the organic layer distilled to give 4-methyl-5-ethoxyoxazole (I) (60%). The resulting oxazole (I) is condensed readily with a number of appropriate dienophiles to form 2-methyl-3-hydroxy-4,5-disubstituted-pyridines containing substituents (III, a, b, c) which could be converted to pyridoxine as follows ... 

Oxazole A is often used as a diene in Diels-Alder reactions. However, isoxazole B appears to be inert. Their different reactivities are surprising, considering that their MOs are similar. Propose an explanation. Bond lengths and strengths CC 1.54 A and 82.6 kcalmoU1 C=C 1.34 A and 144 5 kcalmoU1 CN 1.47 A and 72.8 kcalmol-1 C=N 1.27 A and 147 kcal/mol-1 NO 1.40 A and 48 kcalmol-1.86... 

The instability of 1-azabuta-1,3-dienes arising from the imine moiety and the low reactivity as dienes in the Diels-Alder reaction are sometimes problems. Benzylidene(cyano)methyl-l,3-benzothia/oxazoles, featuring a stabilized imine moiety in the form of a heteroaromatic ring... 

Although oxazole possesses a sextet of 7r-electrons, all its properties indicate that the delocalization is quite incomplete hence it has but little aromatic character. There is considerable bond fixation (see Section 4.18.2.3.1), hydroxyoxazoles are unstable relative to their oxo tautomers, oxazolediazonium salts are unknown, oxazoles function as dienes in the Diels-Alder reaction (see Section 4.18.3.1.2(vii)) and electrophilic substitution is rare. The chemistry of oxazole is dominated by its tendency to undergo ring-opening rather than preserve its type. 

Five-membered heteroaromatic systems that possess an electron-deficient azadiene substructure, e.g., oxazoles and thiazoles, are suitable for participation in Diels-Alder reactions with inverse electron-demand [49JA3062 59JA4342 62AG(E)329]. The introduction of strongly electron-donating substituents in many cases is sufficient to overcome the electron-deficient nature of the azadiene moiety and permits normal HOMO diene/ LUMO dienophile controlled Diels-Alder reactions (87MI6). 

Since perfluoroalkyl-substituted olefins and alkynes possess low-lying frontier orbitals, [4 + 2] cycloaddition reactions to oxazoles and thiazoles without strongly electron-donating substituents are unfavorable. On the other hand, five-membered heteroaromatic compounds possessing an electron-rich diene substructure, like furans, thiophenes, and pyrroles, should be able to add perfluoroalkyl-substituted olefins as well as alkynes in a normal Diels-Alder process. A reaction sequence consisting of a Diels-Alder reaction with perfluoroalkyl-substituted alkynes as dienophile, and a subsequent retro-Diels-Alder process of the cycloadduct initially formed, represents a preparatively valuable method for regioselective introduction of perfluoroalkyl groups into five-membered heteroaromatic systems. 

Oxazol 2-Methyl-5-pyrro idino-E8a, 933 (R2N-CO-CH2-NH-CO-CHj + R3PBr2) 1,2-Oxazolidin 4-Cyan-5-methylen-2,3,8-trimethyl- E15/1, 363 (1,2-Dien + Nitron)... 

Oxazoles are anodier class of heteroaromatic dienes which readily undergo Diels-Alder reactions with benzynes. For example, slow, simultaneous injection of solutions of triazole (483) and lead tetraacetate to a solution of oxazole (515) in CH2CI2 at 0 C afforded cycloadduct (516) in essentially quantitative yield. The latter is a convenient source for the unstable isobenzofiiran (517), which can be trapped by [4 + 2] cycloaddition to a variety of dienophiles, e.g. by -methylmaleimide (Scheme 121). 

Diels-Alder reactions of oxazoles have proven to be quite versatile and continue to attract attention. Oxazoles have traditionally been used as the diene component and react with alkyne dienophiles to give furan products after extrusion of a nitrile molecule via a reverse-cycloaddition process. This method has been used to access highly substituted furans and has been utilized in numerous natural product syntheses. The reaction typically requires the use of high temperatures for efficient conversion. The furan intermediate 67 was obtained by a thermal intermole-cular Diels-Alder reaction between oxazole 66 and an acetylene. Furan 67 was a key intermediate for the synthesis of (—)-teubrevin G (Scheme 10) <2000JA9324>. Similarly, furan 68, obtained from a Diels-Alder reaction between 4-phenyloxazole and an acetylene, served as an intermediate in the total synthesis of the natural product cornexistin (Scheme 10) <20030L89>. 

The last step involves a Diels-Alder reaction between the oxazole as diene and the alkyne as tlvnophile followed by a reverse Diels-Alder reaction to give the required furan. The other product I issrns out to be benzonitrile PhCN ... 

Maleic anhydride adds to androst-14,16-diene to give the 14/8,17/8 Diels-Alder adduct. A pregn-16-en-20-one undergoes cycloadditions with the nitronic esters (113) to give the tetrahydro-oxazoles (114), which lose methanol with a trace of boron trifluoride to give the dihydro-oxazoles (115). The remarkable feature of the... 

Similarly, ra 5-cyclopropanes were obtained from alkenes, such as styrene and 2,5-dimethyl-hexa-2,4-diene, with relative yields > 90% when a diazoacetate bearing a bulky ester group was decomposed by a copper catalyst with bulky salicylaldimato ligands. Several metal complexes with bulky Cj-symmetrlc chiral chelating ligands are also suitable for this purpose, e.g. (metal/ligand type) copper/bis(4,5-dihydro-l,3-oxazol-2-yl)methane copper/ethyl-enediamine ruthenium(II)/l,6-bis(4,5-dihydro-l, 3-oxazol-2-yl)pyridine cobalt(III)/ salen. The same catalysts are also suited for enantioselective reactions vide infra). For the anti selectivity obtained with an osmium-porphyrin complex, see Section 1.2.1.2.4.2.6.3.1. 

On the other hand, the stereoselective synthesis of the masked half of the disorazole Al involved the Stille couphng of oxazole-dibromoolefine 62 with diene 63 and the expected key intermediate, bromotriene 64, was assembled in excellent yield [15],... 

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