Oxazoles, cycloaddition reactions

In 1965, Ishikawa and co-workers investigated the oxazole cycloaddition reactions of 4-methyloxazole, 5, with a variety of dienophiles (Fig. 3.3). The product distribution for these reactions was found to depend on the substituents on the dienophile as well as the reaction conditions. For example, the reaction of 4-methyloxazole with diethyl fumarate gave a mixture of pyridinols 6 and 7. 

In contrast to oxazole, thiazole does not undergo the Diels-Alder cycloaddition reaction (331). This behavior can be correlated with the more dienic character of oxazole, relative to thiazole, as shown by quantochemical calculations (184). 

The current paradigm for B syntheses came from the first report in 1957 of a synthesis of pyridines by cycloaddition reactions of oxazoles (36) (Fig. 5). This was adapted for production of pyridoxine shordy thereafter. Intensive research by Ajinomoto, BASF, Daiichi, Merck, Roche, Takeda, and other companies has resulted in numerous pubHcations and patents describing variations. These routes are convergent, shorter, and of reasonably high throughput. 

Cycloaddition of 3-methylenephthalide with ot./V-diphenylnitrone gave two diastereoisomers of 2,3-diphenyl-2,3-dihydrospiro 1,3-oxazole-5(47/ )l (3 H)-2-benzoluran]-3 -one (805). The 1,3-dipolar cycloaddition reaction of /V-benzyl-C-(2-furyl)nitrones with electron-rich alkenes gave preferentially trans-3,5-disubstituted isoxazolidines (endo approach). These experimental results are in good qualitative agreement with those predicted from semiempirical (AMI and PM3) and ab initio (HF/3-21G) calculations (806). 

The weak aromaticity of oxazole is reflected by its chemical behavior, demonstrating a high degree of bond localization (illustrated by the propensity for cycloaddition reactions),137 and is supported by theoretical calculations (ring current indices, i.e., the bond... 

Cycloaddition reactions involving thermal/photochemical/catalytic decomposition of iodonium ylides are applicable to oxazole derivatives... 

The meso-ionic 1,3-oxazol-S-ones show an incredible array of cycloaddition reactions. Reference has already been made to the cycloaddition reactions of the derivative 50, which are interpreted as involving cycloaddition to the valence tautomer 51. In addition, an extremely comprehensive study of the 1,3-dipolar cycloaddition reactions of meso-ionic l,3-oxazol-5-ones (66) has been undertaken by Huisgen and his co-workers. The 1,3-dipolarophiles that have been examined include alkenes, alkynes, aldehydes, a-keto esters, a-diketones, thiobenzophenone, thiono esters, carbon oxysulfide, carbon disulfide, nitriles, nitro-, nitroso-, and azo-compounds, and cyclopropane and cyclobutene derivatives. In these reactions the l,3-oxazol-5-ones (66)... 

The photochemical addition of both aliphatic and aromatic aldehydes to o-quinones monoimines has been widely used in the preparation of oxazoles [Eq. (92)].340 An intermediate amide has been isolated in a number of cases, and can be thermally converted into the oxazole. The reaction, therefore, does not appear to be a cycloaddition. An analogous addition occurs between o-quinones and aldehydes, and the photoproducts have been shown to have an acyclic structure341 rather than the previously assigned 1,3-dioxole structure. 

The oxazole cycloaddition implies the transformation of two C=C bonds into two C-C bonds, but the isoxazole converts one C=N and one C=C bond into a C-C and a C-N bond. The data given above show that the reaction involving A is more exothermic than for B by approximately 10 kcal/mol-1. According to MP2/6-31G //3-21G calculations, the reaction of ethylene with A is exothermic by 19.7 kcal/mol-1 and endothermic with B by 4 kcal/mol-1.87... 

Intermediate three-membered rings have never been detected in the cycloaddition reaction and a direct route to the five-membered rings is probable in most cases. For example, benzoyl nitrene adds to triple bonds and in contrast to the addition to nonpolar double bonds, a five-membered oxazole is obtained (Sch. 22) [21,38]. An azirine intermediate is not detected, however it cannot be excluded that the three-membered ring containing a 7i-bond rearranges rapidly giving rise to the oxazole. 

Photolytic (68CB302) or rhodium-catalyzed decomposition of alkyl 3,3,3-trifluoro-2-diazopropionates gives carbenes and carbene complexes, respectively, which exhibit an enormous synthetic potential. [3 + 2] cycloaddition reactions have been performed, e.g., with nitriles to give 4-trifluoromethyl-substituted oxazoles [90JOC3383 9IJFC(52)149]... 

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. 

The mesoionic oxazol-5-one 245 is in equilibrium with an acylaminoketene 246, which undergoes a [2+2] cycloaddition reaction with diisopropylcarbodiimide to give the cycloadduct 247, mp 159-160 °C in 63 % yield. ... 

Oxazoles represent the most widely recognized heteroaromatic azadiene capable of [4 + 2] cycloaddition reactions. The course of the oxazole Diels-Alder reaction and the facility with which it proceeds are dependent upon the dienophile structure (alkene, alkyne), the oxazole and dienophile substitution, and the reaction conditions. Alkene dienophiles provide pyridine products derived from fragmentation of the [4 + 2] cycloadducts which subsequently aromatize through a variety of reaction pathways to provide the substituted pyridines (Scheme 14). In comparison, alkyne dienophiles provide substituted fiirans that arise from the retro Diels-Alder reaction with loss of R CN from the initial [4 + 2] cycloadduct (Scheme 15,206 Representative applications of the [4 + 2] cycloaddition reactions of oxazoles are summarized in Table 14. Selected examples of additional five-membered heteroaromatic azadienes participatiitg in [4 + 2] cycloaddition reactions have been detailed and include the Diels-Alder reactions of thiazoles, - 1,3,4-oxadiazoles, isoxazoles, pyrroles and imidazoles. ... 

The Hantzch-Panek condensation of ethylpyruvate with acrylamide followed by treatment with trifluoroaceticanhydride (TFAA) provided 2-vinyloxazole-4-ethylcarboxylate 37 in good yield [57]. The Stille coupling of 2-chlorooxazole-4-ethylcarboxylate with vinyltrimetbylstannane also provided 2-vinyloxazole 37 [26]. The reactivity of 37 towards cycloaddition reactions with enone and coupling reactions with aryl halides were explored [57]. Heck reaction of vinyloxazole with p-iodoanisole gave the cinnamyl oxazole 97 in 71% yield [57]. 

One of the key steps in the total synthesis of phorboxazole A and B is the Rh(II)-catalyzed cycloaddition reaction of diethyl cyanomethylphosphonate with dimethyl diazomalonate to form the desired phosphonylated oxazole. ... 

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