Oxazoles cycloaddition

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... 

Oxazole cycloadditions have been reported with alkyne dienophiles (tandem Diels-Alder addition and retro Diels-Alder loss of a nitrile leads on to furans), benzyne (the primary adduct can be isolated), and with typical alkene dienophiles and the adducts can be transformed into pyridines (8.14.1.4). 

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. 

With acetylenic dienophiles, the primary products of oxazole cycloaddition may undergo cycloreversion (cf. p. 67) to furan derivatives and nitriles. 

The reaction of cyclohexene with the diazopyruvate 25 gives unexpectedly ethyl 3-cyclohexenyl malonate (26), involving Wolff rearrangement. No cyclo-propanation takes place[28]. 1,3-Dipolar cycloaddition takes place by the reaction of acrylonitrile with diazoacetate to afford the oxazole derivative 27[29]. Bis(trimethylstannyl)diazomethane (28) undergoes Pd(0)-catalyzed rearrangement to give the A -stannylcarbodiimide 29 under mild conditions[30]. 

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. 

The distinction between these two classes of reactions is semantic for the five-membered rings Diels-Alder reaction at the F/B positions in (269) (four atom fragment) is equivalent to 1,3-dipolar cycloaddition in (270) across the three-atom fragment, both providing the 47t-electron component of the cycloaddition. Oxazoles and isoxazoles and their polyaza analogues show reduced aromatic character and will undergo many cycloadditions, whereas fully nitrogenous azoles such as pyrazoles and imidazoles do not, except in certain isolated cases. 

TosMIC reagents. For example, glyoxylic acid ethyl ester undergoes cycloaddition with (2-naphthyl) tosylmethyl isonitrile (17) to produce oxazole 18 in good yield. ... 

An example of this methodology was its use in the synthesis of vitamin Be, pyridoxine 12. Cycloaddition of oxazole 9, prepared from ethyl A-acetylalanate and P2O5, with maleic anhydride initially gave 10. Upon exposure to acidic ethanol, the oxabicyclooctane system fragments to afford pyridine 11. Reduction of the ester substituents with LiAlIU generated the desired product 12. 

Oxazole formation can be envisaged as proceeding by three possible pathways 1,3-dipolar cycloaddition of a free ketocarbene to the nitiile (Path A), the formation and subsequent 1,5-cyclisation of a nitrile ylide (Path B) or the formation and subsequent rearrangement of a 2-acyl-2//-azirine (Path C) (Scheme 9). 

An intermolecular version of a [4+2] cycloaddition-retrofragmentation of alkyne-oxazoles can be adapted to the synthesis of 2,3,4-trisubstituted furan in high regioselectivity if acetylenic aldehydes are used as starting materials. The product of this reaction is a pivotal intermediate for the synthesis of (-)-teubrevin G <00JA9324>. 

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). 

A more elaborate approach was taken by Kaffy et al. [94], The goal of the research was a series of compounds with greater stability and a higher affinity for endothelial cells within tumor vessels than CA-4, 7 however, the paper described a method that was purely synthetic. The synthetic strategy involved a 1,3-dipolar cycloaddition of a nitrile oxide 186 with a substituted aryl alkyne 187 to form the oxazole 188. 

Interestingly, the alkyne-oxazole Diels-Alder cycloaddition strategy provides a unique entry to some furyl stannanes [52]. Thus, thermolysis of bis(tributylstannyl)acetylene (50) and 4-phenyloxazole (51) led to a separable mixture of 3,4-bis(tributylstannyl)furan (52, 19% yield) and 3-tributylstannylfuran (53, 23% yield). 

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... 

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