Oxazoles cycloadditions with acetylenic

In contrast, acetylenic dienophiles including benzynes51 participate in a well-defined [4 + 2] cycloaddition with oxazoles to provide substituted furans 15 which arise from the retro-Diels-Alder reaction with loss of... 

A variety of substituents—including alkyl, alkenyl, cyano, acetyl, and alkoxy— is tolerated at the 2 and 5 positions of the oxazole ring for these cycloadditions. Acetylenic dienophiles with alkyl, trialkylsilyl, phenyl, ester, ketone, and acetal substituents, as well as terminal alkynes, are precedented. Ab initio calculations predict a slightly higher activation energy for the cycloaddition of oxazole with acetylene compared to the oxazole-ethylene reaction. ... 

Similar to oxazole-olefin cycloadditions, the rate of Diels-Alder reactions of oxazoles with acetylenes depends on the electron-donating ability of the oxazole substituents. Rates decrease with decreasing electron-donating capacity of the substituents, in the order OR > NR1R2 > alkyl > 4-phenyl > COCH3 > CO2CH3 2-,5-phenyl. 5-Alkoxyoxazoles are approximately equivalent in reactivity to an all-carbon diene. 

Imembrine, a tropolone natural product related to colchicine was also synthesized via an oxazole-acetylene Diels-Alder reaction followed by a [4 -H 3]-oxyallyl cycloaddition.Here, 8-iodo-5,6,7-trimethoxyisoquinoline 269 was converted to 5-substituted oxazole 270 in four steps and 42% overall yield (Fig. 3.81). Thermolysis of 270 in refluxing o-dichlorobenzene effected the desired intramolecular Diels-Alder cycloaddition with concomitant loss of the Boc-protecting group to afford the tetracyclic furan 271 in 90% yield. At this point, 271 was subjected to the [4 + 3] cycloaddition in the presence of l,3,3-trichloro-2-propanone and 2,2,2-trifluoroethanol. Subsequent dechlorination of the intermediate (not shown) with zinc provided the oxabicyclic 272 as a single regioisomer in 73% yield. The synthesis of imembrine was completed in three steps from 272. 

While the cycloaddition of oxazole with acetylene is a well-established method for furan synthesis [36], the corresponding reaction of 5-amino oxazole was unknown at the outset of this work. As shown in Eq. (3) of Scheme 15.19, the reaction of 24b with 3-phenyl-2-propynoyl chloridephenylpropioloyl chloride (55a) proceeded smoothly to provide the 5,6-dihydro-furo[2,3-c]pyrrol-4-one (56) in greater than 95% yield. A triple domino sequence involving acylation/intramolecular DA cycloaddition/retro DA could explain the reaction outcome. That the domino process was initiated by acylation was evidenced by the fact that 24b failed to react with dimethyl acetylenedicarboxylate (DMAD) under the identical conditions. 

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

The ring fused pyrroles 480 have been prepared by in situ trapping of the meso-ionic l,3-oxazol-5-ones (479) with alkynes. This 1,3-dipolar cycloaddition was found to be regiospecific when phenyl acetylene was used as 1,3-dipolarophile, the only products being 480, R = H or MeO, R = Ph, R2 =... 

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 thermal or photolytic decomposition of carbonyl azides in the presence of dipole acceptors such as acetylenes provides a valuable method for the construction of oxazoles. Thus the reaction of ethyl azidoformate with either diphenyl- or diethylacetylene produces mainly the 2-ethoxy-oxazole (77 ).166 166 The reaction involves the 1,3-dipolar cycloaddition of carbethoxy nitrene (76b) to the alkyne to give the oxazole (77). On the... 

Since the early demonstrations of the participation of substituted 1,2,4,5-tetrazines and oxazoles in Diels-Alder reactions with olefinic and acetylenic dienophiles, the potential utilization of the [4 + 2] cycloaddition reactions of heteroaromatic systems possessing a suitable azadiene arrangement has been the focus of extensive investigations. In general, the heteroaromatic systems which possess an electron-deficient azadiene... 

Diethylacetylene reacted with 4-phenyloxazole 55 in an autoclave for 3 days at 250°C to afford a 70% yield of 3,4-diethylfuran 124 (Fig. 3.35). This furan was then converted into the interesting tetraoxaporphyrin 125 in two steps. The novel diimidazole copper ligand 127 is formed in 84% yield by the cycloaddition of 4-phenyloxazole with the acetylenic diimidazole 126 at 185°C for 18 h (Fig. 3.36). An application of the oxazole-alkyne Diels-Alder reaction in natural product synthesis is exemplified by the construction of the maleic anhydride portion of the... 

Paniculide-A is structurally the least complicated of the paniculides, a family of highly oxygenated sesquiterpenes from Andrographis paniculata. Jacobi s synthesis of paniculide-A began with a four-step conversion of 3-methyl glutaric anhydride 175 to the oxazole acetylenic ketone 176 (Fig. 3.54). Cycloaddition of... 

The application of this cycloaddition strategy to the synthesis of norsecurinine was then undertaken. Thus the oxazole-pyrrolidine derivative 188 was prepared in four steps from o-proline (Fig. 3.57). Coupling 188 with enynone 189, prepared in four steps from maleic anhydride, afforded a near-quantitative yield of the acetylenic ketone 190 as a 2 1 mixture of C-7 epimers. After refluxing for 30 min in mesitylene, 190 underwent cycloaddition to produce a 2 1 mixture of the tricyclic furano-ketone 191 and the C-7 epimer in 50% overall yield from 189. The undesired epimer could be recycled by epimerizing with sodium carbonate to give a 1 1 mixture of epimers. The tricyclic furano-ketone 191 was then converted to (-)-norsecurinine in six steps. (+)-Norsecurinine was synthesized using an identical route starting with L-proline. 

Thermal IMDA reaction of acetylene-tethered oxazoles was a key step in the synthesis of tropoloisoquinoline alkaloids <01JA3242>, while the analogous conversion of suitable oxazole-olefins to cyclopenta[c]pyridines was promoted by catalytic amounts of Cu(II) triflate <01H(55)823>. DA cycloadditions of methyleneoxazolones 150 with dienes afforded spirooxazolones 151 which were legio- and diastereoselectively converted to carbocyclic... 

---