Oxazole-acetylenes

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... 

Selnick and Brookes prepared a series of thiopyrans as carbonic anhydrase 11 inhibitors via intramolecular oxazole-alkyne cycloadditions. The starting 4-methyl-2-thiooxazole-alkyne 215 was readily constructed from 2-mercapto-4-methyloxazole (Fig. 3.62). Refluxing 215 in toluene afforded an 88% yield of the furanothiopyran 216. Varying the length of the oxazole-acetylene linker provided furans fused to 5- and 7-membered rings as well. 

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. 

Flassner A., Fischer B. New Chemistry of Oxazoles Heterocydes 1993 351441-1465 Keywords Diels-Alder reactions of oxazoles with olefins or acetylenes, het-erodienophiles... 

Jacobi reports using a variant of method A to access the A,B,E-ring system of wortmannin.14 The sequential addition of methyl lithium and acetylenic Grignard reagent followed by triflation proceeds from 7 to the corresponding triflate 8 in 74% yield (Fig. 4.13). Subsequent carbonylation of the alkyne and the phenol produces the acyl oxazole 9, which is smoothly converted into the furanolactone 10 over three more steps. 

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>. 

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). 

In general, acyl azides are too unstable to survive at the temperatures required for addition to acetylenes, although benzoyl azide adds readily to ynamines in toluene. Ethoxycarbonyl azide also gives triazoles in good yield with ynamines. The azide adds to propargylic alcohols in boiling ethanol, and to acetylene at 100° under pressure. Addition to phenylacetylene and to electron-deficient acetylenes has been carried out at 130°. Oxazoles are also formed at this temperature by competing thermal decomposition of the azide, and addition of ethoxycarbonylnitrene to the acetylenes. The triazole obtained from phenylacetylene is 2-ethoxycarbonyl-4-phenyltriazole the two 1-ethoxycarbonyltriazoles can be isolated if the addition is carried out at 50° over several weeks. Since the IH- to -triazole isomerization takes place readily in these systems, a IH-structure cannot be assumed for a triazole formed by addition of these azides. 

Similar to 136, furan 137 was also prepared via the oxazole route. Yun Yang, a student from Guangzhou Institute of Chemistry, thermolyzed oxazole 139 and bis(tri-n-butylstannyl)acetylene 155 in a sealed tube to afford a separable mixture... 

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 =... 

The halogenated derivatives of oxazoles, thiazoles80 and benzothiazoles81 were also the subject of palladium catalyzed coupling with terminal acetylenes. 5-Bromo-2-methyl-4-phenyloxazole for example coupled efficiently with phenylacetylene using a conventional catalyst system to give an excellent yield of the desired product (6.53.),82... 

Huisgen s group488 have described a new synthesis of pyrroles (26) from oxazol-5-ones (azlactones) (25) with DMAD and MP. The pyrrole derivatives formed in situ from 2,4-dimethyl- and 4-benzyl-2-methyloxazolone with DMAD underwent nucleophilic addition to a second mole of the acetylenic ester to give the Michael adducts 27 and 28... 

According to the literature data, the nature of the interaction of oximes with acetylenes depends on many factors. Winterfeldt and Kronh (69-CB2336) obtained oxazoles from ketoximes and dimethyl acetylenedicar-boxylate by carrying out the reaction in DMSO at 20-25°C. Their work shows that the nitrogen atom of the oxime initially attacks the triple bond to form the intermediate 108 (Scheme 51). 

The addition of a nitrene to an acetylene would appear to be another direct route to 2-azirines. The reaction of ethyl azidoformate (12) with either diphenyl- or diethylacetylene (15) produces mainly the oxazole (16).6,7... 

Acetylenic dienophiles react with oxazoles to provide furans, which arise from the retro Diels-Alder reaction with loss of RCN from the initially formed alkyne/oxazole Diels-Alder adduct. Olefinic dienophiles and oxazoles react to give pyridine derivatives resulting from a fragmentation of the initial [4 + 2] cycloadducts with subsequent aromatization. 

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>. 

Intramolecular Diels-Alder reactions between oxazoles and acetylenes have also been used as a key step in a number of natural product syntheses. For example, cycloadducts 69 and 70 were derived from intramolecular Diels-Alder reactions of their respective acylic 2-substituted oxazole precursors. These cycloadducts were key intermediates in the syntheses of natural products (—)-stemoamide and (- -)-colchicine, respectively (Scheme 11) <2000JA4295, 2000T10175>. 

This concept was applied in an efficient synthesis of oxazole-containing natural product muscoride A. The acetylene intermediate 180 was not isolated and the cyclization and desilylation occurred upon basic work-up of the reaction mixture leading to the oxazole (Scheme 50) <2003AGE1411>. 

It is well known that Diels-Alder reaction of oxazoles as azadienes with acetylenic dienophiles result in the formation of furan derivatives via elimination of a nitrile from the adduct in a retro Diels-Alder process... 

Moreover, aryl-oxazoles, -imidazoles [17], or-thiazoles [18], anhydrides [19], and imides [20] are accessible via intramolecular Heck-type carbonylations. In addition to typical acid derivatives, aldehydes [21], ketones [22], aroyl cyanides, aroyl acetylenes, and their derivatives [23] could be synthesized via nucleophilic attack of the acyl metal complex with the corresponding hydrogen or carbon nucleophiles. Even anionic metal complexes like [Co(CO)4] can act as nucleophiles and lead to aroylcobalt complexes as products [24]. 

Padwa and co-workers have shown that the amides 55 can be conveniently prepared in high yield by [4 + 2]-cycloaddition of an acetylenic dienophile to the corresponding 2-amino oxazole derivative 54 (Eq. (6)). The reaction was extended to intramolecular reactions (e.g. 56 - 57, Eq. (7)), giving convenient 2-aminofuran precursors for further intramolecular Diels Alder furan (IMDAF) reactions (see Section Il.C.l.e) (99JOC3595, 99TL1645). 

A very neat method for the synthesis of furanoeremophilanes has been devised which incorporates a so-called bis-heteroannulation process.318 This is achieved by an intramolecular Diels-Alder reaction between an oxazole and an acetylenic grouping and is nicely demonstrated by the synthesis of ligularone (711) and petasalbine (712) (Scheme 67).319 A number of straightforward syntheses of... 

Some multicomponent syntheses of trisubstituted oxazoles were described. a-Isocyano-a-alkyl(aryl)acetamides, as 131 <05S161>, was demonstrated to be a useful starting material for a three-component reaction involving isoquinoline 129 <05SL532>. A four-component synthesis was also published starting from an aldehyde, a silylamide, an acyl chloride and a terminal acetylene derivative. The overall process is a modification of a four-component synthesis of a propargylic amide 134 which can be eventually isolated <05T 11317>. 

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