Disubstituted oxazoles, synthesis

The boron trifluoride etherate catalysed formation of oxazoles has been used in synthesis. Doyle has successfully employed the reaction in the synthesis of annuloline 20, a disubstituted oxazole isolated from the roots of the annual rye grass. Thus, l-diazo-4 -methoxy-acetophenone 19 was reacted with 3,4-dimethoxycinnamonitrile in the presence of boron trifluoride etherate to yield the natural product 20 in 48% yield (Scheme 11).<80JOC3657>... 

A new approach to the synthesis of 2,4,5-trisubstituted and 2,5-disubstituted oxazoles, 97 and 98, used l-(methylthio)acetone 95 with nitriles in the presence of trifluoromethanesulfonic anhydride. The proposed mechanism involves an unstable 1-(methylthio)-2-oxopropyl triflate 96 which was detected using NMR spectroscopy <06JOC3026>. 

A multipurpose mesofluidic flow reactor was developed for the automated synthesis of libraries of 4,5-disubstituted oxazoles. The process was based on the known reaction of alkylisocyanoacetates and acylchlorides <06OL5231>. 

Baumann M, Baxendale IR, Ley SV, Smith CD, Tranmer GK (2006) Fully Automated Continuous Flow Synthesis of 4,5-Disubstituted Oxazoles. Org Lett 9 1521-1524... 

Natural product o-methylhalfordinol 117 is a basic principle of the oxa-zole alkaloids of Halfordia scleroxyla and Aegle marmelos. Annuloline 119, a blue fluorescent pigment, has been isolated from the roots of rye stalk Lolium multifiorum. The total synthesis of 2,5-disubstituted oxazole alkaloids o-methylhalfordinol and annuloline is based on the aza-Wittig reaction (Scheme 48). Thus 4-methoxyphenacylazide 115, triphenylphos-... 

Smith and co-workers adapted Sheehan and Izzo s original synthesis of 2-aryl-4(57/)-oxazolones and developed a general synthesis of 2-aIkylA(57/)-oxazo-lones. Teatment of an acid halide with AgNCO followed by diazomethane produced 344 that were immediately converted to the 2-alkylA-oxazole triflates 345. The authors noted that ethanol-free diazomethane was required to prepare 344. The oxazole triflates 345 were, in turn, key intermediates leading to a variety of 2,4-disubstituted oxazoles required for natural products (Scheme 6.73). 

Thus, an oxygen nucleophile reacted intramolecularly with the alkynyl triple bond, and another example of this is provided by the synthesis of 2,5-disubstituted oxazoles from 7V-propargylcarboxamides under mild conditions using 5 mol% AUCI3 in acetonitrile 22... 

Oxazole IV-oxides cannot be made by oxygenation of oxazoles. The only method of synthesis remains the condensation of monooximes of 1,2-dicarbonyl compounds with aldehydes in the presence of hydrogen chloride (equation 132) (15CB897). The aldehyde may be aromatic or aliphatic (including formaldehyde) and the oxime may be derived from an aromatic diketone or it may be an a-keto aldoxime, leading to a 2,5-disubstituted oxazole IV-oxide. It may also contain an additional carbonyl group as in equation (133). 

Chiral isocyanides such as 198 have also been used for the synthesis of chiral 4,5-disubstituted oxazoles such as 199, which are potentially useful in fluorescence-detected circular dichroism for on-column capillary electrophoresis (Equation 12) <1996JOC8750>. 

The readily available ethyl 2-chlorooxazole-4-carboxylate proved to be a versatile scaffold for the synthesis of 2,4-disubstituted oxazoles and 2,4,5-trisubstituted oxazoles. 

In recent years, several natural products containing 2,4-disubstituted oxazoles have been isolated and their synthetic routes were investigated. Several key intermediates required for the synthesis of target compounds were achieved via the Stille, Suzuki, Heck, and Sonogashira reactions. In addition, several 2,5-diaryloxzoles were prepared from 2-halo-... 

A novel oxazole building block, 4-bromomethyl-2-chlo oox lzole, has been synthesised and exploited in palladium-catalysed cross-coupling reactions to give a range of 2,4-disubstituted oxazoles in satisfactory yields <04TL3797>. The synthesis of previously inaccessible 2-amino-4-benzyloxeizoles has also been reported <04TL867>. 

The synthesis of Bliimlein82 and Lewy,83 which affords moderate yields of 2,4-disubstituted oxazoles (29) (having at least one aryl group) by the condensation of a-halo ketones with amides (other than formamide) is even at present a method of choice because of the ready availability of the starting materials. It has been extensively applied to the preparation of many 2,4-disubstituted oxazoles20 21 40 84-86 and is equally applicable... 

Perhaps the simplest method of oxazole synthesis would involve bromina-tion of a ketone in the presence of an amide as shown in Eq. (6), that is, generating the required a-bromo ketone in situ. Marquez88 thus prepared several 4-phenyl 2,5-disubstituted oxazoles by adding calculated amounts of bromine to a heated mixture of ketone and amide. With unsymmetrical... 

In the Schollkopf synthesis, a-metalated isocyanides 13 (from isocyanides and /z-butyllithium) react with acid chlorides to give 4,5-disubstituted oxazoles 14 via C-acylation and electrophilic C-O bond formation. 

Scheme 6.18 Automated flow synthesis of 4,5-disubstituted oxazoles...

Oxidation of oxazolines using Mn02 was also employed in the synthesis of a beminamycin A fragment by Shin and co-workers ° and in the preparation of the naturally occiuring 2,4-disubstituted oxazole, phenoxan 28, by Yamamura s group" (Scheme 1.5). For beminamycin, the oxazoline 25 was synthesized in 61% yield by Mitsunobu dehydration of the serine-derived amide 24. 

Balaban and co-workers " prepared 2,5-disubstituted oxazoles via side-chain bromination with NBS, followed by dehydrobromination with pyridine. Kashima and Arao described a synthesis of oxazoles using NBS/AIBN to effect oxidation of an oxazoline. In this case, the product was a 5-bromooxazole, e.g., 63 (Scheme 1.19). This study was limited to only three examples of 2-aryloxazoles. 

Schollkopf and Gerhart " pioneered the use of metallated isocyanides in organic synthesis. This section discusses the versatility of such intermediates for preparing monosubstituted and disubstituted oxazoles as well as the parent 1, itself. In addition, continuing advances in solid-phase synthesis have enhanced the use of tosylmethyl isocyanide (TosMIC) for oxazole synthesis several examples are presented. 

Early in their approach to calycuUns, Armstrong and co-workers" " described an efficient, general synthesis of oxazole phosphonium salts and phosphonates (Scheme 1.296). Olefination of these salts produced 2,4-disubstituted oxazoles containing a trans alkene with up to 99 1 trans.ds ratios using 1137b (Ri =sec-... 

Radspieler and Liebscher prepared several 4-chloro-2,5-disubstituted oxazoles 1520 from aromatic acyl cyanides 1519. These oxazoles are the first examples in which the 2-substitutent was not derived from an aromatic aldehyde. They extended this methodology to prepare suitably functionalized dichloro indole bis-oxazole C-D-E fragments. Their approach is noteworthy as the first synthesis of such fragments that does not involve chlorination of an intact oxazole ring. 

Searle chemists described an improved synthesis of 2-(bromomethyl)-4-oxazolecarboxylic acid ethyl ester 957. Thus slow addition of ethyl 2-diazo-3-oxo-propanoate in bromoacetonitrile to Rh2(OAc)4 in bromoacetonitrile at 70°C gave 957 in 78% yield (Scheme 1.409). Incorporation of 957 into a series of PGE2 antagonists 1604 was straightforward. Here, the 2,4-disubstituted oxazole was an isostere for a diacylhydrazine moiety. 

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