Ketones 2- alkyl oxazoles

The same reaction applied to 2-styryl-5(4/l/)-oxazolone 282 gives simultaneous acylation and alkylation of the arene to produce the corresponding a-acylamino ketones 283. ° Cyclodehydration of 283 then readily affords a 2,5-disubstimted oxazole (e.g. 284 as shown in Scheme 7.92). 

The oxazoles and their derivatives have played a variety of fascinating roles in the preparation of new molecular systems. Much of this chemistry stems from their ability to serve as diene components (azabutadiene equivalents) in reactions with a variety of dienophilic agents, to undergo nuclear metallation, to activate attached aryl or alkyl groups to deprotonation (thus functioning as masked aldehydes, ketones or carboxylic acid groups), and to serve as useful electrophiles on conversion to AT-alkylated salts. 

The reactivity of halogen atoms in position 2 of oxazoles is considerably enhanced by quaternization. This is best illustrated by the synthetic utility of the salt (141) which, like other Ar-alkyl-2-halogeno-azolium and -azinium salts, effects a number of condensation reactions but it far surpasses these other salts in activity (79AG(E)707). Thus it activates carboxylic acids and it dehydrates formamides to isocyanides (Scheme 6). Amides are similarly converted into cyanides, ketones (RCH2COAr) into alkynes (RC=CAr), and cyanohydrins (RCH(OH)CN) are transformed into the corresponding chloro compounds <79CL1117>. 

The imidazo[5,l-A]oxazole ring system has been synthesized. Nitroimidazole 221 was alkylated with an a-bromo acetophenone to give a mixture of ketones 222 and 223 in a 1 3 ratio. Compound 223 was then cyclized under basic conditions to give the corresponding imidazo[5,l-A]oxazoles 224 (Scheme 66) <1999H1081>. 

Kawano Y, Togo H (2009) lodoarene-catalyzed one-pot preparation of 2,4,5-trisubstituted oxazoles from alkyl aryl ketones with mCPBA in nitriles. Tetrahedron 65 6251-6256 Jarikote DV, Siddiqui SA, Rajagopal R, Daniel T, Lahoti RJ, Srinivasan KV (2003) Room temperature ionic liquid promoted synthesis of 1,5-benzodiazepine derivatives under ambient conditions. Tetrahedron Lett 44 1835-1838... 

According to Carlin et al. (1986), the exact mechanism of oxazole formation is not known, despite the previous schemes proposed by Vitzthum and Werkhoff (1974a,b) and by Ohloff and Flament (1978). Formation pathways were proposed by Baltes and Bochmann (1987d) and Mottram (1991). For Vitzthum and Werkhoff (1974b), one pathway could be the decarboxylation of serine or threonine into ethanolamine or methylethanolamine condensation with an aldehydic compound into an oxazolidine, then oxidation into an oxazole unsubstituted or methylated on position 5 and bearing an alkyl or an acyl radical on position 2. Another pathway could be the condensation of amino acids with a-dicarbonyl compounds, followed by a Strecker degradation, formation of an a-amino ketone which, after acylation... 

A truncated Passerini reaction between various aldehydes or ketones and a-alkyl-a-isocyanoacetamides in toluene at 70 °C in the presence of LiBr afforded 2,4,5-trisubstituted oxazoles in satisfactory yields (38-98%). For instance, stereoselective nucleophilic addition of 110 to A,A-dibenzylphenylalanal 111 led predominantly to the awfi-adduct 112 (dr = 9 1) which was smoothly converted after acidic hydrolysis of the oxazole ring into the dipeptide 113, containing an a-hydroxy-P-amino acid (norstatine) component <04T4879>. 

It has been suggested that aryl groups favor structure 65, derived from the enediol form of the hydroxy ketones (and hence the formation of oxazoles), whereas the alkyl groups favor 66 and consequently yield imidazoles. The observation that higher amidines give only imidazoles... 

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. ... 

The Diels-Alder reaction of oxazoles with alkynes has become a preferred method for the synthesis of substituted furans with diverse applications. A large number of early examples of this reaction have been tabulated. Activated dienophiles such as acetylenic ketones and esters can be used, although unactivated alkyl, aryl, and silyl alkynes have been used as well. In particular, the reaction of 4-phenyloxazole with substituted acetylenes is frequently used for preparing 3,4-disubstimted furans. Cycloadducts derived from 4-phenyloxazole typically decompose under milder conditions than 4-alkyloxazoles, allowing the synthesis of a wider range of functionalized furans. Several examples are shown below. 

The Schollkopf reaction additionally serves as a useful method for the preparation of a-amino ketones (c/, 14 32 33). Aeid-eatalyzed hydrolysis of the oxazole products of the Schollkopf reaction (e.g., 18) leads initially to a-amino ketone intermediates cf, 32), which can either be isolated or—in the case of intermediates derived from oxazoles bearing C-4 ester substituents—de-alkylated and deearboxylated to provide the related a-amino ketones cf, 33). ... 

Quaternization of the nitrogen atom in a heterocyclic system can activate the ring towards addition reactions. An oxazoline moiety was converted to an aldehyde in 97% overall yield by alkylation of oxazoline with MeOTf, reduction with sodium boro-hydride, and hydrolysis of the resulting aminal (eq 10). Alternatively, treatment of an TV-methylated oxazolium triflate with a Grignard reagent followed by aqueous acid produced a ketone. Reaction of alkenyl oxazoles with MeOTf induced spontaneous intramolecular [4 -i- 2] cycloaddition at room temperature leading to a hydroindole or a hydroisoquinoline after reduction by sodium borohydride (eq 11). ... 

The first iodine-catalyzed synthesis of 2-alkyl substituted oxazoles 130 by a decarboxylative domino reaction was reported. Aryl methyl ketones 128 were transformed in situ into a-iodo ketones and then, by the Kornblum oxidation, into 1,2-diketones. After the addition of the a-amino acid 129, an l2-mediated cyclization/decarboxylation gave oxazoles 130. The reaction proceeds better if the Ar has electron-donating substituents and if the R group is a branched alkyl chain or phenyl residue. The reaction used oxone to regenerate iodine (13JOC6065). 

As described in Sect. 2.1.2, the a-functi(Mialization (tosylation, triflation) of ketones with hypervalent iodine, followed by nucleophilic attack by diverse nucleophiles in an intramolecular fashion offers a convenient entry to various heterocycles [6]. Such a transformation can also be realized in an intermolecular fashion. Along these lines, Togo and coworkers [97] reported an elegant one-pot synthesis of 2,4,5-trisubstituted oxazoles 142 from alkyl aryl ketones 140 and nitriles 141 via an iodoarene-catalyzed oxidation reaction (Scheme 35). In this reaction sequence, reactive aryliodonium species were generated in situ by the reaction of aryl iodide with mCPBA and trifluoromethanesulfonic acid (TfOH). Afterwards, aryliodOTiium species reacted with alkyl aryl ketone to form a fi-keto aryliodonium species. 

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