Trisubstituted oxazoles, synthesis

In 2007, Tron and Zhu reported the multicomponent synthesis of 5-iminoox-azolines (42) starting from a,a-disubstituted secondary isocyano amides (41), amines, and carbonyl components (see Fig. 15) [155]. The reaction presumably follows a similar mechanism as in the 2,4,5-trisubstituted oxazole MCR (described in Fig. 11) however, because of the absence of a-protons at the isocyano amide 41, the nonaromatized product is obtained. As in the 2,4,5-trisubstituted oxazole MCR, toluene was found to be the optimal solvent in combination with a weak Brpnsted acid. The reaction was studied for a range of aldehydes and secondary amines. In addition, a variety of functionalities such as acetate, free hydroxyl group, carbamate, and esters are tolerated. Clean conversions were observed for this MCR as indicated by NMR analysis of the crude products (isolated yield 50-68%). The... 

Davidson s synthesis consists of the cydization of a-acyloxyketones with ammonia or ammonium acetate to give 2,4,5-trisubstituted oxazoles. The Passerini reaction between arylglyoxals, carboxylic acids, and isocyanides afforded N-substituted 2-acyloxy-3-aryl-3-oxopropionamides 83 in high yields. Upon heating with an excess of ammonium acetate in acetic acid, compounds 83 were cydized to N,2,4-trisubstituted oxazole-5-carboxamides 84 in fair yields [59]. A large number of a-acyloxy-jS-ketoamides can be prepared by changing the reaction components, so the method provides straightforward access to a variety of oxazole-5-carboxamides (Scheme 2.30). 

A microwave-assisted one-pot approach towards 2,4,5-trisubstituted oxazoles employed a hypervalent iodine (III) catalyst to bring about the reaction of ketones, 1,3-diketones and /3-keto-carboxylic acid derivatives with amides [75]. Microwave dielectric heating was also successfully utilized in a solid-supported, solvent-free synthesis of 2-phenyl-oxazol-5-ones (azlac-tones) [76] as well as in a solution phase synthesis of isomeric 2-phenyl-oxazol-4-ones (oxalactims) [77]. 

N—C—O + C—C. The construction of the oxazole ring by the condensation of a-halogeno ketones with primary amides (equation 122) is the Bliimlein-Lewy synthesis (1884/1888). The method succeeds best when the resulting oxazole contains one or more aryl substituents. The use of formamide leads to oxazoles with a free 2-position and in this case it is possible that the reaction proceeds as in equation (113). 2-Aminooxazoles are produced by the action of a-halogeno ketones on urea and its derivatives (equation 123) or on cyanamide (80ZOR2185). The mercury(II) sulfate-catalyzed condensation of alkynic alcohols or their esters with primary amides leads to trisubstituted oxazoles (equation 124). 

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. 

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... 

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>. 

Eguchi and co-workers ° developed a general synthesis of 2,5-disubstituted and 2,4,5-trisubstituted oxazoles from an intramolecular Aza-Wittig reaction of (Z)-p-(acyloxy)vinyl azides (Scheme 1.74). An a-bromoketone 277 was converted to an a-azidoketone 278, which was O-acylated at 78°C to give, exclusively, a (Z)-p-(acyloxy)vinyl azide 279. This was attributed to intramolecular chelation of lithium by the enol oxygen and the a-nitrogen atom of the azide. 

Previously, these authors reported a general synthesis of 2,4,5-trisubstituted oxazoles 561 from 558 (Scheme 1.153). Addition of an alkyUithium reagent to 558 generated a lithium p-bis(trimethylsilyl)amino enolate 559 that was acylated in situ to produce a p-(acyloxy)-A,A-bis-(trimethylsilyl) enamine 560. Cyclization of 560 to 561 was accomplished using FVP or TMSOTf. 

Vedejs and Grissom" described the synthesis and reactions of azomethine ylides generated from 4-oxazolines. They found that alkylation of a 2,5-disubsti-tuted or a 2,4,5-trisubstituted oxazole 15 gave an A -alkyloxazolium salt, which was... 

In a number of multicomponent condensation reactions, TMSCl has also been utilized to improve the yield or efficacy of the desired product, or is directly incorporated into the final molecules. Examples include the synthesis of Al-aryl-3-arylamino acids from a three-coir onent reaction of phenols, glyoxylates, and anilines, preparation of 2,4,5-trisubstituted oxazoles, or 4-cyanooxazoles, and the three-component BigmeUi reaction... 

The Davidson oxazole synthesis is the reaction of an acylated a-hydroxy carbonyl with an ammonium cation, typically ammonium acetate to yield oxazoles. The Davidson synthesis is also linear, as all three substituents are contained in the precursor. The reaction is most efficient in preparing 2,4,5-trisubstituted oxazoles, where C5 is aryl substituted. Yields suffer when preparing a 2,4-disubstituted or a mono-substituted oxazole. The COX-2 inhibitor tilmacoxib was prepared by Haruta in this manner. ... 

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. 

By using a sequence of regiocontrolled halogenation and palladium-catalyzed coupling reactions, the synthesis of variously substituted oxazoles from 2-chlorooxazole-4-carboxylate was accomplished. The methodology was applied to the synthesis of a series of 2,4-disubstituted, 2,5-disubstituted, and 2,4,5-trisubstituted oxazoles (Equation 37) [37]. 

An efficient synthesis of trisubstituted oxazoles via chemoselective D-acylations and intramolecular Wittig reactions has been also reported. A plausible reaction mechanism was based on the existence of expected and rearranged isomeric oxazoles. 

The original method for the synthesis of triflnoromethyl-snbstitnted oxazoles is based on the transformation of acyloxazolin-5-ones. Thus, 2-acyl-2-trifluoromethyl-A -oxazolin-5-ones 38 undergo cycloelimination of CO2 on heating at 200-230 °C to yield trisubstituted oxazoles 39. In this case snbstituents at positions 2 and 4 of the oxazole ring are formally interchanged [37]. Flash vacnnm pyrolysis (540-600 °C/0.01 mm Hg) of N-trifluoroacetylisoxazole-5-one also leads to 2-trifiuoro-methyloxazole [38]. 

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>. 

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>. 

A one-pot synthesis of di- and trisubstituted furans from acyl isocyanates using trimethylsilyldiazomethane has been developed, which improves the synthesis of such oxazole intermediates (Scheme 20) <2004S1359>. 

A one-pot synthesis of furan 2-substituted-3-carboxylic and 2-substituted-3,4-dicarboxylic esters was reported. Thus, reaction of an acyl isocyanate with trimethylsilyldiazomethane, a safe replacement for hazardous diazomethane, gave 2-substituted oxazoles, which were treated with dimethyl acetylenedicarboxylate or ethyl propiolate to afford the corresponding di- and trisubstituted furans in good yields <04S1359>. 

Hojo and co-workers " described a novel synthesis of 4-aryl-5-(trifluoro-methyl)oxazoles 331, starting from aldehyde tert-butyl(methyl)hydrazones (Scheme 1.89). Triiluoroacetylation of a tert-butyl(methyl)hydrazone 327 yields 328 that cyclizes to a 4,5,5-trisubstituted oxazoline 329 upon refluxing in toluene in the presence of silica gel. Dehydration of 329 was then accomplished in two steps using POCI3 and a base to generate the 4-aryl-5-(trifluoromethyl)oxazoles 331. 

Aoyama and co-workers used this approach in their synthesis of 2,3,4-trisubstituted furan derivatives. Reaction of 2-cyclohexyl-4-(trimethylsilyl)oxazole with dimethyl acetylenedicarboxylate under thermal conditions gave the corresponding derivative in good yield. 

Synthesis. The preparation of these heterocycles was accomplished using traditional methodology. 2,4-Disubstituted and 2,4,5-trisubstituted compounds were prepared via the Hantzsch (21) synthesis. The Gabriel (22) and Robinson-Gabriel (23) syntheses were used to prepare the 2,5-disubstituted thiazoles and oxazoles, respectively. The intermediate keto-amides could be converted into thiazoles by heating with P4S] q pyridine or with Lawesson s reagent (24). 

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