Nitriles 5-aryl-2- oxazoles

Application of the Ritter reaction conditions on y-hydroxy-a,P-alkynoic esters, 102, produced ethyl 5-oxazoleacetates 103 or y-A-acylamino-P-keto ester 104 by reaction with aryl or alkyl nitriles respectively. The y-A-acylamino-P-keto ester 104 can also be transformed into oxazole derivatives using an additional step involving POCI3 <06TL4385>. 

A more elaborate approach was taken by Kaffy et al. [94], The goal of the research was a series of compounds with greater stability and a higher affinity for endothelial cells within tumor vessels than CA-4, 7 however, the paper described a method that was purely synthetic. The synthetic strategy involved a 1,3-dipolar cycloaddition of a nitrile oxide 186 with a substituted aryl alkyne 187 to form the oxazole 188. 

Cycloadditions have been carried out to 37/-indoles (222, 223) (125,126), N-arylmaleimides (224) (127,128), l,2), -azaphospholes (225) (129), 5(47/)-oxazo-lones (226) (130), and 4,5-dihydrooxazoles (230) (131). The primary cycloadducts from the reaction of oxazolones (e.g., 226 with diaryl nitrile imines), derived from tetrazoles in refluxing anisole, do not survive. They appear to lose carbon dioxide and undergo a dimerization-fragmentation sequence to give the triazole 228 and the diarylethene 229 as the isolated products (130). In cases where the two aryl substituents on the oxazole are not the same, then, due to tautomerism, isomeric mixtures of products are obtained. 

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... 

Several new syntheses of 2,5-disubstituted oxazoles have been reported. The reaction of allyl zinc bromides with )V-cyanomethylimidates (136) leads to 2-alkyl- or aryl-5-allyloxazoles in 50-65% yields after hydrolysis of intermediate imine salts (137) <91SC1501>. The allyl zinc reagents add to the nitrile, in contrast to organolithium and magnesium reagents, which are too basic (Scheme 62). 

There has been continued interest in the synthesis of oxazoles from a-diazo carbonyl compounds and nitriles catalyzed by Lewis acids. The BFa-catalyzed reaction of a-diazoacetophenones or methyl p-nitrophenyldiazoacetate with chloroacetonitrile affords 5-aryl-2-chloromethyloxazoles or 2-chloromethyl-5-methoxy-4-(p-nitrophenyl)oxazole, respectively (Equation (19)) <89BCJ618>. The former products react with primary, secondary, and tertiary amines by nucleophilic displacement of the chloride group. Methyl or ethyl isocyanate may be used as the nitrile component to prepare... 

The starting nitrile may be alkyl, aryl, or even hydrogen cyanide, which leads to the synthesis of oxazole itself180 by hydrolysis and decarboxylation of the oxazole-4-carboxylate (89, R = H). Various exten-... 

In medicinal chemistry nitriles are very useful because they can be transformed into biologically important structures such as tetrazoles, triazoles, oxazoles, thia-zoles, oxazolidinones. .. A variety of aryl nitriles has been prepared in excellent yields by Pd-catalyzed coupling of aryl halides with Zn(CN)2 using polymer-supported triphenylphosphine as the ligand and DMF as the solvent under micro-wave irradiation conditions (Scheme 10.34) [76], Products were obtained in high yields and excellent purity without the need for purification. 

Early work from Moody s laboratories extended the rhodium-carbene methodology to include a-diazosulfones (Scheme 1.40). Selected examples of 2-alkyl (aryl)-5-ethoxy-4-(phenylsulfonyl)oxazoles 146 prepared from ethyl phenylsul-fonyldiazoacetate 145 and nitriles are shown in Table 1.7. 

The continuing development of solid-phase synthesis and combinatorial chemistry has led to solid-phase oxazole syntheses with a minimum of purification. Iso and co-workers generated ot-(trimethylsilyl)diazoketones on a Wang resin and employed rhodium-catalyzed diazo transfer methodology to prepare oxazoles (Scheme 1.47). Reaction of the resin-bound benzoyl chloride 169 with (trimethyl-silyl)diazomethane gave the corresponding a-(trimethylsilyl)diazoketone 170 in excellent yield. Treatment of 170 with an aryl nitrile in the presence of catalytic Rh2(OAc)4 then furnished a resin-bound 2,5-diaryl-4-(trimethylsilyl)oxazole 171. 

Ducept and Marsden described a general synthesis of 5-ethoxy-2-substituted 4-(triethylsilyl)oxazoles 176 from the rhodium(II)octanoate-catalyzed diazo-transfer reaction of ethyl (triethylsilyl)diazoacetate 175 and nitriles (Scheme 1.48). The reaction conditions tolerate a wide variety of functional groups on the nitrile, including alkyl, aryl, heteroaryl, vinyl, carbonyl, sUyloxy, and dialkylamino. Desilylation of 176 with TBAF afforded the corresponding 2-alkyl(aryl)-5-ethoxy-oxazoles 177, which are normally inaccessible from diazoesters using conventional rhodium-carbene methodology. The authors noted that carbonyl groups in the 2 position of 176 are not compatible with TBAF deprotection. 

Lewis acids efficiently catalyze the transfer of diazoketones and diazoesters to amides and nitriles to furnish 2,4,5-trisubstimted oxazoles (Scheme 1.49). In particular, Eguchi and co-workers found that BF3 OEt2 was the best catalyst for reaction of the adamantyl diazoketoester 180 with acetonitrile. Attempts to prepare 181 using Rh(II)acetate or photolysis were unsuccessful. Similarly, Ibata and Isogami °° described a general synthesis of 5-aryl-2-(chloromethyl)oxazoles 183 from a BF3.0Et2-catalyzed addition of a-diazoacetophenones 182 with chloro-acetonitrile. The yields were quite respectable (Table 1.12). 

Scheme 6.3 Another cycloaddition/cycloreversion protocol with an oxazole moiety exploiting the extrusion of an aryl nitrile.

Substituted 5-alkoxyoxazoles reacted with dimethyl acetylenedicarboxyl-ate to give a nitrile [145] by 1,4-addition for example, 5-butoxy-4-methoxy-oxazole gave acetonitrile and dimethyl 2-butoxyfuran-3,4-dicarboxylate. When 5-acyl-3-aryl-2-isoxazolines react with a strong base such as sodium hydride or triethylamine, nitriles are produced in moderately good yields [146]. 

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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