Nitriles 2-alkyl oxazoles

Much of the early work into the rhodium(II)-catalysed formation of oxazoles from diazocarbonyl compounds was pioneered by the group of Helquist. They first reported, in 1986, the rhodium(II) acetate catalysed reaction of dimethyl diazomalonate with nitriles.<86TL5559, 93T5445, 960S(74)229> A range of nitriles was screened, including aromatic, alkyl and vinyl derivatives with unsaturated nitriles, cyclopropanation was found to be a competing reaction (Table 3). 

To date most of the nitriles studied have been simple alkyl or aromatic derivatives with little other functionality. We recently attempted to extend the reaction to iV-protected a-aminonitriles, derived by dehydration of a-aminoacid amides (Path A, Scheme 25), but this proved unsatisfactory, and therefore we investigated an alternative diazocarbonyl based route in which the order of steps was reversed, i.e. a rhodium catalysed N-H insertion reaction on the amide followed by cyclodehydration to the oxazole (Path B, Scheme 25). 

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>. 

Photolytic (68CB302) or rhodium-catalyzed decomposition of alkyl 3,3,3-trifluoro-2-diazopropionates gives carbenes and carbene complexes, respectively, which exhibit an enormous synthetic potential. [3 + 2] cycloaddition reactions have been performed, e.g., with nitriles to give 4-trifluoromethyl-substituted oxazoles [90JOC3383 9IJFC(52)149]... 

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). 

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-... 

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. 

Gogonas and Hadjiarapgolu described the synthesis of oxazoles via a Rh2(OAc)4-catalyzed [3 + 2]-cycloaddition reaction of phenyliodonium salts with nitriles (Scheme 1.46). The starting phenyliodonium salt 167 was prepared from dimedone and diacetoxyiodobenzene in 95% yield. Reaction of 167 with nitriles in the presence of Rh2(OAc)4 gave fused 2-alkyl-, 2-aralkyl-, or 2-aryloxazoles 168 in modest yields. It is noteworthy that the reaction conditions do not require an inert atmosphere. The mechanistic details of this reaction are not yet clear. Selected examples are shown in Table 1.10. 

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. 

Kozmin s synthesis of the side chain was more efficient than Leighton s method (Scheme 60). Oxazole 285 was synthesized by Rh-catalyzed condensation of alkynyl nitrile 283 with diazo malonate 284 using the Helquist protocol [116]. Lindlar reduction of alkyne, reduction by Super-H, and bromi-nation afforded bromide 216, which was employed for the alkylation of metalloenamine to afford the aldehyde 200. Subsequent (Z)-olefination and saponification furnished the side chain subunit 269. 

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. 

---