Oxazoles substitution, electrophilic

A multiply bonded nitrogen atom deactivates carbon atoms a or y to it toward electrophilic attack thus initial substitution in 1,2- and 1,3-dihetero compounds should be as shown in structures (110) and (111). Pyrazoles (110 Z = NH), isoxazoles (110 Z = 0), isothiazoles (110 Z = S), imidazoles (111 Z = NH, tautomerism can make the 4- and 5-positions equivalent) and thiazoles (111 Z = S) do indeed undergo electrophilic substitution as expected. Little is known of the electrophilic substitution reactions of oxazoles (111 Z = O) and compounds containing three or more heteroatoms in one ring. Deactivation of the 4-position in 1,3-dihetero compounds (111) is less effective because of considerable double bond fixation (cf. Sections 4.01.3.2.1 and 4.02.3.1.7), and if the 5-position of imidazoles or thiazoles is blocked, substitution can occur in the 4-position (112). 

Thieno[3,4-d]oxazole-3a(4H)-carboxylic acid, dihydro-2-methyl-synthesis, 6, 1020 Thieno[2,3-d Joxazoles synthesis, 6, 990 Thieno[3,2-g]pteridine structure, 3, 284 lH-Thieno[3,4-c]pyran-2-ones synthesis, 4, 1032 Thienopyrazines synthesis, 4, 1022-1024 Thieno[2,3-6]pyrazines, 4, 1023 electrophilic substitution, 4, 1024 Thieno[3,4-6]pyrazines, 4, 1024 Thieno[3,4-c]pyrazole, 4,6-dihydro-3-hydroxy-carbamates... 

Thus attack of the TosMlC anion 9 on a carbonyl carbon is followed (or accompanied) by ring closure of the carbonyl oxygen to the electrophilic isocyano carbon to form an oxazoline (12). Loss of p-tolylsulfinic acid provides the 5-substituted oxazole 13. ... 

Like thiazole, oxazole is a jt-electron-excessive heterocycle. The electronegativity of the N-atom attracts electrons so that C(2) is partially electropositive and therefore susceptible to nucleophilic attack. However, electrophilic substitution of oxazoles takes place at the electron-rich position C(5) preferentially. More relevant to palladium chemistry, 2-halooxazoles or 2-halobenzoxazoles are prone to oxidative addition to Pd(0). Even 2-chlorooxazole and 2-chlorobenzoxazole are viable substrates for Pd-catalyzed reactions. 

The regiochemistry for trapping lithiooxazole depends upon the oxazole substituents as well as the nature of the electrophile. Hodges, Patt and Connolly observed that the major product of reaction between lithiated oxazole (5 + 6) and benzaldehyde was the C(4)-substituted oxazole 7, resulting from reaction of the dominant acyclic valence bond tautomer 5 via the initial aldol adduct 6 followed by proton transfer and recyclization [3]. 

Interestingly, deprotonation of the 3-oxo-pyrrolo[l,2-f]oxazole 277 with r-BuLi at —78°C took place at the C-5 position. Addition of an electrophile provided the substituted products 278 in good yields. Stannyl and silyl chlorides, dimethyl sulfate, ketones, and benzaldehyde were successfully used as electrophiles. A significant feature of this lithiation-substitution reaction is the generally high Ar-diastereoselectivity only single diastereomers of products were isolated (Scheme 41) <2001JA315>. 

Oxazoles resemble 1-substituted imidazoles in their positional reactivity order for electrophilic substitution, 5 > 4 > 2 [59LA(626)83, 59LA(626)92 74AHC(17)99 84MI29]. The compounds can be regarded as hybrids of... 

Although thiazoles structurally resemble imidazoles and oxazoles, they are less reactive with electrophiles. Calculated 7r-densities (48BSF1021) and localization energies (61CCC156) largely agree with experimental observations that positional specificities for electrophilic substitution are 5... 

Electrophilic substitutions Although oxazole, imidazole and thiazoles are not very reactive towards aromatic electrophilic substitution reactions, the presence of any electron-donating group on the ring can facilitate electrophilic substitution. For example, 2-methoxythiazole is more reactive... 

Electrophilic substitution reactions of oxazoles, imidazoles, and thiazoles... 

Although oxazole possesses a sextet of 7r-electrons, all its properties indicate that the delocalization is quite incomplete hence it has but little aromatic character. There is considerable bond fixation (see Section 4.18.2.3.1), hydroxyoxazoles are unstable relative to their oxo tautomers, oxazolediazonium salts are unknown, oxazoles function as dienes in the Diels-Alder reaction (see Section 4.18.3.1.2(vii)) and electrophilic substitution is rare. The chemistry of oxazole is dominated by its tendency to undergo ring-opening rather than preserve its type. 

A systematic study of substitution reactions of oxazole itself has not been reported. Bromination of 2-methyl-4-phenyloxazole or 4-methyl-2-phenyloxazole with either bromine or NBS gave in each case the 5-bromo derivative, while 2-methyl-5-phenyloxazole was brominated at C(4). Mercuration of oxazoles with mercury(II) acetate in acetic acid likewise occurs at C(4) or C(5), depending on which position is unsubstituted 4,5-di-phenyloxazole yields the 2-acetoxymercurio derivative. These mercury compounds react with bromine or iodine to afford the corresponding halogenooxazoles in an electrophilic replacement reaction (81JHC885). Vilsmeier-Haack formylation of 5-methyl-2-phenyloxazole with the DMF-phosphoryl chloride complex yields the 4-aldehyde. 

Lithiooxazoles exist in equilibrium with their open chain forms one solution for the synthesis of 2-substituted oxazoles involves 2-silylation (and then reaction with an electrophile). By correct choice of silylating agent, it is possible to trap the ring-closed or ring-opened forms (Scheme 58) <2002TL935>. 

Abstract Synthesis methods of various C- and /V-nitroderivativcs of five-membered azoles - pyrazoles, imidazoles, 1,2,3-triazoles, 1,2,4-triazoles, oxazoles, oxadiazoles, isoxazoles, thiazoles, thiadiazoles, isothiazoles, selenazoles and tetrazoles - are summarized and critically discussed. The special attention focuses on the nitration reaction of azoles with nitric acid or sulfuric-nitric acid mixture, one of the main synthetic routes to nitroazoles. The nitration reactions with such nitrating agents as acetylnitrate, nitric acid/trifluoroacetic anhydride, nitrogen dioxide, nitrogen tetrox-ide, nitronium tetrafluoroborate, V-nitropicolinium tetrafluoroborate are reported. General information on the theory of electrophilic nitration of aromatic compounds is included in the chapter covering synthetic methods. The kinetics and mechanisms of nitration of five-membered azoles are considered. The nitroazole preparation from different cyclic systems or from aminoazoles or based on heterocyclization is the subject of wide speculation. The particular section is devoted to the chemistry of extraordinary class of nitroazoles - polynitroazoles. Vicarious nucleophilic substitution (VNS) reaction in nitroazoles is reviewed in detail. 

The synthesis of 2-acyloxazoles has always been a challenging task. Their synthesis through the use of metallated oxazole is troubled by its ring opened form (as an enolate isonitrile) which is predominant. A very useful new procedure for this synthetic approach is offered by the use of i-PrMgCl as a metallating reagent and a Weinreb amide 102 as the electrophile. This procedure was applied both to 5-(hetero)-aryl substituted oxazoles and unsubstituted oxazoles <07JOC5828>. 

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