Electrophilic substitution oxazole

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]. 

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. 

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>. 

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>. 

Substituted oxazoles can typically be prepared by C-2 lithiation followed by quenching with an electrophile. However, this protocol suffers from an accompanying side reaction as the lithiated ring system is in equilibrium with its open-chain form and does not reliably afford the expected C-substituted products. 

Although oxazoles generally are poor substrates for electrophilic substitution because of their electron-deficient nucleus, both experimental findings and MO calculations indicate that when they do react, the order of preference for reaction site is the 4 > 5 > 2 position. Siuprisingly, the deu-teration of oxazole using CF3CO2D/D2O was reported to occur exclusively at the 2 position... 

Five-membered rings with two or more heteroatoms are usually good at electrophilic substitution as one of the heteroatoms must be either O or S or a pyrrole-like nitrogen atom any of which supply lone pair electrons. Pyrazole 12, imidazole 13, oxazole 17, thiazole 18, isoxazole 19 and isothiazole 20 are examples. Multiple substitution can be a problem but is less so than for pyrrole because there are fewer carbon atoms available and the pyridine-like nitrogen atoms deactivate the ring. 

There is a differential reactivity to nitrogen heterocycles between Hg(II) and other types of electrophile, such as bromine, possibly due to a weaker coordination of the mercuric ion to a ring nitrogen for example mercuration is more successful in electrophilic substitutions for oxazoles. In both oxazoles and thiazoles, the preferred position for mercuration is C-5, but in the latter, trimercuration occurs quite readily. 

The amino-l,3-azoles behave as normal arylamines, for example undergoing carbonyl condensation reactions, easy electrophilic substitutions and diazotisation, though 2-amino-oxazoles cannot be diazo-tised, presumably due to the greater electron withdrawal by the oxygen. 

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