Benzoxazole reactivity

Azoles having heteroatoms in the 1,3-orlentatlon are more reactive than those in which the arrangement is 1,2. However, the magnitude of the factor varies. Thus oxazole is 68 times more reactive than Isoxazole, whereas benzoxazole quaternlzes 26 times faster than does 1,2-benzisoxazole (78AHC(22)71). 

Palladium chemistry involving heterocycles has its unique characteristics stemming from the heterocycles inherently different structural and electronic properties in comparison to the corresponding carbocyclic aryl compounds. One example illustrating the striking difference in reactivity between a heteroarene and a carbocyclic arene is the heteroaryl Heck reaction (vide infra, see Section 1.4). We define a heteroaryl Heck reaction as an intermolecular or an intramolecular Heck reaction occurring onto a heteroaryl recipient. Intermolecular Heck reactions of carbocyclic arenes as the recipients are rare [12a-d], whereas heterocycles including thiophenes, furans, thiazoles, oxazoles, imidazoles, pyrroles and indoles, etc. are excellent substrates. For instance, the heteroaryl Heck reaction of 2-chloro-3,6-diethylpyrazine (1) and benzoxazole occurred at the C(2) position of benzoxazole to elaborate pyrazinylbenzoxazole 2 [12e]. 

This surprising reactivity of extremely weakly acidic methyl groups has resulted in extending the Anil Synthesis to a number of heterocyclic systems in which activation in the sense of the benzoxazole group would not be expected. 

The reactivity of 2-alkyloxazoles in base-catalyzed additions and condensations is due to the intermediacy of delocalized anions analogous to (142). 2-Methyl-4,5-diphenyloxazole forms the adduct (278) by the action of benzophenone in liquid ammonia containing lithium amide (equation 89), and 2-methylbenzoxazole condenses with diethyl oxalate in the presence of potassium ethoxide to yield the keto ester (279). Anions with more extended conjugation are involved in the condensation of 2-(propen-l-yl)benzoxazole with diethyl oxalate (equation 90) and in the formation of the stilbene derivative (280) from 5-phenyl-2-p-tolyloxazole and benzylideneaniline (78AHC(23)l7l). 

V. Metallation. Benzoxazole (83JOM159), benzothiazole (85H-295), and benzimidazole (76CHE1399) are each lithiated in the expected 2-position. In magnesiation with EtMgBr, the reactivity order at the 2-positions was benzothiazole > 4- and 5-chloro-l-methylimidazole > 1-methylbenzimidazole >> 1-methylimidazole (69JGU1816). 

Previous observations on the high reactivity of (benzoxazol-2-yl) thioesters toward various aminest prompted the development of uronium salts HSBTU (ll)t l as well as HATTU (13) and HAPyTU (29).t 9 However, HATTU and HAPyTU were less reactive and provoked more epimerization in both cyclization studies and fragment condensations than the corresponding oxygen analogues HATU (12) and HAPyU (28).f 9... 

Doucet has reported that activated aryl chlorides can be employed in the arylation of thiazoles if PdCl(dppb)C3H5 catalyst is used (Scheme 6) [42], Acetyl, formyl, nitro, cyano, ester, and trifluoromethyl substituted aryl chlorides are reactive. However, 4-chlorofluorobenzene was not reactive. Use of the same catalyst system was shown to be effective for the arylation of oxazole and benzoxazole with activated aryl chlorides [43],... 

Miura has recently shown that benzoazoles can be arylated by aryl iodides in the presence of catalytic or stoichiometric copper iodide [100], Sodium carbonate base was found to be optimal, and triphenylphosphine additive was found to increase yields. Benzoxazole, benzothiazole, and IV-methylbenzimidazole were shown to be reactive (Scheme 26). 

The scope of the reaction includes I //-benzimidazole, 1-methylbenzimidazole, benzoxazole, 4,4-dimethyloxazoline, and 3,4-dihydroquinazoline as the heterocyclic partners, but in the latter case only the dehydrogenated product 2-arylquinazoline was isolated. Iodobenzene, p-iodoanisole, and p-iodotrifluoromethylbenzene are suitable coupling partners. Limited reactivity was observed with bromobenzene, and other aryl halides and pseudohalides (Cl, OTf) were unreactive. The reactivity of... 

Methyl substituents in the 2-position of oxazoles, as in other azoles, are reactive toward electrophiles in the presence of bases, but those in the 4- and 5-positions act as if they were attached to a benzene ring.87 121385 Accordingly, 2-methyl-4,5-diphenyloxazole condenses with benzaldehyde or benzophenone in liquid ammonia containing lithium amide, to form 2- (/J-hydroxyethyl) derivatives (233, R = H or Ph) which on dehydration give 2-styryl oxazoles (234).385 The 2-methyl group in benzoxazoles and... 

Fig. 5.17 Reactivity and selectivity of the reactions of five-membered heteroarenes with electrophiles E and nucleophiles Nu (1,2-benzoxazoles and 1,2-benzothiazoles are also known but are not discussed in this book).

The stereochemistry of alkylation of chiral phosphorus-stabilised carbanions (138) has been investigated and shown to be highly sensitive to the nature of the nitrogen substituent. Phase-transfer catalysed alkylation of 2-(diethoxyphosphinyl)cyclohexanone (139) gives bothO-(140) and C-(141) alkylated products. The latter predominate when reactive, non-sterically demanding alkyl halides are used. a-Arylphosphonates (142) have been synthesised in good yields by the copper(l) salt-mediated arylation of phosphonate carbanions. Under similar conditions A-(2-iodophenyl)-substituted phosphonates provide benzoxazole-(143) and oxindole-(144) substituted phosphonates. 

As mentioned above, the heterocycles can be easily metalated with a variety of bases. The oxazole ring and the benzoxazole ring can be metalated at C2 with a variety of strong bases. The major limitation of metalated oxazoles and benzoxazoles is their equilibrium with an open chain p-alkoxynitrile (see Section 6.3.1). In the ring-closed form, the oxazole is nucleophilic at C2. In the open chain form, the anion is nucleophilic at C4. This dual reactivity of the oxazole anion can lead to undesired regiochemistry unless carefiilly monitored. 

Stabilizers UVA 2-(2H-benzotriazol-2-yl)-p-cresol phenol, 2-(5-chloro-2H-benzotriazole-2-yl)-6-(1,1 -dimethylethyl)-4-methyl- 2-(2H-benzotriazol-2-yl)-4,6-bis(1 -methyl-1 -phenylethyl)phenol isopropenyl ethinyl trimethyl piperidol (cellulose diacetate), biphenyl cellulose (UV absorber fro paper), phenylbenzimid-azole (reactive stabilizer for application in cellulosic textiles) Optical brighteners 2,2 -(2,5-thiophenediyl)bis(5-tert-butyl-benzoxazole) Mixtures an ortho-hydroxy tris-aryl-s-triazine compound+hindered hydroxybenzoate compound+hindered amine compound containing a 2,2,6,6-tetraalkylpiperidine or 2,2,6,6-tetraalkylpiperazinone radical ... 

In an alternative to Buchwald-Hartwig aminations, obviating the need for reactive aryl halides, sulfonates, expensive palladinm catalysts and ligands, Li, Dean et al. have recently described the successfnl amination of substituted benzoxazoles in the 2-position, with a range of secondary amines. Their optimized conditions used Ni(OAc)2 4H2O as catalyst with TBHP as oxidant, propionic acid in aceto nitrile. 

The high reactivity of N-aLkyl-2-halogenobenzoxazolium salts allows attack at weakly nucleophilic functionaHties. Thus, ketones of the type Ar-CH2-CO-R are transformed to aUcynes by 4 [279] in a formal dehydration process with transfer of the C=0 oxygen to the heterocycle due to formation of the benzoxazol-2-one 6 (presumably via intermediates 5 and 7) ... 

Direct Amination of Azoles, Decarbonylative amidation and amination of benzoxazole andbenzothiazole couldbe achieved using a Pd VAg system, promoted by carboxylic acid additives. Silver(I) fluoride performed inferiorly to Ag2C03 (30 vs. 78%). Stoichiometric amounts of silver salt were required to maximize reactivity no reaction occurred using only catalytic silver. Silver is postulated to help rearomatize the heteroarene following amination. Diversely substituted benzoxazoles and benzothiazoles afforded the C2-aminated product in moderate to excellent yield (eq 18). 

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