Metalated benzoxazoles

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). 

Oxazoles are acidic at C2 with a theoretical pKg value of 21 Metalation is facile at C2 with strong bases. C2-metalated oxazoles are in equilibrium with their ring-opened isonitrile. Due to this equilibrium, C2-metalated oxazoles are nucleophilic at either C2 or C4, and care must be taken when quenching the C2-metalated oxazole to ensure proper chemoselectivity (see Section 6.3.3). Benzoxazoles are acidic at C2 like oxazoles (experimental pKa 24.8), and the metalated benzoxazole is also in equilibrium with its ring opened isonitrile. Isoxazoles, without a C-H group flanked by two heteroatoms, are acidic at the C5 position with a theoretical pKa value of 27 however, in practice, deprotonation with hydroxide occurs at C3 to give a ring-opened P-ketonitrile intermediate. All of these heterocycles can be deprotonated with metal amides or carbanion bases. 

Oxygen-containing azoles are readily reduced, usually with ring scission. Only acyclic products have been reported from the reductions with complex metal hydrides of oxazoles (e.g. 209 210), isoxazoles (e.g. 211 212), benzoxazoles (e.g. 213 214) and benzoxazolinones (e.g. 215, 216->214). Reductions of 1,2,4-oxadiazoles always involve ring scission. Lithium aluminum hydride breaks the C—O bond in the ring Scheme 19) 76AHC(20)65>. 

Thienyl-substituted benzoxazoles have been studied for their potential application for fluorescent sensors of metals. They showed absorption bands near 315 nm and emission at 393-394 nm (Of = 0.66-0.80) (07MI2096). Thienyl-substituted imidazopyridines show absorption bands in the range 309-340 nm and emit in the range 474-533 nm (09T5062). Bithienyl-imidazo-anthraquinone derivatives were studied showing an absorption band at 444 nm (070L3201). 

The tetrahydro-derivatives of the oxazole and isoxazole system are unstable. As a consequence, only acyclic products have been reported from the reductions with complex metal hydrides. 2,5-Diphenyl-oxazole (119) gave 2-benzylamino-l-phenylethanol (120),141 and 3,5-diphenyl-2-isoxazoline (121) was converted to 3-amino-l,3-diphenylpropanol (122)142 on reduction with lithium aluminum hydride. 3-Phenylbenzisoxazole was resistant to reduction with lithium aluminum hydride and sodium borohydride,143 but benz-oxazole (123), benzoxazol-2-one (124), and benzoxazol-2-thione (125) have been reported 141 to yield 2-methylaminophenol (126) on reduction with lithium aluminum hydride. 

McKee LM, Kerwin SM (2008) Synthesis, metal ion binding, and biological evaluation of new anticancer 2-(2 -hydroxyphenyl)benzoxazole analogs of UK-1. Bioorg Med Chem 16 1775-1788... 

The tridentate monobasic ligand l-(2-pyridylazo)-2-naphtholate (pan) has been used to prepare seven-coordinate complexes R2(pan)M(L) (L = ACAC derivative, M = Sn, R = Bu, Me M = Pb, R = Me). For both metals the difference in 8 is distinct from lower coordination numbers, both showing an upfield shift in b of ca. 200" typical for such a change in coordination number." The dianionic tetracyclic ligand (168) is prepared from the lithiation of 2-Me-benzoxazole and reacts with tin(II) chloride to form (169)." ... 

Rai V. K., Sriva stava R., Kamalasanan M.N. White oreanic light-emittine diodes based on blue fluorescent bis(2-(2hvdroxvphenvl)benzoxazolate)zinc (Zn(hpb)fl doped with PCM dve. Synthetic Metals, 159, 3-4, (February 2009), 234-237... 

Benzoxazole (L) derivatives of the stoicheiometry M(XCN)2L2 (M = Zn or Cd X = S or Se) and Cd(NCSe)2L have been prepared the former are pseudotetrahedral while the latter is polymeric. The ligand is N-bonded in all cases. Benzoxazole-2-thione(L) forms the similar MX2L2 complexes (M = Zn, Cd, Hg X = Q, Br, I) and Cdl2L co-ordination is via nitrogen, and not sulphur or oxygen. The complexes ML2 (M = Zn or Cd) have been isolated from reaction of the metal acetate or nitrate with the iV,0-chelating 2-(o-hydroxyphenyl)benzoxazole (HL). ... 

Barbituric acid, methyl-5-nitroso-zinc complexes, 958 Bayldonite, 960 Benzeneselenic acid metal complexes, 977 Benzimidazole metal complexes, 949 Benzoquinoline zinc complexes, 953 Benzothiazole zinc complexes, 981 Benzotriazole zinc complexes, 950 Benzoxazole metal complexes, 951 Berry twist... 

Coordination compounds of 2-hydrox3 henyloxazole are rarely studied, e.g., 350 (03CM4949). For a similar benzoxazole derivative, however, there are various metal complexes differing in the number of the chelate fragments. Mono-chelate coordination compounds include neutral platinum 351 (M = Pt, L = = Cl) (91BCJ149) and rhenium 352... 

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. 

A metal-free protocol for amination of azoles has recently been reported [98]. It includes two steps (1) the ring opening of benzoxazoles or oxadiazoles on heating with secondary aliphatic amines and (2) oxidative ring closure of the resulting amidines on their treatment with (diacetoxyiodo)benzene as oxidant within a short time at room temperature (Scheme 41). The same process can also be performed as a one-pot synthesis without isolation of the amidine intermediate. 

Scheme 41 Metal-free two-step amination of benzoxazoles and 1,3,4-oxadiazoles...

Some current preparations of poly(arylene ether)s are carried out by nucleophilic displacements of activated aromatic dihalides or dinitro groups by alkali metal bisphenates. The reactions take place in polar aprotic solvents. The glass transition temperatures, tensile strengths, and tensile moduli of these materials tend to increase when heterocyclic units are incorporated into the backbones. Poly(arylene ether)s containing imide, phenylquinoxaline, imidazoles, pyrazoles, l,3,4-oxadiazoles, benzoxazoles, and benzimidazoles groups were prepared. 

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