Lithiation of oxazoles

Iodooxazoles. After lithiation of oxazoles with LHMDS at C-2, subsequent treatment with iodine effects iodination at C-4. 

As noted earlier in this section lithiation of oxazoles with -butyllithium can be plagued by the formation of products derived from the tautomeric isocyanovinyl-lithium alkoxide species. Vedejs and Monahan conceived an elegant solution to avoid this side reaction (Scheme 1.245). The authors precomplexed an oxazole 896 with THF-borane to form the stable, isolable Lewis acid-base complex 914. This complex effectively coordinated the lone pair of electrons on nitrogen that is essential for the undesired electocyclic ring opening reaction. In addition, the authors anticipated that the coordination would enhance the acidity of the C(2)-H. Deprotonation of the complex with LiTMP (n-BuLi and i-BuLi are also effective)... 

If the 2-position of oxazole is substituted by a group other than an alkyl group, then lithiation occurs at the 5-position (Scheme 82)(84JOC4325 91JOC3058). 

The addition of carbonylated electrophiles to the 2-lithio derivative of 4-oxazolinyloxazole 132 allowed the efficient preparation of 5-phenyloxazoles 134 bearing a variety of hydroxyalkyl groups at C-2 position and a carboxyl (or formyl) function at C-4. This protocol suppresses the troublesome electrocyclic ring-opening reaction and allows access to the target compounds by simple chemical transformation of the oxazoline moiety of 133 <02JOC3601>. A direct chemoselective C-2 silylation of oxazoles was performed by treatment of the lithiated parent compounds with silyl triflates <02TL935>. 

The additives (MeaSiCl or BF3 Et20) may activate the carbonyl compound or stabilize the intermediate. BF3 Et20 has been used as an activator in the reaction of aldehydes with lithiated phenylsulfones [111] although its fimc-tion remains vague. It may be noted that acyclic products were formed on silylation of the hydroxy sulfides obtained in the reaction of oxazol-2-yl sulfides with aldehydes [80]. 

The directed metalation of aromatic systems that was discussed in Section 2.1.3.3 has one ramification that was not mentioned there the directed lithiation of an o-methyl group. Although the resultant species is formally a resonance-stabilized anion, and therefore covered in Volume 2 of this series, we mention it here for consistency with the other topics covered. In particular, the examples that have appeared in recent years involve substrates having a methyl ortho to a tertiary amide. Intentional use of such a directed lithiation has been used in the synthesis of the isocoumarin natural products hydrangenol and pyllodul-cin.137,138 Interestingly, the directed metalation of 5-methyl-oxazoles and -thiazoles occurs in preference to deprotonation at a 2-methyl group (azaenolate) (Scheme 33). ... 

Lithiation of the methyl derivatives of such five-membered heteroaromatics as pyrrole , thiophene , l,3-thiazole ° , 1,3-oxazole , isoxazole , 1,3,4-thiadiazole , 1,3,4-oxadiazole and imidazole also occurs. For the sulfur heterocyclics, ring metallations and ring opening after lithiation are complications. 

Another carboxylic acid derivative which is also used as a lithiation directing group is the oxazole. The ortho lithiation of these compounds proceeds in high yield... 

Hydroxyphthalide is. the cyclic lactol of phthalaldehydic acid. This compound can be readily obtained by lithiation of a benzoic acid derivative (N-methyl amide, N,N-diethy amide or oxazole derivative) and treatment either with N-methylform-anilide (MFA) or DMF. When an N-methylamide is the starting compound quite often, the intermediate 25 can be isolated which can be hydrolysed to 3-hydroxy-phthalide . 

The lithiation of isophthalic acid can be achieved either at 2- or 4- position after conversion of the carboxylic acid groups to oxazole derivatives or N,N -butylamide derivatives respectively. Conversion to N-methyl amide derivative leads to the precipitation of the N-lithio salt on treatment with BuLi which fails to lithiate further. The N-lithio salt of the N-butylamide, however, remains in solution under the experimental conditions. It may be noted that the two lithiation reactions furnish two different carboxydihydroisocoumarins. The 5-carboxy dihydroisocoumarin can be converted to erythrocentaurine, which is naturally occurring... 

Although oxazoles follow the pattern and lithiate at C-2, 4-substituted products are produced with some electrophiles this is explained by a ring opening of the anion, to produce an enolate, which after C-electrophilic attack, recloses. An estimate by NMR spectroscopy showed the ring-cleaved tautomer to dominate the equilibrium." Some electrophiles produce good yields of oxazole products reaction of lithi-ated oxazole with hexachloroethane produces 2-chlorooxazole in good yield." The open enolates can be... 

Reactions of Oxazoles. 2-, 4-, and 5-Nitro-oxazoles can be prepared by the action of dinitrogen tetroxide on the corresponding iodo-compounds. Whereas oxazoles are metallated at C-5, the acid (371) undergoes lithiation at the methyl substituent.The reaction of 2,4-dimethyloxazole with ethyl propiolate yields a mixture of the furans (373) and (374) these are formed by extrusion of acetonitrile from intermediate Diels—Alder adducts such as (372). s3... 

Protection of oxazoles. 2-Lithiooxazoles are liable to undergo ring opening thus, alkylation of the heterocycle via the lithiated species is problematic. On the other hand, oxazole-borane complexes behave normally during deprotonation. The borane moiety is easily removed after the alkylation by treatment with HOAc. 

The ring opening of oxazoles can be avoided by transmetallation, or by first forming a borane complex which is then lithiated as shown below. " ... 

Hughes and co-workers " studied the lithiation of 5-(3-methyl-5-isoxazolyl) oxazole 891 as part of their program to prepare suitable species for cross-coupling reactions (Scheme 1.239). They investigated the equilibrium of the 2-lithiooxazole 892 and the acyclic isocyanovinyUithium alkoxide 893 using H-NMR and C-NMR spectroscopy. The authors concluded that 893 was the predominant species under the reaction conditions investigated based on comparison of the H-NMR and C-NMR spectra with the spectra of 894 together with an extensive series of deuterium quenches. However, they also cautioned that the results of deuterium quenches of systems where dynamic equilibria are possible or expected must be interpreted with care. ... 

Shioiri s group also employed a 2-lithiooxazole to construct the bis-oxazolyl methanol core of 904. Here, lithiation of a silyl-protected 4-oxazolemethanol 905a/ b followed by condensation with 902 afforded a racemic bis-oxazolyl methanol 906a/b in modest yield (Scheme 1.242). Attempts to improve the yield of 906 using a Lewis acid to coordinate the oxazole nitrogen, alternate bases, or addition of cosolvents were not successful. Barton-McCombie radical deoxygenation was used... 

Williams and co-workers ° described a regioselective metalation of 2,4 -bis-oxazoles in the context of natural product synthesis. Regioselective lithiation of 4-(methoxymethyl)-2 -methyl-2,4 -bis-oxazole 924 followed by quenching with a variety of electrophiles produced the 4-(methoxymethyl)-2 -methyl-5-substituted-2,4 -bis-oxazoles 925, respectively, in modest to excellent yield (Scheme 1.248). 

TABLE 1.65. 5-SUBSTITUTED OXAZOLES VIA LITHIATION OF 2-(METHYLTHIO)OXAZOLE AND REDUCTIVE DESULEURIZATION-... 

Liu and Panek also investigated lithiation of a dithiane containing oxazole during their synthesis of kabiramide C. Lithiation of 940 with excess LDA followed by D2O produced the 5,5, 5"-trideutero analog (not shown). Similarly, treatment of... 

Dondoni s group also studied the synthesis and coupling reactions of 2-(stannyl)oxazoles. This work was part of their extensive investigations of the synthetic utility of stannylated and silylated azoles. Lithiation of 4-methyloxazole 3 followed by quenching with trimethyltin chloride gave the air- and moisture-sensitive 4-methyl-2-(trimethylstannyl)oxazole 993 in 60% yield after distillation... 

Dondoni s groups reported the first synthesis of a 2-(trimethylsilyl)oxazole (Scheme 1.269). Lithiation of 4-methyloxazole 3 and trapping with... 

Aryl-2-(trimethylsilyl)oxazoles can be prepared similarly. For example, lithiation of 5-phenyloxazole 1006 (X = H) and reaction with chlorotrimethylsilane... 

Meyers and co-workers" also investigated lateral lithiation of a 2-methyloxazole derivative during their synthesis of the oxazole dienyl amine moiety 1203, common to 1183 and 1184. The authors proposed a retrosynthetic path, wherein selective functionalization of a 2-methyl-4-oxazolecarboxylic acid ester would be the starting point for 1203 (Scheme 1.305). 

TABLE 1.66 4-(METH0XYMETHYL)-2 -METHYL-5-SUBSTITUTED-2,4 -BIS-0XAZ0LES VIA REGIOSELECTIVE LITHIATION OF 4-(METH0XYMETHYL)-2 -METHYL-2,4 -BIS-OXAZOLE, 203... 

The same group reported an extension of the direct alkylation of (benz)oxazoles with various alkyl bromides and chlorides by using the stronger base lithium tert-butoxide (Scheme 19.23) [38]. 5-Aryloxazoles containing electronically diverse substituents such as CFj and OMe were also alkylated successfully. Various linear alkyl chains were introduced, such as phenylpropyl, citronellyl, or octyl, affording interesting lipophilic molecules. The optimized reaction conditions failed to apply to benzothiazoles, and the authors had to turn their attention to nickel catalysis to achieve the corresponding alkylation (Section 19.2.3). Experiments were run to understand the reaction mechanism that presumably involves Sj 2-type oxidative addition of the alkyl halide to palladium(O) followed by transmetallation by the in situ-lithiated (benz)oxazole (Scheme 19.24). 

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