Lithiation 5-substituted oxazoles

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>. 

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. 

Shafer and Molinski described a two-step, general method of preparing 5-substituted oxazoles. This method is complementary to the work of Vedejs and Monahan (vide supra). The authors found that with introduction of a methylthio group at C(2), lithiation occurs smoothly at C(5) and subsequent reaction with an electrophile affords 922 readily (Scheme 1.247). Reductive desulfurization of 922 then yields 923. 

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

Evans and co-workers developed a regioselective lithiation protocol of 2-methyl-4-substituted oxazoles 945 during their synthesis of phorboxazoles. In particular, the authors required a general method to generate regioselectively a 2-(lithiomethyl)oxazole and to functionalize the intermediate without competitive lithiation and reaction at C(5). Among the bases investigated, lithium diethylamide was particularly effective and selective for the required transformation (Scheme 1.253, p. 206). 

Vedejs utilized a Negishi reaction in synthesizing the core of aziridinomitosene A. The C5 position of a C2-substituted oxazole was lithiated and transmetalated with ZnCh. The 5-oxazolylzinc chloride was utilized in an intermolecular Negishi reaction with a vinyl triflate in 70% yield with no reported intramolecular reaction at the alkyl iodide. ... 

Zinc Derivatives Oxazole and 5-substituted oxazoles are lithiated in the 2-position. Subsequent zincation gives the corresponding 2-oxazolylzinc chloride 112 for alkenylation (Scheme 48). Excess of zinc chloride was used in the zincation. Subsequent cross-coupling with a 1-butenyl iodide yields 2-alkenyl derivatives. The Pd-catalyst was pregenerated by reduction with DlBALH.t The alkenylated oxazole 113 was formed in a corresponding coupling reaction with a cyclic vinyl triflate. ... 

Fluorine atom can be incorporated into oxazole core via the selective C(5) lithiation of 2-substituted oxazole followed by treatment of electrophile, -N-fluorobenzenesulfonimide [3,4] ... 

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). 

A review on the metaiation and metal-h ogen exchange reactions of imidazole appeared in 1985. Generally, A -protected imidazoles metalate at the 2-position 1,2-disubstituted imidazoles usually met-alate at the 5-position, unless sterically hindered. Even 2,5-dilithiation of imidazoles has been achieved. 1-Substituted 1,3,4-triazoles can be metalated at the S-position and added to carbonyls in good yield. Oxazoles are easily lithiated at the 2-position, but the resultant anion readily fragments. l-(Phenylthiomethyl)benzimidazole can be lithiated at the 2-position at low temperature (Scheme 21), but higher temperatures afford rearrangement products. ... 

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... 

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

Zinc Derivatives Oxazoles and benzoxazoles can be lithiated in the 2-position by alkyllithium. In transmetallation of lithiated oxazole excess zinc dichloride gave the highest yield. The zincated substrates 106 and 107 were used in Negishi-type coupling (Scheme 45). Reactions of zincated oxazoles and benzoxazole with aryl halides all proceed well. A similar reaction sequence was used in the preparation of a 2-oxazolyl-substituted tricyclic structure 108. 

Lithiated alkoxyallenes, nitriles, and TFA have been employed as precursors in a three-component reaction leading to highly substituted enamides 42a-d. Upon treatment with trifluoroacetic acid, these enamides could be easily cyclized to 2-trifluoromethyl-5-acetyloxazole derivatives 43a-d [47]. Two most probable pathways for oxazole formation from enamides were proposed. 

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