Lithiations oxazole

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]. 

Several examples of other metallooxazoles prepared from lithiated oxazoles by transmetalation reactions are discussed in the remaining portion of this section. 

The sUylation of aromatic or heteroaromatic compounds can be performed via magnesiated or lithiated intermediates, which can be accessed by hydrogen-metal or halogen-metal atom exchange. Thus, C-4 silylation of imidazoles is achieved from4-iodo imidazoles (eq 45), while C-2 silylated oxazoles are prepared by addition of TMSOTf to the lithiated oxazole (eq 46) interestingly, for this reaction, the employment of TMSCl as electrophile... 

Vedejs and co-workers developed a regioselective iodination of lithiated oxazole. Iodination at the C4-position can be affected by dissolution of the oxazole substrate in THF with DMPU co-solvent prior to deprotonation and iodination by I2. Without DMPU as co-solvent, C2 iodination can be aeeomplished using less-reactive 1,2-diiodoethane as the electrophile. 

As shown previously, C2-lithiated oxazoles are in equilibrium with their ring-opened counterpart. C2-unsusbtituted oxazoles are therefore potentially unstable to strongly basic conditions. 

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. 

Scheme 1-174. Equilibration of 2-lithiated oxazoles (Y = O), thiazoles (Y = S), and imidazoles (Y = NCH3) with the corresponding acyclic enolates.

Lithiated 2-alkyl-4,5-dihydro-l,3-oxazoles (363) react with nitrones in high stereoselectivity to give initially 1,6-dioxa -2,9-diazaspiro [4.4] nonane (364). Upon further treatment with oxalic acid it is quantitatively converted to 4,4-dimethyl-2-( 1 -methyl-2-phenylvinyl)-4,5-dihydro-1,3-oxazole (365) (diastereo-meric mixture E/Z = 9 1) with elimination of tert-buthylhydroxylamine (Scheme 2.157) (598, 599). 

Lithiated 2-(chloromethyl)- and 2-(l-chloroethyl)-4,5-dihydro-l,3-oxazoles (366) and (367) behave in a different way. The reaction of (366) with nitrones leads stereoselectively to 2-[(Z)-alkenyl]-4,5-dihydro-l,3-oxazoles (368a) and (368b) (Scheme 2.158), while the 2-(l-chloroethyl)-derivative (367) gives... 

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>. 

Silicon protection is also commonly used to direct lithiation chemistry in five-membered heterocycles. For example, oxazoles , thiazoles and Ai-alkylimidazoles ° ° lithiate preferentially at C-2, where the inductive effect of the heteroatoms is greatest. If C-2 is blocked, lithiation occurs at C-5, where there is no adjacent lone pair to destabilize the organolithium. Functionalization of these heterocycles at C-5 can therefore be achieved by first silylating C-2, reacting at C-5 and then removing the silyl group. The synthesis of 666 illustrates this sort of sequence (Scheme 258) °. ... 

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 least acidic of the three available position on oxazole is the 4-position, but even this can be lithiated under the appropriate conditions (86CRV845). Thus, while 2,5-diphenyloxazole gives a mixture of products on treatment with n-BuLi, clean metalation at C-4 can be achieved using LDA or KDA (86CRV845), or with 5-BuLi and a catalytic amount of LiTMP (Scheme 86)(91JOC3058). 

Oxazolines and thiazolines are lithiated at the 2-position to give species that, like oxazole (Section III,B,1), are in equilibrium with ring-opened forms [70JA6676 90H(31) 1213]. Subsequent reaction with electrophiles can occur via either form (Scheme 139), with soft electrophiles (e.g.,... 

Arenes and heteroarenes which are particularly easy to metalate are tricarbo-nyl( 76-arene)chromium complexes [380, 381], ferrocenes [13, 382, 383], thiophenes [157, 158, 181, 370, 384], furans [370, 385], and most azoles [386-389]. Meta-lated oxazoles, indoles, or furans can, however, be unstable and undergo ring-opening reactions [179, 181, 388]. Pyridines and other six-membered, nitrogen-containing heterocycles can also be lithiated [59, 370, 390-398] or magnesiated [399], but because nucleophilic organometallic compounds readily add to electron-deficient heteroarenes, dimerization can occur, and alkylations of such metalated heteroarenes often require careful optimization of the reaction conditions [368, 400, 401] (Schemes 5.42 and 5.69). 

Formation of the racemate of the oxazole 196 was effected by Schollkopf s method addition of lithiated methyl isonitrile to the amide function of 201 (102, 103). The most efficient dimerization of seco acid derivatives 196-196b entailed... 

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>. 

---