Lithiation a to oxygen

Formation of vinylic (trigonal C-Li), allylic or benzylic organolithiums a to O is more favourable. The useful acyl anion equivalent methoxyvinyllithium 11, for example, is formed on treatment of methyl vinyl ether with f-BuLi at -65 °C,13 and furan is lithiated by BuLi in Et20 at 0 °C to give 12.14 More complex carbohydrate-derived vinyl ethers such as 13 also lithiate readily.15 

Allyl carbamates 19 are even more versatile, and the lithio derivatives 20 of allyl carbamates are the most important class of homoenolate equivalents.17 Lithiated allyl carbamates react reliably at the y-position with aldehydes and ketones but less regioselectively with alkylating and silylating agents. O-Benzyl carbamates 21 are readily deprotonated and can be quenched with electrophiles.17 20 

Allyl acetals,21 and carbamates,17 can be lithiated and quenched with metallic electrophiles at the a-position to provide allylmetals, for example, the allyl boronate 22.21 Allyl and benzyl esters have also been lithiated a to O.22 

Lithiation and alkylation of the doubly allylic ether 23 with alkyl halides provides a useful synthesis of 1,3-butadienes. Alkyl triflates and tosylates, and carbonyl electrophiles, react with a-selectivity and give skipped dienes 24.23 

Hoppe has shown12 that lithiation a to O of a simple alkoxy group is best achieved with carabamates and s-BuLi-(-)-sparteine (see section 5.4) but provided attack at C=0 is prevented by steric hindrance, even alkyl esters can be lithiated a to O. 25 and its O-methyl analogue can be lithiated and functionalised.24 

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More versatile are the lithiations of carbamates (N-Boc amines) - as with lithiation a to oxygen, the lack of electrophilicity in a carbamate C=0 group and its particularly electron-rich oxygen lone pairs conspire to facilitate lithiation. In their Boc protected form, even simple amines such as 45 may be lithiated.37... 

Thiophenes are readily lithiated next to sulfur 122 gives 123 with BuLi in THF at 0 °C.89 Interestingly, lithiation a to oxygen (124) occurs in a non-coordinating solvent - presumably coordination to oxygen becomes more important than acidification by sulfur under these conditions. A similar contrast, probably for similar reasons, is evident in the lithiation of 125 with LDA and with BuLi.90... 

Certain functionalised vinyl bromides can similarly be lithiated the Z-enol ether 121 gives 122, which is stable up to -30 °C without elimination.105 121105 and 124106 are readily transmetallated, while the F-enol ether 123105 is preferentially lithiated a to oxygen and will not undergo transmetallation. 

A completely different approach to lithium homoenolate synthons uses a carbon-oxygen bond cleavage. Lithiation of acrolein diethyl acetal 180 with lithium and a catalytic amount of DTBB (2.5%) in the presence of different carbonyl compounds in THF at 0°C gave, after final hydrolysis, the corresponding y-products 181 in different diastereomeric ratios (Z/ 3/1 to 20/1) (Scheme 63) . 

The rate of rotation about the C-N bond in 2,4,6-triisopropylbenzamides 4 is so slow that the groups cis and trans to oxygen about the C-N bond do not exchange, and compounds 4 may exhibit geometrical isomerism. Lithiation can therefore be shown always to occur syn to oxygen, consistent with delivery of the base by coordination to the amide.4 5 Calculations show that in the absence of a lithium atom a trans anion would be more stable, as it would benefit from a bonding interaction with the C-0 a orbital.6... 

Fluoroanisoles 95 and 97 each have two different sites that could be lithiated.19 In each case, the site next to oxygen can be lithiated if a coordination mechanism is operative and the site next to fluorine can be lithiated if an acid-base mechanism is operative. If o/t/zo-fluoroanisolc 97 is... 

Enantioselective deprotonations a to the oxygen or nitrogen atoms of carbamates 4.1 and 4.2 can be performed with s-BuLi in the presence of sparteine 2.5. The pro (5)-hydrogen atom is selectively removed, and lithiated carbanions 4.3 are formed. These carbanions are stabilized by dipolar interactions [982] and coordination to sparteine [564, 983-987], Such species are stable up to -30°C, and react with electrophiles at -78°C with retention of configuration [984-987]-... 

Sometimes, specific lithium enolates of unsymmetrical carbonyl compounds are formed because of chelation of the Uthium atom with a suitably placed substituent. For example, lithiation and alkylation of the mixed ester 1 took place a- to the MEM ester group, presumably as a result of intramolecular chelation of the lithium atom with the ethereal oxygen atom (1.14). ... 

Exposure of ketone oximes which have an a-hydrogen, to two mol equivalents of butyllithium leads to C-lithiation syn to the oxygen reaction with dimethyl-formamide as electrophile then allows C-formylation and ring closure in situ to an isoxazole. " ... 

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