Reactions of the C-lithio derivatives

In order to exploit the reactions of the C-lithio derivatives of iV-unsubstituted pyrroles and indoles, protecting groups such as t-butoxycarbonyl, benzenesulfonyl and dimethyl-amino have been used 81JOC157). This is illustrated by the scheme for preparing C-acylated pyrroles (211) (8UOC3760). 

To exploit the reactions of the C-lithio derivatives of N-unsubstituted pyrroles and indoles, N-protecting/masking groups such as ferf-butoxycarbonyl, terZ-biitylcarbamoyl, benzenesulfonyl, dimethylamino, and dimethylaminomethyl must be used. This is illustrated by a route to G-acylated pyrroles 441. Another very useful process involves N-lithiation, N-carbonation, and lithiation of the resulting indol-l-ylcarboxylate at C(2) reaction with an electrophile and loss of carbon dioxide during work-up give N-unsubstituted 2-substituted indoles, for example, 2-haloindoles in excellent yields. 

The reaction sequence in steps two and three is known as the Corey-Fuchs method to create an alkyne from an aldehyde 10 Reaction of triphenylphosphane with carbontetrabromide gives phenylphosphane-dibromomethylene. This reagent then transforms aldehyde 19 into the corresponding dibromoalkene 20 thereby extending the chain by one carbon. Reaction of the bromo compound with two equivalents of n-butyllithium in THF at -78 °C results in the rapid formation of the acetylenic lithio derivative which forms the terminal acetylene 21 upon aqueous work-up. 

The optimum conditions for the formation of the 3-lithio derivative of diazepam involved the use of 2 equivalents of LDA in THE at 25 °C. The anion so formed reacted with alkyl halides (e.g., Mel) and esters (e.g., ethyl acetate) to give the 3-alkyl and 3-acyl derivatives (Scheme 12) (77 R = alkyl, acyl). The reaction with aldehydes and ketones furnished carbinols and in the case of benzaldehyde the initially formed carbinol (78 R = Ph) dehydrated to the alkylidene derivative (79) on longer reaction times <81JOC3945>. A similar dehydration was noted also with cyclohexanone. 

Addition of BuLi to a 0.3 M solution of chloromethyl phenyl sulfoxide in THF at — 78 "C yields an immediate bright-yellow solution containing the lithio derivative which is stable for at least 2 h at —78 rC. Decomposition occurs rapidly above —20 C with the solution becoming turbid and the color changing to dark brown. Reaction of the lithiated solution of chloromethyl phenyl sulfoxide with cyclohexanone, acetone, or ben/ophenone for 10 min at —78 °C followed by 30 min at —20 rC yields one diastereomeT in 79, 75 and 68 % yields, respectively, after hydrolysis of the corresponding adducts. 

Scheme 57 illustrates an example of this process coupling of the lithio reagent derived from vinyl stannane 237 with epoxide 242 leads to the C-disaccharide derivative 243 in good yield. A double transmetallation to give an organocopper reagent 244 can facilitate the C-glycosylation reaction with allyl halides [80] (Scheme 58). 

The treatment of thiazole with n-butyl- or phenyllithium leads to exclusive deprotonation at C-2. When the 2-position is blocked, deprotonation occurs selectively at C-5. However, if the substituent at C-2 is an alkyl group, the kinetic acidities of the protons at the a-position and at the 5-position are similar. The reaction of 2,4-dimethylthiazole with butyllithium at -78°C yields the 5-lithio derivative (289) as the major product but if the reaction is carried out at higher temperature the thermodynamically more stable 2-lithiomethyl derivative (290) is obtained (Scheme 37). The metallation at these two positions is also dependent on the strength and bulk of the base employed (74JOC1192) lithium diisopropylamide is preferred for selective deprotonations at the 5-position. 

A 3-lithioindole has been obtained by the reaction of l-benzenesulfonyl-3-iodoindole with f-butyllithium at -100 °C, but on allowing the reaction mixture to come to room temperature, it is found that the 3-lithio derivative has isomerized to give the thermodynamically more stable 2-lithioindole (82JOC757). The reaction of l-benzenesulfonyl-3-iodoindole with LDA yields l-benzenesulfonyl-3-iodo-2-lithioindole. 

Butylpotassium and butylcesium deprotonate furan at the 2-position (75BSF1302), but butyllithium is the reagent of choice. When furan is treated with butyllithium the reactions in Scheme 114 occur (77JCS(P1)887>. The conditions, however, may be controlled to yield predominantly the mono- or the di-lithio derivative. By carbonation and esterification of the reaction mixture obtained by treatment of furan with butyllithium and TMEDA (1 1 1) in ether at 25 °C for 30 min, a 98% yield of methyl furan-2-carboxylate is obtained. Similarly, a butyllithium TMEDA furan ratio of 2.5 2.5 1 in boiling hexane for 30 min results in 91% of dimethyl furan-2,5-dicarboxylate and 9% of the monoester. Competition experiments indicate that furan reacts with butyllithium faster than thiophene under non-ionizing conditions but that the order is reversed in ether or in the presence of TMEDA. 

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