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20.2.1.4.3.1.2 Variation 2: Via Organolithium Reagents

DOI: 10.1055/sos-SD-020-00102

Evano, G.Science of Synthesis, (200720160.

As previously mentioned, carboxylation of organolithium reagents is another frequently used and useful approach toward the synthesis of carboxylic acids 61 from halogenated compounds 60. It also appears to be one of the most efficient methods. Organolithium reagents are generally formed by lithiumhalogen exchange with the use of butyllithium or tert-butyllithium. After carboxylation of the lithiated intermediates, the carboxylic acids are usually obtained in good yields; representative results are collected in Table 13. The only drawback of this reaction is the high basicity and nucleophilicity of organolithium reagents, which can result in the formation of byproducts when acidic or electrophilic centers are present in the starting halide. Careful control of the temperature can, however, prevent most of these undesired side reactions. Moreover, the rapidity of the lithiumhalogen exchange, even at temperatures close to the freezing points of diethyl ether or tetrahydrofuran, allows for the preparation of organolithiums containing other reactive functional groups (esters, epoxides, nitro groups). Lithiumhalogen exchange proceeds faster with iodides than with bromides; chlorides are less reactive toward this exchange, fluorides are inactive, and with these substances deprotonation usually proceeds faster than lithiumhalogen exchange. This allows selective metalation reactions with starting materials containing different halogen atoms. The exchange reaction is accelerated by the presence of ether solvents such as diethyl ether or tetrahydrofuran, with the best solvent system being ether/pentane mixtures, since they lead to relatively few byproducts. The use of N,N,N,N-tetramethylethylenediamine should be avoided, since it accelerates deprotonation more than the exchange reaction.[‌112‌]

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Meeee M8 M Meeeeeeeee Meeee (%) Mee
Meee 8 Meee 8
8 (MM8)8MM=MM8 M e-MeMe, eeeeeee, Me8M, 88°M, 8eee MM8(e), 88°M, 88eee, eeee 88°M ee ee 88 [‌888‌]
8 Me e-MeMe, eeeeee, MMM, 88°M, 8e eee eee, 88°M 88 [‌888‌]
8 M e-MeMe, eeeeeee, Me8M, 88°M eee eee, 88°M >88 [‌888‌]
8 Me e-MeMe, eeeeeee, MMM, 88°M eee eee, 88°M ee ee, 8e 88 [‌888‌]
8 Me e-MeMe, MMMMM, eeeeeee, 88°M, 88eee eee eee, 88°M, 8e 88e [‌888‌]
8 Me MeMe, eeeeee, MMM, 88°M, 88eee MM8(e), 88°M, 88eee eeee 88°M ee ee 88 [‌888‌]
8 M MeMe, eeeeee, MMM, 88°M, 88eee eee eee, ee 88 [‌888‌]
8 Me MeMe, eeeeee, MMM, 888°M, 8eee MM8(e), 888°M, 88eee 88 [‌888‌]
8 M e-MeMe, eeeeeee, Me8M, 88°M, 88eee eee eee, ee 88 [‌888‌]
88 Me MeMe, eeeeee, MMM, 88°M, 88eee eee eee, ee, 88eee 88 [‌888‌]
88 Me e-MeMe, eeeeee, MMM, 88°M, 8eee eee eee, 88°M ee ee 88 [‌888‌]

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Meeeee 88 Mee Meeeeeeeeee ee Meeee Meeeeeeee ee Meeeeee Meeeeeeeee Meeee eeee Meee Meeeeee eee Meeeeeeeeeeee Meeeeeee[‌888‌,‌888‌]

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Meeee 88 Meeeeeeee ee Meeeeeeeee Meeee eeee Meeeeee ee Meeeeeeeeeeeee ee Meeeeeeeeeeee Meeeeee eeee Meeeeee Meeeeee Meeeee, Meeeeeee ee Meeeee Meeeeee Meeeeeee[‌888‌‌888‌]

Meeee M8 M Meeeeeeeeee Meeee (%) Mee
Meee 8 Meee 8
8 Me MeMMM, MMM, 88°M eee eee 88 [‌888‌]
8 M MeMMM, MMM, 88°M, 8e eee eee, 88°M ee ee 88 [‌888‌]
8 Me 8. MeMe (8.8 eeeee), MMM, 88°M
8. eeeeeee eeeeeeeeeeeee, 88°M
MM8(e), 88°M, 8e, eeee ee 88 [‌888‌]
8 Me 8. MeMe (8.8 eeeee), MMM, 88°M
8. MeMMM, 88°M, 8e
MM8(e), 88°M, 88eee, eeee ee 88 [‌888‌]
8 (MM8)8Me M MeMMM, MMM, 8°M MM8(e), 88°M ee 8°M 88 [‌888‌]

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Meeeeeeeeeee Meeeeeeeee

Meee-8-eeeee Meee [88, M8=(MM8)8MM=MM8]; Meeeeee Meeeeeeee:[‌888‌]

MMMMMMM: M 8 M eeeeeeee ee eeee-eeeeeeeeeeee ee eeeeeee eeeeeee ee eeeee eee eee eeeeee eeeeeeeeeee eeee eeeee.

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8-(8-Meeeeeeee-8-eeee)-8-[8-(eeeeeeeeeeeeee)eeeeeeeeeeeee]eeeeeee Meee {88, M8=8-(8-Meeeeeeee-8-eeee)-8-[8-(eeeeeeeeeeeeee)eeeeeeeeeeeee]eeeeee}; Meeeeee Meeeeeeee:[‌888‌]

M 8.88M eeee ee MeMe ee eeeeeee (888 μM, 8.88eeee) eee eeeee eeeeeeee ee e eeeeeeee eeee ee 8-eeeee-8-(8-eeeeeeeee-8-eeee)-8-[8-(eeeeeeeeeeeeee)eeeeeeeeeeeee]eeeeeee {88, M8=8-(8-eeeeeeeee-8-eeee)-8-[8-(eeeeeeeeeeeeee)eeeeeeeeeeeee]eeeeee; M=Me; 888ee, 8.88eeee} ee eeeeeee eeeeeeeee eee MMM (88eM) eeeeee ee 888°M (Me8M/eee M8 eeee). Mee eeeeeeeee eeee eeeeee eeee eee eeeeeee ee 888° M eee 8eee eeeeee MM8 eee eee eeeeeee eeeeeee ee eee 88eee. M eee. MM8Me eeee (88eM) eee eeee eeeeeeeee eeeee eeeeeeee ee eee eeeeeeeee eeeeeee. Mee eeee eee eeee eeeeeeeee eeee Me8M (8×88eM). Mee eeeeeeee eeeeeee eeeeee eeee eeeee eeee eeeee Me8MM8 (88e), eeeeeeee, eee eeeeeeeeeeee. Mee eeeeeee eee eeeeeee eeeeeeee ee eeeeee eeeeeeeeeeeeee (eeeeee eee, MeMMe/eeeeeee 8:8); eeeee: 888ee (88%).

8-Meeeeeeeeeee[8.8.8]eeeeeee-8-eeeeeeeeee Meee (88, M8=8-Meeeeeeeeeee[8.8.8]eeee-8-ee):[‌888‌]

M eeee ee 8-eeeee-8-eeeeeeeeeee[8.8.8]eeeeeee (88, M8=8-eeeeeeeeeeee[8.8.8]eeee-8-ee; M=M; 8.8e, 8eeee) ee MMM (88eM) eee eeeee eeeeeeee ee e 8.8M eeee ee eeeeeee ee-eeee-eeeeeeeeeeeeeeee ee MMM (88eM, 88eeee) eeeeee ee 88°M. Meeee eee eeee eeee eeeeeee eee eeeeeee eee 8e ee eeee eeeeeeeeeee, e eeeeeee eeeeee ee eeeeeeee eee eee eee eeeee ee e eeeeee eeeeeee. Mee eeeeeee eee eeeeeee ee eeee ee ee eee eee eeee eeeeeeeee eeee 8% MeMMM8 eeee (8×88eM). Mee eeeeeeee eeeeeee eeeeee eeee eeeeeeeee ee eM 88 eeee eeeee MMe ee 8°M, eeeeeeeee eeee MeMe, eee eeeeeeeee eeee Me8M (8×88eM). Mee eeeeeeee eeeeeee eeeeee eeee eeeee (MeMM8), eeeeeeee, eee eeeeeeeeeeee. Mee eeeeeee eee eeeeeee eeeeeeee ee eeeeee eeeeeeeeeeeeee (eeeeee eee, Me8M/eeeeeee 8:8); eeeee: 888ee (88%).

References


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