Exchange chlorine-lithium

Although organolithium compounds are commonly prepared by a halogen (iodine, bromine or chlorine)-lithium exchange other methodologies involving different starting mate-... 

Also in this case, the use of the chloro thioether 479 allowed the introduction of two different electrophiles in a sequential process. Using lithium naphthalene (the stoichiometric version of the arene-promoted lithiation) in THF at — 78°C, only a chlorine-lithium exchange occurred, so the first electrophile R R CO was introduced (—78 to —50°C). Then the second lithiation (sulfur-lithium exchange) takes place under catalytic conditions (naphthalene) and the second electrophile R R CO was introduced. After final hydrolysis, differently substituted 1,5-diols 476 were isolated (Scheme 134) °. 

The carbolithiation reaction followed by additions of various reagents usually renders a mixture of open-chain and cyclic products, as observed in the conventional Barbier reaction122. Nevertheless, Yus and coworkers40 found that when the alkene is substituted by aromatic moieties, only the cyclization reaction takes place (Schemes 59 and 60). They have previously found that the use of an excess of lithium powder and a catalytic amount of an arene (4,4 -di-tert-butylbiphenyl, DTBB, is most commonly used) is an adequate procedure to carry out chlorine-lithium exchange under very mild reaction conditions123. 

When (Z)-6-chloro-l-phenylhex-l-ene 200 was lithiated under DTBB catalysis, the cyclized product 202 was always obtained either at —78 or at —30 °C. After the first chlorine-lithium exchange a carbolithiation took place to yield the intermediate 201, which by reaction with electrophiles, E, and final hydrolysis gave products 202 (Scheme 60). At —78 °C the reaction under Barbier-type conditions did not work. Also in this case, the corresponding reduced product (202 with E = H) was the main by-product detected. 

Carbamoyllithiums can be prepared by four general methods (a) Lithium amides car-bonylation (b) deprotonation of formamides with alkyllithiums (c) tellurium-lithium or chlorine-lithium exchange and (d) tin-lithium transmetallation. 

Simple enamines cannot be deprotonated directly at the a-position due to their low acidity, but starting from a-chloroenamines 685, a-lithioenamines 686991 have been prepared by chlorine-lithium exchange using an arene-catalyzed lithiation992. The treatment of compounds 685 with an excess of lithium and a catalytic amount of 4,4 -di-tert-butylbiphenyl (DTBB) in THF at —90 °C allowed the preparation of intermediates 686, which were trapped with a variety of electrophiles (Scheme 177). For aldol reactions, the arene-catalyzed lithiation has to be performed in the presence of aldehydes (Barbier conditions) at —40 °C. These adducts were transformed into a-hydroxy ketones after acid hydrolysis with hydrochloric acid or silica gel. 

The 2-chloroimidazole 240 undergoes chlorine-lithium exchange to give the 2-lithiated species which could then be quenched by an electrophile with benzyl chloroformate 241 the imidazole-2-carboester 242 was obtained (Scheme 57) <2005BML1441>. 

In the case of benzyl chloride, the transition state TS-2/C1 for a chlorine-lithium exchange is situated about 12.9 kJ/mol higher in energy than the alternative path through direct substitution of the halogen (TS-l/Cl). However, for benzyl bromide these energy relationships are reversed, and the bromine-lithium exchange (TS-2/Br) is favored by 9.5 kJ/mol over the substitution (TS-l/Br). Likewise, the ate-complex MIN-I/Br can be characterized as a minimum. 

The regioselectivity of bromine-lithium exchange reactions in dibromoindole substrates has been studied by Li [381, 382]. With both 4,7-dibromoindoles (e.g., 145) [382] and 5,7-dibromoindoles (e.g., 146) [381], bromine-lithium exchange occurs preferentially at C7 (Fig. 5) upon treatment with ferf-butyllithium. A similar result was reported recently by Lachance involving the selective chlorine-lithium exchange observed with 6-azaindole 147 [383]. 

Recently, different a-lithioenamines 75 have been prepared by chlorine-lithium exchange from the corresponding chloroenamines 74 and reacted with electrophiles to give functionalized enamines 76. A mixture of lithium and a catalytic amount of DTBB was used as the lithiating reagent (Scheme 2.12) [67]. The process can be performed either step-by-step (lithiation-reaction with the electrophile) at -90 °C or under Barbier-reaction conditions at -40 °C. In the case of using carbonyl compounds as electrophiles, after acidic hydrolysis, a-hydroxyketones were obtained, intermediates 74 acting in this case as acyl anion equivalents [41]. 

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