Bromine—lithium exchange reaction

Chelation is another driving force that provides diastereoselective bromine-lithium exchange reactions to give cyclopropyl carbenoids. Thus, the exo-bromine atom in dibro-mocyclopropane 25 is exchanged exclusively due to the methoxy substituent, which encourages the lithium to occupy the cis orientation (equation 16) ° Several representative examples of cyclopropyl bromo lithium carbenoids obtained by bromine-lithium exchange reactions are given in Table 1. 

Recently, two more stereoselective cases of bromine-lithium exchange reactions have been observed. Both the glyceraldehyde-derived bromoalkene 45 and lactaldehyde-derived 47 yield the -configurated lithium carbenoids 46 and 48, respectively, when treated with... 

Interestingly, if the tribromo compound is treated with five equivalents of n-BuLi, then tetralithiation occurs, as was shown by the isolation of an a-butyl-2,4,5-trimethylthio derivative after reaction with excess dimethyl-disulfide [87JCS(P1)1453]. The a-butyl group in the product is derived from reaction of the a-benzyl carbanion with the n-butyl bromide produced by the initial bromine-lithium exchange reaction (Scheme 59). However,... 

Mixed trialkylstannyl and silyl derivatives have also been used in coupling reactions, with subsequent replacement of the silyl substituent by bromine, leading to species that are capable of undergoing further coupling reactions. This process was amply demonstrated by the recent synthesis of micrococcinic acid 203, which involved four palladium-catalyzed crosscoupling reactions on stannylated substrates, two palladium-catalyzed trimethylstannane replacements of bromine, two trimethylsilyl displacements by bromine, and a total of four bromine-lithium exchange reactions, on three different thiazole derivatives and one pyridine derivative (91-TL4263). 

The mixed 1,2-bimetallic Zn/Si-reagent 47 is a versatile species which reacts with aldehydes in high diastereoselectivity . It is prepared by a bromine/lithium exchange reaction starting from 48 followed by a transmetalation with ZnCl2 (Scheme 21). The... 

Let us focus on the generation and reactions of o-bromophenyllithium without deceleration. Ortho-lithiation of bromobenzene is not suitable for the generation of o-bromophenyllithium, because the bromine-lithium exchange reaction is very fast. Therefore, the bromine-lithium exchange reaction of o-dibromobenzene using butyllithium (BuLi) is the method of choice (Scheme 6.8). 

Scheme 6.8 Bromine-lithium exchange reaction of o-dibromobenzene...

The bromine-lithium exchange reaction of o-dibromobenzene is usually carried out at — 110°C or below in flask chemistry because the elimination of LiBr to form benzyne is very fast even at — 78 °C. However, by reducing the residence time using a microflow system, the reaction can be conducted at —78°C and o-bromophenyllithium can be effectively trapped with an electrophile before decomposition. Figure 6.23 shows a schematic diagram of the microflow system, in which reactions using methanol as an electrophile are conducted with varying temperatures and flow rates. 

As profiled in Figure 6.24, the yield is very low at temperatures higher than —60°C, presumably because of the decomposition of the o-bromophenyllithium intermediate to benzyne. At lower temperatures, the yield increases with a decrease in the temperature because of slower benzyne formation. A further decrease in temperature, however, results in a decrease in the yield, because the bromine-lithium exchange reaction does not complete at such low temperatures within the residence time. 

Bromine-lithium exchange reactions of p- and m-dibromobenzenes can be conducted in a microflow system at 20 which is much higher... 

Bromothiophene is an important starting compound for the synthesis of other 3-substituted thiophenes. The very facile bromine-lithium exchange reaction proceeds almost qualitatively and the butyl bromide present in the solution does not interfere in subsequent reactions with reactive electrophilic reagents. The following procedures are examples of smooth reactions with the intermediary 3-lithiothiophene. 

Lithiated polystyrene resins can be obtained either via convenient bromine-lithium exchange reaction using nBuLi starting from 4-bromo-substituted polystyrene 102,111-115 qj. jjy direct lithiation of polystyrene using nBuLi in cyclohexane in the presence of TMEDA 11L116 pjjjj method, however, yields a mixture of para- and meta isomers. The bromination of microporous resins in the presence of the Lewis-acid catalysts was carried out in the dark whereby the degree of functionalisation could conveniently be controlled by the amount of bromine used in the reaction.iii Macroreticular resins were brominated using Br and FeClj or stoichiometric amounts of thallium acetate as Lewis acid catalysts. 2 ... 

The bromine-lithium exchange reaction on macroreticular PS-resins using nBuLi in THE could be driven to completion by repetitive lithiation as described by Frechet. The lithiation of highly loaded microporous resins, however, were successfully carried out in toluene or benzene. The direct lithiation reaction of microporous polystyrene-derived resins (2% DVB) using nBuLi in cyclohexane in the presence of TMEDA is much faster than that of macroreticular resins (20% DVB).l It is interesting to note that for this reaction THE and benzene are not the solvents of choice. Using cyclohexane as solvent allows the synthesis of resins with a low or medium degree... 

Scheme 29 Double bromine-lithium exchange reaction...

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]. 

Buszek has used bromine-lithium exchange reactions to generate 4,5-, 5,6-, and... 

L. S. Fuller, B. Iddon and K. A. Smith, Thienothiophenes. 2. Synthesis, metallation and bromine—>lithium exchange reactions of thieno[3,2-i>]thiophene and its polybromo derivatives, /. Chem. Soc., Perkin Trans. 1, 3465-3470 (1997). 

Reaction of 1,4-dilithio-l,3-dienes 1 with 1.1 or 1.2 equiv of CeFe at room temperature afforded the multi-substituted partially fluorinated naphthalene derivatives 2/6 in good to high isolated yields (Scheme 12) [56]. The reaction is assumed to proceed via double nucleophilic substitution. The naphthalene derivatives with different substitution patterns could be prepared conveniently by this method. Instead of nucleophilic substitution, when di-lithio reagents 1 were treated with hexachlorobenzene, chloropentafluorobenzene, or bromopentafluorobenzene, chlorine-lithium or bromine-lithium exchange reactions took place to afford the 1,4-dichloro- or 1,4-dibromo-l,3-diene derivatives. Preliminary results demonstrate that these partially fluorinated multi-substituted naphthalene derivatives show unique stacking fashions. 

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