Br-Li exchange reaction

Nagaki A, Tomida Y, Usutani H et al (2007) Integrated micro flow synthesis based on sequential Br-Li exchange reactions of p-, m-, and o-dibromobenzenes. Chem Asian J 2(12) 1513-1523... 

Aryl bromides can be converted to aryl Grignard or aryllithium compounds in three ways (Figure 5.41). In the first two methods, the aryl bromide is reacted with Mg shavings or with Li wire, respectively (see Section 17.4.1 for the mechanism). In the third method—which is especially convenient for small-scale preparations—aryl bromides are converted into aryllithium compounds either with 1 equivalent of butyllithium (w-BuLi) or with 2 equivalents of fert-butyllithium (terf-BuLi) by the so-called Br/Li exchange reaction. 

I f n-BuLi is used for the Br/Li exchange in Figure 5.41, the reaction is completed when the lithio-aromatic compound and n-butyl bromide have formed. It is different when this Br/Li exchange is carried out with ierf-BuLi, where tert-BuLi and /erf-butyl bromide necessarily would have to coexist during the reaction. However, tert-BuLi reacts very fast as a base with tert-butyl bromide via an E2 elimination. Therefore, Br/Li exchange reactions with ferf-BuLi can go to completion only when 2 equivalents of the reagent are used. 

When one is working on a very small scale, one can prepare aryllithium compounds through a Br/Li exchange reaction (path 3 in Figure 5.34) in a much simpler way than aryl Grignard reagents. 

The rather unstable 1,1-difluoroallyllithium has been prepared by transmetallation from the corresponding tin derivative, according to Seyferth et al. 65). These authors 66) have also reported a more efficient access to this carbenoid, and a possible appli-tability is achieved by Br/Li exchange reaction with 3,3-difluoroallyl bromide, as outlined by Eq. (60). 

Another example is a Br-Li exchange reaction of p-dibromobenzene with nBuLi [73]. The reaction is exothermic and requires very low temperature (< — 48 °C) in a batch system. With an integrated microflow system, reaction could be performed at 20 °C followed by reaction with an electrophile at 0°C. 

Figure 11.26 Synthesis scheme of photochromic diarylethenes. (a) Generation of heteroaryllithiums through the Br-Li exchange reaction of heteroaryl bromides and (b) the reaction of octafluorocyclopentene with heteroaryllithium.

Preparation of Z-propenylzinc bromide (281) via Br/Li exchange reaction and its asymmetric addition to cyclohexane carbaldehyd ... 

Fig. 4.5 Br-Li exchange reaction of alkyl o-bromobenzoates using i-BuLi followed by protonation in batch...

Br-Li Exchange Reactions of Alkyl o-Bromobenzoates in a Batch Reactor [7, 8]... 

For example, the Br-Li exchange reaction of ethyl o-bromobenzoate was carried out using 5-BuLi at -48 °C, and the resulting aryllithium species was then reacted with ethanol to give a protonated product. The results are shown in Fig. 4.7. The starting material, ethyl o-bromobenzoate, is consumed almost entirely within the residence time of 0.1 s, generating the protonated product in about 90 % yield. The yield of the product is lower at a longer residence time, presumably because the aryllithium intermediate should decompose. The optimal residence time at this temperature is ca. 0.1 s. 

The rate of Br/Li exchange reaction, as well as that of the decomposition of the aryllithium, is dependent on temperature. The temperature-residence time map is thus useful in analyzing the reactions and optimizing the reaction conditions. In addition to the temperature-residence time map for an ethyl ester, those for other esters are also prepared (Fig. 4.8). 

Fig. 4.10 Br-Li exchange reaction of alkyl p-bromobenzoates using s-BuLi followed by protonation using a flow microreactor system...

The product is a bromobenzene derivative with a benzene ring to which one electrophile has been added. The remaining Br group can further undergo a Br-Li exchange reaction if n-BuLi is added, and the resultant aryllithium species can react with another electrophile. 

The Br-Li exchange reaction of p-methoxybromobenzene and the cross-couphng reaction of the resulting p-methoxyphenyllithium with bromobenzene, catalyzed by PEPPSI-SIPr, were carried out using a flow microreactor system shown in Fig. 9.6,... 

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