Exchange bromine-lithium

Treatment of bromoarenes with butyllithium generally proceeds smoothly and quantitatively [4, 168]. The halogenated arenes are accessible by electrophilic substitution or diazotation. The exchange reaction can be carried out in Et20 as well as in THF but in the latter solvent the reaction is considerably faster. However, Et20 may be preferred in some syntheses, since in this solvent the undesired alkylation reaction between ArLi and butyl bromide is relatively slow. 

This circumstance offers the possibility for subsequent coupling of the lithiated arenes with paraformaldehyde (introduction of a CH2OH group) or with oxiranes (introduction of a C—C—OH function). Reaction of organolithium derivatives RLi with paraformaldehyde in most cases proceeds at acceptable rates only at temperatures in the region of -F 20 °C, irrespective of whether the solvent is THF or 

---

Since double bonds may be considered as masked carbonyl, carboxyl or hydroxymethylene groups, depending on whether oxidative or reductive methods are applied after cleavage of the double bond, the addition products from (E)-2 and carbonyl compounds can be further transformed into a variety of chiral compounds. Thus, performing a second bromine/lithium exchange on compound 4, and subsequent protonation, afforded the olefin 5. Ozonolysis followed by reduction with lithium aluminum hydride gave (S)-l-phenyl-l,2-ethanediol in >98% ee. 

H), followed by bromine-lithium exchange using 2 equivalents of tert-butyllithium to give the desired intermediate. This intermediate readily picked up carbon monoxide and work-up of the reaction mixture gave indigo (Fig. 17) (ref. 31). 

Therefore, it has been considered that the formation of the dimer involves a mechanism different to the simple head-to-head radical coupling of the parent monomer. As suggested by the authors, it is likely that the overall mechanistic sequence is initiated by the radical-anion 472 of compound 469 formed by a single electron transfer (SET) process, which is the first stage of the bromine-lithium exchange (Scheme 68) [128],... 

The power of Muchowski s method is seen by the fact that these bromopyrroles can be subjected to bromine-lithium exchange to afford the versatile 3-lithio species that can be quenched with a variety of electrophiles in good to excellent yields [18-21]. This is illustrated by a synthesis of verrucarin E (11) [19]. 

Mono- or bis-bromine-lithium exchange on dibromopyrrole 77 affords stannylpyrroles 78 or 79, respectively, and N-BOC-2-trimethylstannylpyrrole is obtained in 75% yield from N-BOC pyrrole by lithiation with LTMP and quenching with Me3SnCl [15]. 

Bromodesilylation T-methoxy-l-indanones. Cyclization contrary to the normal para-selectivity of anisole derivatives can be effected by temporary use of an ort/jo-trimethylsilyl group introduced by directed orf/io-metallation (11,75). Thus the anisole derivative 1 undergoes bromodesilylation and hydrolysis to provide 2. This product undergoes cyclization to 3 in good yield on conversion to the lithio salt followed by bromine-lithium exchange (8,65-66). 

A similar bromine-lithium exchange mediated isomerization of 2-lithiopyridine 219 (Scheme 106) was used in a synthesis of atpenin B (see below). ... 

Miscellaneous The treatment of allyl 1-bromo-2-naphthyl ether 43 with f-BuLi affords benzyl alcohol 44 via a sequential reaction consisting of bromine-lithium exchange, and anion translocation, followed by a [1,2]-Wittig rearrangement (equation 23). ... 

At a glance, this result shows that the carbenoid 16 is configurationally stable at — 110°C. When, however, the same carbenoid 16 has been generated by means of a bromine-lithium exchange, partial epimerization leading to 18 occurs (equation 9) . 

In the latter reaction, remarkable examples of diastereoselectivity have been reported. Thus, the treatment of 7,7-dibromonorcarane 22 with n-butyllithium leads to exo-7-bromo-ewdo-7-lithiobicyclo[4.1.0]heptane23 exclusively, as shown by carboxylation (Scheme 8). It turns out that a slight excess of dibromonorcarane 22 relative to butyllithium is prerequisite to that high degree of stereoselectivity. The result is explained as follows the exo-bromine atom in 22 is exchanged first in a kinetically controlled reaction so that the ewrfo-bromo-exo-lithio-isomer 24 is formed. In a second step, an equilibration occurs by means of another bromine-lithium exchange, which takes place between 24 and the dibromonorcarane 22 (still present because used in excess). Thus, the thermodynamically... 

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. 

TABLE 1. Representative examples of a-halo-o -Uthiocyclopropanes generated by bromine-lithium exchange see also Reference 19... 

The influence that a possible chelation has on the stereochemistry of the bromine-lithium exchange in dibromoaUcenes was first studied in the chiral MEM (methoxyethoxymethyl) ether 40. When this compound is treated with 1.2 equivalents of n-butyllithium in tetrahydrofnran, the acids E- and Z-42 are obtained in a ratio of 32 68 after carboxylation. Obvionsly, a kinetically favored substitution of the more easily accessible trans bromine atom occurs. When, however, slightly less than one equivalent (0.95-0.98 equiv) of -bntyllithinm is slowly added to a solution of 40 in diethyl ether at — 105°C, the -confignrated carbenoid 41 forms almost exclusively, and the carboxylic acids E- and Z-42 are obtained after reaction with dry ice in a ratio of over 99 1 (Scheme 9) ,i93 ... 

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... 

When the bromoalkenes 146, which are obtained in 88 to over 98% de, are submitted to another bromine-lithium exchange, the dilithium compound 148 is generated. This reaction takes place under complete retention of the configuration, as proven by the protonation that yields the Z-alkenes 149 . A debromination protocol that is based on a free... 

The 3-thienyl substituted silane 30 was trilithiated by Nakayama and coworkers, when reacted with a three-fold excess of n-butyllithium (Scheme 11). Target molecule 31 can also be obtained by bromine-lithium exchange, but with a reduced yield. 

By a two-fold bromine-lithium exchange on l,2-bis(2-bromo-3,5-di-f-butylphenyl)-ethane (73), Yoshifuji and coworkers were able to generate 1,6-dilithium compound 74 . The reaction was carried out using n-butyllithium in THF at — 78°C (Scheme 26). 

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 4-sodio and 4-potassio derivatives are known but are less convenient to obtain than the 4-lithio derivative, which is readily available by metallation of dibenzofuran with butyllithium. Metallation can also be achieved with cross-linked poly(p-lithiosytrene) but offers no advantage in yield. The 4,6-dimetallo derivatives of dibenzofuran can be made by treatment of dibenzofuran with butyllithium or butylsodium. Lithiodiben-zofurans and dilithiodibenzofurans are also available by bromine-lithium exchange with butyllithium. " ... 

Condensation of the alkoxynaphthyldihydrooxazoles with 2-methoxy-l-naphthyllithium, prepared by bromine-lithium exchange, did not lead to the same product as the corresponding reactions with the magnesium compound, but, unexpectedly, to a rearranged isomeric 1 -bi-naphthyl derivative with high enantiomeric excess28. 

---