The lithiation of fluorinated benzenes and its dependence on solvent and temperature

Abstract

The formation of lithio derivatives from fluorinated benzenes and fluorinated bromobenzenes has been studied. The bases used were lithium diisopropylamide (LDA) in THF-hexane, butyllithium in diethyl etherhexane and butyllithium in THF-hexane. The lithiated intermediates have been trapped using acetone, to form fluorinated 2-arylpropan-2-ols, or have been warmed to produce benzynes which have been trapped by furan in Diels-Alder additions. The use of LDA allows clean removal of the most acidic proton in the aromatic ring: butyllithium in ether-hexane kings about clean bromine-lithium exchange. In contrast, the use of butyllithium in THF-hexane at -78 "C results in autometallation and the formation of more complex product mixtures. For the formation of the benzynes involved in the Diels-Alder reactions it is necessary to warm the reaction mixtures. When ether-hexane is used as solvent the reactions remain fairly clean, but when THF is added the increasing autometallation again results in more complex reaction mixtures.

Effect of substituents and benzyne generating bases on the orientation to and reactivity of haloarynes

“…However, the yields of norbornadienes were severely compromised by the unavoidable amination side reaction. Encouraged by several reports on the use of t-BuLi to generate benzyne, [10][11][12][13][14] we treated the 4-chloro (1a)-, 4-bromo (1b)-, 4-fluoro (1c)-and 4-iodo (1f) derivatives of fluorobenzene with tert-BuLi in the presence of furan in THF. The reaction of 1b was first carried using the same reaction conditions as the LDA mediated ones.…”

Enantiopure 3-methyl-3,4-dihydroisocoumarins and 3-methyl-1,2,3,4-tetrahydroisoquinolines via chemoenzymatic asymmetric transformations

“…However, for the 4-fluorinated derivative 1f, 2-bromo-4-fluoro-3-(2-hydroxypropyl) benzonitrile was isolated as the unique reaction product due to the fluorine promoted metallation at the C3-position. 11 The use of Et 2 O instead of THF as reaction medium led to the bromine-lithium exchange, the desired alcohol 2f being obtained in 73% isolated yield. Lipase-catalyzed acetylation led to the production of all the acetates (R)-3b-f in a range between 92 and 99% ee using TBME as solvent (entries [8][9][10][11][12].…”

“…11 The use of Et 2 O instead of THF as reaction medium led to the bromine-lithium exchange, the desired alcohol 2f being obtained in 73% isolated yield. Lipase-catalyzed acetylation led to the production of all the acetates (R)-3b-f in a range between 92 and 99% ee using TBME as solvent (entries [8][9][10][11][12]. However only non-substituted alcohol 2a (entry 3, E = 194) and 4-substituted 2b,f (E > 200, entries 8 and 12) were acetylated with very good to excellent enantioselectivities.…”

Functionalization of Dihalophenylboronic Acids by Deprotonation of Their N‐Butyldiethanolamine Esters

“…The acid 2b could potentially be prepared from the commercially available 1-bromo-3,5-fluorobenzene (14) by lithiation/silylation with LDA/Me 3 SiCl, [20] followed by Br-Li exchange and boronation (Scheme 5). However, the isomeric acid 4a is not easily accessible by the same route from 1-bromo-3,4-fluorobenzene (15), because this substrate deprotonates between Br and F [21] rather than at the 5-position. Another problematic example would be the synthesis of 7a and 7b starting with deprotonation of 1-bromo-3,5-dichlorobenzene (16), because this reaction would be expected to be unselective, due to the similar ortho-directing abilities of chlorine and bromine.…”