Aryl halides lithiation

Like most aryl halides, furyl halides and furyl triflates have been coupled with a variety of organostannanes including alkenyl, aryl, and heteroaryl stannanes in the presence of catalytic palladium. Carbamoylstannane 66 was prepared by treating lithiated piperidine with carbon monoxide and tributyltin chloride sequentially. The Stille reaction of 66 and 3-bromofuran then gave rise to amide 67 [61]. In another example, lithiation of 4,4-dimethyl-2-oxazoline followed by quenching with MesSnCl resulted in 2-(tributylstannyl)-4,4-dimethyl-2-oxazoline (68) in 70-80% yield [62], Subsequent Stille reaction of 68 with 3-bromofuran afforded 2-(3 -furyl)-4,4-dimethyl-2-oxazoline (69). 

Successful lithiation of aryl halides—carbocyclic or heterocyclic—with alkyUithiums is, however, the exception rather than the rule. The instability of ortholithiated carbocyclic aryl halides towards benzyne formation is always a limiting feature of their use, and aryl bromides and iodides undergo halogen-metal exchange in preference to deprotonation. Lithium amide bases avoid the second of these problems, but work well only with aryl halides benefitting from some additional acidifying feature. Chlorobenzene and bromobenzene can be lithiated with moderate yield and selectivity by LDA or LiTMP at -75 or -100 °C . 

The equilibria mean that n-BuLi can be used to form organolithiums from aryl halides at low temperature (the subsequent reaction of ArLi with the BuX formed in the exchange is slow6) r-BuLi will form organolithiums from primary alkyl halides.7 The formation of secondary organolithiums by halogen-metal exchange is difficult,9 and reductive lithiation is usually preferable. 

In 1972, Screttas10 reported that the reductive lithiation of aryl halides (including fluorobenzene) and (to a lesser extent) alkyl halides was successful even at -50 °C when carried out in THF in the presence of a stoichiometric quantity of naphthalene. Carbonation of the products gave carboxylic acids in high yields.11... 

Zincio-I,3-dithianes are valuable reagents. Based on reactions of organozincs 4-acetoxy-l,3-dioxanes serve as precursors of anti-l,3-diols." A synthesis of 1,1-diarylallenes involves Pd-catalyzed coupling of the organozinc species which are derived from 1-arylpropynes by lithiation and Li/Zn exchange with aryl halides. By an sp -sp bond formation process to introduce a dienyl substituent to C-2 of 2-cyclopentenones a facile synthesis of nakienone-A was developed. - ... 

A related method is lithiation of an aryl halide with subsequent treatment by means of chloroalkylsilanes to achieve alkyl aryl silanes as can be shown by the synthesis of bis[3,4-dimethylphenyl]dimethylsilane (229) (equation 109)138. 

Reactions of Pyrroles. 1,3-Di-t-butylpyrrole forms the first stable protonated pyrrole, the salt (104). Electrophilic substitution of pyrrole with MeaC or Me FC in the gas phase occurs mainly at the j3-position, as does nitration and Friedel-Crafts acylation of l-phenylsulphonylpyrrole2 Pyrrole-2,5-dialdehyde has been prepared by Vilsmeier-Haack formylation of the ester (105), followed by hydrolysis. A similar method has been used to convert the di-acetal (106) into pyrrole-2,3,5-tricarbaldehyde. AT-Benzoyl-pyrrole reacts with benzene in the presence of palladium(II) acetate to yield a mixture of l-benzoyl-2,5-diphenylpyrrole, the bipyrrolyl (107), and compound (108). Treating lithiated A-methylpyrrole with nickel(II) chloride results in the polypyrrolyls (109 = 0-4). 2-Aryl-1-methylpyrroles are obtained by cross-coupling of l-methylpyrrol-2-ylmagnesium bromide with aryl halides in the presence of palladium(0)-phosphine complexes. ... 

This approach, which obviates the formation of symmetrical products, was also applied to the synthesis of unsymmetrical biaryls [15]. The aryl-copper compound was prepared from corresponding aryl-lithium obtained by direct lithiation of an aryl halide and was coupled with the other aryl halide. 

Concerning the nucleophilic cyclization, the reaction sequence usually employs the transformation of an aryl halide to the lithiated salt and its subsequent reaction with alkyl or aryl nitriles. The formed intermediate anion is readily cyclized to provide the 1,4-substituted isoquinolines. 

An established synthetic method for arylsilanes is lithiation of aryl halides, followed by the reaction with RsSiCl. Alkenylsilanes are produced by hydrosilylation of 1-alkynes catalyzed by Rh or Pt complexes. Also aryl- and alkenylsilanes 2 are synthesized by Pd-catalyzed reaction of hexamethyldisilane with halides in the presence of TASF [78,79],... 

Arylpyrroles are available from 3-iodopyrroles (Scheme 10). Lithiation in the 3-position in l-(triisopropylsilyl)-3-iodopyrrole followed by reaction of the lithio species with trimethyl borate and hydrolysis of the product gives the boronic acid. Coupling of the crude boronic acid with aryl halides under Suzuki conditions leads to the formation of... 

Zinc Derivatives Oxazoles and benzoxazoles can be lithiated in the 2-position by alkyllithium. In transmetallation of lithiated oxazole excess zinc dichloride gave the highest yield. The zincated substrates 106 and 107 were used in Negishi-type coupling (Scheme 45). Reactions of zincated oxazoles and benzoxazole with aryl halides all proceed well. A similar reaction sequence was used in the preparation of a 2-oxazolyl-substituted tricyclic structure 108. 

Nagaki A, Uesugi Y, Tomida Y et al (2011) Homocoupling of aryl halides in flow space integration of lithiation and FeCl3 promoted homocoupling. Beilstein J Org Chem 7 1064-1069... 

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