Regioselective metallation

Several different approaches have been employed to prepare pyridylstannanes, one of which involves direct metalation followed by transmetalation with RjSnCl. A regioselective metalation of 2-methoxypyridine was achieved using a mixture of bases comprised of BuLi-LiO(CH2)2NMe2 [53], Subsequent transmetalation with BujSnCl led to 2-methoxy-6-(tributylstannyl)pyridine (68), which was then coupled with pyridyl-, pyrimidyl-, and quinolinyl bromides in 31-56% yield. 

Substituted 3,6-dialkoxy-2,5-dihydropyrazines are regioselectively metalated by strong alkyl-lithium bases, such as butyllithium, (l-methylpropyl)lithium, fcrf-butyllithium, or lithium diiso-propylamide, at the less substituted carbon atom (C5). Metalation proceeds at low temperatures (in general, below — 70 C) in THF as solvent. Electrophiles suitable for alkylation of the lithiated derivatives include alkyl iodides, bromides and chlorides, as well as alkyl methanesulfonates, 4-methylbenzenesulfonates and trifluoromethanesulfonates. The electrophile adds trans to the substituent at C2 in a highly stereoselective fashion, with typical diastereomeric excesses of greater than 90% (syn addition has been reported in only one case where a-methylphenyl alanine was used as chiral auxiliary and an alkyl trifluoromethanesulfonate as electrophile18). 

The expedient and regioselective metalation of unprotected biphenyl-2-, -3-, and -4-carboxylic acids has been reported.59 Unprotected biphenyl-2-carboxylic acid has been cleanly metalated with. sex-butyllithium at the position adjacent to the carboxylate and can then be subjected to site-selective electrophilic substitution (Scheme 8). The remote C(2 )-position has been attacked by the superbasic mixture of n-BuLi and t-BuOK (LICKOR) in THF or benzene. The resulting dianion cyclizes to give the fluorenone skeleton. The mechanism of the metalation of homologous compounds, 2-(pyridin-3-yl)benzoic acid derivatives, with strong bases has also been discussed.60... 

For other polysubstituted arenes or heteroarenes, deprotonation at different sites can compete and yield product mixtures. The first reaction in Scheme 5.46 is an example of kinetically controlled carbanion formation, which shows that for some substrates regioselective metalations might be achieved by careful control of the reaction conditions. 

Scheme5.46. Regioselective metalation of a substituted thiophene [384] and MOM-protected 4-fluorophenol [377],...

Ebden, M. R. Simpkins, N. S. Fox, D. N. A. Activation of benzylic amines towards regioselective metalation by borane complex formation. Tetrahedron Lett. 1995, 36, 8697—8700. Ariffin, A. Blake, A. J. Ebden, M. R. H, W.-S. Simpkins, N. S. Fox, D. N. A. The diastereose-lective and enantioselective substitution reactions of an isoindoline-borane complex. 

Paulson, A. S. Eskildsen, J. Vedso, P. Begtrup, M. Sequential functionalization of pyrazole 1-oxides via regioselective metalation synthesis of 3,4,5-trisubstituted 1-hydroxypyra-zoles. /. Org. Chem. 2002, 67, 3904-3907. 

Cabiddu, M. G. Cabiddu, S. Cadoni, E. Corrias, R. Fattuoni, C. Floris, C. Melis, S. Metalation reactions XXII. Regioselective metalation of (trifluoromethyl)(alkylthio)-benzenes./. Organomet. Chem. 1997, 531, 125-140. 

The presence of a heterosubstituent facilitates deprotonation. 4-Methyl-4H-pyran and 1,4-dimethyldihydropyr-idine are regioselectively metallated at the position next to the heteroatom by LIC-KOR or trimethylsilylmethylpotassium.47 The metallation of cyclic vinyl ethers with Schlosser s base has been successfully used in the synthesis of C-glycosides48 50 via metallation of the glucal followed by a reaction with tributyltin chloride to afford the corresponding tin derivative that could be submitted to coupling reactions with various electrophiles.48... 

Figure 2.27 (a) Regioselective metal protonation (R = C6H4Me L = PPhg) (b) non- or weakly coordinating anions... 

The C-2 proton of benzo[/ ]furan 82 underwent regioselective metallation by treatment with -butyllithium to form 2-lithiated benzo[/ ]furan, which directly reacted with electrophiles, such as 1,4-cyclohexadienone to form 4-(ben-zo[/ ]furan-2-yl) -hydroxy-2,5-cyclohexadien-l-one in high yield, as shown in Equation (71) <2005TL7511>. 

Controlled hydrogenolysis of a methoxy substituent has been used to advantage in an expeditious synthesis of the tetrahydronaphthoic acid (122), an important starting material for the total synthesis of gib-berellins, i.e. regioselective metallation of 1,6-dimethoxynaphthalene (120) at C-7 followed by carboxylation to afford (121) and then reduction furnished (122) in 71% overall yield (Scheme 21). ... 

Sequential functionalization of pyrazole-l-oxides via regioselective metallation led to the synthesis of 3,4,5-trisub-stituted-l-hydroxypyrazoles <2002JOC3904>. 3-Acylated-2-(4-methoxybenzyl)-2//-pyrazole 1-oxides were formed by the reaction between a 3-magnesium 2//-pyrazole-l-oxide and acid chlorides <2002J(P1)428>. 3-Arylated-l-hydroxypyrazoles were synthesized from 3-metallated-pyrazole 1-oxides <2001JOC8654>. The reaction between hexafluorobenzene and the anion of 1-hydroxypyrazole affords a mixture of the products of bis-, tetrakis-, and hexakis-substitution <2004ARK100>. In the case of hexakis(bromomethyl)benzene, its reaction with 1-hydroxy-pyrazole leads to the hexakis-substituted product. 

In pyridines, the ortho lithiation of 2-substituted secondary and tertiary amides and sulfonamides has been reported. All three afford regioselective metalation at the 3-position, as illustrated by Kelly s synthesis of beminamycinic acid (23 Scheme 30). A recent development is the use of catalytic amounts of diisopropylamine for the ortho metalation of 2-methoxypyridine. ... 

Regioselective metalation of pyrazines and cross-coupling reactions provided an easy... 

Regioselective metallation at an a-position of a pyridine can be achieved with the mixed base prodnced from two mole equivalents of n-butyllithium with one of dimethylaminoethanol i.e. it is a 1 1 mixtnre of n-BuLi and Me2N(CH2)20Li (BuLi-LiDMAE). The regioselectivity is ascribed to intramolecular delivery... 

The combination of metal-halogen exchange with the presence of a directing substituent can lead to regioselective metallation. ... 

Development of a highly regioselective metal-mediated allylation reaction IN AQUEOUS MEDIA... 

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