Directed metalation regioselective lithiation

Regioselective substitution reactions of a series of 2- and 3-hydroxybiaryls including BINOL have been performed via a new directed orf/io-metallation procedure.75 O-Aryl AMsopropylcarbamates, conveniently prepared from phenols and isopropyl isocyanate, have been temporarily and in situ N-protected by means of silyl inflates to form stable intermediates for low-temperature lithiation reactions using n-BuLi-TMEDA in diethyl ether. The IV,IV-dialkyl aryl O-sulfamate has been reported as a new directed metallation group.76... 

Certain derivatives of benzene and naphthalene can be lithiated with sec-butyllithium (sec-BuLi). This reaction is regioselective. It takes place exclusively in the ortho-position (Directed ortho Metalation, DoM) to a so-called Directed-Metalation Group (DMG), whose presence, accordingly, is a prerequisite for such a metalation. Figure 5.37 gives examples of DMGs that are bound through a C, an O, or an N atom to the aromatic compound. 

Directed metallation (DoM) is extremely useful in heterocyclic chemistry. Just as in carbocyclic chemistry. Metallation ortho to the directing group is promoted by either inductive effects (e.g. Cl, F), or chelation (e.g. CH2OH — CH20Li), or a combination of these, and may overcome the intrinsic regioselectivity of metallation of a particular heterocycle. When available, this is by far the most important additional factor influencing the regioselectivity of lithiation. 

These directed metalations are regioselective for lithiation at carbons ortho to the substituent. The substituents contain atoms, especially oxygen and nitrogen, capable of coordinating to lithium. This coordination is reflected in the transition state for proton abstraction and causes lithiation to be fastest at the carbons ortho to the substituent. 

The presence of a sulfonyl group in 1-azulenyl p-tolylsulfone directs lithiation, by lithium tetramethylpiperidide, to ortho-positions. " Regioselective lithiation, at the 2- and 6-positions, has also been observed in the reaction of l-chloro-3-(trifluoromethyl)benzene with lithium diisopropylamide in tetrahydrofuran (THF). The metalation involves a rate-limiting deaggregation process with a dimer-based transition state. In the presence of lithium chloride, monomer-based pathways are favoured. ... 

Starting from fluoropyrazine, a regioselective synthesis of iodo- and Iributylstannyl substituted fluoropyrazines has been elaborated. Lithiation of fluoropyrazine with stoichiometric amounts of LTMP and iodine afforded the 2-fluoro-3-iodopyrazine 366 (E=I) as sole product otherwise a mixture of mono-, di-, and triiodo derivatives were formed (Scheme 62, Table 14) [147]. In a similar manner, use of tributyltin chloride as electrophile led to mono and di-stannylpyrazines [215]. Formation of compounds 369, 370 and 371 is a result of metalation at the position adjacent to the nitrogen atom without assistance of the fluorine atom as DMG. Such a metalation without a DMG has been previously reported during direct metalation of bare pyrazine by use of an excess of LTMP (4 equiv.) with very short reaction time (5 min) at low temperature -78 °C [216]. 

A flexible means of access to functionalized supports for solid-phase synthesis is based on metallated, cross-linked polystyrene, which reacts smoothly with a wide range of electrophiles. Cross-linked polystyrene can be lithiated directly by treatment with n-butyllithium and TMEDA in cyclohexane at 60-70 °C [1-3] to yield a product containing mainly meta- and para-Iithiated phenyl groups [4], Metallation of noncross-linked polystyrene with potassium ferf-amylate/3-(lithiomethyl)heptane has also been reported [5], The latter type of base can, unlike butyllithium/TMEDA [6], also lead to benzylic metallation [7]. The C-Iithiation of more acidic arenes or heteroar-enes, such as imidazoles [8], thiophenes [9], and furans [9], has also been performed on insoluble supports (Figure 4.1). These reactions proceed, like those in solution, with high regioselectivity. 

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>. 

The metaiation of heterocycles is possible without the aid of a directing group. This type of reaction is most common in the ir-excessive heterocycles, and is most important for thiophenes. For nitrogen heterocycles, examples of unactivated lithiation of ir-excessive azoles have been reported, and are summarized below. ir-Deficient heterocycles such as pyridine are resistant to unactivated lithiation, although pyridine can be metalated with low regioselectivity using butylsodium. Pyridines also form weak complexes with fluoro ketones the complex of 4-r-butylpyridine and hexafluoroacetone can be lithiated and added to benzaldehyde in 60% yield. ... 

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