Regioselectivity directed lithiation

To summarize, ortholithiation is a reaction with two steps (complex-formation and deprotonation) in which two features (rate and regioselectivity of lithiation) are controlled by two factors (coordination between organolithium and a heteroatom and acidity of the proton to be removed). In some cases, some of these points are less important (acidity, for example, or the coordination step). The best directing groups tend to have a mixture of the basic properties required for good coordination to lithium and the acidic properties required for rapid and efficient deprotonation. 

For cases where the regioselectivity of lithiation cannot be biased in the required direction, silylation can be used to block acidic sites while further lithiations are carried out. The blocking silyl group is later readily removed with fluoride . This method was used to avoid a competing lateral lithiation in the synthesis of the aldehyde 665 (Scheme 251... 

The phosphine oxide (-)-(5 )-[2-(dimethylamino)ethyl]methyloxophenylphosphorane85 was treated with butyllithium or LDA to give, via directed lithiation, the methylene-deprotonated compound regioselectively. Alkylation with bromomethylbenzene gave (S)-[l-benzyl-2-(di-methylamino)ethyl]methyloxophenylphosphorane with low diastereoselectivity (d.r. 55 45)86. 

Iwao, M. Directed lithiation of chlorobenzenes. Regioselectivity and application to a short synthesis ofbenzocyclobutenes./. Org. Chem. 1990, 55, 3622-3627. 

Directed lithiations of a,3- and -y.b-unsaturated amides " have been extensively studied. Illustrative examples are shown in Scheme 44. Prior complexation of the alkyllithium base with the amide carbonyl oxygen directs the base to the thermodynamically less acidic -position in a,3-unsaturated amide (31), which adds to benzophenone and subsequently lactonizes. Analysis of the NMR spectrum reveals that the organolithium added the benzophenone in the equatorial position. A Afferent kinetic deprotonation is seen in y,8-unsaturated amide (32), where -lithiation to form an allylic anion predominates over a-lithiadon to form an enolate. > Addition of the lithium anion to acetone affords poor regioselectivity, but transmetalation to magnesium before carbonyl addition yields a species which adds exclusively at the 8-position. ... 

Directed lithiation. 2-Arenesul gioselective fashion, furnishing thio 157-96%). 3-Halopyridines, includm lithiation and regioselective reaction that 3-chloro-4-iodopyridine generate t-BuLi. Halogen dance is also obsersx Vinyl esters are silylated at the esters of silyl ketones. The regiosel and the ability of the lithio derivative tion with suitable acceptors are expio cyclopentenones. ... 

Directed lithiation. 2-Arenesulfonyl benzamides are deprotonated in a re-gioselective fashion, furnishing thioxanthen-9-one 10,10-dioxides in good yields (57-96%). 3-Halopyridines, including the iodo compounds, manifest directed o-lithiation and regioselective reaction (at C-4) with electrophiles. It should be noted that 3-chloro-4-iodopyridine generates 3,4-pyridyne on treatment with either BuLi or f-BuLi. Halogen dance is also observed. ... 

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. 

When pyridine is heated to 165 °C in MeONa-MeOD, H-D exchange occurs at all positions via small concentrations of deprotonated species, at the relative rates a (3 7, 1 9.3 12. However, using the combination n-butyllithium/potassium t-butoxide, efficient formation of 2-pyridylpotassium or 4-pyridylpotassium has been achieved." Some pyridines have been selectively lithiated at C-2 via complexes with hexafluoroacetone " complexation removes the lone pair (cf. section 5.5.1) and additionally provides inductive and chelation effects to assist the regioselective metallation. In practice, simple lithiopyridines are generally prepared by metal-halogen exchange, however the presence of chlorine or fluorine, or other substituents which direct ortho metallation, allows direct lithiation (section 5.5.1). 

Direct regioselective a lithiation of pyridine, 2-methoxypyridine, or 2-methylthio-pyridine, can be carried out using a complex base consisting of a mixture of butyllithium and the lithium salt of 2-dimethylaminoethanol. The process may be more complex than simple deprotonation, possibly involving a radical anion intermediate. ... 

Regioselective metalation of a wide variety of trifluoromethylated pyridines and quinolines was exhaustively studied by the Schlosser research group." " It was demonstrated that regioselectivity of direct lithiation of fluorinated heterocycles depends signihcantly on reagents, reaction conditions and type of solvent. For example, the lithiation of 2-CF3-pyridine using lithium 2,2,6,6-tetramethylpiperidine (LiTMP) in THF at —75°C results in exclusive formation of acid 109, while the reaction with BuLi in the presence of Et2NCH2CH20Li in less polar ether leads to selective formation of isomeric acid 110 (Fig. 7.39). ... 

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. ... 

This procedure illustrates a general method for the preparation of alkenes from the pal 1 adium(Q)-cata1yzed reaction of vinyl halides with organo-lithium compounds, which can be prepared by various methods, including direct regioselective lithiation of hydrocarbons. The method is simple and has been used to prepare a variety of alkenes stereoselectively. Similar stoichiometric organocopper reactions sometimes proceed in a nonstereoselective... 

The ort/to-directing effect of the carbonyl group in the regioselective lithiation of 2( 1/f) quinolinone has been studied by Avendano <9581362>. 

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