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Heteroatom-promoted lateral lithiation
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Heteroatom-promoted lateral lithiation
Heteroatom-promoted lateral lithiation is the site-selective replacement of a benzylic hydrogen atom for lithium for the purpose of further functionalization. Heteroatom-containing substituents may direct metalation to the benzylic site closest to the heteroatom or increase the acidity of the ring carbons via an inductive effect.
Toluene derivatives with heteroatom-containing substituents in the ortho position undergo site-selective benzylic lithiation in the presence of organolithium compounds (either alkyllithiums or lithium dialkylamides). Coordination of the Lewis acidic lithium atom to the Lewis basic heteroatom, as well as inductive effects derived from the electronegativity of the heteroatom, encourage selective deprotonation at the benzylic position. Competitive ring metalation (directed ortho-metalation) is an important side reaction, but a judicious choice of base often allows for selective benzylic metalation. Useful heteroatom-containing directing groups include dialkylamines, amides (secondary or tertiary), ketone enolates, carbamates, and sulfonates. Lateral lithiation of alkyl-substituted heterocycles incorporating heteroatom-containing substituents is also possible, although ring lithiation α to the ring heteroatom may compete with lateral lithiation. The products of lateral lithiation react with a variety of electrophiles, including reactive alkyl halides (allylic, benzylic, and primary), carbonyl compounds, silyl and stannyl chlorides, disulfides and diselenides, and others. A general, highly selective method for benzylic metalation using a mixed lithium and potassium metal amide (LiNK chemistry) has been developed which permits metalation regardless of the relative position (ortho, meta or para) of the methyl group to the heteroatom containing substituent
(1)
Two limiting mechanisms, one operating under kinetic and the other thermodynamic control, have been identified for lateral lithiation reactions. The mechanisms of most lateral lithiations fall somewhere between these two limiting mechanisms, and the precise mechanism of a particular lithiation depends on two factors:
When both the Lewis acidity of the organolithium compound and the Lewis basicity of the substituent are high, as in lithiations of ortho-(dialkylamino)methyl toluenes with n-butyllithium in a non-coordinating solvent, coordination of the base to the heteroatom substituent takes place. Lithiation then occurs at the most kinetically accessible ortho benzylic position; ortho lithiation is slower in this case.
(2)
As either the Lewis acidity of the base or the coordinating ability of the substituent decrease, a mechanism involving purely inductive effects becomes more important. For instance, the lithiation of 1 with lithium di(isopropyl)amide (LDA) affords only the product of benzylic metalation 2; none of the ortho-lithiated product 3 is observed. This result is explained by a mechanism in which the amide substituent affects the acidity of the para benzylic position solely through inductive effects and coordination of the base is not operative. Deprotonation occurs to afford the most thermodynamically stable product.
(3)
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Heteroatom-promoted lateral lithiation AI simulator
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Heteroatom-promoted lateral lithiation
Heteroatom-promoted lateral lithiation is the site-selective replacement of a benzylic hydrogen atom for lithium for the purpose of further functionalization. Heteroatom-containing substituents may direct metalation to the benzylic site closest to the heteroatom or increase the acidity of the ring carbons via an inductive effect.
Toluene derivatives with heteroatom-containing substituents in the ortho position undergo site-selective benzylic lithiation in the presence of organolithium compounds (either alkyllithiums or lithium dialkylamides). Coordination of the Lewis acidic lithium atom to the Lewis basic heteroatom, as well as inductive effects derived from the electronegativity of the heteroatom, encourage selective deprotonation at the benzylic position. Competitive ring metalation (directed ortho-metalation) is an important side reaction, but a judicious choice of base often allows for selective benzylic metalation. Useful heteroatom-containing directing groups include dialkylamines, amides (secondary or tertiary), ketone enolates, carbamates, and sulfonates. Lateral lithiation of alkyl-substituted heterocycles incorporating heteroatom-containing substituents is also possible, although ring lithiation α to the ring heteroatom may compete with lateral lithiation. The products of lateral lithiation react with a variety of electrophiles, including reactive alkyl halides (allylic, benzylic, and primary), carbonyl compounds, silyl and stannyl chlorides, disulfides and diselenides, and others. A general, highly selective method for benzylic metalation using a mixed lithium and potassium metal amide (LiNK chemistry) has been developed which permits metalation regardless of the relative position (ortho, meta or para) of the methyl group to the heteroatom containing substituent
(1)
Two limiting mechanisms, one operating under kinetic and the other thermodynamic control, have been identified for lateral lithiation reactions. The mechanisms of most lateral lithiations fall somewhere between these two limiting mechanisms, and the precise mechanism of a particular lithiation depends on two factors:
When both the Lewis acidity of the organolithium compound and the Lewis basicity of the substituent are high, as in lithiations of ortho-(dialkylamino)methyl toluenes with n-butyllithium in a non-coordinating solvent, coordination of the base to the heteroatom substituent takes place. Lithiation then occurs at the most kinetically accessible ortho benzylic position; ortho lithiation is slower in this case.
(2)
As either the Lewis acidity of the base or the coordinating ability of the substituent decrease, a mechanism involving purely inductive effects becomes more important. For instance, the lithiation of 1 with lithium di(isopropyl)amide (LDA) affords only the product of benzylic metalation 2; none of the ortho-lithiated product 3 is observed. This result is explained by a mechanism in which the amide substituent affects the acidity of the para benzylic position solely through inductive effects and coordination of the base is not operative. Deprotonation occurs to afford the most thermodynamically stable product.
(3)