Page 652 - Advanced Organic Chemistry Part B - Reactions & Synthesis

7.1.2.2. Preparation by Lithiation. There are three other general methods that are 627
very useful for preparing organolithium reagents. The first of these is hydrogen-metal
exchange or metallation, which for the specific case of lithium is known as lithiation. SECTION 7.1
This reaction is the usual method for preparing alkynylmagnesium and alkynyllithium Preparation and
Properties of
reagents. The reactions proceed readily because of the relative acidity of the hydrogen Organomagnesium
bound to sp carbon. and Organolithium
Reagents
H C C R +R′MgBr BrMgC C R + R′H

H C C R + R′Li LiC C R + R′H

Although of limited utility for other types of Grignard reagents, metallation is an
important means of preparing a variety of organolithium compounds. The position
of lithiation is determined by the relative acidity of the available hydrogens and the
directing effect of substituent groups. Benzylic and allylic hydrogens are relatively
reactive toward lithiation because of the resonance stabilization of the resulting anions. 46
Substituents that can coordinate to the lithium atom, such as alkoxy, amido, sulfoxide,
and sulfonyl, have a powerful influence on the position and rate of lithiation of aromatic
47
compounds. Some substituents, such as t-butoxycarbonylamido and carboxy, undergo
deprotonation during the lithiation process. 48 The methoxymethoxy substituent is
particularly useful among the alkoxy directing groups. It can provide selective lithiation
49
and, being an acetal, is readily removed by hydrolysis. In heteroaromatic compounds
the preferred site for lithiation is usually adjacent to the heteroatom.
The features that characterize the activating groups include an electron pair that
50
can coordinate lithium and polarity that can stabilize the anionic character. Geometric
factors are also important. For amido groups, for example, it has been deduced by
comparison of various cyclic systems that the preferred geometry is for the activating
51
amide group to be coplanar with the position of lithiation. If competing nucleophilic
attack is a possibility, as in tertiary amides, steric bulk is also an important factor.
Consistent with the importance of polar and electrostatic effects in lithiation, a fluoro
substituent is a good directing substituent. Amide bases such as LDA and LTMP
give better results than alkyllithium reagents. With these bases, fluorine was found
to promote ortho lithiation selectively over such directing groups as methoxy and
diethylaminocarbonyloxy. 52

46 R. D. Clark and A. Jahangir, Org. React., 47, 1 (1995).
47
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49
C. A. Townsend and L. M. Bloom, Tetrahedron Lett., 22, 3923 (1981); R. C. Ronald and M. R. Winkle,
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52
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