Page 674 - Advanced Organic Chemistry Part B - Reactions & Synthesis

The interpretation of the basis for this stereoselectivity can be made in terms of the 649
steric, torsional, and stereoelectronic effects discussed in connection with reduction by
hydrides. It has been found that crown ethers enhance stereoselectivity in the reaction SECTION 7.2
of both Grignard reagents and alkyllithium compounds. 119 This effect was attributed Reactions of
Organomagnesium and
to decreased electrophilicity of the metal cations in the presence of the crown ether. Organolithium
The attenuated reactivity leads to greater selectivity. Compounds
For ketones and aldehydes in which adjacent substituents permit the possibility
of chelation with a metal ion, the stereochemistry can often be interpreted in terms
of the steric requirements of the chelated TS. In the case of
-alkoxyketones, for
example, an assumption that both the alkoxy and carbonyl oxygens are coordinated
with the metal ion and that addition occurs from the less hindered face of this chelate
correctly predicts the stereochemistry of addition. The predicted product dominates by
as much as 100:1 for several Grignard reagents. 120 Further supporting the importance
of chelation is the correlation between rate and stereoselectivity. Groups that facilitate
chelation cause an increase in both rate and stereoselectivity. 121 This indicates that
chelation not only favors a specific TS geometry, but also lowers the reaction barrier
by favoring metal ion complexation.

R CH 3 THF R CH 3 R″ OMgX
H +C 4 H 9 MgBr H C 4 H 9 XMg R′O
R′O O –78 °C R′O OH R′O O R R″
R H R
R C 7 H 15 R′ CH 2 OCH 3 H R
CH 2 OCH 2 CH 2 OCH 3
CH 2 Ph
CH 2 OCH 2 Ph

The addition of a Grignard reagent to an unsymmetrical ketone generates a new
stereogenic center and is potentially enantioselective in the presence of an element of
chirality. Perhaps because the reactions are ordinarily very fast, there are relatively
few cases in which such reactions are highly enantioselective. The magnesium salt
of TADDOL promotes enantioselective additions to acetophenone. 122 These particular
reactions occur under heterogeneous conditions and are quite slow at −100 C.

Although the details of the mechanism are unclear, the ligand must establish a chiral
environment that controls the facial selectivity of the additions.

O
Mg(TADDOL) OH
PhCCH 3 + RMgX CH 3
–100°C Ph R

R % yield e.e.(%)
62 98
C 2 H 5
84 > 98
n-C 3 H 7
75 > 98
n-C 4 H 9
58 > 98
n-C 8 H 17

119
Y. Yamamoto and K. Maruyama, J. Am. Chem. Soc., 107, 6411 (1985).
120
W. C. Still and J. H. McDonald, III, Tetrahedron Lett., 1031 (1980).
121 X. Chen, E. R. Hortelano, E. L. Eliel, and S. V. Frye, J. Am. Chem. Soc., 112, 6130 (1990).
122
B. Weber and D. Seebach, Tetrahedron, 50, 6117 (1994).