Page 711 - Advanced Organic Chemistry Part B - Reactions & Synthesis

The mechanism of conjugate addition reactions probably involves an initial 687
complex between the cuprate and enone. 51 The key intermediate for formation of the
new carbon-carbon bond is an adduct formed between the enone and the organocopper SECTION 8.1
reagent. The adduct is formulated as a Cu(III) species, which then undergoes reductive Organocopper
Intermediates
elimination. The lithium ion also plays a key role, presumably by Lewis acid coordi-
nation at the carbonyl oxygen. 52 Solvent molecules also affect the reactivity of the
complex. 53 The mechanism can be outlined as occurring in three steps.
complex oxidative reductive
formation addition elimination
Li +
–
–
R 2 Cu – O Li + O Li +
O O
III
+
R 2 Cu CH CH CZ RCH CH CZ RCu I
–
R 2 Cu + R′CH CHCZ R′CH CHCZ
R′ R′
Isotope effects indicate that the collapse of the adduct by reductive elimination is the
54
rate-determining step. Theoretical treatments of the mechanism suggest similar inter-
mediates. (See Section 8.1.2.7 for further discussion of the computational results.) 55
There is a correlation between the reduction potential of the carbonyl compounds
56
and the ease of reaction with cuprate reagents. The more easily it is reduced, the more
reactive the compound toward cuprate reagents. Compounds such as -unsaturated
esters and nitriles, which are not as easily reduced as the corresponding ketones, do not
react as readily with dialkylcuprates, even though they are good acceptors in classical
Michael reactions with carbanions. -Unsaturated esters are marginal in terms of
reactivity toward standard dialkylcuprate reagents, and -substitution retards reactivity.
The RCu-BF reagent combination is more reactive toward conjugated esters and
3
57
nitriles, and additions to hindered -unsaturated ketones are accelerated by BF . 58
3
There have been many applications of conjugate additions in synthesis. Some
representative reactions are shown in Scheme 8.2. Entries 1 and 2 are examples of
addition of lithium dimethylcuprate to cyclic enones. The stereoselectivity exhibited in
Entry 2 is the result of both steric and stereoelectronic effects that favor the approach
syn to the methyl substituent. In particular, the axial hydrogen at C(6) hinders the
approach.
CH 3
O CCH 3
2
H
O
51
S. R. Krauss and S. G. Smith, J. Am. Chem. Soc., 103, 141 (1981); E. J. Corey and N. W. Boaz,
Tetrahedron Lett., 26, 6015 (1985); E. J. Corey and F. J. Hannon, Tetrahedron Lett., 31, 1393 (1990).
52
H. O. House, Acc. Chem. Res., 9, 59 (1976); H. O. House and P. D. Weeks, J. Am. Chem. Soc., 97,
2770, 2778 (1975); H. O. House and K. A. J. Snoble, J. Org. Chem., 41, 3076 (1976); S. H. Bertz,
G. Dabbagh, J. M. Cook, and V. Honkan, J. Org. Chem., 49, 1739 (1984).
53 C. J. Kingsbury and R. A. J. Smith, J. Org. Chem., 62, 4629, 7637 (1997).
54 D. E. Frantz, D. A. Singleton, and J. P. Snyder, J. Am. Chem. Soc., 119, 3383 (1997).
55
E. Nakamura, S. Mori, and K. Morukuma, J. Am. Chem. Soc., 119, 4900 (1997); S. Mori and
E. Nakamura, Chem. Eur. J., 5, 1534 (1999).
56 H. O. House and M. J. Umen, J. Org. Chem., 38, 3893 (1973); B. H. Lipshutz, R. S. Wilhelm,
S. T. Nugent, R. D. Little, and M. M. Baizer, J. Org. Chem., 48, 3306 (1983).
57 Y. Yamamoto and K. Maruyama, J. Am. Chem. Soc., 100, 3240 (1978); Y. Yamamoto, Angew. Chem.
Int. Ed. Engl., 25, 947 (1986).
58
A. B. Smith, III, and P. J. Jerris, J. Am. Chem. Soc., 103, 194 (1981).