Page 81 - Advanced Organic Chemistry Part B - Reactions & Synthesis

of the stereochemistry of the hydrazone. 120 Two successive alkylations of the N,N- 53
dimethylhydrazone of acetone provides unsymmetrical ketones.
SECTION 1.3
N(CH ) N(CH 3 2 O The Nitrogen Analogs of
)
3 2
N 1) n-BuLi, 0°C N 1) n-BuLi, –5°C Enols and Enolates:
CH 3 (CH 2 ) 5 CCH 2 CH 2 CH CH 2 Enamines
CH CCH 3 2) C H I CH (CH ) CCH 3 2) BrCH CH CH 2 and Imine Anions
2
5 11
2 5
3
3
+
3) H , H O
2
Ref. 121
The anion of cyclohexanone N,N-dimethylhydrazone shows a strong preference
for axial alkylation. 122 2-Methylcyclohexanone N,N-dimethylhydrazone is alkylated
by methyl iodide to give cis-2,6-dimethylcyclohexanone. The 2-methyl group in the
hydrazone occupies a pseudoaxial orientation. Alkylation apparently occurs anti to the
lithium cation, which is on the face opposite the 2-methyl substituent.
N N N CH 3
N(CH ) LDA N(CH ) CH I N(CH ) H O
3
2
3 2
Li 3 2 3 2
CH 3 CH 3 H C CH 3 CH 3 O
3
The N,N-dimethylhydrazones of , -unsaturated aldehydes give -alkylation,
similarly to the enolates of enones. 123
1) LDA
CH CH CHCH NN(CH ) 2) CH (CH ) CH Br CH (CH ) CHCH NN(CH )
3
3 2
3 2
2 5
3
3
2
2 4
CH CH
2
69%
Chiral hydrazones have also been developed for enantioselective alkylation
of ketones. The hydrazones are converted to the lithium salt, alkylated, and then
hydrolyzed to give alkylated ketone in good chemical yield and with high diastereo-
selective 124 (see Table 1.4, Entry 4). Several procedures have been developed for
conversion of the hydrazones back to ketones. 125 Mild conditions are necessary
to maintain the configuration at the enolizable position adjacent to the carbonyl
group. The most frequently used hydrazones are those derived from N-amino-2-
methoxymethypyrrolidine, known as SAMP. The R -enantiomer is called RAMP. The
crystal structure of the lithium anion of the SAMP hydrazone from 2-acetylnaphthalene
has been determined 126 (Figure 1.7). The lithium cation is chelated by the exocyclic
nitrogen and the methoxy group.
120 D. E. Bergbreiter and M. Newcomb, Tetrahedron Lett., 4145 (1979); M. E. Jung, T. J. Shaw, R. R. Fraser,
J. Banville, and K. Taymaz, Tetrahedron Lett., 4149 (1979).
121
M. Yamashita, K. Matsumiya, M. Tanabe, and R. Suetmitsu, Bull. Chem. Soc. Jpn., 58, 407 (1985).
122 D. B. Collum, D. Kahne, S. A. Gut, R. T. DePue, F. Mohamadi, R. A. Wanat, J. Clardy, and G. Van
Duyne, J. Am. Chem. Soc., 106, 4865 (1984); R. A. Wanat and D. B. Collum, J. Am. Chem. Soc., 107,
2078 (1985).
123
M. Yamashita, K. Matsumiya, and K. Nakano, Bull. Chem. Soc. Jpn., 60, 1759 (1993).
124 D. Enders, H. Eichenauer, U. Baus, H. Schubert, and K. A. M. Kremer, Tetrahedron, 40, 1345 (1984);
D. Enders, H. Kipphardt, and P. Fey, Org. Synth., 65, 183 (1987); D. Enders and M. Klatt, Synthesis,
1403 (1996).
125 D. Enders, L. Wortmann, and R. Peters, Acc. Chem. Res., 33, 157 (2000).
126
D. Enders, G. Bachstadtler, K. A. M. Kremer, M. Marsch, K. Hans, and G. Boche, Angew. Chem. Int.
Ed. Engl., 27, 1522 (1988).