Page 430 - Advanced Organic Chemistry Part B - Reactions & Synthesis

This method can be used in conjunction with addition of cyanide to prepare -hydroxy 403
aldehydes from ketones. 90
SECTION 5.3
Group III
O 1) TMS-CN HO Hydride-Donor Reagents
ZnI 2 1) NH Cl CH O
4
CH (CH ) C(CH ) CH 3 (CH ) (CH ) CH
2 4
2 4
3
2
2) (i-Bu) AlH 2 ) HCl, H 2 O CH 3 2 4 2 4 3
79 %
5.3.1.2. Reduction of Imines and Amides to Amines. A second type of chemoselec-
tivity arises in the context of the need to reduce one functional group in the presence of
another. If the group to be reduced is more reactive than the one to be left unchanged,
it is simply a matter of choosing a reducing reagent with the appropriate level of
reactivity. Sodium borohydride, for example, is very useful in this respect since it
reduces ketones and aldehydes much more rapidly than esters. Sodium cyanoboro-
hydride is used to reduce imines to amines, but this reagent is only reactive toward
iminium ions. At pH 6–7, NaBH CN is essentially unreactive toward carbonyl groups.
3
When an amine and ketone are mixed together, equilibrium is established with the
imine. At mildly acidic pH only the protonated imine is reactive toward NaBH CN. 91
3
This process is called reductive amination.

H
R C O + R′NH + H + R C NR′
2
2
2
+
H
R C NR′ + BH CN – R CHNHR′
2
+ 3 2
Reductive amination by NaBH CN can also be carried out in the presence of
3
Ti O-i-Pr . These conditions are especially useful for situations in which it is not
4
practical to use the amine in excess (as is typically done under the acid-catalyzed
conditions) or for acid-sensitive compounds. The Ti O-i-Pr may act as a Lewis acid
4
in generation of a tetrahedral adduct, which then may be reduced directly or via a
transient iminium intermediate. 92
OTi(O-i-Pr) 3
Ti(O-i-Pr) 4 NaBH CN
3
+
R 2 C O + HNR′ 2 R 2 C NR′ 2 R 2 C N R′ 2 R 2 CHNR′ 2
Sodium triacetoxyborohydride is an alternative to NaBH CN for reductive
3
amination. This reagent can be used with a wide variety of aldehydes or ketones with
primary and secondary amines, including aniline derivatives. 93 This reagent has been
used successfully to alkylate amino acid esters. 94

90 M. Hayashi, T. Yoshiga, and N. Oguni, Synlett, 479 (1991).
91 R. F. Borch, M. D. Bernstein, and H. D. Durst, J. Am. Chem. Soc., 93, 2897 (1971).
92
R. J. Mattson, K. M. Pham, D. J. Leuck, and K. A. Cowen, J. Org. Chem., 55, 2552 (1990).
93 A. F. Abdel-Magid, K. G. Carson, B. H. Harris, C. A. Maryanoff, and R. D. Shah, J. Org. Chem., 61,
3849 (1996).
94
J. M. Ramanjulu and M. M. Joullie, Synth. Commun., 26, 1379 (1996).