Page 172 - Advanced Organic Chemistry Part B - Reactions & Synthesis

144 With aromatic aldehydes, d.r. ranged up to more than 10:1 for propanal.

CHAPTER 2 NHAr′
1) proline
Reactions of Carbon 30 mol %
Nucleophiles with CH CH CH O + ArCH NAr′ Ar
2
3
Carbonyl Compounds 2) NaBH 4 HO
CH
Ar′ = 4-methoxyphenyl 3
The proline-catalyzed reaction has been extend to the reaction of propanal, butanal, and
pentanal with a number of aromatic aldehydes and proceeds with high syn selectivity. 197
The reaction can also be carried out under conditions in which the imine is formed
in situ. Under these conditions, the conjugative stabilization of the aryl imines leads
to the preference for the aryl imine to act as the electrophile. A good yield of the
expected -aminoalcohol was obtained with propanal serving as both the nucleophilic
and the electrophilic component. The product was isolated as a -amino alcohol after
reduction with NaBH .
4
1) proline NHAr
10 mol % CH 3
CH CH CH O + H NAr
2
2
3
2) NaBH 4 HO
70% yield
Ar′ = 4-methoxyphenyl CH 3
dr > 95:5, 96% e.e.
Ketones such as acetone, hydroxyacetone, and methoxyacetone can be condensed with
both aromatic and aliphatic aldehydes. 198
20–35 mol % O NHAr′
O
proline
OCH 3 + ArCH O + Ar′NH 2 CH Ar
CH 3 3
Ar' = 4-methoxyphenyl OCH 3
The TS proposed for these proline-catalyzed reactions is very similar to that
for the proline-catalyzed aldol addition (see p. 132). In the case of imines, however,
the aldehyde substituent is directed toward the enamine double bond because of the
dominant steric effect of the N-aryl substituent. This leads to formation of syn isomers,
whereas the aldol reaction leads to anti isomers. This is the TS found to be the most
stable by B3LYP/6-31G computations. 199 The proton transfer is essentially complete
∗
at the TS. As with the aldol addition TS, the enamine is oriented anti to the proline
carboxy group in the most stable TS.

N O
Ar O
N H
H
H R
R

197
Y. Hayashi, W. Tsuboi, I. Ashimine, T. Urushima, M. Shoji, and K. Sakai, Angew. Chem. Int. Ed.
Engl., 42, 3677 (2003).
198 B. List, P. Pojarliev, W. T. Biller, and H. J. Martin, J. Am. Chem. Soc., 124, 827 (2002).
199
S. Bahmanyar and K. N. Houk, Org. Lett., 5, 1249 (2003).