Page 303 - Advanced Organic Chemistry Part B - Reactions & Synthesis

group and facilitate hydrolysis. Among the reagents that have been found effective are 275
nitrous acid, t-butyl hypochlorite, NaClO , PhI O CCF , DDQ, SbCl , and cupric
2 2 3 2 5
salts. 266 SECTION 3.5
Installation and Removal
R C SR′ + H O of Protective Groups
2
2
R C(SR′) +X + + SR′ R 2 C SR′ R C SR′ R C O
2
2
2
2
OH
X
3.5.4. Carboxylic Acid–Protecting Groups
If only the O–H, as opposed to the carbonyl, of a carboxyl group has to be masked,
it can be readily accomplished by esterification. Alkaline hydrolysis is the usual way
for regenerating the acid. t-Butyl esters, which are readily cleaved by acid, can be
used if alkaline conditions must be avoided. 2,2,2-Trichloroethyl esters, which can be
reductively cleaved with zinc, are another possibility. 267 Some esters can be cleaved by
treatment with anhydrous TBAF. These reactions proceed best for esters of relatively
acidic alcohols, such as 4-nitrobenzyl, 2,2,2-trichloroethyl, and cyanoethyl. 268
The more difficult problem of protecting the carbonyl group can be accomplished
by conversion to a oxazoline derivative. One example is the 4,4-dimethyl derivative,
which can be prepared from the acid by reaction with 2-amino-2-methylpropanol or
with 2,2-dimethylaziridine. 269

CH 3
N
RCO H + HOCH C(CH ) R C CH 3
2
2
3 2
O
NH 2
CH 3 O CH 3 H + CH 3
RCO H + HN CH 3 CH O CH 3
2
RC N 3 R
N
The heterocyclic derivative successfully protects the acid from attack by Grignard
or hydride-transfer reagents. The carboxylic acid group can be regenerated by acidic
hydrolysis or converted to an ester by acid-catalyzed reaction with the appropriate
alcohol.
Carboxylic acids can also be protected as orthoesters. Orthoesters derived
from simple alcohols are very easily hydrolyzed, and the 4-methyl-2,6,7-
trioxabicyclo[2.2.2]octane structure is a more useful orthoester protecting group. These

266
M. T. M. El-Wassimy, K. A. Jorgensen, and S. O. Lawesson, J. Chem. Soc., Perkin Trans. 1, 2201 (1983);
J. Lucchetti and A. Krief, Synth. Commun., 13, 1153 (1983); G. Stork and K. Zhao, Tetrahedron Lett.,
30, 287 (1989); L. Mathew and S. Sankararaman, J. Org. Chem., 58, 7576 (1993); J. M. G. Fernandez,
C. O. Mellet, A. M. Marin, and J. Fuentes, Carbohydrate Res., 274, 263 (1995); K. Tanemura, H. Dohya,
M. Imamura, T. Suzuki, and T. Horaguchi, J. Chem. Soc., Perkin Trans. 1, 453 (1996); M. Kamata,
H. Otogawa, and E. Hasegawa, Tetrahedron Lett., 32, 7421 (1991); T. Ichige, A. Miyake, N. Kanoh,
and M. Nakata, Synlett, 1686 (2004).
267 R. B. Woodward, K. Heusler, J. Gostelli, P. Naegeli, W. Oppolzer, R. Ramage, S. Ranganathan, and
H. Vorbruggen, J. Am. Chem. Soc., 88, 852 (1966).
268 M. Namikoshi, B. Kundu, and K. L. Rinehart, J. Org. Chem., 56, 5464 (1991); Y. Kita, H. Maeda,
F. Takahashi, S. Fukui, and T. Ogawa, Chem. Pharm. Bull., 42, 147 (1994).
269
A. I. Meyers, D. L. Temple, D. Haidukewych, and E. Mihelich, J. Org. Chem., 39, 2787 (1974).