Page 290 - Advanced Organic Chemistry Part B - Reactions & Synthesis

262 MgBr removal of SEM groups is also useful for deprotection of carboxy groups in
2
N-protected amino acids.
CHAPTER 3
Functional Group H O MgCl H
Interconversion 2
2
3 3
2 2
3 3
2
2
by Substitution, (CH ) CO CNCHCOCH O(CH ) Si(CH ) CH Cl (CH ) CO HNCHCO H
3 3
2
Including Protection and 2
Deprotection Ph Ph
Ref. 167
3.5.1.2. Ethers as Protective Groups. The simple alkyl groups are generally not very
useful for protection of alcohols as ethers. Although they can be introduced readily
by alkylation, subsequent cleavage requires strongly electrophilic reagents such as
boron tribromide (see Section 3.3). The t-butyl group is an exception and has found
some use as a hydroxy-protecting group. Owing to the stability of the t-butyl cation,
t-butyl ethers can be cleaved under moderately acidic conditions. Trifluoroacetic acid
in an inert solvent is frequently used. 168 t-Butyl ethers can also be cleaved by acetic
anhydride–FeCl in ether. 169 The t-butyl group is normally introduced by reaction of
3
the alcohol with isobutylene in the presence of an acid catalyst. 170 Acidic ion exchange
resins are effective catalysts. 171
H +
ROH + CH2 C(CH ) ROC(CH )
3 3
3 2
The triphenylmethyl (trityl, abbreviated Tr) group is removed under even milder
conditions than the t-butyl group and is an important hydroxy-protecting group,
especially in carbohydrate chemistry. 172 This group is introduced by reaction of the
alcohol with triphenylmethyl chloride via an S 1 substitution. Owing to their steric
N
bulk, triarylmethyl groups are usually introduced only at primary hydroxy groups.
Reactions at secondary hydroxy groups can be achieved using stronger organic bases
such as DBU. 173 Hot aqueous acetic acid suffices to remove the trityl group. The
ease of removal can be increased by addition of ERG substituents. The p-methoxy

(PMTr) and p,p -dimethoxy (DMTr) derivatives are used in this way. 174 Trityl groups
can also be removed oxidatively using Ce NH NO (CAN) on silica. 175 This
3 6
3 3
method involves a single-electron oxidation and, as expected, the rate of reaction is
DMTr > PMTr > Tr. The DMTr group is especially important in the protection of
primary hydroxy groups in nucleotide synthesis (see Section 13.3.2).
The benzyl group can serve as a hydroxy-protecting group if acidic conditions
for ether cleavage cannot be tolerated. The benzyl C−O bond is cleaved by catalytic
hydrogenolysis, 176 or by electron-transfer reduction using sodium in liquid ammonia or

167 W.-C. Chen, M. D. Vera, and M. M. Joullie, Tetrahedron Lett., 38, 4025 (1997).
168
H. C. Beyerman and G. J. Heiszwolf, J. Chem. Soc., 755 (1963).
169 B. Ganem and V. R. Small, Jr., J. Org. Chem., 39, 3728 (1974).
170 J. L. Holcombe and T. Livinghouse, J. Org. Chem., 51, 111 (1986).
171
A. Alexakis, M. Gardette, and S. Colin, Tetrahedron Lett., 29, 2951 (1988).
172 O. Hernandez, S. K. Chaudhary, R. H. Cox, and J. Porter, Tetrahedron Lett., 22, 1491 (1981);
S. K. Chaudhary and O. Hernandez, Tetrahedron Lett., 20, 95 (1979).
173
S. Colin-Messager, J.-P. Girard, and J.-C. Rossi, Tetrahedron Lett., 33, 2689 (1992).
174 M. Smith, D. H. Rammler, I. H. Goldberg, and H. G. Khorana, J. Am. Chem. Soc., 84, 430 (1962).
175 J. R. Hwu, M. L. Jain, F.-Y. Tsai, S.-C. Tsay, A. Balakumar, and G. H. Hakimelahi, J. Org. Chem., 65,
5077 (2000).
176
W. H. Hartung and R. Simonoff, Org. React., 7, 263 (1953).