Page 298 - Advanced Organic Chemistry Part B - Reactions & Synthesis

270 reason, only amides that can be removed under mild conditions are useful as amino-
protecting groups. Phthalimides, which are used to protect primary amino groups,
CHAPTER 3 can be cleaved by treatment with hydrazine, as in the Gabriel synthesis of amines
Functional Group (see Section 3.2.4). This reaction proceeds by initial nucleophilic addition at an imide
Interconversion
by Substitution, carbonyl, followed by an intramolecular acyl transfer.
Including Protection and
Deprotection O O
HN
RN + NH NH 2 RNH 2 +
2
HN
O
O
A similar sequence that takes place under milder conditions uses 4-nitrophthalimides as
the protecting group and N-methylhydrazine for deprotection. 234 Reduction by NaBH 4
in aqueous ethanol is an alternative method for deprotection of phthalimides. This
reaction involves formation of an o-(hydroxymethyl)benzamide in the reduction step.
Intramolecular displacement of the amino group follows. 235
O H
– OH CH O – CH 2 OH
BH 4 BH O + H NR
NR NR 4 2
CNHR CNHR
O O O
O O
Owing to the strong EWG effect of the trifluoromethyl group, trifluoroacetamides
are subject to hydrolysis under mild conditions. This has permitted trifluoroacetyl
groups to be used as amino-protecting groups in some situations. For example, the
amino group was protected by trifluoroacetylation during BBr demethylation of 2.
3
O
H N CCHN H N
2
2
CH O 1) (CF CO) O HO F 3 NaOH HO
3
2
3
2) BBr 3 H O
2
2
Ref. 236
Amides can also be deacylated by partial reduction. If the reduction proceeds only
to the carbinolamine stage, hydrolysis can liberate the deprotected amine. Trichloroac-
etamides are readily cleaved by sodium borohydride in alcohols by this mechanism. 237
Benzamides, and probably other simple amides, can be removed by careful partial
reduction with diisobutylaluminum hydride (see Section 5.3.1.1). 238

O OAlR 2
R AlH H +
2
R NCPh R NCPh R NH + PhCH O
2
2
2
H O
2
H
234 H. Tsubouchi, K. Tsuji, and H. Ishikawa, Synlett, 63 (1994).
235
J. O. Osborn, M. G. Martin, and B. Ganem, Tetrahedron Lett., 25, 2093 (1984).
236
Y.-P. Pang and A. P. Kozikowski, J. Org. Chem., 56, 4499 (1991).
237 F. Weygand and E. Frauendorfer, Chem. Ber., 103, 2437 (1970).
238
J. Gutzwiller and M. Uskokovic, J. Am. Chem. Soc., 92, 204 (1970); K. Psotta and A. Wiechers,
Tetrahedron, 35, 255 (1979).