Page 258 - Advanced Organic Chemistry Part B - Reactions & Synthesis

230 The enhanced acidity of the NH group in phthalimide permits formation of the anion,
which is readily alkylated by alkyl halides or tosylates. The amine can then be liberated
CHAPTER 3
by reaction of the substituted phthalimide with hydrazine.
Functional Group
Interconversion
by Substitution, Br phthal NH 2
Including Protection and NH 2 NH 2 HCl HO 2 CCHCH 2 CHCO 2 H
Deprotection CH 3 O 2 CCHCH 2 CHCO 2 CH 3 CH 3 O 2 CCHCH 2 CHCO 2 CH 3 H 2 O
CH 3 OH
Br phthal NH 2
phthal phthalimido
Ref. 60

It has been found that the deprotection phase of the Gabriel synthesis is accelerated
by inclusion of NaOH. 61
Secondary amides can be alkylated on nitrogen by using sodium hydride for
deprotonation, followed by reaction with an alkyl halide. 62

O 1) NaH, O
benzene
NH NCH
2) CH I 3
3
Neutral tertiary and secondary amides react with very reactive alkylating agents,
such as triethyloxonium tetrafluoroborate, to give O-alkylation. 63 The same reaction
occurs, but more slowly, with tosylates and dimethyl sulfate. Neutralization of the
resulting salt provides iminoethers.

O OCH 3
2
1) (CH 3 O) SO 2
RCNHR′ RC
–
2) OH
NR′
Sulfonamides are relatively acidic and their anions can serve as nitrogen nucle-
ophiles. 64 Sulfonamido groups can be introduced at benzylic positions with a high
level of inversion under Mitsunobu conditions. 65
TsNCH CH(OCH )
OH 2 3 2
DEAD, PPh OCH Ph
OCH Ph 3 2
2
TsNHCH CH(OCH )
3 2
2
CH 3 OCH Ph CH 3 OCH 2 Ph
2
OCH 3 OCH 3
60 J. C. Sheehan and W. A. Bolhofer, J. Am. Chem. Soc., 72, 2786 (1950).
61 A. Ariffin, M. N. Khan, L. C. Lan, F. Y. May, and C. S. Yun, Synth. Commun., 34, 4439 (2004);
M. N. Khan, J. Org. Chem., 61, 8063 (1996).
62
W. S. Fones, J. Org. Chem., 14, 1099 (1949); R. M. Moriarty, J. Org. Chem., 29, 2748 (1964).
63 L. Weintraub, S. R. Oles, and N. Kalish, J. Org. Chem., 33, 1679 (1968); H. Meerwein, E. Battenberg,
H. Gold, E. Pfeil, and G. Willfang, J. Prakt. Chem., 154, 83 (1939).
64 D. Papaioannou, C. Athanassopoulos, V. Magafa, N. Karamanos, G. Stavropoulos, A Napoli, G. Sindona,
D. W. Aksnes, and G. W. Francis, Acta Chem. Scand., 48, 324 (1994).
65
T. S. Kaufman, Tetrahedron Lett., 37, 5329 (1996).