Page 259 - Advanced Organic Chemistry Part B - Reactions & Synthesis

The Mitsunobu conditions can be used for alkylation of 2-pyridones, as in the course 231
of synthesis of analogs of the antitumor agent camptothecin.
SECTION 3.2
CH
CH 3 3 Introduction of
N O N N Functional Groups by
N H O Nucleophilic Substitution
3
N O Ph P O CH at Saturated Carbon
O CH OH + 2 N O
2
O DEAD
O N I C H OH O N I O
2 5
OH
C H 5
2
Ref. 66
Proline analogs can be obtained by cyclization of -hydroxyalkylamino acid
carbamates.
PPh Ph
C H 3
HO NHCO 2 2 5 N CO C H
2 2 5
Ph CO C H DEAD
2 2 5
CO C H Ref. 67
2 2 5
Mitsunobu conditions are effective for glycosylation of weak nitrogen nucleophiles,
such as indoles. This reaction has been used in the synthesis of antitumor compounds.
CH 3
CH 3
O N O
O N O
PhCH 2 O + Ph 3 P
PhCH 2 O
N N
iPrO 2 CN NCO 2 i Pr N N
O
H CO 2 C(CH 3 ) 3 PhCH 2 OCH 2
CO 2 C(CH 3 ) 3
O OH
PhCH 2 OCH 2 OCH 2 Ph
PhCH 2 O
OCH 2 Ph
PhCH 2 O
Ref. 68
Azides are useful intermediates for synthesis of various nitrogen-containing
compounds. They can also be easily reduced to primary amines and undergo cycload-
dition reactions, as is discussed in Section 6.2. Azido groups are usually introduced
into aliphatic compounds by nucleophilic substitution. 69 The most reliable procedures
70
71
involve heating an appropriate halide with sodium azide in DMSO or DMF. Alkyl
azides can also be prepared by reaction in high-boiling alcohols. 72
CH CH (OCH CH ) OH
2
2 2
3
2
CH (CH ) CH I + NaN 3 CH (CH ) CH N
3
2
2 3
3
2 3
2 3
O
H 2 84%
66 F. G. Fang, D. D. Bankston, E. M. Huie, M. R. Johnson, M.-C. Kang, C. S. LeHoullier, G. C. Lewis,
T. C. Lovelace, M. W. Lowery, D. L. McDougald, C. A. Meerholz, J. J. Partridge, M. J. Sharp, and
S. Xie, Tetrahedron, 53, 10953 (1997).
67
J. van Betsbrugge, D. Tourwe, B. Kaptein, H. Kierkals, and R. Broxterman, Tetrahedron, 53, 9233
(1997).
68 M. Ohkubo, T. Nishimura, H. Jona, T. Honma, S. Ito, and H. Morishima, Tetrahedron, 53, 5937 (1997).
69 M. E. C. Biffin, J. Miller, and D. B. Paul, in The Chemistry of the Azido Group, S. Patai, ed., Interscience,
New York, 1971, Chap. 2.
70
R. Goutarel, A. Cave, L. Tan, and M. Leboeuf, Bull. Soc. Chim. France, 646 (1962).
71 E. J. Reist, R. R. Spencer, B. R. Baker, and L. Goodman, Chem. Ind. (London), 1794 (1962).
72
E. Lieber, T. S. Chao, and C. N. R. Rao, J. Org. Chem., 22, 238 (1957); H. Lehmkuhl, F. Rabet, and
K. Hauschild, Synthesis, 184 (1977).