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Monday, December 27, 2004
Douglass Taber
University of Delaware

Advances in Nitrogen Protection and Deprotection

Nitrogen has a central role in medicinally-oriented organic synthesis. As it may not be convenient to carry an unprotected amine through several steps of a synthesis, N protection and deprotection becomes important.

The hydrolysis of a hindered amide can often be difficult. V. Bavetsias of the Cancer Research UK Laboratory in Surrey reports (Tetrahedron Lett. 2004, 45, 5643. ) that methanolic Fe(NO3)3 . 9 H2O will smoothly hydrolyze pivalamides such as 1 at room temperature. If this proves to be a general procedure for hindered amides, it will be a welcome addition to the armamentarium of organic synthesis.

Usually, amides 7 are prepared from acids 6 and amines. C. Gürtler of Bayer MaterialScience AG in Leverkusen reports (Tetrahedron Lett. 2004, 45, 2515. ) the development of catalysts for the alternative condensation of an acid 6 with an isocyanate 4. It is particularly exciting that isocyanates are intermediates in the one-carbon degradation of an acid 3 to the corresponding amine. Current practice, if the protected amine were desired, is that the intermediate isocyanate 4 would be trapped with an alcohol, leading to the urethane 5. This newly-reported observation offers the alternative of ending with the amide 7, or perhaps with the sulfonamide 9.

For amine protection, sulfonamides such as 9 offer several advantages over urethanes 5 or amides 7. In particular, secondary amines protected as the urethane or the amide exist as mixtures of rotational isomers, confusing NMR characterization and making crystallization more difficult. The limitation has been that sulfonamides have been difficult to remove. Masanobu Uchiyama of the University of Tokyo reports (J. Am. Chem. Soc. 2004, 126, 8755. ) the development of transition metal ate complexes that catalyze electron-transfer reduction. While the sulfonamide 10 is inert to Mg in THF, inclusion of a catalytic amount of the ate complex 11 led to 12 in quantitative yield.

D. F. Taber, Org. Chem. Highlights 2004, December 27.