Amines reaction with pyridine-sulfur trioxide

One of the first compounds to be introduced to the clinic, aztreonam (40-9), has been produced by total synthesis. Constmction of the chiral azetidone starts with amide formation of L-threonine (40-1) via its acid chloride treatment with ammonia leads to the corresponding amide (40-2). The primary amino group in that product is then protected as its carbobenzyloxy derivative (40-3). Reaction of that product with methanesulfonyl chloride affords the mesylate (40-4). Treatment of that intermediate with the pyridine sulfur trioxide complex leads to the formation of the A -sulfonated amide (40-5). Potassium bicarbonate is sufficiently basic to ionize the very acidic proton on the amide the resulting anion then displaces the adjacent mesylate to form the desired azetidone the product is isolated as its tetrabutyl ammonium salt (40-6). Catalytic hydrogenation over palladium removes the carbobenzyloxy protecting group to afford the free primary amine (40-7). The... 

The use of sulfur trioxide as a sulfonating agent is often inconvenient, and reactions carried out with it are usually vigorous and difficult to control. The addition compounds-that sulfur trioxide forms with tertiary amines and other strong electron donors, however, have been found to be very convenient sulfonating agents. Procedures for the preparation of three typical compounds, pyridine-sulfur trioxide, CsHsN-SOa dimethylaniline-sulfur trioxide, CeHs-N(CH3)2 SOs and dioxane-sulfur trioxide, 0(CH2 CH2)20 -SO3, are presented here. 

Pyridine 23 (two equivalents) reacts with chlorosulfonic acid in an inert organic solvent, e.g. carbon tetrachloride, to yield equimolar quantities of the pyridine-sulfur trioxide complex and pyridinium chloride this behaviour is typical of the reaction of a tertiary amine with the reagent (see Chapter 4, p 101). The potentiometric curve for the neutralization of chlorosulfonic acid by pyridine in nitromethane has been determined and showed two steps. Pyridine 1-oxonium chloride similarly yields the pyridine-sulfur trioxide adduct on treatment with chlorosulfonic acid. ... 

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