In principle, the acid-catalyzed cyclodehydration of amino alcohols is an attractive way to make saturated nitrogen heterocycles since it avoids having to make the alcohol into a leaving group such as a halide or sulfonate. And acid is cheap.
Unfortunately, this reaction doesn’t work well for underivatized amines because the amine is converted to a non-nucleophilic ammonium salt.
Enter the Mitsunobu reaction, which works quite well with simple amino alcohols (despite their low pKa) as well as their derivatives (amides, sulfonamides, etc.) The literature is filled with examples of such intramolecular Mitsunobu reactions.
However, if you play your cards right, acid-catalyzed cyclodehydrations can be practical and even preferred over the Mitsunobu method. The rule of thumb is that the alcohol should be able to form a reasonable carbocation. Park and co-workers recently published a nice example that compares these two methods in the context of 2,3-disubstituted indoline synthesis.
An attempted Mitsunobu reaction on the amido alcohol shown gave the indoline in low yield; the major product was elimination of water. Resorting to aqueous HCl in dioxane afforded the desired indolines in good yield with a small amount of elimination. Inversion at the secondary alcohol was observed. Substrates with a secondary benzylic or allylic alcohol worked, whereas those with a secondary alcohol (or an electron-poor benzylic alcohol) failed.
The authors propose a rather implausible nitrogen-complexed cation intermediate and don’t speculate on the why acid catalysis beats the Mitsunobu reaction. I suspect it’s related to leaving group ability and subtleties wherein the amide carbonyl oxygen is involved in a balancing act between assisting the departure of the leaving group by neighboring group participation (for hydronium ion) and acting as an internal acceptor of the benzylic proton in an E2-like mechanism (for oxyphosphonium ion). Your thoughts?
The starting materials were made by a diastero- and enantioselective reaction of the sparteine-complexed dianion shown below. While the authors don’t show it this way, I’ve taken the liberty of drawing the organolithium as internally complexed. It is believed that the benzylic organolithium equilibrates to the most stable diasteromeric sparteine complex, which then reacts with inversion of configuration with aldehydes to give the desired secondary alcohols in good yield with high er and dr. As a reminder, most configurationally stable organolithiums react with retention of configuration, but it’s not a certainty; there are numerous examples where inversion is observed.
In summary, if your alcohol is reasonably capable of ionization, the acid-catalyzed method is worth a shot. Otherwise, the Mitsunobu is generally a nice way to make saturated nitrogen heterocycles. Of course, classic chemistry involving halides and sulfonates is also viable if you don’t mind the extra work.