Classics in Organic Chemistry, Part XXVII

One of the key concepts students often struggle with when learning organic chemistry is understanding how different functional groups react with each other. Knowing which groups are inert to each other and the conditions under which transformations can be induced is second nature to experienced chemists, but this intuition takes time to develop. For instance, amines and carboxylic acids will generally react by an acid-base reaction, resulting in protonation of the amine. However, amines and aldehydes will react rather quickly. These will give imines, and this reaction can be utilized to synthesize more substituted amines from less-substituted ones (this process is called reductive amination).

This same logic generally means that compounds with 2 or more functional groups that will react with each other will not be very stable. For example, you can’t have a molecule with acid chloride and amine functionalities unless they are somehow prevented from reacting each other (e.g. geometry, sterics, or by quaternizing the amine). And so, when I found this paper (DOI below)…my mind was blown. This is about the isolation of molecules with unprotected amines and aldehyde functionalities (amino aldehydes), and the trick is to make the amine an aziridine, which is a 3-membered ring, the nitrogen counterpart of epoxides.

Aziridines are not as commonly encountered in organic chemistry compared to their oxygen counterparts – most undergrad organic chemistry courses will give 0 coverage of aziridines. However, if you’re an organic chemist trying to see what to research next, these are exactly the kind of understudied areas to look into. And that’s what Prof. Andrei Yudin did! I should also specially mention Prof. Yudin here since he and I are alumni of the same research group at USC, although he preceded me by over a decade. While he was a PhD student Prof. Yudin did a lot of work towards the synthesis and uses of TMSCF₃.

Prof. Yudin and his student Ryan Hili took epoxy esters and converted them to aziridine aldehydes by simple reactions to see if these could be isolated at all:

The first reaction to convert the epoxide to an aziridine is a variation of the Staudinger reaction. The aziridine aldehyde of ethyl 3-phenylglycidate (above) ended up forming a homodimer (2a) which was a stable crystalline solid. But what is even more interesting is that even though the aldehyde functionality is not expressly present in the dimer, it is nonetheless there in a masked form and can be accessed selectively from the amine:

The aldehyde can be reduced to give an amino alcohol, or can undergo reductive amination, all independent of the aziridine. Prof. Yudin has published a lot more in this area (“amphoteric molecules”) – the utility of these types of molecules is that they allow you to build up molecular complexity very quickly and with minimal use of protecting groups. One can definitely see the influence of Prof. K. B. Sharpless, who was Prof. Yudin’s postdoc advisor – Prof. Yudin was working in Prof. Sharpless’ lab at the time he received the first Nobel Prize in 2001 for work in asymmetric oxidations, and that was also the time Prof. Sharpless was beginning his work in ‘Click Chemistry’, for which he later also received the Nobel Prize in 2022.

DOI: 10.1021/ja065898s