When looking for a mild synthetic method which could interconvert an alcohol functional group into a nitrile I came across this 2014 paper by Jean-Michel Vatèle published in Synlett. Vatèle has previously published some interesting papers using 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) with a co-oxidant such as a practical one-pot procedure for the oxidation/olefination of primary alcohols using a TEMPO – Bis(acetoxy)iodobenzene (BIAB) system and stabilized phosphouous ylides.
There have been many publications describing the sequential oxidation-imination-aldimine oxidation of an alcohol to yield a nitrile. However, Vatèle’s metal free method uses cheap reagents and a simple reaction procedure which made it the most appealing of the methods that I looked into.
Vatèle had previously seen that a TEMPO/BIAB system can oxidise aldimines to nitriles and so wanted to investigate, if with the addition of an ammonium salt, the process could be extended to sequentially oxidise an alcohol to a nitrile. A small selection of solvents and ammonium salts were screened (table 1) using TEMPO (5 mol%) and BIAB (2.2 eq) as a co-oxidant. The conditions in entry 1 were chosen to investigate the scope of this reaction.
There were 22 alcohols subjected to these optimised reaction conditions and they all gave the desired product in >80% yields (summary in table 2). It was observed that in general alkyl alcohols were oxidised faster than benzyl alcohols (entries 1,2,3 vs 4,5). Acid sensitive groups such as TBS, Boc (entry 3), trityl and acetyl groups were stable under the reaction conditions. No racemisation was seen where chiral centres were present (entry 3) and electron withdrawing/donating groups on the aromatic ring had little effect on the oxidation (entry 4 and 5). There was no scrambling of cis or trans (entry 7) double bond geometry and chemoselectivity for a primary over a secondary alcohol was achieved (entry 8).
Table 2 Summary of products (table from Organic Chemistry Portal)
In addition to all of these examples we at the SDDC have used Vatèle’s conditions on a variety of 5 and 6-membered heterocyclic alcohols in which we generally isolated the corresponding nitriles in >80% yields. The only exception was when a quinone like motif was present and in this case a large volume of gas was produced and no starting material or product could be isolated.
In summary this is a very simple, cheap and general method for the oxidation of alcohols to nitriles. The reactions are relatively quick and high yielding. There is a simple work up and as there are minimal by-products the final product isolation is fairly simple. I would fully recommend giving these condition a try the next time you need to synthesise a nitrile.
Blog written by Lewis Pennicott