5.2 Copper-catalyzed dehydration of N-acyl α-amino aldoximes and
5.2.2 Copper-catalyzed dehydration of N-acyl α-amino aldoximes
To circumvent these issues, suitable reagents and reaction conditions had to be identified that would allow for a less waste intensive synthetic route towards Vildagliptin. It was decided to approach the synthesis of the key intermediate, the N-acyl pyrrolidine, via a two-step approach that started off from the N-acyl α-amino aldehyde. By condensation with hydroxylamine, one can obtain the corresponding aldoxime that can subsequently be dehydrated towards the nitrile. The big advantage of this route compared to the amide dehydration is the fact that aldoximes can quite elegantly be dehydrated in comparison to the amides. There are plenty of possibilities for aldoxime dehydration; however one must carefully evaluate the practicability and economic impact of each route.
From the broad selection of methods for nitrile synthesis out of aldehydes over aldoximes, some of the inventions in this field have focused on one-pot strategies to skip workup procedures. While some of these approaches seem attractive at first glance, one has to evaluate the economical impact and workload to prepare the required reagents for these one-pot procedures. For example, An et al. reported in 2015 that they can convert 40 examples of aldehydes directly into the nitriles by employing the reagent O-(4-CF3 -benzoyl)-hydroxylamine (CF3-BHA) and Brønsted acid catalysis at ambient conditions.[151]
However, they did not discuss that the synthesis of their reagent requires four steps to be synthesized! These steps included acyl chloride formation with toxic thionyl chloride or oxalyl chloride, extremely atom inefficient protection of hydroxylamine with
Di-tert-butyldicarbonat (Boc2O), coupling of both compounds and final deprotection of the amine group by trifluoroacetic acid (Scheme 44).[152] Furthermore, CF3-BHA is not recycled and has to be disposed as environmentally hazardous halogenated, organic waste. As a consequence, their proposed one-pot procedure for the nitrile synthesis is simply not practicable and is in reality not a one-pot procedure but rather a five step sequence.
Scheme 44: Waste intensive synthesis of the reagent CF3-BHA for the one-pot synthesis of nitriles out of aldehydes.[152]
While this example may seem drastic, the drawbacks of many reported one-pot procedures for the nitrile synthesis out of aldehydes are in the same range as the one discussed above, eliminating most approaches if environmental, cost and waste issues are considered.
Examples of such procedures include the utilization of hexamethyldisilazane (HMDS)[153], expensive derivatives of (2,2,6,6-tetramethylpiperidin-1-yl)oxyl (TEMPO) in stoichiometric amounts[154] or highly toxic ethyl dichlorophosphate.[155] Additionally, these procedures require excessive usage of Brønsted bases like DBU or pyridine.[154,155] Apart from one-pot procedures, many methods for the dehydration of oximes towards their nitriles have been disclosed. However, most of these methods lack the practicability like most of the one-pot procedures. For example, Denton et al. reported a method in 2012 that relies on activation of triphenylphosphine oxide (Ph3PO) by oxalyl chloride to dehydrate the aldoximes.[62]
While this protocol is broadly applicable, oxalyl chloride is a highly toxic and corrosive compound. Furthermore, triphenylphosphine oxide (Ph3PO) is a highly unwanted side product, which is also one of the biggest concerns with Wittig olefinations up to this day.
Another method reported by Hendrickson et al. in 1976 utilizes triflic anhydride, stoichiometric amounts of triethyl amine and operates at -78 °C to dehydrate the oximes.[156] This combination makes the method unattractive for further consideration.
There are plenty of different methods to obtain the corresponding nitriles from aldoximes and if one wishes to dwelve deeper into this matter, several book chapters and reviews regarding this matter are present in the literature.[57,58,157] Additionally, a vast amplitude for the preparation of oximes, also out of other compound classes (like amines or nitro compounds) exists.[91,97,158,159] The same is true for nitriles.[63,160]
After critical assessment of this vast amplitude of synthetic possibilities, it was decided to investigate a copper-catalyzed dehydration of aldoximes into nitriles in acetonitrile as reaction medium for the synthesis of the required N-acyl α-aminonitrile motif. In 1983, Attanasi et al. discovered that a wide variety of aliphatic and aromatic aldoximes was smoothly converted into their nitriles if they were treated with copper(II) acetate (Cu(OAc)2) in boiling acetonitrile.[161] In their study, they used 5-10 mol% of Cu(OAc)2 and obtained eight different nitriles with yields ranging from 85-98%. In 2013, Ma et al.
extended this method to a broader substrate scope screening and identifying the transformation of the aldoxime into the corresponding amide if no acetonitrile is present.[59]
Chiral N-Acyl-α-aminonitriles
Additionally, they demonstrated the high tolerance against other functional groups of this method and conducted a parameter screening.
To rationalize the mechanism of the aldoxime dehydration in acetonitrile, Tambara et Dan Pantoş conducted a more detailed mechanistic study in 2013, when they investigated the palladium-catalyzed dehydration of aldoximes into nitriles (Scheme 45). They proposed that the aldoxime is coordinated to the metal center via its nitrogen atom and after coordination of a nitrile molecule to the metal center, an in situ H2O transfer takes place to yield the former nitrile as the corresponding amide and the former aldoxime as the nitrile. In case of the absence of acetonitrile, the H2O transfer is conducted between the already desired nitrile product and the substrate, which in the long run ends with complete conversion towards the unwanted amide product. By adding acetonitrile in an excessive amount, the equilibrium for the in situ H2O transfer is drastically shifted towards the hydration of acetonitrile, yielding one equivalent of acetamide as side product.
Scheme 45: Proposed mechanism for the metal-catalyzed dehydration of aldoxime to nitriles in the presence of acetonitrile, reported by Tambara et Pantoş.[162]
Due to the high polarity and boiling point of acetamide, its separation from the nitrile products via distilliation or chromatography can be easily achieved. Additionally, acetamide can be recovered and reused since it is part of several industrial segments, e.g. as solvent or softener additive.
This method incorporates many aspects that allow for a less waste and hazard intensive approach to N-acyl α-aminonitriles and was hence chosen for further investigation. The side product can be reused, the utilized metal catalyst is very cheap and relatively low toxic, the utilized solvent can be recycled for further reaction cycles and the separation of the product from the catalyst and side product is easily conducted. Apart from the chosen method, a later reported method in 2016 from Hyodo et al. utilizes Fe(III) catalysts in boiling toluene to dehydrate the aldoximes towards the nitriles without the need for acetonitrile.[61] The authors stated that they were inspired by the mechanism of aldoxime dehydratases, which shows the high value and impact of aldoxime dehydratase catalysis even among synthetic chemists that are not familiar with biocatalysis. A slight drawback of their method is, however, the rather low maximum substrate concentration of 50 mM to circumvent the amide formation, high temperature (refluxing toluene) and long reaction time of 24 hours.