Process Development of the Copper(II)‐Catalyzed Dehydration of a Chiral Aldoxime and Rational Selection of the Co‐Substrate

Abstract The access towards chiral nitriles remains crucial in the synthesis of several pharmaceuticals. One approach is based on metal‐catalyzed dehydration of chiral aldoximes, which are generated from chiral pool‐derived aldehydes as substrates, and the use of a cheap and readily available nitrile as co‐substrate and water acceptor. Dehydration of N‐acyl α‐amino aldoximes such as N‐Boc‐l‐prolinal oxime catalyzed by copper(II) acetate provides access to the corresponding N‐acyl α‐amino nitriles, which are substructures of the pharmaceuticals Vildagliptin and Saxagliptin. In this work, a detailed investigation of the formation of the amide as a by‐product at higher substrate loadings is performed. The amide formation depends on the electronic properties of the nitrile co‐substrate. We could identify an acceptor nitrile which completely suppressed amide formation at high substrate loadings of 0.5 m even when being used with only 2 equivalents. In detail, utilization of trichloroacetonitrile as such an acceptor nitrile enabled the synthesis of N‐Boc‐cyanopyrrolidine in a high yield of 92 % and with full retention of the absolute configuration.


Analytical Data
Chemical were purchased from TCI Chemicals, Fluorochem, Sigma Aldrich and VWR Chemicals and were used without further purification.
NMR-spectra were recorded on a Bruker Avance III at a frequency of 500 MHz ( 1 H) or 126 MHz ( 13 C). The chemical shift δ is given in ppm and referenced to the solvent signal of deuterized Chloroform. Coupling constants (J) were given in hertz.
Nano-ESI mass spectra were recorded using an Esquire 3000 ion trap mass spectrometer from Bruker Daltonik GmbH equipped with a nano-ESI source. Samples were induced by static nano-ESI using inhouse pulled glass emitters. Nitrogen served as nebulizer and dry gas.
Helium was used as cooling gas for the ion trap. The mass axis was externally calibrated with the ESI-L Tuning Mix from Agilent Technologies. The spectra were recorded by accumulation and averaging of every single spectra using Bruker Daltonik esquireNT 5.2. esquireControl software. For processing of the spectra, DataAnalysis software 3.4 was used.
Conversions were determined by GC measurements using a GC-2010 Plus from Shimadzu in comparison to GC-areas . Following methods were used.

General Procedure 2 (GP2): Synthesis of amides
The synthesis was done according to Sharma et al. [4] Copper(II) acetate (

4-Chlorobenzamide
The synthesis was done according to GP2 using copper(II) acetate (

4-(N,N-Dimethylamino)benzamide
The synthesis was done according to GP2 using copper(II) acetate (1. The 1 H-NMR spectroscopic data are in accordance with the literature. [

Investigation of copper-catalyzed dehydration of 4-substitued benzaldoximes
Copper(II) acetate (2 mol%) and acetonitrile (10 eq.) were added to a solution of 4-substituted benzaldoxime (1.0 eq., 150 mg) in ethyl acetate (total substrate loading of 0.5 M). The solution was heated to 70 °C and stirred for 4 h. An aliquot (50 µL) was taken and analyzed via 1 H-NMR spectroscopy. The conversions and σ p -values were shown in Table 6.