Palladium(II)‐Catalysed Aminocarbonylation of Terminal Alkynes for the Synthesis of 2‐Ynamides: Addressing the Challenges of Solvents and Gas Mixtures

Abstract 2‐Ynamides can be synthesised through PdII catalysed oxidative carbonylation, utilising low catalyst loadings. A variety of alkynes and amines can be used to afford 2‐ynamides in high yields, whilst overcoming the drawbacks associated with previous oxidative methods, which rely on dangerous solvents and gas mixtures. The use of [NBu4]I allows the utilisation of the industrially recommended solvent ethyl acetate. O2 can be used as the terminal oxidant, and the catalyst can operate under safer conditions with low O2 concentrations.


General Information
Unless otherwise stated, all reagents were purchased from Sigma-Aldrich and used without further purification. The following chemicals were purchased from The GC yield of products and conversion of alkyne were determined by using an internal standard (biphenyl). The response factor (R f ) of an analyte was determined by analysing known quantities of internal standard (biphenyl) against known quantities of substrate and product according to the following equation: The quantity of an analyte was then determined by the following equation:

Safety Considerations
Catalytic oxidative carbonylations should be carried out by trained personnel, with suitable safety measures and utilizing appropriate equipment. Suitable precautions should be taken by those wishing to reproduce or extend this type of work.
In these studies, high pressure O 2 gas mixtures (air and 8% O 2 ) are employed with organic solvents and CO. We use pressures which are significantly below the pressure ratings of the vessels, and vessels are equipped with safety relief valves (set to release pressure at 100 bar). Carbon monoxide is a flammable and highly toxic gas. The CO cylinder was stored in a ventilated cylinder cupboard adjacent to the fume hood. A CO monitor / alarm was used in order to detect any leaks.
Pressurized tubing and reactors were all vented in the fume hood.

General notes
Pd(OAc) 2 which was ≥99.9% trace metal basis purity (from Sigma Aldrich) was used and it was found that lower grades of Pd(OAc) 2 led to reduced yields. (See Table 1 in paper for more information) Pd(OAc) 2 was added to the reactions via stock solution. Stock solutions were kept for a maximum of three days.
Reactions were all carried out in pressure vessels which were heated and stirred on a hotplate stirrer. Reactions were carried out in glass liners and stirred using Teflon coated magnetic stirrer bars. If reactions were carried out without using a glass liner, it was found that the Hastelloy C276 reactor body caused a dramatic reduction in the yield of product produced (and selectivity).

General Method for Optimisation of Catalytic System
Reactions were performed in 45 mL high-pressure reactors made of hastelloy and the reaction mixture was placed in a glass liner, equipped with a magnetic stirrer.
To the glass liner, tetrabutylammonium iodide (2.5 mol%, 0.05 mmol, 0.0185 g) and Pd(OAc) 2 (0.2 mol%, 0.004 mmol, 0.0009 g) from a stock solution in ethyl acetate (4 mL) were added. This was followed by the addition of alkyne (2 mmol) and amine (4 mmol). The glass liner was placed in a reactor and then pressurized with 5 bar of carbon monoxide gas, followed by O 2 :N 2 (8:92) to give a total reaction pressure of 35 bar. The reactor was then stirred on a pre-heated heating block at 80 °C for six hours. Once the reaction was complete, the reactor was cooled in an ice bath and slowly depressurised in a fume hood. Internal standard (biphenyl) (~0.2 g) was added, and the glass liner magnetically stirred for 1 minute to ensure all standard was fully dissolved. A sample was then prepared for GC analysis by filtration through a silica plug with diethyl ether to remove any catalyst components.
The sample was then submitted for GC analysis.

General Method for Preparation of Isolated Substrates
Procedure was the same as described above, however at the end of the reaction the reactor was cooled and depressurized, then poured into a separating funnel and brine added. The aqueous layer was then separated and back extracted with ethyl acetate twice. The combined organic layers were dried over magnesium sulphate, filtered and concentrated under reduced pressure. The product was purified by silica gel flash column chromatography, and the appropriate fractions combined and concentrated under reduced pressure. The product was then dried under high vacuum.