Ethyl chlorooxoacetate is a highly reactive acylating organic reagent commonly used in the fields of fine chemicals and pharmaceutical synthesis. Its molecular structure contains both acyl chloride and ester groups as active functional groups, giving it strong electrophilic reactivity. It serves as an important raw material for constructing ketone-ester structures and heterocyclic compounds in organic synthesis. In industrial and manufacturing applications, ethyl chlorooxoacetate is primarily used in the synthesis of pharmaceutical intermediates, particularly for the side-chain modification of β-lactam cephalosporin antibiotics. It is also frequently employed in the synthesis and processing of highly effective pesticide fungicides, herbicides, and various fine chemicals.

Pt-Catalyzed Direct C–H Acylation with Ethyl Chlorooxoacetate

α-Keto ester derivatives are important not only because they are present in many biologically and medicinally important organic molecules but also because α-keto esters are immediate precursors to other important organic compounds such as α-hydroxy acids and α-amino acids. α-Keto esters also have important applications in other organic synthesis including the synthesis of heterocycles. Introduction of an α-keto ester functional group is therefore of great importance, and various methods have been developed for this purpose. One of the most straightforward methods involves the use of readily accessible and inexpensive ethyl chlorooxoacetate that already possesses the α-keto ester functionality. There are two common ways to utilize this reagent. One involves the coupling of an organometallic reagent with ethyl chlorooxoacetate, but the drawback is that the commonly used organometallic reagents such as Grignard reagents are too reactive so the reaction has to be performed at very low temperatures or side products may be expected. The other is through the Friedel–Crafts acylation reaction of arenes with ethyl chlorooxoacetate. This method suffers from a limited substrate scope because of issues of reactivity and selectivity associated with Friedel–Crafts acylation and the use of excess amounts of strong Lewis acids. A potentially more attractive method is the transition metal-catalyzed C–H acylation reaction with ethyl chlorooxoacetate as the acylating reagent. However, so far, there has been no report of such a transition metal-catalyzed C–H acylation reaction to synthesize α-keto esters.[1]

The challenge with using ethyl chlorooxoacetate in the transition metal-catalyzed C–H acylation reaction or cross coupling is probably the decarbonylation side reaction. In fact, decarbonylation is so common that it has been frequently exploited in metal-catalyzed decarbonylative coupling reactions. For example, in an attempt to synthesize α-keto esters through Pd-catalyzed acylation with ethyl glyoxylate as the acylating reagent and tert-butyl hydrogen peroxide as the oxidant, the desired product was not formed, but interestingly, the decarbonylative product was formed exclusively. Herein, we report a highly efficient method to introduce an α-keto ester functional group to 2-aryloxypyridines through platinum-catalyzed direct C–H functionalization with ethyl chlorooxoacetate. It should be noted that aryl heteroaryl ethers are frequently found in biologically active compounds. There has been considerable interest in modifying aryl heteroaryl ethers through transition metal-catalyzed C–H functionalization reactions, where the heteroaryl also serves as the directing group.

Platinum-catalyzed selective C–H acylation of 2-aryloxypyridines with ethyl chlorooxoacetate provides an efficient way of introducing an α-keto ester functional group. The reaction is oxidant-free, additive-free, and, more significantly, free of any decarbonylative side reactions. The reaction tolerates a variety of substituents from strongly electron-donating to strongly electron-withdrawing groups. Double acylation is feasible for 2-phenoxypyridine and its derivatives with only one substituent at the para position. Although the reaction of 2-(2-methylphenoxy)pyridine with ethyl malonyl chloride did not produce the desired β-keto ester, the reaction with ethyl succinyl chloride proceeded smoothly to give the γ-keto ester. Ethyl chlorooxoacetate is much more reactive than ethyl succinyl chloride in this Pt-catalyzed C–H acylation reaction.

References

[1]Javed E, Guthrie JD, Neu J, Chirayath GS, Huo S. Introducing an α-Keto Ester Functional Group through Pt-Catalyzed Direct C-H Acylation with Ethyl Chlorooxoacetate. ACS Omega. 2020 Apr 3;5(14):8393-8402. doi: 10.1021/acsomega.0c00982. PMID: 32309750; PMCID: PMC7161214.