Green chem.: electrochemical synthesis of ketene by decarboxylation coupling reaction

Ketene amine is an important target molecule existing in natural products, materials science and pharmaceutical preparations They are also used to synthesize heterocyclic and pharmaceutical compounds and ligands for transition metal catalysis Therefore, the development of efficient conversion of simple and easily available raw materials for the preparation of ketene amine has attracted widespread attention Recently, researchers have reported a novel Cui catalyzed decarboxylation coupling of α - ketoacids with scheme 1a and scheme 1b to synthesize enaminones However, α - ketoacids are limited to aromatic oxocarboxylic acids Recently, Wang and Hu team reported that strong Lewis acid (BF 3 · OET 2) catalyzes the cyclization of 1-iododeyne and α - ketoacid in series amine mediated ring opening reaction to directly synthesize enaminone However, it is still necessary to synthesize functionalized ketene in metal free and mild conditions to facilitate its application in drug synthesis Recently, Professor Xu Bo of Donghua University and researcher Chen Qianjin reported the environmentally friendly electrocatalytic decarboxylation of vinyl azide and α - ketoacid, and synthesized a series of enaminone derivatives There is no need for chemical oxidant, metal catalyst and additional supporting electrolyte In addition, the anode (graphite felt) used is relatively cheap and can be reused Relevant research results were published in green chem (DOI: 10.1039/c9gc01098j) (source: Green chem.) at the beginning of the study, the author optimized the reaction conditions with α - toluenyl vinyl azide (1a) and α - ketoacid (2a) as model substrates (Table 1) Using NH4I as the medium and MeCN as the solvent, different electrode materials were first investigated at 3.0 Ma and 50 ℃, and it was found that the target product (table S1) was obtained in 19% yield with carbon as anode and platinum as cathode After that, the author screened the reaction medium, solvent, temperature and the ratio of substrate, and finally determined that the best reaction conditions were as follows: 5% n-bu4ni as the redox medium, 10:1 CH3CN and H 2O as the mixed solvent, substrate 1a and 2A were electrolyzed in a constant current of 3.0 Ma at 40 ℃, and the required product 3A could be obtained in 89% yield (source: Green chem.) under the optimal reaction conditions, the author first investigated the application range of vinyl azide in electrochemical acylation (Table 2) The phenylvinyl azide with different electrical substituents (e.g halogen, cyano, ester, etc.; electron donor: methyl) in o-p-linkage was synthesized in good yield (49-89%) to obtain the corresponding ketene product (3a-3t) It is important that heterocyclic derivatives (pyridine, thiophene, pyrimidine) can form corresponding products (3U - 3W) in good yield (69-78%) On the other hand, alkyl vinyl azides do not produce the desired product (3x) (source: Green chem.) next, the author studied the substrate range of α - oxocarboxylic acid (Table 3) All kinds of α - oxocarboxylic acids with different substituents on the benzene ring can be tolerated, and the desired product (3AB - 3AK) can be successfully obtained with a yield of 65-83% In addition, aliphatic α - ketoacids with linear and cyclic alkyl groups are also suitable substrates, although the yield of the product (3Al - 3an) is low (source: Green chem.) in addition, α - (biaryl-2-yl) vinyl azide can also react with a variety of α - oxocarboxylic acids, and the corresponding aza condensed ring aromatic hydrocarbons (3ao-3at) can be obtained in good yield, which further confirms the universality of the electrochemical method (Table 4) (source: Green chem.) in order to prove the practicability of this method, the author reacted 1a and 2a of 10 mmol scale at a constant current of 5 mA, and obtained 1.81 g final product (scheme2) in 81% yield In addition, the author further proved that the product of ketene can be transformed into a variety of important skeletons (scheme 3) (source: Green chem.) based on the control experiments and previous literature reports, the author proposed a reasonable mechanism of electrochemical acylation (scheme 5) The control experiment shows that the anion of 2A (2a ') is the key intermediate, and it is easy to form 2A' in the cathode, at the same time, it consumes protons to produce H2 I 2 can be produced by the anodization of iodine ion, which reacts with α - keto carboxylate anion (2a ') to form acyl hypoiodate and iodine ion Then, the free radicals of iodine and aryloxy were obtained by electrolysis Acyloxy radical is decarboxylated to produce acyloxy radical C, which is added with vinyl azide to release N 2 to form intermediate D Finally, intermediate f protonated to form final compound 3a (source: Green chem.) in a word, the author reported an environmentally friendly method of electrocatalytic synthesis of ketene without the participation of transition metals Chemical oxidants and additional supporting electrolytes are not needed in this electrolysis process It is expected that the electrochemical method can provide a favorable way for the direct and rapid synthesis of related pharmacophores under mild conditions.