Angelw: decarboxylation coupling reaction of alkenylborate, halogenated compound and carboxylic acid

In organic synthesis, it is the pursuit of chemists to transform bulk chemicals into products with more complex structure and higher added value Among them, multicomponent reaction is one of the methods to achieve this goal In multicomponent reactions, there are often three or more substrates involved in the reaction, so the construction of complex molecules can be realized quickly The three-component coupling reaction of C-C π bond is a three-component coupling reaction (scheme 1a) based on the traditional coupling reaction, which can be realized by introducing intermediate coupling reagent Although chemists have made a series of progress in this field, these methods rely heavily on organometallic reagents, and require pre functionalized raw materials and precious metal catalysts Carboxylic acid, as a large number of existing chemicals, is often used as a nucleophilic coupling agent to participate in traditional coupling reactions in recent years Especially the recently developed "metal photocatalyst" catalyzed reactions, in which carboxylic acids can produce alkyl radicals through the single electron transfer mediated decarboxylation process, and can participate in the subsequent Ni catalyzed coupling reactions Although this kind of reaction has been widely used, there are few reports about the application of this kind of reaction in the three-component coupling reaction involving olefins Up to now, the three-component coupling reaction of "metal photocatalyst" is limited to the use of activated substrates, such as oxalate or alkylsilicates, which need to be synthesized now, increasing the reaction steps Therefore, it is of great significance to develop similar reactions in which carboxylic acids are directly involved Recently, varinder K Aggarwal group of the University of Bristol reported the photocatalytic decarboxylation of carboxylic acid and alkenylborate In this reaction, the production of A-B radical 3 is the key to the whole reaction Then, the team proposed to combine the generated α - boron radicals with the Ni catalyzed coupling reaction, and realized the three-component decarboxylation coupling reaction participated by the "metal photocatalyst", which realized the rapid construction of molecular complexity At the same time, the resulting carboxylate can be used for further conversion (scheme 1a) The related research results were published in angelw Chem Int ed (DOI: 10.1002/anie.201916340) (source: angelw Chem Int ed.) the author envisions the following reaction process (scheme 2): first, the photosensitizer is activated to the excited state under light, and a single electron mediated decarboxylation process occurs with carboxylic acid substrate, producing α - aminoalkyl radical 8; then 8 is added with alkenyl radical to generate α - boron radical 3; on the other hand, zero valent Ni After the addition of aryl halides, Ni intermediate 9 was formed, and α - boron radical 3 was trapped and then reduced to the target product The monovalent Ni produced can be regenerated to zero valent Ni active catalyst under the action of photosensitizer In this process, two challenging steps need to be regulated: 1) the addition rate of free radical 8 to alkenylborate is faster than that of divalent Ni intermediate 9; 2) the addition rate of α - boron free radical 3 to divalent Ni intermediate 9 is faster than that of photosensitizer reduction (source: angelw Chem Int ed.) firstly, the author used proline 1a, alkenylborate 2a and 4-fluoroiodobenzene 10A protected by BOC as template substrates to optimize the conditions (Table 1) By optimizing the conditions of alkenylborate ester, aryl halide and solvent, the author determined the optimal reaction conditions as follows: NiCl2 · dtbbpy as metal catalyst 4czipn was used as photosensitizer, caesium carbonate as base and DMA as solvent The substrate reacted under blue light for 16 h, and the final yield was 79% (source: angelw Chem Int ed.) determined the optimal reaction conditions, and then the author expanded the range of reaction substrate (Table 2) The cyclic second and third amino acids can participate in the reaction, and the non cyclic first, second and third amino acids are also good substrates However, the yield of the substrate with NH group is low In addition to α - amino substituted carboxylic acids, α - oxygen substituted carboxylic acids are also suitable substrates Then, the effects of amino acids with different steric hindrances on the product were compared It is found that the proportion of three-component coupling products is higher with the increase of amino acid steric hindrance, while the proportion of two-component coupling products is higher with the decrease of amino acid steric hindrance Then, the effects of different alkyl iodides on the reaction were investigated, in which the electroactive substrate could participate in the reaction well Although the electrodynamic substrate can participate in the reaction, the product is not stable Other Michael receptors, such as acrylates, can not get corresponding products (source: angelw Chem Int ed.) finally, in order to illustrate the practicability of the reaction (scheme 4), the alkaloids sedamine and allosedamine were synthesized by this method (source: angelw Chem Int ed.) Summary: varinder K Aggarwal group has developed the three-component decarboxylation coupling reaction of nickel and photocatalysis, and synthesized a series of complex alkylborate compounds, and completed the synthesis of a class of alkaloids by this method.