Nat. Commun.: domino reaction of α - alkynic acid to β - aromatic aldehyde catalyzed by substrate recognition

It is an area of great concern for researchers to develop catalytic systems that can achieve efficient direct and selective chemical conversion In this sense, supramolecular catalysis based on substrate recognition is a promising strategy, which is recognized by the specific reversible interaction between substrate and enzyme mimicking catalyst At present, Crabtree, reek, Bach, Zhang, Breit and other research groups have developed many methods with excellent regioselectivity and enantioselectivity by using substrate recognition catalysis technology Although some progress has been made in this field, the scope and applicability of many methods are limited to special substrates, which results in low molecular diversity of products On the other hand, domino reaction is a simple and effective method to synthesize complex molecules Based on this, recently, the research team of Professor Bernhard Breit of Freiburg University in Germany has developed a method for preparing a variety of β - arylaldehydes via three consecutive reactions of rhodium catalyzed α - alkynic acid by combining domino reaction with supramolecular substrate recognition Relevant research results were published in NAT Commun (DOI: 10.1038/s41467-019-12770-w) (source: Nat Commin.) recently, Breit group realized the hydroformylation hydrogenation process catalyzed by RH using the designed supramolecular ligand (L1) The ligand can efficiently convert asymmetric β - alkynic acid to aliphatic aldehydes with high regioselectivity and chemical selectivity (Fig 1b) The mechanism study shows that unsaturated aldehyde II is the key intermediate of the reaction Considering that α, β - unsaturated carboxylic acids can be hydroformylated and decarboxylated smoothly, the author expects to use supramolecular ligand L1 to realize hydroformylation of α - alkynic acid Based on the previous reports, the author speculated that the reaction first formed intermediate III; then, due to the activation of carboxyl group and space effect, the Michael addition reaction of unsaturated aldehyde III with suitable aromatics (such as indole derivatives) was faster than the competitive double bond hydrogenation reaction; finally, the decarboxylation of intermediate IV produced β - arylaldehydes (Fig 1c) In order to verify the above conjecture, the author selected 2-butyric acid (S1) and 1,3,5-trimethoxybenzene (TMB) as model substrates At first, in the presence of 1 mol% [Rh (CO) 2 ACAC] and 5 mol% L1 ligands, S1 and TMB (1:1, N / N) can obtain the target product 1 in 35% yield at 55 ℃ in DCE at 6 bar Co / H2 (1:1) Then, the conditions of ligands, additives and pressure were investigated The optimum conditions were determined as follows: 1 mol% [Rh (CO) 2 ACAC] and 6 mol% L1 ligands as catalysts, 6 mol% camphor sulfonic acid (CSA) as additives, S1 and TMB (1.5:1) reacted in DCE at 35 ℃ for 20 hours, and the yield of compound 1 was 90% (source: Nat Commun.) after obtaining the best reaction conditions, the author investigated the universality of the reaction (Table 2) When 1,3,5-trimethoxybenzene is used as nucleophilic reagent, a variety of α - alkynic acids can be successfully converted into corresponding β - arylaldehydes in good yield The length of alkyl chain (from me to n-c14h19) had little effect on the yield (1-11, 73-90%) Even the substituents with large steric hindrance and the substrates of other functional groups are compatible with the reaction, and the corresponding product 12 - 16 is obtained in good yield Surprisingly, 3 - (trimethylsilyl) - 2-propargylic acid S17 can yield 3 - (2,4,6-trimethoxyphenyl) - propionalde17 in 51% yield, while 2-propargylic acid cannot be converted to 17 under the same conditions (source: Nat Commun.) since indole is widely found in natural products and drugs with biological activity, the author also investigated the scope of application of indole derivatives as nucleophiles (Table 3) Under the improved condition, the nitrogen protected indole can react with alkynic acid of different chain length smoothly, and the corresponding product 18 - 23 can be obtained with high yield The substituents at 2 and 5 positions of indole had little effect on the reaction efficiency (25 - 30) In addition, 1-dimethylamino-3-methoxybenzene is also a suitable nucleophilic reagent The products 31 and 32 were obtained in 90% and 66% yields respectively (source: Nat Commun.) in order to further prove the potential application of this method in bioactive targets, the author rapidly prepared the key intermediate 35A of avitriptan (candidate of anti migraine drugs), and realized the simple total synthesis of avitriptan (Fig 2) (source: Nat Commun.) based on the control test and previous literature reports, the author proposed a reaction mechanism consisting of three consecutive steps: hydroformylation, Michael addition and decarboxylation (Fig 3) The mechanism may start from the coordination of the substrate with Rh complex a to form complex B, where the substrate is activated by recognizing and predetermining to the RH center Due to this interaction, B may selectively undergo α - hydroformylation to produce intermediate C Subsequently, C releases intermediate D and regenerates the initial Rh complex a Intermediate D was further added with arene nucleophile to obtain intermediate e, which was decarboxylated to obtain the final product (source: Nat Commun.) conclusion: the author has successfully developed a domino reaction for the synthesis of β - arylaldehydes from α - alkynic acid This method has a high yield and can tolerate a variety of functional groups In addition, the key intermediate of avitriptan, a drug candidate, was synthesized by this method, and the whole synthesis of avitriptan was realized.