New progress has been made in the study of carbon metallization of unsaturated hydrocarbons in East China University of Science and Technology

On January 5, 2023, Yifeng Chen’s team and UCLA Houk’s team published an article titled “Nickel-catalysed regio- and stereoselective acylzincation of unsaturated hydrocarbons with organozincs and CO” in Nature Synthesis. Research results.

The research group used organozinc reagent and atmospheric pressure carbon monoxide to form the key active species of acyl nickel in situ under the action of nickel catalyst, and realized the highly selective acyl zincation reaction of unsaturated hydrocarbons. This method develops a new mode of carbon metallization reaction of unsaturated hydrocarbons, which provides a new idea for the highly selective conversion of unsaturated hydrocarbons.

The corresponding authors of the paper are Houk and Chen Yifeng. The co-first authors are Dr. Yangyang Weng, Yetong Zhang, Dr. Aneta Turlik, and Dr. Xianqing Wu.

Transition metals catalyze the carbon metallization of unsaturated hydrocarbons through the process of migration and insertion of unsaturated hydrocarbons by organometallic reagents, generating carbon-carbon bonds and generating a new organometallic species. This method is one of the most direct and effective means in the functional grouping reaction of unsaturated hydrocarbons, and is widely used in the construction of various carbon-carbon bonds in organic synthesis. Although organometallic reagents that have been developed today cover a wide range of functional groups, the extremely important carbonyl functional groups in organic chemistry are excluded. The main difficulty of this conversion is the lack of reliable methods to prepare highly active acyl metal reagents, and the electro-deficient acyl metal intermediates are prone to side reactions such as carbonyl removal during intermolecular migration and insertion. Therefore, the acyl metallization reaction of unsaturated hydrocarbons has not been achieved so far.

Recently, the research interest of Chen Yifeng’s research group based on stereospecific coupling of unsaturated hydrocarbons (J. Am. Chem. Soc. 2022, 144, 8389.; Angew. Chem. Int. Ed. 2022, 61, e202207536.; Angew. Chem. Int. Ed. 2022, 61, e202111598.; Angew. Chem. Int. Ed. 2022, e202210484.; Nat. Commun. 2022, 13, 5964.; CCS Chem. 2022, DOI:10.31635/ccschem.022.202202010.; Angew. Chem. Int. Ed. 2021, 60, 2699.; J. Am. Chem. Soc. 2020, 142, 15646.; Nat. Commun. 2020, 11, 392.), using organozinc reagent and atmospheric pressure carbon monoxide under the action of nickel catalyst to generate key active species of acyl nickel in situ, the acyl zincation reaction of a variety of unsaturated hydrocarbons is realized, and the newly generated organozinc intermediate can also be further captured by various electrophiles, or the intramolecular Truce-Smiles reaction and Aldol condensation reaction occur, and a series of ketone carbonyl compounds with potential application value are synthesized modularly. In addition, the research group also collaborated with K. K. Smith of the University of California, Los Angeles (UCLA). N. Houk’s research group cooperated with DFT theory analysis and found that the acyl metallization process under this reaction system has lower energy than the alkyl metallization process, which explains the excellent chemical and regional selectivity of the acyl metallization reaction.

Figure 1: Conception of an acyl metallization reaction catalyzed by transition metals

Starting from alkymide substrates, the authors can rapidly construct a series of tetrasubstituted eniminedos by nickel-catalyzified acylzincation and electrophilic trapping one-pot method (Figure 2). The reaction has a high degree of regional and stereoselectivity, and the substrate is suitable for a wide range of applications. Acylzincated intermediates of endoalkyne, end alkyne or open-chain alkyne amides can be captured by various (hetero)aryl halides, hydrogen protons, iodine elements and electrophiles such as allyl bromide. When the substituent on the nitrogen of the alkyne amide substrate is arylsulfonyl, the alkyne amide tandem acyl zincation/Truce-Smiles rearrangement reaction can be realized.

Figure 2: Excerpt substrate for acylzincation reaction of alkyneamide

The authors also used oxadicyclic olefins as substrates to achieve nickel-catalyzed acylzincation of olefins, further broadening the application range of this acyl metallization (Figure 3). Oxadicyclic olefin acyl zincation intermediates can be captured by a range of electrophiles. The product obtained by using this strategy21It can rapidly synthesize daunorubicin, a key intermediate of anticancer drug daunorubicin, and improve the synthesis efficiency, which fully proves the potential application value of this reaction mode. α, β-unsaturated ketones can also undergo acyl zincation reaction, followed by intramolecular Aldol condensation, which can achieve highly selective synthesis of a series of multisubstituted cyclopentenones.

Figure 3: Selected substrates for acylzincation reaction of olefins

By studying the photophysical properties of the product, the authors found that the electron-deficient cyano- or ester-substituted aryl 1,3-dienone product has typical aggregation-induced luminescence (AIE) properties, which exhibit significant fluorescence in the solid state (Figure 4). This reaction also provides a rapid synthesis method for novel AIE molecular building blocks.

Figure 4: Photophysical properties of novel AIE molecules

The authors, in collaboration with Houk’s group, made theoretical calculations of the reaction (Figure 5). DFT calculation results show that the intermediate state energy of nickel complexes obtained by acylation reaction is lower than that obtained by alkylation. The transition state energy of the major regional isomer is 2.8 kcal/mmol lower than that of the secondary isomer. Finally, the authors propose possible reaction pathways: first, the alkyl zinc reagent is converted to metal with a nickel catalyst to obtain an alkylnickel speciesA, followed by the insertion of carbon monoxide to form the acylnickel speciesB, the species cis-transports unsaturated hydrocarbons to generate intermediatesC。 IntermediatesCThe second conversion with excess organozinc reagents can generate organozinc intermediatesD, while regenerating alkyl nickel speciesA。 Organozinc intermediatesDIt is further captured by various electrophiles to generate the corresponding target product.

Figure 5: Theoretical calculations and reaction mechanisms

The above research work has been supported by the National Natural Science Foundation of China, Shanghai “Daystar” Program, Shanghai Natural Science Foundation, Frontier Science Center of Materials Biology and Dynamic Chemistry of the Ministry of Education, Feringa Nobel Prize Scientists Joint Research Center, Central University Basic Research Funds and other project funds, as well as China Postdoctoral Science Foundation. (Source: Science Network)

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