General construction method of antiaromatic butyfulene
Since Kekuleh first proposed the structure of benzene ring in 1865, people have developed a large number of synthetic methods for benzene and its derivatives. In the structure of the benzene ring, due to the presence of the π electron structure of the six-membered ring, the structure has abnormal stability. We call this property aromaticity. In contrast, the five-membered cyclic isomers of benzene exhibit very different reactivity, resulting from exocyclic double bonds. If the ring size of the triconjugated carbocyclic ring is further reduced, it will form an unusual isomeric body, antiaromatic butfulene, which consists of a cyclobutene with two exocyclic methylene units. Based on experimental and computational results, the three isomers - benzene, pentafulne and butalfulne - may exhibit very different properties.
Compared with the well-established synthesis schemes of benzene and pentafulene derivatives, the synthesis of butfulene remains a great challenge due to its inherently high strain energy and antiaromatic properties, which have become the basis for exploring its properties. bottleneck. Although previous synthetic methods were reported by early scientists, these solutions made it difficult to separate antiaromatic butyfulene due to low yields, so this bottleneck has not been truly effectively solved. In this work, academician Aso Ming from Zhejiang University, researcher Zheng Jian's team, and researcher Chen Qing'an's team from Dalian Institute of Chemical Physics, Chinese Academy of Sciences, developed a high-efficiency palladium catalysis involving propargyl compounds. Coupling scheme that provides a reliable and versatile strategy for the rapid assembly of symmetric butfulene derivatives . The work was published in Nature Chemistry under the title "Palladium-catalysed construction of butafulvenes".
[Construction of palladium-catalyzed symmetric butfulenes]
In order to synthesize 1,2-alkenyl borates, the author first used palladium-catalyzed reaction of propargyl carbonate 1a in the presence of B2Pin2. Using X-Phos as the ligand, the highly strained butfulene 2a was observed in 12% yield (5% yield) as well as the α,β-H elimination of enyne product 3a in 12% yield. After screening various types of phosphine ligands, it was found that using the monophosphine ligand Gorlos-Phos L2·HBF4 developed earlier by the author's team, high selectivity of butyl-rich 2a (93% yield) can be observed. Further solvent screening showed that reactions in N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), or toluene all gave poorer results than reactions in dioxane. Add an appropriate amount of water to increase the solubility of the inorganic base in the solvent, thereby improving the selectivity of 2a/3a. Furthermore, tetrahydrofuran (THF) containing H2O was found to provide better results compared to dioxane containing H2O. Based on these studies, the optimal conditions can be defined as follows: Pd(OAc)2 (1 mol%), Gorlos-Phos·HBF4 (4 mol%), B2Pin2 (1.1 equiv.), KHCO3 (3.0 equiv.) and H2O (2.0 equiv.) at 40 °C THF react.
Figure 1. Screening of reaction conditions
[Substrate expansion]
Based on the optimal reaction conditions obtained through screening, the author further screened the range of substrates applicable to this reaction. For 3-aryl substituted propargyl carbonate, the authors conducted a molar scale screening of its scope of application and found that in addition to the parent phenyl group, the substrates of aryl with electron-donating or electron-withdrawing substituents can be application, providing highly strained butfulene 2a-2f in 72-85% yield. Furthermore, this method is well tolerated by synthetic multifunctional functional groups such as -OMe, -Cl, and -CO2Me. 3-Thienyl-substituted propargyl carbonates are also compatible, for example butfulene 2g was obtained in 80% yield. In addition to methyl , the propargyl substituent can also be tetramethylene (2h), pentamethylene (2i and 2n), 4-oxapentamethylene (2j), diethyl base (2k) and dipropyl (2l).It is worth mentioning that this reaction can be easily performed on the gram scale (1i), providing butfulene 2i in 75% yield.
However, the primary propargyl substrate is completely incompatible with current optimal reaction conditions. This may be due to too low reactivity of the primary propargyl carbonate toward in situ generated Pd(0). After adjusting the allenyl precursor, it is interesting to find that the allenyl indium reagent prepared in situ can react smoothly with 3-phenyl bromide propargyl bromide 4a in the presence of Pd(PPh3)4 to synthesize terminal butyl Fulene 5a. In addition to propargyl bromide, propargyl iodide and chloride are also suitable coupling partners for this transformation, affording butfulene 5a in 42% and 74% yields, respectively. The reaction of the substrate with the electron-donating substituent (4b-4e) and the electron-withdrawing substituent (4f-4h) at the para position of the benzene ring proceeds smoothly, and the butulfene product 5b-5h is obtained with a yield of 55-87%. The substituent at the meta position of the propargyl bromobenzene ring has no obvious effect on the yield (5i-5k). Notably, the synthesis of versatile groups such as esters, acyl , and nitriles were well tolerated under this protocol, providing butfulene 5f-5j. For the highly sterically hindered 2,6-disubstituted substrate 4l, the expected butfulene product 5l was also obtained in 56% yield. To further highlight the practicality of this method, the authors successfully completed the gram-scale synthesis of 5a (1.03 g, 89% yield) under standard conditions.
Figure 2. Applicability of substrate
[Reaction mechanism]
Based on experimental research, the author proposed a possible reaction mechanism for this reaction. The initial oxidative addition of the Pd(0) catalyst to propargyl carbonate produces alkenylpalladium intermediate A, which reacts with B2Pin2 to give alkenylpalladium intermediate B. After reduction elimination, the boronic acid alkenyl 6 is produced and the catalytically active Pd(0) is regenerated. On the other hand, another molecule of allenyl palladium species A will be coupled with the allenyl borate 6 to give bis allenyl palladium C, which after reduction and elimination will give bis allenyl 7. Subsequently, LnPd+Bpin can be generated through the oxidative addition of LnPd to B2Pin2, followed by ligand exchange with KHCO3. One of the two allene units in bispropadiene 7 was inserted into LnPd+-BPin to form D, which further underwent intramolecular carbon palladation to give cyclobutadiene E. Finally, butfulene 2 is released after the release of LnPd+-Bpin.
Figure 3. Possible reaction mechanism
[Construction of palladium-catalyzed asymmetric butfulene]
Based on the above mechanism, the author passed the cross-coupling reaction between propargyl carbonate 1 and allyl borate 6 A method to obtain asymmetric butfulene 12 was further developed. The Heck reaction of 5a with aryl iodides was developed to provide the asymmetric butulfene 13a-c (E/Z 10:1) in moderate yields and good stereoselectivity. In addition, asymmetric butfulene 15 can also be formed by the reaction of tert-propargyl acetate and propargyl bromide. In general, tert-3-aryl-substituted propargyl acetates with phenyl substituents (R1) of different electronic properties were found to be compatible with this strategy (15a-15e), and other 3-alkyl-substituted propargyl Corresponding products 15g and 15h can also be provided.
Figure 4. Construction of an asymmetric four-membered ring
[Conversion of butfulene]
The [2 + 2] cycloaddition of butfulene 5a with a benzene intermediate provides a highly strained spiro with two four-membered rings. Loop 16, leaving an extra terminal C=C bond for further synthetic operations. The cyclopropanation reaction of butfulene 5a and 2-diazo-2-phenylacetic acid methyl ester can be successfully carried out to obtain the bicyclic product 17 with a higher degree of fusion. Furthermore, the visible light -induced reaction of -benzenethiol between the diene unit in 2a and 4-chloro or 4-bromine afforded the 1,4-adducts 18a and 18b in considerable yields.Furthermore, we found that one of the two exo-C=C bonds in 2a can be hydrohydroxylated in HBr aqueous solution with significant regioselectivity to form cyclobut-2-enol 19a, the conjugate addition product 19b as fewer additional products. When the R group is an allyl unit, the ring-closing metathesis of 2o can provide the [4.2.0]-bicyclic product 20 in 94% yield, which can be further aromatized to give benzo cyclobutane 21. In the presence of different amounts of m-CPBA, epoxy of 21 can provide highly strained benzocyclobutanebispirocyclic oxirane 22 and benzocyclobutane monospirocyclic oxirane 23.
Figure 5. Further conversion of butfulene
Summary, In this work, the author developed a general method for synthesizing butfulene and its derivatives. The method is easy to operate, has high yield, and can be modified according to the synthesis conditions. Modifications can also facilitate the selective synthesis of asymmetric related products. This work will make a foundational contribution to the study of four-membered cyclic antiaromatic compounds.
About the author:
Aso Akira , born on May 29, 1965 in Dongyang, Zhejiang, an organic chemist, graduated from Hangzhou University with a bachelor's degree, and received a master's and doctorate from the Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences. From 1992 to 1997, he worked at ETH in Switzerland and Purdue University in the United States. Carry out postdoctoral research work. Currently he is a professor at Fudan University, a distinguished researcher at the Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, a distinguished professor at Qiu Shi at Zhejiang University, the editor-in-chief of Chin. J. Chem. and the founding editor-in-chief of Org. Chem. Front. In 1995, he was awarded the Funding Committee for Outstanding Young Scholars (30 years old). In 2003, he was awarded the Yangtze River Scholars Program of the Ministry of Education. In 2005, he was elected as an academician of the Chinese Academy of Sciences (40 years old). In 2008, he was elected as an academician of TWAS. Currently, he is mainly engaged in the application of allene synthesis, reactivity, target molecule synthesis, discovery of bioactive molecules, and research on highly selective clean oxidation reactions using oxygen as the oxidant. Since working independently, he has published more than 500 papers, which have been cited by others more than 16,000 times. Authored 2 Chinese monographs, co-authored 1 Chinese monograph, 9 English chapters, and 2 sets of English monographs. Obtained more than 60 invention patent authorizations. He has won 2 second-class National Natural Science Awards, 1 first-class Shanghai Science and Technology Progress Award, 1 first-class Shanghai Natural Science Award, the World Chinese Organic Chemistry Award and the IUPAC OMCOS Award.
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Source: Frontiers of Polymer Science
