Highly selective olefin-assisted palladium-catalyzed oxidative carbocyclization via remote olefin insertion

An olefin-assisted palladium-catalyzed oxidative carbocyclization of enallenes to afford cyclohexene skeletons involving ligand exchange of olefins has been established.

A highly selective olefin-assisted palladium-catalyzed oxidative carbocyclization via remote olefin insertion to afford cyclohexenes has been developed.It was shown that the assisting olefin moiety was indispensable for the formation of the cyclohexene product.Furthermore, preliminary studies on chiral anion-induced asymmetrical carbocyclization-borylation of enallenes have been carried out.
The development of modern methodologies for the efficient synthesis of carbocycles is of central importance in modern organic chemistry, 1 given the fact that carbocycles are basic units in pharmacologically active skeletons, as well as in natural products. 2Among these methodologies, transition metal-catalyzed carbocyclizations with the involvement of p-bonds have emerged as an effective strategy for the preparation of carbocycles, 3,4 considering that the p-bond moiety would not only perform as the assisting group for the formation of the carbon-metal (C-M) bond, but also as the building block for the subsequent carbocyclization.In this way, an atom-economical transformation can be achieved.
We recently reported on an olen-directed palladium-catalyzed oxidative carbocyclization-borylation of allenes to cyclobutenes (Scheme 1a). 5 In this reaction, the coordination of the olen in Int-A triggers the allene attack on palladium, 6 which results in the formation of Int-B.Subsequent olen insertion to form a cyclobutene intermediate Int-C, followed by transmetallation and reductive elimination afforded the borylated cyclobutene derivatives A.
On the basis of these observations, we were particularly interested in the involvement of an additional double bond in a carbocyclization (Scheme 1b).We envisioned that the olen insertion of intermediate Int-1 could lead to intermediate Int-2, and that coordination of the additional olen to palladium would lead to a second carbocyclization to form spirocyclic intermediate Int-3, which on reaction with B 2 pin 2 would give B. Alternatively, Int-1 may undergo ligand exchange and olen insertion to give Int-5, which can be quenched by either B 2 pin 2 or ArB(OH) 2 to give either 2 or 3, respectively (Scheme 1b).
Based on this concept, we initially chose a readily accessible 3,4-dienoate 1a as the standard substrate.When 1a bearing an extra olen was treated with Pd(OAc) 2 (5 mol%), B 2 pin 2 (1.3 equiv.), and BQ (p-benzoquinone) (1.1 equiv.) in THF at room temperature for 12 h, the envisioned spirocyclic product B was not observed (Scheme 2).Interestingly, the cyclohexene product 2a was obtained in 76% yield instead.It is obvious that intermediate Int-2 was not formed from intermediate Int-1 via olen insertion as we had envisioned, but rather the ligand exchange, from proximal olen to remote olen occurred in Int-1 to produce Int-4.Subsequent olen insertion 7 to give cyclic intermediate Int-5 followed by B 2 pin 2 quenching would produce 2a (Scheme 1b).During this transformation, the proximal olen is acting as the assisting group for the generation of palladium intermediate Int-1, while the remote olen participates in the carbocyclization (Scheme 1c).To the best of our knowledge, 8-10 the formation of six-membered rings in palladium-catalyzed oxidative carbocyclization of enallenes via olen exchange has been rarely reported. 11o demonstrate the necessity of the assisting olen group, we rst investigated comparative experiments with enallenes lacking the additional olen (Scheme 3).When substrate 1f with an assisting olen was allowed to react under the same reaction conditions as those in Scheme 2, the cyclohexene product 2f was formed in 70% yield (Scheme 3a).However, when substrate 1, lacking the additional double bond, was subjected to the reaction conditions of Scheme 2 the corresponding six-membered ring product 2 was not formed; instead 1 was recovered in 88% (Scheme 3b).Importantly, we also observed the exclusive formation of 2h in 68% yield from substrate 1h (Scheme 3c).We also examined the reaction of a malonate-tethered substrate 1l, but the envisioned product 2l was not observed (Scheme 3d).These comparative experiments indicate that the assisting olen of the substrate is an indispensable group for the formation of the palladium intermediate Int-4.
The substrate scope for the formation of cyclohexene boron compounds 2 12,13 was then studied under the optimized reaction conditions (Scheme 4): in addition to methyl substituents on the enallene moiety, cyclobutylidene, cyclopentylidene, and cyclohexylidene enallenes (1b, 1c, and 1d) also gave the corresponding products 2b, 2c, and 2d in good yields.To our delight, enallenes with functional groups, such as free hydroxyl in 1e and imide in lk, furnished cyclohexene derivatives 2e and 2k in 83% and 76% yield.Furthermore, the reaction tolerates R to be different alkyl groups in this reaction, e.g.n-butyl (1f), or benzyl (1g). 14It is worth noting that the product 2h was exclusively obtained in 84% yield.Finally, the reaction of a dissymmetric allene 1i, bearing Me and phenyl, or 1j, bearing Me and i-Pr, afforded 2i in 86% yield, and 2j and 2j 0 in 60% yield, respectively.The ratio of 2j and 2j 0 was 1 : 2 due to the selective C-H bond cleavage, which occurred during allene attack forming Int-1 (see Scheme 1b).Notably, the reaction could be easily extended to a scale of 4.5 mmol of 1a (1.053 g) to afford the corresponding cyclohexene compound 2a (1.551 g, 90% yield).
Aer realization of the borylative carbocyclization, we next turned our attention to the arylating carbocyclization of enallenes.We were pleased to nd that the arylative products 15 could be obtained in good yields with a catalyst loading of 2 mol% Pd(OAc) 2 (Scheme 5).The reaction of substrates with two methyls, cyclopentylidene, and cyclohexylidene, afforded the corresponding product 3a, 3c, and 3d in good yields.Interestingly, the substrate containing a free hydroxyl group could also be employed.Different alkyl substituents on the starting materials, such as n-butyl, benzyl, and 4-pentenyl groups were tolerated (3f-h).We also examined the scope of arylboronic acids, and electron-donating substituents such as 3-Me, and 3-MeO reacted smoothly under the standard conditions in good yields.Notably, the procedure tolerates a range of additional functional groups on the arylboronic acid, including bromo (3ad), vinyl (3ae), formyl (3af), and acetyl (3ag) groups, which is useful for further functionalization.Finally, it is worth noting that 2-naphthylboronic acid and 1-naphthylboronic acid also worked well, affording 3ah and 3ai in 84% and 55% yield, respectively.
Interestingly, this new olen-assisting strategy could also be applied to an oxidative carbonylating carbocyclization 9c,f,g for the preparation of cyclohexene esters (Scheme 6). 16When the substrate 1a was treated with Pd(OAc) 2 (2 mol%), and BQ (1.1 equiv.)under carbon monoxide (1 atm) in methanol at room temperature for 12 h the carbonylation product 4a was formed in 82% yield (Scheme 6).Under the optimal reaction conditions, cyclopentylidene and cyclohexylidene substrates 1c and 1d afforded 4c and 4d, respectively in good yields.The substrate bearing the free hydroxyl group (1e) also worked well.Different allenes with alkyl substituents such as n-butyl, benzyl, and 4-pentenyl group, were also tested and worked well in this reaction.The reaction of a dissymmetric allene 1i, bearing Me and phenyl, afforded 4i in 70% yield.Finally, the scope of the alcohol partners in the carbocyclization carbonylation reaction was explored, and in addition to MeOH, ethanol and isopropanol were shown to react smoothly to provide the desired esters in good yield.
The biomimetic approach with the use of electron-transfer mediators (ETMs) is known to decrease the kinetic barrier for the reoxidation. 17In this aerobic approach the high kinetic barrier will be divided into several smaller units, and catalytic amounts of oxidant (BQ) would be enough to realize these transformations.When the reaction of 1a was treated with B 2 pin 2 (1.3 equiv.),BQ (20 mol%), Pd(OAc) 2 (5 mol%), and cobalt(salophen) (5 mol%) in the presence of O 2 (1 atm), borylated product 2a was obtained in 89% yield.Phenylated product 3a was provided in 86% yield when PhB(OH) 2 was used in place of B 2 pin 2 (Scheme 7).
Preliminary attempt to develop an enantioselective carbocyclization-borylation of enallenes revealed that a reasonably good er value (83 : 17) was observed in the presence of catalytic amounts of Pd(OAc) 2 and biphenol-type phosphoric acid C 9d while poor enantiocontrol (55 : 45 er) was obtained with VAPOL phosphoric acid (Scheme 8). 18,19ased on the experiments in Scheme 3 and the reaction outcome, a possible mechanism for the olen-assisted palladium-catalyzed oxidative carbocyclization of enallenes via remote olen insertion is given in Scheme 9.The reaction of palladium with enallene 1 bearing the assisting olen forms vinylpalladium intermediate Int-1 via allene attack involving allenic C-H bond cleavage, which is promoted by the coordination of allene and the assisting olen to Pd(II). 5,6Then, the vinylpalladium intermediate Int-4 would be generated from Int-1 via ligand exchange (from proximal olen to remote olen), instead of a direct olen insertion to form cyclobutene complex Int-2.

Conclusions
In conclusion, we have developed a highly selective olenassisted palladium-catalyzed oxidative carbocyclization of enallenes via remote olen insertion for the selective formation of the cyclohexene skeleton.It was demonstrated that the assisting olen moiety is essential for the formation of the cyclohexene derivatives.These reactions all show a broad substrate scope and good tolerance for various functional groups, and the catalyst loading could be decreased to 2 mol% in the arylative and carbonylative reactions with good to excellent yields.The biphenol-type chiral phosphoric acid was used in preliminary experiments of enantioselective carbocyclization-borylation of enallene.Further studies on the scope, synthetic application, and asymmetric variants of these reactions are currently carried out in our laboratory.