Efficient Palladium‐Catalyzed Aerobic Oxidative Carbocyclization to Seven‐Membered Heterocycles

Abstract The use of molecular oxygen in palladium‐catalyzed oxidation reactions is highly widespread in organic chemistry. However, the direct reoxidation of palladium by O2 is often kinetically unfavored, thus leading the deactivation of the palladium catalyst during the catalytic cycle. In the present work, we report a highly selective palladium‐catalyzed carbocyclization of bisallenes to seven‐membered heterocycles under atmospheric pressure of O2. The use of a homogenous hybrid catalyst (Co(salophen)‐HQ, HQ=hydroquinone) significantly promotes efficient electron transfer between the palladium catalyst and O2 through a low‐energy pathway. This aerobic oxidative transformation shows broad substrate scope and functional group compatibility and allowed the preparation of O‐containing seven‐membered rings in good yields in most cases.

Abstract: The use of molecular oxygen in palladium-catalyzed oxidationr eactions is highly widespread in organic chemistry.H owever,t he directr eoxidation of palladium by O 2 is often kinetically unfavored, thusl eading the deactivation of the palladium catalyst during the catalytic cycle. In the present work, we report ah ighly selective palladium-catalyzed carbocyclization of bisallenes to seven-membered heterocyclesu nder atmospheric pressure of O 2 .T he use of ah omogenoush ybrid catalyst (Co(salophen)-HQ, HQ = hydroquinone) significantly promotese fficient electron transfer between the palladium catalyst and O 2 through al ow-energy pathway.T his aerobic oxidative transformation shows broad substrate scope and functional group compatibility and allowed the preparation of Ocontaining seven-memberedr ings in good yields in most cases.
Over the past decades, palladium-catalyzed oxidations have emergeda sp owerful andv aluable tools in moderno rganic synthesis. [1] Various protocols have been developed for the assembly of carbon-carbon and carbon-heteroatom bonds that provide useful applications in biology, medicine, and materials science. [2] However,i nm ost cases the use of stoichiometric oxidants such as Cu II ,Ag I ,and peroxideso ften leads to poor selec-tivity,l ow atom economy,a nd considerable amountso fu ndesired waste. In the perspective of synthetic organic chemistry, molecular oxygen is an inexpensive, abundant, and highly atom-efficient oxidant, which does not generate anyt oxic byproducts,t hus fulfillingt he requirements of "green chemistry". [3] Despite significant advances in palladium-catalyzed aerobic oxidations, asevere problem is that fast aggregation of palladium black from the active palladium species( Pd-H or Pd 0 ) slows down and finally stops the homogenousr eaction. [4] Extensivee ndeavors for solving this problem have focused on the use of air-stable ligands to restrain Pd 0 precipitation during the catalytic cycle (Scheme 1a). [5] Moreover,J iang and co-workers recently developeda ne legant protocol that utilizes an efficient metal-organic framework (MOF) for the stabilization of the palladium catalyst in aerobic functionalizations (Scheme 1b). [6] Although ap lethora of strategies to circumvent this oxidation problemh ave been reported,t he development of highly active catalytic systems that enablem ild Pd-catalyzed aerobic oxidations continues to be an important topici nt his area.
Our research group has al ong-standing interest in palladium-catalyzed oxidations where molecular oxygen is used as a green oxidant. [7] However,a ss tated above, the direct reoxidation of palladium by molecular oxygen is often kinetically unfavored. [4] To solve this problem, we and others have employed coupled catalytic systemsw ith electron transfer mediators (metal-macrocycle and quinone) to facilitatet he relay of electrons between the palladium catalyst and O 2 (Scheme 1c). [8] These coupled catalytic systems have been demonstrated to be highly efficient in Wacker oxidations [8b, 9] alcoholo xida-tions, [10] oxidative olefin functionalizations, [11] and oxidative CÀ Ha ctivations [12] where molecular oxygen is the oxidant. In 1993, am ore efficient hybrid catalyst, involving ac obalt-porphyrin with pendanth ydroquinone groups in one molecule, was reported by our group as well. [13] Later on, an improved hybrid Schiff base-hydroquinone [Co(salophen)-HQ]a saredox relay catalyst for aerobic oxidation was reported. [14] The latter bifunctional catalyst led to af aster reaction rate compared to the system with the quinone and metal-macrocycle as separate molecules in Pd-catalyzed aerobic carbocyclization of enallenynes and dienallenes. [8h, 15] During the past decade, our research group has been involved in the development of palladium-catalyzed oxidative carbocyclizations of allenes bearing an additional unsaturated moiety,s uch as an olefin, alkyne, or allene. [16] Interestingly,w e found that an assisting group (AG), [17] such as an olefin, alkyne or hydroxyl group, is required to make6 -membered rings [8e,h, 15, 18] from enallenes and allenynes and to make 7-membered rings from bisallenes due to the initial allenic CÀ Hc leavage by Pd II (Scheme 2a). Afterward, cascade carbocyclization and transmetallation with an ucleophile can occur and give the cyclic product. However,w ithout an activating group, no reactiont akes place with the distal p-bond to give the larger rings. This interesting neighboring group effect allows for palladium-catalyzed carbocyclization in ah ighly selective manner. We recently reported an efficient approachf or the synthesis of seven-membered rings via olefin-assisted palladium-catalyzed carbonylative carbocyclization of bisallenes. [19] However,O -containing seven-memberedr ings were not explored in the previouss tudy.A lso, there is no example on the use of oxidative carbocyclization of bisallenes for the synthesis of useful organoboron molecules. [20] Herein we report ag eneral and efficient catalytic system for the synthesis of O-containing seven-membered heterocycles via cascade borylative carbocyclizations( Scheme 2b). This catalytic system involves the use of aP d II catalystw ith ah ybrid ETM catalystf or the biomimeticaerobic oxidations.
Initially,ac lass of bifunctionalS chiff base-hydroquinone catalysts were prepared from the ligand precursor salicylaldehyde-hydroquinone, which was covalently synthesized according to our previous report. [14] As shown in Scheme 3, the synthetic route to these oxidationc atalysts commences with con-densation of two equivalents of salicylaldehyde-hydroquinone with various diamines such as o-phenylenediamine, 4-chloro and 4-methoxyl-o-phenylenediamine,e thylenediamine and N-(3-aminopropyl)-N-methylpropane-1,3-diamine. The resulting salen-hydroquinone ligands could be directly used for the next step without further purification. Subsequently,c oordination of these ligands with 3d metal salts (Co, Fe, Ni, and Cu) afforded the corresponding hybrid catalysts (Cat. 1-9)i ng eneral yields of 78-95 %.
At the outset of our investigations,t he palladium-catalyzed aerobic oxidation of ar eadily accessible bisallene 1a with B 2 pin 2 2a was chosen as the benchmarkr eaction( Ta ble 1). In the absence of electron transfer mediators (ETMs), we did not observe any formation of the desired borylation product under aerobic conditions and the starting material 1a was recovered in 93 %y ield (entry 1). When catalytic amountso fp-benzoquinone (BQ) was added, the seven-membered carbocycle 3a was selectively formed in low yield (15 %, entry 2). Notably,t he use Scheme2.(a) Palladium-catalyzed oxidative carbocyclization with an assisting group;( b) Current work.
After optimizing of the reaction conditions, we explored the substrate scope with the optimal oxidation catalystC o(salophen)-HQ (Scheme 4). The benchmark borylative carbocyclization gave the corresponding product 3a in 75 %i solated yield. With R 1 being ab enzylo rac yclohexyl group, the corresponding products 3b and 3c were obtained in 78 %a nd 60 % yields,r espectively.U nder the optimal aerobic reactionc onditions, cyclohexylidene bisallene 1d afforded 3d in only 30 % yield. We attributet his diminished reactivity to the increased steric bulk of the cyclohexyl group. Not only can at erminal olefin act as an assisting group, but also internal olefins were found to promote the reaction as shown by the formationo f products 3e and 3f in 59 %a nd 65 %y ield, respectively.I na ddition to an ester group on R 2 ,v ariousf unctionalg roups at R 2 such as alkyl 1g,h ydroxyl 1h,s ilyl 1i,a cetate 1j,s ulfonamide 1k,a nd imide 1l were compatible with the reaction conditions, highlighting the broad substrate scope of this protocol (52-75% yields). As an example of late-stage oxidative functionalization,a ne strone-derived substrate 1m efficientlyp articipated in this reactiont oa fford af unctionalized complex molecule 3m in au seful yield (78 %). Unfortunately,a ttempts to synthesize the N-containing seven-membered heterocycle Figure 1. Evaluationo fthe bifunctional catalysts for aerobic carbocyclization of bisallene 1a with B 2 pin 2 to seven membered cycle 3a.U nless otherwise noted, the following reaction condition were employed with 1a (0.1 mmol, 1.0 equiv), B 2 pin 2 2a (0.13 mmol, 1.3 equiv), Pd(OAc) 2 (5 mol %), Schiff basehydroquinone catalyst (10 mol %) in 0.1 m acetone,O 2 (1 atm) at roomtemperature(25 8C) for 30 h. Yields weredetermined by 1 HNMR usinga nisolea s internal standard.
using the nitrogen analogueo f3g (whereo xygen in the ring had been replaced by NTs) were unsuccessful (See Supporting Information). Bis(neopentyl glycolato)diborona nd bis(hexylene glycolato)diboron also workeda st he borylatingr eagent and afforded the corresponding borylation products 3n and 3o in moderate yields (40 %a nd 52 %, respectively). The seven-membered borylation product from 1s was not observed due to the steric hindrance of substrate 1s.
To further confirm the effect of the pending olefin group in bisallene 1,w ecarried out control experimentsw ith 1a' as the substrate, in which the vinyl group in 1a had been replaced by an ethyl group [Eq. (1)].A ttempted reaction of 1a' under standard conditions did not give any product. This result shows that the pending olefin is an indispensable elementf or this oxidativec arbocyclization, which is in accordance with our previouswork. [17] In addition to borylative oxidative carbocyclization, the use of phenylboronic acid as atransmetallating agentunder similar reactionc onditions also afforded the carbocyclization-arylation product 4 in 48 %y ield (Scheme 5a). Furthermore, an efficient cascade reactiono fb isallene 1a via an oxidative carbocyclization-methoxycarbonylation is demonstrated here (Scheme 5b) and gave the seven-membered carbocycle 5 in 78 %y ield. In the absence of at rapping reagent, an intramolecular oxidative coupling ending with b-H elimination produced ahighly conjugated seven-membered ring 6 in 79 %y ield (Scheme 5c).
In analogy with our previous report, [15] there wasarate enhancement with the hybrid catalyst compared to the use of Co(salophen) and quinone as separatem olecules as shown in Figure 2. Co(salophen)-HQ hybrid (Cat. 1)r esulted in fast borylative carbocyclization of 1g to 3g (Figure 2a), as well as the direct carbocyclization of 1s to 6 ending with b-H elimination (Figure 2b). These results indicatet hat the intramolecular electron transfer between the hydroquinone and the oxidized metal-macrocycle of this bifunctionalc atalystl eads to am ore efficient palladium reoxidationp rocess under aerobic conditions. [23] On the basis of these experimental findings, ap ossible mechanism for the oxidative coupling reaction is proposed in Scheme6.I nitially,t he coordination of allene and olefin units to the Pd II center leads to ac helate palladium complex Int-I. This special coordinationo ft he close-by olefin to Pd II is essential for triggering the allenic C(sp 3 )ÀHc leavage and generating av inylpalladiumi ntermediate Int-II. [17] Next, the envisioned ligand exchange of olefin by the distanta llene moiety takes place to give Int-III. Subsequent carbocyclization of Int-III by the second allene insertion gives as even-membered (p-allyl)palladium intermediate Int-IV. Reaction of Int-IV with at rapping reagent such as B 2 pin 2 ,P hB(OH) 2 or CO/MeOH provides the target product and aP d 0 species, respectively.F inally,w ith the assistance of the cobalt hybrid catalyst, aerobic oxidation of Pd 0 regenerates Pd II to closethe catalytic cycle.  In summary,w eh ave developed an efficient and selective palladium-catalyzed carbocyclization of bisallenes under aerobic oxidative conditions. This reactiona voids overstoichiometric amounts of non-environmentally friendly oxidants( Cu II ,A g I , peroxide etc.) for the activation of allenic CÀHb onds. The use of molecular oxygen as ag reen oxidant allows for synthesis of important seven-membered heterocycles in moderate to good yields. The key to successo ft his transformationi st he application of as pecial hybrid electron transfer mediator[ Co(salophen)-HQ]-a bifunctional catalyst consisting of am etal-macrocycle and quinone moieties. Thish ybrid catalysts ignificantly facilitatest he reoxidation of Pd 0 to Pd II using molecular oxygen as the terminal oxidant. In view of the high reactione fficiency and selectivity, this protocol is expected to complement the current approachf or oxidative functionalization in the synthesis of natural products and pharmacologically active substances.