Palladium-Catalyzed Oxidative Domino Carbocyclization-Arylation of Bisallenes.

Herein we report a highly efficient and site-selective palladium-catalyzed oxidative carbocyclization-arylation reaction of bisallenes and arylboronic acids under operationally simple conditions for the selective synthesis of cyclohexadiene derivatives. The palladium source and the solvent proved to be crucial for the selectivity and the reactivity displayed. Interestingly, in the absence of the nucleophile, an oxidative carbocyclization-β-elimination pathway predominates. The reaction conditions are compatible with a wide range of functional groups, and the reaction exhibits broad substrate scope. Furthermore, key information regarding the mechanism was obtained using control experiments and kinetic studies.

Carbocyclization reactions of allenes[1] have attracted considerable attention in the past few years, and the versatile reactivity of allenes has been exploited in the synthesis of a diverse range of natural products and biologically active compounds.[2] Various transition-metal-catalyzed cyclization reactions of allenes have been established for the preparation of a variety of carbo- and heterocyclic derivatives.[3] In particular, novel strategies based on palladium catalysis have been studied for the construction of complex molecular structures from simple starting materials.[4] Although allenes have been widely utilized in the carbocyclization reactions, more challenging bisallenes were largely ignored, and the state-of-the-art of the cyclization reactions of bisallenes is mostly limited to cycloaddition and cycloisomerization reactions.[5] Therefore, there is an increasing demand to develop novel and efficient carbocyclizations reaction of bisallenes.[6] In particular, transition-metal-catalyzed cascade carbocyclization reactions have attracted attention as they allow the construction of complex molecular structures from simple starting materials.[7,8]

Our group has been largely interested in the development of palladium-catalyzed oxidative carbocyclization reactions of various unsaturated systems such as enallenes,[9] dienallenes,[10] and allenynes.[11] In recent studies, we have described carbocyclization reactions of enallenes followed by arylation, borylation, or carbonylation.[12] In these carbocyclizations, we noticed that the cyclization was highly sensitive toward the size of the carbocycle being formed. Enallenes 1a (n = 1) led to the functionalized cyclopentenes 4 via the intermediacy of 2 and 3 using catalytic amounts of Pd(II)-salt and oxidant (Scheme a). In sharp contrast, enallenes 1b (n = 2) failed to provide the corresponding cyclohexene derivatives 7 under these oxidative conditions. Very recently, we reported that coordination of the pendent olefin with palladium is vital for the subsequent attack of the allene moiety to palladium for the formation of intermediate 2.[13,14] Weaker coordination of enallene 1b (n = 2) might be the reason for its limited reactivity, and we envisaged that replacing the alkene unit by an allene would resolve the coordination issues and would give access to the cyclohexene derivatives, which are found in many natural products (Scheme b).[15]

Scheme 1

Oxidative Pd-Catalyzed Carbocyclization of (a) Enallenes and (b) Bisallenes

Controlling the chemoselectivity of insertion of organopalladium(II) intermediate with allenes is the key challenge associated with the envisioned project (Scheme b). Insertion of vinylpalladium(II) 9 with allene can take place either on C2–C3 or C1–C2 of the allene leading to either cyclopentene 11 or cyclohexene 13 intermediate.[16] Quenching these intermediates with a suitable nucleophile will give the corresponding carbocycle 12 or 14. Arylboronic acids were chosen as coupling reagents as they are known to undergo fast transmetalation with Pd(II). In addition they are nontoxic, easily available, and stable.[17] A further challenge is to control the site-selectivity for the formation of dienylpalladium(II) intermediate (cf. 9) when both the allene moieties are substituted in 8 (R and/or R′ = alkyl) as other cyclization pathways also compete.

In initial studies, bisallene 8a was allowed to react with 5 mol % of Pd(OAc)2 in DCE solvent at room temperature overnight. The reaction was sluggish and afforded a mixture of unidentified products along with starting material. However, we were pleased to find that the reaction proceeded smoothly at 60 °C and led to selective formation of methylencyclohexadiene 15 in 72% isolated yield after 3 h (Scheme ). Isolation of 15 as the only product supports our initial proposal of insertion of dienylpalladium(II) intermediate 9 selectively at the C1–C2 of the allene.

Scheme 2

Initial Studies for the Pd-Catalyzed Carbocyclization of Bisallenes

Intrigued by these initial results, we set out to achieve Pd(II)-catalyzed oxidative cascade carbocyclization–arylation of bisallenes (Table ). For the initial studies, p-tolylboronic acid was used as the nucleophile in reaction with 8a. We were pleased to find that 5 mol % of Pd(OAc)2 and 1.5 equiv of BQ in DCE solvent at rt overnight afforded the envisioned product in 47% yield along with 12% of 8a (Entry 1). At slightly higher temperature (50 °C), the reaction was completed in 4 h and selectively afforded 18a in 65% NMR yield (Entry 2). No β-elimination product 15 was observed in the 1H NMR spectrum of the crude reaction mixture. Various solvents were screened to improve the yield, and it was found that the reaction has a strong dependence on the solvent. Although no reaction was observed in polar solvents such as DMSO and acetonitrile (Entries 8 and 9), other solvents such as THF, acetone, methanol, and 1,4-dioxane led to the product in 51–71% yields (Entries 3–6). Gratifyingly, toluene provided cleanly the product 18b in 81% NMR yield (79% isolated yield) at 50 °C after 4 h (Entry 7). Screening of the different Pd(II)-salts was done in toluene solvent (Entries 10–14), among which Pd(OAc)2 was found to be the best catalyst.

Table 1

Optimization of Reaction Conditions

Yield was detected by 1H NMR using mesitylene as an external standard.

Reaction was done at room temperature for overnight.

Yield in parentheses refers to the isolated yield.

After having the optimized reaction conditions in hand for the cascade carbocyclization–arylation of bisallenes, we investigated the scope of the reaction using bisallene 8a. As can be seen from Scheme , various functionalized arylboronic acids reacted efficiently with 8a to give the corresponding products in good to high yields (18a–18p). Both electron-donating and electron-withdrawing substituted arylboronic acids resulted in full conversion in reaction with 8a after 4–5 h. Arylboronic acids with electron-donating substituents such as alkyl or methoxy groups on the aromatic ring resulted in slightly higher yields (18a, 18c–18f) compared to those with electron-withdrawing groups (18g–18m). Halogen substituents such as F, Cl, Br, and I at different positions of the aromatic ring are compatible with the reaction conditions to afford the corresponding derivatives 18g–18j in good yields (60–78%).

Scheme 3

Scope of the Reaction with Various Boronic Acids

The reaction also tolerates different functional groups such as formyl, acetyl, nitro, and vinyl on the aromatic ring of the arylboronic acids providing the corresponding products 18k–18n in 71%, 79%, 69%, and 77% respectively. Interestingly, trans-2-phenylvinylboronic acid also reacted with bisallene 8a to afford the product 18p in 45% yield.

The optimized reaction conditions established for the reaction of bisallene 8a were also tested with other bisallenes 8b–8f (Table ). When the dimethyl groups of the allene moiety were replaced by more bulky groups such as pentamethylene 8b or diethyl 8c, the corresponding products 18q and 18r were isolated in 74% and 69% yields, respectively (Entries 2–3). Unsymmetrical allene 8d also showed a similar reactivity to provide a mixture of 18s and 18s′ in a 2.7:1 ratio (Entry 4). Deuterated cyclohexadiene derivative [d]-18b was obtained in 68% yield using bisallene [d]-8a (Entry 5). Despite the possibility of cross-carbocyclization reaction with substituted bisallenes 8e and 8f, we were pleased to find that the reaction gave selectively the carbocyclic products 18t–18v in 57–74% yields under the optimized conditions (Entries 6–8).

Table 2

Scope of the Various Bisallenes in the Pd-Catalyzed Carbocyclization

Tetramethyl-substituted bisallene 8g required a slightly higher temperature (70 °C) for completion and provided the product 18w in 46% yield along with a cyclopentene byproduct 19 in 18% (Scheme ). These results indicate the high selectivity of the methodology to form the dienylpalladium(II)-intermediate (cf. 9) by the nucleophilic attack of the more substituted allene moiety selectively on the palladium(II) center. Nucleophilic attack of the second allene moiety of 18w onto Pd(II) affords Int, which after carbopalladation onto C2–C3 of allene and arylation leads to 19.

Scheme 4

Pd-Catalyzed Carbocyclization–Arylation Cascade with Bisallene 8g

To gain some insight into the reaction mechanism, several control experiments were performed. In the absence of benzoquinone, only traces of the product were observed using 1.0 equiv of Pd(OAc)2 in reaction with 8a, suggesting that BQ is playing a more pivotal role than acting only as a simple oxidant for this transformation. Enallene 20 was treated with phenylboronic acid (Scheme a) under the standard conditions. No formation of the corresponding cyclized product 21 was observed, suggesting that the allene moiety was crucial for the successful Pd(II)-catalyzed carbocyclization. In another control experiment, differently substituted enallene 22 was treated with phenyboronic acid under the optimized conditions (Scheme b). Even at a higher temperature with prolonged reaction time, no product was observed. Comparison of this outcome with the isolation of 19 as a byproduct in reaction with 8g (Scheme ), clearly suggests the importance of the formation of π-complex between Pd(II) and the allene unit of bisallene for the nucleophilic addition of the allene moiety to the palladium center to form the required dienylpalladium(II)-complex.

Scheme 5

Attempted Pd-Catalyzed Carbocyclization Reactions with Enallenes

To gain more insight into the reaction mechanism, deuterium kinetic isotopic effect studies were performed. To investigate whether there is any competitive kinetic isotopic effect, a 1:1 mixture of 8a and [d]-8a was allowed to react with phenylboronic acid under optimized reaction conditions. A ratio of 4.4:1.0 between 18b and [d]-18b was observed (21% conversion, 15 min), from which the KIE (kH/kD) was determined to be 5.17 (Scheme a). The large KIE value in the competitive experiment requires that the C–H bond cleavage has to occur prior to any irreversible step of the reaction. Furthermore, parallel kinetic experiments were also performed where phenylboronic acid was allowed to react with 8a and [d]-8a in separate experiments. The progress of both the reactions was monitored by 1H NMR at different time intervals (Scheme b). From these parallel kinetic experiments, an intermolecular KIE (kH/kD from initial rate) of 4.7 was obtained. The large KIE value of 4.7 indicates that the allylic C–H bond cleavage is involved in the rate-determining step.

Scheme 6

(a) Competitive Kinetic Isotopic Effect; (b) Parallel Kinetic Experiments; (c) Kinetic Isotopic Effect for β-Elimination

In addition, competitive deuterated kinetic studies were also performed for the Pd(II)-catalyzed oxidative carbocyclization-β-elimination process leading to 15 (Scheme c). A mixture of 8a and [d]-8a was subjected to the conditions that favored the formation of 15, which afforded a competitive kinetic isotope effect of kH/kD = 6.1.

On the basis of the control experiments in Scheme and the deuterium kinetic isotopic experiments, the mechanism in Scheme is proposed. Pd(OAc)2 forms a π-complex (24), in which both allene units are coordinated to Pd(II). Nucleophilic attack of the more substituted allene moiety on the palladium center followed by rate-determining allylic C–H bond cleavage leads to the selective formation of dienylpalladium(II) species 25 co-ordinatinated with BQ. The intermediate 25 undergoes intramolecular carbopalladation of the C1–C2 double bond of the second allene generating the (σ-allyl)palladium(II)-intermediate 26. Subsequent transmetalation with arylboronic acid 17 leads to the formation of 27. Reductive elimination from 27 affords the product 18. Competing rearrangement of (σ-allyl)palladium(II) intermediate 26 to the other (σ-allyl)palladium(II)-intermediate 28 proceeds through the (π-allyl)palladium(II) complex 16, which gives 15 after β-elimination.

Scheme 7

Proposed Mechanism

In conclusion, we have developed a novel palladium(II)-catalyzed oxidatative carbocyclization–arylation cascade reaction of bisallenes and arylboronic acids, providing access to a wide range of functionalized cyclohexadiene derivatives. Despite the possibility of various side reactions, the reaction conditions allowed the selective formation of the carbocyclic products under operationally simple reaction conditions. We propose that the facile formation of six-membered rings is due to the fact that the carbocyclization of the allene is geometrically favored due to perpendicular π-systems of the allene. The selectivity for six-membered rings and the compatibility of the various functional groups are highlights of the current reaction. Further studies to increase the scope of this carbocyclization beyond arylation and the synthetic application of this protocol are underway in our group.