Synthesis of Cross-Conjugated Polyenes via Palladium-Catalyzed Oxidative C–C Bond Forming Cascade Reactions of Allenes

An efficient palladium-catalyzed oxidative C–C bond forming cascade reaction of allenes involving a coupling between an enallene and an allenyne followed by a carbocyclization of the generated Pd-intermediate was developed. This cascade reaction afforded functionalized cross-conjugated polyenes. The enallene is initially activated by palladium and reacts with the allenyne to give the cross-conjugated polyenes.


■ INTRODUCTION
Stereo-or regiocontrolled selective construction of unsaturated molecular scaffolds through sequential multiple carbon−carbon (C−C) bond formation remains one of the major challenges in organic chemistry. In particular, in cascade reactions, transitionmetal-catalyzed cyclizations of allenes provide efficient and atom-economical routes to polyunsaturated molecules. 1 Polyenes and oligoenes occur as structural elements in pharmaceutically active compounds and important natural products such as Vitamin A, Lycopene, β-carotene, Lutein, lissoclinolide, naturally occurring [3]dendralenes, etc. (Scheme 1). 2 The synthesis of such nonaromatic cross-conjugated [3]dendralenes have recently attracted considerable interest. 3,4 In recent years, acyclic cross-conjugated polyenes (dendralenes) have been used in diene transmissive Diels−Alder (DTDA) sequences for rapid generation of complex scaffolds bearing multiple stereogenic centers (Scheme 2). 5 Due to regioselective functionalization of the multiple olefinic sites, other applications of dendralenes are found in the synthesis of ivyane family compounds, 6 vinylogous Nazarov reactions, 7 organocatalytic domino cyclizations, 8 oxidative reactions, 9a and metathesis of [3]dendralene−Fe(CO) 3 complexes. 9b However, synthetic methods for the preparation of higher crossconjugated polyenes are quite limited as one-step reactions. In this respect, Hopf, Sherburn, Shimizu and their co-workers reported on acyclic cross conjugated polyenes. 3b, 10−12 Recently, the Lipshutz group reported a tandem borylation/Suzuki− Miyaura reaction for the synthesis of cross-conjugated polyenes such as [4]-and [5]dendralene (Scheme 3A). 13 In the past decade, our research group has focused on Pd(II)catalyzed oxidative carbocyclization reactions of allenes 1h and we reported the synthesis of various types of [3]dendralenes via C−C bond formation. 3d Compared to intramolecular reactions of allenes, intermolecular couplings of allenes are more challenging and would provide an array of novel conjugated structures. To the best of our knowledge, intermolecular cascade reactions between allenes with C−C bond formation for the synthesis of cross-conjugated polyenes have not yet been reported in a one-pot reaction. We therefore decided to study palladium(II)-catalyzed oxidative coupling and carbocyclization reactions of enallenes with allenynes for the synthesis of polyenes (Scheme 3 B). These cross-conjugated polyenes will have the (Z)-configuration at the middle double bond. The synthesis of the unsubstituted (E)-isomer of the corresponding polyene has been reported by Paddon-Row and Sherburn (lower box, Scheme 3B). 9b In this report, palladium-catalyzed intermolecular carbocyclization cascade reactions provide a wide variety of interesting polyene products in high yield and with excellent regio-and stereoselectivity (Scheme 3, B).

■ RESULTS AND DISCUSSION
In our initial investigation, allenyne 1a and enallene 2a were chosen as the substrates for this challenging transformation (Scheme 4).
Preparation of Starting Materials. All allenynes 1 were prepared from propargyl malonate and the corresponding bromoallenes (Scheme 5 and Experimental Section). The eneallenes 2 were synthesized from propargyl alcohol derivatives and subsequent 1,3-rearrangement or iron-catalyzed S N 2′ Grignard reaction (see Supporting Information).
In preliminary experiments, we observed that treatment of 1a and 1.1 equiv of 2a with 5 mol % of Pd(OAc) 2 and 1.1 equiv of benzoquinone (BQ) in DCE at 80°C gave a 64% NMR yield of the regio-and stereodefined dendralene derivative 3a together with 6% of cycloisomerization product 5 ( To demonstrate the necessity of the olefin group in the enallene 2a, 15 comparative experiments with allenes lacking the pending olefin were carried out. Without the pending olefin, these reactions failed to give any cross-conjugated polyene product 3 with Method A in CH 3 CN (Scheme 6). Thus, when 4a and 4b were allowed to react with 1a, no detectable amounts of 3 were formed. These results are in accordance with previous results that the olefin group of 2a is an indispensable assisting/ directing group for activation of the allene. 15 In further studies, we investigated Pd(II)-catalyzed aerobic oxidative coupling−carbocyclization reactions between allenyne 1a and enallene 2a for the synthesis of 3a (Scheme 4, Method B). We have previously developed various biomimetic methods for palladium-catalyzed aerobic oxidation of unsaturated substrates. 16 The employment of an aerobic biomimetic oxidation system is an environmentally benign process associated with high atom economy. 17 A key feature of Scheme 4, Method B is the multistep electron transfer occurring, which enables a mild aerobic oxidation. This multistep electron transfer system involves three redox pairs: Pd II /Pd 0 , (BQ)/HQ, and Co(salophen) ox /Co(salophen). The BQ and Co(salophen) are used as electron transfer mediators (ETMs), and molecular oxygen is applied as the oxidant. We found that reaction of 1a with 2a in the presence of catalytic amounts of Pd(OAc) 2 (5 mol %), BQ (20 mol %), and Co(salophen) (5 mol %) in CH 3 CN at 80°C under molecular oxygen (1 atm) for 24 h afforded 3a in 85% yield (Method B). Under optimized reaction conditions Methods A and B, we investigated the scope of the reaction by using different allenyne substrates ( Table 2, 1a−1j).
Under standard nonaerobic conditions (Method A), with methyl groups at the terminal position of the allene moiety of the allenenyne or when these methyl groups were changed to cyclohexylidene or one of them to t-Bu, the reaction with 2a gave the corresponding cross-conjugated polyene ( Table 2, 3a−3d) in good yields (82−90%). The use of either stoichiometric amounts of BQ (Method A) or catalytic amounts of BQ under aerobic conditions (Method B) afforded similar results, as shown in Table 2 from the examples 3a and 3d. It is worth noting that the reaction of allenyne substrates 1e−1j (Table 2) having two methyl ethers, a 1,3 dioxane, or two benzyl ethers in place of the two carboalkoxy groups, along with cyclohexylidene or tertiary butyl on the allene moiety, afforded the corresponding polyene derivatives ( Table 2, 3e−3j) selectively in good yields (70−83%), except for 1i, which afforded 3i in 34% yield. These results show that the malonate group of the tether is not necessary for a successful transformation.
To gain further insight into the reaction mechanism, the deuterium kinetic isotope effects (KIE) were studied (eqs 1−3).
An intermolecular competition experiment was conducted at 75°C using a 1:1 mixture of 2a and 2a-d 6 (eq 1). The products ratio 3a and 3a-d 5 was measured as 1.8:1, from which the competitive KIE was determined to be k H /k D = 3.5 (see Supporting Information). Furthermore, parallel kinetic experiments afforded a KIE (k H /k D from initial rate) value of 3.4 (eqs 2 and 3) which indicates the initial allenylic C(sp 3 )−H bond cleavage is involved in the rate-determining step in the reaction. The large competitive KIE (k H /k D = 3.5) in C−H bond cleavage requires that this step is the first irreversible step.

Scheme 7. Proposed Mechanism for the Formation of 3
The Journal of Organic Chemistry pubs.acs.org/joc Article not the allenyne. 19 Initial reaction of Pd(OAc) 2 with enallene 2 would give dienyl−Pd II complex Int-2 via allenic C−H bond cleavage of chelated π-complex Int-1 (Scheme 7). This activation of the allene is triggered by the coordination of the assisting olefin. 15 Vinylpalladium intermediate Int-2 would then undergo an insertion of the vinylpalladium bond into the alkyne of allenyne 1, which leads to Int-3. Subsequent intramolecular insertion of the vinylpalladium bond of Int-3 into the allene would lead to (π-allyl)-palladium intermediate Int-4. Subsequent β-hydride elimination via C(sp 3 )−H bond cleavage would provide the cross-conjugated polyene 3 and release Pd 0 for the next cycle.

■ CONCLUSION
We have developed an efficient one-pot Pd II -catalyzed oxidative coupling−carbocyclization cascade reaction for the synthesis of cross-conjugated polyene via intermolecular C−C bond formation and subsequent carbocyclization. This transformation allows highly regio-and stereoselective formation of crossconjugated polyenes using enallene and allenyne under aerobic conditions with environmentally friendly O 2 as the terminal oxidant. These important cross-conjugated polyenes, which are readily obtained in a one-pot cascade reaction in the present work, are difficult to prepare by other methods. Further studies on the scope of natural product synthesis and other synthetic application of this new cascade reaction are currently underway in our laboratory.

■ EXPERIMENTAL SECTION
General Information. For the synthesis of complex molecules, unless otherwise noted, all reagents were used as received from the commercial suppliers. Pd(OAc) 2 was obtained from Pressure Chemicals and used without further purification. Alkynes were commercially available from Sigma-Aldrich or Acros. The palladiumcatalyzed cascade reactions could be performed without any efforts to exclude moisture. DCE was distilled using CaH 2 , Dry THF and toluene, were obtained froma VAC Solvent Purifier. The other dry solvents were purchased from Sigma-Aldrich. Reactions were monitored using thinlayer chromatography (TLC) (SiO 2 ). TLC plates were visualized with UV light (254 nm) or KMnO 4 stain. Flash chromatography was carried out with 60 Å (particle size 35−70 μm) normal flash silica gel. NMR spectra were recorded at 400 MHz ( 1 H) or 500 MHz ( 1 H) and at 100 MHz ( 13 C) or 125 MHz ( 13 C), respectively. Chemical shifts (δ) are reported in ppm, using the residual solvent peak in CDCl 3 (H = 7.26 and C = 77.0 ppm) as the internal standard, and coupling constants (J) are given in Hz. HRMS data were recorded using ESI-TOF techniques.
Allenynes 1a 20 and 1c 21 were prepared as described in literature. Allenynes 1b and 1d were prepared from propargylmalonate and the corresponding bromoallene in a similar manner. 20 All allene derivatives 2a, 2k−2v, and 4a−4b were prepared according to a previously described procedures. 3d, 15,18c,22 Representative Procedure for the Synthesis of 1b and 1d: Synthesis of 1b. To a suspension of NaH (60% in mineral oil, 0.456 g, 11.4 mmol) in anhydrous THF (60 mL) was added a solution of diethyl propargylmalonate (2.0 g, 8.83 mmol) in anhydrous THF (5 mL) at 0°C . After the addition, the mixture was stirred for another 20 min at room temperature Then a solution of bromoallene (2. 6 g, 17.6 mmol) in anhydrous THF (5 mL) was added at room temperature and the resulting mixture was refluxed for 20 h. After the reaction was complete as monitored by TLC, it was cooled to room temperature. Most of the solvent was removed under vacuum, and then the reaction mixture was diluted with 50 mL of Et 2 O and quenched with 10 mL of water. The organic layer was separated, and the aqueous layer was extracted with diethyl ether (2 × 20 mL). The combined organic layers were dried over Na 2 SO 4 . Evaporation and column chromatography on silica gel (pentane/ethyl acetate = 30/1) afforded 1b (0. 71 g, 31%).
Compounds 1cx and 1dx were prepared from 1c and 1d, respectively, in the same manner.
In the same manner, 1f and 1g were obtained from 1cx and 1dx, respectively.