A Study of Palladium Catalyzed Intra/Intermolecular Cascade Cross Coupling/Cyclizations Involving Bicyclopropylidene

The compounds [3-(2-Bromocyclohex-2-enyloxy)prop-1-ynyl]-tert-butyl-dimethylsilane 3, [4-(2-bromocyclohex-2-en-1-yloxy)but-2-yn-1-yloxy]tert-butyldimethylsilane 5 and dimethyl 2-(2-bromocyclohex-2-enyl)-2-(3-(tert-butyldimethylsilanyl)prop-2-ynyl)malonate 9 were prepared and subjected to palladium-catalyzed intra-intermolecular cascade cross couplings incorporating bicyclopropylidene 10 under two types of conditions. In the presence of Pd(OAc)2, PPh3 and K2CO3 in acetonitrile at 80 °C, the products were indene analogues, cross-conjugated tetraenes 11, 12 and 13, respectively. The corresponding spirocyclopropanated tricycle 16 in dimethylformamide at 110 °C was obtained, albeit in low yield (24%), and observed as an equimolar mixture of diastereomers, whereas 14, 15 were not fully isolated.


Introduction
Intra-as well as intermolecular so-called domino or cascade reactions is particularly efficient in terms of increasing the molecular complexity in a minimum number of steps [1][2][3][4][5][6][7][8][9][10][11][12]. Especially, palladium-catalyzed carbon-carbon bond forming reactions that involve carbopalladations of carbon-carbon double bonds can favorably be combined in all-intra-, intra-inter-and intermolecular cascade reactions [5][6][7][8][9][10][11][12]. The so-called Mizoroki-Heck reaction, i.e., the palladium-catalyzed arylation or alkenylation of alkenes has been applied in a variety of new concepts . In view of the steadily growing number of oligocyclic compounds with cyclopropyl moieties that show interesting biological activities [27][28][29], it is noteworthy and helpful that the highly reactive building block bicyclopropylidene 10 [30,31] can participate in various palladium-catalyzed cascade reactions to OPEN ACCESS furnish complex skeletons containing cyclopropyl groups [17][18][19][20] A particularly high increase in molecular complexity can be achieved with sequential reactions starting with an intramolecular carbopalladation (the first step of a Heck reaction) of a 2-bromo-1-ene-6-yne and trapping of the formed reactive vinylpalladium halide intermediate by bicyclopropylidene 10 and subsequent transformations [32]. We have been working on synthesis of fused ring systems, for indene [33,34] utilizing the intramolecular addition of alkenyl radicals to furans, for benzofuran and benzothiophene [35] towards indene also utilizing the thermal intramolecular Diels Alder cycloadduct. As this cascade reaction principle appeared to deserve further development, we embarked on a project to prepare a few more 2-bromo-1-ene-6-ynes and employ them in palladium-catalyzed cocyclizations involving bicyclopropylidene 10.

Results and Discussion
Two major routes for the synthesis of 2-bromo-1,6-enynes as precursors for palladium-catalyzed cascade cyclizations have previously been developed [32]. Employing experimental procedures from both of these routes; three new 2-bromo-1,6-enynes with a 2-bromocyclohexene moiety for application in palladium-catalyzed cascade cyclizations with incorporation of bicyclopropylidene 10 [32] were prepared.

Br
Mechanistically the reactions can be explained by the following sequences; initial oxidative addition of the bromo-ene onto a palladium(0) species, followed by the intramolecular carbopalladation of the triple bond to give vinyl palladium moiety, then cabopalladation of bicyclopropylidene furnish a (cyclopropylcarbynyl)palladium moiety at the intermediate which directly undergoes a cyclopropylmethyl-to-homoallyl rearrangement to bring palladium species to subsequent syn-β-hydride elimination stage which generates the conjugated tetraene. This corresponds to the previous observation in that the expected 6π-electrocyclizations of such initially formed tetraenes do not occur at 80 °C [32]. In the current case the tetraenes 11, 12 and 13 did not undergo 6π-electrocyclization to the corresponding skeletons even upon heating at 100 °C for four days in a sealed tube.
The development of the yields in series 11, 12 and 13 corresponds to that previously observed for another series with a similar substitution pattern [32]. The highest yield obtained for compound 13 obviously is due to the Thorpe-Ingold gem-disubstitution effect [38]. Precursors with heteroatoms in the chain consistently give lower yields than their all-carbon atoms. Presumably, heteroatoms in the chain may coordinate to the active metal catalyst and there by disturb the course or even alter mode of the reaction. When treated with palladium acetate in the presence of triphenylphosphane and potassium carbonate in N,N-dimethylformamide at 110 °C (instead of 80 °C), the bromoenynes 3, 5, 9 and bicyclopropylidene 10 underwent the desired intra-intermolecular cascade cross-coupling with subsequent 6π-electrocyclization to furnish the spirocyclopropanated tricycles for 16, albeit in low yields (24%) as 1:1 mixtures of diastereomers regarding to NMR data, on the other hand of 14 and 15 were not obtained and observed clearly only trace besides not cyclized 11 and 12. (Scheme 4). Presumably, molecular structural features behave main role like angular torsion-difficulty, structural rigidity obstruct the 6π electrocyclization sequence or probably make reversible whereas scissor (Thorpe-Ingold) effect, with TBDMS group on compound 16 case possibly force tetraenes towards the 6π electrocyclization progress under thermal condition in a polar solvent system [33,34].

Experimental
General Information 1 H-NMR spectra were obtained with a Bruker 300 MHz DPX 300 spectrometer. Chemical shifts are quoted as δ values in ppm downfield from tetramethylsilane. Infrared (IR) spectra were recorded on thin films with a Perkin-Elmer 1720 spectrophotometer; Elemental analyses were carried out by TUBITAK (The Scientific and Research Council of Turkey) Marmara Research Centre on a Thermo Finnigan Flash EA 1112, (C, H, N). Electron impact (EI, 70 eV) ionization mass spectra were recorded on a Finnigan MAT 95 mass spectrometer. All reagents were used as purchased from commercial suppliers without further purification. All reactions in non-aqueous solvents were carried out using standard Schlenk techniques under a dry nitrogen atmosphere. Solvents were purified and dried according to conventional methods prior to use; tetrahydrofuran (THF), diethyl ether, dimethoxyethane (DME) were distilled from sodium/benzophenone; dichloromethane was distilled from calcium hydride. Acetonitrile and dimethylformamide were initially stirred over potassium carbonate (1 day), then over phosphorus pentoxide (1 day) and distilled (DMF was distilled under reduced pressure) onto 3Å molecular sieves. Reactions were monitored by thin layer chromatography (TLC) using pre-coated silica plates (Macherey Nagel SIL G UV 254 ). Compounds were visualized using a UV lamp, alkaline potassium permanganate or acidic cerium(IV) sulfate solutions. Column chromatography was carried out on Macherey Nagel Kieselgel 60 (230−240 mesh). (2): 2-Bromocyclohexen-3-ol (1) [38] (2.58 g, 16 mmol) in THF (10 mL) was added dropwise to the suspension of sodium hydride (60% in mineral oil, 0.75 g, 18 mmol) in THF (50 mL) kept at 0 °C. The mixture was stirred at room temperature for 30 min. Subsequently, propargyl bromide (2, 1.9 g, 16 mmol) was added dropwise at 0 °C. The mixture was stirred at room temperature overnight. The reaction was quenched by careful addition of brine (50 mL). The aqueous phase was extracted with diethyl ether (2 × 50 mL), the organic extracts were dried with MgSO 4 and concentrated under reduced pressure. The residue was purified by column chromatography, eluting with pentane/diethyl ether 4:1 (R f = 0.81), to afford 2 (2.50 g, 73%) as a pale yellow oil. IR     (9) n-Butyllithium (2.5 M in hexane, 1.36 mL, 3.4 mmol) was added dropwise to a solution of 8 (1.12 g, 3.46 mmol) in THF (30 mL) kept at −78 °C. The mixture was stirred at this temperature for 30 min, then tert-butyldimethylsilyl chloride (0.53 g, 3.4 mmol) in THF (5 mL) was added, and the mixture was stirred at room temperature for 4 h. The reaction mixture was poured into water (75 mL), the aqueous mixture was extracted with diethyl ether (3 × 50 mL) and washed with 50 mL brine. The organic extracts were dried over MgSO 4 (10) to Yield Tetraenes: Palladium acetate (11.2 mg, 49.9 µmol, 10 mol %), triphenylphosphane (39.3 mg, 150 µmol, 30 mol %) and potassium carbonate (138 mg, 998 µmol) were suspended in anhydrous acetonitrile (5 mL) in a screw-cap Pyrex bottle. The respective bromoenyne (0.5 mmol) was added and argon gas was bubbled through the mixture for 5 min. Then bicyclopropylidene 10 (80 mg, 1 mmol) was added, the bottle was tightly closed, and the mixture heated in a preheated oil bath at 80 °C for the given period of time. After cooling down to room temperature, the reaction mixture was taken up in diethyl ether (10 mL), the mixture filtered through a pad of Celite (5 cm) and the solvent evaporated in vacuo to leave about 1 mL. The crude product was purified by flash column chromatography on silica gel, eluting with pentane/diethyl ether.

GP2: General Procedure for the Palladium-Catalyzed Cocyclization of 2-Bromo-1,6-enynes and
Bicyclopropylidene (10) with Subsequent 6π-Electrocyclization: Palladium acetate (11.2 mg, 49.9 µmol, 10 mol %), triphenylphosphane (39.3 mg, 150 µmol, 30 mol %) and potassium carbonate (138 mg, 998 µmol) were suspended in anhydrous DMF (5 mL) in a screw-cap Pyrex bottle. The respective bromoenyne (0.5 mmol) was added and argon gas was bubbled through the mixture for 5 min. Then bicyclopropylidene 10 (80 mg, 1 mmol) was added, the bottle was tightly closed, and the mixture was heated at 110 °C in a preheated oil bath for the given period of time. After cooling down to room temperature, the reaction mixture was directly added onto a pre-packed column of silica gel and the column eluted with pentane/diethyl ether. (11)

Conclusions
The new 2-bromo-2-en-6-ynes 3, 5 and 9 each containing a bromocyclohexene initiator, like the previously investigated completely acyclic analogues, [32] undergo palladium-catalyzed intra-intermolecular cascade cross coupling reactions in the presence of bicyclopropylidene 10 to give indene analogues, conjugated tetraenes, 11, 12, 13 (in MeCN at 80 °C). The reaction, under different conditions (in dimethylformamide at 110 °C) the desired spirocyclopropanated tricycle 16 was obtained albeit in low yield (24%) and observed as an equimolar mixture of diastereomers, whereas others 14, 15 were not fully isolated. Although the yield of spirocyclopropanated tricycle 16 was rather disappointing, the concept of the 6π-electrocyclizations proved to be feasible on less strained compounds. Additionally, an alternative palladium-mediated process rather than its free radical version we studied before [33][34][35] give indene skeletons with higher yield.