A highly efficient synthesis of 1-trimethylsilyl-2-arylcyclopentenes using two consecutive stages of aqueous and anhydrous reactions

A consecutive sequential two stage synthetic strategy for the preparation of eleven novel 1-trimethylsilyl-2-arylcyclopentenes is reported. In the first stage, the Suzuki reaction of 1-bromo-2-chlorocyclopentene with eleven arylboronic acids in aqueous conditions yielded the novel 1-chloro-2-arylcyclopentenes in 91-96% yields. The single crystal XRD structures of two representative 1-chloro-2-arylcyclopentenes are highlighted. In the second stage, the Wurtz–Fittig coupling reaction of the 1-chloro-2-arylcyclopentenes with metallic sodium and chlorotrimethylsilane in anhydrous ether afforded the anionic synthons: 1-trimethylsilyl-2-arylcyclopentenes in 62-82% yields. A library of twenty-two novel compounds from the two stages is reported


Introduction
Microwave assisted organic synthesis (MWAOS) has gained significant importance in recent years.Use of aqueous conditions has rendered the technique more advantageous due to green chemistry protocol principles. 1 Sequential transformations have come of age in recent years.The strategy has been used in the synthesis of complex organic molecules. 2][10][11][12] One of the recent areas of interest among scientists worldwide is to employ the green chemistry strategies which aim at reducing reaction times.
4][15] In order to increase the solubility of organic compounds in water, the use of phase transfer catalysts such as tetraalkylammonium salts/crown ethers has been employed. 16,17][27][28][29][30][31][32][33] Since the first use of microwave conditions for Suzuki couplings by Larhed and Hallberg, using Pd(PPh 3 ) 4 as the catalyst, 29 to our knowledge, there exist no reports in the literature for the use of microwaves for the coupling of vinylhalides/triflates with arylboronic acid under palladium catalyzed conditions in aqueous conditions.
In continuation of our previous work, 34 we now wish to report the microwave assisted sequential regiospecific conversion of 1-bromo-2-chlorocyclopentene (1) with eleven arylboronic acids 2a-k to 1-chloro-2arylcyclopentenes 3a-k, under aqueous conditions employing the Suzuki coupling reaction and their subsequent transformation into the vinylsilanes: 1-trimethylsilyl-2-arylcyclopentenes 4a-k as depicted in Scheme 1, employing the Wurtz-Fittig coupling reaction.The first stage employs aqueous reaction conditions, whereas the second stage involves total anhydrous conditions and metallic sodium in ether solvent.

Results and Discussion
The work presented in this article is summarized in Scheme 1, which consecutively and sequentially employs the Suzuki coupling reaction in aqueous conditions in the first stage; and the Wurtz-Fittig coupling reaction in completely anhydrous conditions in the second stage.decomposition of the compounds.The compounds 3a-k were finally isolated in pure form after column chromatography over silica gel (100-200 mesh) using ethyl acetate -petroleum benzine (60 -74 °C) as eluent.
The products were completely characterized spectroscopically.The recrystallization of the compounds 3a-k was further carried out in petroleum benzine (60 -74 °C) solvent.We found that the compounds 1-chloro-2-biphenylcyclopentene (3j) and 1-chloro-2naphthylcyclopentene (3k) gave best crystals when recrystallized from petroleum ether (60-74 °C) solvent.The compounds 3j and 3k were subjected to single crystal XRD studies and the ORTEP view of the representative molecule 1-chloro-2-biphenylcyclopentene 3j with atomic labeling (thermal ellipsoids drawn at 50% probability) is given in Figure 1.The ORTEP diagram unambiguously confirms the regiospecific formation of the product 3j and 1-chloro-2-arylcyclopentenes in general.The ORTEP view of compound 1-chloro-2-napthylcyclopentene (3k) along with other crystallographic details is furnished in supplementary data.
The mechanism for the Suzuki-Miyaura cross coupling reaction is postulated to proceed through established routes. 37We postulate the regiospecific formation of 1-chloro-2-arylcyclopentenes 3a-k due to the different bond strengths of C-Br and C-Cl of 1.The C-Cl bond energy is 335 kJ mol -1 whereas C-Br bond strength is 268 kJ mol -1 . 38Due to the lesser C-Br bond strength, the regioselective oxidative addition of the carbon-bromine bond to the palladium catalyst preferentially occurs, followed by trans-metalation and reductive elimination of the products 3a-k.

Stage 2. The Wurtz-Fittig cross-coupling reaction
Our laboratory is primarily involved in the synthesis and reactions of cyclic vinylsilanes 39 employing the Wurtz-Fittig coupling reaction.A wide range of simple and substituted cyclic vinylsilanes, which are anionic synthons, have been synthesized in our laboratory.Some of our molecules have found utility as starting materials for the total synthesis of natural products.The reaction involves the cross-coupling of cyclic vinyl halides with sodium and chlorotrimethylsilane in suitable solvent.The Wurtz-Fittig coupling reaction in contrast to the Suzuki-Miyaura coupling reaction, as performed in stage 1 above, requires completely anhydrous conditions.
In further extension of our previous work of the preparation of the 1-trimethylsilyl-2-arylcyclohexenes, 34 the 1-chloro-2-arylcyclopentenes 3a-k obtained through the Suzuki cross-coupling reaction under aqueous microwave conditions, were next subjected to the Wurtz-Fittig cross-coupling reaction to obtain the novel aryl substituted cyclic vinylsilanes 4a-k.Individually refluxing 3a-k with chlorotrimethylsilane and sodium in dry ether solvent afforded the products 4a-k in 62-82% yields (Table 1).Table 1.Optimized yields of 1-chloro-2-arylcyclopentenes 3a-k and 1-trimethylsilyl-2-arylcyclopentenes 4a-k  We postulate the mechanism for the formation of the five-membered anionic synthons 4a-k from 3a-k to traverse the mechanistic pathway as reported by us earlier. 34n this article, we would wish to report that in our experience over the years, it is found that the synthesis of the six-membered cyclic vinylsilanes is most favorable and requires less reaction time. 34In comparison, the synthesis of other medium sized rings, including the five membered rings 4a-k, requires more time and the overall yields are comparatively lesser.We reason that due to ring strain, the isolated yields of the products 4a-k, have been reduced and the time for formation increased.

Conclusions
1-Bromo-2-chlorocyclopentene (1) which possesses differing carbon-halogen bond strengths was exploited for the regioselective synthesis of 1-chloro-2-arylcyclopentenes 3a-k by the Suzuki-Miyaura cross coupling reaction.Aqueous conditions and microwave assisted organic synthesis methodology yielded the best results.The compounds 3a-k were converted to the anionic synthons: the five membered 1-trimethylsilyl-2arylcyclopentenes 4a-k employing the Wurtz-Fittig coupling reaction under completely anhydrous conditions.

Experimental Section
General.All reactions were performed in oven dried glass apparatus.The fine chemicals and solvents were purchased from Sigma-Aldrich, Merck and Spectrochem, Bangalore.Palladium catalysts were procured from Avra, Alfa -Aesar, Spectrochem and SD Fine Chemicals, Bangalore.Chlorotrimethylsilane was freshly distilled over Na before use.Anhydrous diethylether was distilled over Na/benzophenone ketyl radical before use.All reactions were monitored by Mayura 9800 GC instrument; and Merck F-254 pre-coated TLC plastic sheets using petroleum benzine (60 -74 °C) as mobile phase using iodine crystals as TLC visualization charring agent.Preliminary gas chromatograms were recorded using a Mayura 9800 gas chromatograph with OV-101 SS 2m x 1/8" column, using the temperature program 80 o C (2 mins.hold, 5 o C/min.riseto 180 o C,12 mins.hold); injector temperature 200 o C, detector temperature 220 o C. IR spectra were recorded on Shimadzu FT-IR 8400S (KBr die method); Cary 630 FT-IR, Bruker ALPHA-P spectrometers (ATR) and the values are reported in wave number (cm −1 ). 1 H NMR and 13 C NMR were obtained on a Bruker AMX 400 spectrometer using CDCl 3 with tetramethylsilane as internal standard.Chemical shifts are reported in  (ppm downfield) with reference to tetramethylsilane for non trimethylsilyl-containing compounds 3a-k and CDCl 3 with  7.26 for compounds 4a-k possessing the trimethylsilyl-group. EI-MS spectra were obtained using Perkin Elmer Clarus 680 C, employing a fused silica column, packed with Elite-5MS (5% biphenyl 95% dimethylpolysiloxane, 30 m × 0.25 mm ID × 250μm df).The components were separated using Helium as carrier gas at a constant flow of 1 ml/min.The injector temperature was set at 260°C during the chromatographic run.The 1μL of extract sample injected into the instrument the oven temperature was as follows: 60 °C (2 mins.hold, 10 °C/min.rise to 300 °C, 6 mins.hold).The mass detector conditions were: transfer line temperature 240 °C; ion source temperature 240 °C; and ionization mode electron impact at 70 eV, a scan time 0.2 sec and scan interval of 0.1 sec.The fragments were from 40 to 600 Da.Elemental analyses were obtained with a VarioMicro Cube V1.9.7 CHNS mode elemental analyzer.Microwave reactions were performed using CEM DISCOVER-SP W/ACTIVENT (Matthews NC, USA) microwave reactor model no 909155, in a 5 mL reactor vials using Teflon caps, under completely sealed environment with reactor specifications: Voltage -180/240 V AC; Max Cur.-6.3 A; Freq.-50/60 Hz; Mag.Freq.-2455MHz; Max Microwave power -300W; Max power output option -1100Hz.The microwave reactor, provided with a stirring option, was used for all the reactions.The reaction temperature, 80 °C, was reached in a ramp time of 2 minutes and hold time was set for 13 minutes.After the completion of the reaction, the reactor vials were cooled with a jet of compressed air for 3 -6 minutes.The reactor utilizes automatic pressure control, monitoring the pressure of the reaction and avoiding the loss of reaction mixture.

General procedure for the preparation of 1-chloro-2-arylcyclopentenes 3a-k Method 1. Conventional Suzuki coupling.
To 250 mg of 1-bromo-2-chlorocyclopentene (1) taken in a pressure tube was added arylboronic acids 2a-k (1.4 mmol equiv), Pd(dppf) 2 Cl 2 (0.03 mol %) catalyst, K 2 CO 3 (3.82mmol equiv) and anhydrous 1,4-dioxane (2.5 mL).The pressure tube was purged with Argon gas, capped and then introduced to a preheated oil bath at 110 ºC.The reaction mixture was heated for 4-6 hours under magnetic stirring.The reaction mixture was cooled, diluted with 30 mL ethyl acetate and filtered through a Celite bed.The excess solvent was removed on a rotary evaporator and crude residue purified by column chromatography using silica gel (100-200 mesh) and 1: 5 ethyl acetate -petroleum benzine (60 -74 °C).Method 2. MWAOS-Suzuki couplingin aqueous media using phase transfer catalyst.To 250 mg of 1-bromo-2chlorocyclopentene (1, 1 mmol equiv) taken in a 5 mL microwave vessel equipped with a stirring bar was added arylboronic acids 2a -k (1.4 mmol equiv), Pd(OAc) 2 catalyst (0.03 mol %), Na 2 CO 3 (556mg, 3.82 mmol equiv), TBAB (442mg, 1 mmol equiv) in water.The microwave vessel was purged with argon gas and stirred for 2 minutes before introducing into the microwave reactor.The temperature was ramped from room temperature to 80 °C in 2 minutes and held at same temperature for 13 min.The microwave reaction vessel was allowed to cool for 6 minutes.Confirming the completion of the reaction by GC analysis of aliquots, the reaction mixture was extracted with 10 mL ethyl acetate, separated and organic layer was filtered through a Celite bed.The excess solvent was removed on a rotary evaporator and crude residue purified by column chromatography using silica gel (100-200 mesh) using 1: 5 ethyl acetate -petroleum ether (60 -74 °C) as eluent.The pure compounds 3a-k, which appeared as single spot on TLC under UV lamp, were isolated and characterized completely.The optimized yields are given in Table 1.General procedure for the preparation of 1-trimethylsilyl-2-arylcyclopentenes 4a-k.To a suspension of finely cut sodium metal (3 g atom equiv), pre-sonicated for 10 minutes in petroleum ether (60 -74 °C) and chlorotrimethylsilane (4 mmol equiv) in 3 mL dry ether was added the individual 1-chloro-2-arylcyclopentene (1 mmol equiv) 3a-k, in 5 mL anhydrous ether.The mixture was heated on an oil bath to reflux temperature employing a Graham water-cooled condenser with CaCl 2 guard tube.The reflux was continued until the appearance of deep navy-blue coloration, and then the reactions were monitored by TLC and GC through micro work-up of aliquots.After completion of the reaction as indicated by the chromatograms, the reaction mixture was cooled to ambient temperature, the precipitated solid and remaining sodium were removed by filtering on a plug of glass wool and washed with ether (2 × 5 mL).The combined organic extract was washed with saturated sodium bicarbonate (15 mL), saturated brine (15 mL), water (3 × 10 mL), and dried over anhydrous K 2 CO 3 .The combined extract was concentrated on a rotary evaporator and purified by column chromatography, using silica gel (230-400 mesh) and petroleum benzine (60 -74 °C) as mobile phase, to obtain the pure compounds 4a-k.The spectral characterization is summarized in experimental.The optimized yields are tabulated in Table 1.Spectral details of compounds 3a-kand 4a-k.