A Novel Regiospecific Synthesis of 1-Chloro-2-arylcyclohexenes

An efficient high yielding chemoselective synthesis of eleven novel 1-chloro-2-arylcyclohexenes employing the Suzuki cross coupling of 1-bromo-2-chlorocyclohexene with eleven different aryl boronic acids and Pd(dppf)Cl 2 ⋅ CH 2 Cl 2 catalyst is reported.


Introduction
Cross-coupling reactions of unsaturated carbon centres bearing halogens/triflates with aryl boronic acids catalyzed by palladium metal complexes have become a powerful tool in organic synthesis for the formation of carbon-carbon bonds.One of the important cross-coupling reactions in this genre is the Suzuki reaction [1][2][3][4].These organopalladium complex catalyzed couplings of unsaturated halides with boronic acids/esters have been employed in key steps to form a wide variety of pharmaceuticals and natural products [5][6][7][8][9][10].
Our laboratory is involved in the synthesis and reactions of some novel cyclic vinyl silanes.We employ the Wurtz-Fittig coupling reaction of corresponding cyclic vinyl halide with sodium and chlorotrimethylsilane in suitable solvent to prepare the cyclic vinylsilanes.Using the Wurtz-Fittig reaction, we have been able to synthesize a large number of simple and substituted cyclic vinylsilanes [15][16][17][18][19].The organosilicon compounds are anionic synthons serving as the starting materials in the total synthesis of natural products [20][21][22][23].
In this paper, we report for the first instance the synthesis of 1-bromo-2-chlorocyclohexene (2) and the chemoselective Suzuki cross-coupling reaction with eleven different aryl boronic acids (3a-k) to form eleven novel 1-chloro-2arylcyclohexenes (4a-k) in high yields.

Materials and Methods
All reactions were performed in oven dried apparatus.Reactions were monitored on Merck F-254 precoated TLC plastic sheets using hexane (60-80 ∘ C) fraction as mobile phase.GC was run on SE-30 SS 2 m × 1/8  column on Mayura 9800 gas chromatograph.IR spectra were recorded on Shimadzu FT-IR 8400S using NaCl flats as neat thin liquid film samples.The values are reported in wave numbers (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 from tetramethylsilane).Coupling constants are reported in Hz with multiplicities denoted as s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), and br (broad).GC-MS spectra were obtained using a Shimadzu GC-MS QP 5050A instrument equipped with a 30 mm × 0.32 mm BP-5 capillary column.Elemental analyses were obtained using Elementar Vario Microcube-15106062 instrument.All yields refer to the isolated yields of the products.

Synthesis of 1-Bromo-2-chlorocyclohexene (2).
To a stirred suspension of PCl 5 (1.4 g, 6.723 mmol) in 10 mL anhydrous ether was added a 10 mL ethereal solution of 1 (1.0 g, 5.525 mmol), dropwise over 30 min.The mixture was stirred for further 8 hours, when all the starting material disappeared as followed by GC.The reaction mixture was poured into crushed ice (50 g) and extracted with ether (3 × 30 mL).The combined organic extracts were washed with brine (20 mL), dried over anhydrous Na 2 SO 4 , and concentrated in vacuo to isolate 1.05 g of concentrate.
To 0.63 g (5.614 mmol) of potassium tert-butoxide in 10 mL tert-butyl alcohol was added the 1.05 g of crude in 10 mL tert-butyl alcohol drop wise over 15 min and refluxed for 2 hours, when the aliquot indicated a single peak in gas chromatogram.The mixture was diluted with water (150 mL), extracted with ether (4 × 30 mL), washed with brine (20 mL), dried (an.Na 2 SO 4 ), and concentrated.Distillation under reduced pressure gave pure 2 (0.62 g, 56%).
Our investigations have shown that the best catalyst for the cross-coupling reaction of 2 to be Pd(dppf)Cl 2 ⋅CH 2 Cl 2 under inert nitrogen atmosphere and sealed tube conditions (Scheme 1).
The reaction of 2 was extended to a wide variety of aryl boronic acids 3b-k to isolate the products 4b-k.Each coupling reaction was repeated for a minimum of three trials and the optimum yields of the products are indicated in Table 2.All products 4a-k were characterised completely by IR, 1 H-NMR, 13 C-NMR, GC-MS, and elemental analysis.
The mechanism for the formation of the 1-chloro-2arylcyclohexenes may be explained based on the bond dissociation energies of the carbon-bromine and carbonchlorine which are 289 and 335 kJ moL −1 , respectively.In the first step, due to the lower bond energy between carbon and bromine, oxidative addition of the Pd(dppf)Cl 2 ⋅CH 2 Cl 2 catalyst to 2 occurs across the carbon-bromine bond.In presence of potassium carbonate/arylboronic acid 3a-k, the species eliminates KBr, CO 2 , and KOB(OH) 2 followed by reductive elimination of the 1-chloro-2-arylcyclohexene 4ak.The restored palladium catalyst further continues the cycle.

Conclusion
A general methodology for the regiospecific replacement of bromine in 1-bromo-2-chlorocycloalkenes and formation of some novel 1-chloro-2-arylcyclohexenes using the Suzuki cross-coupling reaction are reported.The method is simple and cost efficient and yields the 1-chloro-2-aryl-cyclohexenes in high yields in short duration of time.