Synthesis of fluorine containing 3-cyano / ethoxycarbonyl-2-ethyl-benzo [ b ] furans via microwave assisted tandem intramolecular Wittig and Claisen rearrangement reactions †

Microwave irradiation of [{2-(fluorophenoxy)propanoyl}-(cyano/ethoxy-carbonyl) methylene] triphenylphosphoranes resulted in the exclusive formation of fluoro-substituted 2-ethylbenzo[b]furan-3-carbonitriles and ethyl 2-ethyl-benzo[b]furan-3-carboxylic acid esters, respectively, along with triphenylphosphine oxide. The aryl propargylic ethers formed initially by the intramolecular Wittig reaction of the ylides underwent Claisen rearrangement reaction under the same reaction conditions and the resulting ortho-allenyl phenol intermediates cyclised to yield benzofurans.

The regioselectivity for the 2H-chromene or benzo [b]furan derivatives depended on the nature of substituents present on the aryloxy-moiety.Earlier, we have reported an improved synthesis of fluorine containing disubstituted alkynes by microwave induced intramolecular Wittig reaction of [acyl-(cyano / ethoxycarbonyl)methylene]triphenylphosphoranes, 22 where in, the problems associated with prolonged heating were avoided.We have successfully adopted this technique for the synthesis of various benzo[b]furan derivatives. 19The advantages of microwave technology over conventional methods in heterocyclic synthesis have been recently reviewed. 23n the present study, we wish to report a regioselective and efficient one pot synthesis of halogen containing 3-cyano/ethoxycarbonyl-2-ethyl-benzo[b]furan derivatives 8a-f by the microwave assisted tandem intramolecular Wittig and Claisen rearrangement reactions of the corresponding [{2-(aryloxy)propanoyl}-(cyano / ethoxycarbonyl) methylene]triphenylphosphoranes 4a-f.
The oxo-ylides 4a-f were subjected to controlled microwave irradiation, individually, for 6-9 min to carry out intramolecular Wittig reaction. 19,22The product mixture from each of the experiments was purified by column chromatography over silica gel to isolate the new compounds free from triphenylphosphine oxide 6, an expected common product in all the cases.

Scheme 1
[{2-(Aryloxy)propanoyl}-(cyano)methylene]triphenylphosphoranes 4a-d on microwave irradiation furnished a new product in each case, in over 80 percent yield, along with triphenylphosphine oxide 6.The formation of triphenylphosphine oxide 6 was the direct result of an intramolecular Wittig reaction of the oxo-ylides 4a-d.The IR spectra of the products revealed the presence of a nitrile group around 2230 cm -1 .The 1 H NMR spectra of all the products showed the presence of an ethyl group attached to an aromatic ring [around δ 1.4 (t, 3H) and 3.0 ppm (q, 2H)], which was not present in the parent oxo-ylides 4a-d.Microwave irradiation of [{2-(4-fluoro-phenoxy)propanoyl}-(ethoxycarbonyl)methylene]triphenylphosphorane 4e resulted in a single new product in 83 percent yield, while [{2-(2-chloro-4fluorophenoxy)propanoyl}-(ethoxycarbonyl)methylene] triphenylphosphorane 4f gave two new compounds in 78 and 8 percent isolated yield respectively.The IR spectra of these products also did not contain absorption bands due to acetylenic triple bond.The ester carbonyl absorption band was observed at 1735 cm -1 for the product of 4e and at 1715 cm -1 for the major product of 4f.The 1 H NMR spectra of these two products revealed the presence of a -CH 2 CH 3 group [around δ 1.4 (t, 3H) and 3.2 ppm (q, 2H)] attached to an aromatic ring and a -OCH 2 CH 3 group [around δ 1.3 (t, 3H) and 4.4 ppm (q, 2H)] each.
Claisen rearrangement Claisen rearrngement of aryl propargylic ethers 5a-f results in the orthoallenylcyclohexadienone intermediate 7, which enolises to a more stable ortho-allenylphenol intermediates 8a-f.Enolisation of 7 to 8 is a favored step because of aromatisation.The presence of electron-withdrawing substituents and a polar medium was reported 11 to enhance the acidity of the phenolic intermediates 8.The halogen substituents on the phenyl ring, polar medium in the form of triphenylphosphine oxide and microwave energy could be favouring dissociation of the allenylphenol 8 into a phenolate anion 9.The α,β-unsaturated nitrile or ester group present in 9 enhances the electrophilicity of the allenyl carbon, favouring intramolecular nucleophilic addition of the phenolate anion on to this carbon leading to the 2-alkylidene-2,3dihydrobenzofuran 10 formation.Alternatively, under the influence of microwave energy, the dihydrobenzofuran 10 could have been formed directly from the enone 7 by simultaneous aromatisation and cyclisation as depicted in scheme 2. This type of cyclisation was reported in the flash vacuum pyrolysis of phenyl propargyl ether leading to the formation of dihydrobenzofuran. 25The dihydrobenzofuran 10 rearranges to give more stable 2,3disubstituted-benzo[b[furans 11a-f.The regioselectivity observed in the case of 11d was attributed to the highly electronegative and bulky chlorine in

Experimental Section
General Procedures.Melting points were determined in open glass capillaries on a Fisher Johnes melting point apparatus and are uncorrected.IR spectra were recorded on FT-IR Perkin-Elmer 1310 infrared spectrophotometer. 1 H NMR (200 MHz) and 13 C NMR (50 MHz) spectra were recorded on Varian Gemini spectrometer in CDCl 3 solvent using TMS as internal standard.Mass spectra were recorded on a VG-micro mass 7070H instrument at 70eV.Elemental analyses were carried out on Elemental Vario EL (Germany) apparatus.Microwave irradiations were carried out using thick walled glass tube fitted with teflon screw cap (Aldrich, Ace pressure tube, 10.2 cm, 15 ml) in a domestic microwave oven (BPL BMO 700T).

General procedure for the synthesis of [{2-(aryloxy)propanoyl}-(cyano/ ethoxycarbonyl) methylene]triphenylphosphoranes (4a-f)
To a well stirred suspension of (cyano)methyltriphenylphosphoniumchloride/(ethoxycarbonyl) methyltriphenyl phosphonium chloride (2 mmol) in dry dichloromethane (8 ml) placed in a two necked round bottom flask equipped with a dropping funnel and a nitrogen balloon adopter, cooled to 10-15 o C, a solution of triethylamine (2 mmol) in dry dichloromethane (3 ml) was added dropwise and the reaction mixture was stirred for another 1h to generate the [(cyano) methylene] triphenylphosphoranes / [(ethoxycarbonyl) methylene] triphenylphosphorane.A solution of aryloxypropanoyl chloride (1 mmol) in dichloromethane (3 ml) was added slowly through the dropping funnel to the reaction mixture and the stirring continued for another 12 h at room temperature The reaction mixture was diluted with dichloromethane (10 ml) and washed with water (2x15 ml).The organic layer was separated and dried over anhydrous sodium sulphate.The solvent was removed on rotavapor and the crude product was purified by recrystalisation from a 1:4 mixture of hexane and ethyl acetate.The yields based on the acid chloride were given along with the physical properties for the individual phosphoranes 4a-f.

General procedure for the synthesis of 3-cyano/ethoxycarbonyl-2-ethyl-benzo[b] furans (11a-f)
Suitably substituted [{2-(4-Fluorophenoxy)propanoyl}-(cyano/ethoxycarbonyl) methylene] triphenylphosphorane 1 (2.0 g) was taken in a sealed tube and subjected to controlled microwave irradiation for a specified time at 600 watts microwave power.The dark brown reaction mixture was cooled to room temperature, dissolved in dichloromethane (10 ml) and purified by column chromatography on silica gel (100-200 mesh) using hexane as eluent.Concentration of the initial fractions afforded 3-cyano/ethoxycarbonyl-2-ethyl-benzo[b]furan 8a-f.The later fractions eluted with a 1: 1 mixture of hexane and ethyl acetate contained triphenylphosphine oxide.The reaction time and yield of the products are given in Table 1.