Studies on the synthesis of 3-substituted benzo[ b ]furanes by intramolecular S N Ar on 2-(2´-fluoroaryl)-2-(1-azolylmethyl)oxiranes

The synthesis of substituted benzo[ b ]furan derivatives by an approach involving opening of 2-(2’-halogenoaryl)oxiranes with base and subsequent cyclization of the alkoxide intermediate by an intramolecular S N Ar reaction has been studied. Our results show that an azole moiety (imidazole, triazole) is required for the formation of benzo[ b ]furans. The negative charge in the intermediate carbanion is delocalized through the conjugated azole moiety (dipole stabilized side chain N-C α carbanions). Electron-withdrawing groups in the aromatic ring favour the intramolecular cyclization. This is the case when using 2’-fluoroaryl rather than 2’-chloroaryl groups, in accordance with the leaving-group ability of fluoro and chloro groups in the S N Ar reaction. This methodology involves the formation of O(1)-C(7a) bond of benzo[ b ]furan in the cyclization step.


Introduction
Several synthetic strategies can be found in the literature 1 for the preparation of benzo[b]furans based on the building of the benzene ring from a properly substituted furan derivative or, much more often, on the building of the furan ring from substituted benzene derivatives.In the latter case, the formation of different bonds can be envisaged in the cyclization step: O-C2, C2-C3, C3-C3a and O1-C7a.The synthetic approach involving formation of the bond between the furane oxygen and the benzene ring is scarcely documented in the literature and no general method is available based on this approach.
On the other hand, in the course of an industrial research project aimed at the development of antifungal agents, we found an unexpected result when treating 2-(2'-fluoroaryl)-2-(1azolylmethyl)oxiranes with a non-nucleophilic base such as sodium tert-butoxide: the oxirane ring was opened by the effect of the base and the intermediate allylic alkoxide underwent spontaneous cyclization with displacement of a fluoro group to give the corresponding benzo[b]furane derivative.Presumably, the fluorine atom was activated as leaving group in a S N Ar type process by the presence of a second fluoro group in the aromatic ring.Moreover, the negative charge in the intermediate carbanion was delocalized through the conjugated azole moiety (dipole stabilized side chain N-Cα carbanions) 2 (Scheme 1).We were interested in determining the scope of the synthesis of benzo[b]furans by the above described approach (formation of O-aromatic benzene carbon bond in the cyclization step).Several questions arise: a) is the presence of the azole moiety required for an effective cyclization?, b) what is the influence of additional electron-withdrawing substituents in the aromatic ring?, c) would chloro derivatives also lead to successful cyclization?.To answer these questions we prepared some 2-(2'-haloaryl)oxiranes and we tested the reaction of these substrates with base.

Preparation of substituted 3-(1H-1,2,4-triazol-1-ylmethyl)benzo[b]furans and 3-(1H-1imidazolylmethyl)benzo[b]furans
The proposed synthetic route leading to these 3-substituted benzo[b]furans 3 is outlined in Scheme 2, and involves the preparation of the required oxiranes 2 from the corresponding ketones 1. Base-induced opening of the epoxides 2 and subsequent cyclization would afford the heterocycles 3. Table 1 summarizes the substituents and the numbering of compounds 1-3 prepared.Ketones 1 were prepared by standard methodologies summarized in Scheme 3. Method A 3 was used for the synthesis of 1a-b and method B 4 for the preparation of 1d-g.Both procedures involve the α-bromination of the starting ketone and the nucleophilic substitution of the bromo group by the corresponding azole.Compound 1a was also obtained from commercial 2-chloro-1-(2',4'-dichlorophenyl)ethanone.HMBC (Heteronuclear Multiple Bond Connectivity) 5 experiments confirmed the structure 1b, the regioisomer containing a 4-nitro-1-imidazolyl group being selectively formed.Conditions B provided better yields than conditions A for ketones featuring an imidazole moiety.However, conditions B were less satisfactory for the triazole derivatives, by-products being obtained.Therefore, ketones 1i-j bearing a triazole moiety were obtained by an alternative procedure (Method C), 6 involving nucleophilic displacement by 4-amino-1,2,4-triazole and subsequent removal of the amino group via diazonium salt.Compound 1c was kindly provided by Ferrer Internacional S.A. Ketone 1h was prepared from 1c in modest yield (26%) by treatment with methyl iodide in THF in the presence of sodium hydride.

Scheme 3
Oxiranes 2 were obtained by methylenation of ketones 1.Two sets of conditions were used (Scheme 4).Epoxides 2a-c, 2f-g, 2i-j were prepared with trimethylsulfoxonium iodide as methylenating agent, 7 sodium hydroxide as base, in water-dichloromethane in the presence of a phase-transfer catalyst.Oxiranes 2d, 2e, 2h were obtained by treatment of the corresponding ketones with dimethylsulfonium methylide, generated from methyl trimethylsulfonium sulfate and sodium hydroxide, in water-dichloromethane in the absence of a phase-transfer agent. 8In general, the isolated yields were good, but the reaction failed for ketone 1b and total conversion was not achieved with ketone 1g.Oxirane 2g decomposed upon attempted chromatographic purification.In all other cases the crude products were pure enough ( 1 H NMR) to be used directly in the next step without further purification.Compounds 2e, 2h-j were obtained as diastereoisomeric mixtures, which were not separated.
Once the oxiranes 2 became available we undertook the preparation of benzo[b]furans 3 by treatment of 2 with sodium tert-butoxide in anhydrous dimethylsulfoxide (Scheme 5, Table 2).

Scheme 5
When performing the reaction with 2a at room temperature, only an 18% isolated yield of the desired benzo[b]furan 3a was obtained, together with a 13% of a mixture of (E, Z) isomers of the allylic alcohol 4 (Scheme 5).When the isolated 4 was treated with the same base in anhydrous DMSO at 60ºC, a mixture of 3a and 4 was again observed.Complete conversion to the cyclized compound 3a was not possible.It was clear from this result that the chloro group was not a good enough leaving group in the intramolecular S N Ar process.Then, we turned to fluorinated oxiranes.Benzo[b]furan 3c and 3j were obtained from epoxides 2c and 2j at room temperature in fairly good yields after chromatographic purification.In the other cases, heating of the solution at 60ºC for one or two days was required for complete conversion, and the isolated yields of 3 after chromatography were modest.For 3d and 3i, although the presence of the desired compounds could be observed in the 1 H NMR spectra of the crude mixtures, the high complexity of these mixtures precluded the isolation of pure compounds.In an attempt to improve the results another base was tested.Thus, oxirane 2c was treated with lithium diisopropylamide in THF at room temperature.The 1 H NMR spectrum of the crude mixture showed the presence of compounds with a benzofuran moiety and an allylic alcohol moiety in a 1:6 ratio.Addition of a radical scavenger (galvinoxyl) to the reaction between 2c and sodium tert-butoxide did not affect the course of the process, excluding a pathway through radical intermediates.

Attempted preparation of substituted 3-methyl(or ethyl)benzo[b]furans
The general synthetic pathway for the preparation of benzo[b]furan derivatives 7 which do not bear the azole moiety is outlined in Scheme 6.The corresponding epoxides 5 were prepared by standard methodologies, by direct methylenation of commercial ketones or by a two step strategy involving Wittig olefination of ketones to give compounds 6 and subsequent epoxidation with m-chloroperbenzoic acid.However, all attempts to promote the formation of heterocycles 7 from oxiranes 5 were unsuccessful.Several basic conditions were tested.When 5k and 5l were treated with one equivalent of lithium diisopropylamide (LDA) in THF at -78ºC and then at reflux temperature, complex mixtures were obtained (GC-MS, 1 H NMR) containing regioisomeric oxirane products resulting from the substitution of one halogen atom of the aromatic ring by the diisopropylamino group.This was an indication that the base had acted also as a nucleophile through a benzyne intermediate.Treatment of oxiranes 5k and 5m with sterically hindered and non nucleophilic bases such as potassium bis(trimethylsilyl)amide (KHMDS) produced also substitution of the halogen group.Treatment of 5k with sodium tert-butoxide in anhydrous DMSO at 60ºC gave no reaction, the starting compound being recovered.Complex mixtures were obtained from 5k and 5l by using phosphazene or Schwesinger bases 9 in THF at -78ºC, no defined products being isolated. ARKAT

Conclusions
The scope of the synthesis of benzo[b]furans by an approach involving opening of 2-(2'halogenoaryl)oxiranes with base and subsequent cyclization of the alkoxide intermediate by an intramolecular S N Ar reaction has been studied.It seems clear from our results that an azole moiety (imidazole, triazole) is required for the formation of benzo[b]furan derivatives.The reason is that the negative charge in the intermediate carbanion is delocalized through the conjugated azole moiety (dipole stabilized side chain N-Cα carbanions).As expected from an S N Ar process, electron-withdrawing groups in the aromatic ring favour the intramolecular cyclization and this is also much more successful with 2'-fluoroaryl than with 2'-chloroaryl groups, in accordance with the leaving-group ability of fluoro and chloro groups in this type of reactions.This methodology involves the formation of O1-C7a bond of the heterocycle in the cyclization step.

Experimental Section
General Procedures.Melting points were measured with a Kofler Reicherdt apparatus and are uncorrected.GC analyses were performed in a Hewlett-Packard 5890 II Plus, with a column HP-5 (cross-linked 5%, Ph-Me silicone, 30 m x 0.32 mm x 0.25 µm).IR data were obtained on a Nicolet 510 ZDX FTIR spectrophotometer. 1 H NMR spectra (250 MHz) and 13 C NMR (62.5 MHz) were recorded on a Bruker AC-250.Chemical shifts (δ, ppm) were referenced to Me 4 Si ( 1 H and 13 C).The abbreviations used are s for singlet, d for doublet, dd for double doublet, t for triplet, q for quartet and m for multiplet.Mass spectra (MS-EI) were determined at the Servei d'Anàlisi de la Universitat Autònoma de Barcelona on a Hewlett-Packard 5989A spectrometer, using impact ionization at 70 eV.HRMS have been determined at the Servicio de Espectrometría

2-(2'-Fluoro-5'-trifluoromethylphenyl)-2-(1H-1-imidazolylmethyl)oxirane (2g).
A 50% aqueous solution of NaOH (7 mL, 87.5 mmol) was slowly added to a stirred solution of 1g (2.44 g, 8.9 mmol) and methyl trimethylsulfonium sulfate (2.73 g, 14.5 mmol) in dichloromethane (15 mL).The mixture was heated under reflux for 24 h.Water was added (30 mL) and it was extracted with dichloromethane.The organic phase was dried with anhydrous sodium sulfate and the solvent was evaporated to afford a red oil (2.21 g) in which the presence of 2g was identified by 1 H NMR, but no defined compound could be obtained after column chromatography of the residue; 1  The mixture was heated under reflux for 12 h.Water was added (20 mL) and it was extracted with dichloromethane.The organic phase was dried with anhydrous sodium sulfate and the solvent was evaporated to afford 2h 13a,18 as a mixture of diastereoisomers (0.568 g, 49%), ratio 2.5/1 by 1 H NMR) as a yellow oil; the mixture was not further purified and it was used directly in the next step; IR (film, cm

3-[1-(1H-1-Imidazolyl)ethyl]benzo[b]furan (3e).
A solution of sodium tert-butoxide (0.15 g, 1.5 mmol) in anhydrous DMSO (2 mL) was added at RT and under an inert atmosphere to a stirred solution of 2e (0.29 g, 1.3 mmol) in anhydrous DMSO (3 mL).After stirring the mixture at RT for 24 h and at 60ºC for 48 h, water was added (10 mL) and it was extracted with dichloromethane.The organic phase was washed with water and with a saturated NaCl aqueous solution, it was dried with anhydrous sodium sulfate and the solvent was evaporated.The residue was purified by column chromatography through silica gel with mixtures of dichloromethane/ethyl acetate of increasing polarity as eluent.Compound 3e was obtained as an oil (0.055 g, 16%); 1 H NMR (CDCl 3 ) δ 1.89 (d, J = 7.3 Hz, 3H), 5.54 (q, J = 7. 3

6-Methoxy-3-(1H-1-imidazolylmethyl)benzo[b]furan (3f).
A solution of sodium tert-butoxide (0.12 g, 1.2 mmol) in anhydrous DMSO (2 mL) was added at RT and an under inert atmosphere to a stirred solution of 2f (0.207 g, 0.8 mmol) in anhydrous DMSO (3 mL).After stirring the mixture at RT for 24 h and at 60ºC for 24 h, water was added (10 mL) and it was extracted with dichloromethane.The organic phase was washed with water and with a saturated NaCl aqueous solution, it was dried with anhydrous sodium sulfate and the solvent was evaporated.The residue (0.105 g, red oil) was purified by column chromatography through silica gel with mixtures of dichloromethane/ethyl acetate of increasing polarity as eluent.Compound 3f was obtained as an oil (0.032 g, 17%); 1  A solution of sodium tertbutoxide (0.19 g, 2.04 mmol) in anhydrous DMSO (2 mL) was added at RT and under an inert atmosphere to a stirred solution of 2h (0.350 g, 1.4 mmol) in anhydrous DMSO (6 mL).After stirring the mixture at RT for 24 h and at 60ºC for 20 h, water was added (20 mL) and it was extracted with dichloromethane.The organic phase was washed with water and with a saturated NaCl aqueous solution, it was dried with anhydrous sodium sulfate and the solvent was evaporated.The residue (0.315 g, red oil) was purified by column chromatography through silica gel with ethyl acetate as eluent.Compound 3h was obtained as an oil (0.053 g, 18%); IR (film, cm -1 ) 3121, 2994, 2931, 1618, 1490, 1437, 1276, 1138, 807; 1 H NMR (CDCl 3 ) δ 1.95 (d, J = 7.0 Hz, 3H), 5.75 (q, J = 7.0 Hz, 1H), 6

Table 2 .
Conditions and yields for the preparation of 3