Microwave-assisted synthesis of (2-butyl-5-nitrobenzo[ b ]furan-3-yl)-[4-(substituted ethynyl)phenyl]methanones

We report a new method for the efficient and rapid synthesis of (2-butyl-5-nitrobenzo[ b ]furan-3-yl)[4-(substituted ethynyl)phenyl]methanones using a Pd-Cu catalyzed microwave-assisted Sonogashira coupling reaction. In comparison to the conventional heating procedure, the time of synthesis and effort are significantly reduced in the present method, without side-product formation. Microwave irradiation considerably accelerated the formation of (2-butyl-5-nitrobenzo[ b ]furan-3-yl)[4-(substituted ethynyl)phenyl]methanone analogues.


Introduction
Oxygen containing heterocycles form one of the largest group of compounds in organic chemistry.Among them, one of the most important are benzo[b]furans, a class of fused-ring heterocyclic compounds.Several derivatives of benzo [b]furan have been recognized as biologically and pharmacologically relevant molecules. 1enzo[b]furan derivatives exhibit significant activity against various therapeutic areas including antifungal, 2 antitubercular, 3 antiinflammatory, 4 anticonvulsant, 5 anticancer, 6 anti-HIV, 7 analgesic, 8 antiparasitic, 9 antihyperlipidemic, 10 antioxidant, 11 antidiabetic, 12 antihypertensive, 13 hypotensive, 14 arrhythmic activities, 15 and so on.Additionally, such heterocyclic compounds are found in various branches of chemical research, such as in polymer, 16 dyes industries, 17 and in silver photography. 18Benzo[b]furan derivatives are important heterocycles which are frequently found as both bioactive compounds and organic materials.The benzo[b]furan moiety is found in structurally simple drugs like Ramelteon 19 I, Amiodarone 20 II, Vilazodone 21 III, Dronedarone 22 IV, Pyridylbenzofuran 23 V, Methoxsalen 24 VI (Figure 1).[27] Figure 1 Representative examples of some drugs containing the benzo[b]furan moiety.
The palladium catalyzed coupling of terminal acetylenes with aryl triflates (the Sonogashira cross-coupling reaction) is an effective and widely-used method to form new carbon-carbon bonds. 28,29At present, the Sonogashira reaction has been widely used to couple a terminal sp-hybridized carbon of an alkyne with an sp 2 carbon of an aryl or vinyl halide (or triflate), 30,31 It also plays a key role in the synthesis of many natural products, 32 pesticides, pharmaceuticals 33 and new materials and nano-molecular devices. 34Since the discovery of the Sonogashira reactions, the most widely used catalysts are Pd-type compounds.Many cross-coupling reactions catalyzed by Pd/Cu co-catalyst involve cross-coupling of a terminal alkyne with a halogenated or triflyloxy-benzene, however the reactions coupling of terminal alkynes with halogenated or trifloxy heterocycles have been investigated in very few numbers.
Microwave irradiation is used to promote chemical reactions, and a number of reviews have advocated the use of microwave technology in organic synthesis. 35Microwaves provide a powerful way to carry out synthetic chemistry and the ability of microwaves to shorten reaction times, increase reaction yields and to facilitate reactions that are otherwise unsuccessful under conventional conditions, are properties that medicinal chemists often look for to optimize their everyday procedures. 36erein, we report a synthesis of novel (2-butyl-5-nitrobenzo[b]furan-3-yl)[4-(substituted ethynyl)phenyl]methanones employing an environment-friendly microwave irradiation method via benzo[b]furan derivatives as intermediates.

Results and Discussion
The synthesis of the title compounds was carried out by both microwave irradiation and conventional heating procedures as shown in Scheme 1. 2-(Bromomethyl)-4-nitrophenol (1) was taken as starting material.The first step involved formation of 2-butyl-5-nitrobenzo[b]furan (2) from 1 in a two-step in situ synthesis, where firstly triphenylphosphine in DCM as solvent was added, followed by reflux for one hour, then triethylamine and pentanoyl chloride were added and the mixture heated at reflux in toluene for three hours to form 2-butyl-5nitrobenzo[b]furan (2)
Sonogashira coupling of the triflate 4 with various substituted terminal acetylene derivatives under microwave irradiation and conventional heating, followed by simple work-up yielded (2-butyl-5nitrobenzo[b]furan-3-yl) [4-(substituted ethynyl)phenyl]methanones (5a-k).The microwave irradiation provided excellent yields compared to conventional heating.The structures of compounds 5a-k were characterized by various spectroscopic techniques such as FT-IR, 1 H NMR, 13 C NMR, mass spectral and elemental analyses; e.g. the IR spectrum of compounds 5a, 5b, 5c, 5d, 5e, 5h, 5j, and 5k showed an acetylenic band at 2220 cm -1 , and C=O stretching at 1630 cm -1 ; the 1 H NMR spectrum of all products showed signals in the aromatic region, between or near about 7-8 ppm and in the aliphatic region in between or near about 0-3 ppm ; the 13 C NMR spectrum of compound 5b, 5c, 5d, 5e, 5f, 5g, 5i, and 5j showed acetylenic carbons in the regions 91-98 and 75-88 ppm.LC-MS analysis of compounds 5a and 5b showed 100% purity.The mass spectra and C, H, N analysis results of all compounds are in agreement with the assigned structures.The reaction times and yields of compounds 5a-k by microwave and conventional methods are given in Table 1.
The acetylenes with aliphatic substituents (entries 5f, 5g, 5h and 5i) were formed in slightly higher yields than those with aromatic substituents (entry-5a, 5b, 5c, 5d, 5e and 5j) under microwave irradiation at 110 o C and 70-80 W for 5-10 minute in a sealed vessel, as compared with the conventional heating.Compound 5k was formed in higher yield by both microwave and conventional methods at 80 o C, compared to all other compounds due to the use of trimethylsilylacetylene. Formation of all the desired compounds was accelerated by microwave irradiation, being obtained in 5-10 minutes with higher yields as compared with the conventional heating method.

Conclusions
In conclusion, we report a simple, efficient, rapid and environment-friendly method for the synthesis of novel (2-butyl-5-nitrobenzo[b]furan-3-yl)[4-(substituted ethynyl)phenyl]methanones employing various acetylene substrates using microwave-assisted Pd-catalysed and Cu(Xantphos)I co-catalysed Sonogashira coupling reactions.The advantages of microwave irradiation were avoidance of the formation of side products, and also useful in the case of catalyst, to avoid the formation of palladium oxide and triphenylphosphine oxide (TPPO) complex.Furthermore, we found that the reaction is generally tolerant of all electron-withdrawing, electron-donating, aromatic and aliphatic substituents.The structures of all compounds were supported by mass and elemental analyses as well as spectral data such as FT-IR and 1 H NMR, and some of the compounds were characterized by 13

Experimental Section
General.All purchased chemicals were used without further purification.Reactions were monitored by thin layer chromatography (TLC) on silica gel-G plates (G60 F254 (Merck)) of 0.5 mm thickness, visualizing with ultraviolet light (254 and 365 nm), or with iodine vapor or aq.KMnO4.Melting points were determined using a Buchi B-540 capillary apparatus.IR data were recorded on a Shimadzu FT-IR-8400 instrument using DRS (diffusive reflectance system) method and are reported in cm -1 (KBr).NMR spectra were recorded on a Bruker Avance 400 MHz spectrometer (400 MHz for 1 H NMR and 101 MHz for 13 C NMR) respectively in deuterated solvents like CDCl3 or DMSO-d6 and chemical shifts are referenced to the solvent residual signals with respect to tetramethylsilane; 1 H NMR chemical shifts are designated using the following abbreviations as well as their combinations: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad signal, coupling constants in Hz.Elemental analysis was carried out on Euro EA 3000 elemental analyser and the results are in agreement with the structures assigned.Microwave experiments were carried out in an Anton-Paar Monowave 300 synthesizer using borosilicate glass G10 vial sealed with PTFE-coated silicone septum.The control of reaction temperature was monitored by ruby thermometer.Mass spectra were recorded on a Shimadzu GC-MS-QP-2010 mass spectrometer in ESI (70eV) model using direct inlet probe technique and m/z is reported in atomic units per elementary charge.Solvents were evaporated with a Büchi rotary evaporator.Purification was performed by column chromatography using silica gel 40-63 µm (230-400 mesh size), and borosil glass column having a length about 1000 mm.(2).A mixture of 2-hydroxy-5-nitrobenzyl bromide 1 (5.0 g, 21.5 mmol), triphenylphosphine (5.65 g, 21.5 mmol) and dichloromethane (80 mL) was heated to reflux for 1 h.On cooling to rt, a white precipitate of phosphonium bromide salt separated.To the phosphonium bromide in toluene (100 mL), was added triethylamine (7.5 mL, 53 mmol) and pentanoyl chloride (5.19 g, 43 mmol).The mixture was heated and stirred under reflux for 3 h.After completion of the reaction (checked by TLC), It was allowed to cool, the triphenylphosphine oxide formed was filtered off, and washed with EtOAc and the filtrate was concentrated in vacuo.The viscous residue obtained is dissolved in water and extracted with EtOAc.The combined organic layers was dried over anhydrous Na2SO4 and the solvent removed to provide 2-butyl-5nitrobenzo 6 mmol) and dichloromethane (40 mL) were stirred together to obtain a homogeneous solution.The flask was cooled in an ice-bath and SnCl4 (4.8 mL, 41.0 mmol) was added dropwise, with stirring.The mixture was stirred for 30 min with ice cooling and then for 2 h at rt.After completion of the reaction (checked on TLC), the mixture was poured into ice cold water and extracted with CH2Cl2 (20 mL × 2).The organic layer washed with saturated aq.NaHCO3 (30 mL × 2).The combined organic layer was dried over anhydrous Na2SO4 and the solvent was removed in a Büchi evaporator to obtain a crude solid, titurated with Et2O (10 mL × 3) to obtain (

Table 1 .
Synthesis of compounds 5a-k by microwave and conventional heating C NMR and LC-MS analysis.The straightforward synthesis of these compounds from readily available starting materials should open a new access for novel benzo[b]furan heterocycles with potentially interesting biological and pharmaceutical activities.