Mizoroki-Heck cross-couplings of 2-acetyl-5-bromobenzofuran and aryl halides under microwave irradiation

Mizoroki-Heck cross-coupling reactions of 2-acetyl-5-bromobenzofuran as well as activated and deactivated aryl bromides with various olefins were investigated under both thermal as well as microwave irradiating conditions in open air using water solvent


Introduction
Palladium-catalyzed cross-coupling reactions leading to the formation of carbon-carbon bonds are among the most powerful transformations in organic synthesis. 1,2Mizoroki-Heck crosscoupling reaction is a powerful and widely used method to couple aryl halides with terminal olefins to form cinnamates and stilbenes which are of industrial importance. 3The possibility of carrying out Mizoroki-Heck cross-coupling reactions in water and under open air could be of great interest for the development of industrial processes. 4,5One of the challenges that are facing organic chemists now is focused on the design of new methodologies able to make the already known chemical transformations simpler, faster, cheaper, and in general, more efficient processes.In particular, increasing attention has been paid to the 'green chemistry' of these processes; this concept being understood as a set of principles 6 that reduce or eliminate the use or generation of hazardous substances. 7,8Furthermore, microwave irradiation methodology assists in achieving rapid incorporation of organic synthesis into broad research diversities. 9,10ntense efforts have been made directed towards the synthesis of benzofuran derivatives due to their biological and pharmacological properties, 11,12 and to their natural occurrence. 13,14In continuation of our recent research work directed to the use of Pd (II)-complexes as precatalysts solvents tested, water as an eco-friendly solvent provided full conversion (85% isolated yield), in the presence of KOH as base and TBAB as additive, after 90 min of thermal heating at 100 o C (entry 1, Table 1).Under this condition, using K2CO3 and Et3N as bases gave 90 and 45% GCconversions, respectively (entries 3 and 4, Table 1).When the reaction was performed in DMF/Et3N/TBAB at reflux temperature for 90 min, full conversion with 92% isolated yield was obtained.No coupling product was detected when the last catalytic system was applied at r.t. for 24h.Using DMF as solvent with KOH as base in the presence of TBAB resulted in 89% GCconversion into 4-acetylstilbene 4 (entry 5, Table 1).Toluene was not a suitable solvent for this reaction regardless the used base (entries 9-11, Table 1).The TLC and 1 H NMR spectrum of the crude reaction product 4, were more clear and less contaminated with by-products when DMF was the reaction solvent (run 6, Table 1) than when water was used as a solvent (run 1, Table 1), in addition to the higher isolated yield (92%) after run 6 comparing to that obtained after run 1 (85%).Therefore, DMF was the proper solvent for this reaction.The catalytic system (DMF/TBAB/Et3N) was applied for the same cross coupling reaction under microwave irradiation instead of thermal heating and the reaction was completed within 5 min to give 4 in 88% yield.The optimized catalytic condition using DMF/TBAB/Et3N under microwave irradiation was applied for carrying out Mizoroki-Heck reactions of activated and deactivated aryl bromides 1, 5 and 6 with various olefins 2a-d as outlined in Table 2. Thus, microwave-assisted Heck crosscoupling of the aryl bromides 1, 5 and 6 with styrene 2a resulted in full conversion into the corresponding stilbenes 4, 17 and 21 in very good isolated yields (entries 1, 5 and 9, Table 2).Repeating the latter Heck cross-coupling reactions under thermal heating at 130 o C in DMF/ TBAB/ Et3N for 90 min gave 100% GC-conversion of the corresponding stilbenes 4, 17 and 21 in 92, 97 and 82% isolated yields, respectively.
Further, arylation of acrylonitrile 2b, ethyl acrylate 2c and with n-butyl acrylate 2d with aryl bromides 1, 5 and 6 proceeded smoothly under microwave irradiation at 160 ºC to furnish, in all cases, the corresponding cinnamates 14-16, 18-20 and 22-24, respectively, in high isolated yields after a reaction time 4~7 min.The high conversion in the cross-coupling of the less active 4bromoanisole 6 with the olefins 2a-d (runs 9-12, Table 2) within 7 min of microwave irradiation gives a good support for the high catalytic activity of the Pd complex 3.It was reported that strong bases such as KOH decompose n-butyl acrylate to give n-butanol and acrylic acid 21 and hence was not used in this study.
Interestingly, the cross-coupling arylation process was highly regio-and stereoselective and provided only the thermodynamically more stable trans-isomer of stilbenes, cinnamonitriles and cinnamates 4, 14-24, where GC, GC-MS and 1 H NMR of the crude reaction mixture showed no evidence for other isomers.The stereochemistry of the double bond in the reaction products was easily established.For example, the protons around the double bond were found to resonate within the aromatic region with a coupling constant about 16 Hz attributed to related olefinic hydrogens.a Conditions: Aryl bromide: 1 mmol; olefin: 1.5 mmol; TBAB: 0.6 mmol; Et3N: 3 mmol; DMF: 3 mL, Pd-complex: 0.25 mol% under microwave heating (250 Watt) at 160 ºC.b Conversions were based on GC-analysis and the values in parentheses refer to the isolated yields.c Repeating this reaction under thermal heating at reflux for 90 min gave full conversion with 92% isolated yield.d Thermal heating for 90 min gave 97% isolated yield.e Thermal heating for 90 min gave 82% isolated yield.
Next, the applicability of complex 3 in Heck cross-coupling reaction of further activated and deactivated aryl and pyridyl bromides 7-13 with styrene 2a were carried out under thermal heating as well as microwave irradiation conditions was investigated as described in Table 3.In all cases, styrene was arylated smoothly resulting in the formation of the corresponding stilbenes 25-29 and styrylpyridines 30, 31 in good to excellent isolated yields.As can be seen in Table 3, high chemoselectivity was observed in the case of 1-bromo-4-chlorobenzene (entry 2), where the more reactive bromine atom was replaced with styryl group to give 4-chlorostilbene 26 with 100% conversion under microwave irradiation.Similar cross coupling of 1-bromonaphthalene under the same conditions afforded the cross coupled product 28 in excellent isolated yield with full GC-conversion under both thermal as well as microwave irradiation (entry 4, Table 3).In addition, the Pd(II)-complex 3 was found to efficiently catalyze the coupling of 2-amino-5bromopyridine 12 and 2-amino-6-bromopyridine 13 to give the corresponding 5-styryl-and 6styrylpyridines 30 and 31, respectively, in good yields under thermal and microwave heating modes (entries 6 and 7, Table 3).2-Amino-6-bromopyridine 12 consumed longer reaction time than 2-amino-5-bromopyridine 13 under both thermal-and MW-heating reflecting the high activity of 5-bromopyridine than 6-bromopyridine.In all cases, the products were established to have the trans-configuration of 1,2-disubstituted ethylenes.The other regioisomers; 1,1disubstituted ethylenes due to -arylation 22 were not detected in the crude reaction products.In addition, a recent publication reported the partial or complete hydrogenation of the double bond when the reaction was carried out at high temperature, however we could not detect any hydrogenated product during this work. 23ryl chlorides are cheaper and more easily available than bromides and iodides, but less reactive.Efficient catalyst systems for the Heck reactions of aryl chlorides have been extensively studied. 24Herein, the reactivity of the Pd-complex 3 (0.25 mol%) in the Heck coupling of activated aryl chlorides (4-chloroacetophenone 32 and 4-chloronitrobenzene 33) with styrene 2a was studied under thermal heating as well as microwave irradiation conditions as shown in Scheme 1.Under this condition, very good yields of 4-acetylstilbene 4 and 4-nitrostilbene 17 were obtained.It is noteworthy to mention here that the catalytic activity of the Pd-complex 3 is more efficient in the Heck coupling of aryl chlorides if compared with similar reactions using our previously reported analogous Pd(II)-complexes. 15

Heck cross-coupling of 2-acetyl-5-bromobenzofuran
In the next section, we examined the catalytic activity of the Pd(II) complex 3 in the Heck crosscoupling reaction of 2-acetyl-5-bromobenzofuran 34 with styrene 2a under various reaction conditions as outlined in Table 4.The reaction was carried out in different solvent such as water, dimethylformamide and toluene using Et3N and KOH as examples of organic and inorganic bases and TBAB as additive was used in order to achieve good yields.In this aspect, water/KOH/TBAB and water/Et3N/TBAB catalytic systems provided good results 91 and 95% GC-conversions, respectively, into (E)-2-acetyl-5-(-styryl)benzofuran 35, (entries 1 and 2, Table 4).The use of DMF/Et3N/TBAB as catalytic system (entry 5) was more efficient resulting in full conversion with excellent isolated yield (99%) of the product 35 after 4 h of thermal heating at 130 o C using 0.25 mol% of Pd-complex 3.This condition (DMF/Et3N/TBAB) was repeated under microwave heating at 160 ºC (250 Watt) for 20 min to obtain 100% GCconversion (92% isolated yield) of 35, and at room temperature (about 30 ºC) for 24 h with stirring to give no reaction at all based on GC-analysis with full recovering of the bromide 34.
On the other hand, when the same reaction was carried out using DMF/KOH/TBAB catalytic system for 4 h of thermal heating it gave lower GC-conversion (85%) than in the case of using DMF/Et3N/TBAB (entry 4, Table 4).Toluene was found to be not appropriate for cross coupling of the bromide 34 with styrene 2a in either KOH or Et3N as bases to give either nil or 4% GCconversions, respectively (entries 7 and 8, Table 4).The presence of TBAB is essential for carrying out Heck cross-coupling reactions 19 as shown in Table 4 (entries 1, 2, 4 and 5) and its absence resulted in sharp decrease of the coupling product regardless the used solvent (water or DMF) in the reaction between 2-acetyl-5bromobenzofuran 34 and styrene under thermal heating (entries 3 and 6, Table 4).Based on the foregoing results, vinylation of 2-acetyl-5-bromobenzofuran 34 with acrylic systems such as acrylonitrile 2b, ethyl acrylate 2c, n-butyl acrylate 2d, tert-butyl acrylate 2e and methyl acrylate 2f under both microwave irradiation and thermal heating is illustrated in Table 5.For the synthesis of E-3-(2-acetylbenzofuran-5-yl)acrylonitrile 36 from the cross-coupling of 34 with 2b, the reaction was conducted in DMF/Et3N/TBAB as catalytic system using 0.25 mol% of the Pd-complex 3. Full conversion was obtained after 3 hours of thermal heating (isolated yield 88%) and after 20 min of microwave irradiation (isolated yields 88%) of the benzofuranylacrylonitrile 36 (entry 1, Table 5).Under similar catalytic cross-coupling condition, 2-acetyl-5-bromobenzofuran 34 was vinylated with further acrylates 2c-f and the Heck coupling reaction was completed within 3-4 hours under thermal heating and after 20 min of microwave irradiation with high isolated yields (>80%) of the corresponding 5-(benzofuranyl)acrylates 37-40 (Table 5, entries 2, 3, 4, 6).The role of TBAB as an additive was crucial for the effective vinylation in the synthesis of the cross-coupled products 36-40, however in the absence of TBAB a dramatic effect appeared as no conversion at all after 16 h of thermal heating or 30 min of microwave irradiation during the coupling of tert-butyl acrylate 2e with 2-acetyl-5bromobenzofuran 34 (Table 5, entry 5).The same effect for absence of TBAB was encountered in the coupling of methyl acrylate 2f with 34 giving only 17% conversion after 16 h of thermal heating (entry 7, Table 5) reflecting the essential role of TBAB in such cross coupling reactions.The structures of the newly synthesized cross-coupled products 36-40 were established on the basis of their elemental and spectral analyses as described in the experimental section.In conclusion, the Pd(II)-complex 3 was found to be efficient and highly active precatalyst for Mizoroki-Heck cross-coupling reactions of activated and deactivated aryl halides with styrene and acrylates under thermal heating as well as microwave irradiation conditions.Complex 3 was also highly active precatalyst when applied to the first vinylation reactions of 2acetyl-5-bromobenzofran.In all studied cases, 0.25 mol% of the Pd-complex 3 were sufficient for full conversion within short reaction times.

Experimental Section
General.Melting points were determined in open glass capillaries with a Gallenkamp apparatus.The infrared spectra were recorded in potassium bromide disks on a Pye Unicam SP 3-300 and Shimaduz FTIR 8101 PC infrared spectrophotometer.NMR spectra were recorded with a Varian Mercury VXR-300 NMR spectrometer at 300 MHz ( 1 H NMR) and at 75 MHz ( 13 C NMR) using CDCl3 as solvent and internal standard ( 7.27 and 77.36 ppm, for 1 H NMR and 13 C NMR, respectively).Capillary GC analyses were performed with a Shimadzu GC-14A or GC-14B, a Shimadzu C-R6A integrator, and an HP 5 column (25 m length, 0.25 mm i.d., 0.25 μm film) or recorded with an Agilent GC 6890N.Mass spectra (EI) were obtained at 70 eV with a type Shimadzu GCMQP 1000 EX spectrometer.Analytical thin-layer chromatography was performed using pre-coated silica gel 60778 plates (Fluka), and the spots were visualized with UV light at 254 nm.Fluka silica gel 60741 (70-230 mesh) was used for flash column chromatography.Microwave experiments were carried out using a CEM Discover Labmate TM microwave apparatus (300 W with ChemDriver TM Software).

Heck coupling of styrene with aryl halides in DMF under thermal heating
A mixture of the appropriate aryl halide 7-13, 32 and 33 (1 mmol) and styrene 2a (1.5 mmol), TBAB (0.6 mmol), Pd-complex 3 (0.25 mol%), and Et3N (303 mg, 3 mmol) in DMF (3 mL) was stirred at 130 °C under open air for the appropriate reaction time as listed in Table 3.After the reaction was almost complete (monitored by TLC), the reaction mixture was left to cool to room temperature.The reaction mixture was then extracted three times with EtOAc (3 x 20 mL) and then the organic fractions were combined together, dried over MgSO4, filtered and then the solvent was removed under vacuum.The residue was then subjected to purification via flash column chromatography with petroleum n-hexane-EtOAc (10:1) as eluent to give the corresponding pure products 25-31, 4 and 17, respectively.
After the reaction was almost complete (monitored by TLC), the reaction mixture was left to cool to room temperature.The reaction mixture was then extracted three times with EtOAc (3 x 20 mL) and then the organic fractions were combined together, dried over MgSO4, filtered and then the solvent was removed under vacuum.The residue was then subjected to purification via flash column chromatography with petroleum n-hexane-EtOAc (7:1) as eluent to give the corresponding pure products of 5-(benzofuranyl)acrylates 36-40.Heck coupling of 2-acetyl-5-bromobenzofuran (34) with acrylates in DMF under microwave heating A mixture of 2-acetyl-5-bromobenzofuran 34 (239 mg, 1 mmol) and appropriate olefin 2b-f (1.5 mmol), TBAB (0.6 mmol), complex 3 (0.25 mol%), and Et3N mg, 3 mmol) in DMF (3 mL) was mixed in a process vial.The vial was capped properly, and the mixture was then heated under microwave irradiating conditions at 160 °C and 250 Watt for 20 min.After the reaction was almost complete (monitored by TLC), the reaction mixture was left to cool to room temperature.The reaction mixture was then extracted three times with EtOAc (3 x 20 mL) and then the organic fractions were combined together, dried over MgSO4, filtered and then the solvent was removed under vacuum.The residue was then subjected to purification via flash column chromatography with petroleum n-hexane-EtOAc (7:

Table 1 .
Effect of base and solvent on Heck coupling of p-bromoacetophenone with styrene  ARKAT USA, Inc.
Pd-complex: 0.25 mol% at reflux condition for 90 min.b Conversions were based on GC-analysis and the values in parentheses refer to the isolated yields.c Repeating this condition at r.t. for 24h resulted in no reaction based on GC-analysis.d Repeating this condition under microwave heating (250 Watt) at 160 ºC for 5 min resulted full conversion with 88% isolated yield after 5 min.

Table 2 .
Heck cross-coupling of aryl bromides with olefins under microwave irradiation

Table 3 .
Heck cross-coupling of aryl and pyridyl bromides with styrene All values refer to the isolated yields.c Conversions were based on GCanalysis and the values in parentheses refer to the isolated yields.Scheme 1. Heck cross-coupling of activated aryl chlorides with styrene.Reaction conditions: a Thermal heating at 130 ºC for 6h.b Microwave heating at 160 ºC and 250 Watt for 10 min.All values refer to isolated yields.

Table 4 .
Base and solvent effect on Heck coupling of 2-acetyl-5-bromobenzofuran 34 with styrene 2a a Conditions: Bromide: 1 mmol; styrene: 1.5 mmol; TBAB: 0.6 mmol; base: 3 mmol; solvent: 3 mL, Pd-complex 3: 0.25 mol% at reflux condition for 4h.b Conversions were based on GCanalysis and the values in parenthesis refer to the isolated yields.c Repeating this condition at r.t. for 24h resulted in no reaction.d Repeating this condition under MW at 160 ºC (250 Watt) resulted in 92% yield with full conversion after 20 min.