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Palladium-Catalyzed Paraformaldehyde Insertion: A Three-Component Synthesis of Benzofurans Received 00th January 20xx, Accepted 00th January 20xx
Xiufang Cheng,a Yi Peng,a Jun Wu,a Guo-Jun Denga*
DOI: 10.1039/x0xx00000x www.rsc.org/
An efficient procedure for 2-aroylbenzofuran preparation from 2-bromophenols, phenacyl bromides and paraformaldehyde is described. The cheap and stable paraformaldehyde served as the carbon source via an in situ formylation reaction. Benzofuran is one of the commonly encountered structural motifs in natural products. 1 In recent years, benzofuran derivatives have seen numerous applications in the development of pharmaceutical drugs and functionalized materials.2 Particularly, the 2-aroylbenzofuran structural motifs have displayed a range of biological activities. 3 These heterocyclic compounds can be used as tubulin polymerization inhibitors,4 antimitotic agents,5 and antimicrobials.6 Meanwhile, 2-aroylbenzofurans also could be used as key precursors for the preparation of multisubstituted benzofurans such as 2-aroyl-3arylbenzofurans and 2-aroyl-3-alkylbenzofurans which both showed important biological activities. 7 Therefore, the development of efficient methods for rapid construction of 2aroylbenzofurans attracted considerable interests. The classic method for the synthesis of these compounds depends on the Rap-Stoermer condensation of salicylaldehydes with αbromoketones.8 Recently, this reaction has been extensively investigated and could be carried out under microwaves 9 or solvent-free conditions10 with good functional group tolerance. Besides the Rap-Stoermer condensation reaction, few other methods are also available to prepare 2-aroylbenzofuran derivatives, including palladium-catalyzed arylation of benzofuran-2-carbaldehydes with aryl boronic acids, acylation of benzofurans and oxidative dehydrogenation of 2-aroyl dihydrobenzofurans.11 The aforementioned procedures for the synthesis of 2aroylbenzofurans are mainly based on 2-hydroxybenzaldehydes which could be prepared from phenols via an ortho-selective
a
Key Laboratory of Environmentally Friendly Chemistry and Application of Ministry of Education, College of Chemistry, Xiangtan University, Xiangtan, 411105, China. Fax: (+86)-731-58292251; Tel: (+86)-731-58298280; E-mail: [email protected] Electronic Supplementary Information (ESI) available: [details of any supplementary information available should be included here]. See DOI: 10.1039/x0xx00000x
formylation procedure using various formylating reagens.12 Paraformaldehyde is an abundant, easy to handle, and inexpensive one carbon source. In recent years, various methods have been developed to introduce paraformaldehyde into more complex molecules as carbonyl or carbon source. 13 Most of the developed methods are based on the condensation of paraformaldehyde with active amino group or enamides. 14, 15 Formylation of aromatic ring with paraformaldehyde is less studied. Very recently, the Beller and Wu groups developed palladium-catalyzed carbonylation of aryl bromides to selectively afford aromatic aldehydes or heterocycles using paraformaldehyde as the carbonyl source. 16 We also developed a palladium-catalyzed phthalazinone synthesis using paraformaldehyde as the carbon source via an in situ ortho formylation of 2-halomethylbenzoates. 17 It is highly desirable to use paraformaldehyde as the carbon source for construction of heterocyclic compounds. Based on our continuous interest in heterocyclic compound preparation using readily available materials,18 herein, we disclose an alternative route for the three-component synthesis of 2-aroylbenzofurans from 2bromophenols, phenacyl bromides and paraformaldehyde under palladium-catalyzed reaction conditions.
Scheme 1 2-Aroylbenzofurans formation using paraformaldehyde as carbon source.
Initial reaction optimization was performed with 2bromophenol (1a), paraformaldehyde, 2-bromo-1phenylethanone (2a), 1,1'-bis(diphenylphosphino)ferrocene (dppf) and K2CO3 in toluene at 120 oC under air atmosphere (Table 1). Catalyst screening showed that Pd(COD)Cl 2 gave the best yield of the desired product (Table 1, entry 5). Then various ligands were screened using Pd(COD)Cl2 as the catalyst. The yield could be improved to 41% when dpppy (diphenyl-2pyridylphosphine) was used (Table 1, entry 9). Notably, the base played an important role in this kind of transformation. Among the various bases screened, K 2CO3 showed the best efficiency (Table 1, entries 9−13). Besides toluene, DMF and DMSO are also good reaction media for this kind of reaction to
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provide 3a in 46% and 65% yield, respectively (Table 1, entries 15 and 16). Other organic solvents such as 1,2-dichloroethane (DCE) and dioxane were much less efficient (Table 1, entries 14 and 17). The reaction yield could be improved to 80% when the reaction temperature was increased to 140 oC (entry 18). The product 3a could be further improved to 86% yield when 1.5 equiv of 2a was employed to the reaction (Table 1, entry 19).
(Table 2, entry 8). Hindered substrate such as 2i could smoothly View Article Online DOI: 10.1039/C6OB00198J react with 1a to give the product 3i in 45% yield (Table 2, entry 9). To our delight, hetero ketones such as 2-bromo-1-(thiophen2-yl)ethanone (2j) also participated in the reaction to provide the corresponding benzofuran product 3j in moderate yield (Table 2, entry 10). Table 2 Reactions of 1a with various ketones 2a
Table 1 Optimization of the reaction conditionsa
a
Conditions: 1a (0.2 mmol), 2a (0.24 mmol), paraformaldehyde (0.5 mmol), catalyst (5 mol %), ligand (10 mol %), base (0.6 mmol), solvent (0.8 mL), 24 h, 120 oC under air. b GC yield. c At 140 oC. d 2a (0.3 mmol).
With the optimized reaction conditions in hand, we then investigated the scope of the reaction with respect to 2bromophenol (1a) and various phenacyl bromides (2) in the presence of paraformaldehyde (Table 2). The model reaction of 1a with 2a and paraformaldehyde gave the desired product 3a in 81% isolated yield (Table 2, entry 1). Substituents on the phenyl ring of 2-bromo-1-arylethanone significantly affected the reaction yields (Table 2, entries 2-8). When a methoxy group was present, the corresponding product 3b was obtained in 64% yield. Good yield could be achieved when a phenyl group was located at the phenyl ring of 1a (Table 2, entry 3). Moderate to good yields were obtained when fluoro and chloro substituents were present (Table 2, entries 4 and 5). The position of substituent profoundly affected the reaction yield. When 2-bromo-1-(2-chlorophenyl)ethanone (2f) and 2-bromo1-(3-chlorophenyl)ethanone (2g) were employed, the corresponding product 3f and 3g were obtained in only 40% and 41% yields, respectively (Table 2, entries 6 and 7). Under the optimized reaction conditions, trifluoromethyl group was well tolerated to give the corresponding product in 60% yield
a
Conditions: 1a (0.2 mmol), 2 (0.3 mmol), paraformaldehyde (0.5 mmol), Pd(COD)Cl2 (5 mol %), dpppy (10 mol %), K2CO3 (0.6 mmol), DMSO (0.8 mL), 24 h, 140 oC under air. b Isolated yields based on 1a.
To further explore the scope of the reaction, a number of substituted 2-halophenols (1) were employed to react with 2a and paraformaldehyde (Table 3). Moderate to good yields were obtained when electron-donating groups such as methyl, ethyl, propyl, methoxy and electron-withdrawing groups such as fluoro, chloro, cyano and trifluoromethyl were present at the para position of the hydroxy group (Table 3, entries 1-7, 9-11). When 2-bromo-4,5-dimethylphenol (1m) was used, the desired product 3v could be obtained in 68% yield (Table 3, entry 12). Lower yield was obtained when 3-bromonaphthalen-2-ol (1n) was used as the substrate (Table 3, entry 13). To our delight, 2bromopyridin-3-ol (1p) could smoothly react with 2a to provide the corresponding product 3x in 70% yield (Table 3, entry 15). Similar yield could be achieved when 2-iodopyridin-3-ol (1q) was employed (Table 3, entry 16). However, much lower yield was obtained when 2-chloropyridin-3-ol (1o) was used as the substrate due to the low reactivity (Table 3, entry 14). It should be noted that when 3-bromo-(1,1'-biphenyl)-4-ol (1i) and 1((1,1'-biphenyl)-4-yl)-2-bromoethanone (2c) were used as the
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substrates, bioactive (1,1'-biphenyl)-4-yl(5-phenylbenzofuran2-yl)methanone (3y) was obtained in 65% yield (Table 3, entry 17).6c The low reaction yields obtained in these reactions mainly due to low conversions of substrates 1.
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Table 3 Reactions of 2a with various phenols 1a
absence of palladium catalyst, reaction intermediate AView wasArticle obtained Online DOI: 10.1039/C6OB00198J in 72% yield after 18 h (Scheme 2, a). Compound A could further react with paraformaldehyde under the standard reaction conditions to convert into the desired products 3a in 82% yield (Scheme 2, b). No desired product was observed when chemical A was treated with the optimized reaction conditions in the absence of paraformaldehyde (Scheme 2, c). These control experiments showed that A is a key intermediate and paraformaldehyde serves as an one carbon source in the whole process.
Scheme 3 Possible reaction mechanism.
a
Conditions: 1 (0.2 mmol), 2a (0.3 mmol), paraformaldehyde (0.5 mmol), Pd(COD)Cl2 (5 mol %), dpppy (10 mol %), K2CO3 (0.6 mmol), DMSO (0.8 mL), 24 h, 140 oC under air. b Isolated yields based on 1.
Scheme 2 Control experiments.
On the basis of the above observation and previous works done by our group17 and others,16 a plausible mechanism for the threecomponent reaction is proposed in Scheme 3. Substitution reaction of 1a with 2a in the presence of base forms an intermediate A. Oxidative addition of the C-Br bond of A to the Pd(0) species affords intermediate B. Then, a migratory insertion of paraformaldehyde into the Ar-Pd bond provides intermediate C, with a subsequent -hydrogen elimination to produce a formylation product D. Cyclization reaction of compound D in the presence of base affords intermediate E which can provide the final product 3a by loss H2O. The catalytic active Pd(0) is regenerated through reductive elimination of the Pd(II)HBr complex to complete the catalytic cycle. In another possible reaction pathway, paraformaldehyde is decomposed into CO and H2. Subsequently, H2 is used as the hydride source reduces acyl palladium(II) complex (similar to intermediate C) to the corresponding aldehyde D.16a In summary, we have developed a straightforward and efficient access to 2-aroylbenzofurans from 2-bromophenols, phenacyl bromides and paraformaldehyde through palladiumcatalyzed transformations. The cheap and stable paraformaldehyde served as the carbon source via in situ formylation reaction. Functional groups such as halogen and trifluoromethyl were well tolerated under the optimized reaction conditions. This three-component approach affords an efficient route for the rapid synthesis of 2-aryl substituted benzothiophenes. The scope, mechanism, and synthetic application of this reaction are under investigation.
To have a better understanding of the reaction, several control experiments were performed. When 1a reacted with 2a in the
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Acknowledgements This work was supported by the National Natural Science Foundation of China (21372187, 21572194), the Program for Innovative Research Cultivation Team in University of Ministry of Education of China (1337304) and the Hunan Provincial Innovative Foundation for Postgraduate (CX2014B264).
Notes and references 1
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12 For reviews on formylation, see: (a) G. A. Olah, L. Ohannesian, M. View Article Online Arvanaghi, Chem. Rev., 1987, 87, 671; (b) W.10.1039/C6OB00198J Kantlehner, Eur. J. DOI: Org. Chem., 2003, 2530. For selected examples on formylation of phenols, see: (c) K. Chiba, T. Arakawa, M. Tada, Chem. Commun., 1996, 1763; (d) S. P. Cook, A. Polara, S. J. Danishefsky, J. Am. Chem. Soc., 2006, 128, 16440; (e) S. Tang, Y. Xu, J. He, Y. He, J. Zheng, X. Pan, X. She, Org. Lett., 2008, 10, 1855; (f) K. B. Bahnck, S. D. Rychnovsky, J. Am. Chem. Soc., 2008, 130, 13177; (g) D. H. T. Phan, B. Kim, V. M. Dong, J. Am. Chem. Soc., 2009, 131, 15608. 13 For recent selected reviews on applications of paraformaldehyde, see: (a) B. Sam, B. Breit, M. J. Krische, Angew. Chem. Int. Ed., 2015, 54, 3267; (b) L. P. Wu, Q. Liu, R. Jackstell, M. Beller, Angew. Chem. Int. Ed., 2014, 53, 6310; (c) W. F. Li and X. F. Wu, Adv. Synth. Catal., 2016, 357, 3393. 14 For recent selected examples on applications of paraformaldehyde, see: (a) J. M. Carcí a, G. O. Jones, K. Virwani, B. D. McCloskey, D. J. Boday, G. Huurne, H. W. Horn, D. J. Coady, A. M. Bintaleb, A. Alaldulrahman, F. Alsewailem, H. Almegren, J. L. Hedrick, Science, 2014, 344, 732; (b) A. Khan, R. Zheng, Y. Kan, J. Ye, J. Xing, Y. J. Zhang, Angew. Chem. Int. Ed., 2014, 53, 6439; (c) K. Park, Y. Heo, S. Lee, Org. Lett., 2013, 15, 3322; (d) Z. Quan, W. Hu, Z. Zhang, Y. Da, X. Jia, X. C. Wang, Adv. Synth. Catal., 2013, 355, 891; (e) C. Bausch, R. Patman, B. Breit, M. J. Krische, Angew. Chem. Int. Ed., 2011, 50, 5687; (f) A. Köpfer, B. Sam, B. Breit, M. J. Krische, Chem. Sci., 2013, 4, 1876; (g) T. Smejkal, H. Han, B. Breit, M. J. Krische, J. Am. Chem. Soc., 2009, 131, 10366; (h) Q. Liu, L. Wu, R. Jackstell, M. Beller, ChemCatChem., 2014, 6, 2805; (i) Z. G. Ke, Y. Zhang, X. J. Cui, F. Shi, Green Chem., 2016, DOI: 10.1039/c5gc01992c; (j) D. M. Kaphan, F. D. Toste, R. G. Bergman, K. N. Raymond, J. Am. Chem. Soc., 2015, 137, 9202. 15 For selected examples on using paraformaldehyde for aromatic heterocycle construction, see: (a) X. D. Tang, L. B. Huang, J. D. Yang, Y. L. Xu, W. Q. Wu, H. F. Jiang, Chem. Commun., 2014, 50, 14793; (b) H. F. Jiang, J. D. Yang, X. D. Tang, J. X. Li, W. Q. Wu, J. Org. Chem., 2015, 80, 8763; (c) T. Morimoto, K. Yamasaki, A. Hirano, K. Tsutsumi, N. Kagawa, K. Kakiuchi, Y. Harada, Y. Fukumoto, N. Chatani, T. Nishioka, Org. Lett., 2009, 11, 1777. 16 (a) K. Natte, A. Dumrath, H. Neumann, M. Beller, Angew. Chem. Int. Ed., 2014, 53, 10090; (b) W. F. Li, X. F. Wu, J. Org. Chem., 2014, 79, 10410. 17 H. M. Wang, J. H. Cai, H. W. Huang, G. J. Deng, Org. Lett., 2014, 16, 5324. 18 For our recent selected examples, see: (a) H. W. Huang, J. H. Cai, X. C. Ji, F. H. Xiao, Y. Chen, G. J. Deng, Angew. Chem. Int. Ed., 2016, 55, 307; (b) J. J. Chen, G. Z. li, Y. J. Xie, Y. F. Liao, F. H. Xiao, G. J. Deng, Org. Lett., 2015, 17, 5870; (c) S. W. Liu, R. Chen, H. Chen, G. J. Deng, Tetrahedron Lett., 2013, 54, 3838; (d) X. X. Cao, X. F. Cheng, Y. Bai, S. W. Liu, G. J. Deng, Green Chem., 2014, 16, 4644; (e) Y. F. Liao, Y. Peng, H. R. Qi, H. Gong, G. J. Deng, C. J. Li, Chem. Commun., 2015, 51, 1031.
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This article can be cited before page numbers have been issued, to do this please use: G. Deng, X. Cheng, Y. Peng and J. Wu, Org. Biomol. Chem., 2016, DOI: 10.1039/C6OB00198J.
This is an Accepted Manuscript, which has been through the Royal Society of Chemistry peer review process and has been accepted for publication. Accepted Manuscripts are published online shortly after acceptance, before technical editing, formatting and proof reading. Using this free service, authors can make their results available to the community, in citable form, before we publish the edited article. We will replace this Accepted Manuscript with the edited and formatted Advance Article as soon as it is available. You can find more information about Accepted Manuscripts in the Information for Authors. Please note that technical editing may introduce minor changes to the text and/or graphics, which may alter content. The journal’s standard Terms & Conditions and the Ethical guidelines still apply. In no event shall the Royal Society of Chemistry be held responsible for any errors or omissions in this Accepted Manuscript or any consequences arising from the use of any information it contains.
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Palladium-Catalyzed Paraformaldehyde Insertion: A Three-Component Synthesis of Benzofurans Received 00th January 20xx, Accepted 00th January 20xx
Xiufang Cheng,a Yi Peng,a Jun Wu,a Guo-Jun Denga*
DOI: 10.1039/x0xx00000x www.rsc.org/
An efficient procedure for 2-aroylbenzofuran preparation from 2-bromophenols, phenacyl bromides and paraformaldehyde is described. The cheap and stable paraformaldehyde served as the carbon source via an in situ formylation reaction. Benzofuran is one of the commonly encountered structural motifs in natural products. 1 In recent years, benzofuran derivatives have seen numerous applications in the development of pharmaceutical drugs and functionalized materials.2 Particularly, the 2-aroylbenzofuran structural motifs have displayed a range of biological activities. 3 These heterocyclic compounds can be used as tubulin polymerization inhibitors,4 antimitotic agents,5 and antimicrobials.6 Meanwhile, 2-aroylbenzofurans also could be used as key precursors for the preparation of multisubstituted benzofurans such as 2-aroyl-3arylbenzofurans and 2-aroyl-3-alkylbenzofurans which both showed important biological activities. 7 Therefore, the development of efficient methods for rapid construction of 2aroylbenzofurans attracted considerable interests. The classic method for the synthesis of these compounds depends on the Rap-Stoermer condensation of salicylaldehydes with αbromoketones.8 Recently, this reaction has been extensively investigated and could be carried out under microwaves 9 or solvent-free conditions10 with good functional group tolerance. Besides the Rap-Stoermer condensation reaction, few other methods are also available to prepare 2-aroylbenzofuran derivatives, including palladium-catalyzed arylation of benzofuran-2-carbaldehydes with aryl boronic acids, acylation of benzofurans and oxidative dehydrogenation of 2-aroyl dihydrobenzofurans.11 The aforementioned procedures for the synthesis of 2aroylbenzofurans are mainly based on 2-hydroxybenzaldehydes which could be prepared from phenols via an ortho-selective
a
Key Laboratory of Environmentally Friendly Chemistry and Application of Ministry of Education, College of Chemistry, Xiangtan University, Xiangtan, 411105, China. Fax: (+86)-731-58292251; Tel: (+86)-731-58298280; E-mail: [email protected] Electronic Supplementary Information (ESI) available: [details of any supplementary information available should be included here]. See DOI: 10.1039/x0xx00000x
formylation procedure using various formylating reagens.12 Paraformaldehyde is an abundant, easy to handle, and inexpensive one carbon source. In recent years, various methods have been developed to introduce paraformaldehyde into more complex molecules as carbonyl or carbon source. 13 Most of the developed methods are based on the condensation of paraformaldehyde with active amino group or enamides. 14, 15 Formylation of aromatic ring with paraformaldehyde is less studied. Very recently, the Beller and Wu groups developed palladium-catalyzed carbonylation of aryl bromides to selectively afford aromatic aldehydes or heterocycles using paraformaldehyde as the carbonyl source. 16 We also developed a palladium-catalyzed phthalazinone synthesis using paraformaldehyde as the carbon source via an in situ ortho formylation of 2-halomethylbenzoates. 17 It is highly desirable to use paraformaldehyde as the carbon source for construction of heterocyclic compounds. Based on our continuous interest in heterocyclic compound preparation using readily available materials,18 herein, we disclose an alternative route for the three-component synthesis of 2-aroylbenzofurans from 2bromophenols, phenacyl bromides and paraformaldehyde under palladium-catalyzed reaction conditions.
Scheme 1 2-Aroylbenzofurans formation using paraformaldehyde as carbon source.
Initial reaction optimization was performed with 2bromophenol (1a), paraformaldehyde, 2-bromo-1phenylethanone (2a), 1,1'-bis(diphenylphosphino)ferrocene (dppf) and K2CO3 in toluene at 120 oC under air atmosphere (Table 1). Catalyst screening showed that Pd(COD)Cl 2 gave the best yield of the desired product (Table 1, entry 5). Then various ligands were screened using Pd(COD)Cl2 as the catalyst. The yield could be improved to 41% when dpppy (diphenyl-2pyridylphosphine) was used (Table 1, entry 9). Notably, the base played an important role in this kind of transformation. Among the various bases screened, K 2CO3 showed the best efficiency (Table 1, entries 9−13). Besides toluene, DMF and DMSO are also good reaction media for this kind of reaction to
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provide 3a in 46% and 65% yield, respectively (Table 1, entries 15 and 16). Other organic solvents such as 1,2-dichloroethane (DCE) and dioxane were much less efficient (Table 1, entries 14 and 17). The reaction yield could be improved to 80% when the reaction temperature was increased to 140 oC (entry 18). The product 3a could be further improved to 86% yield when 1.5 equiv of 2a was employed to the reaction (Table 1, entry 19).
(Table 2, entry 8). Hindered substrate such as 2i could smoothly View Article Online DOI: 10.1039/C6OB00198J react with 1a to give the product 3i in 45% yield (Table 2, entry 9). To our delight, hetero ketones such as 2-bromo-1-(thiophen2-yl)ethanone (2j) also participated in the reaction to provide the corresponding benzofuran product 3j in moderate yield (Table 2, entry 10). Table 2 Reactions of 1a with various ketones 2a
Table 1 Optimization of the reaction conditionsa
a
Conditions: 1a (0.2 mmol), 2a (0.24 mmol), paraformaldehyde (0.5 mmol), catalyst (5 mol %), ligand (10 mol %), base (0.6 mmol), solvent (0.8 mL), 24 h, 120 oC under air. b GC yield. c At 140 oC. d 2a (0.3 mmol).
With the optimized reaction conditions in hand, we then investigated the scope of the reaction with respect to 2bromophenol (1a) and various phenacyl bromides (2) in the presence of paraformaldehyde (Table 2). The model reaction of 1a with 2a and paraformaldehyde gave the desired product 3a in 81% isolated yield (Table 2, entry 1). Substituents on the phenyl ring of 2-bromo-1-arylethanone significantly affected the reaction yields (Table 2, entries 2-8). When a methoxy group was present, the corresponding product 3b was obtained in 64% yield. Good yield could be achieved when a phenyl group was located at the phenyl ring of 1a (Table 2, entry 3). Moderate to good yields were obtained when fluoro and chloro substituents were present (Table 2, entries 4 and 5). The position of substituent profoundly affected the reaction yield. When 2-bromo-1-(2-chlorophenyl)ethanone (2f) and 2-bromo1-(3-chlorophenyl)ethanone (2g) were employed, the corresponding product 3f and 3g were obtained in only 40% and 41% yields, respectively (Table 2, entries 6 and 7). Under the optimized reaction conditions, trifluoromethyl group was well tolerated to give the corresponding product in 60% yield
a
Conditions: 1a (0.2 mmol), 2 (0.3 mmol), paraformaldehyde (0.5 mmol), Pd(COD)Cl2 (5 mol %), dpppy (10 mol %), K2CO3 (0.6 mmol), DMSO (0.8 mL), 24 h, 140 oC under air. b Isolated yields based on 1a.
To further explore the scope of the reaction, a number of substituted 2-halophenols (1) were employed to react with 2a and paraformaldehyde (Table 3). Moderate to good yields were obtained when electron-donating groups such as methyl, ethyl, propyl, methoxy and electron-withdrawing groups such as fluoro, chloro, cyano and trifluoromethyl were present at the para position of the hydroxy group (Table 3, entries 1-7, 9-11). When 2-bromo-4,5-dimethylphenol (1m) was used, the desired product 3v could be obtained in 68% yield (Table 3, entry 12). Lower yield was obtained when 3-bromonaphthalen-2-ol (1n) was used as the substrate (Table 3, entry 13). To our delight, 2bromopyridin-3-ol (1p) could smoothly react with 2a to provide the corresponding product 3x in 70% yield (Table 3, entry 15). Similar yield could be achieved when 2-iodopyridin-3-ol (1q) was employed (Table 3, entry 16). However, much lower yield was obtained when 2-chloropyridin-3-ol (1o) was used as the substrate due to the low reactivity (Table 3, entry 14). It should be noted that when 3-bromo-(1,1'-biphenyl)-4-ol (1i) and 1((1,1'-biphenyl)-4-yl)-2-bromoethanone (2c) were used as the
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substrates, bioactive (1,1'-biphenyl)-4-yl(5-phenylbenzofuran2-yl)methanone (3y) was obtained in 65% yield (Table 3, entry 17).6c The low reaction yields obtained in these reactions mainly due to low conversions of substrates 1.
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Table 3 Reactions of 2a with various phenols 1a
absence of palladium catalyst, reaction intermediate AView wasArticle obtained Online DOI: 10.1039/C6OB00198J in 72% yield after 18 h (Scheme 2, a). Compound A could further react with paraformaldehyde under the standard reaction conditions to convert into the desired products 3a in 82% yield (Scheme 2, b). No desired product was observed when chemical A was treated with the optimized reaction conditions in the absence of paraformaldehyde (Scheme 2, c). These control experiments showed that A is a key intermediate and paraformaldehyde serves as an one carbon source in the whole process.
Scheme 3 Possible reaction mechanism.
a
Conditions: 1 (0.2 mmol), 2a (0.3 mmol), paraformaldehyde (0.5 mmol), Pd(COD)Cl2 (5 mol %), dpppy (10 mol %), K2CO3 (0.6 mmol), DMSO (0.8 mL), 24 h, 140 oC under air. b Isolated yields based on 1.
Scheme 2 Control experiments.
On the basis of the above observation and previous works done by our group17 and others,16 a plausible mechanism for the threecomponent reaction is proposed in Scheme 3. Substitution reaction of 1a with 2a in the presence of base forms an intermediate A. Oxidative addition of the C-Br bond of A to the Pd(0) species affords intermediate B. Then, a migratory insertion of paraformaldehyde into the Ar-Pd bond provides intermediate C, with a subsequent -hydrogen elimination to produce a formylation product D. Cyclization reaction of compound D in the presence of base affords intermediate E which can provide the final product 3a by loss H2O. The catalytic active Pd(0) is regenerated through reductive elimination of the Pd(II)HBr complex to complete the catalytic cycle. In another possible reaction pathway, paraformaldehyde is decomposed into CO and H2. Subsequently, H2 is used as the hydride source reduces acyl palladium(II) complex (similar to intermediate C) to the corresponding aldehyde D.16a In summary, we have developed a straightforward and efficient access to 2-aroylbenzofurans from 2-bromophenols, phenacyl bromides and paraformaldehyde through palladiumcatalyzed transformations. The cheap and stable paraformaldehyde served as the carbon source via in situ formylation reaction. Functional groups such as halogen and trifluoromethyl were well tolerated under the optimized reaction conditions. This three-component approach affords an efficient route for the rapid synthesis of 2-aryl substituted benzothiophenes. The scope, mechanism, and synthetic application of this reaction are under investigation.
To have a better understanding of the reaction, several control experiments were performed. When 1a reacted with 2a in the
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Acknowledgements This work was supported by the National Natural Science Foundation of China (21372187, 21572194), the Program for Innovative Research Cultivation Team in University of Ministry of Education of China (1337304) and the Hunan Provincial Innovative Foundation for Postgraduate (CX2014B264).
Notes and references 1
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