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Cite this: Chem. Commun., 2014, 50, 463 Received 26th September 2013, Accepted 30th October 2013
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Synthesis of dihydrobenzo[b]furans by diastereoselective acyloxyarylation† Kazuhiro Hata,a Zhiheng He,b Constantin Gabriel Daniliuc,b Kenichiro Itami*ac and Armido Studer*b
DOI: 10.1039/c3cc47350c www.rsc.org/chemcomm
A highly diastereoselective synthesis of 2-aryl-3-acyloxy-2,3-dihydrobenzofurans by palladium-catalyzed acyloxyarylation involving dearomatization of benzofurans with arylboronic acids and carboxylic acids occurring under mild conditions has been developed.
Structures containing the 2,3-dihydrobenzofuran core can be found in many natural products and pharmaceutically relevant compounds (Fig. 1). Therefore, the development of novel synthetic methods for their direct preparation from readily accessible benzofurans is very important. Along these lines, hydrogenation of substituted benzofurans is an obvious and valuable strategy.1 However, prior installation of substituents at the 2 and 3 positions in the parent benzofuran requests for a multi-step synthesis and the build-up of quaternary C-centers at C2 or C3 is not possible following this route. A more straightforward and convenient
Fig. 1
Natural products bearing dihydrobenzo[b]furan structure.
a
Institute of Transformative Bio-Molecules (WPI-ITbM) and Graduate School of Science, Nagoya University, Chikusa, Nagoya 464-8602, Japan. E-mail: [email protected]; Web: http://synth.chem.nagoya-u.ac.jp/; Fax: +81-52-788-6098; Tel: +81-52-788-6098 b ¨lische Wilhelms-Universita ¨t Mu ¨nster Organisch-Chemisches Institut, Westfa ¨nster, Germany. E-mail: [email protected]; Corrensstrasse 40, 48149 Mu Web: http://www.uni-muenster.de/Chemie.oc/studer/; Fax: +49-251-83-36523; Tel: +49-251-83-33291 c JST, ERATO, Itami Molecular Nanocarbon Project, Nagoya University, Chikusa, Nagoya 464-8602, Japan † Electronic supplementary information (ESI) available: Detailed experimental procedures, and spectral data for all compounds, including scanned images of 1H and 13C NMR spectra. CCDC 963178 (4baa) and 963177 (2-methyl-2-phenyl-2,3dihydrobenzofuran-3-ol). For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c3cc47350c
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approach to 2,3-dihydrobenzofurans bearing two substituents at the C2 and C3 positions would be direct 2,3-functionalization involving dearomatization of benzofurans. The highly challenging 2,3-difunctionalization of 2- or 3-substituted benzofurans will result in 2,3-dihydrobenzofurans bearing quaternary C-centers. In that regard, the intramolecular Diels–Alder reaction as a reliable method was successfully applied to natural product synthesis, as demonstrated in a recent morphine total synthesis.2 It is obvious that such dearomatizing functionalization3 offers great potential for efficient synthesis of natural products or pharmaceutical compounds bearing the dihydrobenzofuran core structure, and investigations of new dearomatization reactions are required. Transition metal-catalyzed acyloxyarylation of carbon–carbon double bonds has been successfully used for vicinal alkene difunctionalization.4–6 The acyloxy group in the products is readily further chemically modified rendering this approach synthetically highly valuable. Acyloxyarylation of terminal and internal alkenes has been achieved.5,6 However, to the best of our knowledge, the vicinal acyloxyarylation of aromatic compounds has not been disclosed to date. Herein we report dearomatizing regio- and diastereoselective acyloxyarylation of various 2-substituted benzofurans by using readily available starting materials (Fig. 2). We will show that the three-component vicinal difunctionalization reaction allows building up quaternary C-centers at C2. It is worth mentioning that direct acyloxylation of benzofurans at the C3 position is unprecedented. After extensive investigation, we found that the treatment of 2-methylbenzofuran (1a) with phenylboronic acid (2a: 1.5 equiv.) in the presence of palladium acetate (5 mol%), 2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO: 3 equiv.)7 and MeCOOH (3a: solvent) for 5 h at room temperature furnished the target 2,3-difunctionalized
Fig. 2
Vicinal dearomatizing acyloxyarylation of benzofurans.
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Fig. 3 Discovery of Pd/TEMPO-catalyzed acyloxyarylation of benzofurans with phenylboronic acids and acetic acid.
product (Fig. 3). Thus, 2-methyl-2-phenyl-2,3-dihydrobenzofuran-3-yl acetate (4aaa) was produced in excellent yield (93%) and high diastereoselectivity (93% ds). Remarkably, the acyloxyarylation reaction displays virtually complete regioselectivity; 3-aryl-2-acyloxylated products (regioisomers of 4aaa) were not detected. The reaction with extended time (12 h) did not improve the yield (95% yield, 93% ds). The fact that the diastereoselectivity remained unchanged upon exposure of the product for longer reaction time indicates that no epimerization occurs under the applied conditions. Addition of KF to the catalytic reaction led to a lower yield (47%) but achieved the best selectivity (95% ds). Replacing Pd(OAc)2 by Pd(OCOCF3)2 as a precatalyst provided a nearly identical result. It should be also noted that, unlike the related direct C–H arylation with arylboronic acids under oxidative conditions,8–10 biphenyl derived from oxidative homocoupling of phenylboronic acid (2a) was not observed under the present reaction conditions. As part of our campaign exploring dearomatizing difunctionalization of heteroarenes, we have recently reported Pd-catalyzed arylcarboaminoxylation of heteroarenes with TEMPO and arylboronic acids.11 Unfortunately, this method does not allow the formation of quaternary C-centers and the cleavage of the N–O bond in the product, TEMPO-alkoxyamines, can sometimes be difficult to achieve under mild conditions.12 In contrast, the present reaction not only creates quaternary centers at the C2 position, but also allows installing the acetoxy group, which can be readily converted to other functional groups. For example, the acetyl moiety in 4aaa is easily removed by hydrolysis under mild conditions to provide the corresponding alcohol in excellent yield without epimerization (see the ESI† for details). Thus, the rapid access to the privileged 2-aryl-3-oxy-2,3-dihydrobenzofuran structure has been established.13 We propose the following mechanism to explain the regio- and diastereoselective acyloxyarylation (Fig. 3). Transmetalation of Pd(OAc)2 with arylboronic acid generates the Ph–Pd–OAc species. Electrophilic palladation at the C2 position of benzofuran gives the benzylic cation. Alternatively, this cation can also be generated via initial electrophilic palladation of the sterically less shielded C3 position with subsequent 1,2-palladium migration. The cation species is then diastereoselectively trapped with acetic acid at the
464 | Chem. Commun., 2014, 50, 463--465
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C3 position. Reductive elimination of the product 4aaa from the diorganopalladium intermediate provides Pd(0), which is then oxidized by 2 equivalents of TEMPO in acetic acid to regenerate Pd(OAc)2. Addition of TEMPO to the reaction system is critically important since no acyloxyarylation product was formed in the absence of TEMPO.7 With the optimized conditions in hand, we then examined the scope of acyloxyarylation by applying various sterically and electronically diverse benzofurans (1), arylboronic acids (2), and carboxylic acids (3) (Table 1). 2-n-Butylbenzofuran (1b) was converted under these conditions to the desired 4baa in high yield and good diastereoselectivity. The relative configuration of the major isomer of 4baa was unambiguously confirmed by X-ray crystal structure analysis, which showed that the phenyl and the acetoxy groups are trans oriented (Fig. 4). The stereochemistry of all other compounds was assigned in analogy. The C2 substituent R1 is important for the reaction outcome: transformation of benzofuran (R1 = H) with PhB(OH)2 under the optimized conditions provided 2-phenylbenzofuran as the product of the direct CH arylation in 82% yield. We also varied the acid source and propionate 4aab was obtained in good yield with moderate diastereoselectivity by Table 1 Scope of Pd/TEMPO-catalyzed acyloxyarylation of benzofurans with arylboronic acids and carboxylic acidsa
a
0.2 mmol scale of 1 in 0.4 mL of carboxylic acid at room temperature for 5 h.
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Notes and references
Fig. 4 X-ray crystal structure of 4baa (thermal ellipsoids are shown with 30% probability).
running the reaction in EtCOOH (3b). Substituents such as methyl or methoxy groups in positions C4–7 and benzannulation of the benzofuran core were tolerated. The corresponding acetyloxyarylation products were isolated in very good yields with moderate to good diastereoselectivities (4caa–4iaa, 66–96%). To study the scope with respect to the boronic acid component, various arylboronic acids were reacted with 2-methylbenzofuran (1a) in MeCOOH (3a) under optimized conditions. Substituents at the para position were tolerated but lower yields resulted for all arylboronic acids tested in this series (4aba–4aga). Whereas with the halides moderate to good yields were achieved the electron rich para-methoxy congener afforded a significantly lower yield (see 4aga). Diastereoselectivities ranging from 83 to 91% were measured for these transformations. meta-Substituted arylboronic acids were suitable substrates as documented for the successful acetoxyarylation of 1a with m-MeC6H4B(OH)2 (see 4afa); however, the reaction with sterically more hindered boronic acids such as 2-methylphenyl or 1-naphthylboronic acid failed. We have developed highly diastereoselective palladiumcatalyzed dearomatizing 2,3-difunctionalization of benzofurans under mild conditions. The starting benzofurans were readily prepared and all other reagents used (arylboronic acids, carboxylic acids, Pd(OAc)2 and TEMPO) are commercially available. The three-component reaction afforded 2-alkyl-2-aryl-3-acyloxy-2,3dihydrobenzofurans in moderate to excellent yields with good diastereoselectivity and complete regioselectivity. The established method should afford valuable building blocks for the synthesis of natural products and pharmaceutical compounds. Further synthetic and mechanistic studies are ongoing. We thank the Deutsche Forschungsgemeinschaft (DFG) and ¨nster/Nagoya the JSPS for supporting our research within the Mu International Research Training Group (IRTG) program. The Chinese Scholarship Council is also acknowledged (stipend to Z.H.). ITbM is supported by the World Premier International Research Center (WPI) Initiative, Japan.
This journal is © The Royal Society of Chemistry 2014
1 (a) Hydrogenation; Y. G. Zhou, Acc. Chem. Res., 2007, 40, 1357–1366; (b) N. Ortega, S. Urban, B. Beiring and F. Glorius, Angew. Chem., Int. Ed., 2012, 51, 1710–1713; (c) N. Ortega, B. Beiring, S. Urban and F. Glorius, Tetrahedron, 2012, 5185–5192. 2 G. Stork, A. Yamashita, J. Adams, G. R. Schulte, R. Chesworth, Y. Miyazaki and J. J. Farmer, J. Am. Chem. Soc., 2009, 131, 11402–11406. 3 (a) For review on total synthesis by dearomatization strategies, see: S. P. Roche and J. A. Porco Jr., Angew. Chem., Int. Ed., 2011, 50, 4068–4093; (b) C.-X. Zhuo, W. Zhang and S.-L. You, Angew. Chem., Int. Ed., 2012, 51, 12662–12686. 4 R. F. Heck, J. Am. Chem. Soc., 1968, 90, 5542–5546. 5 (a) Acyloxyarylation of terminal olefins; K. K. Mayer, S. Prior and W. Wiegrebe, Monatsh. Chem., 1986, 117, 511–532; (b) R. C. Larock and H. Song, Synth. Commun., 1989, 19, 1463–1470; (c) R. C. Larock and L. Guo, Synlett, 1995, 465; (d) F. Ek, L.-G. Wistrand and T. Frejd, J. Org. Chem., 2003, 68, 1911–1918; (e) S. Protti, M. Fagnoni and A. Albini, J. Am. Chem. Soc., 2006, 128, 10670–10671; ( f ) M. D. Obushak, V. S. Matiychuk and V. V. Turytsya, Tetrahedron Lett., 2009, 6112–6115; ( g) V. Dichiarante, M. Fagnoni and A. Albini, J. Org. Chem., 2010, 75, 1271–1276; (h) G. Zhang, L. Cui, Y. Wang and L. Zhang, J. Am. Chem. Soc., 2010, 132, 1474–1475; (i) A. D. Melhado, W. E. Brenzovich Jr, A. D. Lackner and F. D. Toste, J. Am. Chem. Soc., 2010, 132, 8885–8887; ( j) L. T. Ball, M. Green, G. C. Lloyd-Jones and C. A. Russell, Org. Lett., 2010, 12, 4724–4727; (k) W. E. Brenzovich Jr, J.-F. Brazeau and F. D. Toste, Org. Lett., 2010, 12, 4728–4731; (l ) A. D. Satterfield, A. Kubota and M. S. Sanford, Org. Lett., 2011, 13, 1076–1079; (m) E. T. da Penha, J. A. Forni, A. F. P. Biajoli and C. R. D. Correia, Tetrahedron Lett., 2011, 6342–6345; (n) L. T. Ball, G. C. Lloyd-Jones and C. A. Russell, Chem.–Eur. J., 2012, 18, 2931–2937; (o) C. Raviola, S. Protti, D. Ravelli, M. Mella, A. Albini and M. Fagnoni, J. Org. Chem., 2012, 77, 9094–9101. 6 (a) Acyloxyarylation of internal olefins; J. F. Jamie and R. W. Rickards, J. Chem. Soc., Perkin Trans. 1, 1997, 3613–3622; (b) K. Saito, K. Ono, M. Sano, S. Kiso and T. Takeda, Heterocycles, 2002, 57, 1781–1786. 7 (a) Reviews on the use of TEMPO in synthesis: T. Vogler and A. Studer, Synthesis, 2008, 1979–1993; (b) L. Tebben and A. Studer, Angew. Chem., Int. Ed., 2011, 50, 5034–5068; (c) S. Wertz and A. Studer, Green Chem., 2013, 15, 3116–3134. 8 (a) C–H-arylations with arylboronic acids using TEMPO as an oxidant: T. Vogler and A. Studer, Org. Lett., 2008, 10, 129–131; (b) S. Kirchberg, T. Vogler and A. Studer, Synlett, 2008, 2841–2846; (c) S. Kirchberg, S. Tani, K. Ueda, J. Yamaguchi, A. Studer and K. Itami, Angew. Chem., Int. Ed., 2011, 50, 2387–2391; (d) M. Steinmetz, K. Ueda, S. Grimme, J. Yamaguchi, S. Kirchberg, K. Itami and A. Studer, Chem.–Asian. J., 2012, 7, 1256–1260; (e) K. Yamaguchi, J. Yamaguchi, A. Studer and K. Itami, Chem. Sci., 2012, 3, 2165–2169; ( f ) Z. He, ¨hlich and A. Studer, Angew. Chem., Int. Ed., 2012, 51, S. Kirchberg, R. Fro 3699–3702. 9 S.-D. Yang, C.-L. Sun, Z. Fang, B.-J. Li, Y.-Z. Li and Z.-J. Shi, Angew. Chem., Int. Ed., 2008, 47, 1473–1476. 10 S. K. Guchhait, M. Kashyap and S. Saraf, Synthesis, 2010, 1166–1170. ¨hlich and A. Studer, Angew. Chem., Int. Ed., 2010, 11 S. Kirchberg, R. Fro 49, 6877–6880. ¨hlich and A. Studer, Angew. Chem., Int. Ed., 2009, 12 S. Kirchberg, R. Fro 48, 4235–4238. 13 (a) Natural products having 2-aryl-3-oxy-2,3-dihydrobenzofuran structure: G. Brader, S. Vajrodaya, H. Greger, M. Bacher, H. Kalchhauser and O. Hofer, J. Nat. Prod., 1998, 61, 1482–1490; (b) H.-L. Liu, X.-F. Huang, X. Wan and L.-Y. Kong, Helv. Chim. Acta, 2007, 1117–1132; (c) C.-C. Huang, Y.-T. Tung, K.-C. Cheng and J.-H. Wu, Food Chem., 2011, 726–731; (d) J. M. Chambers, L. M. Lindqvist, A. Webb, D. C. S. Huang, G. P. Savage and M. A. Rizzacasa, Org. Lett., 2013, 15, 1406–1409; (e) Y.-C. Tsai, S.-Y. Chiang, M.-E. Shazly, C.-C. Wu, L. Beerhues, W.-C. Lai, S.-F. Wu, M.-H. Yen, Y.-C. Wu and F. R. Chang, ˜a, J. Li, N. Jena, Food Chem., 2013, 305–314; ( f ) L. Pan, U. M. Acun T. N. Ninh, C. M. Pannell, H. Chai, J. R. Fuchs, E. J. C. de Blanco, D. D. Soejarto and A. D. Kinghorn, J. Nat. Prod., 2013, 76, 394–404.
Chem. Commun., 2014, 50, 463--465 | 465
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COMMUNICATION
Cite this: Chem. Commun., 2014, 50, 463 Received 26th September 2013, Accepted 30th October 2013
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Synthesis of dihydrobenzo[b]furans by diastereoselective acyloxyarylation† Kazuhiro Hata,a Zhiheng He,b Constantin Gabriel Daniliuc,b Kenichiro Itami*ac and Armido Studer*b
DOI: 10.1039/c3cc47350c www.rsc.org/chemcomm
A highly diastereoselective synthesis of 2-aryl-3-acyloxy-2,3-dihydrobenzofurans by palladium-catalyzed acyloxyarylation involving dearomatization of benzofurans with arylboronic acids and carboxylic acids occurring under mild conditions has been developed.
Structures containing the 2,3-dihydrobenzofuran core can be found in many natural products and pharmaceutically relevant compounds (Fig. 1). Therefore, the development of novel synthetic methods for their direct preparation from readily accessible benzofurans is very important. Along these lines, hydrogenation of substituted benzofurans is an obvious and valuable strategy.1 However, prior installation of substituents at the 2 and 3 positions in the parent benzofuran requests for a multi-step synthesis and the build-up of quaternary C-centers at C2 or C3 is not possible following this route. A more straightforward and convenient
Fig. 1
Natural products bearing dihydrobenzo[b]furan structure.
a
Institute of Transformative Bio-Molecules (WPI-ITbM) and Graduate School of Science, Nagoya University, Chikusa, Nagoya 464-8602, Japan. E-mail: [email protected]; Web: http://synth.chem.nagoya-u.ac.jp/; Fax: +81-52-788-6098; Tel: +81-52-788-6098 b ¨lische Wilhelms-Universita ¨t Mu ¨nster Organisch-Chemisches Institut, Westfa ¨nster, Germany. E-mail: [email protected]; Corrensstrasse 40, 48149 Mu Web: http://www.uni-muenster.de/Chemie.oc/studer/; Fax: +49-251-83-36523; Tel: +49-251-83-33291 c JST, ERATO, Itami Molecular Nanocarbon Project, Nagoya University, Chikusa, Nagoya 464-8602, Japan † Electronic supplementary information (ESI) available: Detailed experimental procedures, and spectral data for all compounds, including scanned images of 1H and 13C NMR spectra. CCDC 963178 (4baa) and 963177 (2-methyl-2-phenyl-2,3dihydrobenzofuran-3-ol). For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c3cc47350c
This journal is © The Royal Society of Chemistry 2014
approach to 2,3-dihydrobenzofurans bearing two substituents at the C2 and C3 positions would be direct 2,3-functionalization involving dearomatization of benzofurans. The highly challenging 2,3-difunctionalization of 2- or 3-substituted benzofurans will result in 2,3-dihydrobenzofurans bearing quaternary C-centers. In that regard, the intramolecular Diels–Alder reaction as a reliable method was successfully applied to natural product synthesis, as demonstrated in a recent morphine total synthesis.2 It is obvious that such dearomatizing functionalization3 offers great potential for efficient synthesis of natural products or pharmaceutical compounds bearing the dihydrobenzofuran core structure, and investigations of new dearomatization reactions are required. Transition metal-catalyzed acyloxyarylation of carbon–carbon double bonds has been successfully used for vicinal alkene difunctionalization.4–6 The acyloxy group in the products is readily further chemically modified rendering this approach synthetically highly valuable. Acyloxyarylation of terminal and internal alkenes has been achieved.5,6 However, to the best of our knowledge, the vicinal acyloxyarylation of aromatic compounds has not been disclosed to date. Herein we report dearomatizing regio- and diastereoselective acyloxyarylation of various 2-substituted benzofurans by using readily available starting materials (Fig. 2). We will show that the three-component vicinal difunctionalization reaction allows building up quaternary C-centers at C2. It is worth mentioning that direct acyloxylation of benzofurans at the C3 position is unprecedented. After extensive investigation, we found that the treatment of 2-methylbenzofuran (1a) with phenylboronic acid (2a: 1.5 equiv.) in the presence of palladium acetate (5 mol%), 2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO: 3 equiv.)7 and MeCOOH (3a: solvent) for 5 h at room temperature furnished the target 2,3-difunctionalized
Fig. 2
Vicinal dearomatizing acyloxyarylation of benzofurans.
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Fig. 3 Discovery of Pd/TEMPO-catalyzed acyloxyarylation of benzofurans with phenylboronic acids and acetic acid.
product (Fig. 3). Thus, 2-methyl-2-phenyl-2,3-dihydrobenzofuran-3-yl acetate (4aaa) was produced in excellent yield (93%) and high diastereoselectivity (93% ds). Remarkably, the acyloxyarylation reaction displays virtually complete regioselectivity; 3-aryl-2-acyloxylated products (regioisomers of 4aaa) were not detected. The reaction with extended time (12 h) did not improve the yield (95% yield, 93% ds). The fact that the diastereoselectivity remained unchanged upon exposure of the product for longer reaction time indicates that no epimerization occurs under the applied conditions. Addition of KF to the catalytic reaction led to a lower yield (47%) but achieved the best selectivity (95% ds). Replacing Pd(OAc)2 by Pd(OCOCF3)2 as a precatalyst provided a nearly identical result. It should be also noted that, unlike the related direct C–H arylation with arylboronic acids under oxidative conditions,8–10 biphenyl derived from oxidative homocoupling of phenylboronic acid (2a) was not observed under the present reaction conditions. As part of our campaign exploring dearomatizing difunctionalization of heteroarenes, we have recently reported Pd-catalyzed arylcarboaminoxylation of heteroarenes with TEMPO and arylboronic acids.11 Unfortunately, this method does not allow the formation of quaternary C-centers and the cleavage of the N–O bond in the product, TEMPO-alkoxyamines, can sometimes be difficult to achieve under mild conditions.12 In contrast, the present reaction not only creates quaternary centers at the C2 position, but also allows installing the acetoxy group, which can be readily converted to other functional groups. For example, the acetyl moiety in 4aaa is easily removed by hydrolysis under mild conditions to provide the corresponding alcohol in excellent yield without epimerization (see the ESI† for details). Thus, the rapid access to the privileged 2-aryl-3-oxy-2,3-dihydrobenzofuran structure has been established.13 We propose the following mechanism to explain the regio- and diastereoselective acyloxyarylation (Fig. 3). Transmetalation of Pd(OAc)2 with arylboronic acid generates the Ph–Pd–OAc species. Electrophilic palladation at the C2 position of benzofuran gives the benzylic cation. Alternatively, this cation can also be generated via initial electrophilic palladation of the sterically less shielded C3 position with subsequent 1,2-palladium migration. The cation species is then diastereoselectively trapped with acetic acid at the
464 | Chem. Commun., 2014, 50, 463--465
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C3 position. Reductive elimination of the product 4aaa from the diorganopalladium intermediate provides Pd(0), which is then oxidized by 2 equivalents of TEMPO in acetic acid to regenerate Pd(OAc)2. Addition of TEMPO to the reaction system is critically important since no acyloxyarylation product was formed in the absence of TEMPO.7 With the optimized conditions in hand, we then examined the scope of acyloxyarylation by applying various sterically and electronically diverse benzofurans (1), arylboronic acids (2), and carboxylic acids (3) (Table 1). 2-n-Butylbenzofuran (1b) was converted under these conditions to the desired 4baa in high yield and good diastereoselectivity. The relative configuration of the major isomer of 4baa was unambiguously confirmed by X-ray crystal structure analysis, which showed that the phenyl and the acetoxy groups are trans oriented (Fig. 4). The stereochemistry of all other compounds was assigned in analogy. The C2 substituent R1 is important for the reaction outcome: transformation of benzofuran (R1 = H) with PhB(OH)2 under the optimized conditions provided 2-phenylbenzofuran as the product of the direct CH arylation in 82% yield. We also varied the acid source and propionate 4aab was obtained in good yield with moderate diastereoselectivity by Table 1 Scope of Pd/TEMPO-catalyzed acyloxyarylation of benzofurans with arylboronic acids and carboxylic acidsa
a
0.2 mmol scale of 1 in 0.4 mL of carboxylic acid at room temperature for 5 h.
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Fig. 4 X-ray crystal structure of 4baa (thermal ellipsoids are shown with 30% probability).
running the reaction in EtCOOH (3b). Substituents such as methyl or methoxy groups in positions C4–7 and benzannulation of the benzofuran core were tolerated. The corresponding acetyloxyarylation products were isolated in very good yields with moderate to good diastereoselectivities (4caa–4iaa, 66–96%). To study the scope with respect to the boronic acid component, various arylboronic acids were reacted with 2-methylbenzofuran (1a) in MeCOOH (3a) under optimized conditions. Substituents at the para position were tolerated but lower yields resulted for all arylboronic acids tested in this series (4aba–4aga). Whereas with the halides moderate to good yields were achieved the electron rich para-methoxy congener afforded a significantly lower yield (see 4aga). Diastereoselectivities ranging from 83 to 91% were measured for these transformations. meta-Substituted arylboronic acids were suitable substrates as documented for the successful acetoxyarylation of 1a with m-MeC6H4B(OH)2 (see 4afa); however, the reaction with sterically more hindered boronic acids such as 2-methylphenyl or 1-naphthylboronic acid failed. We have developed highly diastereoselective palladiumcatalyzed dearomatizing 2,3-difunctionalization of benzofurans under mild conditions. The starting benzofurans were readily prepared and all other reagents used (arylboronic acids, carboxylic acids, Pd(OAc)2 and TEMPO) are commercially available. The three-component reaction afforded 2-alkyl-2-aryl-3-acyloxy-2,3dihydrobenzofurans in moderate to excellent yields with good diastereoselectivity and complete regioselectivity. The established method should afford valuable building blocks for the synthesis of natural products and pharmaceutical compounds. Further synthetic and mechanistic studies are ongoing. We thank the Deutsche Forschungsgemeinschaft (DFG) and ¨nster/Nagoya the JSPS for supporting our research within the Mu International Research Training Group (IRTG) program. The Chinese Scholarship Council is also acknowledged (stipend to Z.H.). ITbM is supported by the World Premier International Research Center (WPI) Initiative, Japan.
This journal is © The Royal Society of Chemistry 2014
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