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ChemComm View Article Online Published on 14 March 2013. Downloaded by Xian Jiaotong University on 08/12/2013 23:43:12. COMMUNICATION Cite this: Chem. Commun., 2013, 49, 3543 Received 24th February 2013, Accepted 13th March 2013 View Journal | View Issue Distinct reactivity of Morita–Baylis–Hillman acetates as a novel C2 component in amine-catalyzed [2 + 2 + 2] and [2 + 4] annulations† Rongshun Chen,a Silong Xu,*b Liyi Wang,a Yuhai Tangb and Zhengjie He*a DOI: 10.1039/c3cc41419a www.rsc.org/chemcomm Amine-catalyzed [2 + 2 + 2] and [2 + 4] annulations of Morita–Baylis– Hillman (MBH) acetates with cyano activated alkenes and 1,3-azadienes have been developed to provide cyclohexanes and tetrahydropyridines. In the annulations, MBH acetates serve as a novel C2 component with an inactive homoallylic methyl involved in the bond formation. Lewis base catalysis1 using phosphines and amines as catalysts has emerged as a powerful tool to facilitate chemical transformation. Intensive investigations into this area have predominantly focused on a group of prevailing substrates including electron-deficient allenes.2 Recently, a class of so-called modified allylic derivatives 1 (Y = OAc, OBoc, halo, etc.; EWG = ester, acyl, etc.), which could be conveniently prepared from Morita–Baylis–Hillman (MBH) adducts,3 have been proven to be attractive and versatile substrates in many important Lewis base catalyzed annulation reactions (Scheme 1).4–6 The pioneering and extensive studies by Lu and others have disclosed that MBH allylic derivatives 1 could be used as a C3 unit in a series of inter- or intramolecular phosphine-catalyzed [3 + n] annulations (n = 2, 3, 4, 6)4 to build various ring structures (Scheme 1, path a). The latest reports by Zhang, Huang, Shi, and He also illustrated that, in the catalysis of tertiary phosphines, 1 could serve as a C1 unit to produce rings like dihydrofurans, pyrrolines and cyclopentenes in a [1 + 4] cyclization fashion (Scheme 1, path b).5 Interestingly, in the catalysis of amine Lewis bases, MBH derivatives 1 may undertake distinct annulation modes. Very recently, we have successfully developed an amine-catalyzed [4 + 2] annulation of MBH derivatives 1 with a variety of electrondeficient alkenes and diazenes, in which the allylic derivatives 1 act as a C4 unit (Scheme 1, path c).6 As part of our continuous Scheme 1 Divergent annulation modes of MBH allylic derivatives 1 in phosphine and amine catalysis. efforts on further exploring divergent catalysis between amines and phosphines, we herein report another amine-catalyzed new annulation mode of MBH allylic compounds 1 as a C2 unit in [2 + 2 + 2] and [2 + 4] annulations (Scheme 1, path d).7 Our initial investigation showed that DABCO-catalyzed reaction of MBH acetate 1a (0.5 mmol) with doubly activated olefin benzylidenemalononitrile 2a (0.5 mmol) produced a novel [2 + 2 + 2] annulation8 product 3a in 54% yield as a single diastereomer {Scheme 2, eqn (1) DABCO = 1,4-diazabicyclo[2.2.2]octane}. Formation of 3a accordingly illustrated an interesting annulation mode of the MBH allylic derivatives 1 as a C2 unit, in which the inactive homoallylic methyl of the MBH acetate 1a was involved in the C–C bond formation, while the electrophilic alkene subunit remained intact. It is also noteworthy that the above [2 + 2 + 2] annulation represents divergent catalysis between amines and phosphines, since the MBH acetate 1a and alkene 2a only a The State Key Laboratory of Elemento-Organic Chemistry and Department of Chemistry, Nankai University, Tianjin 300071, P.R. China. E-mail: zhengjiehe@nankai.edu.cn b Department of Chemistry, School of Science, Xi’an Jiaotong University, Xi’an 710049, P.R. China. E-mail: silongxu@mail.xjtu.edu.cn † Electronic supplementary information (ESI) available: Detailed surveys for reaction conditions; experimental procedures; characterization data and NMR spectra of all new compounds. CCDC 913766 (3a) and 913769 (6a). For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/ c3cc41419a This journal is c The Royal Society of Chemistry 2013 Scheme 2 Distinct annulation modes between 1a and 2a. Chem. Commun., 2013, 49, 3543--3545 3543 View Article Online Communication Published on 14 March 2013. Downloaded by Xian Jiaotong University on 08/12/2013 23:43:12. Table 1 ChemComm DABCO-catalyzed [2 + 2 + 2] annulation between 1 and 2a Entry 1 R in 2 Time (h) Yieldb (%) 1 2 3 4 5 6 7 8 9 10 11 12 13c 14c 15c 16 17 18 19 20 21 22d 23 24 1a 1a 1a 1a 1a 1a 1a 1a 1a 1a 1a 1a 1a 1a 1a 1a 1a 1a 1b 1c 1d 1e 1f 1g C6H5 (2a) 2-Cl-C6H4 (2b) 3-Cl-C6H4 (2c) 4-Cl-C6H4 (2d) 2-Br-C6H4 (2e) 3-Br-C6H4 (2f) 3-F-C6H4 (2g) 4-F-C6H4 (2h) 4-CH3-C6H4 (2i) 2-OCH3-C6H4 (2j) 3-OCH3-C6H4 (2k) 4-OCH3-C6H4 (2l) 2-CF3-C6H4 (2m) 4-CF3-C6H4 (2n) 4-NO2-C6H4 (2o) 2-Thienyl (2p) 3-Pyridyl (2q) C2H5 (2r) C6H5 (2a) C6H5 (2a) C6H5 (2a) C6H5 (2a) C6H5 (2a) C6H5 (2a) 12 24 36 7 8 36 12 16 12 20 48 12 48 36 12 24 20 48 24 24 24 24 48 48 3a, 93 3b, 77 3c, 87 3d, 88 3e, 54 3f, 88 3g, 77 3h, 84 3i, 78 3j, 69 3k, 84 3l, 40 3m, 73 3n, 95 3o, 84 3p, 40 3q, 56 / 3r, 99 3s, 99 3a, 72 3a, 65 / / a Typical conditions: under a N2 atmosphere, to a stirred solution of 1 (0.3 to 0.5 mmol) and 2 (0.5 mmol) in DMF (3 mL) DABCO (0.05 mmol) was added and the resulting mixture was stirred at rt. b Isolated yield based on 2. c Solvent THF was used. d K2CO3 (0.5 mmol) was added. underwent the known [3 + 2] annulation4b in the catalysis of PPh3 {Scheme 2, eqn (2)}. Under optimized conditions as shown in Table 1 {for details, see ESI†}, we further studied the substrate scope of the aminecatalyzed [2 + 2 + 2] annulation (Table 1). A variety of arylmethylidenemalononitriles 2 were tested with 1a. Phenyl-substituted methylidenemalononitriles 2 bearing a halogen (Cl, Br, F) or an electron-donating substituent at the phenyl ring worked well, providing the annulation products 3 in good to excellent yields (entries 2–12). For these arylmethylidenemalononitriles 2 bearing electron-withdrawing groups, their cyclizations with 1a were better conducted in THF, readily furnishing the annulation products in good yields (entries 13–15). Heteroaryl substituted methylidenemalononitriles 2 were also effective candidates to give the corresponding products 3 in moderate yields (entries 16 and 17). However, aliphatic propylidenemalononitrile 2r bearing acidic methylene was ineffective, only producing a complex mixture (entry 18). Several structurally similar MBH allylic derivatives 1 were also tested in the annulation reaction with representative 2a. The analogues of MBH acetate 1a with varied electron-withdrawing groups (EWG) such as a bulky tert-butoxycarbonyl (1b) or an acetyl (1c) all behaved similarly, delivering 3544 Chem. Commun., 2013, 49, 3543--3545 Table 2 DMAP-catalyzed [2 + 4] annulation between 1 and 5a Entry 1 R 0 in 5 Solvent Yieldb (%) 1 2 3 4 5 6c 7d 8d 9d 10d 1c 1c 1c 1c 1c 1c 1a 1a 1h 1h H (5a) 6-Cl (5b) 6-Br (5c) 6-CH3 (5d) 6,7-Benzo (5e) H (5f) H (5a) 6-Br (5c) H (5a) 6-Br (5c) CHCl3 CHCl3 CHCl3 CHCl3 CHCl3 CHCl3 THF THF THF THF 6a, 79 6b, 77 6c, 71 6d, 76 6e, 97 6f, 75 6g, 46 6h, 33 6i, 47 6j, 46 a Typical conditions: a mixture of MBH acetate 1 (0.3 mmol), azadiene 5 (0.2 mmol), and DMAP (0.04 mmol) in solvent (2.0 mL) was refluxed for 24 h. b Isolated yield based on 5. c 5f refers to 3-(N-phenylsulfonyliminomethyl)chromone. d MBH acetates 1 (0.4 mmol) were used. products 3 in excellent yields (entries 19 and 20). Other allylic derivatives like tert-butyl carbonate 1d and bromide 1e also possessed similar reactivity and smoothly produced 3a in satisfactory yields (entries 21 and 22). In the case of bromide 1e, an inorganic base K2CO3 was needed to facilitate the reaction.9 However, structural modification of the MBH allylic derivatives 1 at the d- or a-carbon was found to significantly affect their reactivity as a C2 unit. MBH acetates 1f and 1g both failed to afford the corresponding [2 + 2 + 2] products with 2a (entries 23 and 24). Based upon the above [2 + 2 + 2] annulation, we reasoned that MBH acetates 1 might be also used as a feasible C2 unit in amine-catalyzed [2 + 4] annulations. To our delight, electrophilic azadienes such as 3-(N-tosyliminomethyl)chromones 5 emerged as competent partners of the [2 + 4] annulation. Using DMAP (20 mol%) as the catalyst and in refluxing chloroform (DMAP = 4-dimethylaminopyridine, for a condition survey, see ESI†), the [2 + 4] annulation of MBH acetate 1c and a series of substituted 3-(N-tosyliminomethyl)chromones 5 proceeded smoothly, delivering chroman-fused tetrahydropyridine products 6 in good to excellent yields with exclusive trans diastereoselectivity (Table 2, entries 1–6). The ester group-activated allylic acetates 1a and 1h appeared less reactive and their DMAP-catalyzed [2 + 4] annulations with representative 3-(N-tosyliminomethyl)chromones 5 were better carried out in refluxing THF to generate the corresponding products 6 in modest yields (entries 7–10). It is noteworthy that all annulation products 3 and 6 were obtained as a single diastereomer. Their structures and stereochemistry were well identified using 1H and 13C NMR, COSY, HSQC, NOESY, HRMS, and X-ray crystallographic analysis of 3a and 6a (for details, see ESI†). Based on our latest report and others’ work,6,10 a plausible mechanism is depicted in Scheme 3 to rationalize the aminecatalyzed [2 + 2 + 2] and [2 + 4] annulations of MBH acetate 1a. Initially, nucleophilic attack of the catalyst amine at the MBH acetate 1a generates ammonium acetate A via an SN2 0 pathway. Since the N-atom lacks the suitable ability to stabilize its N-ylide This journal is c The Royal Society of Chemistry 2013 View Article Online ChemComm Communication Published on 14 March 2013. Downloaded by Xian Jiaotong University on 08/12/2013 23:43:12. complements well the intensely studied phosphine-induced annulation modes as C3 and C1 units.4,5 As two pillars of the organic Lewis base catalyst, divergent catalysis between amines and phosphines has recently aroused considerable interest.12 We believe that our findings in this study may further intrigue the research interest in this area. Financial support from National Natural Science Foundation of China (Grant no. 21072100; 21121002; 21272119) is gratefully acknowledged. Notes and references Scheme 3 A proposed mechanism. intermediate,10 with the aid of the in situ generated acetate anion as a base, deprotonation of intermediate A takes place regioselectively at its d-carbon rather than at its a-carbon, leading to a resonance-stabilized intermediate B. Theoretically, the putative intermediate B could be fairly stabilized by the electron-withdrawing ester group. When exposed to a doubly activated olefin 2a, intermediate B is entrapped by a tandem double Michael addition process to generate intermediate C. Through a more stable six-membered chair-like transition state, intermediate C undergoes a 6-exo-trig ring closure via a SN2 0 pathway to accomplish the stereoselective formation of [2 + 2 + 2] product 3a and release of the catalyst amine. In another scenario, when reactive intermediate B is exposed to azadiene 5a, 1,4-conjugate addition leads to intermediate D, which subsequently undergoes a 6-exo-trig cyclization via the SN2 0 pathway to generate the [2 + 4] annulation product 6g (Scheme 3). At the current stage, another possible Diels–Alder pathway of the [2 + 4] annulation could not be completely ruled out: product 6g could be generated from a Diels–Alder cycloaddition of the azadiene 5a with 2-carboethoxy-1,3-diene which results from elimination of the amine of intermediate B.6 However, the trans stereochemistry of product 6g points to an unfavored exo Diels–Alder pathway.11 In conclusion, we have developed new amine-catalyzed [2 + 2 + 2] and [2 + 4] annulation reactions of MBH acetates 1 with activated alkenes and azadienes, respectively, which provide facile access to cyclohexanes and tetrahydropyridines in good yields and exclusive diastereoselectivity. These reactions unveiled an expedient annulation mode of the versatile allylic derivatives 1 as a C2 unit in the Lewis base catalysis, in which the inactive homoallylic methyl of the MBH acetates 1 is directly involved in the C–C bond formation. Together with the annulation mode as a C4 unit disclosed recently by us,6 the divergent amine-catalyzed annulation mode as a C2 unit This journal is c The Royal Society of Chemistry 2013 1 S. E. Denmark and G. L. Beutner, Angew. Chem., Int. Ed., 2008, 47, 156. 2 For reviews, see: (a) X. Lu, C. Zhang and Z. Xu, Acc. Chem. Res., 2001, 34, 535; (b) J. L. Methot and W. R. Roush, Adv. Synth. Catal., 2004, 346, 1035; (c) S. Ma, Chem. Rev., 2005, 105, 2829; (d) A. Marinetti and A. Voituriez, Synlett, 2010, 174; (e) L.-W. Ye, J. Zhou and Y. Tang, Chem. Soc. Rev., 2008, 37, 114; ( f ) B. J. Cowen and S. J. Miller, Chem. Soc. Rev., 2009, 38, 3102; ( g) S. Xu and Z. He, Sci. Sin. Chim., 2010, 40, 856; (h) Q.-Y. Zhao, Z. Lian, Y. Wei and M. Shi, Chem. Commun., 2012, 48, 1724. 3 (a) D. Basavaiah, A. J. Rao and T. Satyanarayana, Chem. Rev., 2003, 103, 811; (b) D. Basavaiah, B. S. Reddy and S. S. Badsara, Chem. Rev., 2010, 110, 5447. 4 (a) Y. Du, X. Lu and C. Zhang, Angew. Chem., Int. Ed., 2003, 42, 1035; (b) J. Feng, X. Lu, A. Kong and X. Han, Tetrahedron, 2007, 63, 6035; (c) S. Zheng and X. Lu, Org. Lett., 2008, 10, 4481; (d) R. Zhou, J. Wang, H. Song and Z. He, Org. Lett., 2011, 13, 580; (e) H.-P. Deng, Y. Wei and M. Shi, Org. Lett., 2011, 13, 3348; ( f ) D. Basavaiah and S. Roy, Org. Lett., 2008, 10, 1819; ( g) L.-W. Ye, X.-L. Sun, Q.-G. Wang and Y. Tang, Angew. Chem., Int. Ed., 2007, 46, 5951; (h) Q.-G. Wang, S.-F. Zhu, L.-W. Ye, C.-Y. Zhou, X.-L. Sun, Y. Tang and Q.-L. Zhou, Adv. Synth. Catal., 2010, 352, 1914; (i) B. Tan, N. R. Candeias and C. F. Barbas III, J. Am. Chem. Soc., 2011, 133, 4672; ( j) F. Zhong, X. Han, Y. Wang and Y. Lu, Angew. Chem., Int. Ed., 2011, 50, 7837; (k) S. Zheng and X. Lu, Tetrahedron Lett., 2009, 50, 4532; (l ) S. Zheng and X. Lu, Org. Lett., 2009, 11, 3978; (m) Y. Du, J. Feng and X. Lu, Org. Lett., 2005, 7, 1987. 5 (a) Z. Chen and J. Zhang, Chem.–Asian J., 2010, 5, 1542; (b) P. Xie, Y. Huang and R. Chen, Org. Lett., 2010, 12, 3768; (c) J. Tian, R. Zhou, H. Sun, H. Song and Z. He, J. Org. Chem., 2011, 76, 2374; (d) X. N. Zhang, H. P. Deng, L. Huang, Y. Wei and M. Shi, Chem. Commun., 2012, 48, 8664. 6 S. Xu, R. Chen, Z. Qin, G. Wu and Z. He, Org. Lett., 2012, 14, 996. 7 The base-promoted self-dimerization of MBH adducts via a Diels– Alder mode was previously reported, see: (a) H. M. R. Hoffmann and J. Rabe, Angew. Chem., Int. Ed. Engl., 1983, 22, 795; (b) W. Poly, D. Schomburg and H. M. R. Hoffmann, J. Org. Chem., 1988, 53, 3701. 8 For selected examples of Lewis base catalyzed [2 + 2 + 2] annulations, see: (a) X. F. Zhu, C. E. Henry, J. Wang, T. Dudding and O. Kwon, Org. Lett., 2005, 7, 1387; (b) X.-G. Liu and M. Shi, Eur. J. Org. Chem., 2008, 6168; (c) L. Cai, B. Zhang, G. Wu, H. Song and Z. He, Chem. Commun., 2011, 47, 1045; (d) K. Jiang, Z.-J. Jia, S. Chen, L. Wu and Y.-C. Chen, Chem.–Eur. J., 2010, 16, 2852. 9 In the reaction of MBH acetate 1a or carbonate 1d, the in situ generated acetate or tert-butoxide anion acted as a base to effect the deprotonation step, while in the reaction of allylic bromide 1e additional base K2CO3 was required to drive the same step (see a plausible mechanism in Scheme 3). 10 (a) S. L. Riches, C. Saha, N. F. Filgueira, E. Grange, E. M. McGarrigle and V. K. Aggarwal, J. Am. Chem. Soc., 2010, 132, 7626; (b) C. A. Evans and S. J. Miller, J. Am. Chem. Soc., 2003, 125, 12394. 11 (a) O. Diels and K. Alder, Justus Liebigs Ann. Chem., 1928, 460, 98; (b) U. Pindur, G. Lutz and C. Otto, Chem. Rev., 1993, 93, 741. 12 (a) Ref. 10b; (b) Y.-L. Shi and M. Shi, Org. Lett., 2005, 7, 3057; (c) L. B. Saunders and S. J. Miller, ACS Catal., 2011, 1, 1347; (d) T. Wang, X.-Y. Chen and S. Ye, Tetrahedron Lett., 2011, 52, 5488; (e) K. D. Ashtekar, R. J. Staples and B. Borhan, Org. Lett., 2011, 13, 5732; ( f ) X. Wang, T. Fang and X. Tong, Angew. Chem., Int. Ed., 2011, 50, 5361; ( g) X.-Y. Chen, R.-C. Lin and S. Ye, Chem. Commun., 2012, 48, 1317. Chem. Commun., 2013, 49, 3543--3545 3545