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Cite this: Chem. Commun., 2014, 50, 222 Received 3rd September 2013, Accepted 25th October 2013 DOI: 10.1039/c3cc46710d
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Enantioselective organocatalytic oxidative enamine catalysis–1,5-hydride transfer– cyclization sequences: asymmetric synthesis of tetrahydroquinolines† Young Ku Kang and Dae Young Kim*
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The first organocatalytic enantioselective intramolecular oxidative enamine catalysis and 1,5-hydride transfer–ring closure reaction cascade is described. This neutral reaction cascade allows for the efficient formation of ring-fused tetrahydroquinolines with high enantioselectivities.
The development of C–C bond formation via C–H bond activation has become an area of intense interest in synthetic organic chemistry because such reactions offer practical methods for the construction of structurally complex and biologically active organic molecules with atom- and step economy.1 Direct oxidative b-functionalization of simple aldehydes to b-substituted ones is highly desirable, given this highly efficient and waste reduced process.2 However, the enantioselective routes for the oxidative b-functionalization of simple aldehydes have been rare.3 Recently, three examples of organocatalytic enantioselective b-functionalization of aldehydes were reported by Wang,4 Hayashi5 and Xu6 groups. In this oxidative enamine catalysis, oxidants converted the enamines to iminium ions in the presence of an amine catalyst, which facilitated the further nucleophilic addition to afford the b-functionalized products. In 2013, the Enders group reported the use of an aldehyde both as a nucleophile and an electrophile in a branched domino reaction for the formation of six-membered-ring derivatives through oxidative enamine catalysis.7 The 1,5-hydride transfer and the subsequent cyclization process is a well-known C–H bond functionalization strategy and has attracted considerable interest for its application in the synthesis of heterocyclic compounds. Sames and other groups successfully applied the intramolecular 1,5-hydride transfer–cyclization strategy to the functionalization of ethers, carbamates, and benzylic C–H bonds bearing unsaturated moieties.8 The tert-amino effect and related 1,5-hydride transfer–subsequent cyclization of o-(dialkylamino)aryl derivatives have attracted much attention due to their unique features to afford tetrahydroquinolines.9,10 Chiral tetrahydroquinoline derivatives have attracted considerable attention in organic synthesis and medicinal Department of Chemistry, Soonchunhyang University, 22 Soonchunhyang-Ro, Asan, Chungnam 336-745, Korea. E-mail: [email protected]; Fax: +82-41-530-1247; Tel: +82-41-530-1244 † Electronic supplementary information (ESI) available: Experimental details and characterisation data. See DOI: 10.1039/c3cc46710d
222 | Chem. Commun., 2014, 50, 222--224
chemistry due to their importance as building blocks and a diverse array of biological activities.11 Therefore, the development of new and efficient synthetic routes for the preparation of chiral tetrahydroquinoline analogues is of importance to both organic and medicinal chemistry.12 Recently, several groups reported the synthesis of tetrahydroquinolines via the catalytic enantioselective internal redox reaction of o-dialkylamino-substituted alkylidene malonates, a,bunsaturated aldehydes, and acyl oxazolidinones using metal complexes such as magnesium, cobalt, and gold complexes as well as organocatalysts such as phosphoric acid and pyrrolidine derivatives.13 As part of the research program related to the enantioselective construction of stereogenic centers,14 we recently reported the asymmetric internal redox reaction of cinnamaldehyde derivatives using secondary amines.15 Organocatalytic enantioselective hydride transfer–cyclization reaction cascade sequences involving the in situ oxidation of saturated aldehydes have not been reported. We became interested in an oxidation protocol where the saturated aldehyde is converted in situ into the corresponding a,b-unsaturated aldehyde which can then be manipulated by 1,5-hydride transfer– cyclization. Herein, we describe the first intramolecular version of oxidative enamine catalysis and 1,5-hydride transfer–cyclization sequences towards the asymmetric synthesis of tetrahydroquinolines (Scheme 1). In an attempt to validate the feasibility of the proposed organocatalytic oxidative enamine catalysis and intramolecular redox reactions, 3-(2-(azepan-1-yl)phenyl)propanal (1a) was reacted in the presence of an oxidant and a secondary amine as an organocatalyst in dichloromethane. The results of a representative selection of oxidative enamine catalysis and intramolecular redox reactions are summarized in Table 1. We started the study on the effect of various oxidants for the oxidative coupling reaction of 3-(2-(azepan-1-yl)phenyl)propanal (1a) in the presence of catalyst I (20 mol%) and ( )-camphorsulfonic acid (CSA) in CH2Cl2. The reaction gave a high yield (75%) with low enantioselectivity (19% ee) when using a 1.0 equiv. of DDQ (Table 1, entry 1). Screening of several organic oxidants showed that the use of IBX was encouraging. In this case, the desired tetrahydroquinoline 2a was obtained albeit with low yield (25%) and with only a high degree of enantioselectivity (81% ee, entry 3).
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Scheme 1 Organocatalytic oxidative enamine catalysis and intramolecular redox reaction.
Table 1
Optimization of the reaction conditionsa
A survey of the reaction media indicated that the presence of common solvents, such as dichloromethane, toluene, chloroform, THF, acetonitrile, methanol, DMF, DMSO, dibromomethane, 1,2-dichloroethane (DCE), and 1,1,2-trichloroethane (TCE) showed that this reaction was highly solvent-dependent. Solvent optimization results showed that chloroform was a better solvent with regard to the yield, diastereoselectivity, and enantioselectivity (Table 1, entry 9). Among the additives proved, the best result was achieved when the reaction was conducted in 2,4-dinitrobenzensulfonic acid (DNBS, 62% yield, 4:1 dr, 93% ee, Table 1, entry 18). With optimal reaction conditions in hand, the scope of the reaction was explored. As presented in Table 2, organocatalyst I-catalyzed enantioselective oxidative enamine catalysis and intramolecular redox reactions of 3-arylpropanals 1 proved to be a general approach for the synthesis of versatile chiral tetrahydroquinolines 2. Notably, high to excellent enantiomeric excess was obtained (up to 99% ee). Table 2 Catalytic enantioselective oxidative enamine catalysis and hydride transfer–cyclizationa–d
Entry
Cat.
Additive
Oxidant
Solvent
Yieldb (%)
drc
eed (%)
1e 2e 3e 4e 5e 6e 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22
I I I II III IV I I I I I I I I I I I I I I I I
( )-CSA ( )-CSA ( )-CSA ( )-CSA ( )-CSA ( )-CSA ( )-CSA ( )-CSA ( )-CSA ( )-CSA ( )-CSA ( )-CSA ( )-CSA ( )-CSA ( )-CSA ( )-CSA ( )-CSA DNBS HCl TsOH TFA HOTf
DDQ DMP IBX IBX IBX IBX IBX IBX IBX IBX IBX IBX IBX IBX IBX IBX IBX IBX IBX IBX IBX IBX
CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 PhMe CHCl3 THF MeCN MeOH DMF DMSO CH2Br2 DCE TCE CHCl3 CHCl3 CHCl3 CHCl3 CHCl3
75 20 25 15 nr nr 41 Trace 63 Trace 20 Dec. Dec. Dec. 10 15 45 62 nr nr nr nr
4:1 2:1 2:1 2:1
19 81 81 25
2:1 nd 4:1 nd 3:1
81 nd 91 nd 59
3:1 2:1 2:1 4:1
85 67 81 93
a
Reactions were carried out with 1a (0.1 mmol), IBX (0.2 mmol), catalyst (20 mol%) and additive (20 mol%) in solvent (1.0 mL) at room temperature for 2 d. b Combined yield of both diastereomers. c Diastereomeric ratio is determined by 1H NMR spectroscopic analysis. d Enantiopurity of the major diastereomer was determined by HPLC analysis using a chiralpak IC column. e IBX (1.0 equiv.) was used. a
Screening analogues II–IV of catalyst I revealed that reactivities and enantioselectivities decreased (Table 1, entries 4–6) and III and IV did not promote the process at all (Table 1, entries 5 and 6). Increasing the IBX loading (2.0 equiv., Table 1, entry 7) led to an improvement in the reaction yield without affecting the level of enantioselectivity.
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Reactions were carried out with 3-arylpropanals 1 (0.1 mmol), IBX (0.2 mmol), catalyst I (11.9 mg, 0.02 mmol), and DNBS (4.9 mg, 0.02 mmol) in CHCl3 (0.1 M). b Combined yield of both diastereomers. c Diastereomeric ratio was determined by 1H NMR spectroscopic analysis. d Enantiopurity of major diastereomer was determined by HPLC analysis using chiralpak AS-H (for 2d, 2e, 2f, 2g, 2i, 2j, 2l, 2m, 2n and 2q), IC (for 2a, 2c, 2h, 2o, 2p and 2r–2t), OJ-H (for 2b), and IB (for 2k) columns. e IBX (1.0 equiv.) was used. f 50 mol% catalyst loading. g DMP (1.0 equiv.) was used instead of IBX. h 40 mol% catalyst loading. i DDQ (1.0 equiv.) was used instead of IBX.
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7 Fig. 1
Proposed stereochemical model.
Products 2a–2q which incorporated five to nine-membered azacycles were formed with moderate yields, moderate to high diastereoselectivities, and excellent enantioselectivities (40–84% yield, 4 : 1–15 : 1 dr, and 80–99% ee). A range of electron-withdrawing and electron-donating substituents on the aryl ring of 3-arylpropanal derivatives 1 provided corresponding products 2b and 2c, 2e–2h, 2j–2n, and 2p with excellent enantioselectivities (82–99% ee). And, products 2r–2t which incorporated bicyclic azacycles were formed with low selectivity (1.2 : 1 dr and 10–33% ee). Unfortunately, the intramolecular redox reaction of 3-arylpropanals 1 containing acyclic amino groups as ortho-substituents of aryl groups under optimum conditions gave no desired product. The absolute configuration of products 2 was determined by comparing the optical rotation and chiral HPLC data with the literature values.15 Although the reason for the observed enantioselectivity is still unclear, we suppose that the enamine intermediate attacks the re-face of the iminium ion, as shown in Fig. 1. In summary, we have presented the first example of an organocatalytic enantioselective oxidative enamine catalysis and a hydride transfer–ring closure reaction cascade. The synthetically useful ring-fused tetrahydroquinoline derivatives were obtained in moderate yields and with high levels of enantioselectivity. Further investigations into organocatalytic oxidative enamine catalysis and internal redox reactions are being pursued. This research was supported by the Soonchunhyang University Research Fund and the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (2013-052688).
8
9
10
11
12
Notes and references 1 For recent reviews on C–H activation, see: (a) F. Kakiuchi and N. Chatani, Adv. Synth. Catal., 2003, 345, 1077; (b) H. M. L. Davies, Angew. Chem., Int. Ed., 2006, 45, 6422; (c) K. Godula and D. Sames, Science, 2006, 312, 67; (d) R. G. Bergman, Nature, 2007, 446, 391; (e) K. R. Campos, Chem. Soc. Rev., 2007, 36, 1069; ( f ) D. Alberico, M. E. Scott and M. Lautens, Chem. Rev., 2007, 107, 174; (g) R. Jazzar, J. Hitce, A. Renaudat, J. Sofack-Kreutzer and O. Baudoin, Chem.–Eur. J., 2010, 16, 2654. 2 For reports of reactions involving b-functionalization of carbonyl compounds, see: (a) S. Ueno, R. Shimizu and R. Kuwano, Angew. Chem., Int. Ed., 2009, 48, 4543; (b) M. Wasa, K. M. Engle and J.-Q. Yu, J. Am. Chem. Soc., 2010, 132, 3680; (c) T. W. Lyons and M. S. Sanford, Chem. Rev., 2010, 110, 1147; (d) M. Wasa, K. S. L. Chan, X.-G. Zhang, J. He, M. Miura and J.-Q. Yu, J. Am. Chem. Soc., 2012, 134, 18570; (e) L. D. Tran and O. Daugulis, Angew. Chem., Int. Ed., 2012, 51, 5188; ( f ) M. V. Leskinen, K.-T. Yip, A. Valkonen and P. M. Pihko, J. Am. Chem. Soc., 2012, 134, 5750; (g) S. Aspin, A.-S. Goutierre, P. Larini, R. Jazzar and O. Baudoin, Angew. Chem., Int. Ed., 2012, 51, 10808; (h) T. M. U. Ton, C. Tejo, D. L. Y. Tiong and P. W. H. Chan, J. Am. Chem. Soc., 2012, 134, 7344; (i) M. T. Pirnot, D. A. Rankic, D. B. C. Martin and D. W. C. MacMillan, Science, 2013, 339, 1593. 3 J. Xiao, ChemCatChem, 2012, 4, 612. 4 (a) S.-L. Zhang, H.-X. Xie, J. Zhu, H. Li, X.-S. Zhang, J. Li and W. Wang, Nat. Commun., 2011, 2, 211; (b) J. Zhu, S.-T. Yu, W.-C. Lu, J. Deng, J. Li and W. Wang, Tetrahedron Lett., 2012,
224 | Chem. Commun., 2014, 50, 222--224
13
14
15
53, 1207; (c) H.-X. Xie, S.-L. Zhang, H. Li, X.-S. Zhang, S.-H. Zhao, Z. Xu, X.-X. Song, X.-H. Yu and W. Wang, Chem.–Eur. J., 2012, 18, 2230. Y. Hayashi, T. Itoh and H. Ishikawa, Angew. Chem., Int. Ed., 2011, 50, 3920. Y.-L. Zhao, Y. Wang, X.-Q. Hu and P.-F. Xu, Chem. Commun., 2013, 49, 7555. X. Zeng, Q. Ni, G. Raabe and D. Enders, Angew. Chem., Int. Ed., 2013, 52, 2977. For recent selected examples, see: (a) S. J. Pastine, K. M. McQuaid and D. Sames, J. Am. Chem. Soc., 2005, 127, 12180; (b) S. J. Pastine and D. Sames, Org. Lett., 2005, 7, 5429; (c) K. M. McQuaid and D. Sames, J. Am. Chem. Soc., 2009, 131, 402; (d) K. M. McQuaid, J. Z. Long and D. Sames, Org. Lett., 2009, 11, 2972; (e) P. A. Vadola and D. Sames, J. Am. Chem. Soc., 2009, 131, 16525; ( f ) M. Haibach, I. Deb, C. K. De and D. Seidel, J. Am. Chem. Soc., 2011, 133, 2100; (g) K. Mori, S. Sueoka and T. Akiyama, J. Am. Chem. Soc., 2011, 133, 2424; (h) K. Mori, T. Kawasaki and T. Akiyama, Org. Lett., 2012, 14, 1436; (i) P. A. Vadola, I. Carrera and D. Sames, J. Org. Chem., 2012, 77, 6689; ( j) Z.-W. Jiao, S.-Y. Zhang, C. He, Y.-Q. Tu, S.-H. Wang, F.-M. Zhang, W.-Q. Zhang and H. Li, Angew. Chem., Int. Ed., 2012, 51, 8811. For selected reviews on the tert-amino effect, see: (a) O. Meth-Cohn, Adv. Heterocycl. Chem., 1996, 65, 1; (b) J. M. Quintela, Recent Res. Dev. Org. Chem., 2003, 7, 259; (c) P. Matyus, O. Elias, P. Tapolcsanyi, A. Polonka-Balint and B. Halasz-Dajka, Synthesis, 2006, 2625; (d) S. C. Pan, Beilstein J. Org. Chem., 2012, 8, 1374. For selected examples, see: (a) C. Zhang, C. Kanta De, R. Mal and D. Seidel, J. Am. Chem. Soc., 2008, 130, 416; (b) J. Barluenga, ˜ana ´s-Mastral, F. Aznar and C. Valde ´s, Angew. Chem., Int. Ed., M. Fan 2008, 47, 6594; (c) J. C. Ruble, A. R. Hurd, T. A. Johnson, D. A. Sherry, M. R. Barbachyn, P. L. Toogood, G. L. Bundy, D. R. Graber and G. M. Kamilar, J. Am. Chem. Soc., 2009, 131, 3991; (d) D. Shikanai, H. Murase, T. Hata and H. Urabe, J. Am. Chem. Soc., 2009, 131, 3166; (e) S. J. Mahoney, D. T. Moon, J. Hollinger and E. Fillion, Tetrahedron Lett., 2009, 50, 4706; ( f ) K. Mori, Y. Ohshima, K. Ehara and T. Akiyama, Chem. Lett., 2009, 524; (g) C. Zhang, S. Murarka and D. Seidel, J. Org. Chem., 2009, 74, 419; (h) S. Murarka, C. Zhang and M. D. Konieczynska, Org. Lett., 2009, 11, 129; (i) K. Mori, T. Kawasaki, S. Sueoka and T. Akiyama, Org. Lett., 2010, 12, 1732. (a) D. H. R. Barton, K. Nakanishi and O. Meth-Cohn, Comprehensive Natural Products Chemistry, Elsevier, Oxford, vol. 1–9, 1999; (b) A. R. Katritzky, S. Rachwal and B. Rachwal, Tetrahedron, 1996, 52, 15031; (c) Y.-G. Zhou, Acc. Chem. Res., 2007, 40, 1357. (a) T. Akiyama, H. Morita and K. Fuchibe, J. Am. Chem. Soc., 2006, 128, 13070; (b) M. Rueping, A. P. Antonchick and T. Theissmann, Angew. Chem., Int. Ed., 2006, 45, 3683; (c) Q. S. Guo, D. M. Du and J. Xu, Angew. Chem., Int. Ed., 2008, 47, 759; (d) X. B. Wang and Y. G. Zhou, J. Org. Chem., 2008, 73, 5640; (e) V. A. Glushkov and A. G. Tolstikov, Russ. Chem. Rev., 2008, 77, 137; ( f ) A. O’Byrne and P. Evans, Tetrahedron, 2008, 64, 8067; (g) V. V. Kouznetsov, Tetrahedron, 2009, 65, 2721; (h) H. Liu, G. Dagousset, G. Masson, P. Retailleau and J. P. Zhu, J. Am. Chem. Soc., 2009, 131, 4598; (i) G. Bergonzini, L. Gramigna, A. Mazzanti, M. Fochi, L. Bernardi and A. Ricci, Chem. Commun., 2010, 46, 327. (a) S. Murarka, I. Deb, C. Zhang and D. Seidel, J. Am. Chem. Soc., 2009, 131, 13226; (b) Y. K. Kwon, Y. K. Kang and D. Y. Kim, Bull. Korean Chem. Soc., 2011, 32, 1773; (c) W. Cao, X. Liu, W. Wang, L. Lin and X. Feng, Org. Lett., 2011, 13, 600; (d) G. Zhou, F. Liu and J. Zhang, Chem.–Eur. J., 2011, 17, 3101; (e) K. Mori, K. Ehara, K. Kurihara and T. Akiyama, J. Am. Chem. Soc., 2011, 133, 6166; ( f ) Y.-P. He, Y.-L. Du, S.-W. Luo and L.-Z. Gong, Tetrahedron Lett., 2011, 52, 7064; (g) L. Zhang, L. Chen, J. Lv, J.-P. Cheng and S. Luo, Chem.–Asian. J., 2012, 7, 2569; (h) L. Chen, L. Zhang, J. Lv, J.-P. Cheng and S. Luo, Chem.–Eur. J., 2012, 18, 8891. For selected our work on synthetic methodology using organocatalysts, see: (a) J. H. Lee and D. Y. Kim, Adv. Synth. Catal., 2009, 351, 1779; (b) Y. K. Kang and D. Y. Kim, J. Org. Chem., 2009, 74, 5734; (c) Y. Oh, S. M. Kim and D. Y. Kim, Tetrahedron Lett., 2009, 50, 4674; (d) H. W. Moon, M. J. Cho and D. Y. Kim, Tetrahedron Lett., 2009, 50, 4896; (e) J. H. Lee and D. Y. Kim, Synthesis, 2010, 1860; ( f ) H. J. Lee, S. H. Kang and D. Y. Kim, Synlett, 2011, 1559; ( g) S. J. Yoon, Y. K. Kang and D. Y. Kim, Synlett, 2011, 420; (h) H. J. Lee, S. B. Woo and D. Y. Kim, Tetrahedron Lett., 2012, 53, 3374; (i) Y. K. Kang, H. J. Lee, H. W. Moon and D. Y. Kim, RSC Adv., 2013, 3, 1332; ( j) C. W. Suh, C. W. Chang, K. W. Choi, Y. J. Lim and D. Y. Kim, Tetrahedron Lett., 2013, 54, 3651. Y. K. Kang, S. M. Kim and D. Y. Kim, J. Am. Chem. Soc., 2010, 132, 11847.
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Cite this: Chem. Commun., 2014, 50, 222 Received 3rd September 2013, Accepted 25th October 2013 DOI: 10.1039/c3cc46710d
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Enantioselective organocatalytic oxidative enamine catalysis–1,5-hydride transfer– cyclization sequences: asymmetric synthesis of tetrahydroquinolines† Young Ku Kang and Dae Young Kim*
www.rsc.org/chemcomm
The first organocatalytic enantioselective intramolecular oxidative enamine catalysis and 1,5-hydride transfer–ring closure reaction cascade is described. This neutral reaction cascade allows for the efficient formation of ring-fused tetrahydroquinolines with high enantioselectivities.
The development of C–C bond formation via C–H bond activation has become an area of intense interest in synthetic organic chemistry because such reactions offer practical methods for the construction of structurally complex and biologically active organic molecules with atom- and step economy.1 Direct oxidative b-functionalization of simple aldehydes to b-substituted ones is highly desirable, given this highly efficient and waste reduced process.2 However, the enantioselective routes for the oxidative b-functionalization of simple aldehydes have been rare.3 Recently, three examples of organocatalytic enantioselective b-functionalization of aldehydes were reported by Wang,4 Hayashi5 and Xu6 groups. In this oxidative enamine catalysis, oxidants converted the enamines to iminium ions in the presence of an amine catalyst, which facilitated the further nucleophilic addition to afford the b-functionalized products. In 2013, the Enders group reported the use of an aldehyde both as a nucleophile and an electrophile in a branched domino reaction for the formation of six-membered-ring derivatives through oxidative enamine catalysis.7 The 1,5-hydride transfer and the subsequent cyclization process is a well-known C–H bond functionalization strategy and has attracted considerable interest for its application in the synthesis of heterocyclic compounds. Sames and other groups successfully applied the intramolecular 1,5-hydride transfer–cyclization strategy to the functionalization of ethers, carbamates, and benzylic C–H bonds bearing unsaturated moieties.8 The tert-amino effect and related 1,5-hydride transfer–subsequent cyclization of o-(dialkylamino)aryl derivatives have attracted much attention due to their unique features to afford tetrahydroquinolines.9,10 Chiral tetrahydroquinoline derivatives have attracted considerable attention in organic synthesis and medicinal Department of Chemistry, Soonchunhyang University, 22 Soonchunhyang-Ro, Asan, Chungnam 336-745, Korea. E-mail: [email protected]; Fax: +82-41-530-1247; Tel: +82-41-530-1244 † Electronic supplementary information (ESI) available: Experimental details and characterisation data. See DOI: 10.1039/c3cc46710d
222 | Chem. Commun., 2014, 50, 222--224
chemistry due to their importance as building blocks and a diverse array of biological activities.11 Therefore, the development of new and efficient synthetic routes for the preparation of chiral tetrahydroquinoline analogues is of importance to both organic and medicinal chemistry.12 Recently, several groups reported the synthesis of tetrahydroquinolines via the catalytic enantioselective internal redox reaction of o-dialkylamino-substituted alkylidene malonates, a,bunsaturated aldehydes, and acyl oxazolidinones using metal complexes such as magnesium, cobalt, and gold complexes as well as organocatalysts such as phosphoric acid and pyrrolidine derivatives.13 As part of the research program related to the enantioselective construction of stereogenic centers,14 we recently reported the asymmetric internal redox reaction of cinnamaldehyde derivatives using secondary amines.15 Organocatalytic enantioselective hydride transfer–cyclization reaction cascade sequences involving the in situ oxidation of saturated aldehydes have not been reported. We became interested in an oxidation protocol where the saturated aldehyde is converted in situ into the corresponding a,b-unsaturated aldehyde which can then be manipulated by 1,5-hydride transfer– cyclization. Herein, we describe the first intramolecular version of oxidative enamine catalysis and 1,5-hydride transfer–cyclization sequences towards the asymmetric synthesis of tetrahydroquinolines (Scheme 1). In an attempt to validate the feasibility of the proposed organocatalytic oxidative enamine catalysis and intramolecular redox reactions, 3-(2-(azepan-1-yl)phenyl)propanal (1a) was reacted in the presence of an oxidant and a secondary amine as an organocatalyst in dichloromethane. The results of a representative selection of oxidative enamine catalysis and intramolecular redox reactions are summarized in Table 1. We started the study on the effect of various oxidants for the oxidative coupling reaction of 3-(2-(azepan-1-yl)phenyl)propanal (1a) in the presence of catalyst I (20 mol%) and ( )-camphorsulfonic acid (CSA) in CH2Cl2. The reaction gave a high yield (75%) with low enantioselectivity (19% ee) when using a 1.0 equiv. of DDQ (Table 1, entry 1). Screening of several organic oxidants showed that the use of IBX was encouraging. In this case, the desired tetrahydroquinoline 2a was obtained albeit with low yield (25%) and with only a high degree of enantioselectivity (81% ee, entry 3).
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Scheme 1 Organocatalytic oxidative enamine catalysis and intramolecular redox reaction.
Table 1
Optimization of the reaction conditionsa
A survey of the reaction media indicated that the presence of common solvents, such as dichloromethane, toluene, chloroform, THF, acetonitrile, methanol, DMF, DMSO, dibromomethane, 1,2-dichloroethane (DCE), and 1,1,2-trichloroethane (TCE) showed that this reaction was highly solvent-dependent. Solvent optimization results showed that chloroform was a better solvent with regard to the yield, diastereoselectivity, and enantioselectivity (Table 1, entry 9). Among the additives proved, the best result was achieved when the reaction was conducted in 2,4-dinitrobenzensulfonic acid (DNBS, 62% yield, 4:1 dr, 93% ee, Table 1, entry 18). With optimal reaction conditions in hand, the scope of the reaction was explored. As presented in Table 2, organocatalyst I-catalyzed enantioselective oxidative enamine catalysis and intramolecular redox reactions of 3-arylpropanals 1 proved to be a general approach for the synthesis of versatile chiral tetrahydroquinolines 2. Notably, high to excellent enantiomeric excess was obtained (up to 99% ee). Table 2 Catalytic enantioselective oxidative enamine catalysis and hydride transfer–cyclizationa–d
Entry
Cat.
Additive
Oxidant
Solvent
Yieldb (%)
drc
eed (%)
1e 2e 3e 4e 5e 6e 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22
I I I II III IV I I I I I I I I I I I I I I I I
( )-CSA ( )-CSA ( )-CSA ( )-CSA ( )-CSA ( )-CSA ( )-CSA ( )-CSA ( )-CSA ( )-CSA ( )-CSA ( )-CSA ( )-CSA ( )-CSA ( )-CSA ( )-CSA ( )-CSA DNBS HCl TsOH TFA HOTf
DDQ DMP IBX IBX IBX IBX IBX IBX IBX IBX IBX IBX IBX IBX IBX IBX IBX IBX IBX IBX IBX IBX
CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 PhMe CHCl3 THF MeCN MeOH DMF DMSO CH2Br2 DCE TCE CHCl3 CHCl3 CHCl3 CHCl3 CHCl3
75 20 25 15 nr nr 41 Trace 63 Trace 20 Dec. Dec. Dec. 10 15 45 62 nr nr nr nr
4:1 2:1 2:1 2:1
19 81 81 25
2:1 nd 4:1 nd 3:1
81 nd 91 nd 59
3:1 2:1 2:1 4:1
85 67 81 93
a
Reactions were carried out with 1a (0.1 mmol), IBX (0.2 mmol), catalyst (20 mol%) and additive (20 mol%) in solvent (1.0 mL) at room temperature for 2 d. b Combined yield of both diastereomers. c Diastereomeric ratio is determined by 1H NMR spectroscopic analysis. d Enantiopurity of the major diastereomer was determined by HPLC analysis using a chiralpak IC column. e IBX (1.0 equiv.) was used. a
Screening analogues II–IV of catalyst I revealed that reactivities and enantioselectivities decreased (Table 1, entries 4–6) and III and IV did not promote the process at all (Table 1, entries 5 and 6). Increasing the IBX loading (2.0 equiv., Table 1, entry 7) led to an improvement in the reaction yield without affecting the level of enantioselectivity.
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Reactions were carried out with 3-arylpropanals 1 (0.1 mmol), IBX (0.2 mmol), catalyst I (11.9 mg, 0.02 mmol), and DNBS (4.9 mg, 0.02 mmol) in CHCl3 (0.1 M). b Combined yield of both diastereomers. c Diastereomeric ratio was determined by 1H NMR spectroscopic analysis. d Enantiopurity of major diastereomer was determined by HPLC analysis using chiralpak AS-H (for 2d, 2e, 2f, 2g, 2i, 2j, 2l, 2m, 2n and 2q), IC (for 2a, 2c, 2h, 2o, 2p and 2r–2t), OJ-H (for 2b), and IB (for 2k) columns. e IBX (1.0 equiv.) was used. f 50 mol% catalyst loading. g DMP (1.0 equiv.) was used instead of IBX. h 40 mol% catalyst loading. i DDQ (1.0 equiv.) was used instead of IBX.
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7 Fig. 1
Proposed stereochemical model.
Products 2a–2q which incorporated five to nine-membered azacycles were formed with moderate yields, moderate to high diastereoselectivities, and excellent enantioselectivities (40–84% yield, 4 : 1–15 : 1 dr, and 80–99% ee). A range of electron-withdrawing and electron-donating substituents on the aryl ring of 3-arylpropanal derivatives 1 provided corresponding products 2b and 2c, 2e–2h, 2j–2n, and 2p with excellent enantioselectivities (82–99% ee). And, products 2r–2t which incorporated bicyclic azacycles were formed with low selectivity (1.2 : 1 dr and 10–33% ee). Unfortunately, the intramolecular redox reaction of 3-arylpropanals 1 containing acyclic amino groups as ortho-substituents of aryl groups under optimum conditions gave no desired product. The absolute configuration of products 2 was determined by comparing the optical rotation and chiral HPLC data with the literature values.15 Although the reason for the observed enantioselectivity is still unclear, we suppose that the enamine intermediate attacks the re-face of the iminium ion, as shown in Fig. 1. In summary, we have presented the first example of an organocatalytic enantioselective oxidative enamine catalysis and a hydride transfer–ring closure reaction cascade. The synthetically useful ring-fused tetrahydroquinoline derivatives were obtained in moderate yields and with high levels of enantioselectivity. Further investigations into organocatalytic oxidative enamine catalysis and internal redox reactions are being pursued. This research was supported by the Soonchunhyang University Research Fund and the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (2013-052688).
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