Synlett, Table of Contents Synlett 2013; 24(5): 625-629DOI: 10.1055/s-0032-1318300 letter © Georg Thieme Verlag Stuttgart · New York Diastereoselective Synthesis of 1,3-syn-Oxazines via a Tandem Hemiaminalization and Tsuji–Trost Reaction Bin Tang a Ruprecht-Karls-Universität Heidelberg, Institut für Organische Chemie, INF 270, 69120 Heidelberg, Germany , Liang Wang a Ruprecht-Karls-Universität Heidelberg, Institut für Organische Chemie, INF 270, 69120 Heidelberg, Germany , Dirk Menche* b Rheinische Friedrich-Wilhelms-Universität Bonn, Institut für Organische Chemie und Biochemie, Gerhard-Domagk-Str 1, 53121 Bonn, Germany Fax: +49(228)735813 Email: dirk.menche@uni-bonn.de › Author Affiliations Recommend Article Abstract Buy Article All articles of this category Abstract A novel domino sequence for the rapid assembly of 1,3-syn-substituted oxazines is reported. Mechanistically, the one-pot procedure is based on a three-step sequential process involving a hemiaminalization and Tsuji–Trost reaction. The process generates up to two new stereogenic centers in a concise and convergent fashion from simple and readily available starting materials. Key words Key wordssynthetic methodology - tandem reaction - catalysis - allylic substitution - oxazines Full Text References References and Notes 1 Present address: University of Basel, Switzerland. 2a Pinder AR. Nat. Prod. Rep. 1992; 9: 491 2b Plunkett AO. Nat. Prod. Rep. 1994; 11: 581 2c Cossy J, Willis C, Bellosta V, BouzBouz S. J. Org. Chem. 2002; 67: 1982 2d Fustero S, Jimenéz D, Moscardó J, Catalán S, Pozo C. Org. Lett. 2007; 9: 5283 For examples of bioactive 1,3-amino alcohols, see: 3a Wang Y.-F, Izawa T, Kobayashi S, Ohno M. J. Am. Chem. Soc. 1982; 104: 6465 3b Colau B, Hootelk C. Can. J. Chem. 1983; 61: 470 3c Benz G, Henning R, Stasch J.-P. Angew. Chem. Int. Ed. 1991; 30: 1702 3d Boyd SA, Fung AK. L, Baker WR, Mantei RA, Armiger Y.-L, Stein HH, Cohen J, Egan DA, Barlow JL, Klinghofer V, Verburg KM, Martin DL, Young GA, Polakowski JS, Hoffman DJ, Garren KW, Perun TJ, Kleinert HD. J. Med. Chem. 1992; 35: 1735 3e Jacobi PA, Murphree S, Rupprecht F, Zheng W. J. Org. Chem. 1996; 61: 2413 3f Steinmetz H, Glaser N, Herdtweck E, Sasse F, Reichenbach H, Höfle G. Angew. Chem. Int. Ed. 2004; 43: 4888 3g Lee JS, Kim D, Lozano L, Kong SB, Han H. Org. Lett. 2013; 15: 554 For selected alternative approaches to the chiral 1,3-amino alcohol functionality, see: 4a Pilli RA, Russowsky D, Dias LC. J. Chem. Soc., Chem. Commun. 1987; 1053 4b Pilli RA, Russowsky D, Dias LC. J. Chem. Soc., Perkin Trans. 1 1990; 1213 4c Ghosh AK, Bilcer G, Schiltz G. Synthesis 2001; 2203 4d Keck GE, Truong AP. Org. Lett. 2002; 4: 3131 4e Olofsson B, Somfai P. J. Org. Chem. 2002; 67: 8574 4f Benedetti F, Berti F, Norbedo S. J. Org. Chem. 2002; 67: 8635 4g Wabnitz TC, Spencer JB. 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Chem. 2012; 77: 10811 6 For a domino reaction involving a hemiaminalization, see: Urushima T, Sakamoto D, Ishikawa H, Hayashi Y. Org. Lett. 2010; 12: 4588 7 van Benthem RA. T. M, Hiemstra H, Michels JJ, Speckamp WN. J. Chem. Soc., Chem. Commun. 1994; 357 8 All required homoallylic substrates were readily prepared by allylation of the respective aldehyde and subsequent cross-metathesis, as previously described; see ref. 4. 9 N-Arenesulfonyl aldimines were readily prepared from aliphatic and aromatic aldehydes in a two-step transformation. See: Chemla F, Hebbe V, Normant J.-F. Synthesis 2000; 75 10 Trost BM, Crawley ML. Chem. Rev. 2003; 103: 2921 11 In all cases, stereochemical assignment was based on NMR methods. Scheme 4 shows an example. 12 A yield of 56% was obtained in the absence of base for the analogous reaction described in entry 5 (Table 2). 13 Experimental Procedure: Under an argon atmosphere, imine 10 (62.2 mg, 0.24 mmol), allylpalladium(II) chloride dimer (7.3 mg, 10 mol%) and triphenylphosphine (15.8 mg, 30 mol%) were added to a well-dried Schlenk flask. Then, a solution of the respective carbonate (0.2 mmol) in anhyd toluene (0.33 M, 0.61 mL) was added to the flask and stirred until all solids were dissolved. After cooling to –78 °C, the potassium bis(trimethylsilyl)amide solution (0.5 M in toluene) was added dropwise (40 μL, 10 mol%). After 15 min the reaction mixture was warmed to r.t. and stirred at this temperature until complete conversion. After addition of a sat. aq solution of NH4Cl (2 mL), the mixture was extracted with EtOAc (3 ×), washed with H2O and brine and dried over Na2SO4. The solvent was removed in vacuo and the residue was purified by column chromatography on silica gel with EtOAc–hexane (1:16) as eluent to afford the oxazines with the indicated yields and selectivities. 14 All new compounds had spectroscopic data in support of the assigned structures. Oxazine 11a: 1H NMR (500.13 MHz, CDCl3): δ = 7.97 (d, J = 8.5 Hz, 1 H), 7.95 (d, J = 8.5 Hz, 1 H) 7.63 (d, J = 8.2 Hz, 1 H), 7.58 (d, J = 8.2 Hz, 1 H), 7.29–7.42 (m, 5 H), 7.12–7.19 (m, 2 H), 7.07 (d, J = 7.9 Hz, 1 H), 7.00 (d, J = 7.9 Hz, 1 H), 6.75 (s, 1 H), 5.78 (ddd, J = 17.3, 10.4, 7.7 Hz, 1 H), 5.02 (d, J = 17.3 Hz, 1 H), 4.96 (d, J = 10.3 Hz, 1 H), 4.40 (ddd, J = 8.5, 8.2, 7.7 Hz, 1 H), 3.86 (dd, J = 10.2, 4.7 Hz, 1 H), 2.50 (s, 3 H), 2.35 (s, 3 H), 1.93 (ddd, J = 13.7, 10.2, 8.2 Hz, 1 H), 1.54 (ddd, J = 13.7, 8.5, 4.7 Hz, 1 H). 13C NMR (125.76 MHz, CDCl3): δ = 143.93, 141.52, 139.12, 137.74, 137.48, 137.36, 129.78, 129.19, 129.14, 128.27, 128.02, 127.82, 127.63, 127.29, 126.81, 126.17, 125.71, 115.73, 83.83, 73.15, 56.10, 33.62, 21.58, 21.08. HRMS (ESI): m/z [M + H]+ calcd for C26H28NO3S: 434.17844; found: 434.17839. Oxazine 12a: 1H NMR (500.13 MHz, CDCl3): δ = 7.91–7.96 (m, 4 H), 7.71 (d, J = 7.7 Hz, 2 H), 7.50 (d, J = 7.7 Hz, 2 H), 7.32–7.40 (m, 5 H), 6.73 (s, 1 H), 5.78 (ddd, J = 17.3, 10.4, 6.6 Hz, 1 H), 5.02 (d, J = 17.3 Hz, 1 H), 4.94 (d, J = 10.4 Hz, 1 H), 4.50 (ddd, J = 8.2, 8.0, 6.6 Hz, 1 H), 4.34 (dd, J = 11.5, 2.2 Hz, 1 H), 3.71 (s, 3 H), 2.48 (s, 3 H), 2.07 (ddd, J = 13.7, 8.0, 2.2 Hz, 1 H), 1.82 (ddd, J = 13.7, 11.5, 8.0 Hz, 1 H). 13C NMR (125.77 MHz, CDCl3): δ = 155.85, 143.35, 141.45, 139.34, 131.19, 129.72, 129.06, 128.57, 128.00, 127.90, 127.65, 126.89, 126.29, 120.62, 115.46, 110.29, 84.36, 68.03, 55.78, 55.09, 33.19, 21.54. HRMS (ESI): m/z [M + K]+ calcd for C26H27NO4SK: 488.12924; found: 488.12948. 15 For a more detailed mechanistic discussion of a related cyclization, see ref. 4d. Supplementary Material Supplementary Material Supporting Information
