Subscribe to RSS
DOI: 10.1055/s-2007-984877
Synthesis of trans-3-Substituted Cyclohexylamines via Brønsted Acid Catalyzed and Substrate-Mediated Triple Organocatalytic Cascade Reaction
Publication History
Publication Date:
12 July 2007 (online)
Abstract
We report a new organocatalytic cascade reaction. A combination of the amine substrate with a catalytic amount of a Brønsted acid merges enamine and iminium catalysis with Brønsted acid catalysis in a new organocatalytic cascade reaction. We found that the aniline substrate itself in combination with a catalytic amount of PTSA·H2O can function as an aminocatalyst accomplishing an aldol condensation-conjugate reduction cascade, which terminates in a Brønsted acid catalyzed reductive amination incorporating the amine substrate into the final product. This transformation furnishes trans-3-substituted cyclohexyl amines in good yields and good diastereoselectivities.
Key words
organocatalytic cascade reaction - substrate co-catalyzed - 3-substituted cyclohexyl amine - organocatalysis
- For leading reviews, see:
-
1a
Ramón DJ.Yus M. Angew. Chem. Int. Ed. 2005, 44: 1602 -
1b
Nicolaou KC.Montagnon T.Snyder SA. Chem. Commun. 2003, 551 -
1c
Tietze LF. Chem. Rev. 1996, 96: 115 -
1d
Wasilke J.-C.Obrey SJ.Baker RT.Bazan GC. Chem. Rev. 2005, 105: 1001 - 2 For an excellent review, see:
Enders D.Grondal C.Hüttl MRM. Angew. Chem. Int. Ed. 2007, 46: 1570 - For important reviews, see:
-
3a
List B.Yang JW. Science 2006, 313: 1584 -
3b
Seayad J.List B. Org. Biomol. Chem. 2005, 3: 719 -
3c
Dalko PI.Moisan L. Angew. Chem. Int. Ed. 2004, 43: 5138 -
4a
List B. Chem. Commun. 2006, 819 -
4b
Lelais G.MacMillan DWC. Aldrichimica Acta 2006, 39: 79 -
4c
Palomo C.Mielgo A. Angew. Chem. Int. Ed. 2006, 45: 7876 - For recent examples, see:
-
5a
Yang JW.Hechavarria Fonseca MT.List B. J. Am. Chem. Soc. 2005, 127: 15036 -
5b
Huang Y.Walji AM.Larsen CH.MacMillan DWC. J. Am. Chem. Soc. 2005, 127: 15051 -
5c
Marigo M.Schulte T.Franzén J.Jørgensen KA. J. Am. Chem. Soc. 2005, 127: 15710 -
5d
Enders D.Hüttl MRM.Grondal C.Raabe G. Nature (London) 2006, 441: 861 -
5e
Wang W.Li H.Wang J.Zu L. J. Am. Chem. Soc. 2006, 128: 10354 -
5f
Brandau S.Maerten E.Jørgensen KA. J. Am. Chem. Soc. 2006, 128: 14986 -
5g
Enders D.Hüttl MRM.Runsink J.Raabe G.Wendt B. Angew. Chem. Int. Ed. 2007, 46: 467 -
5h
Carlone A.Cabrera S.Marigo M.Jørgensen KA. Angew. Chem. Int. Ed. 2007, 46: 1101 -
5i
Li H.Wang J.E-Nunu T.Zu L.Jiang W.Wei S.Wang W. Chem. Commun. 2007, 507 - For reviews, see:
-
6a
Taylor MS.Jacobsen EN. Angew. Chem. Int. Ed. 2006, 45: 1520 -
6b
Akiyama T.Itoh J.Fuchibe K. Adv. Synth. Catal. 2006, 348: 999 -
6c
Connon SJ. Angew. Chem. Int. Ed. 2006, 45: 3909 -
6d
Takemoto Y. Org. Biomol. Chem. 2005, 3: 4299 -
6e
Bolm C.Rantanen T.Schiffers I.Zani L. Angew. Chem. Int. Ed. 2005, 44: 1758 -
6f
Schreiner PR. Chem. Soc. Rev. 2003, 32: 289 -
7a
Mayer S.List B. Angew. Chem. Int. Ed. 2006, 45: 4193 -
7b
Martin NJA.List B. J. Am. Chem. Soc. 2006, 128: 13368 - For chiral amine-catalyzed conjugate reductions of α,β-unsaturated carbonyl compounds, see:
-
8a
Yang JW.Hechavarria Fonseca MT.List B. Angew. Chem. Int. Ed. 2004, 43: 6660 -
8b
Yang JW.Hechavarria Fonseca MT.Vignola N.List B. Angew. Chem. Int. Ed. 2005, 44: 108 -
8c
Ouellet SG.Tuttle JB.MacMillan DWC. J. Am. Chem. Soc. 2005, 127: 32 -
8d
Tutlle JB.Ouellet SG.MacMillan DWC. J. Am. Chem. Soc. 2006, 128: 12662 -
9a
Hoffmann S.Seayad AM.List B. Angew. Chem. Int. Ed. 2005, 44: 7424 -
9b
Hoffmann S.Nicoletti M.List B. J. Am. Chem. Soc. 2006, 128: 13074 - Also see:
-
9c
Rueping M.Sugiono E.Azap C.Theissmann T.Bolte M. Org. Lett. 2005, 7: 3781 -
9d
Storer RI.Carrera DE.Ni Y.MacMillan DWC. J. Am. Chem. Soc. 2006, 128: 84 - For the reduction of quinolines, benzoxazines, benzothiazines, and benzoxazinones, see:
-
9e
Rueping M.Antonchick AP.Theissmann T. Angew. Chem. Int. Ed. 2006, 45: 3683 -
9f
Rueping M.Antonchick AP.Theissmann T. Angew. Chem. Int. Ed. 2006, 45: 6751 - For achiral version, see:
-
9g
Rueping M.Azap C.Sugiono E.Theissmann T. Synlett 2005, 2367 -
9h
Rueping M.Theissmann T.Antonchick AP. Synlett 2006, 1071 - 10 For a review on amine-catalyzed aldol reactions, see:
List B. In Modern Aldol Reactions Vol. 1:Mahrwald R. Wiley-VCH; Weinhein Germany: 2004. p.161-200 - 11 For a recent nonasymmetric amine mediated aldol condensation, Pd-catalyzed hydrogenation-reductive amination cascade in the synthesis of Fenpropimorph, see:
Forsyth SA.Gunaratne HQN.Hardacre C.McKeown A.Rooney DW. Org. Process Res. Dev. 2006, 10: 94 - 12 For the determination of the relative configuration and a highly enantioselective synthesis of the corresponding cis-products, see:
Zhou J.List B. J. Am. Chem. Soc. 2007, 129: 7498 - 14 This is in contrast to the corresponding NaOH-catalyzed cyclization of 2,6-heptanediones, see:
Danishefsky S.Zimmer A. J. Org. Chem. 1976, 41: 4059 - 15 For a related investigation, see:
De Nie-Sarink MJ.Pandit UK. Tetrahedron Lett. 1979, 26: 2449 - 16
Verkade JMM.van Hermert LJC.Quaedflieg PJLM.Alsters PL.van Delft FL.Rutjes FPJT. Tetrahedron Lett. 2006, 47: 8109 - Based on a SciFinder survey, there are more than 300 patented structures containing a 3-methylcyclohexylamine moiety. For selected pharmaceutically active compounds incorporating a 3-substituted cyclohexylamine, see:
-
17a
Johnston TP.McCaleb GS.Clayton SD.Frye JL.Krauth CA.Montgomery JA. J. Med. Chem. 1977, 20: 279 -
17b
Palomba M.Pau A.Boatto G.Asproni B.Auzzas L.Cerri R.Arenare L.Filippelli W.Falcone G.Motola G. Arch. Pharm. Pharm. Med. Chem. 2000, 333: 17 -
17c
Norman BH.Lander PA.Gruber JM.Kroin JS.Cohen JD.Jungheim LN.Starling JJ.Law KL.Self TD.Tabas LB.Williams DC.Paul DC.Dantzig AH. Bioorg. Med. Chem. Lett. 2005, 15: 5526
References and Notes
Typical Procedure: To a Schlenk tube was added 2,6-dione 1 (0.2 mmol), p-ethoxyphenyl amine 2 (0.3 mmol), Hantzsch ester 3 (0.45 mmol) and PTSA·H2O (2 mg, 0.01 mmol), and then charged with argon, followed by adding MS 5 Å (50 mg) and anhyd toluene (0.5 mL). The mixture was stirred at 40 °C for 24-72 h. To determine the ratio of trans- to cis-product, 20 µL of the reaction mixture was taken for GC-MS analysis, or 0.2 mL of crude mixture for 1H NMR analysis. The sample for analysis and the rest were emerged together for column chromatography purification using hexane-EtOAc (96:4) or CH2Cl2 as eluent. Compound trans-4a was obtained as colorless liquid (0.144 mmol, 72%) after chromatography with hexane-EtOAc (96:4). 1H NMR (300 MHz, CDCl3): δ = 0.91 (d, J = 6.4 Hz, 3 H), 0.99-1.10 (m, 1 H), 1.27-1.37 (m, 1 H), 1.36 (t, J = 6.9 Hz, 3 H), 1.47-1.78 (m, 7 H), 3.20-3.50 (s, br, 1 H), 3.56-3.60 (m, 1 H), 3.95 (q, J = 6.9 Hz, 2 H), 6.53-6.58 (m, 2 H), 6.74-6.79 (m, 2 H). 13C NMR (75 MHz, CDCl3): δ = 15.05, 20.52, 21.69, 27.13, 30.54, 33.98, 38.96, 48.54, 64.17, 114.60, 115.88, 141.68, 151.04. MS (EI): m/z (%) = 233 (100) [M+], 234 (14) [M + H]+, 190 (40), 108 (39), 176 (32), 204 (22), 137 (18), 97 (10). HRMS (EI): m/z calcd for C15H24NO [M + H]+: 234.1852; found: 234.1852.