Download PDF
Synlett 2008(20): 3167-3171  
DOI: 10.1055/s-0028-1087359
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Enantioselective Synthesis of Chromanes by Iridium-Catalyzed Asymmetric Hydrogenation of 4H-Chromenes

Carine Valla, Alejandro Baeza, Frederik Menges, Andreas Pfaltz*
Department of Chemistry, University of Basel, St. Johanns-Ring 19, 4056 Basel, Switzerland
Fax: +41(61)2671103; e-Mail: andreas.pfaltz@unibas.ch;
Further Information

Publication History

Received 13 June 2008
Publication Date:
24 November 2008 (online)

    Permissions and Reprints All articles of this category

Abstract

Iridium complexes of chiral oxazoline-based P,N-ligands proved to be efficient catalysts for the enantioselective hydrogenation of 2-aryl- and 2-alkyl-4H-chromenes. The best results were obtained with a ligand derived from threonine (ThrePHOX), which induced ee values of 95% to >99% in the hydrogenation of 2-methyl-, 2-cyclohexyl- and various 2-aryl-substituted chromenes.

Key words

asymmetric hydrogenation - iridium - P,N-ligands - fla­vanes - chromanes

    References and Notes

  • 1 Pan WB. Chang FR. Wei L. Wu YC. J. Nat. Prod.  2003,  66:  161 
    CrossrefGoogle Scholar
  • 2a Gomez F. Quijano L. Calderon JS. Rodriguez C. Tirso R. Phytochemistry  1985,  24:  1057 
    Google Scholar
  • 2b Arnone A. Nasini G. Merlini L. J. Chem. Soc., Perkin Trans. 1  1990,  2637 
    Google Scholar
  • 3a Bauer DJ. Selway JWT. Batchelor JF. Tisdale M. Caldwell IC. Young DA. Nature (London)  1981,  292:  369 
    Google Scholar
  • 3b Batchelor JF, Bauer DJ, Hodson HF, Selway JWT, and Young DAB. inventors; U.S. Patent, US  4461907. 
  • 4 Chandrasekhar S. Reddy MV. Tetrahedron  2000,  56:  6339 
    CrossrefGoogle Scholar
  • 5a Hodgetts KJ. Tetrahedron Lett.  2000,  41:  8655 
    Google Scholar
  • 5b Hodgetts KJ. Tetrahedron Lett.  2001,  42:  3763 
    Google Scholar
  • 5c Hodgetts KJ. Tetrahedron  2005,  61:  6860 
    Google Scholar
  • 5d The same strategy, but using a previous kinetic resolution of β-hydroxy esters is described in: Choi ET. Lee MH. Kim Y. Park YS. Tetrahedron  2008,  64:  1515 
    Google Scholar
  • 6a Pfaltz A. Blankestein J. Hilgraf R. Hörmann E. McIntyre S. Menges F. Schonleber M. Smidt SP. Wüstenberg B. Zimmermann N. Adv. Synth. Catal.  2003,  345:  33 
    Google Scholar
  • 6b Bell S. Wüstenberg B. Kaiser S. Menges F. Netscher T. Pfaltz A. Science  2006,  311:  642 
    Google Scholar
  • 6c Roseblade SJ. Pfaltz A. Acc. Chem. Res.  2007,  40:  1402 
    Google Scholar
  • For contributions of other research groups, see:
  • 6d Cui X. Burgess K. Chem. Rev.  2005,  105:  3272 
    Google Scholar
  • 6e Källström K. Munslow I. Andersson PG. Chem. Eur. J.  2006,  12:  3194 
    Google Scholar
  • 6f Zhu Y. Burgess K. Adv. Synth. Catal.  2008,  350:  975 
    Google Scholar
  • 6g Kaukoranta P. Engman M. Hedberg C. Bergquist J. Andersson PG. Adv. Synth. Catal.  2008,  350:  1168 
    Google Scholar
  • 7 Setchell KDR, and Sorokin VD. inventors; U.S. Patent, US  2007/0027329A1. During the realization of this work a method for the preparation of 3-substituted chromanes(isoflavanes) using iridium-catalyzed asymmetric hydrogenation of the corresponding chromenes was reported:
  • For example, see:
  • 8a Bird TGC. Brown BR. Stuart IA. Tyrrell AWR. J. Chem. Soc., Perkin Trans 1  1983,  1831 
    Google Scholar
  • 8b Fichtner C. Remmenikov G. Mayr H. Eur. J. Org. Chem.  2001,  4451 ; and references therein
    Google Scholar
  • 9 Trost BM. Shen HC. Dong L. Surivet J.-P. Sylvain C. J. Am. Chem. Soc.  2004,  126:  11966 
    Google Scholar
  • For example, see:
  • 10a Nam NH. Kim Y. You YJ. Hong DH. Kim HM. Ahn BZ. Eur. J. Med. Chem.  2003,  38:  179 
    Google Scholar
  • 10b Joo YH. Kim JK. Kang S.-H. Noh M.-S. Ha J.-Y. Choi JK. Lim KM. Lee CH. Chung S. Bioorg. Med. Chem. Lett.  2003,  13:  413 
    Google Scholar
  • 10c Miyake H. Takizawa E. Sasaki M. Bull. Chem. Soc. Jpn.  2003,  76:  835 
    Google Scholar
  • 10d Bianco A. Cavarischia C. Guiso M. Eur. J. Org. Chem.  2004,  2894 ; and references therein
    Google Scholar
  • 11 Cechinel V. Vaz ZR. Zunino L. Calixto JB. Yunes RA. Eur. J. Med. Chem.  2003,  38:  179 
    CrossrefGoogle Scholar
  • 12 Gupta SC. Sharma S. Saini A. Dhawan SN. J. Chem. Soc., Perkin Trans. 1  1999,  2391 
    CrossrefGoogle Scholar
  • 14 Zacheis D. Dhar A. Lu S. Madler MM. Klucik J. Brown CW. Liu S. Clement F. Subramanian S. Weerasekare GM. Berlin KD. Gold MA. John R. Houck J. Fountain KR. Benbrook DM. J. Med. Chem.  1999,  42:  4434 ; and references therein
    CrossrefGoogle Scholar
  • 16 Baker W. Walker J. J. Chem. Soc.  1935,  646 
    Google Scholar
  • 18 Ohta T. Miyake T. Seido N. Kumobayashi H. Takaya H. J. Org. Chem.  1995,  60:  357 
    Google Scholar
13

The chromenes were fully characterized. For the known compounds, the spectroscopic and physical data are in agreement with those previously reported in literature. These chromenes are generally air and temperature sensitive, and therefore should be stored under argon at -20 ºC to avoid decomposition.
Representative example:
2-(4-Bromophenyl)-4 H -chromene (3c): The product was isolated after flash chromatography on silica gel (pentane-EtOAc, 99:1) as a white solid in 95% yield; mp 105 ºC; R f 0.42 (pentane-EtOAc, 9:1). IR (KBr): 3043, 2830, 1667, 1583, 1488, 1239 cm-¹. ¹H NMR (500 MHz, C6D6): δ = 3.12 (δ, J = 3.9 Hz, 2 H), 4.99 (t, J = 3.9 Hz, 1 H), 6.78 (m, 1 H), 6.84 (m, 1 H), 6.97 (m, 2 H), 7.26-7.29 (m, 4 H). ¹³C NMR (125 MHz, C6D6): δ = 24.5, 97.2, 117.0, 119.7, 122.5, 123.7, 126.5, 128.0, 129.2, 131.7, 133.8, 148.4, 152.2. MS (EI): m/z (%) = 226.2 (66.3) [M+], 225.1 (100), 131.1 (19.3). Anal. Calcd for C15H11OBr: C, 62.74; H, 3.86. Found: C, 62.79; H, 3.85.

15

2-Cyclohexyl-4 H -chromene (5): The product was isolated after flash chromatography on silica gel (100% pentane) as a pale yellow oil (23% yield); R f 0.75 (pentane-EtOAc, 9:1). IR (neat): 3026, 2926, 1693, 1586, 1488, 1235 cm-¹. ¹H NMR (500 MHz, C6D6): δ = 1.06-1.22 (m, 3 H), 1.33 (m,
2 H), 1.57 (m, 1 H), 1.68 (m, 2 H), 1.94 (m, 2 H), 2.04 (m,
1 H), 3.17 (d, J = 3.5 Hz, 2 H), 4.49 (br dt, J = 0.7, 3.5 Hz,
1 H), 6.78-6.83 (m, 2 H), 6.92-6.95 (m, 2 H). ¹³C NMR (125 MHz, C6D6): δ = 24.2, 26.6, 26.7, 30.9, 42.2, 93.2, 116.7, 120.5, 123.1, 127.6, 129.3, 152.9, 156.3. MS (EI): m/z (%) = 214.2 (18.2) [M+], 213.3 (21.3), 131.1 (100). Anal. Calcd for C15H18O: C, 84.07; H, 8.47. Found: C, 83.83; H, 8.60.

17

2-Methyl-4 H -chromene (15): Salicylaldehyde (0.53 mL,
5 mmol) was added to a solution of dl-proline (99 mg, 20 mol%) and acetone (7.4 mL, 20 equiv) in DMF-H2O (1:1, 20 mL). The mixture was heated for 48 h at 90 ºC. The mixture was cooled to r.t., extracted with EtOAc (2 ×) and washed with brine (4 ×), affording, after removal of the organic solvent, the corresponding hydroxy chalcone as an orange solid. The crude product was dissolved in EtOH (5 mL) and hydrogenated under 1 bar H2 pressure using Raney-Ni as catalyst. The reaction was monitored by GC (Machary-Nagel, Optima Amin-5 column). When the reaction was complete, the solution was filtered through celite, extracted with Et2O (2 ×) and washed with brine (2 ×). The organic layer was concentrated under reduced pressure to give the corresponding hydroxy ketone, which, without purification, was refluxed in toluene (10 mL) with a catalytic amount of p-toluenesulfonic acid (100 mg) and 4 Å molecular sieves (2 g) for 2 h. After this time, the mixture was cooled to r.t., filtered, washed with sat. aq NaHCO3 solution, and brine. The organic solvent was then removed and the crude product was purified by flash chromatography to give the pure 15 in 29% yield as colorless oil.

19

The reaction failed even at high catalyst loadings of up to
4 mol%, 100 bar hydrogen pressure, and with long reaction times.

20

For other products the absolute configuration was assumed to be the same because the same catalysts were used in the hydrogenation.

21

Typical Procedure for the Catalytic Asymmetric Hydrogenation of Chromenes: A solution of chromene (0.5 mmol) and iridium complex 10b (8.7 mg, 5 µmol, 1 mol%) in anhyd dichloromethane (2.5 mL, Fluka anhyd solvents grade) under an argon atmosphere was placed in an autoclave, which was sealed, pressurized (50 bar hydrogen gas) and stirred at r.t. for 2 h. The solvent was evaporated and the catalyst was removed by filtration through a short silica gel column (3 × 1 cm) with a mixture of pentane and ethyl acetate (1:1) as eluent to give the desired chromane after evaporation of the solvent.
For catalyst screening, reactions were carried out on a
0.1-mmol scale.
Analytical data for new compounds are given below. For known compounds, the observed spectra were in agreement with the reported data.5,¹8 For products which were reported in the literature as racemates, only [α]D, ¹H, ¹³C NMR and HPLC data are listed.
( R )-2-(2-Fluorophenyl)chromane (11b): [α]D ²0 +28.9 (c = 0.5, CHCl3; >99% ee); R f 0.82 (pentane-EtOAc, 9:1). IR (KBr): 2929, 1582, 1488, 1234 cm-¹. ¹H NMR (400 MHz, CDCl3): δ = 2.06 (m, 1 H), 2.26 (m, 1 H), 2.79 (ddd, J = 3.8, 4.8, 16.5 Hz, 1 H), 3.03 (ddd, J = 5.8, 11.4, 16.5 Hz, 1 H), 5.40 (dd, J = 2.2, 10.1 Hz, 1 H), 6.88 (m, 2 H), 7.05-7.20 (m, 4 H), 7.30 (m, 1 H), 7.55 (dt, J = 1.5, 7.6 Hz, 1 H). ¹³C NMR (100 MHz, CDCl3): δ = 25.4, 29.3, 72.2 (d, J = 3.5 Hz), 115.7 (d, J = 21.5 Hz), 117.3, 120.9, 122.2, 124.7 (d, J = 3.5 Hz), 127.8 (d, J = 3.8 Hz), 127.9, 129.4 (d, J = 12.6 Hz), 129.5 (d, J = 8.4 Hz), 130.0, 158.7, 160.0 (d, J = 276.3 Hz). MS (EI): m/z (%) = 228.2 (100) [M+], 119.1 (46.4). Anal. Calcd for C15H13FO: C, 78.93; H, 5.74. Found: C, 78.65; H, 5.93. HPLC: Chiracel OD-H, 100% heptane, 20 ºC, flow rate: 0.5 mL/min, t R(R) = 27.6 min, t R(S) = 29.6 min.
( R )-2-(4-Bromophenyl)chromane (11c): [α]D ²0 +22.4 (c = 0.5, CHCl3; 91% ee, 95% conversion); mp 85 ºC; R f 0.80 (pentane-EtOAc, 9:1). IR (KBr): 2926, 1579, 1487, 1235 cm-¹. ¹H NMR (400 MHz, CDCl3): δ = 2.04 (m, 1 H), 2.20 (m, 1 H), 2.79 (br ddd, J = 3.9, 5.0, 16.7 Hz, 1 H), 2.99 (ddd, J = 5.8, 11.4, 16.7 Hz, 1 H), 5.03 (dd, J = 2.5, 10.1 Hz, 1 H), 6.87-6.91 (m, 2 H), 7.06-7.15 (m, 2 H), 7.31 (m, 2 H), 7.51 (m, 2 H). ¹³C NMR (100 MHz, CDCl3): δ = 25.3, 30.3, 77.6, 117.3, 120.9, 122.0, 122.1, 127.8, 128.1, 130.0, 132.0, 141.2, 155.2. MS (EI): m/z (%) = 290.1 (76.2) [M+], 289.1 (15.8), 209.1 (100). Anal. Calcd for C15H13OBr: C, 62.30; H, 4.53. Found: C, 62.27; H, 4.49. HPLC: Chiracel OD-H, heptane-2-propanol, 99.5/0.5, 20 ºC, flow rate: 0.5 mL/min, t R(S) = 18.0 min, t R(R) = 20.6 min.
( R )-7-Methoxy-2-phenylchromane(11e): [α]D ²0 +26.7 (c = 1.0, CHCl3; >99% ee). ¹H NMR (400 MHz, CDCl3): δ = 2.06 (m, 1 H), 2.26 (m, 1 H), 2.76 (m, 1 H), 2.94 (m, 1 H), 3.77 (s, 3 H), 5.40 (dd, J = 2.2, 10.1 Hz, 1 H), 6.49 (m, 2 H), 6.96 (br d, J = 7.2 Hz, 1 H), 7.31-7.34 (m, 1 H), 7.38-7.41 (m,
4 H). ¹³C NMR (100 MHz, CDCl3): δ = 24.7, 30.6, 55.0, 78.0, 102.2, 108.2, 114.2, 126.5, 128.2, 128.7, 130.4, 142.6, 156.7, 160.1. HPLC: Chiracel OD-H, 100% heptane, 20 ºC, flow rate: 0.5 mL/min, t R(R) = 49.2 min, t R(S) = 54.6 min.
( R )-2-(2-Furanyl)chromane (11f): [α]D ²0 -4.7 (c = 0.9, CHCl3; 97% ee); mp 50 ºC; R f 0.85 (pentane-EtOAc, 9:1). IR (KBr): 2932, 1562, 1456, 1232 cm-¹. ¹H NMR (400 MHz, C6D6): δ = 1.84 (m, 1 H), 2.07 (m, 1 H), 2.48 (m, 2 H), 4.92 (dd, J = 2.5, 9.8 Hz, 1 H), 6.14 (dd, J = 1.8, 3.3 Hz, 1 H), 6.24 (d, J = 3.3 Hz, 1 H), 6.87 (br dt, J = 1.5, 7.1 Hz, 1 H), 6.94 (d, J = 7.1 Hz, 1 H), 7.04-7.10 (m, 2 H), 7.15 (d, J = 1.0 Hz, 1 H). ¹³C NMR (100 MHz, C6D6): δ = 24.7, 26.4, 71.5, 107.5, 110.6, 117.5, 120.9, 121.9, 128.1, 129.9, 142.4, 154.7, 155.3. MS (EI): m/z (%) = 240.2 (100) [M+], 136.1 (20.5). Anal. Calcd for C13H12O2: C, 77.98; H, 6.04. Found: C, 78.11; H, 5.99. HPLC: Chiracel OD-H, 100% heptane, 20 ºC, flow rate: 0.5 mL/min, t R(R) = 27.9 min, t R(S) = 31.4 min.
( R )-2-Cyclohexylchromane (12): [α]D ²0 -62.1 (c = 1.0, CHCl3; 95% ee); R f 0.88 (pentane-EtOAc, 9:1). IR (neat): 2925, 1582, 1488, 1236 cm-¹. ¹H NMR (400 MHz, CDCl3): δ = 1.11-1.43 (m, 6 H), 1.55-1.80 (m, 5 H), 1.94-2.00 (m,
2 H), 2.70-2.85 (m, 2 H), 3.73 (ddd, J = 2.8, 5.9, 9.8 Hz, 1 H), 6.88 (br ddd, J = 1.7, 7.4, 8.6 Hz, 1 H), 7.02 (d, J = 7.3 Hz, 1 H), 7.05-7.12 (m, 2 H). ¹³C NMR (100 MHz, CDCl3): δ = 24.7, 25.5, 26.7, 28.8, 30.2, 42.5, 80.3, 117.4, 120.3, 122.6, 127.7, 129.9, 156.2. MS (EI): m/z (%) = 216.2 (29.5) [M+], 120.1 (100). Anal. Calcd for C15H20O: C, 83.28; H, 9.32. Found: C, 83.01; H, 9.33. HPLC: Chiracel OD-H, 100% heptane, 15 ºC, flow rate: 0.5 mL/min, t R(S) = 18.6 min, t R(R) = 19.9 min.
( R )-2-Phenyl-3,4-dihydro-2 H -benzo[ h ]chromene (14): [α]D ²0 +139.5 (c = 0.6, CHCl3; 96% ee). ¹H NMR (400 MHz, CDCl3): δ = 2.17 (m, 1 H), 2.34 (m, 1 H), 2.88 (m, 1 H), 3.13 (m, 1 H), 5.25 (dd, J = 2.3, 9.9 Hz, 1 H), 7.18 (d, J = 8.3 Hz, 1 H), 7.33-7.46 (m, 6 H), 7.51 (d, J = 7.4 Hz, 2 H), 7.76 (m, 1 H), 8.25 (m, 1 H). ¹³C NMR (125 MHz, CDCl3): δ = 25.3, 30.2, 77.9, 115.8, 120.2, 122.2, 125.6, 126.1, 126.3, 127.0, 127.9, 128.0, 128.7, 128.8, 134.0, 142.5, 150.3. HPLC: Chiracel OD-H, heptane-2-propanol, 98:2, 20 ºC, flow rate: 0.5 mL/min, t R(R) = 11.4 min, t R(S) = 13.2 min.
( R )-2-Phenylthiochromane (18): [α]D ²0 -98.5 (c = 0.4, CHCl3; 91% ee, 73% conversion); mp 53 ºC; R f = 0.48 (pentane). IR (KBr): 2932, 1452, 1436 cm-¹. ¹H NMR (400 MHz, CDCl3): δ = 2.19-2.28 (m, 1 H), 2.38-2.44 (m, 1 H), 2.95 (m, 2 H), 4.45 (dd, J = 3.3, 7.6 Hz, 1 H), 6.99 (m, 1 H), 7.06-7.12 (m, 3 H), 7.29 (m, 1 H), 7.30-7.36 (m, 2 H), 7.41 (dd, J = 1.3, 8.1 Hz, 2 H). ¹³C NMR (100 MHz, CDCl3): δ = 30.0, 31.1, 46.3, 124.0, 125.9, 126.5, 127.6, 127.7, 128.6, 129.8, 133.0, 134.0, 141.9. Anal. Calcd for C15H14S: C, 79.60; H, 6.23. Found: C, 79.29; H, 6.47. HPLC: Chiracel OD-H, heptane-2-propanol, 80:20, 20 ºC, flow rate: 0.5 mL/min, t R(R) = 10.1 min, t R(S) = 11.3 min.