Download PDF
Synlett 2010(6): 970-972  
DOI: 10.1055/s-0029-1219571
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

An Efficient and Short Synthesis of 4-Aryl-3-methyltetrahydroquinolines from N-Benzylanilines and Propenylbenzenes through Cationic Imino Diels-Alder Reactions

Arnold R. Romero Bohórquez, Vladimir V. Kouznetsov*
Laboratorio de Química Orgánica y Biomolecular, CIBIMOL, Universidad Industrial de Santander, A.A. 678, Bucaramanga, Colombia
Fax: +57(76)349069; e-Mail: kouznet@uis.edu.co;
Further Information

Publication History

Received 27 January 2010
Publication Date:
05 March 2010 (online)

   Permissions and Reprints All articles of this category
Preview

Abstract

A new, simple protocol for the BF3˙OEt2-catalyzed synthesis of diverse 3-methyl-4-aryl-1,2,3,4-tetrahydroquinolines ­using easily available starting materials and renewable phenylpropenoid reagents is described. These compounds could serve as interesting models in pharmacological studies.

Key words

cationic imino Diels-Alder reaction - 4-aryl-3-methyl­tetrahydroquinolines - propenylbenzenes - N-benzylanilines

    References and Notes

  • 1a Buonora P. Olsen J.-C. Oh T. Tetrahedron  2001,  57:  6099 
    Search in Google Scholar
  • 1b Kouznetsov VV. Tetrahedron  2009,  65:  2721 
    Search in Google Scholar
  • 2a Grieco PA. Bahsas A. Tetrahedron Lett.  1988,  29:  5855 
    Search in Google Scholar
  • 2b Katritzky A. Rachwal B. Rachwal S. J. Org. Chem.  1995,  60:  7631 
    Search in Google Scholar
  • 3a Kim Y. Shin E.-K. Beak P. Park Y.-S. Synthesis  2006,  3805 
  • 3b Gogte VN. Salama MA. Tilak BD. Tetrahedron  1970,  26:  173 
    Search in Google Scholar
  • 4 Shono T. Matsumura Y. Inoue K. Ohmizu H. Kashimura S. J. Am. Chem. Soc.  1982,  104:  5753 
    CrossrefSearch in Google Scholar
  • 5 Katritzky AR. Nichols DA. Qi M. Yang B.
    J. Heterocycl. Chem.  1997,  34:  1359 
    Search in Google Scholar
  • 6a Dehnhardt CM. Espinal Y. Venkatesan AM. Synth. Commun.  2008,  38:  796 
    Search in Google Scholar
  • 6b Beifuss U. Ledderhose S. Chem. Commun.  1995,  20:  2137 
    Search in Google Scholar
  • 6c Beifuss U. Ledderhose S. Ondrus V. ARKIVOC  2005,  (v):  147 
    Search in Google Scholar
  • 6d Beifuss U. Kunz O. Ledderhose S. Taraschewski M. Tonko C. Synlett  1996,  34 
  • 6e Chen R. Qian C. Synth. Commun.  2002,  16:  2543 
    Search in Google Scholar
  • 7a Kametani T. Takeda H. Suzuki Y. Honda T. Heterocycles  1984,  22:  275 
    Search in Google Scholar
  • 7b Zhang W. Jia X. Yang L. Liu Z.-L. Tetrahedron Lett.  2002,  43:  9433 
    Search in Google Scholar
  • 7c Hesse KD. Justus Liebigs Ann. Chem.  1970,  741:  117 
    Search in Google Scholar
  • 8a Kouznetsov VV. Merchan Arenas DR. Romero Bohórquez AR. Tetrahedron Lett.  2008,  49:  3097 
    Search in Google Scholar
  • 8b Kouznetsov VV. Romero Bohórquez AR. Stashenko EE. Tetrahedron Lett.  2007,  48:  8855 
    Search in Google Scholar
  • 8c Kouznetsov VV. Bello JS. Amado Torres DF. Tetrahedron Lett.  2008,  49:  5855 
    Search in Google Scholar
  • 9a Gómez-Barrio A. Montero-Pereira D. Nogal-Ruiz JJ. Escario JA. Muelas-Serrano S. Kouznetsov VV. Vargas Méndez LY. Urbina Gonzáles JM. Ochoa C. Acta Parasitologica  2006,  51:  73 
    Search in Google Scholar
  • 9b Kouznetsov VV. Ochoa Puentes C. Romero Bohórquez AR. Zacchino SA. Sortino M. Gupta M. Vázquez Y. Bahsas A. Amaro-Luis J. Lett. Org. Chem.  2006,  3:  300 
    Search in Google Scholar
  • 10a Billman JH. Diesing AC. J. Org. Chem.  1957,  22:  1068 
    Search in Google Scholar
  • 10b Kouznetsov VV. Astudillo Saavedra L. Vargas Méndez LY. Cazar Ramírez ME. J. Chil. Chem. Soc.  2004,  49:  319 
    Search in Google Scholar
  • 12a Greene TW. Wuts PGM. Protecting Groups in Organic Synthesis   3rd ed.:  Wiley; New York: 1999. 
    Search in Google Scholar
  • 12b Bull SD. Davies SG. Fenton G. Mulvaney AW. Prasad RS. Smith AD. J. Chem. Soc., Perkin Trans. 1  2000,  3765 
11

Synthesis of N -Benzyl-4-aryl-3-methyltetrahydro-quinoline Derivatives 4; General Procedure: A mixture of N-benzylaniline 1 (1 mmol) and formaldehyde (37% in MeOH, 1.1 mmol) in MeCN (10 mL) was stirred at r.t. for 10 min. The system was cooled to 0 ˚C and BF3˙OEt2 (154.27 mL, 1.1 mmol) was added dropwise into the mixture. After 30 min, dienophile reagent (trans-anethole 3a or trans-isoeugenol 3b; 1.1 mmol) was added over 5 min to the reaction mixture. The resulting mixture was stirred at 70 ˚C for 8 h. After completion of the reaction as indicated by TLC, the reaction mixture was extracted with EtOAc (3 × 15 mL). The organic layer was separated and dried (Na2SO4), concentrated in vacuo and the crude product was purified by column chromatography using silica gel (60-120 mesh; petroleum ether-EtOAc) to afford pure tetrahydroquinoline 4a-h. Selected spectral data for trans-N-benzyl-6-methoxy-4-(4-methoxyphenyl)-3-methyl-1,2,3,4-tetrahydroquinoline (4c): Beige solid. IR (KBr): 2949, 1657, 1608, 1506 cm-¹; ¹H NMR (400 MHz, CDCl3, TMS): δ = 0.92 (d, J = 6.7 Hz, 3 H, 3-CH3), 2.21 (m, 1 H, H-3), 3.04 (dd, J = 11.3, 8.4 Hz, 1 H, H-2ax), 3.25 (dd, J = 11.3, 3.7 Hz, 1 H, H-2eq), 3.58 (s, 3 H, 6-OCH3), 3.62 (d, J = 8.3 Hz, 1 H, H-4), 3.79 (s, 3 H, 4′-OCH3), 4.46 (s, 2 H, N-CH2Ph), 6.29 (d, J = 2.8 Hz, 1 H, H-5), 6.51 (d, J = 8.9 Hz, 1 H, H-8), 6.59 (dd, J = 8.9, 2.9 Hz, 1 H, H-7), 6.84 (d, J = 8.6 Hz, 2 H, 2′-ArH), 7.03 (d, J = 8.6 Hz, 2 H, 3′-ArH), 7.23-7.34 (m, 5 H, PhH); ¹³C NMR (100 MHz, CDCl3, TMS): δ = 158.0, 150.9, 140.2, 139.4, 137.4, 130.0, 128.5, 126.8, 126.7, 126.4, 116.6, 113.7, 112.6, 112.0, 56.1, 55.6, 55.2, 54.9, 51.1, 34.9, 18.2; MS (EI): m/z (%) = 373 (80) [M]+, 250 (12), 174 (82), 121 (27), 91 (100); Anal. Calcd for C25H27NO2: C, 80.40; H, 7.29; N, 3.75. Found: C, 80.21; H, 7.44; N, 3.66. trans-N-Benzyl-6-chloro-4-(4-methoxy-phenyl)-3-methyl-1,2,3,4-tetrahydroquinoline (4d): White solid. IR (KBr): 2952, 1640, 1601, 1502 cm-¹; ¹H NMR (400 MHz, CDCl3, TMS): δ = 0.91 (d, J = 6.6 Hz, 3 H, 3-CH3), 2.20 (m, 3 H, H-3), 3.10 (dd, J = 11.5, 8.1 Hz, 1 H, H-2ax), 3.30 (dd, J = 11.6, 3.7 Hz, 1 H, H-2eq), 3.60 (d, J = 8.0 Hz, 1 H, H-4), 3.81 (s, 3 H, 4′-OCH3), 4.50 (s, 2 H, N-CH2Ph), 6.46 (d, J = 8.8 Hz, 1 H, H-8), 6.63 (br s, 1 H, H-5), 6.85 (d, J = 8.4 Hz, 2 H, 2′-ArH), 6.91 (dd, J = 7.7, 2.1 Hz, 1 H, H-7), 7.01 (d, J = 8.4 Hz, 2 H, 3′-ArH), 7.24-7.35 (m, 5 H, PhH); ¹³C NMR (100 MHz, CDCl3, TMS): δ = 158.2, 143.9, 138.4, 136.7, 129.9, 129.8, 128.7, 127.0, 127.0, 126.5, 126.2, 120.6, 113.9, 112.0, 55.4, 55.2, 54.6, 50.6, 34.3, 18.2; MS (EI): m/z (%) = 377 (60) [M]+, 254 (36), 178 (39), 121 (29), 91 (100). Anal. Calcd for C24H24ClNO: C, 76.28; H, 6.40; N, 3.71. Found: C, 76.43; H, 6.32; N, 3.89. trans-N-Benzyl-6-methoxy-4-(4-hydroxy-3-methoxyphenyl)-3-methyl-1,2,3,4-tetrahydroquinoline (4g): Beige solid. IR (KBr): 3542, 2936, 1638, 1603, 1511 cm-¹; ¹H NMR (400 MHz, CDCl3, TMS): δ = 0.92 (d, J = 6.6 Hz, 3 H, 3-CH3), 2.22 (m, 1 H, H-3), 3.04 (dd, J = 11.2, 8.7 Hz, 1 H, H-2ax), 3.27 (dd, J = 11.4, 3.7 Hz, 1 H, H-2eq), 3.58 (s, 3 H, 6-OCH3), 3.59 (d, J = 8.5 Hz, 1 H, H-4), 3.80 (s, 3 H, 3′-OCH3), 4.46 (d, J = 2.6 Hz, 2 H, N-CH2Ph), 5.55 (s, 1 H, 4′-OH), 6.32 (d, J = 2.6 Hz, 1 H, H-5), 6.53 (d, J = 8.9 Hz, 1 H, H-8), 6.59 (m, 2 H, 2′-ArH and 6′-ArH), 6.63 (dd, J = 8.2, 1.3 Hz, 1 H, H-7), 6.84 (d, J = 8.0 Hz, 1 H, 5′-ArH), 7.23-7.32 (m, 5 H, PhH); ¹³C NMR (100 MHz, CDCl3, TMS): δ = 150.9, 146.5, 144.0, 140.1, 139.3, 137.1, 128.5, 126.8, 126.7, 126.3, 122.2, 116.6, 114.0, 112.6, 111.9, 111.1, 56.1, 55.9, 55.6, 55.1, 51.7, 34.8, 18.2. MS (EI): m/z (%) = 389 (66) [M]+, 250 (21), 174 (100), 131 (16), 91 (99). Anal. Calcd for C25H27NO3: C, 77.09; H, 6.99; N, 3.60. Found: C, 77.23; H, 7.17; N, 3.41. trans-N-Benzyl-6-chloro-4-(4-hydroxy-3-methoxyphenyl)-3-methyl-1,2,3,4-tetrahydro-quinoline (4h): White solid. IR (KBr): 3539, 2944, 1641, 1594, 1510 cm-¹; ¹H NMR (400 MHz, CDCl3, TMS): δ = 0.91 (d, J = 6.6 Hz, 3 H, 3-CH3), 2.20 (m, 1 H, H-3), 3.10 (dd, J = 11.5, 8.3 Hz, 1 H, H-2ax), 3.32 (dd, J = 11.6, 3.8 Hz, 1 H, H-2eq), 3.57 (d, J = 8.2 Hz, 1 H, H-4), 3.82 (s, 1 H, 3′-OCH3), 4.50 (s, 2 H, N-CH2Ph), 5.57 (s, 1 H, 4′-OH), 6.47 (d, J = 8.8 Hz, 1 H, H-8), 6.58 (br s, 1 H, H-5), 6.59 (dd, J = 8.2, 1.5 Hz, 1 H, 6′-ArH), 6.65 (d, J = 2.2 Hz, 1 H, 2′-ArH), 6.86 (d, J = 7.9 Hz, 1 H, 5′-ArH), 6.91 (dd, J = 8.8, 2.4 Hz, 1 H, H-7), 7.22-7.34 (m, 5 H, PhH); ¹³C NMR (100 MHz, CDCl3, TMS): δ = 146.6, 144.2, 143.8, 138.3, 136.4, 129.8, 128.6, 127.1, 127.0, 126.5, 126.2, 122.1, 120.5, 114.2, 111.9, 110.9, 55.9, 55.4, 54.7, 51.1, 34.2, 18.1. MS (EI): m/z (%) = 393 (37) [M]+, 254 (30), 178 (40), 137 (20), 91 (100). Anal. Calcd for C24H24ClNO2: C, 73.18; H, 6.14; N, 3.56. Found: C, 72.93; H, 6.32; N, 3.31.

13

Synthesis of N- H-4-Aryl-3-methyltetrahydroquinoline Derivatives 5; General Procedure: A mixture of tetrahydroquinoline 4a-h (1 mmol), wet 10% Pd/C (cat.) and MeOH-CH2Cl2 (3:1, 20 mL) was stirred under H2 (1 atm) at r.t. for 14-16 h. The reaction mixture was filtered and the filtrate was concentrated in vacuo and extracted with CH2Cl2 (3 × 15 mL). The organic layer was separated and dried (Na2SO4), concentrated in vacuo and the resulting product was purified by flash column chromatography (silica gel; petroleum ether-EtOAc) to afford the respective pure tetrahydroquinoline 5a-h.Selected spectral data for trans-6-methoxy-4-(4-methoxyphenyl)-3-methyl-1,2,3,4-tetrahydroquinoline (5c): Reddish oil. IR (KBr): 3387, 1604, 1509 cm-¹; ¹H NMR (400 MHz, CDCl3, TMS): δ = 0.91 (d, J = 6.7 Hz, 3 H, 3-CH3), 2.10 (m, 1 H, H-3), 2.98 (dd, J = 11.1, 8.9 Hz, 1 H, H-2ax), 3.25 (dd, J = 11.2, 3.4 Hz, 1 H, H-2eq), 3.57 (d, J = 9.0 Hz, 1 H, H-4), 3.59 (s, 3 H, 6-OCH3), 3.78 (s, 3 H, 4′-OCH3), 6.24 (d, J = 2.7 Hz, 1 H, H-5), 6.51 (d, J = 8.6 Hz, 1 H, H-8), 6.61 (dd, J = 8.6, 2.8 Hz, 1 H, H-7), 6.83 (d, J = 8.6 Hz, 2 H, 2′-ArH), 7.04 (d, J = 8.6 Hz, 2 H, 3′-ArH); ¹³C NMR (100 MHz, CDCl3, TMS): δ = 158.0, 151.9, 138.8, 137.6, 130.0, 125.9, 116.0, 115.2, 113.6, 113.1, 55.6, 55.2, 50.7, 47.6, 35.4, 17.9; MS (EI): m/z (%) = 283 (100) [M]+, 268 (51), 240 (25), 174 (24), 160 (60); Anal. Calcd for C18H21NO2: C, 76.29; H, 7.47; N, 4.94. Found: C, 76.02; H, 7.63; N, 4.78. trans-6-Methoxy-4-(4-hydroxy-3-methoxyphenyl)-3-methyl-1,2,3,4-tetrahydroquinoline (5g): Beige solid. IR (KBr): 3302, 1603, 1506 cm-¹; ¹H NMR (400 MHz, CDCl3, TMS): δ = 0.91 (d, J = 6.6 Hz, 3 H, 3-CH3), 2.10 (m, 1 H, H-3), 2.99 (dd, J = 10.9, 9.4 Hz, 1 H, H-2ax), 3.27 (dd, J = 11.1, 3.3 Hz, 1 H, H-2eq), 3.54 (d, J = 9.0 Hz, 1 H, H-4), 3.59 (s, 3 H, 6-OCH3), 3.81 (s, 3 H, 3′-OCH3), 6.26 (d, J = 2.4 Hz, 1 H, H-5), 6.52 (d, J = 8.6 Hz, 1 H, H-8), 6.59 (br s, 1 H, 2′-ArH), 6.61 (dd, J = 8.8, 2.7 Hz, 2 H, 6′-ArH), 6.65 (dd, J = 8.2, 1.3 Hz, 1 H, H-7), 6.84 (d, J = 8.0 Hz, 1 H, 5′-ArH); ¹³C NMR (100 MHz, CDCl3, TMS): δ = 152.0, 146.6, 144.1, 138.6, 137.2, 126.1, 122.4, 116.0, 115.3, 113.8, 113.3, 111.0, 55.9, 55.7, 51.5, 48.0, 35.4, 18.0; MS (EI): m/z (%) = 299 (100) [M]+, 284 (28), 270 (15), 256 (18), 174 (35), 160 (68). Anal. Calcd for C17H19NO2: C, 75.81; H, 7.11; N, 5.20. Found: C, 75.65; H, 7.31; N, 5.13.

14

trans-Anethole is the main component of the anise essential oil, which is extracted from the seeds of the star anise (Illicium verum Hook fillius). trans-Isoeugenol could be easily prepared from eugenol, which is the main component of the clove fruit essential oil, and can be extracted from the flower buds of clove trees (fam. Myrtaceae). Therefore, both reagents can be considered to be renewable materials.