A Practical Synthetic Pathway to Polysubstituted Tetrahydropyridines via Multicomponent Reactions Catalyzed by BF₃·OEt₂

Abstract

BF₃·OEt₂-catalyzed solvent-free synthesis of tetrahydropyridines has been developed through a one-pot multicomponent reaction of aldehydes, anilines and Brassard’s diene under mild reaction conditions. A gram scale synthesis was achieved in 62% yield. A two-step condensation pathway (firstly aldol and then aza Diels-Alder condensation) was proposed.

BF₃·OEt₂ - tetrahydropyridine - multicomponent reaction - aldol condensation - aza Diels-Alder condensation

References

1a Roth HJ. Kleeman A. Pharmaceutical Chemistry   John Wiley and Sons; New York: 1988. 

1b Gogfraid T. Miller R. Wibo M. Pharmacol. Rev.  1986,  38:  321 

2a Jørgensen KA. Angew. Chem. Int. Ed.  2000,  39:  3558 ; and references therein

2b Ali T. Chauhan KK. Frost CG. Tetrahedron Lett.  1999,  40:  5621 

2c Yuan Y. Li X. Ding K. Org. Lett.  2002,  4:  3309 

2d Loncaric C. Manabe K. Kobayashi S. Chem. Commun.  2003,  574 

2e Loncaric C. Manabe K. Kobayashi S. Adv. Synth. Catal.  2003,  345:  475 

2f Josephsohn NS. Snapper ML. Hoveyda AH. J. Am. Chem. Soc.  2003,  125:  4018 

2g Mancheňo OG. Arrayás RG. Carretero JC. J. Am. Chem. Soc.  2004,  126:  456 

2h Di Bari L. Guillarme S. Hermitage S. Howard JAK. Jay DA. Pescitelli G. Whiting A. Yufit DS. Synlett  2004,  708 

2i Guillarme S. Whiting A. Synlett  2004,  711 

3a Knapp S. Hale JJ. J. Org. Chem.  1993,  58:  2650 

3b Herdeis C. Kaschinski C. Karla R. Lotter H. Tetrahedron: Asymmetry  1996,  7:  867 

3c Bousquet Y. Anderson PC. Bogri T. Duceppe J.-S. Grenier L. Guse I. Tetrahedron  1997,  53:  15671 

3d Bonjoch J. Sole D. Garcia-Rubio S. Bosch J. J. Am. Chem. Soc.  1997,  119:  7230 

3e Billon-Souquet F. Martens T. Royer J. Tetrahedron Lett.  1999,  40:  3731 

3f Johnson TA. Curtis MD. Beak P. J. Am. Chem. Soc.  2001,  123:  1004 

4a Ma D. Sun H. Tetrahedron Lett.  1999,  40:  3609 

4b Knight DW. Lewis N. Share AC. Haigh D. J. Chem. Soc., Perkin Trans. 1  1998,  3673 

5a Lindemann U. Wulff-Molder D. Wessig P. Tetrahedron: Asymmetry  1998,  9:  4459 

5b Ferroud C. Cocquet G. Guy A. Tetrahedron Lett.  1999,  40:  5005 

5c Pandey G. Das P. Tetrahedron Lett.  1997,  38:  9073 

6 See a recent review: Deiters A. Martin SF. Chem. Rev.  2004,  104:  2199 

7a Zhu X. Lan J. Kwon O. J. Am. Chem. Soc.  2003,  125:  4716 

7b Huang H. Spande TF. Panek JS. J. Am. Chem. Soc.  2003,  125:  626 

8a Ruggeri RB. Hansen MM. Heathcock CH. J. Am. Chem. Soc.  1988,  110:  8734 

8b Laschat S. Grehl M. Angew. Chem., Int. Ed. Engl.  1994,  33:  458 

8c Tanner D. Hagberg L. Tetrahedron  1998,  54:  7907 

For reviews see:

9a Bailey PD. Millwood PA. Smith PD. Chem. Commun.  1998,  633 

9b Sardina FJ. Rapoport H. Chem. Rev.  1996,  96:  1825 

9c Laschat S. Dikner T. Synthesis  2000,  13:  1781 

9d Varela JA. Saá C. Chem. Rev.  2003,  103:  3787 

10 Midland MM. Koops RW. J. Org. Chem.  1990,  55:  5058 

For reviews see:

11a Aspinall HC. Chem. Rev.  2002,  102:  1807 

11b Bochkarev MN. Chem. Rev.  2002,  102:  2089 

11c Inanaga J. Furuno H. Hayano T. Chem. Rev.  2002,  102:  2211 

12 See a recent review: Tanaka K. Toda F. Chem. Rev.  2000,  100:  1025 

13

A Typical Procedure for Synthesis of 4a.
Brassard’s diene (0.7 mmol) and BF₃·OEt₂ (0.1 mmol) were successively added to a mixture of benzaldehyde (0.2 mmol) and aniline (0.2 mmol). The reaction mixture was stirred for 8 h at r.t., and then quenched with sat. aq NaHCO₃ (10 mL), extracted with CH₂Cl₂ (3 × 10 mL). The organic layer was dried over Na₂SO₄ and concentrated. The residue was purified by silica gel column chromatography with eluent of hexane-EtOAC (10:1, v/v) to give the desired product 4a as white crystal (mp 162-164 °C) in 85% yield. ¹H NMR (400 MHz CDCl₃): δ = 10.27 (s, 1 H), 7.25-6.31 (m, 19 H), 5.10 (d, J = 4.8 Hz, 1 H), 3.92 (s, 3 H), 3.76 (s, 3 H), 3.71 (s, 3 H), 2.91 (m, 1 H), 2.76 (m, 1 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 168.5, 159.8, 159.5, 156.4, 146.8, 145.8, 144.5, 137.8, 129.6, 129.1, 128.8, 125.9, 125.8, 119.0, 118.8, 116.2, 113.0, 112.9, 112.7, 111.7, 110.9, 97.5, 58.1, 55.1, 55.0, 33.4. HRMS (ESI): m/z calcd for C₃₃H₃₂N₂O₄ [M + Na⁺]: 543.2254; found: 543.2242.

Examples of activated diene condense with aldehydes in the presence of Lewis acid to afford corresponding aldol adducts, see:

14a Yamashita Y. Saito S. Ishitani H. Kobayashi S. J. Am. Chem. Soc.  2003,  125:  3793 

14b Soriente A. De Rosa M. Stanzione M. Villano R. Scettri A. Tetrahedron: Asymmetry  2001,  12:  959 

14c Motoyama Y. Koga Y. Nishiyama H. Tetrahedron  2001,  57:  853 

15

The mixture of aldehydes and anilines will generate imines 7 in situ: see ref. 2c-e.