Facile Synthesis of Tetrahydroquinolines and Julolidines through ­Multicomponent Reaction

Abstract

Aldehydes, anilines and enol ethers react in trifluoro­ethanol (TFE) through an aza-Diels-Alder reaction (Povarov reaction) to afford the corresponding substituted tetrahydroquinolines. This reaction occurs, without any catalyst, under sequential three-component conditions, allowing thus the use of aliphatic aldehydes. In the presence of formaldehyde and an excess of dienophile, the product undergoes a second Povarov reaction affording new ­julolidine derivatives.

domino reaction - cycloaddition - fluorous alcohols - ­heterocycles - solvent effect

References and Notes

1a Multicomponent Reactions   Zhu J. Bienaymé H. Wiley-VCH; Weinheim: 2005. 

1b Orru RVA. de Greef M. Synthesis  2003,  1471 

1c Bienaymé H. Hulme C. Oddon G. Schmitt P. Chem. Eur. J.  2000,  6:  3321 

For leading references, see:

2a Povarov LS. Makhailov BM. Izv. Akad. Nauk. SSSR  1963,  955 

2b Narasaka K. Shibata T. Heterocycles  1993,  35:  1039 

2c Kobayashi S. Nagayama S. J. Am. Chem. Soc.  1996,  118:  8977 

2d Crousse B. Bégué J.-P. Bonnet-Delpon D. J. Org. Chem.  2000,  65:  5009 

2e Cheng D. Zhou J. Saiah E. Beaton G. Org. Lett.  2002,  4:  4411 

2f Zhou Y. Jia X. Li R. Liu Z. Liu Z. Wu L. Tetrahedron Lett.  2005,  46:  8937 

2g Lin X.-F. Cui S.-L. Wang Y.-G. Tetrahedron Lett.  2006,  47:  3127 

2h See also: Jiménez O. de la Rosa G. Lavilla R. Angew. Chem. Int. Ed.  2005,  44:  6521 

For some representative examples of the use of fluorous alcohols in organic synthesis, see:

3a Ravikumar KS. Kesavan V. Crousse B. Bonnet-Delpon D. Bégué J.-P. Organic Syntheses   Vol. 80:  Wiley; New York: 2003.  p.184 

3b Spanedda MV. Hoang VD. Crousse B. Bonnet-Delpon D. Bégué J.-P. Tetrahedron Lett.  2003,  44:  217 

3c Di Salvo A. Spanedda MV. Ourévitch M. Crousse B. Bonnet-Delpon D. Synthesis  2003,  2231 

3d Magueur G. Crousse B. Ourévitch M. Bégué J.-P. Bonnet-Delpon D. J. Org. Chem.  2003,  68:  9763 

TFE has already been used as a superior solvent in other MCR’s:

3e Park SJ. Keum G. Kang SB. Koh HY. Kim Y. Lee DH. Tetrahedron Lett.  1998,  39:  7109 

3f Cristau P. Vors J.-P. Zhu J. Org. Lett  2001,  3:  4079 

Reviews on fluorous alcohols:

4a Bégué J.-P. Bonnet-Delpon D. Crousse B. Synlett  2004,  18 

4b Bégué J.-P. Bonnet-Delpon D. Crousse B. In Handbook of Fluorous Chemistry   Gladysz JA. Curran DP. Horvath IT. Wiley-VCH; Weinheim: 2004.  p.341 

5

In the presence of styrene or N-vinyl pyrrolidine as dienophile, no reaction occurred over 24 h, while the alkyl aldimine decomposed in the medium.

6

Typical Procedure for the Synthesis of cis -4-Ethoxy-1,2,3,4-tetrahydro-2-isopropylquinoline ( 1b).
Isobutyraldehyde (1.2 mmol, 86 mg) and ethyl vinyl ether (1.2 mmol, 86 mg) were dissolved in TFE (1 mL) in a 5 mL test tube. A solution of aniline (1 mmol, 93 mg) in TFE (1 mL) was then slowly added over 15 min to the previous mixture under stirring. After stirring for 2 h, the solvent was evaporated in vacuo. The crude product was then purified by chromatography on florisil (cyclohexane-EtOAc, 9:1) to afford 1b as yellow crystals (171 mg, 78%); mp 74-76 °C. ¹H NMR (300 MHz, CDCl₃): δ = 1.02 (d, 3 H, J = 6.7 Hz), 1.03 (d, 3 H, J = 6.7 Hz), 1.33 (t, 3 H, J = 7.0 Hz), 1.75 (m, 2 H), 2.24 (ddd, 1 H, J = 2.5, 5.5, 12.1 Hz), 3.23 (ddd, 1 H, J = 2.5, 5.3, 11.2 Hz), 3.63 (m, 1 H), 3.79 (m, 1 H), 4.68 (dd, 1 H, J = 5.6, 10.2 Hz), 6.51 (d, 1 H, J = 7.8 Hz), 6.71 (t, 1 H, J = 7.4 Hz), 7.04 (t, 1 H, J = 7.6 Hz), 7.36 (d, 1 H, J = 7.6 Hz), NH not observed. ¹³C NMR (300 MHz, CDCl₃): δ = 15.6, 18.0, 18.3, 30.3, 32.4, 56.1, 63.4, 74.1, 113.8, 117.1, 122.8, 126.9, 127.91, 144.6. Anal. Calcd for C₁₄H₂₁NO (219.32): C, 76.67; H, 9.65; N, 6.39. Found: C, 76.33; H, 9.99; N, 6.35.

7a Grieco PA. Bahsas A. Tetrahedron Lett.  1988,  29:  5855 

7b See also: Mellor JM. Derryman GD. Tetrahedron  1995,  21:  6115 

8 Haidekker MA. Brady TP. Lichlyter D. Theodorakis EA. Bioorg. Chem.  2005,  33:  415 ; and references therein

9 Vejdelek Z. Protiva M. Collect. Czech. Chem. Commun.  1990,  55:  1290 

10a Glass DB. Weissberger A. Org. Synth., Coll. Vol. III   Wiley; New York: 1955.  p.504 

10b Katayama H. Abe E. Kaneko K. J. Heterocycl. Chem.  1982,  19:  925 

See also:

10c Palma A. Carrillo C. Stashenko E. Kouznetsov V. Bahsas A. Amaro-Luis J. Tetrahedron Lett.  2001,  42:  6247 

10d Palma A. Agredo JS. Carrillo C. Kouznetsov V. Stashenko E. Bahsas A. Amaro-Luis J. Tetrahedron  2002,  58:  8719 

11a Katritzky AR. Rachwal B. Rachwal S. J. Org. Chem.  1996,  61:  3117 

11b Katritzky AR. Luo Z. Cui X.-L. J. Org. Chem.  1999,  64:  3328 

12

Typical Procedure for the Synthesis of cis , cis -1,7-Diethoxy-3-isopropyljulolidine (2). Isobutyraldehyde (1.2 mmol, 103 mg) and ethyl vinyl ether (1.2 mmol, 86 mg) were dissolved in TFE (0.5 mL) in a 5 mL test tube. A solution of aniline (1 mmol, 93 mg) in TFE (0.5 mL) was then slowly added over 15 min to the previous mixture under stirring. After stirring for 2 h, a solution of formaldehyde (35% aq; 2 mmol, 172 mg) and ethyl vinyl ether (1.2 mmol, 86 mg) in TFE (1 mL) was added to the reaction mixture. After further stirring for 1 h, the solvent was evaporated in vacuo. The crude product was then purified by filtration on florisil (cyclohexane-EtOAc, 7:3) to afford 2 as an orange oil (218 mg, 72%). ¹H NMR (400 MHz, CDCl₃): δ = 0.88 (d, 3 H, J = 6.7 Hz), 1.00 (d, 3 H, J = 6.8 Hz), 1.25 (q, 6 H, J = 7.5 Hz), 2.00 (m, 4 H), 2.23 (oct, 1 H, J = 6.8 Hz), 3.00 (m, 1 H), 3.20 (m, 2 H), 3.60 (m, 2 H), 3.70 (m, 2 H), 4.26 (t, 1 H, J = 3.6 Hz), 4.42 (t, 1 H, J = 5.7 Hz), 6.60 (t, 1 H, J = 7.4 Hz), 7.09 (d, 1 H, J = 7.7 Hz), 7.20 (d, 1 H, J = 7.4 Hz). ¹³C NMR (400 MHz, CDCl₃): δ = 15.6, 15.7, 17.2, 20.5, 27.0, 27.5, 29.0, 42.6, 62.0, 63.3, 63.7, 73.0, 73.9, 114.9, 121.7, 122.6, 128.2, 129.5, 142.1.

13

The cis-configuration was established by means of NOE experiments (NOESY) on product 3. The correlations are shown on the under drawing. Relative configurations of products 2 and 4 have been deduced by analogy (Figure [2] ).