A Novel Three-Component Reaction of Anilines, Formaldehyde and β-Dike­tones: Simple Synthesis of 3-Spirosubstituted 1,2,3,4-Tetrahydroquinolines

Aliaksei P. Kadutskii; Nikolas G. Kozlov

doi:10.1055/s-2006-956450

LETTER

A Novel Three-Component Reaction of Anilines, Formaldehyde and β-Diketones: Simple Synthesis of 3-Spirosubstituted 1,2,3,4-Tetrahydroquinolines

Aliaksei P. Kadutskii*, Nikolas G. Kozlov
Laboratory of Organic Catalysis, Institute of Physical Organic Chemistry, The National Academy of Sciences of Belarus, 13 Surganov st., Minsk 220072, Belarus
Fax: +375(17)2841679; e-Mail: kadutskii@gmail.com;

Abstract

Alle Artikel dieser Rubrik

Abstract

A new three-component reaction of cyclic β-diketones, formaldehyde and substituted anilines is described. The reaction provides a simple synthetic method for the one-pot preparation of 3-spirosubstituted 1,2,3,4-tetrahydroquinolines containing different substituents at the N-atom. This reaction also gives the opportunity to unite in one molecule the 1,2,3,4-tetrahydroquinoline, cyclic β-dicarbonyl, 2-azaspiro and some other (e.g., benzylic, bicyclic, adamantyl) fragments.

Key words

β-diketones - multicomponent reaction - Mannich reaction - azaspiro compounds - 1,2,3,4-tetrahydroquinolines

Volltext

Referenzen

References and Notes

<A NAME="RG24606ST-1A">1a</A> Perry NB. Blunt JW. Munro MHG. Sakai R. J. Org. Chem. 1988, 53: 4127

<A NAME="RG24606ST-1B">1b</A> Konishi M. Zercher CK. Bechkam S. Haubold E.-M. J. Am. Chem. Soc. 1990, 112: 3715

<A NAME="RG24606ST-1C">1c</A> Wender PA. Zercher CK. Bechkam S. Haubold E.-M. J. Org. Chem. 1993, 58: 5867

<A NAME="RG24606ST-1D">1d</A> Uchida M. Chihiro M. Morita S. Kanbe T. Yamashita H. Yamasakai K. Yabuuchi Y. Nakagawa K. Chem. Pharm. Bull. 1989, 37: 2109

<A NAME="RG24606ST-1E">1e</A> Carling RW. Leeson PD. Mosely AM. Smith JD. Saywell K. Tricklebank MD. Kemp JA. Marshal GR. Foster AC. Grimwood S. Bioorg. Med. Chem. Lett. 1993, 3: 65

<A NAME="RG24606ST-1F">1f</A> Kam T.-S. Subramaniam G. Tetrahedron Lett. 2004, 45: 3521

<A NAME="RG24606ST-2A">2a</A> Weinreb SM. In Comprehensive Organic Synthesis Vol. 5: Trost BM. Fleming I. Pergamon; Oxford: 1991. p.401

<A NAME="RG24606ST-2B">2b</A> Bunce RA. Herron DM. Johnson LB. Kotturi S. J. Org. Chem. 2001, 66: 2822

<A NAME="RG24606ST-2C">2c</A> Jia X. Lin H. Huo C. Zhang W. Lu J. Yang L. Zhao G. Liu Z.-L. Synlett 2003, 1707

<A NAME="RG24606ST-2D">2d</A> Nagarajan R. Magesh CJ. Perumal PT. Synthesis 2004, 69

<A NAME="RG24606ST-2E">2e</A> Yadav JS. Reddy BVS. Padmavani B. Synthesis 2004, 405

<A NAME="RG24606ST-2F">2f</A> Ding K. Flippen-Anderson J. Deschamps JR. Wang S. Tetrahedron Lett. 2004, 45: 1027

<A NAME="RG24606ST-2G">2g</A> Fadel F. Titouani SL. Soufiaoui M. Ajamay H. Mazzah A. Tetrahedron Lett. 2004, 45: 5905

<A NAME="RG24606ST-2H">2h</A> Ori M. Toda N. Takami K. Tago K. Kogen H. Tetrahedron 2005, 61: 2075

<A NAME="RG24606ST-2I">2i</A> Zhang W. Guo Y. Liu Z. Jin X. Yang L. Liu Z.-L. Tetrahedron 2005, 61: 1325

<A NAME="RG24606ST-3A">3a</A> Katritzky AR. Rachwal S. Rachwal B. Tetrahedron 1996, 52: 15031

<A NAME="RG24606ST-3B">3b</A> Baraznenok IL. Nenajdenko VG. Churakov AV. Nesterenko PN. Balenkova ES. Synlett 2000, 514

<A NAME="RG24606ST-3C">3c</A> De D. Seth M. Bhadori AP. Indian J. Chem., Sect. B: Org. Chem. Incl. Med. Chem. 1990, 29: 70

<A NAME="RG24606ST-3D">3d</A> Lombardo LJ. Camuso A. Clark J. Fager K. Gullo-Brown J. Hunt JT. Inigo I. Kan D. Koplowitz B. Lee F. McGlinchey K. Qian L. Ricca C. Rovnyak G. Traeger S. Tokarski J. Williams DK. Wu LI. Zhao Y. Manne V. Bhide RS. Bioorg. Med. Chem. Lett. 2005, 15: 1895

<A NAME="RG24606ST-3E">3e</A> Santangelo F. Casagrande C. Miragoli G. Vecchietti V. Eur. J. Med. Chem. 1994, 29: 877

<A NAME="RG24606ST-3F">3f</A> Lewis RJ. Francis ChA. Lehr RE. Blank CL.-R. Tetrahedron 2000, 56: 5345

General Procedure for Preparation of 1′,4′-dihydro-2 H ,2′ H ,6 H -spiro[cyclohexane-1,3′-quinoline]-2,6-diones (4a-i).
A solution of amine 1 (2 mmol) and paraformaldehyde (8 mmol) in EtOH (25 mL) was prepared by gentle warming (2-3 min). Diketone 3 (2 mmol) was added to this solution in one portion and the mixture was heated under reflux for 5 min. After cooling to r.t. the colourless precipitate was filtered off, washed with EtOH (2 × 5 mL) and dried to give 4. The yields reported in Table [1] are unoptimised and additional crops of 4 could be obtained upon concentration of the mother liquors.

<A NAME="RG24606ST-5A">5a</A> Abdel-Magid AF. Carson KG. Harris BD. Maryanoff CA. Shah RD. J. Org. Chem. 1996, 61: 3849

<A NAME="RG24606ST-5B">5b</A> Abdel-Magid AF. Maryanoff CA. Carson KG. Tetrahedron Lett. 1990, 31: 5595

<A NAME="RG24606ST-5C">5c</A> Salvatore RN. Yoon ChH. Jung KW. Tetrahedron 2001, 57: 7785

The N-monosubstituted anilines were prepared by reductive amination of the desired ketones with the corresponding primary anilines. Sodium triacetoxyborohydride was used as a reducing agent in the reaction as reported in ref. 5a.

All new compounds gave satisfactory 500 MHz ¹H NMR and 100 MHz ¹³C NMR and IR spectral data.
Selected Physical Data.
1′-(1,3-Benzodioxol-5-ylmethyl)-6′-methoxy-1′,4′-dihydro-2 H ,2′ H ,6 H -spiro[cyclohexane-1,3′-quinoline]-2,6-dione ( 4b).
Mp 148 °C. IR (KBr): 3439, 3404, 2931, 2904, 2830, 1726, 1701, 1504, 1489, 1444, 1242, 1151, 1036 cm^-1. ¹H NMR (CDCl₃): δ = 1.82 (m, 1 H), 2.02 (m, 1 H), 2.60-2.75 (m, 4 H), 3.21 (s, 2 H), 3.46 (s, 2 H), 3.75 (s, 3 H), 4.30 (s, 2 H), 5.95 (s, 2 H), 6.55-6.63 (m, 2 H), 6.71-6.80 (m, 4 H). ¹³C NMR (CDCl₃): δ = 19.05, 30.64, 37.86, 55.21, 56.25, 56.33, 67.07, 101.69, 108.37, 109.03, 113.10, 113.72, 115.39, 120.92, 123.33, 132.85, 139.13, 147.41, 148.70, 152.88, 206.33. MS (70 eV): m/z (%) = 135 (82), 252 (100), 393 (23) [M⁺], 394 (5) [M + H⁺]. Anal. Calcd for C₂₃H₂₃NO₅: C, 70.21; H, 5.89; N, 3.56. Found: C, 70.21; H, 5.90; N, 3.57.
1′-(3,4-Dimethoxybenzyl)-6′-methoxy-4,4-dimethyl-1′,4′-dihydro-2 H ,2′ H ,6 H -spiro[cyclohexane-1,3′-quinoline]-2,6-dione ( 4g). Mp 159 °C. IR (KBr): 2963, 2916, 2834, 1722, 1691, 1511, 1459, 1259, 1229, 1201, 1160, 1137, 1053, 1026 cm^-1. ¹H NMR (CDCl₃): δ = 0.88 (s, 3 H), 1.05 (s, 3 H), 2.43 (d, J = 14.0 Hz, 2 H), 2.63 (d, J = 14.0 Hz, 2 H), 3.20 (s, 2 H), 3.41 (s, 2 H), 3.75 (s, 3 H), 3.85 (s, 3 H), 3.89 (s, 3 H), 4.31 (s, 2 H), 6.55-6.63 (m, 2 H), 6.76-6.86 (m, 4 H). ¹³C NMR (CDCl₃): δ = 27.77, 29.99, 30.62, 31.51, 51.65, 55.51, 55.90, 56.24, 56.57, 56.65, 65.89, 66.51, 110.96, 111.83, 112.95, 113.64, 115.37, 119.98, 123.65, 131.53, 139.32, 148.83, 150.04, 152.93, 206.16. MS (70 eV): m/z (%) = 151 (100), 252 (63), 437 (12) [M⁺], 438 (3) [M + H⁺]. Anal. Calcd for C₂₆H₃₁NO₅: C, 71.37; H, 7.14; N, 3.20. Found: C, 71.37; H, 7.14; N, 3.21.
1′-Cyclododecyl-6′-methoxy-1′,4′-dihydro-2 H ,2′ H ,6 H -spiro[cyclohexane-1,3′-quinoline]-2,6-dione ( 4i). Mp 186 °C. IR (KBr): 3431, 2937, 2925, 2859, 1717, 1692, 1611, 1580, 1505, 1256, 1239, 1052 cm^-1. ¹H NMR (CDCl₃): δ = 1.30-1.50 (m, 20 H), 1.59-1.70 (m, 2 H), 1.74-1.88 (m, 1 H), 2.06-2.18 (m, 1 H), 2.62-2.67 (m, 2 H), 2.81-2.87 (m, 2 H), 3.15 (s, 2 H), 3.35 (s, 2 H), 3.74 (s, 3 H), 3.88 (t, J = 5.8 Hz, 1 H), 6.68 (br s, 2 H), 6.37 (s, 1 H). ¹³C NMR (CDCl₃): δ = 18.31, 22.47, 22.60, 23.01, 23.77, 23.97, 26.42, 29.65, 37.22, 48.07, 50.91, 55.42, 65.98, 111.58, 112.12, 115.02, 123.10, 138.75, 151.28, 205.74. Anal. Calcd for C₂₇H₃₉NO₃: C, 76.20; H, 9.24; N, 3.29. Found: C, 76.21; H, 9.22; N, 3.28.

1′-(5,5,6-Trimethylbicyclo[2.2.1]hept-2-yl)-6′-methyl-1′,4′-dihydro-2 H ,2′ H ,6 H -spiro[cyclohexane-1,3′-quinoline]-2,6-dione ( 4j). Mp 156 °C. IR (KBr): 3407, 2964, 2893, 2865, 2833, 1728, 1702, 1619, 1505, 1416, 1265, 1170, 1019, 819, 812 cm^-1. ¹H NMR (CDCl₃): δ = 0.87 (s, 3 H), 0.91 (s, 3 H), 1.03 (d, J = 7.5 Hz, 3 H), 1.31 (dd, J = 1.1, 10.3 Hz, 1 H), 1.49 (dt, J = 3.6, 13.0 Hz, 1 H), 1.70 (d, J = 3.7 Hz, 1 H), 1.75-1.95 (m, 3 H), 2.00 (dq, J = 1.1, 7.4 Hz, 1 H), 2.05-2.13 (m, 1 H), 2.16 (d, J = 2.0 Hz, 1 H), 2.26 (s, 3 H), 2.51 (dt, J = 5.3, 15.5 Hz, 1 H), 2.72 (dt, J = 5.3, 15.5 Hz, 1 H), 2.81-2.97 (m, 2 H), 2.88 (d, J = 11.0 Hz, 1 H), 2.91 (d, J = 13.0 Hz, 1 H), 3.16 (d, J = 13.0 Hz, 1 H), 3.36 (dt, J = 3.9, 9.7 Hz, 1 H), 3.71 (d, J = 11.0 Hz, 1 H), 6.61 (d, J = 8.0 Hz, 1 H), 6.85 (s, 1 H), 6.97 (d, J = 8.0 Hz, 1 H). ¹³C NMR (CDCl₃): δ = 15.81, 17.96, 20.50, 24.72, 26.31, 32.46, 34.84, 35.80, 37.03, 37.40, 37.88, 39.67, 48.17, 49.38, 49.93, 60.55, 71.76, 114.87, 125.63, 127.47, 127.86, 128.07, 146.13, 205.77, 206.23. Anal. Calcd for C₂₅H₃₃NO₂: C, 79.11; H, 8.76; N, 3.69. Found: C, 79.10; H, 8.74; N, 3.70.
1′-(2-Adamantyl)-6′-methyl-4,4-dimethyl-1′,4′-dihydro-2 H ,2′ H ,6 H -spiro[cyclohexane-1,3′-quinoline]-2,6-dione ( 4k).
Mp 205 °C. IR (KBr): 3440, 2919, 2900, 2862, 1725, 1695, 1502, 1248, 1155, 819, 519 cm^-1. ¹H NMR (CDCl₃): δ = 0.94 (s, 3 H), 1.07 (s, 3 H), 1.56 (d, J = 12.5 Hz, 2 H), 1.75 (s, 2 H), 1.83-1.96 (m, 6 H), 2.06 (d, J = 12.5 Hz, 2 H), 2.24 (s, 3 H), 2.28 (br s, 2 H), 2.56 (d, J = 14.0 Hz, 2 H), 2.80 (d, J = 14.0 Hz, 2 H), 3.05 (s, 2 H), 3.51 (s, 3 H), 6.56 (d, J = 8.0 Hz, 1 H), 6.88 (s, 1 H), 6.93 (d, J = 8 Hz, 1 H). ¹³C NMR (CDCl₃): δ = 20.45, 27.02, 27.51, 28.02, 29.00, 29.77, 30.65, 32.26, 34.37, 37.57, 37.59, 46.18, 51.21, 60.98, 69.57, 114.64, 125.76, 127.58, 127.84, 128.30, 144.59, 206.01. Anal. Calcd for C₂₇H₃₅NO₂: C, 79.96; H, 8.70; N, 3.45. Found: C, 80.00; H, 8.73; N, 3.42.

For the original work, see:

<A NAME="RG24606ST-8A">8a</A> Hofmann AW. Martius CA. Ber. Dtsch. Chem. Ges. 1871, 4: 742

<A NAME="RG24606ST-8B">8b</A> For mechanistic considerations, see: Drumm PJ. O’Connor WF. Reilly J. J. Am. Chem. Soc. 1940, 62: 1241

For synthetic applications of the rearrangement, see:

<A NAME="RG24606ST-8C">8c</A> Martínez R. Cortés E. Toscano RA. Linzaga I. J. Heterocycl. Chem. 1990, 27: 363

<A NAME="RG24606ST-8D">8d</A> Martínez R. Cortés E. Toscano RA. Alfaro LJ. J. Heterocycl. Chem. 1990, 27: 1273

<A NAME="RG24606ST-8E">8e</A> Martínez R. Cortés E. Toscano RA. Alfaro LJ. Avila JG. J. Heterocycl. Chem. 1991, 28: 589

<A NAME="RG24606ST-9">9</A> For chemistry of 2-azaspiro compounds, see: Alonso ER. Tehrani KA. Boelens M. De Kimpe N. Synthesis 2005, 1726 ; and literature cited therein

A Novel Three-Component Reaction of Anilines, Formaldehyde and β-Dike­tones: Simple Synthesis of 3-Spirosubstituted 1,2,3,4-Tetrahydroquinolines

A Novel Three-Component Reaction of Anilines, Formaldehyde and β-Diketones: Simple Synthesis of 3-Spirosubstituted 1,2,3,4-Tetrahydroquinolines