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

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.

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

References and Notes

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4

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.

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6

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.

7

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:

8a Hofmann AW. Martius CA. Ber. Dtsch. Chem. Ges.  1871,  4:  742 

8b 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:

8c Martínez R. Cortés E. Toscano RA. Linzaga I. J. Heterocycl. Chem.  1990,  27:  363 

8d Martínez R. Cortés E. Toscano RA. Alfaro LJ. J. Heterocycl. Chem.  1990,  27:  1273 

8e Martínez R. Cortés E. Toscano RA. Alfaro LJ. Avila JG. J. Heterocycl. Chem.  1991,  28:  589 

9 For chemistry of 2-azaspiro compounds, see: Alonso ER. Tehrani KA. Boelens M. De Kimpe N. Synthesis  2005,  1726 ; and literature cited therein