Synthesis of Hexahydroindole Carboxylic Acids by Intramolecular Diels-Alder Reaction

Anne Friedrich; Manuel Jainta; Carl F. Nising; Stefan Bräse

doi:10.1055/s-2008-1032085

LETTER

Synthesis of Hexahydroindole Carboxylic Acids by Intramolecular Diels-Alder Reaction

Anne Friedrich, Manuel Jainta, Carl F. Nising, Stefan Bräse*
Institute of Organic Chemistry, University of Karlsruhe (TH), Fritz-Haber-Weg 6, 76131 Karlsruhe, Germany
Fax: +49(721)608858; e-Mail: braese@ioc.uka.de;

Abstract

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Abstract

By applying an intramolecular Diels-Alder reaction highly functionalized Δ^6,7-hexahydroindoles were prepared in good yields.

Key words

Diels-Alder reactions - heterocycles - rostratins - hexahydroindoles

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References

References and Notes

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Solvents and chemicals used for reactions were purchased from commercial suppliers. Solvents were dried under standard conditions and chemicals were used without further purification. All reactions were carried out under Ar in flame-dried glassware. Evaporation of solvents and concentration of reaction mixtures were performed in vacuo at 40 °C on a Büchi rotary evaporator. TLC was carried out on silica gel plates (Kieselgel 60, F254, Merck) with detection by UV and visualization by spraying with the Seebach solution. Normal-phase silica gel (Silica gel 60, 230-400 mesh, Merck) was used for preparative chromatography. Melting points were determined on a Laboratory Devices Inc. Mel-Temp II instrument and are uncorrected. IR spectra were recorded on a Bruker IFS88 spectrometer. Absorption is reported as ν values in cm^-1. ¹H NMR and ¹³C NMR spectra were recorded at 346 K(rotamers) on a Bruker-AC-250, AM-400 or DRX 500 spectrometer. Chemical shifts are reported as δ values (ppm) downfield from internal TMS in the indicated solvent. Coupling constants (J) are given in Hz; s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad, p = primary C. High-resolution mass spectra (HRMS) were determined on a Finnigan MAT90 instrument. The apparatus used for elemental analysis was Heraeus CHN-O-Rapid.
Dimethyl 5-[( E )-Buta-1,3-dienyl]aminohex-2-enedicarboxylate (10): In a round-bottomed flask with rubber septum hydrochloride 9 (4.13 g, 18.5 mmol) and Et₃N (2.60 mL, 1.87 g, 18.5 mmol) were dissolved in CH₂Cl₂ (200 mL) and stirred at r.t. for 3 h. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was diluted with Et₂O (150 mL), filtrated and the filtrate was concentrated. The residue was dissolved in CH₂Cl₂ (50 mL) and crotonaldehyde (1.34 mL, 1.16 g, 16.61 mmol) as well as molecular sieves (7.00 g) were added. After stirring at r.t. for 15 h the mixture was filtered and the filtrate was concentrated to give 10 as a pale yellow oil which was used without further purification.
IR (neat): 3434, 2999, 2953, 2850, 1726, 1656, 1620, 1437, 1378, 1273, 1201, 1175, 1103, 1039, 985, 722 cm^-1. ¹H NMR (500 MHz, CDCl₃): δ = 1.90 (d, J = 5.1 Hz, 3 H, Me), 2.63-2.70 (m, 1 H, CH₂), 2.77-2.83 (m, 1 H, CH₂), 3.68 (s, 3 H, OMe), 3.70 (s, 3 H, OMe), 3.86 (dd, J = 5.4, 8.0 Hz, 1 H, CH), 5.85 (d, J = 15.4 Hz, 1 H, H-A), 6.25-6.27 (m, 2 H, H-2, H-3), 6.78 (dd, J = 7.4, 15.4 Hz, 1 H, H-B), 7.78 (d, J = 8.0 Hz, 1 H, H-1). ¹³C NMR (125 MHz, CDCl₃): δ = 18.6 (Me), 36.1 (CH₂), 51.5 (OMe), 52.4 (OMe), 71.6 (CH), 124.0 (C-A) 132.4 (C-2), 143.4 (C-3), 144.0 (C-B), 166.0 (C-1), 166.5 (C=O), 171.4 (C=O). MS (EI, 70 eV): m/z (%) = 239 (8) [M]⁺, 180 (100), 140 (31), 80 (46). HRMS: m/z calcd for C₁₂H₁₇NO₄: 239.1158; found: 239.1160.
General Procedure for the Synthesis of Enamines 11-17: Imine 10 was dissolved in toluene (10 mL/mmol) and added dropwise to a flask containing diethylaniline (1.50 equiv) and the acid chloride (1.20 equiv) at 0 °C. The reaction mixture was warmed to r.t. and stirred overnight. The resulting precipitate was filtered off, washed with Et₂O and the filtrate was concentrated. The residue was purified by column chromatography.
Dimethyl 5-[ N -Buta-1,3-dienyl(methoxy-carbonyl)amino]hex-2-enedicarboxylate (13): IR (neat): 3621, 3453, 3088, 2954, 2850, 1736, 1647, 1606, 1544, 1441, 1384, 1220, 895, 854, 771, 724, 653, 607 cm^-1. ¹H NMR (500 MHz, CDCl₃): δ = 2.77-2.94 (m, 1 H, CH₂), 3.01-3.06 (m, 1 H, CH₂), 3.71 (s, 3 H, OMe), 3.74 (s, 3 H, OMe), 3.79 (s, 3 H, OMe), 4.74 (br s, 1 H, CH), 4.92 (d, J = 10.2 Hz, 1 H, H-4), 5.08 (d, J = 16.9 Hz, 1 H, H-5), 5.49-5.56 (m, 1 H, H-2), 5.88 (d, J = 15.6 Hz, 1 H, H-A), 6.22-6.29 (m, 1 H, H-3), 6.86 (ddd, J = 7.6, 7.6, 15.2 Hz, 1 H, H-B), 6.88-7.04 (m, 1 H, H-1). ¹³C NMR (125 MHz, CDCl₃): δ = 31.3 (CH₂), 51.5 (OMe), 52.8 (OMe), 52.8 (OMe), 56.4 (CH), 112.8 (C-2), 114.7 (C-4), 124.0 (C-A), 129.5 (C-1), 134.6 (C-3), 143.6 (C-1), 154.0 (C=O), 166.4 (C=O), 169.9 (C=O). MS (EI, 70 eV): m/z (%) = 297 (100) [M]⁺, 266 (29) [M - OMe]⁺, 238 (63) [M - CO₂Me]⁺, 111 (75). HRMS: m/z calcd for C₁₄H₁₉NO₆: 297.1210; found: 297.1210.
General Procedure for the Diels-Alder Cyclization: In a pressure vessel the enamine (1 mmol) was dissolved in toluene (10 mL) and N,O-bistrimethylsilylacetamide (1 mmol) was added. The reaction mixture was heated at 130-210 °C for 6-9 d. After cooling to r.t, the solvent was evaporated and the crude product was purified by column chromatography.
Trimethyl 2,3,3a,4,5,7a-Hexahydroindole-1,2,4-tricarboxylate (21): IR (neat): 3496, 2954, 2852, 1734, 1703, 1451, 1384, 1304, 1240, 1197, 1176, 1116, 1083, 1015, 877, 774, 690 cm^-1. ¹H NMR (500 MHz, DMSO-d ₆, 346 K): δ = 1.74-1.82 (m, 1 H, H-3), 2.26 (br s, 2 H, H-3, H-5), 2.34-2.41 (m, 1 H, H-5), 2.67-2.80 (m, 2 H, H-3a, H-4), 3.61 (s, 3 H, OMe), 3.64 (s, 6 H, OMe), 4.29-4.33 (m, 2 H, H-2, H-7a), 5.67-5.69 (m, 1 H, H-6), 5.76-5.78 (m, 1 H, H-7). ¹³C NMR (125 MHz, DMSO-d ₆, 346 K): δ = 22.5 (s, C-5), 36.2 (s, C-3), 36.2 (t, C-3a), 38.1 (t, C-4), 51.1 (p, OMe), 51.2 (p, OMe), 51.6 (p, OMe), 54.0 (t, C-2), 57.6 (t, C-7a), 124.6 (t, C-6), 125.4 (t, C-7), 154.2 (q, C=O), 171.8 (q, C=O), 173.6 (q, C=O). MS (EI, 70 eV): m/z (%) = 297 (6) [M]⁺, 266 (5) [M - OMe]⁺, 238 (100) [M - CO₂Me]⁺, 179 (3) [M - 2 × CO₂Me]⁺. HRMS: m/z calcd for C₁₄H₁₉NO₆: 279.1212; found: 279.1211. Anal. Calcd for C₁₄H₁₉NO₆: C, 56.56; H, 6.44; N, 4.71. Found: C, 56.54; H, 6.54; N, 4.88.

<A NAME="RG39507ST-10">10</A> El-Khawaga AM. Hoffmann HMR. J. Prakt. Chem. 1995, 337: 332

Diels-Alder cyclization of enamines 15-17 was unsuccessful due to poor solubility in various solvents.

<A NAME="RG39507ST-12">12</A> Park H.-G. Jeong B.-S. Yoo M.-S. Lee J.-H. Park M.-K. Lee Y.-J. Kim M.-J. Jew S.-S. Angew. Chem. Int. Ed. 2002, 41: 3036 ; Angew. Chem. 2002, 114, 3162

<A NAME="RG39507ST-13">13</A> For a model dimer, see: Friedrich A. Jainta M. Nieger M. Bräse S. Synlett 2007, 2127