Facile Synthesis of New Substituted Tetrahydro-1H-indoles

Orazio A. Attanasi; Lucia De Crescentini; Gianfranco Favi; Paolino Filippone; Amalija Golobič; Samuele Lillini; Fabio Mantellini

doi:10.1055/s-2006-950275

LETTER

Facile Synthesis of New Substituted Tetrahydro-1H-indoles

Orazio A. Attanasi^a, Lucia De Crescentini^a, Gianfranco Favi^a, Paolino Filippone^a, Amalija Golobič^b, Samuele Lillini^a, Fabio Mantellini*^a
^a Istituto di Chimica Organica della Facoltà di Scienze Matematiche, Fisiche e Naturali, Università degli Studi di Urbino ‘Carlo Bo’, Via Sasso 75, 61029 Urbino, Italy
e-Mail: f.mantellini@uniurb.it;
^b Faculty of Chemistry and Chemical Technology, University of Ljubljana, Aškerčeva 5, 1000 Ljubljana, Slovenia

Abstract

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Abstract

A general procedure for the preparation of different cycloalkenyl-1-diazene derivatives is reported. The utility of these substrates in the preparation of new substituted tetrahydro-1H-indoles by reaction with β-ketoamides is also described.

Key words

tetrahydro-1H-indoles - cycloalkenyl-1-diazenes - Michael additions - [3+2] cyclization - α-substituted hydrazones

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References

References and Notes

<A NAME="RD21606ST-1A">1a</A> Attanasi OA. De Crescentini L. Filippone P. Mantellini F. Santeusanio S. ARKIVOC 2002, (xi): 274 ; and the references cited therein

<A NAME="RD21606ST-1B">1b</A> Attanasi OA. De Crescentini L. Favi G. Filippone P. Giorgi G. Mantellini F. Santeusanio S. J. Org. Chem. 2003, 68: 1947

<A NAME="RD21606ST-1C">1c</A> Attanasi OA. De Crescentini L. Favi G. Filippone P. Mantellini F. Santeusanio S. J. Org. Chem. 2004, 69: 2686

<A NAME="RD21606ST-1D">1d</A> Attanasi OA. Baccolini G. Boga C. De Crescentini L. Filippone P. Mantellini F. J. Org. Chem. 2005, 70: 4033

<A NAME="RD21606ST-1E">1e</A> Attanasi OA. De Crescentini L. Favi G. Filippone P. Lillini S. Mantellini F. Santeusanio S. Org. Lett. 2005, 7: 2469

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<A NAME="RD21606ST-3A">3a</A> South MS. Jakuboski TL. Tetrahedron Lett. 1995, 36: 5703

<A NAME="RD21606ST-3B">3b</A> South MS. Jakuboski TL. Westmeyer MD. Dukesherer DR. Tetrahedron Lett. 1996, 37: 1351

<A NAME="RD21606ST-3C">3c</A> Coates, W. J. Pyridazines and Benzo Derivatives, In Six-Membered Rings with Two or More Heteroatoms and Fused Carbocyclic Derivatives; Boulton, A. J., Ed.; In Comprehensive Heterocyclic Chemistry II Vol. 6: Katritzky AR. Rees CW. Scriven EFV. Pergamon-Elsevier Science; Amsterdam: 1996. Chap. 1.

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<A NAME="RD21606ST-6C">6c</A> Jacques J. Marquet A. Org. Synth., Collect. Vol. VI Wiley; New York: 1988. p.175

General Procedure for the Synthesis of Cycloalkenyl-1-diazenes 5a-d. tert-Butyl carbazate (2a, 1 mmol) or semicarbazide hydrochloride (2b, 1 mmol) were added to a magnetically stirred solution of ethyl 2-cyclopentanon-1-carboxylate (1a, 1 mmol) or ethyl 2-cyclohexanon-1-carboxylate (1b, 1 mmol) or ethyl 4-methyl-2-cyclohexanon-1-carboxylate (1c, 1 mmol) in THF (30 mL) in the case of 2a, or in MeOH in the case of 2b. The semicarbazide hydrochloride 2b was previously treated with an equimolecular amount of NaOAc to give the free form. The reaction was allowed to stand at r.t. until the disappearance of the reagents (4 h). The reaction solvent was then evaporated under reduced pressure and products 3a-d were crystallized by adding to the crude EtOAc-cyclohexane. To a magnetically stirred solution of hydrazones 3a-d in CH₂Cl₂ (150 mL), NBS (1 equiv) was added portionwise at r.t. obtaining α-bromohydrazones 4. Then, the mixture was treated with an aq sat. solution of Na₂CO₃ (3 × 35 mL) and the organic layer was dried on Na₂SO₄. Then, CH₂Cl₂ was evaporated under reduced pressure and the final cycloalkenyl-1-diazenes 5a-d were purified by chromatography on a silica gel column (elution mixtures: EtOAc-cyclohexane).
Data for Ethyl 2-[2-(Aminocarbonyl)hydrazono]-4-methyl-1-cyclohexanecarboxylate (3d).
White powder, mp 128-131 °C. IR (nujol): ν_max = 3407, 3206, 1749, 1693 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 1.02 (d, 3 H, J = 6.0 Hz), 1.29 (t, 3 H, J = 7.2 Hz), 1.54-1.71 (m, 3 H), 1.90-1.97 (m, 2 H), 2.38-2.48 (m, 1 H), 3.03-3.11 (m, 1 H), 4.10-4.28 (m, 2 H), 6.02 and 6.21 (2 br s, 2 H), 9.90 and 9.96 (2 br s, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 14.3 (q), 22.1 (q), 27.1 (d), 28.9 (t), 30.4 (t), 32.7 (t), 49.51 (s), 61.3 (t), 150.7 (s), 155.0 (s), 172.6 (s). MS: m/z (%) = 241 (3)[M⁺], 225 (4), 212 (7), 197 (16), 169 (100). Anal. Calcd for C₁₁H₁₉N₃O₃: C, 54.76; H, 7.94; N, 17.42. Found: C, 54.68; H, 7.98; N, 17.35.
Data for Ethyl 2-[2-(Aminocarbonyl)-1-diazenyl]-4-methyl-1-cyclohexene-1-carboxylate (5d).
Red powder, mp 72-74 °C. IR (nujol): ν_max = 3399, 3180, 1729, 1686 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 1.03 (d, 3 H, J = 6.0 Hz), 1.31 (t, 3 H, J = 7.2 Hz), 1.34-1.42 (m, 1 H), 1.76-1.85 (m, 3 H), 2.54-2.74 (m, 3 H), 4.27 (q, 2 H, J = 7.2 Hz), 6.12 and 6.17 (2 br s, 2 H). ¹³C NMR (100 MHz, CDCl₃): δ = 14.2 (q), 21.2 (q), 27.5 (d), 28.0 (t), 29.3 (t), 29.8 (t), 61.4 (t), 146.7 (s), 151.2 (s), 162.4 (s), 168.6 (s). MS: m/z (%) = 239 (4)[M⁺], 224 (4), 168 (27), 151 (45), 139 (92), 123 (100). Anal. Calcd for C₁₁H₁₇N₃O₃: C, 55.22; H, 7.16; N, 17.56. Found: C, 55.31; H, 7.25; N, 17.50.

General Procedure for the Synthesis of α-Substituted Hydrazones 7a-c and Tetrahydro-1 H -indoles 11a-f. To a magnetically stirred solution of acetoacetanilide (6a) or 4′-methoxyacetoacetanilide (6b) or 4′-chloroacetoacet-anilide (6c) and cycloalkenyl-1-diazenes 5a-d in THF (30 mL) a catalytic amount of NaH (0.1 equiv) was added. The reaction was allowed to stand at r.t. until the disappearance of the reagents (3.5-5 h) and then the solvent was evaporated under reduced pressure. Starting from 1-(1-cyclopentenyl)-1-diazenes 5a,b, only α-substituted cyclopentanone hydrazones 7a,b were obtained by crystallization from EtOAc-cyclohexane. Instead, in the case of 1-(1-cyclohexenyl)-1-diazenes 5c,d, the TLC check revealed the formation of two major products. The crudes were chromatographed on a silica gel column (elution mixtures: EtOAc-cyclohexane). Only in the case of the reaction between 5d and 6a, ethyl 3-[2-(amino-carbonyl)hydrazono]-1-[1-(anilinocarbonyl)-2-oxopropyl]-1-cyclohexanecarboxylate (7c) was isolated together with the corresponding tetrahydro-1H-indole 11d. In the other cases, the chromatographic process furnished only tetrahydro-1H-indoles 11a-c,e,f. All compounds 7c and 11a-f were crystallized from EtOAc-light PE (40-60 °C).
Data for Ethyl 2-[2-(Aminocarbonyl)hydrazono]-[1-(anilinocarbonyl)-2-oxopropyl]-4-methyl-1-cyclohexanecarboxylate (7c).
White powder, mp 132-134 °C. IR (nujol): ν_max = 3482, 3310, 3207, 1720,1 684 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 0.90 (d, 3 H, J = 6.4 Hz), 1.04-1.08 (m, 1 H), 1.16 (t, 3 H, J = 7.2 Hz), 1.27-1.31 (m, 1 H), 1.73-1.76 (m, 2 H), 1.96-2.07 (m, 1 H), 2.09 (s, 3 H), 2.60-2.64 (m, 1 H), 3.33-3.39 (m, 1 H), 4.06 (q, 2 H, J = 7.2 Hz), 4.36 (s,1 H), 5.91 and 6.12 (2 br s, 2 H), 7.07 (t, 1 H, J = 7.2 Hz), 7.30 (t, 2 H, J = 7.6 Hz), 7.53 (d, 2 H, J = 8.0 Hz), 9.47 (s,1 H), 10.24 (s, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 14.5 (q), 15.9 (q), 21.1 (t), 29.5 (q), 30.3 (d), 32.1 (t), 56.9 (t), 61.2 (d), 62.0 (t), 65.6 (s), 120.1 (d), 124.4 (d), 129.5 (d), 139.2 (s), 149.9 (s), 157.8 (s), 167.4 (s), 172.2 (s), 203.8 (s). MS: m/z (%) = 416 (1)[M⁺], 398 (8), 355 (7), 342 (13), 325 (100). Anal. Calcd for C₂₁H₂₈N₄O₅: C, 60.56; H, 6.78; N, 13.45. Found: C, 60.51; H, 6.83; N, 13.52.
Data for Ethyl 1-[(Aminocarbonyl)amino]-3-(anilinocarbonyl)-2,6-dimethyl-3a,4,5,6-tetrahydro-1 H -3a-indolecarboxylate ( R , R / S , S , 11d).
White powder, mp 201-203 °C. IR (nujol): ν_max = 3465, 3353, 3196, 1719, 1709, 1647 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 0.98 (d, 3 H, J = 6.0 Hz), 1.13 (t, 3 H, J = 7.2 Hz), 1.21-1.33 (m, 1 H), 1.36-1.43 (m, 1 H), 1.51 (dt, 1 H, J ^¹ = 12.8 Hz, J ^² = 4.0 Hz), 1.66-1.74 (m, 1 H), 2.11 (s, 3 H), 2.21-2.33 (m, 1 H), 2.52-2.58 (m, 1 H), 4.14 (q, 2 H, J = 7.2 Hz), 4.80 (d, 1 H, J = 3.6 Hz), 6.07 (br s, 2 H), 7.02 (t, 1 H, J = 7.2 Hz), 7.29 (t, 2 H, J = 8.4 Hz), 7.56 (dd, 2 H, J ^¹ = 8.4 Hz, J ^² = 0.8 Hz), 8.41 and 8.58 (2 br s, 1 H), 8.91 and 9.09 (2 br s, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 11.5 (q), 13.7 (q), 22.2 (t), 24.8 (q), 25.9 (t), 26.1 (d), 53.1 (s), 61.6 (t), 102.4 (d), 106.9 (s), 119.0 (d), 122.9 (d), 128.7 (d), 139.1 (s), 143.7 (s), 155.5 (s), 158.4 (s), 162.5 (s), 172.5 (s). MS: m/z (%) = 398 (7)[M⁺], 340 (5), 325 (100). Anal. Calcd for C₂₁H₂₆N₄O₄: C, 63.30; H, 6.58; N, 14.06. Found: C, 63.21; H, 6.63; N, 14.01.
Data for Ethyl 1-[(Aminocarbonyl)amino]-3-[(4-chloro-anilino)carbonyl]-2,6-dimethyl-3a,4,5,6-tetrahydro-1 H -3a-indolecarboxylate ( RR / SS - RS / SR 80:20 mixture, 11f).
White powder, mp 204-206 °C. IR (nujol): ν_max = 3483, 3341, 3232, 1758, 1736, 1612 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 0.93-0.97 (m, 3 H), 1.12-1.17 (m, 3 H), 1.35-1.39 (m, 1 H), 1.45-1.52 (m, 1 H), 1.66-1.74 (m, 1 H), 2.08-2.10 (m, 3 H), 2.32-2.36 (m, 1 H), 2.48-2.56 (m, 1 H), 4.05-4.17 (m, 2 H), 4.62 and 4.79 (2 d, 1 H, J = 3.2 Hz), 5.99 (br s, 2 H), 7.29-7.34 (m, 2 H), 7.58-7.61 (m, 2 H), 8.41 and 8.54 (2 s, 1 H), 9.02 and 9.21 (2 br s, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 11.6 (q), 11,7 (q), 13.8 (q), 13.9 (q), 22.3 (t), 22.5 (q), 24.7 (q), 26.0 (t), 26.1 (d), 26.3 (d), 53.1 (s), 53.2 (s), 61.1 (t), 61.6 (t), 102.5 (d), 107.0 (s), 120.6 (d), 120.7 (d), 126.4 (s), 128.5 (s), 138.2 (s), 138.4 (s), 143.6 (s), 155.5 (s), 158.5 (s), 162.7 (s), 162.8 (s), 172.4 (s). MS: m/z (%) = 434 (3)[M⁺ + 2], 432 (9)[M⁺], 361 (33), 359 (100). Anal. Calcd for C₂₁H₂₅N₄O₄Cl: C, 58.26; H, 5.82; N, 12.94. Found: C, 58.19; H, 5.77; N, 12.91.

<A NAME="RD21606ST-9">9</A> Attanasi OA. Filippone P. Synlett 1997, 1128

The final atomic and geometrical parameters, crystal data and details concerning data collection and refinement have been deposited with the Cambridge Crystallographic Data Centre as supplementary material with the deposition number: CCDC 614163. Copies of the data can be obtained, free of charge via http://www.ccdc.cam.ac.uk/const/retrieving.html. ORTEP-3 was used to produce the drawing of molecule, which is shown in Figure [1] .

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<A NAME="RD21606ST-11B">11b</A> Colca JR. Tanis SP.
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