Download PDF
Synlett 2006(17): 2735-2738  
DOI: 10.1055/s-2006-950275
LETTER
© Georg Thieme Verlag Stuttgart · New York

Facile Synthesis of New Substituted Tetrahydro-1H-indoles

Orazio A. Attanasia, Lucia De Crescentinia, Gianfranco Favia, Paolino Filipponea, Amalija Golobičb, Samuele Lillinia, 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
Further Information

Publication History

Received 27 July 2006
Publication Date:
09 October 2006 (online)

    Permissions and Reprints All articles of this category

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

    References and Notes

  • 1a Attanasi OA. De Crescentini L. Filippone P. Mantellini F. Santeusanio S. ARKIVOC  2002,  (xi):  274 ; and the references cited therein
    CrossrefPubMedGoogle Scholar
  • 1b Attanasi OA. De Crescentini L. Favi G. Filippone P. Giorgi G. Mantellini F. Santeusanio S. J. Org. Chem.  2003,  68:  1947 
    CrossrefPubMedGoogle Scholar
  • 1c Attanasi OA. De Crescentini L. Favi G. Filippone P. Mantellini F. Santeusanio S. J. Org. Chem.  2004,  69:  2686 
    CrossrefPubMedGoogle Scholar
  • 1d Attanasi OA. Baccolini G. Boga C. De Crescentini L. Filippone P. Mantellini F. J. Org. Chem.  2005,  70:  4033 
    CrossrefPubMedGoogle Scholar
  • 1e Attanasi OA. De Crescentini L. Favi G. Filippone P. Lillini S. Mantellini F. Santeusanio S. Org. Lett.  2005,  7:  2469 
    CrossrefPubMedGoogle Scholar
  • 2a Brodka S. Simon H. Justus Liebigs Ann. Chem.  1971,  745:  193 
    CrossrefGoogle Scholar
  • 2b Attanasi OA. Bonifazi P. Foresti E. Pradella G. J. Org. Chem.  1982,  47:  684 
    CrossrefGoogle Scholar
  • 3a South MS. Jakuboski TL. Tetrahedron Lett.  1995,  36:  5703 
    CrossrefGoogle Scholar
  • 3b South MS. Jakuboski TL. Westmeyer MD. Dukesherer DR. Tetrahedron Lett.  1996,  37:  1351 
    CrossrefGoogle Scholar
  • 3c 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.
    CrossrefGoogle Scholar
  • 3d South MS. Jakuboski TL. Westmeyer MD. Dukesherer DR. J. Org. Chem.  1996,  61:  8921 
    CrossrefGoogle Scholar
  • 4 Cycloaddition Reactions in Organic Synthesis   Kobayashi S. Jørgensen KA. Wiley-VCH; Weinheim: 2002. 
    Google Scholar
  • 5 Gilchrist TL. Sanchez Romero OA. Wasson RC. J. Chem. Soc., Perkin Trans. 1  1989,  353 
    CrossrefGoogle Scholar
  • 6a Wisweswariah S. Prakash G. Bhushan V. Chandrasekaran S. Synthesis  1982,  309 
    CrossrefGoogle Scholar
  • 6b Dauben WG. Warshawsky AM. Synth. Commun.  1988,  18:  1323 
    CrossrefGoogle Scholar
  • 6c Jacques J. Marquet A. Org. Synth., Collect. Vol. VI   Wiley; New York: 1988.  p.175 
    CrossrefGoogle Scholar
  • 9 Attanasi OA. Filippone P. Synlett  1997,  1128 
    Article in Thieme ConnectGoogle Scholar
  • 11a Nagarajan K. Talwalker PK. Shenoy SJ. Eur. J. Med. Chem.  1988,  23:  189 
    Google Scholar
  • 11b Colca JR. Tanis SP.
    Ann. Rep. Med. Chem.  1992,  27:  219 
    Google Scholar
7

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): νmax = 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): νmax = 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.

8

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): νmax = 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): νmax = 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): νmax = 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.

10

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] .