Partially Saturated Indeno[1,2-b]indole Derivatives via Deoxygenation of Heterocyclic α-Hydroxy-N,O-hemiaminals

Abstract

A series of 3-aminocyclohex-2-enones were reacted with indane-1,2,3-trione monohydrate (ninhydrin) yielding 4b,9b-dihydroxyindeno[1,2-b]indoles that were deoxygenated to indeno[1,2-b]indoles.

Recently we reported on the reaction of indane-1,2,3-trione monohydrate (ninhydrin, 1) and amidines 2, which gave vic-dihydroxy-substituted indeno[1,2-d]imidazoles. [²]

We found that the resulting N-substituted vic-dihydroxy-indenoimidazoles 3 were deoxygenated by mixtures of thionyl chloride and heterocyclic bases, such as pyridine or imidazole. Furthermore we optimized this reaction and found N,N,N′,N′-tetramethylsulfurous acid diamide (4) or its ethyl analogue as novel reagents, [³] which were well suited to this purpose. In our mechanistic reflections, we postulated the formation of an intermediate β-sultine via an iminium cation and fragmentation with formation of an olefinic bond. [4] Thus the respective indeno[1,2-d]imidazoles 5 were formed by a short and simple procedure in acceptable to good yields. The convenience of this reaction promises to be useful in the preparation of a wide variety of related indene-annulated imidazoles as they are required for structure-activity relationship studies (Scheme  [¹] ).

Continuing this work, we planned to test the synthetic potential of 4 in the deoxygenation of structural different vic-diols, generated by the reaction of 1 with 1,3-dinucleophiles, such as push-pull olefins.

In the literature there is only one short communication on this subject. The reaction of 1 with 4-aminopent-3-en-2-one or 3-aminocrotonic acid derivatives yields vic-dihydroxyindeno[1,2-b]pyrroles. [5]

In our investigations, we chose cyclic enaminones, such as 3-aminocyclohex-2-enones 7, to avoid complications due to E/Z-isomerization of the double bond. Though cyclic enaminones are widely used synthons in heterocyclic chemistry, their reaction with 1 has not been previously reported. [6] [7] Therefore, first the reaction of 1 with cyclic enaminones, such as 7, had to be investigated.

A short retrosynthetic study shows that the reaction of 7 and 1 may provide vic-dihydroxy-indenoindoles 8 or/and 9 (Scheme  [²] ). Both of the possible cyclic products differ from 3 in the presence of only one N,O-hemiaminal substructure, neighboring a tertiary alcohol functionality. The consequences of this structural change on the subsequent deoxygenation reaction with 4 were the second aspect of this investigation. It may lead to the partially saturated indenoindoles 10 or/and its regioisomer, which are new.

Indenoindoles served as an attractive target for pharmacological studies. In the last few years, indeno[1,2-b]indoles have been reported as powerful lipid peroxidation inhibitors, [8] potassium channel openers, [9] DNS intercalators and topoisomerase II inhibitors, [¹0] estrogenic agents, [¹¹] or inhibitors of protein kinase CK 2, [¹²] indicating a growing interest in this class of compounds.

Among the existing procedures for the preparation of indenoindoles, the Fischer indolization starting with an indanone via the respective phenylhydrazones serves as the most common method. [¹³] [¹4] Recently, two new syntheses by transformation and reduction of 2-nitrobenzylidene­phthalide, generated either by intramolecular cyclization of 2-(2-nitrophenylethynyl)benzoic acid [¹5] or by reaction of a phthalidyl-phosphonium bromide with 2-nitrobenzaldehyde, [¹0] and cyclization of the resulting amino compounds, had been published. Some articles have been written about the formation of vic-dihydroxy-indenoindolones by the reaction of 1 with aromatic amines, bearing an electron-donating group para to the amine. [¹6]

We now report on our investigations of the reaction of cyclic enaminones 7 and indane-1,2,3-trione monohydrate (1) to yield vic-dihydroxy-indenoindoles 9 and the subsequent deoxygenation reaction with N,N,N′,N′-tetramethylsulfurous diamide (4), which gave the partially unsaturated indenoindoles 10.

Access to the 3-aminocyclohex-2-enones 7A1-7E2 (Table  [¹] ) was achieved according to published procedures by refluxing cyclohexane-1,3-diones 6 with primary amines in benzene and removal of water as an azeotrope with a Dean-Stark water trap; [¹7] for 7A1, 7A2, 7B1, and 7C1, (R^¹ = H, Me) ammonia or methylamine, respectively, was passed through the boiling solution of the cyclohexane-1,3-dione 6. Compound 7B10 was synthesized by mixing equimolar amounts of cyclohexane-1,3-dione (6B1), glycine methyl ester hydrochloride, and triethyl­amine. The heterocyclic enaminone 7F1 (X = N) was prepared from the analogous piperidine-3,5-dione according to published procedures. [¹8] The reaction products 7 were isolated in good to excellent yields. Most of the enaminones were of sufficient purity to use without further purification.

To prepare the vic-dihydroxy-indenoindoles 9, a solution of equimolar amounts of the corresponding enaminones 7 and 1 in an appropriate solvent were stirred at ambient temperature. The reaction was monitored by TLC and terminated when the substrates had disappeared. Furthermore TLC showed, that only one compound was produced (Table  [²] ). Spectroscopic data (^¹H NMR and ^¹³C NMR, Table  [³] ) revealed that this was a cyclization product with two ^¹H resonances due to OH functionalities, corresponding to the ^¹³C resonances in the range of δ = 83-84 and 93-96. However an unambiguous assignment, which of the two isomeric vic-dihydroxy-indenoindolones 8 or 9 had been produced, could not be made. Therefore, the reaction product of 7B1 and 1 was studied by X-ray diffraction analysis, which clearly confirmed the structure of the 4b,9b-dihydroxy-4b,5,6,7,8,9b-hexahydroindeno[1,2-b]indole-9,10-dione (9B1) (Figure  [¹] ). ^¹H NMR spectra and ^¹³C NMR spectra of 9B9, 9C, 9D, and 9E show a dual set of signals, indicating that mixtures of two diastereomers were obtained.

The deoxygenation of 9 was performed according to a procedure that we have recently published. [4] To a solution of 9 in N,N-dimethylformamide, acetic acid, and 4 were added and the mixture was stirred for 3-8 hours. Immediately after the addition the temperature rose to 30-40 ˚C and the color of the mixture turned red. The products 10 could be isolated by the usual procedures in good to excellent yields (Table  [4] ). Structural proof was obtained from spectroscopic data (^¹H NMR, ^¹³C NMR, IR, MS, Table  [5] ), elemental analysis, and X-ray diffraction analysis of 10B5 (Figure  [²] ). The shielding effect of the N-phenyl ring in 9/10A4, 9/10B19, 9/10D3, 9/10C4, and 9/10E4 respectively accounts for a significant high field shift of H4 to δ = 6.5-6.75 in their ^¹H NMR spectra.

Hydrolysis and decarboxylation of 6C gave 6E (Scheme  [³] , steps i-iv, route A) in only moderate yields, hence an alternative route B for the preparation of 10E may be more efficient with respect to higher overall yields. Route B (Scheme  [³] , step v-viii) starting with aminolysis of 6C to 7C proceeds in a similar sequence to 10C, which gave 10E by hydrolysis and decarboxylation (Scheme  [³] , step viii). In our hands the synthesis of 10E2 via route B with 38% gave somewhat higher yields than via route A with 31%.

In conclusion, we have found that the reaction of indane-1,2,3-trione monohydrate (1) with cyclic enaminones 7 yields vic-dihydroxy-indeno[1,2-b]indoles 9. The vic-deoxygenation of 9 with N,N,N′,N′-tetramethylsulfurous diamide (4) provides an efficient and facile procedure for the synthesis of partially saturated indeno[1,2-b]indoles 10.

Melting points: Büchi melting point apparatus by Dr. Tottoli, not corrected. IR spectra: Perkin Elmer 177 and FT-IR 1600, using KBr discs. ^¹H NMR spectra and ^¹³C NMR spectra: Varian FT 80 (80 MHz/20 MHz), Bruker AC 200F (200 MHz/50 MHz) in the designated solvents with TMS as an internal standard; signals, labeled by * exchanged by addition of D₂O. MS (EI) spectra: Finnigan 4200 quadrupole mass-spectrometer, equipped with a MASPEC datasystem; 70 eV ionizing potential. Microanalyses: Perkin Elmer Elemental Analyzer 2400/II. MPLC or flash chromatography was performed on 230-400 mesh silica (Merck). Solvents were purified by standard methods and dried over molecular sieves or sodium. N,N,N′,N′-Tetramethylsulfurous diamide (4) was prepared according to the literature. [¹9] Yields refer to products after one crystallization and are not optimized.

3-Aminocyclohex-2-enones 7; General Procedure

Method A: A soln containing equimolar quantities of a primary amine and a cyclohexane-1,3-dione 6 in benzene was refluxed at a Dean-Stark trap until the separation of H₂O had finished (ca. 3 h). The solvent was removed in vacuo and the residual solid or viscous oil was triturated (EtOAc) to give 7 as a crystalline solid.

Method B: A soln of a cyclohexane-1,3-dione 6 was refluxed in a Dean-Stark trap and NH₃ or MeNH₂, respectively was passed through until the separation of H₂O had finished (ca. 3 h). The solvent was removed in vacuo and the residual solid or viscous oil was triturated (EtOAc) to give 7A1, 7A2, 7B1, 7C1, 7D1, respectively, as crystalline solids.

4b,9b-Dihydroxy-4b,5,6,7,8,9b-hexahydroindeno[1,2- b ]indole-9,10-diones 9; General Procedure

Equimolar amounts of enaminone 7 (0.05 mol) and 1 (8.91 g, 0.05 mol) were dissolved in CHCl₃ or MeOH (100 mL) and stirred at r.t. The solvent was evaporated in vacuo at max. 60 ˚C. The residue was triturated (acetone-H₂O or EtOAc) to yield a white solid that was isolated by suction. A second quantity was received from the filtrate.

5,6,7,8-Tetrahydroindeno[1,2- b ]indole-9,10-diones 10; General Procedures

Method C: 9 (5 mmol) was dissolved in DMF (15 mL) and AcOH (3 mL) was added. After addition of 4 (2.72 g, 20 mmol), the soln was stirred for 12 h. A precipitate had deposited that was separated by suction. The filtrate was evaporated in vacuo, the viscous residue was diluted with H₂O, and the soln was basified with NaHCO₃. Extraction with CHCl₃ gave a second quantity, which was purified by MPLC (silica gel, EtOAc-hexane or CHCl₃-EtOAc).

Method D: 9 (5 mmol) was dissolved in DMF (15 mL) and AcOH (3 mL) was added. After addition of 4 (2.72 g, 20 mmol), the soln was stirred for 12 h. The soln was then poured into H₂O (500 mL). The suspension was stirred for 3 h and the solid separated by filtration. The solid was air dried and crystallized. The filtrate was evaporated to a small volume and worked up as described under method C.

Method E: 10C (3.51 g, 0.01 mol) was suspended in 5% aq NaOH (100 mL) and refluxed for 36 h. The soln was then neutralized with 10% aq H₂SO₄. The precipitate was separated, washed with H₂O (3 × 20 mL), suspended in 5% aq H₂SO₄ (30 mL), and refluxed for 24 h. The solid was separated, washed with H₂O, air dried, and crystallized to give 10E.

Method F: (One-pot synthesis) Equimolar amounts of 1 (0.89 g, 5 mmol) and 7 (5 mmol) were dissolved in CHCl₃ (50 mL) and stirred at r.t. for 12 h. The solvent was then evaporated in vacuo and the residue dissolved in DMF (15 mL). To the soln AcOH (3 mL) and 4 (2.72 g, 20 mmol) were added and the mixture stirred for 12 h. The mixture was then worked up as described in method D to give 10.

Crystal Data [¹9]

9B1: C₁₆H₁₇NO₅, M _w  = 303.31, monoclinic, P2₁/c, a = 10.571(7) Å, b = 10.740(9) Å, c = 13.639(14) Å, γ = 111.12(7)˚, V = 1444(2) Å^³, Z = 4, D _calcd = 1.395 g˙cm^-³, MoKα radiation (λ = 0.71073 Å), 8.24˚ < 2θ < 50.00˚ (17071 measured reflections), intensity data were collected at 295(2) K with a STOE CCD diffractometer employing ω scans. The structure was solved by direct methods, [²0] all non-hydrogen atoms were refined using anisotropic displacement parameters. Including the hydrogen atoms in the latest stages of the refinement the model converged to R ₁ = 0.0618 [I >2σ(I)], wR ₂ = 0.1238 based on 2535 unique reflections (99.3% completeness). [²¹]

10B5: C₁₈H₁₇NO₂, M _w  = 279.33, monoclinic, P2₁/a, a = 9.667(5) Å, b = 9.120(4) Å, c = 15.890(8) Å, γ = 100.92(6)˚, V = 1375.6(12) Å^³, Z = 4, D _calcd = 1.349 g˙cm^-³, MoKα radiation (λ = 0.71073 Å), 6.2˚ < 2θ < 25.0˚ (14245 measured reflections), intensity data were collected at 295(2) K with a STOE IPDS1 diffractometer employing ω scans. The structure was solved by direct methods, [²0] all non-hydrogen atoms were refined using anisotropic displacement parameters. Including the hydrogen atoms in the latest stages of the refinement the model converged to R ₁ = 0.0369 [I >2σ(I)], wR ₂ = 0.0626 based on 2296 unique reflections (94.8% completeness). [²¹]

References

• 2 Hemmerling H.-J. Janoschka M. Wunderlich H. Z. Naturforsch.  1993,  48b:  1094 
  Search in Google Scholar
• 3 Dorlars A. In Houben-Weyl   4th ed., Vol. 11/2:  Georg Thieme Verlag; Stuttgart: 1958.  p.737 
  Search in Google Scholar
• 4 Hemmerling H.-J. Merschenz-Quack A. Wunderlich H. Z. Naturforsch.  2004,  59b:  1143 
  Search in Google Scholar
• 5 Chatterjie N. Shapiro R. Quo S.-G. Stephani RA. Tetrahedron Lett.  1975,  16:  2535 
  CrossrefSearch in Google Scholar
• 6a Greenhill JV. Chem. Soc. Rev.  1977,  277 
• 6b Kuckländer U. In The Chemistry of Enamines   Rappoport Z. John Wiley & Sons; Chichester: 1994.  p.523 
• 6c Lue P. Greenhill JV. Adv. Heterocycl. Chem.  1997,  67:  207 
  Search in Google Scholar
• 7a McCaldin DJ. Chem. Rev.  1960,  60:  39 
  Search in Google Scholar
• 7b Schönberg A. Singer E. Tetrahedron  1978,  34:  1285 
  Search in Google Scholar
• 8a Brown DW. Graupner PR. Sainsbury M. Shertzer HG. Tetrahedron  1991,  47:  4383 
  Search in Google Scholar
• 9a Butera JA. Antane SA. Hirth B. Lennox JR. Sheldon JH. Norton NW. Warga D. Argentieri TM. Bioorg. Med. Chem. Lett.  2001,  11:  2093 
  Search in Google Scholar
• 9b Antane SA, Butera JA, and Lennox JR. inventors; US  2001047026. 
• 10a Bal Ch. Baldeyrou B. Moz F. Lansiaux A. Colson P. Kraus-Berthier L. Léonce S. Pierre A. Boussard M. Rousseau A. Wierzbicki M. Bailly Ch. Biochem. Pharmacol.  2004,  68:  1911 
  Search in Google Scholar
• 10b Wierzbicki M, Boussard M.-F, Rousseau A, Boutin A, and Delagrange P. inventors; EP  1245565. 
• 11 Miller CP, Collini MD, and Tran BD. inventors; US  6107292. 
• 12a

  Hemmerling H.-J., Götz C., Jose J.; Annual Meeting of the German Pharmaceutical Society (DPhG), Marburg 2006, Poster P32.
• 12b Hemmerling H.-J, Götz C, and Jose J. inventors; EP  2007/008624.  ; WO 2008040547, 2008
• 13 Robinson B. The Fischer Indole Synthesis   John Wiley & Sons; Chichester: 1982. 
• 14a Graham J. Ninan A. Reza K. Sainsbury M. Shertzer HG. Tetrahedron  1992,  48:  167 
  Search in Google Scholar
• 14b Brown DW. Mahon MF. Ninan A. Sainsbury M. Shertzer HG. Tetrahedron  1993,  49:  8919 
  Search in Google Scholar
• 14c Wang J.-B. Ji Q.-G. Xu J. Wu X.-H. Xie Y.-Y. Synth. Commun.  2005,  35:  581 
  Search in Google Scholar
• 15a Estevez JC. Estevez RJ. Castedo L. Tetrahedron Lett.  1993,  34:  6479 
  Search in Google Scholar
• 15b Reboredo FJ. Treus M. Estévez JC. Castedo L. Estévez RJ. Synlett  2002,  999 
• 16a Shapiro R. Chatterjie NJ. J. Org. Chem.  1970,  35:  447 
  Search in Google Scholar
• 16b Bullington JL. Dodd JH. J. Org. Chem.  1993,  58:  4833 
  Search in Google Scholar
• 16c Black DStC. Bowyer MC. Condie GC. Craig DC. Kumar N. Tetrahedron  1994,  50:  10983 
  Search in Google Scholar
• 17a Edafiogho IO. Hinko CN. Chang H. Moore JA. Mulzac D. Nicholson JM. Scott KR. J. Med. Chem.  1992,  35:  2798 
  Search in Google Scholar
• 17b Scott KR. Edafiogho IO. Richardson EL. Farrar VA. Moore JA. Tietz EI. Hinko CN. El-Assadi A. Nicholson JM. J. Med. Chem.  1993,  36:  1947 
  Search in Google Scholar
• 17c Greenhill JV. Chaaban I. Steel PJ. J. Heterocycl. Chem.  1992,  29:  1375 
  Search in Google Scholar
• 17d Kesten SJ. Degnan MJ. Hung J. McNamara DJ. Ortwine DF. Uhlendorf SE. Werbel LM. J. Med. Chem.  1992,  35:  3429 
  Search in Google Scholar
• 18a King JA. McMillan FH. J. Am. Chem. Soc.  1950,  72:  1238 
  Search in Google Scholar
• 18b Ziegler FE. Bennett GB. J. Am. Chem. Soc.  1973,  95:  7458 
  Search in Google Scholar

Present address: Dr. Hans-J. Hemmerling, Großes Feld 21, 40822 Mettmann, Germany.

Scattering factors, dispersion corrections and absorption coefficients were taken from International Tables for Crystallography (1992, Vol. C). Crystallographic data for the structures reported in this paper have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication No. CCDC 694526 (9B1) and CCDC 694527 (10B5). Copies of the data can be obtained, free of charge, on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [fax: +44(1223)336033; or
e-mail: deposit@ccdc.cam.ac.uk].

SHELXS-86: Sheldrick, G. M., Universität Göttingen, 1985.

SHELXL-97: Sheldrick, G. M., Universität Göttingen, 1997.

References

• 2 Hemmerling H.-J. Janoschka M. Wunderlich H. Z. Naturforsch.  1993,  48b:  1094 
  Search in Google Scholar
• 3 Dorlars A. In Houben-Weyl   4th ed., Vol. 11/2:  Georg Thieme Verlag; Stuttgart: 1958.  p.737 
  Search in Google Scholar
• 4 Hemmerling H.-J. Merschenz-Quack A. Wunderlich H. Z. Naturforsch.  2004,  59b:  1143 
  Search in Google Scholar
• 5 Chatterjie N. Shapiro R. Quo S.-G. Stephani RA. Tetrahedron Lett.  1975,  16:  2535 
  CrossrefSearch in Google Scholar
• 6a Greenhill JV. Chem. Soc. Rev.  1977,  277 
• 6b Kuckländer U. In The Chemistry of Enamines   Rappoport Z. John Wiley & Sons; Chichester: 1994.  p.523 
• 6c Lue P. Greenhill JV. Adv. Heterocycl. Chem.  1997,  67:  207 
  Search in Google Scholar
• 7a McCaldin DJ. Chem. Rev.  1960,  60:  39 
  Search in Google Scholar
• 7b Schönberg A. Singer E. Tetrahedron  1978,  34:  1285 
  Search in Google Scholar
• 8a Brown DW. Graupner PR. Sainsbury M. Shertzer HG. Tetrahedron  1991,  47:  4383 
  Search in Google Scholar
• 9a Butera JA. Antane SA. Hirth B. Lennox JR. Sheldon JH. Norton NW. Warga D. Argentieri TM. Bioorg. Med. Chem. Lett.  2001,  11:  2093 
  Search in Google Scholar
• 9b Antane SA, Butera JA, and Lennox JR. inventors; US  2001047026. 
• 10a Bal Ch. Baldeyrou B. Moz F. Lansiaux A. Colson P. Kraus-Berthier L. Léonce S. Pierre A. Boussard M. Rousseau A. Wierzbicki M. Bailly Ch. Biochem. Pharmacol.  2004,  68:  1911 
  Search in Google Scholar
• 10b Wierzbicki M, Boussard M.-F, Rousseau A, Boutin A, and Delagrange P. inventors; EP  1245565. 
• 11 Miller CP, Collini MD, and Tran BD. inventors; US  6107292. 
• 12a

  Hemmerling H.-J., Götz C., Jose J.; Annual Meeting of the German Pharmaceutical Society (DPhG), Marburg 2006, Poster P32.
• 12b Hemmerling H.-J, Götz C, and Jose J. inventors; EP  2007/008624.  ; WO 2008040547, 2008
• 13 Robinson B. The Fischer Indole Synthesis   John Wiley & Sons; Chichester: 1982. 
• 14a Graham J. Ninan A. Reza K. Sainsbury M. Shertzer HG. Tetrahedron  1992,  48:  167 
  Search in Google Scholar
• 14b Brown DW. Mahon MF. Ninan A. Sainsbury M. Shertzer HG. Tetrahedron  1993,  49:  8919 
  Search in Google Scholar
• 14c Wang J.-B. Ji Q.-G. Xu J. Wu X.-H. Xie Y.-Y. Synth. Commun.  2005,  35:  581 
  Search in Google Scholar
• 15a Estevez JC. Estevez RJ. Castedo L. Tetrahedron Lett.  1993,  34:  6479 
  Search in Google Scholar
• 15b Reboredo FJ. Treus M. Estévez JC. Castedo L. Estévez RJ. Synlett  2002,  999 
• 16a Shapiro R. Chatterjie NJ. J. Org. Chem.  1970,  35:  447 
  Search in Google Scholar
• 16b Bullington JL. Dodd JH. J. Org. Chem.  1993,  58:  4833 
  Search in Google Scholar
• 16c Black DStC. Bowyer MC. Condie GC. Craig DC. Kumar N. Tetrahedron  1994,  50:  10983 
  Search in Google Scholar
• 17a Edafiogho IO. Hinko CN. Chang H. Moore JA. Mulzac D. Nicholson JM. Scott KR. J. Med. Chem.  1992,  35:  2798 
  Search in Google Scholar
• 17b Scott KR. Edafiogho IO. Richardson EL. Farrar VA. Moore JA. Tietz EI. Hinko CN. El-Assadi A. Nicholson JM. J. Med. Chem.  1993,  36:  1947 
  Search in Google Scholar
• 17c Greenhill JV. Chaaban I. Steel PJ. J. Heterocycl. Chem.  1992,  29:  1375 
  Search in Google Scholar
• 17d Kesten SJ. Degnan MJ. Hung J. McNamara DJ. Ortwine DF. Uhlendorf SE. Werbel LM. J. Med. Chem.  1992,  35:  3429 
  Search in Google Scholar
• 18a King JA. McMillan FH. J. Am. Chem. Soc.  1950,  72:  1238 
  Search in Google Scholar
• 18b Ziegler FE. Bennett GB. J. Am. Chem. Soc.  1973,  95:  7458 
  Search in Google Scholar

Present address: Dr. Hans-J. Hemmerling, Großes Feld 21, 40822 Mettmann, Germany.

Scattering factors, dispersion corrections and absorption coefficients were taken from International Tables for Crystallography (1992, Vol. C). Crystallographic data for the structures reported in this paper have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication No. CCDC 694526 (9B1) and CCDC 694527 (10B5). Copies of the data can be obtained, free of charge, on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [fax: +44(1223)336033; or
e-mail: deposit@ccdc.cam.ac.uk].

SHELXS-86: Sheldrick, G. M., Universität Göttingen, 1985.

SHELXL-97: Sheldrick, G. M., Universität Göttingen, 1997.