Unexpected synthesis of azepino[4,3,2-cd]indoles from 4-aminoindoles

Article abstract of DOI:10.1016/j.tetlet.2017.02.049

Unexpected regioselectivity for the Skraup-Doebner-Von Miller reaction was observed during the synthesis of quinolines from 4-aminoindoles and acetone in the presence of hydrochloric acid as a catalyst. The products were unambiguously assigned as 1-alkyl-

Full text of DOI:10.1016/j.tetlet.2017.02.049

Accepted Manuscript
Unexpected synthesis of azepino[4,3,2-cd]indoles from 4-aminoindoles
Olexandr Halaiev, Myroslav Garazd, Andrzej Gzella, Roman Lesyk
PII:
S0040-4039(17)30226-5
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.02.049
TETL 48660
Reference:
Tetrahedron Letters
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Revised Date:
Accepted Date:
10 January 2017
11 February 2017
15 February 2017
Please cite this article as: Halaiev, O., Garazd, M., Gzella, A., Lesyk, R., Unexpected synthesis of azepino[4,3,2-
cd]indoles from 4-aminoindoles, Tetrahedron Letters (2017), doi: http://dx.doi.org/10.1016/j.tetlet.2017.02.049
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Unexpected synthesis of azepino[4,3,2-cd]indoles from 4-aminoindoles
Olexandr Halaieva, Myroslav Garazda, Andrzej Gzellab, Roman Lesykc,*
a Eximed, Kharkivske shose 50, Kyiv 02160, Ukraine
b Department of Organic Chemistry, Poznan University of Medical Sciences,
Grunwaldzka 6, Poznan, 60-780, Poland
c Department of Pharmaceutical, Organic and Bioorganic Chemistry, Danylo
Halytsky Lviv National Medical University, Pekarska 69, Lviv 79010, Ukraine
* Corresponding author. Tel.: +38 032 2757734;
E-mail: dr_r_lesyk@org.lviv.net, roman.lesyk@gmail.com (Roman Lesyk)

Abstract
Unexpected regioselectivity for the Skraup-Doebner-Von Miller reaction was
observed during the synthesis of quinolines from 4-aminoindoles and acetone in the
presence of hydrochloric acid as a catalyst. The products were unambiguously
assigned as 1-alkyl-3,5,5-trimethyl-5,6-dihydro-1H-azepino[4,3,2-cd]indoles instead
of 2,2,4-trimethyl-2,7-dihydro-1H-pyrrolo[2,3-h]quinolones based on NMR
spectroscopy and X-ray crystallographic analysis.
Keywords: indoles, 4-aminoindoles, azepino[4,3,2-cd]indoles, Skraup-Doebner-Von
Miller synthesis
Introduction
The indole motif is arguably one of the most significant heterocycles since they
are found in numerous natural products and bioactive molecules.1,2 Among naturally
occurring indole alkaloids, 3,4-fused indoles (in which position 3 of the indole is
bridged to position 4) have been considered as attractive synthetic targets due to their
biological activities3 and challenging synthesis. Various strategies have been
developed for the construction of 3,4-fused tricyclic indoles. For example, 3,4,5,6-
tetrahydro-1H-azepino[4,3,2-cd]indole was synthesized in seven steps from 4-
nitroindole.4-6 Substituted azepino[4,3,2-cd]indoles have also been obtained via an
intramolecular Larock indolization reaction,7 substitution of cyclic Baylis–Hillman
adducts with indoles,8,9 and the three-component condensation reaction of isatins,
indol-4-amines, and Meldrum’s acid.10 Notably, a series of novel 3,4,5,6-tetrahydro-
1H-azepino[4,3,2-cd]indoles have been identified as selective V2 receptor
antagonists.11
Herein, we report an efficient synthetic approach to novel 1-alkyl-3,5,5-
trimethyl-5,6-dihydro-1H-azepino[4,3,2-cd]indoles using the Skraup-Doebner-Von
Miller reaction conditions.
Results and discussion

Starting 4-nitroindole 1 was alkylated to give 1-substituted 4-nitroindoles 2−612-
14
using the corresponding alkyl halides and NaH in DMF at room temperature.15-17
Treatment of compounds 2−6 under Bechamp reduction conditions resulted in the
formation of 4-aminoindoles 7−11 in excellent yields. 4-Aminoindoles have been
widely used for the synthesis of polycyclic systems including 2-
phenylpyrroloquinolin-4-ones,17,18 pyrrolo[3,2-a]phenazines19 and pyroloquinolines.20
However, in these cases intramolecular cyclization was performed via the indole С-5
position. The Skraup-Doebner-Von Miller quinoline synthesis reaction21 of 4-
aminoindoles 7−11 with acetone in the presence of conc. hydrochloric acid as a
catalyst was examined by heating at reflux for 4 h. To our surprise, 3,5,5-trimethyl-
5,6-dihydro-1H-azepino[4,3,2-cd]indoles 12−16 were obtained instead of the expected
2,2,4-trimethyl-2,7-dihydro-1H-pyrrolo[2,3-h]quinolines 17.22
Scheme 1. Synthesis of azepino[4,3,2-cd]indoles 12-16. Reagents and conditions: (a)
1 (50 mmol), NaH (50 mmol), R-Hal (55 mmol), DMF (50 mL), 4 h, r.t., 84–95%;
(b) 2–6 (40 mmol), Fe (60 mmol), conc. HCl (5 mL), EtOH (100 mL), reflux, 1 h,
81–93%; (c) 7–11 (4 mmol), acetone (5 mL), conc. HCl (1 mL), reflux, 4 h, 76–91%.

The structures of azepino[4,3,2-cd]indoles 12−16 were confirmed by NMR
1
spectral data and single crystal X-ray analysis. The H NMR spectra showed the
characteristic sequence of four aromatic 3,4-fused indole protons (H-2, H-5, H-6 and
13
H-7), while the 1H NMR and C NMR spectra also showed typical signals for an
annulated 2,2,4-trimethyl-1,2-dihydropyridine type ring (ESI).
In our opinion, the reaction pathway initially proceeds via the acid catalysed self
aldol condensation of acetone to give α,β-unsaturated ketone 18, followed by Michael
addition of 4-aminoindole to yield aryl amino ketone 19. Subsequent intramolecular
cyclization leads to compound 20, which after acid catalysed dehydration yields the
target 3,5,5-trimethyl-5,6-dihydro-1H-azepino[4,3,2-cd]indole derivatives 12−16
(Scheme 2).
3
3
3
3
3
3
3
3
3
3
3
3
3
3
Scheme 2. Plausible pathway for the formation of 5,6-dihydro-1H-azepino[4,3,2-
cd]indoles 12−16 .
The structure of compound 13 was confirmed by single crystal X-ray
crystallography (Fig. 1, ESI, Fig. S1 and Tables S1–S3).23 Two symmetry-
independent molecules form the asymmetric part of the unit cell. The C10−C11 bond
lengths (1.333(2) Å and 1.344(3)/1.332(8) Å) in the two independent molecules
confirms the presence of a double bond between these atoms (ESI, Fig. S1).

Figure 1. ORTEP view of one of the two symmetry independent molecules of 13
showing the atomic labeling scheme.
Conclusion
In summary, we have developed an efficient procedure for the synthesis of 5,6-
dihydro-1H-azepino[4,3,2-cd]indole derivatives via the Skraup-Doebner-Von Miller
quinoline synthesis reaction conditions.
Supplementary data
Analytical and spectral data for the synthesized compounds as well as single
crystal X-ray data for compound 13.
References and notes
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Molecules 2013; 18, 6620-6662.
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8. Shafiq Z, Qiao Z, Liu L, Zheng Q-Y, Wang D, Chen Y-J. Synlett 2009; 18:
2965-2969..
9. Shafiq Z, Liu L, Liu Z, Wang D, Chen Y-J. Org. Lett. 2007; 9: 2525-2528.
10.Zou B, Chen C, Leong SY, Ding M, Smith PW. Tetrahedron 2014; 70: 578-
582.
11.Matthews JM, Greco MN, Hecker LR, Hoekstra WJ, Andrade-Gordon P, de
Garavilla L, Demarest KT, Ericson E, Gunnet JW, Hageman W, Look R,
Moore JB, Maryanoff BE. Bioorg. Med. Chem. Lett. 2003; 13: 753-756.
12.Bergman J, Sand P. Tetrahedron Lett. 1987; 25: 1957-1960.
13.Bergman J, Sand P. Tetrahedron 1990; 46: 6085-6112.
14.Bergman J, Norrby P-O, Sand P. Tetrahedron 1990; 46: 6113-6124.
15.Somei M, Tsuchiya M. Chem. Pharm. Bull. 1981; 29: 3145-3157.
16.Ple PA, Green TP, Hennequin LF, Curwen J, Fennell M, Allen J, Lambert-van
Der Brempt C, Costello G. J. Med. Chem. 2004; 47: 871-887.
17.Ferlin MG, Conconi MT, Urbani L, Oselladore B, Guidolin D, Di Liddo R,
Parnigotto PP. Bioorg. Med. Chem. 2011; 19: 448-457.
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G, Castagliuolo I. J. Med. Chem. 2005; 48: 3417-3427.
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Mistry P, Vicker N, Charlton PA, Denny WA. J. Med. Chem. 2002; 45: 740-
743.
20.Zhang Z., Tillekeratne LMV, Hudson RA. Synthesis 1996; 3: 377-382.
21.Denmark SE, Venkatraman S. J. Org. Chem. 2006; 71: 1668-1676.
22.General procedure for the synthesis of 1-alkyl-3,5,5-trimethyl-5,6-dihydro-1H-
azepino[4,3,2-cd]indoles 12-16. Conc. HCl (1 mL) was added to a solution of
4-aminoindole 7−11 (5 mmol) in acetone (5 mL) and heated at reflux for 4 h.
Upon reaction completion (TLC), the solvent was removed under vacuum and
the reaction mixture neutralized by the addition of 3N KOH then diluted with
CH2Cl2 (10 mL). The organic phase was washed with brine (10 mL) and water
(2×10 mL), dried over magnesium sulfate and the solvent evaporated. The
crude product was purified by silica gel column chromatography using a

petroleum ether and EtOAc (9:1) as eluent. 1,3,5,5-Tetramethyl-5,6-dihydro-
1
1H-azepino[4,3,2-cd]indole (12). Grey solid, mp 108–109 ºС, yield 86%. H
NMR (300 MHz, CDCl3) δ 7.02 (t, 1H, J = 7.8 Hz, H-8), 6.85 (s, 1H, H-2),
6.72 (d, 1H, J = 8.1 Hz, H-7), 6.28 (d, 1H, J = 7.5 Hz, H-9), 5.43 (s, 1H, H-4),
13
3.68 (s, 3H, CH3-1), 2.06 (s, 3H, CH3-3), 1.37 (s, 6H, CH3-5). C NMR (100
MHz, DMSO-d6) δ 143.26, 137.94, 129.93, 127.82, 124.23, 122.80, 115.49,
115.44, 104.87, 99.09, 53.09, 32.49, 30.35, 21.74. LC−MS calculated for
C15H18N2 [M + H]+ 227.32, found 227.1 (100%). Calcd. for C15H18N2: C,
79.61; H, 8.02; N, 12.38; Found: C, 79.90; H, 8.20; N, 12.50%.
23.Crystallographic data for 13: Empirical formula: C17H22N2, formula weight:
508.73, colourless block crystals, crystal system: monoclinic, space group:
P21/n, a = 8.98861(10), b = 7.86603(8), c = 19.4785(2) Å, β= 99.1695(10)°, V
= 2902.47(4) Å3, Z = 8 (Z’ = 2), Dcalc = 1.580 g/cm3. A colourless crystal
(CH3OH) (0.20 x 0.12 x 0.06 mm) was used to record 36589 (CuKα-radiation,
θ
max
= 76.5°) intensities on a SuperNova Dual A diffractometer. The
supplementary crystallographic data of 13 have been deposited at the
Cambridge Crystallography Data Centre (CCDC) as supplementary publication
CCDC 1523501. Copies of the data can be obtained, free of charge, on
application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK, (fax: +44-
(0)1223-336033 or e-mail: deposit@ccdc.cam.ac.uk).

Graphical abstract

Highlights for “Unexpected synthesis of azepino[4,3,2-cd]indoles from 4-aminoindoles”
by Olexandr Halaiev, Myroslav Garazd, Andrzej Gzella, Roman Lesyk
ꢀ 4-Aminoindoles were utilized for the synthesis of azepino[4,3,2-cd]indoles.
ꢀ Regioselective Skraup-Doebner-Von Miller reaction conditions were used.
ꢀ 5 examples in up to 76% yield.