Regiocontrolled annellation reactions starting from diethoxymethyl protected indole

Article abstract of DOI:10.1055/s-2000-6329

Directed metallation of the diethoxymethyl protected indole 4 followed by treatment with β-nitrostyrene leads to the 1,2- disubstituted indole 5. Using 5 as a central intermediate, the tricyclic annellation products of type 2 and 3 were accessed when the regiochemical outcome of the reactions could be controlled.

Full text of DOI:10.1055/s-2000-6329

SHORT PAPER
1081
Regiocontrolled Annellation Reactions Starting from Diethoxymethyl
Protected Indole
Johannes Kraxner, Peter Gmeiner*
Department of Medicinal Chemistry, Emil Fischer Center, Friedrich-Alexander University, Schuhstraße 19, D-91052 Erlangen, Germany
Fax +49(9131)8522585; E-mail: gmeiner@pharmazie.uni-erlangen.de
Received 14 February 2000; revised 21 March 2000
Abstract: Directed metallation of the diethoxymethyl protected in-
dole 4 followed by treatment with b-nitrostyrene leads to the 1,2-
disubstituted indole 5. Using 5 as a central intermediate, the tricy-
clic annellation products of type 2 and 3 were accessed when the re-
giochemical outcome of the reactions could be controlled.
Key words: indoles, metallation, rearrangements
The selection of protecting groups preventing or modify-
ing functional group transformations during a reaction se-
quence is crucial to the success of chemical syntheses.1
7.74 ppm giving complete H/D exchange and a diagnostic
Our interest was directed to the investigation of di-
absorption at 3400 cm-1 indicated the indole NH function.
ethoxymethyl (DEM) for the nitrogen protection of lac-
It is worthy to note, that the one-pot reaction sequence in-
tams, amides and indoles.2 Due to the simple introduction
volving reduction of the nitro group, ring closure reaction
of DEM, its stability towards various reaction conditions
to give a cyclic imine, further reduction and, finally, rear-
and its ability to act as a N-directed metallation group the
rangement yielded 89% of pure product. Migration reac-
use of DEM turned out as an advantageous synthetic tool
tions of this type have been reported in the literature,
for the preparation of regioselectively substituted indoli-
when a retro-Mannich type reaction leading to an iminium
nones 3 and indoles. Very recently, we developed a trace-
intermediate is reasonably assumed.6
less linkage route based on DEM protected indoles and
In order to isolate synthetic intermediates including the
tetrahydropyrimido[1,6-a]indole 2 which we initially se-
demonstrated the practical utility of this methodology for
the solid phase synthesis of 2- or 3-substituted indole de-
rivatives.4
Besides the above-mentioned talents, the DEM group
should also be able to serve as a C-1 building block. Start-
ing from DEM protected indole; our intention was to in-
corporate DEM into a fused ring system. Thus, we
attempted to approach to pyrimido[1,6-a]indole deriva-
tives, which can be considered as regioisomers and syn-
thetic
precursors
of
antipsychotically
active
g-carbolines.5,6
As a part of our ongoing efforts to design selective
dopamine receptor ligands7 we envisaged the preparation
of the phenyl substituted tetrahydropyrimido[1,6-a]indole
2 and the tetrahydro-g-carboline 3 which can be seen as
heterocyclic analogs8 of the selective D1 receptor agonist
3’,4’-dihydroxynomifensine 1.9
In practice, directed metallation of the diethoxymethyl
protected indole 4 by t-BuLi and subsequent trapping of
the corresponding indole lithium intermediate by b-ni-
trostyrene provided the Michael addition product 5
(Scheme). Interestingly, treatment of 5 with zinc dust in a
mixture of aqueous HCl and THF afforded the rearranged
g-carboline derivative 3, exclusively.8 The analytical data
of the rearranged product 3 clearly indicate the rearranged
ring system. In detail, the structure was elucidated by 1H
NMR and IR spectroscopy when a diagnostic signal at d =
Reagents and conditions: (a) 1. t-BuLi (1.1 equiv), THF, 0 °C, 15
min., then r.t. 0.5 h; 2. b-nitrostyrene (1.0 equiv), -78 °C, 1 h (46%);
(b) Zn (10 equiv), 2N HCl/THF, reflux, 1 h (89%); (c) H2, Pd/C, Me-
OH, r.t., 16 h (41%); (d) p-TsOH, toluene, r.t. 16 h (84%), (e) NaBH4
(7.5 equiv), r.t., MeOH, 14 h (92%); (f) HOAc/THF, 3 h, 60 °C (71%)
Scheme
Synthesis 2000, No. 8, 1081–1083 ISSN 0039-7881 © Thieme Stuttgart · New York

1082
J. Kraxner, P. Gmeiner
SHORT PAPER
matography (CH2Cl2/MeOH, 9:1) to give pure 3 (63 mg, 89%) as a
colorless solid (mp 119-121 °C, Lit.5b 122-124 °C).
lected as a further target compound, we tried to find mild
and chemoselective reaction conditions allowing a step by
step synthesis. Thus, the nitro function of 5 was subjected Method B: A solution of 2 (4.8 mg, 0.02 mmol) in THF (1 mL) and
HOAc (0.5 mL) was stirred at 60 °C for 3 h. After addition of 2 N
NaOH (pH 10) and EtOAc (15 mL) the organic layer was dried
(Na2SO4), evaporated and purified by flash chromatography
(CH2Cl2/MeOH, 9:1) to give pure 3 (3.4 mg, 71%).
IR (KBr): n = 3400, 3055, 2920, 1455, 745, 700 cm-1.
1H NMR (360 MHz): d = 3.05 (dd, 1H, J = 13.0, 7.0 Hz, CHCH2),
3.51 (dd, 1H, J = 13.0, 5.5 Hz, CHCH2), 4.11-4.22 (m, 3H,
ArCH2N, NCHCH2), 7.07-7.36 (m, 8H, H-arom), 7.49 (dd, 1H,
J = 6.9, 1.4 Hz, H-arom), 7.74 (br. s, 1H, NH, H/D exchange).
to catalytic hydrogenation using Pd/C to afford the prima-
ry amine 6. After purification by flash chromatography,
we treated 6 with p-toluenesulfonic acid in toluene to give
the cyclization product 7 in 84% yield. Finally, treatment
of the cyclic imine 7 with NaBH4 in methanol resulted in
formation of target compound 2 in 92% yield. Under these
smooth and non-acidic reduction conditions, rearrange-
ment to give the 2,3-substituted indole 3 could not be ob-
served. On the other hand, g-carboline formation was
observed when 2 was subjected to acidic conditions.
1-Diethoxymethyl-2-(2-nitro-1-phenylethyl)indole (5)
To a solution of 4 (370 mg, 1.7 mmol) in THF (10 mL) was added
t-BuLi (1.1 mL, 1.7 M in pentane) at 0 °C. After stirring for 15 min
at 0 °C and further 30 min at r.t., the mixture was cooled to -78 °C.
Then, a solution of b-nitrostyrene (253 mg, 1.7 mmol) in THF
(2 mL) was added. After being stirred for 1 h at -78 °C sat.
NaHCO3 (1 mL), H2O (5 mL), and EtOAc (20 mL) were added. The
organic layer was dried (Na2SO4) and evaporated and the residue
was purified by flash chromatography (petroleum ether/EtOAc,
9:1) to give pure 5 (289 mg, 46%) as a light orange solid; mp 64 °C.
In conclusion, we have developed a regiodivergent syn-
thetic route for the preparation of tricyclic indole deriva-
tives of type 2 and 3 when we employed a diethoxymethyl
function as a N-directed metallation group and, subse-
quently, as a useful C-1 building block. Investigations
concerning the potency of these compounds to act as
dopamine D1 receptor ligands are currently in progress.
IR (KBr): n = 2980, 1555, 1100, 1060, 750, 705 cm-1.
THF and toluene were distilled from Na immediately before use.
All liquid reagents were purified by distillation. Unless otherwise
noted, reactions were conducted under dry N2. Evaporations of final
product solutions were done under vacuum with a rotary evapora-
tor. Flash chromatography was carried out with silica gel (230-400
mesh). Mps: Büchi melting point apparatus, uncorrected. IR: Jasco
FT/IR-410. Mass spectroscopy: Finnigan MAT TSQ 70. High reso-
lution mass spectroscopy: Finnigan MAT 8200. NMR: Bruker AM
360. NMR spectra were measured in CDCl3 using TMS as an inter-
nal standard. Elemental analyses were performed by Beetz Mi-
croanalysis Laboratory and by the Organic Chemistry Department
of the Friedrich-Alexander University Erlangen-Nürnberg.
1H NMR (360 MHz): d = 0.98 (t, 3H, J = 7.1 Hz, CH3), 1.07 (t, 3H,
J = 7.1 Hz, CH3), 3.10 (dq, 1H, J = 9.3, 7.1 Hz, OCH2CH3), 3.18
(dq, 1H, J = 9.3, 7.1 Hz, OCH2CH3), 3.28 (dq, 1H, J = 9.3, 7.1 Hz,
OCH2CH3), 3.50 (dq, 1H, J = 9.3, 7.1 Hz, OCH2CH3), 4.83 (dd, 1H,
J = 13.1, 7.4 Hz, CHCH2), 5.08 (dd, 1H, J = 13.1, 8.6 Hz, CHCH2),
5.45-5.52 (m, 1H, CHCH2), 6.19 (s, 1H, NCH), 6.55 (s, 1H, H-3),
7.13 (td, 1H, J = 7.3, 0.9 Hz, H-arom), 7.19 (td, 1H, J = 7.7, 1.4 Hz,
H-arom), 7.24-7.31 (m, 5H, H-arom), 7.58 (t, 2H, J = 8.3 Hz, H-
arom).
MS: m/z = 368 (M+).
Anal: C21H24N2O4 (368.4): Calcd: C, 68.46; H, 6.57; N, 7.60.
Found: C, 68.50, H, 6.33; N, 7.60.
4-Phenyl-1,2,3,4-tetrahydropyrimido[1,6-a]indole (2)
A solution of 7 (13 mg, 0.04 mmol) and NaBH4 (10 mg, 0.3 mmol)
in MeOH (5 mL) was stirred at r.t. for 14 h. Then, 2 N NaOH (2 mL)
was added and the mixture was extracted with EtOAc (15 mL). The
organic layer was dried (Na2SO4) and evaporated and the residue
was purified by flash chromatography (CH2Cl2/MeOH, 95:5) to
give 2 (12 mg, 92%) as a colorless solid; mp 44 °C.
2-(1-Diethoxymetylindole-2-yl)-2-phenylethylamine (6)
A mixture of 5 (335 mg, 0.9 mmol) and Pd/C (50 mg, 10%) in
MeOH (10 mL) was stirred under H2 (1 bar) at r.t. for 16 h. The mix-
ture was filtered through Celite and the filtrate was evaporated. The
residue was purified by flash chromatography (CH2Cl2/MeOH,
95:5) to give pure 6 (125 mg, 41%) as a colorless solid; mp 58 °C.
IR (KBr): n = 3315, 3055, 2865, 1455, 740, 700 cm-1.
IR (KBr): n = 2975, 1455, 1310, 1100, 1065, 750, 700 cm-1.
1H NMR (360 MHz): d = 3.15 (dd, 1H, J = 13.7, 7.5 Hz, CHCH2),
3.47 (dd, 1H, J = 13.7, 5.5 Hz, CHCH2), 4.30 (dd, 1H, J = 7.5, 5.5
Hz, CHCH2), 5.09 (d, 1H, J = 11.5 Hz, NCH2N), 5.16 (d, 1H,
J = 11.5 Hz, NCH2N), 6.08 (s, 1H, H-3), 7.10 (td, 1H, J = 7.5, 1.1
Hz, H-arom), 7.14-7.36 (m, 7H, H-arom), 7.53 (d, 1H, J = 7.5 Hz,
H-arom).
13C NMR (90.6 MHz): d = 42.8, 50.3, 59.1, 100.1, 108.7, 119.9,
120.3, 120.9, 127.0, 127.9, 128.3, 128.6, 138.3, 142.2, 149.1.
MS: m/z = 248 (M+).
1H NMR (360 MHz): d = 0.92 (t, 3H, J = 7.1 Hz, CH3), 1.08 (t, 3H,
J = 7.1 Hz, CH3), 2.88 (dq, 1H, J = 9.3, 7.1 Hz, OCH2CH3), 2.97
(dq, 1H, J = 9.3, 7.1 Hz, OCH2CH3), 3.22 (dd, 1H, J = 12.7, 6.9 Hz,
CHCH2), 3.29 (dq, 1H, J = 9.3, 7.1 Hz, OCH2CH3), 3.42 (dd, 1H,
J = 12.7, 7.5 Hz, CHCH2), 3.56 (dq, 1H, J = 9.3, 7.1 Hz,
OCH2CH3), 4.26-4.34 (m, 1H, CHCH2), 6.08 (s, 1H, NCH), 6.55
(s, 1H, H-3), 7.08-7.32 (m, 7H, H-arom), 7.58 (dd, 1H, J = 7.2, 1.3
Hz, H-arom), 7.71 (dd, 1H, J = 7.9, 1.4 Hz, H-arom).
MS: m/z = 338 (M+).
Anal: C17H16N2 (248.3): Calcd: C, 82.22; H, 6.49; N, 11.28. Found:
C, 82.25; H, 6.50; N, 11.06.
Anal: C21H26N2O2 (338.5): Calcd: C, 74.53; H, 7.74; N, 8.28.
Found: C, 74.57; H, 7.67, N, 8.25.
4-Phenyl-2,3,4,5-tetrahydrpyrido[4,3-b]indole (3)
4-Phenyl-3,4-dihydropyrimido[1,6-a]indole (7)
Method A: A mixture of 5 (105 mg, 0.3 mmol), zinc dust (0.2 g, 3
mmol) and 2 N HCl (2 mL) in THF (15 mL) was refluxed for 1 h.
After filtration, 2 N NaOH was added (pH 10) and the mixture was
extracted with EtOAc (30 mL). The organic layer was dried
(Na2SO4) and evaporated and the residue was purified by flash chro-
A solution of 6 (51 mg, 0.15 mmol) and p-toluenesulfonic acid
(10 mg, 0.05 mmol) in toluene (10 mL) was stirred at r.t. for 16h.
Then 2 N NaOH (1 mL) and H2O (3 mL) were added and the mix-
ture was extracted with EtOAc (15 mL). The organic layer was
dried (Na2SO4) and evaporated and the residue was purified by flash
Synthesis 2000, No. 8, 1081–1083 ISSN 0039-7881 © Thieme Stuttgart · New York

SHORT PAPER
Regiocontrolled Annellation Reactions Starting from Diethoxymethyl Protected Indole
1083
chromatography (CH2Cl2/MeOH, 95:5) to give pure 7 (31 mg, 84%)
(5) (a) Harbert, C. A.; Plattner, J. J.; Welch, W. M. J. Med. Chem.
as colorless oil.
1980, 23, 635.
(b) Abou-Gharbia, M.; Patel, U. R.; Webb, M. B.; Moyer, J.
A.; Andree, T. H.; Muth, E. A. J. Med. Chem. 1987, 30, 1818.
(6) Bhandari, K. S.; Snieckus, V. Synthesis 1971, 327.
(7) For examples, see:
IR (NaCl): n = 2925, 2850, 1645, 1460, 750, 700 cm-1.
1H NMR (360 MHz): d = 3.58-3.70 (m, 1H, CHCH2), 3.93-4.08
(m, 1H, CHCH2), 4.24 (ddd, 1H, J = 11.9, 5.7, 1.2 Hz, CHCH2),
6.13 (m, 1H, H-3), 7.17-7.42 (m, 7H, H-arom), 7.50 (d, 1H, J = 7.5
Hz, H-arom), 7.55 (dd, 1H, J = 8.2, 0.7 Hz, H-arom), 8.38 (s, 1H,
NCHN).
Thomas, C.; Ohnmacht, U.; Niger, M.; Gmeiner, P. Bioorg.
Med. Chem. Lett. 1998, 8, 2885.
Löber, S.; Hübner, H.; Gmeiner, P. Bioorg. Med. Chem. Lett.
1999, 9, 97.
Thomas, C.; Hübner, H.; Gmeiner, P. Bioorg. Med. Chem.
Lett. 1999, 9, 841.
HRMS: m/z calcd for C17H14N2: 246.1157. Found: 246.1159.
Acknowledgement
Haubmann, C.; Hübner, H.; Gmeiner, P. Bioorg. Med. Chem.
Lett. 1999, 9, 1969.
Hübner, H.; Haubmann, C.; Gmeiner, P. J. Med. Chem. 2000,
43, 756.
The generous support of the Fonds der Chemischen Industrie is
gratefully acknowledged.
Haubmann, C.; Hübner, H.; Gmeiner, P. Bioorg. Med. Chem.
Lett. 1999, 9, 3143.
(8) Gmeiner, P.; Sommer, J.; Höfner, G. Arch. Pharm.
(Weinheim) 1995, 328, 329.
(9) Dandridge, P. A.; Kaiser, C.; Brenner, M.; Gaitanopoulos, D.;
Davis, L. D.; Webb, R. L.; Foley, J. J.; Sarau, H. M. J. Med.
Chem. 1984, 27, 28.
References
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Article Identifier:
1437-210X,E;2000,0,08,1081,1083,ftx,en;Z00800SS.pdf
Synthesis 2000, No. 8, 1081–1083 ISSN 0039-7881 © Thieme Stuttgart · New York