Palladium(II)-catalyzed heterocyclisation of 8-arylethynyl-1,2,3,4- tetrahydroquinolines: A facile route to 2-aryl-5,6-dihydro-4H-pyrrolo[3,2,1-ij] quinoline derivatives

Article abstract of DOI:10.1016/j.tet.2005.02.041

Dihydropyrroloquinolines have been synthesized reacting 8-arylethynyl-1,2,3,4-tetrahydroquinolines in the presence of palladium(II) chloride catalyst. Heteroannulation has been achieved in good yields and tolerates substituents on the tetrahydroquinoline,

Full text of DOI:10.1016/j.tet.2005.02.041

Tetrahedron 61 (2005) 4035–4041
Palladium(II)-catalyzed heterocyclisation of
8-arylethynyl-1,2,3,4-tetrahydroquinolines: a facile route to
2-aryl-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline derivatives
a
a
b
b
Pascal Marchand,a, Alain Puget, Guillaume Le Baut, Peter Emig, Michael Czech
*
b
¨
and Eckhard Gunther
a
´ ´
Laboratoires de Chimie Organique et de Chimie Therapeutique, UPRES EA 1155, Faculte de Pharmacie, 1 rue Gaston Veil,
F-44035 Nantes, France
bZentaris GmbH, 45 Weismuellerstrasse, D60314 Frankfurt/Main, Germany
Received 19 November 2004; revised 7 February 2005; accepted 17 February 2005
Abstract—Dihydropyrroloquinolines have been synthesized reacting 8-arylethynyl-1,2,3,4-tetrahydroquinolines in the presence of
palladium(II) chloride catalyst. Heteroannulation has been achieved in good yields and tolerates substituents on the tetrahydroquinoline,
including bromo, cyano, and ester.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
led us to envision the incidence of its replacement by an
indole-bridged heterocycle, 5,6-dihydro-4H-pyrrolo[3,2,1-
ij]quinoline (Fig. 3).
The 5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline ring consti-
tutes the central core of different series of compounds
exerting platelet activating factor production inhibition1 or
acting as 5-hydroxytryptamine (5-HT2c) receptor agonists
and exerting antiepileptic or anti-obesity activities2 (Fig. 1).
Access to such compounds is regularly described by the well
known Fischer indole derivatives synthesis.1,4
Herein, we report the strategy for the synthesis of the central
scaffold using a palladium(II)-catalyzed intramolecular
heterocyclisation.
During our work in the field of peptidomimetic antagonists
of G-protein coupled receptors (GPCRs) we were interested
in the synthesis of analogues of the nonpeptidyl luteinizing
hormone-releasing hormone (LHRH) receptor antagonist 3
(Fig. 2).3
2. Results and discussion
Pharmacomodulation at the level of the central indole core
The 5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline is classically
Figure 1. Structures of a PAF antagonist 1 and a 5HT2C receptor agonist 2.
Keywords: 5,6-Dihydro-4H-pyrrolo[3,2,1-ij]quinolines; 1,2,3,4-Tetrahydroquinolines; Palladium(II)-catalyzed intramolecular heterocyclisation.
*
Corresponding author. Tel.: C33 240412874; fax: C33 240412876; e-mail: pascal.marchand@sante.univ-nantes.fr
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.02.041

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P. Marchand et al. / Tetrahedron 61 (2005) 4035–4041
first tried to obtain the tricyclic compound 8 (Scheme 1) by
intramolecular acylation of the 1-indolepropionic acid 6
(obtained by reaction of 5 with propiolactone) followed by
reduction5 of the desired 4,5-dihydro-6H-pyrroloquinolin-
6-one 7; although the starting 2-xylylindole 5 could be
prepared by the Sonogashira8/palladium(II)-catalyzed intra-
molecular cyclisation methods9 in a 70% overall yield,
cyclodehydration of acid 6, using PPA or AlCl3, failed.
Figure 2. Structure of the nonpeptidyl gonadotropin-releasing hormone
(GnRH) receptor antagonist 3.
In a second approach, we tried to obtain directly 1-(2-
aminoethyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline 11
by the elegant Fischer indole synthesis worked out by
Grandberg10 for tryptamine derivatives. Condensation of
1-amino-1,2,3,4-tetrahydroquinoline1 9 with 4-chloro-1-
(3,5-dimethylphenyl)butan-1-one 10 afforded the desired
azaarylethylamine 11 (Scheme 2), but yield remained poor
(15%) and its purification necessitated multiple tedious
column chromatography elutions.
We hypothesized that palladium-catalyzed ring closure of
alkynylanilines to indoles11,12 may be directly applicable to
the preparation of 2-aryl-5,6-dihydro-4H-pyrrolo[3,2,1-
ij]quinolines (Scheme 3). The synthesis began with the
bromination of the commercially available 1,2,3,4-tetra-
hydroquinoline 12 to give 6-bromo-1,2,3,4-tetrahydro-
quinoline 13 as major product in 60% yield. The
Figure 3. Structure of the novel pyrroloquinolines prepared.
Scheme 1. Synthesis of the 5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline 8: (i) (3,5-dimethylphenyl)acetylene 20, Pd(PPh3)2Cl2, CuI, Et3N, 10 8C, 89%;
(ii) PdCl2, CH3CN, reflux, 78%; (iii) propiolactone, NaH, DMF, rt, 72%; (iv) PPA or AlCl3, CH2Cl2.
elaborated by two strategies (Fig. 3): (i) creation of ring A
starting from indole derivative, (ii) creation of ring C using
suitably substituted 1,2,3,4-tetrahydroquinoline. In the first
case, numerous indole cyclisation reactions have been
carried out using N-1 and/or C-7 substituted indoles.5–7 We
temperature must be kept at 0 8C to avoid simultaneous
bromination in position 8. Iodination with iodine mono-
chloride gave the 6-bromo-8-iodo-1,2,3,4-tetrahydro-
quinoline 17. The Sonogashira palladium-catalyzed
cross-coupling reaction8 of amine 17 with (3,5-
Scheme 2. Grandberg synthesis of azaarylethylamine 11. (i) EtOH, reflux, 15%.

P. Marchand et al. / Tetrahedron 61 (2005) 4035–4041
4037
Scheme 3. Synthesis of 1-aminoethyl-2-(3,5-dimethylphenyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline derivatives. (i) NBS, CCl4, 0 8C; (ii) CuCN, DMF,
reflux; (iii) NaOH, H2O2, reflux; (iv) EtOH, HCl, reflux; (v) ICl, CaCO3, MeOH/H2O, 0 8C; (vi) (3,5-dimethylphenyl)acetylene 20, Pd(PPh3)2Cl2, CuI, Et3N,
10 8C; (vii) PdCl2, CH3CN, reflux; (viii) (1) (COCl)2, Et2O, 0 8C (2) 4-(4-methoxyphenyl)butylamine, THF, rt; (ix) (1) BH3:THF, reflux (2) N,N-
dimethylethanolamine, MeOH/THF, reflux; (x) NaOH, EtOH, reflux; (xi) morpholine, PyBOP, N-methylmorpholine, DMF, rt; (xii) BBr3, CH2Cl2, rt.
dimethylphenyl)acetylene 2014 using catalytic amount of
the Pd(PPh3)2Cl2-CuI system in triethylamine under nitro-
gen at 0 8C provided access to the key intermediate, the
6-bromo-8-(3,5-dimethylphenyl)ethynyl-1,2,3,4-tetra-
hydroquinoline 21, in excellent yield.
conditions remained unsuccessful. This problem was solved
by carrying out the cyanation with 6-bromo-1,2,3,4-
tetrahydroquinoline 13 as starting material in the previous
conditions (CuCN/DMF, reflux) to afford 6-cyano-1,2,3,4-
tetrahydroquinoline 14 in 60% yield (Scheme 3). Sub-
sequent reactions of iodination (compound 18), Sonogashira
coupling (compound 22) and palladium-catalyzed cyclisa-
tion gave pyrroloquinoline 25 in a 31% overall yield. The
cyano derivative 25 was converted to the corresponding
carboxylic acid, with aqueous solution of sodium hydroxide
in the presence of hydrogen peroxide, only in very poor
yield. Since the synthetic route to the ester 8 via the
carboxylic acid appeared to be unsuitable, the cyano
derivative 14 was first hydrolysed as described above. The
synthesis of the 1,2,3,4-tetrahydroquinoline-6-carboxylic
acid 15 was achieved easily and in an excellent yield (95%).
Palladium dichloride is a well-established catalyst for
converting 2-alkynylanilines into 2-substituted indoles
through N–C2 ring closure.9 We used such reaction
conditions with refluxing acetonitrile as solvent to obtain
2-phenyl-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline 24
from compound 21, in 70% yield. The corresponding nitrile
25 could not be obtained by heating the bromo derivative 24
at reflux with copper cyanide in dimethylformamide in a
Rosenmund-von Braun reaction.14 Another attempt using
ZnCN2 as cyanation reagent15 in palladium-catalyzed

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P. Marchand et al. / Tetrahedron 61 (2005) 4035–4041
Ethyl ester 16 was synthesized by refluxing the com-
pound 15 in an hydrogen chloride ethanolic solution. The
ethyl pyrroloquinoline-8-carboxylate 8 was then prepared
using a sequence of reactions similar to those described
for compounds 24 and 25, in a satisfactory global yield
(39%).
solvents were removed under reduced pressure, the residue
was purified by chromatography (CH2Cl2) to give 13 as a
yellow oil (4.77 g, 60%). IR (neat) cmK1: 3415 (nNH); 3012
(nCH arom.); 2926, 2836 (nCH alkane); 1598, 1495 (nC]C
1
arom.); 544 (nC–Br). H NMR d 6.98 (d, 1H, JZ2.3 Hz,
H5), 6.96 (d, 1H, JZ9.2 Hz, H8), 6.40 (dd, 1H, JZ9.2 Hz,
JZ2.3 Hz, H7), 5.87 (s, 1H, NH), 3.18 (t, 2H, JZ5.5 Hz,
H2), 2.66 (t, 2H, JZ6.1 Hz, H4), 1.89–1.71 (m, 2H, H3).
MS-ESC (MeOH): m/z 213 (MCHC, 100%).
The aminoethyl chain was built in the position 1 of the
azaheterocycle 8 via the glyoxamide 26 after reaction with
oxalyl chloride and subsequent condensation with 4-(4-
methoxyphenyl)butylamine.1 The glyoxamide 26 was
reduced with a borane–THF complex to give ethylamine
27 after treatment with N,N-dimethylethanolamine to break
down the boron–amine complex intermediate. The ester 27
was hydrolyzed under alkaline conditions to afford the
corresponding carboxylic acid 28, which was condensed
with morpholine using PyBOP as coupling reagent and
N-methylmorpholine in dimethylformamide at room
temperature to yield the morpholide 29. Demethylation of
29 with boron tribromide at room temperature gave the
corresponding phenol 30 in a 45% yield.
4.1.2. 6-Cyano-1,2,3,4-tetrahydroquinoline (14). Com-
pound 13 (3.40 g, 16.0 mmol) was stirred with cuprous
cyanide (1.72 g, 19.2 mmol) in dimethylformamide
(30 mL) and heated to reflux for 16 h. After the mixture
had cooled, 10% ammonium hydroxide solution (50 mL)
was added and the resultant mixture was extracted with
dichloromethane. The aqueous layer was washed with brine
(4!50 mL), water and dried over Na2SO4. After removal of
the solvent under reduced pressure, the residue was purified
by chromatography (CH2Cl2) to give 14 as a white solid
(1.52 g, 60%). Mp 77–79 8C (lit.16 78–80 8C). IR
(KBr) cmK1: 3382 (nNH); 3052 (nCH arom.); 2931, 2853
(nCH alkane); 2210 (nC^N); 1608, 1522 (nC]C arom.).
1H NMR d 7.29–7.21 (m, 2H, H5, H7), 6.78 (s, 1H, NH),
6.50 (d, 1H, JZ8.0 Hz, H8), 3.26 (t, 2H, JZ5.5 Hz, H2),
2.67 (t, 2H, JZ6.1 Hz, H4), 1.89–1.71 (m, 2H, H3). MS-
ESC (MeOH): m/z 159 (MCHC, 100%).
3. Conclusion
Palladium(II)-catalyzed intramolecular heterocyclisation of
8-arylethynyl-1,2,3,4-tetrahydroquinolines provides a
simple and high yield method for the preparation of
2-aryl-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline deriva-
tives (8, 24, 25). They can be modified by substitution to
compounds (26–30), which are of interest as potential
antagonists of GPCRs as pharmacological targets.
4.1.3. 1,2,3,4-Tetrahydroquinoline-6-carboxylic acid
(15). Thirty-five percent aqueous hydrogen peroxide
solution (6 mL) was added to a solution of 14 (1.50 g,
9.5 mmol) in aqueous solution of 2 N NaOH (30 mL) at
room temperature. The mixture was refluxed for 24 h,
cooled to room temperature and acidified with an aqueous
solution of 2 N HCl. The precipitate which resulted was
collected by filtration, washed by water and dried over P2O5
to give 15 as a white solid (1.60 g, 95%). Mp 169–171 8C
(lit.17 168–170 8C). IR (KBr) cmK1: 3600–2900 (nOH);
3425 (nNH); 2981, 2928 (nCH alkane); 1703 (nC]O); 1613
(nC]C arom.). 1H NMR d 7.58–7.41 (m, 2H, H5, H7), 6.55
(s, 1H, NH), 6.44 (d, 1H, JZ9.1 Hz, H8), 3.26–3.22 (m, 2H,
H2), 2.69 (t, 2H, JZ5.8 Hz, H4), 1.89–1.71 (m, 2H, H3).
MS-ESC (MeOH): m/z 178 (MCHC, 100%).
4. Experimental
4.1. General methods
All common chemicals and solvents utilized were reagent
grade and purchased from Sigma-Aldrich (Saint Quentin,
France). Melting points were determined on a Electro-
thermal IA9300 melting point digital apparatus and reported
uncorrected. Infrared (IR) spectra were obtained in KBr
pellets or neat liquid films with a Perkin–Elmer Paragon
FTIR 1000 PC spectrometer. 1H NMR and 13C NMR
spectra were obtained using a Bruker Avance 400 apparatus
operating at 400 MHz in d6-DMSO as solvent. Chemical
shifts are expressed as d values (ppm) relative to Me4Si as
internal standard. Electrospray mass spectrometric analysis
was performed on a Esquire-LC Ion Trap System mass
spectrometer. All reactions were monitored by TLC, using
0.25 mm-thick precoated silica gel plates (E. Merck) eluted
with CH2Cl2/EtOH gradients. Compounds were purified by
column chromatography using silica gel 60 as stationary
phase and eluted with CH2Cl2 or CH2Cl2/hexane gradients.
4.1.4. Ethyl 1,2,3,4-tetrahydroquinoline-6-carboxylate
(16). Carboxylic acid 15 (1.00 g, 5.6 mmol) in ethanolic
solution of 2 N HCl (50 mL) was refluxed for 3 days. The
solution was cooled to room temperature and basified with
an aqueous solution of 1 N NaOH. The precipitate which
resulted was collected by filtration, washed by ethanol and
dried over P2O5 to give 16 as a white solid (0.69 g, 60%).
Mp 80–81 8C (lit.17 82–83 8C, hexane). IR (KBr) cmK1
:
3388 (nNH); 2935 (nCH alkane); 1677 (nC]O); 1608, 1525
(nC]C arom.). 1H NMR d 7.58–7.40 (m, 2H, H5, H7), 6.62
(s, 1H, NH), 6.44 (d, 1H, JZ8.2 Hz, H8), 4.21 (q, 2H, JZ
7.0 Hz, CH2), 3.28–3.24 (m, 2H, H2), 2.70 (t, 2H, JZ
6.1 Hz, H4), 1.89–1.71 (m, 2H, H3), 1.28 (t, 3H, JZ7.0 Hz,
CH3). MS-ESC (MeOH): m/z 206 (MCHC, 100%).
4.1.1. 6-Bromo-1,2,3,4-tetrahydroquinoline.16 (13) To a
solution of 1,2,3,4-tetrahydroquinoline 12 (5.00 g,
37.5 mmol) in carbon tetrachloride (10 mL) at 0 8C, was
added portion wise N-bromosuccinimide (6.68 g,
37.5 mmol). The mixture was stirred at room temperature
for 3 h. The succinimide which resulted as a precipitate was
filtered off and washed with hexane (4!10 mL). The
4.2. General procedure for the synthesis of 8-iodo-
1,2,3,4-tetrahydroquinolines
A solution of iodine monochloride (21 mmol) in methanol

P. Marchand et al. / Tetrahedron 61 (2005) 4035–4041
4039
(25 mL) was added dropwise to a stirred suspension of
1,2,3,4-tetrahydroquinolines 13, 14 or 16 (20 mmol) and
calcium carbonate (30 mmol) in methanol/water (4/1)
(100 mL) at 0 8C. The mixture was allowed to warm to
room temperature and stirred for 2 h before filtering through
a pad of Celite. The filtrate was extracted with dicholoro-
methane and the organic layer was washed with water. The
organic layer was dried over Na2SO4 and evaporated in
vacuo, and the residue was chromatographed on silica gel,
eluting with CH2Cl2 to give 17, 18 or 19.
3,5-dimethyl-1-trimethylsilylethynylbenzene (2.21 g,
10.9 mmol) in tetrahydrofuran (50 mL) at K15 8C. The
mixture was stirred for 30 min and the solvent was
evaporated in vacuo. The residue was purified by chroma-
tography on neutral alumina using hexane as an eluent to
afford 20 as a light yellow liquid (1.13 g, 80%). IR
(neat) cmK1: 3248 (n^C–H); 3105, 3002 (nCH arom.);
2100 (nC^C); 1510, 1482 (nC]C arom.). 1H NMR d 7.12
(s, 2H, H2,6), 7.07 (s, 1H, H4), 4.13 (s, 1H, C^C–H), 2.28
(s, 6H, CH3).
4.2.1. 6-Bromo-8-iodo-1,2,3,4-tetrahydroquinoline (17).
An orange oil was obtained (69%). IR (neat) cmK1: 3399
(nNH); 3020 (nCH arom.); 2928, 2836 (nCH alkane);
4.4. Sonogashira coupling
1
8-Iodo-1,2,3,4-tetrahydroquinolines17, 18or19(16.5 mmol),
(3,5-dimethylphenyl)acetylene 20 (17.3 mmol), bis(tri-
phenylphosphine)palladium dichloride (0.38 mmol) and
copper(I) iodide (0.82 mmol) were dissolved in triethyl-
amine (100 mL) at 0 8C under nitrogen. The reaction
mixture was stirred at 0 8C for 1 h. The precipitate was
filtered off and washed with triethylamine. The filtrate was
concentrated in vacuo and the residue was chromato-
graphed on silica gel, eluting with CH2Cl2 to give 21,
22 or 23.
1586, 1494 (nC]C arom.); 546 (nC–Br). H NMR d 7.54
(s, 1H, H7), 7.09 (s, 1H, H5), 5.28 (s, 1H, NH), 3.32–3.26
(m, 2H, H2), 2.70 (t, 2H, JZ6.2 Hz, H4), 1.78–1.72 (m,
2H, H3). 13C NMR d 20.5, 27.3, 41.8, 82.0, 97.1, 121.1,
133.1, 140.7, 148.6. MS-ESC (MeOH): m/z 339 (MCHC,
100%).
4.2.2. 6-Cyano-8-iodo-1,2,3,4-tetrahydroquinoline (18).
A white solid was obtained (62%). Mp 124–126 8C. IR
(KBr) cmK1: 3350 (nNH); 3015 (nCH arom.); 2930, 2842
(nCH alkane); 2212 (nC^N); 1595, 1512 (nC]C arom.).
1H NMR d 7.84 (s, 1H, H7), 7.31 (s, 1H, H5), 6.13 (s, 1H,
NH), 3.39–3.35 (m, 2H, H2), 2.72–2.68 (m, 2H, H4), 1.79–
1.74 (m, 2H, H3). 13C NMR d 20.3, 27.2, 42.0, 81.8, 97.2,
119.3, 121.4, 132.3, 140.2, 148.4. MS-ESC (MeOH): m/z
285 (MCHC, 100%).
4.4.1. 6-Bromo-8-(3,5-dimethylphenyl)ethynyl-1,2,3,4-
tetrahydroquinoline (21). A white solid was obtained
(97%). Mp 145–147 8C. IR (KBr) cmK1: 3410 (nNH); 3008
(nCH arom.); 2945, 2912 (nCH alkane); 1596, 1494 (nC]C
1
arom.); 548 (nC–Br). H NMR d 7.28 (s, 2H, Har), 7.22 (d,
1H, JZ2.4 Hz, H7), 7.07 (d, 1H, JZ2.4 Hz, H5), 7.05 (s,
1H, Har), 6.49 (s, 1H, NH), 3.37–3.33 (m, 2H, H2), 2.74–
2.70 (m, 2H, H4), 2.31 (s, 6H, CH3), 1.82–1.78 (m, 2H, H3).
13C NMR d 20.3, 20.6, 26.4, 41.2, 84.5, 95.3, 95.7, 105.4,
121.7, 122.4, 129.3, 130.5, 132.4, 134.3, 137.4, 148.5. MS-
ESC (MeOH): m/z 341 (MCHC, 100%).
4.2.3. Ethyl 8-iodo-1,2,3,4-tetrahydroquinoline-6-car-
boxylate (19). An orange oil was obtained (60%). IR
(neat) cmK1: 3368 (nNH); 2929, 2843 (nCH arom.); 1700
1
(nC]O); 1598, 1516 (nC]C arom.). H NMR d 8.00 (s,
1H, H7), 7.50 (s, 1H, H5), 5.97 (s, 1H, NH), 4.23 (q, 2H, JZ
7.1 Hz, CH2), 3.29–3.25 (m, 2H, H2), 2.73 (t, 2H, JZ
6.1 Hz, H4), 1.82–1.78 (m, 2H, H3), 1.28 (t, 3H, JZ7.1 Hz,
CH3). 13C NMR d 14.5, 20.1, 27.1, 41.5, 59.6, 82.6, 96.8,
120.9, 131.6, 140.5, 147.9, 168.1. MS-ESC (MeOH): m/z
332 (MCHC, 100%).
4.4.2. 6-Cyano-8-(3,5-dimethylphenyl)ethynyl-1,2,3,4-
tetrahydroquinoline (22). A white solid was obtained
(96%). Mp 131–133 8C. IR (KBr) cmK1: 3375 (nNH); 3002
(nCH arom.); 2932, 2847 (nCH alkane); 2213 (nC^N);
1
4.3. General procedure for the synthesis of 8-(3,5-
dimethylphenyl)ethynyl-1,2,3,4-tetrahydroquinolines
1599, 1524 (nC]C arom.). H NMR d 7.51 (s, 1H, H7),
7.41–7.38 (m, 3H, 2Har, H5), 7.07 (s, 1H, Har), 6.64 (s, 1H,
NH), 3.37–3.33 (m, 2H, H2), 2.74–2.70 (m, 2H, H4), 2.32 (s,
6H, CH3), 1.82–1.78 (m, 2H, H3). 13C NMR d 20.1, 20.8,
26.7, 41.3, 84.1, 95.2, 95.5, 105.3, 120.1, 121.2, 122.3,
129.2, 130.4, 132.2, 134.1, 137.8, 149.0. MS-ESC (MeOH):
m/z 287 (MCHC, 100%).
4.3.1. (3,5-Dimethylphenyl)acetylene.13 (20) To a mixture
of trimethylsilylacetylene (2.64 g, 26.9 mmol) and 3,5-
dimethyliodobenzene 6.17 g, 26.6 mmol) in triethylamine
(30 mL) was added bis(triphenylphosphine)palladium
dichloride (360 mg, 0.52 mmol) and copper(I) iodide
(49 mg, 0.26 mmol). The reaction mixture was stirred at
room temperature for 4 h under nitrogen and a crystalline
grey-green solid of triethylamine hydroiodide was isolated
by filtration and washed with toluene. The filtrate was
concentrated under reduced pressure and the crude product
was purified by chromatography on neutral alumina using
CH2Cl2/hexane (1/1) as an eluent to afford the 3,5-dimethyl-
1-trimethylsilylethynylbenzene as a yellow oil (5.27 g,
4.4.3. Ethyl 8-(3,5-dimethylphenyl)ethynyl-1,2,3,4-tetra-
hydroquinoline-6-carboxylate (23). An orange solid was
obtained (92%). Mp 84–86 8C. IR (KBr) cmK1: 3403
(nNH); 2926, 2843 (nCH arom.); 1694 (nC]O); 1598,
1
1514 (nC]C arom.). H NMR d 7.71 (s, 1H, H7), 7.50 (s,
1H, H5), 7.32 (s, 2H, Har), 7.06 (s, 1H, Har), 6.49 (s, 1H,
NH), 4.24 (q, 2H, JZ7.1 Hz, CH2), 3.44–3.40 (m, 2H, H2),
2.78–2.74 (m, 2H, H4), 2.31 (s, 6H, CH3), 1.78–1.88 (m, 2H,
H3), 1.31 (t, 3H, JZ7.1 Hz, CH3). 13C NMR d 14.5, 20.5,
20.8, 27.0, 41.4, 59.9, 85.1, 94.8, 104.4, 115.4, 119.9, 122.6,
129.2, 130.2, 130.4, 131.9, 137.7, 149.5, 165.5. MS-ESC
(MeOH): m/z 334 (MCHC, 100%).
1
98%). H NMR d 7.09 (s, 2H, H2,6), 7.04 (s, 1H, H4), 2.54
(s, 6H, CH3), 0.25 (s, 9H, Si(CH3)3).
A solution of TBAF 1 M in tetrahydrofuran (12 mL,
12 mmol) was added dropwise to a stirred solution of

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P. Marchand et al. / Tetrahedron 61 (2005) 4035–4041
4.5. General procedure for the synthesis of 2-(3,5-
dimethylphenyl)-5,6-dihydro-4H-pyrrolo[3,2,1-
ij]quinolines
temperature overnight. The precipitate which resulted was
filtered off and the filtrate was concentrated in vacuo. The
crude mixture was purified by silica gel column chroma-
tography eluting with hexane/ethyl acetate (1/1) to give
oxoacetamide 26 as a white solid (1.24 g, 95%). Mp 128–
130 8C. IR (KBr) cmK1: 3303 (nNH); 2928, 2857 (nCH);
1705, 1651 (nC]O); 1511 (nC]C arom.). 1H NMR d 8.60
(s, 1H, H9), 8.49–8.45 (m, 1H, NH), 7.72 (s, 1H, H7), 7.19–
7.02 (m, 5H, 2H’ar, 3Har), 6.86 (d, 2H, JZ8.5 Hz, 2H’ar),
4.37 (q, 2H, JZ7.0 Hz, CH2), 4.04–3.98 (m, 2H, H4), 3.74
(s, 3H, OCH3), 3.06–3.02 (m, 2H, H6), 2.76–2.72 (m, 2H,
CH2), 2.52–2.48 (m, 2H, CH2), 2.38 (s, 6H, CH3), 2.16–2.12
(m, 2H, H5), 1.59–1.21 (m, 4H, CH2), 1.38 (t, 3H, JZ
7.0 Hz, CH3). 13C NMR d 14.5, 21.0, 22.2, 24.1, 28.1, 28.8,
34.0, 38.3, 43.3, 55.1, 60.6, 110.8, 113.8, 121.1, 121.5,
123.3, 124.4, 128.3, 128.8, 129.3, 129.4, 131.1, 134.0,
136.4, 137.2, 148.9, 157.5, 166.5, 166.8, 187.8. MS-ESC
(MeOH): m/z 568 (MCHC, 100%).
8-(3,5-Dimethylphenyl)ethynyl-1,2,3,4-tetrahydroquino-
lines 21, 22 or 23 (5 mmol) and palladium dichloride
(0.5 mmol) were dissolved in acetonitrile (35 mL) and the
reaction mixture was refluxed for 16 h. The solvent was
removed in vacuo and the residue was chromatographed on
silica gel, eluting with CH2Cl2 to give 24, 25 or 8.
4.5.1. 8-Bromo-2-(3,5-dimethylphenyl)-5,6-dihydro-4H-
pyrrolo[3,2,1-ij]quinoline (24). A white solid was obtained
(70%). Mp 136–138 8C. IR (KBr) cmK1: 2971 (nCH
alkane); 1582, 1464 (nC]C arom.); 545 (nC–Br). 1H
NMR d 7.56 (s, 1H, H9), 7.26 (s, 2H, Har), 7.09 (s, 1H, Har),
7.04 (s, 1H, H7), 6.52 (s, 1H, H1), 4.24–4.20 (m, 2H, H4),
2.99–2.95 (m, 2H, H6), 2.37 (s, 6H, CH3), 2.14–2.10 (m, 2H,
H5). 13C NMR d 21.1, 22.6, 24.2, 43.6, 99.6, 112.3, 119.7,
120.9, 124.8, 126.3, 127.2, 129.7, 131.5, 133.7, 138.1,
141.1. MS-ESC (MeOH): m/z 341 (MCHC, 100%).
4.6.2. Ethyl 1-{N-[4-(4-methoxyphenyl)but-1-yl]amino-
ethyl}-2-(3,5-dimethylphenyl)-5,6-dihydro-4H-pyrrolo-
[3,2,1-ij]quinoline-8-carboxylate (27). Borane–tetrahydro-
furan complex (4.4 mL, 4.4 mmol) was added to a solution
of N-[4-(4-methoxyphenyl)but-1-yl]-2-[8-ethoxycarbonyl-
2-(3,5-dimethylphenyl)-5,6-dihydro-4H-pyrrolo[3,2,1-
ij]quinolin-1-yl]-2-oxoacetamide 26 (0.50 g, 0.87 mmol) in
dry tetrahydrofuran (20 mL) under nitrogen at room
temperature. The reaction mixture was refluxed for 3 h.
The solvent was removed under reduced pressure and the
residue was dissolved in methanol (30 mL). N,N-Dimethyl-
ethanolamine (5 mL) was added and the solution was
refluxed for 3 h. The solvent was removed in vacuo and the
residue was chromatographed on silica gel, eluting with
hexane/ethyl acetate (1/1), to afford ester 27 as a white solid
(197 mg, 42%). Mp 87–89 8C. IR (KBr) cmK1: 3449 (nNH);
2928 (nCH); 1703 (nC]O); 1607, 1512 (nC]C arom.). 1H
NMR d 8.15 (s, 1H, H9), 7.55 (s, 1H, H7), 7.16–7.12 (m, 5H,
2H’ar, 3Har), 6.87 (d, 2H, JZ8.3 Hz, 2H’ar), 4.34 (q, 2H, JZ
8.3 Hz, CH2), 4.01–3.97 (m, 2H, H4), 3.74 (s, 3H, OCH3),
3.02–2.98 (m, 2H, H6), 2.91–2.72 (m, 4H, CH2), 2.57–2.53
(m, 2H, CH2), 2.47–2.43 (m, 2H, CH2), 2.38 (s, 6H, CH3),
2.14–2.10 (m, 2H, H5), 1.59–1.21 (m, 4H, CH2), 1.37 (t, 3H,
JZ8.3 Hz, CH3). 13C NMR d 14.6, 21.1, 21.4, 22.3, 24.2,
25.4, 28.4, 33.7, 42.8, 46.1, 47.3, 55.1, 60.1, 108.3, 113.6,
119.1, 119.4, 121.4, 122.9, 123.4, 127.9, 128.5, 129.0,
129.3, 130.9, 134.4, 136.3, 137.1, 157.2, 185.3. MS-ESC
(MeOH): m/z 540 (MCHC, 100%).
4.5.2. 8-Cyano-2-(3,5-dimethylphenyl)-5,6-dihydro-4H-
pyrrolo[3,2,1-ij]quinoline (25). A white solid was obtained
(87%). Mp 124–126 8C. IR (KBr) cmK1: 2951 (nCH
alkane); 2211 (nC^N); 1596, 1486 (nC]C arom.). 1H
NMR d 7.92 (s, 1H, H9), 7.29 (s, 2H, Har), 7.26 (s, 1H, H7),
7.12 (s, 1H, Har), 6.69 (s, 1H, H1), 4.28–4.24 (m, 2H, H4),
3.03–2.98 (m, 2H, H), 2.39 (s, 6H, CH3), 2.16–2.12 (m, 2H,
H5). 13C NMR d 21.1, 22.4, 24.4, 43.7, 100.8, 101.6, 120.7,
121.2, 123.5, 123.9, 125.2, 126.4, 130.0, 131.1, 136.7,
138.1, 142.4. MS-ESC (MeOH): m/z 287 (MCHC, 100%).
4.5.3. Ethyl 2-(3,5-dimethylphenyl)-5,6-dihydro-4H-
pyrrolo[3,2,1-ij]quinoline-8-carboxylate (8). A white
solid was obtained (70%). Mp 87–88 8C. IR (KBr) cmK1
:
2939 (nCH alkane); 1701 (nC]O); 1594 (nC]C arom.). 1H
NMR d 8.14 (s, 1H, H9), 7.56 (s, 1H, H7), 7.28 (s, 2H, Har),
7.10 (s, 1H, Har), 6.70 (s, 1H, H1), 4.37 (q, 2H, JZ7.1 Hz,
CH2), 4.25 (t, 2H, JZ5.5 Hz, H4), 3.02 (t, 2H, JZ5.8 Hz,
H6), 2.38 (s, 6H, CH3), 2.28–2.15 (m, 2H, H5), 1.37 (t, 3H,
JZ7.1 Hz, CH3). 13C NMR d 14.5, 21.1, 22.7, 24.3, 43.7,
60.2, 101,4, 119.1, 120.5, 121.5, 122.3, 125.0, 126.3, 129.7,
131.5, 137.6, 138.1, 141.6, 167.2. MS-ESC (MeOH): m/z
334 (MCHC, 100%).
4.6. Procedure for the synthesis of 2-[2-(3,5-dimethyl-
phenyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl]-
2-oxoacetamide (26) and ethylamines (27–30)
4.6.3. 1-[N-[4-(4-Methoxyphenyl)but-1-yl]aminoethyl]-
2-(3,5-dimethylphenyl)-5,6-dihydro-4H-pyrrolo[3,2,1-
ij]quinoline-8-carboxylic acid 28. An aqueous solution of
2 N NaOH (10 mL) was added to ester 27 (180 mg,
0.33 mmol) in ethanol (20 mL) at room temperature. The
reaction mixture was refluxed for 2 h, cooled to room
temperature and neutralised with a 6 N solution of HCl. The
precipitate which resulted was collected by filtration,
washed by water and dried over P2O5 to give carboxylic
acid 28 as a white solid (102 mg, 72%). Mp 315 8C
(degradation). IR (KBr) cmK1: 3600–2400 (nOH); 3425
(nNH); 2927, 2856 (nCH); 1701 (nC]O); 1600, 1512
4.6.1. N-[4-(4-Methoxyphenyl)but-1-yl]-2-[8-ethoxy-
carbonyl-2-(3,5-dimethylphenyl)-5,6-dihydro-4H-pyr-
rolo[3,2,1-ij]quinolin-1-yl]-2-oxoacetamide (26).
solution of ethyl 2-(3,5-dimethylphenyl)-5,6-dihydro-4H-
pyrrolo[3,2,1-ij]quinoline-8-carboxylate (0.80 g,
A
8
2.3 mmol) in diethyl ether (10 mL) was added dropwise to
a solution of oxalyl chloride (0.62 mL, 7.0 mmol) in diethyl
ether (5 mL) at 0 8C under nitrogen atmosphere. The
mixture was stirred at room temperature for 1 h and the
solvent was removed with nitrogen flow. The residue was
dissolved in tetrahydrofuran (20 mL) and cooled to 0 8C.
4-(4-Methoxyphenyl)butylamine (1.26 g, 7.1 mmol) was
added portionwise and the mixture was stirred at room
1
(nC]C arom.). H NMR d 8.25 (s, 1H, H9), 7.58 (s, 1H,
H7), 7.16–7.12 (m, 5H, 2H’ar, 3Har), 6.87 (d, 2H, JZ8.3 Hz,
2H’ar), 4.01–3.97 (m, 2H, H4), 3.74 (s, 3H, OCH3),

P. Marchand et al. / Tetrahedron 61 (2005) 4035–4041
4041
3.02–2.98 (m, 2H, H6), 2.97–2.91 (m, 4H, CH2), 2.74–2.70
(m, 2H, CH2), 2.50–2.46 (m, 2H, CH2), 2.40 (s, 6H, CH3),
2.16–2.12 (m, 2H, H5), 1.56–1.52 (m, 4H, CH2), 12.46 (s,
1H, OH). 13C NMR d 21.2, 21.6, 22.5, 24.4, 25.4, 28.3, 33.8,
42.9, 46.5, 47.4, 55.1, 108.3, 113.9, 119.4, 119.9, 121.8,
122.4, 124.5, 127.8, 129.4, 130.1, 133.7, 136.3, 137.8,
138.1, 138.5, 157.6, 169.0. MS-ESC (MeOH): m/z 512
(MCHC, 100%).
3.00–2.96 (m, 2H, H6), 2.88–2.84 (m, 4H, CH2), 2.62–2.58
(m, 2H, CH2), 2.50–2.46 (m, 2H, CH2), 2.39 (s, 6H, CH3),
2.16–2.12 (m, 2H, H5), 1.52–1.48 (m, 4H, CH2). 13C NMR d
21.1, 21.7, 22.6, 24.4, 25.1, 28.6, 34.0, 42.4, 46.1, 47.3,
48.6, 66.4, 115.2, 116.2, 118.0, 122.0, 124.4, 126.1, 127.7,
129.2, 130.4, 131.9, 133.1, 134.4, 135.9, 138.0, 138.1,
155.6, 171.1. MS-ESC (MeOH): m/z 567 (MCHC, 100%).
4.6.4. 4-{1-[N-[4-(4-Methoxyphenyl)but-1-yl]amino-
ethyl]-2-(3,5-dimethylphenyl)-5,6-dihydro-4H-pyrrolo-
[3,2,1-ij]quinolin-8-oyl}morpholine 29. Morpholine
(0.17 mL, 0.58 mmol) and PyBOP (0.56 g, 0.32 mmol)
were added to the solution of N-methylmorpholine
(0.22 mL, 0.58 mmol) and carboxylic acid 28 (0.50 g,
0.29 mmol) in dimethylformamide (5 mL). The mixture
was stirred at room temperature for 3 days. The mixture was
quenched with water and the aqueous solution was extracted
with dichloromethane. The organic layer was washed with
water, dried over Na2SO4 and concentrated in vacuo. The
crude product was purified by silica gel column chroma-
tography eluting with dichloromethane/ethanol (9/1) to give
morpholide 29 as a white solid (109 mg, 65%). Mp 92–
94 8C. IR (KBr) cmK1: 3448 (nNH); 2926, 2855 (nCH);
1604 (nC]O); 1512, 1435 (nC]C arom.). 1H NMR d 7.56
(s, 1H, H9), 6.99 (s, 1H, H7), 7.16–7.12 (m, 3H, 3Har), 7.11
(d, 2H, JZ8.5 Hz, 2H’ar), 6.87 (d, 2H, JZ8.5 Hz, 2H’ar),
4.01–3.97 (m, 2H, H4), 3.74 (s, 3H, OCH3), 3.65–3.61 (m,
2H, CH2 morph.), 3.60–3.57 (m, 2H, CH2 morph.), 3.00–
2.96 (m, 2H, H6), 2.88–2.84 (m, 4H, CH2), 2.68–2.66 (m,
2H, CH2), 2.50–2.46 (m, 2H, CH2), 2.39 (s, 6H, CH3), 2.16–
2.12 (m, 2H, H5), 1.52–1.48 (m, 4H, CH2). 13C NMR d 21.2,
21.9, 22.6, 24.4, 25.5, 28.2, 33.8, 42.8, 46.7, 47.1, 48.3,
55.2, 66.4, 108.1, 113.9, 118.1, 122.1, 124.3, 126.8, 127.7,
129.4, 130.1, 130.3, 133.6, 134.4, 136.6, 138.1, 138.2,
157.6, 173.4. MS-ESC (MeOH): m/z 581 (MCHC, 100%).
References and notes
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4.6.5. 4-{1-[N-[4-(4-Hydroxyphenyl)but-1-yl]amino-
ethyl]-2-(3,5-dimethylphenyl)-5,6-dihydro-4H-pyrrolo-
[3,2,1-ij]quinolin-8-oyl}morpholine 30. A solution of
amide 29 (0.28 g, 0.48 mmol) in dry dichloromethane was
stirred at room temperature during dropwise addition of
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122 8C. IR (KBr) cmK1: 3600–2400 (nOH); 3426 (nNH);
2926, 2856 (nCH); 1600 (nC]O); 1514, 1438 (nC]C
arom.). 1H NMR d 7.56 (s, 1H, H9), 6.99 (s, 1H, H7), 7.14–
7.10 (m, 3H, 3Har), 7.11 (d, 2H, JZ8.5 Hz, 2H’ar), 6.86 (d,
2H, JZ8.5 Hz, 2H’ar), 4.01–3.97 (m, 2H, H4), 3.65–3.61
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