A facile route for the preparation of N-phenyl tetrahydroquinolines and tetrahydroisoquinolines

Article abstract of DOI:10.1081/SCC-100103526

A convenient N-arylation of tetrahydroquinoline and tetrahydroisoquinoline is described using electron-poor, electron-neutral, or electron-rich arylhalide derivatives and palladium(II)-BINAP as a catalyst.

Full text of DOI:10.1081/SCC-100103526

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A FACILE ROUTE FOR THE
PREPARATION OF N-PHENYL
TETRAHYDROQUINOLINES AND
TETRAHYDROISOQUINOLINES
a
a
Jérôme Meneyrol , Philippe Helissey
,
a
b
Christophe Tratrat , Sylviane Giorgi-Renault
&
a
Henri-Philippe Husson
a
Laboratoire de Chimie Thérapeutique Associé
au CNRS et à l'Université René Descartes (UMR
8638) , Faculté des Sciences Pharmaceutiques et
Biologiques, 4 Avenue de l'Observatoire, Paris,
Cedex 06, 75270, France
b
Laboratoire de Chimie Thérapeutique Associé
au CNRS et à l'Université René Descartes (UMR
8638) , Faculté des Sciences Pharmaceutiques et
Biologiques, 4 Avenue de l'Observatoire, Paris,
Cedex 06, 75270, France
Published online: 09 Nov 2006.
To cite this article: Jérôme Meneyrol , Philippe Helissey , Christophe
Tratrat , Sylviane Giorgi-Renault & Henri-Philippe Husson (2001) A FACILE
ROUTE FOR THE PREPARATION OF N-PHENYL TETRAHYDROQUINOLINES AND
TETRAHYDROISOQUINOLINES, Synthetic Communications: An International Journal
for Rapid Communication of Synthetic Organic Chemistry, 31:7, 987-992, DOI:
10.1081/SCC-100103526

To link to this article: http://dx.doi.org/10.1081/SCC-100103526
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SYNTHETIC COMMUNICATIONS, 31(7), 987–992 (2001)
A FACILE ROUTE FOR THE PREPARATION
OF N-PHENYL TETRAHYDROQUINOLINES
AND TETRAHYDROISOQUINOLINES
´
Jerome Meneyrol, Philippe Helissey, Christophe Tratrat,
ˆ
Sylviane Giorgi-Renault,* and Henri-Philippe Husson
Laboratoire de Chimie The
´
´
rapeutique Associe
´
l’Universite Rene Descartes (UMR 8638), Faculte
´
au CNRS et
des
a
`
´
Sciences Pharmaceutiques et Biologiques, 4 Avenue de
l’Observatoire, 75270 Paris Cedex 06, France
ABSTRACT
A convenient N-arylation of tetrahydroquinoline and
tetrahydroisoquinoline is described using electron-poor,
electron-neutral, or electron-rich arylhalide derivatives and
palladium(II)-BINAP as a catalyst.
During the course of our investigations, we wanted to form a bond
between the 1,2,3,4-tetrahydroquinoline nitrogen and various aromatic
nuclei, especially polymethoxylated benzenes. To the best of our knowl-
edge, N-arylation of tetrahydroquinoline with electron-poor, electron-
neutral, or electron-rich halogeno derivatives has been scarcely studied. On
the one hand, four N-o and/or N-p-nitrophenyl derivatives have been
prepared in less than 20% yield by condensation of tetrahydroquinoline
1
–3
and nitrohalogenobenzenes in refluxing collidine.
Barton, on the other
*
Corresponding author.
9
87
Copyright & 2001 by Marcel Dekker, Inc.
www.dekker.com

9
88
MENEYROL ET AL.
hand, has synthesized 1-(4-methylphenyl) and 1-(2,4-dimethoxyphenyl)-
,2,3,4-tetrahydroquinoline in three steps from aryllead triacetate with
1
4
copper (II) acetate as a catalyst in 59% and 25% yields, respectively.
We decided to investigate the efficiency of the palladium-catalyst
arylation of tetrahydroquinoline 1 with arylhalides (Scheme 1) using palla-
0
0
dium (II) acetate, 2,2 -bis(diphenylphosphino)-1,1 -binaphthyl (BINAP).
5
–7
The mild conditions of the palladium-catalyzed aryl amination offer con-
siderable advantages over classic methods, which require either activated
halogenobenzenes or drastic reaction conditions.
Scheme 1.
To examine the scope of this palladium-catalyzed system, the coupling
of various substituted halides 2 with 1 was studied, and the results are
summarized in the Table. The reaction time varied from 15 min to
1
80 min, depending on the nature of the aryl halide. Various N-aryltetra-
hydroquinolines 3 can be prepared not only from bromobenzene (entry 1),
but also from halogenobenzenes bearing electron-donor (entries 3–6) or
electron-attracting groups (entries 8, 9) in good to excellent yields.
There is no difference in reactivity between unsubstituted, trimethoxy,
or monomethoxy halogenobenzenes and this, for the latters, whatever the
position of the methoxy group on the aromatic ring (entries 3–5). A similar
reaction using Ullmann conditions (copper catalyzed) did not allow us to
obtain the expected product. The reaction proceeds also efficiently with
electron-poor derivatives (entries 8–9) although longer reaction times were
necessary. Interestingly, the catalyst system showed efficient even if a much
lower concentration of palladium was used (2.5 mol%, entry 7; 0.5 mol%,
entry 2).
It is worth noting that, compared to the syntheses described in the
1
–4
literature,
this one-step palladium-catalyzed N-arylation of tetrahydro-
quinoline is an improvement in terms of yields, ease of execution and
work-up.
An extension of this reaction was performed on 1,2,3,4-tetrahydroiso-
quinoline 4 (Scheme 2). Unsubstituted, 4-methoxy and 3,4,5-trimethoxy-
phenyl derivatives 5a–c were prepared in lower yields as compared to the
tetrahydroquinoline series (entries 10–12).

TETRAHYDROQUINOLINES
989
Table. Palladium-Catalyzed Coupling of Tetrahydroquinoline 1 and Tetrahydro-
a
isoquinoline 4 with Arylhalides
Pd
Product Time Yield m.p.
ꢀ
Entry Amine
X
R
mol%
(h)
(%)
( C)
b
1
2
3
4
5
6
7
8
9
0
1
2
1
1
1
1
1
1
1
1
1
4
4
4
Br
Br
Br
Br
Br
I
I
I
Br
Br
Br
I
H
H
2-OMe
3-OMe
4-OMe
3,4,5-triOMe
3,4,5-triOMe
4-NO
4-CHO
H
5
0.5
5
5
5
5
2.5
5
5
5
3a
3a
3b
3c
3d
3e
3e
3f
3g
5a
5b
5c
0.25
3
80
82
80
79
79
87
80
62
64
50
39
40
oil
0.25
0.25
0.25
0.25
0.5
2.5
3
0.75
0.75
0.75
oil
oil
69
91
c
2
123
85
d
1
1
1
45
95
e
4-OMe
3,4,5-triOMe
5
5
oil
a
Reactions were performed with 1 equiv. of arylhalide, 1.2 equiv. of amine, 1.4 equiv.
ꢀ
b
of t-BuOK, cat. Pd(OAc) , and BINAP 1.1 equiv./Pd; m.p. of HI salt 147 C, ref.
2
c
d
ꢀ
ꢀ
e
8); no m.p. in ref. (1); m.p. 44.5 –45.5 C., ref. (9); m.p. 93 –95 C, ref. (4).
ꢀ
ꢀ
(
Scheme 2.
In conclusion, we have described the first intermolecular palladium-
catalyzed N-arylation of tetrahydroquinoline with substituted halogenoben-
zenes. This one-step reaction can be carried out using both electron-rich and
electron-poor arylhalides. Consequently, this simple method is very inter-
esting compared to the previously described reactions; furthermore, it gives
us an easy access to many new N-arylated compounds in the quinoline and
isoquinoline series.
EXPERIMENTAL
All melting points were determined on a Maquenne apparatus and
are uncorrected. IR spectra were recorded on Perkin-Elmer 1600 infrared

9
90
MENEYROL ET AL.
spectrophotometer. NMR spectra were recorded on Bruker AC-300 spectro-
meter; chemical shift values are given in ppm (ꢀ). Flash column chromato-
graphies were performed using Merck silica gel 60, 70–230 mesh ASTM.
General Procedure
To a solution of palladium (II) acetate (14 mg, 0.063 mmol), BINAP
43 mg, 0.069 mmol) in dry toluene (2 mL), arylhalide (1.25 mmol), and
(
tetrahydroquinoline or tetrahydroisoquinoline (200 mg, 1.5 mmol) were
added and then t-BuOK (197 mg, 1.75 mmol). The solution was vigorously
ꢀ
stirred at 100 C. The reaction was then quenched with water. After extrac-
tion with dichloromethane and evaporation of the solvents under reduced
pressure, the crude mixture was purified by flash chromatography (eluent:
CH Cl /cyclohexane from 20/80 to 50/50) to give pure 3 or 5.
2
2
1
-(2-Methoxyphenyl)-1,2,3,4-tetrahydroquinoline 3b
1
H NMR (300 MHz, CDCl ) ꢀ: 2.03 (quint., 2H, 6 Hz); 2.88 (t, 2H,
3
6
7
Hz); 3.52 (t, 2H, 6 Hz); 3.78 (s, 3H); 6.24 (d, 1H, 7.5 Hz); 6.60 (t, 1H,
.5 Hz); 6.84 (t, 1H, 7.5 Hz); 6.90–7.00 (m, 3H); 7.20 (t, 2H, 7.5 Hz).
1
3
C NMR (75.43 MHz, CDCl ) ꢀ: 22.2; 28.0; 50.3; 55.6; 112.7; 113.6;
3
116.6; 121.3; 122.1; 126.5; 126.9; 129.1; 129.5; 136.0; 145.1; 156.2.
IR (film): 1499; 1453; 1303; 1248.
1
-(3-Methoxyphenyl)-1,2,3,4-tetrahydroquinoline 3c
1
H NMR (300 MHz, CDCl ) ꢀ: 2.07 (quint., 2H, 6 Hz); 2.87 (t, 2H,
3
6
6
Hz); 3.63 (t, 2H, 6 Hz); 3.80 (s, 3H); 6.68 (d, 1H, 7 Hz); 6.75 (t, 1H, 7 Hz);
.80–6.90 (m, 3H); 6.98 (t, 1H, 7 Hz); 7.07 (d, 1H, 7 Hz); 7.25 (t, 1H, 7 Hz).
1
3
C NMR (75.43 MHz, CDCl ) ꢀ: 22.8; 27.7; 50.6; 55.2; 108.8; 110.0; 116.6;
3
118.5; 124.9; 126.3; 129.3; 129.9; 144.1; 149.6; 160.5. IR (film): 1595; 1575;
1491; 1456; 1197; 1161.
1
-(4-Methoxyphenyl)-1,2,3,4-tetrahydroquinoline 3d
1
H NMR (300 MHz, CDCl ) ꢀ: 2.05 (quint., 2H, 6 Hz); 2.88 (t, 2H,
3
6
8
Hz); 3.56 (t, 2H, 6 Hz); 3.81 (s, 3H); 6.50 (d, 1H, 8.5 Hz); 6.65 (t, 1H,
1
.5 Hz); 6.90 (m, 3H), 7.02 (d, 1H, 8.5 Hz); 7.19 (d, 2H, 9 Hz). C NMR
3

TETRAHYDROQUINOLINES
991
(
75.43 MHz, CDCl ) ꢀ: 22.6; 27.0; 51.7; 55.5; 114.3; 114.9; 117.3; 123.0;
3
1
26.6; 127.7; 129.6; 141.4; 145.6; 156.8; IR (film): 1508; 1492; 1241.
1
-(3,4,5-Trimethoxyphenyl)-1,2,3,4-tetrahydroquinoline 3e
1
H NMR (300 MHz, CDCl ) ꢀ: 2.02 (quint., 2H, 6 Hz); 2.85 (t, 2H,
3
6
6
2
Hz); 3.55 (t, 2H, 6 Hz); 3.78 (s, 6H); 3.84 (s, 3H); 6.44 (s, 2H); 6.62 (m, 2H);
3
1
.89 (t, 1H, 7 Hz); 6.98 (d, 1H, 7 Hz). C NMR (75.43 MHz, CDCl ) ꢀ: 22.5;
3
7.5; 51.1; 55.9; 60.7; 102.7; 115.0; 117.6; 123.5; 144.1; 144.6; 153.6. IR
(
film): 1588; 1504; 1454; 1232; 1127.
1
-(4-Nitrophenyl)-1,2,3,4-tetrahydroquinoline 3f
1
H NMR (300 MHz, CDCl ) ꢀ: 2.05 (quint., 2H, 6 Hz); 2.77 (t, 2H,
3
6
7
1
Hz); 3.72 (t, 2H, 6 Hz); 7.00 (t, 1H, 7 Hz); 7.10–7.30 (m, 5H); 8.11 (d, 2H,
3
1
Hz). C NMR (75.43 MHz, CDCl ) ꢀ: 24.2; 27.3; 48.9; 117.5; 120.7; 123.0;
3
25.6; 126.6; 129.4; 131.1; 140.8; 153.5. IR (film): 1589; 1495; 1311; 1111.
4
-(3,4-Dihydro-2H-quinolin-1-yl)benzaldehyde 3g
1
H NMR (300 MHz, CDCl ) ꢀ: 2.03 (quint., 2H, 6 Hz); 2.75 (t, 2H,
3
6
1
1
1
Hz); 3.71 (t, 2H, 6 Hz); 6.90–7.30 (m, 6H); 7.75 (d, 2H, 7.5 Hz); 9.82 (s,
1
3
H). C NMR (75.43 MHz, CDCl ) ꢀ: 23.8; 27.2; 48.7; 118.5; 119.9; 122.0;
3
26.3; 129.0; 129.1; 129.9; 131.2; 131.9; 153.2; 190.3. IR (film): 1686; 1592;
490; 1328; 1165.
1
-(3,4,5-Trimethoxyphenyl)-1,2,3,4-tetrahydroisoquinoline 5c
1
H NMR (300 MHz, CDCl ) ꢀ: 3.47 (t, 2H, 6 Hz); 3.96 (t, 2H, 6 Hz);
3
4
.30 (s, 3H); 4.38 (s, 6H); 4.82 (s, 2H); 6.70 (s, 2H); 7.60–7.70 (m, 4H).
1
3
C NMR (75.43 MHz, CDCl ) ꢀ: 29.0; 47.2; 51.4; 55.8; 60.7; 93.5; 104.3;
3
1
1
25.8; 126.1; 128.3; 134.0; 134.4; 147.4; 153.4. IR (film): 1605; 1583; 1510;
451; 1238; 1126.
ACKNOWLEDGMENTS
J.M. and C.T. thank MENRT and La Ligue Nationale contre le
Cancer, respectively, for a grant.

9
92
MENEYROL ET AL.
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Accepted June 5, 2000