Synthesis of new 8-arylisoquinoline derivatives by application of palladium-catalyzed Suzuki cross-coupling reactions

Article abstract of DOI:10.1016/j.tet.2005.06.025

New 8-(het)aryltetrahydroisoquinolines (10-14), 8- aryltetrahydroisoquinolin-4-ols (15,16), and 8-phenylisoquinolin-4-ol (17), flexible analogues of aporphine, were synthesized in good yields using palladium-catalyzed Suzuki cross-coupling reactions from

Full text of DOI:10.1016/j.tet.2005.06.025

Tetrahedron 61 (2005) 8282–8287
Synthesis of new 8-arylisoquinoline derivatives by application of
palladium-catalyzed Suzuki cross-coupling reactions
a
b
a,
Inmaculada Andreu,a Nuria Cabedo,a,b Frederic Fabis, Diego Cortes and Sylvain Rault
*
´ ´
a
´ ´
Centre d’Etudes et de Recherche sur le Medicament de Normandie, UFR des Sciences Pharmaceutiques, Universite de Caen,
´
5 rue Vaubenard, 14032 Caen Cedex, France
bDepartamento de Farmacologia, Laboratorio de Farmacognosia, Facultad de Farmacia, Universidad de Valencia, 46100 Burjassot,
Valencia, Spain
Received 18 April 2005; revised 7 June 2005; accepted 8 June 2005
Available online 1 July 2005
Abstract—New 8-(het)aryltetrahydroisoquinolines (10–14), 8-aryltetrahydroisoquinolin-4-ols (15,16), and 8-phenylisoquinolin-4-ol (17),
flexible analogues of aporphine, were synthesized in good yields using palladium-catalyzed Suzuki cross-coupling reactions from
8-bromotetrahydroisoquinolin-4-one (6) as a common intermediate. We also describe the synthesis of this novel intermediate through an easy
and efficient method, which involved intramolecular Friedel–Crafts cyclization.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
pharmacological point of view, we can consider 8-aryliso-
quinoline derivatives as flexible structural analogues of
aporphines without any C-7 methylene bridge (Fig. 1).
For many years, isoquinoline alkaloids have been an
interesting structural class of compounds, which have
found many uses in the field of medicinal chemistry.
Although many methods such as Bischler–Napieralski (this
cyclization requires an electron-donating group to direct the
cyclization to its para position), Pictet–Spengler and
Pomeranz–Fritsch reactions are available for the synthesis
of IQ, none is satisfactory for the one of 8-arylIQ
derivatives. To our knowledge, in the synthesis of
8-arylTHIQ derivatives, only a small number of approaches
have been reported.5 Ellefson accomplished two different
routes following multi-step sequences and using an aryl-
oxazoline as key intermediate.5a,b Hara prepared tetra-
hydroisoquinoline dimers from p-quinol acetate.5c
McKenna et al. prepared a mixture of 6- and 8-arylTHIQ
isomers by Suzuki–Miyaura cross-coupling reactions of
triflates.5d The latter method is complex, and requires the
preparation of a bromo intermediate in order to block the
6-position, so as to avoid a mixture of cyclization products.
An alternative method to prepare 8-arylTHIQ through
catalytic hydrogenation of the parent 8-arylIQ has been
reported without specifying what yield was obtained in the
reduction reaction.5e The 8-arylIQ parents were prepared
(R)-Apomorphine1 as well as many natural2 and synthetic3
aporphines (Fig. 1) have been extensively studied for their
interaction with the receptors of the central nervous
system.4
Figure 1. Structures of isoquinolines.
In this medicinal chemistry context, we have decided to
focus on the preparation of new 8-arylisoquinoline
derivatives (8-arylIQ), first, because only few studies have
been realized on this type of structure and second because
no efficient method of preparation has been reported. From a
using
dichloro[1,3-bis(diphenylphosphino)propane]-
nickel(II) as catalyst in the coupling reaction between
organomagnesium halides and haloisoquinolines. However,
this procedure has some limitations. Indeed, on the one
hand, the availability of many haloisoquinolines, notably of
8-haloisoquinolines is restricted, and on the other hand,
Keywords: 8-Bromotetrahydroisoquinoline; Friedel–Crafts cyclization;
8-Aryltetrahydroisoquinolines; Suzuki cross-coupling reactions.
*
Corresponding author. Tel.: C33 231934169; fax: C33 231931188;
e-mail: rault@pharmacie.unicaen.fr
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.06.025

I. Andreu et al. / Tetrahedron 61 (2005) 8282–8287
8283
many substituents are not compatible with the hydrogen-
ation step. None of these methods can actually be applied to
produce a library of various 8-arylIQ.
2-bromobenzaldehyde and glycine methyl ester10 (1) to
give the secondary amine 2. N-protection of the amine 2
with a p-toluenesulfonyl group, hydrolysis of the ester
function and the subsequent activation into its acid chloride
allowed the required precursor 5 to cyclization (see
Scheme 2).
Herein, in order to construct the structurally flexible
aporphine analogues, we describe an efficient pathway to
the preparation of 8-arylIQ derivatives from the new
8-bromotetrahydroisoquinolin-4-one as a common inter-
mediate. Nevertheless, the synthesis of 8-halogenoIQ is
rarely reported in the literature and often involves tedious
approaches under drastic conditions and in moderate
yields.6 Indeed, 8-bromoTHIQ was synthesized by Pictet–
Spengler reaction from phenylethylamine in low yield
because this reaction requires an electron-donating group on
the aromatic ring.7 It is the reason why, in the first part of
this study, we present a new route for the synthesis of
8-bromoIQ and 8-bromoTHIQ intermediates followed by
the results of their use as partners of palladium-catalyzed
Suzuki cross-coupling reaction with various arylboronic
acids as depicted in the retrosynthetic pathway (Scheme 1).
The treatment of 5 with AlCl3 in CH2Cl2 at K78 8C leads to
8-bromoTHIQ-4-one 6 in a 64% yield showing thus that this
cyclization could be achieved in the presence of an electron-
withdrawing substituent. To obtain a clean and good yield
reaction, it was essential to keep the temperature below
K10 8C (Scheme 2).
Then starting from this 8-bromoTHIQ-4-one (6) all our
attempts to perform palladium catalyzed Suzuki cross-
coupling reactions with arylboronic acids in standard
conditions failed, since it always led to the aromatized
8-bromoIQ-4-ol (7).
Studying the elimination of the tosyl group we demonstrated
that the aromatization of 6 occurred in mild alkaline
medium such as sodium hydrogen carbonate solution. To
overcome this problem, the ketone 6 was reduced by using
the combination of a 0.07% catalytic amount of InCl3 and
Scheme 1. Retrosynthetic pathway.
2. Results and discussion
We first aimed at synthesizing the new 8-bromotetra-
hydroisoquinolin-4-one in a six-step pathway, thanks to an
easy and efficient method based on Nichols et al.8
methodology, which we used to prepare 8-methylTHIQ-4-
one. The key step of this methodology a very mild low
controlled temperature intramolecular Friedel–Crafts type
cyclization. The synthesis of 8-bromoTHIQ-4-one (6) was
started with the standard reductive amination9 of
Scheme 3. Synthesis of 8-aryl(TH)IQ. Reagents and conditions; yields refer
to isolated products after column chromatography on silica gel: (i) aq satd
NaHCO3, EtOH; reflux, 77%; (ii) NaBH4, EtOH, rt. 3 h, 95%; (iii) 0.07%
InCl3, Me2SiHCl, CH2Cl2, reflux, 78%; (iv) 1 equiv 8-BrIQ, 1.3 equiv
RB(OH)2, base (3 equiv 2 M Na2CO3 or 2 equiv NaOH), toluene/EtOH 20:
1, 5% Pd(PPh3)4, 27–66%; (v) Na/NH3 (liq.), THF, 62%.
Scheme 2. Synthesis of 8-bromoTHIQ-4-one. Reagents and conditions:
(i) methylglycinate, Et3N/EtOH, MgSO4, rt, 2 h, followed by NaBH4, rt,
overnight; (ii) PTSCl, 4-DMAP/Et3N, CH2Cl2, 0 8C to rt, 6 h; (iii) 15% aq
NaOH, reflux, 3 h; (iv) SOCl2, CH2Cl2, reflux, 5 h; (v) AlCl3, CH2Cl2, K78
to K10 8C, 4 h.

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I. Andreu et al. / Tetrahedron 61 (2005) 8282–8287
Me2SiHCl (4.7 equiv) in CH2Cl2 at reflux11 to give the
8-Br-THIQ (9). Only partial reduction to the alcohol was
found using other Lewis acid reagents such as AlCl3 in
combination with NaBH4 or AlLiH4. Furthermore, when we
used the hydrogenation standard methods (e.g., H2/Pd–C)
the results were not very satisfactory because of the
debromination or partial cleavage of the N-tosyl group
leading to unusable mixtures. Finally we prepared 8-bromo-
THIQ-4-ol (8) using NaBH4 in ethanol (Scheme 3).
(148 g, 0.57 mol, 71%). Mp: 84–86 8C. IR: 3340, 2942,
1743, 1466, 1438, 1202, 1026, 752 cmK1. 1H NMR (CDCl3,
400 MHz) d 7.50 (d, 1H, JZ8.0 Hz), 7.36 (d, 1H, JZ
7.7 Hz), 7.20 (t, 1H, JZ7.5 Hz), 7.10 (t, 1H, JZ7.5 Hz),
3.81 (s, 2H), 3.70 (s, 3H), 3.42 (s, 2H), 2.10 (br s, 1H). 13C
NMR (CDCl3, 100 MHz) d 172.0, 138.0, 132.2, 129.6,
128.5, 127.0, 123.5, 52.4, 52.1, 49.3. EIMS m/z (%) 257
[M]C(3), 198 (73), 184 (28), 169 (100). Anal. Calcd for
C10H12NO2Br: C, 46.53; H, 4.69; N, 5.43. Found: C, 46.61;
H, 4.73; N, 5.63.
To achieve our goal we submitted the three key
intermediates 7, 8, 9 to palladium catalyzed Suzuki cross-
coupling reactions. In all cases and in standard conditions
the results were satisfactory producing 8-(het)arylTHIQ
(10–14), 8-arylTHIQ-4-ol (15,16) and 8-phenylIQ-4-ol 17
in 27–66% yield. N-Tosyl protecting group can be removed
under standard conditions12 (sodium in ammonia), for
example, N-tosyl derivative (13) gave the corresponding
deprotected 8-(3,4-dimethoxyphenyl)THIQ5e (18) in good
yield (Scheme 3).
3.2.2. Methyl N-(2-bromobenzyl)-N-[(4-methylphenyl)-
sulfonyl]glycinate (3). The p-toluenesulfonyl chloride
(42.51 g, 0.22 mol) was added to a stirred solution of
amine (2, 57.42 g, 0.22 mol) 4-DMAP (1.36 g, 0.011 mol)
and Et3N (62.68 mL, 0.45 mol) in CH2Cl2 (400 mL) at 0 8C.
The reaction mixture was stirred at room temperature for
6 h, and then quenched by addition of 2 N HCl. The layers
were separated and the organic layer was washed with H2O,
brine, dried over MgSO4 and concentrated to provide a
white residue, which crystallized from CH2Cl2/EtOAc
giving the compound 3 as colourless crystals (70.7 g,
0.17 mol, 77%). Mp: 104–106 8C. IR: 3483, 2952, 1751,
These palladium-catalyzed Suzuki cross-coupling reactions,
enabled us to gain access to 8-arylisoquinoline derivatives,
which would have been difficult to prepare via other
methods.
1
1597, 1430, 1311, 1210, 1118, 1095, 768, 548 cmK1. H
NMR (CDCl3, 400 MHz) d 7.75 (d, 2H, JZ8.2 Hz), 7.47–
7.53 (m, 2H), 7.26–7.35 (m, 3H), 7.17 (t, 1H, JZ7.6 Hz),
4.62 (s, 2H), 3.99 (s, 2H), 3.56 (s, 3H), 2.45 (s, 3H). 13C
NMR (CDCl3, 100 MHz) d 169.0, 143.6, 136.5, 134.5,
132.8, 130.3, 129.5, 129.4, 127.8, 127.4, 123.7, 52.0, 51.1,
47.5, 21.5. LC–MS (ES positive mode) m/z 258 [MC1K
Ts]C EIMS m/z (%) 353 [MKCOOCH3]C(35), 257 (70),
198 (10), 169 (100), 91 (80). Anal. Calcd for C17H18NO4-
BrS: C, 49.52; H, 4.40; N, 3.40. Found: C, 49.57; H, 4.63; N,
3.28.
In conclusion, this study demonstrates that, thanks to our
efficient and new method of synthesis, 8-arylIQ derivatives
can be obtained by a straightforward route. Moreover, it also
shows that 8-bromoTHIQ-4-one opens the way to a valuable
medicinal chemistry scaffolding.
3. Experimental
3.1. General instrumentation
3.2.3. N-(2-Bromobenzyl)-N-[(4-methylphenyl)sul-
fonyl)]-glycine (4). The acetic acid methyl ester 3 (64.2 g,
0.16 mol) was treated with a 15% aq NaOH solution
(400 mL) and refluxed for 3 h. The mixture was cooled in an
ice-bath, diluted with H2O and washed with CH2Cl2, and
then the aqueous layer was acidified with 1 M HCl, and
extracted with AcOEt. The combined organic layers were
washed with H2O, brine and evaporated under reduced
pressure. The residue was crystallized from CH2Cl2/EtOAc
to give the acid 4 as white crystals (47.64 g, 0.12 mol, 75%).
IR: 3430, 3055, 2972, 1728, 1597, 1440, 1345, 1167, 1095,
Commercial reagents were used without additional purifi-
cation. Melting points were taken on a Wagner and
Heizbank system Kofler type WME. IR spectra were run
on a Perkin–Elmer BX FT-IR spectrometer using KBr
pellets. EIMS and HREIMS were recorded on a JEOL JMS
GCMate spectrometer. Liquid chromatography with mass
spectrometry detection (LC–MS) with ESI (electrospray
ionization) in positive mode was determined on a HPLC–
MS Waters 2695. 1H NMR and 13C NMR were recorded on
a JEOL Lambda 400 Spectrometer at 400 and 100 MHz,
respectively. Coupling constants (J) are reported in Hz.
NMR chemical shifts are reported in ppm downfield from an
internal solvent peak. All reactions were monitored by
analytical TLC. The residues were purified through silica
gel 60 (0.063–0.2 mm) (Merck). Elemental analyses for new
compounds were performed at the ‘Institut de Recherche en
Chimie Organique Fine’ (Rouen-France).
1
950, 756, 546 cmK1. H NMR (CDCl3, 400 MHz) d 10.49
(br s, 1H), 7.73 (d, 2H, JZ8.2 Hz,), 7.51 (d, 1H, JZ8.0 Hz),
7.45 (d, 1H, JZ7.7 Hz), 7.26–7.30 (m, 3H), 7.16 (t, 1H, JZ
7.8 Hz), 4.61 (s, 2H), 4.01 (s, 2H), 2.43 (s, 3H). 13C NMR
(CDCl3, 100 MHz) d 174.2, 143.7, 136.2, 134.1, 132.7,
130.3, 129.5, 127.7, 127,2, 123.7, 51.2, 47.4, 21.4. LC–MS
(ES positive mode) m/z 398 [MC1]C. EIMS m/z (%) 354
[MKCOO]C(14), 242 (36), 198 (13), 169 (83), 91 (100).
Anal. Calcd for C16H16NO4BrS: C, 48.25; H, 4.05; N, 3.52.
Found: C, 48.43; H, 3.98; N, 3.71.
3.2. General procedure for synthesis of isoquinolines
7, 8, 9
3.2.4. N-(2-Bromobenzyl)-N-[(4-methylphenyl)sul-
fonyl)]-glycyl chloride (5). Under argon, a solution of the
acid 4 (46 g, 0.116 mol) in CH2Cl2 (350 mL) was treated
with SOCl2 (25.4 mL, 0.348 mol) and refluxed for 5 h. The
solvent and the excess of SOCl2 were distilled off under
vacuum. The residue was used directly in the following
3.2.1. Methyl N-(2-bromobenzyl)glycinate (2). Prepared
from glycine methyl ester10 (1, 72 g, 0.8 mol) and
2-bromobenzaldehyde (98 g, 0.53 mol) by standard pro-
cedure.9 The residue was purified by silica gel column
chromatography (cyclohexane/EtOAc, 80:20) to yield 2

I. Andreu et al. / Tetrahedron 61 (2005) 8282–8287
8285
reaction without further purification. 1H NMR (CDCl3,
400 MHz) d 7.73 (d, 2H, JZ8.4 Hz), 7.51 (d, 1H, JZ8.0,
1.2 Hz), 7.45 (dd, 1H, JZ7.8, 1.6 Hz), 7.29–7.34 (m, 3H),
7.18 (td, 1H, JZ7.7, 1.6 Hz), 4.58 (s, 2H), 4.40 (s, 2H), 2.43
(s, 3H).
compound 8 as a white solid (1.9 g, 4.98 mmol, 95%).
Mp: 124–126 8C. IR: 3410, 2921, 2360, 1596, 1432, 1327,
1159, 1091, 967, 814, 666 cmK1 1H NMR (CDCl3,
.
400 MHz) d 7.76 (d, 2H, JZ8.3 Hz), 7.47 (d, 1H, JZ
7.8 Hz), 7.41 (d, 1H, JZ7.8 Hz), 7.37 (d, 2H, JZ8.3 Hz),
7.15 (t, 1H, JZ7.8 Hz), 4.75 (m, 1H), 4.48 (d, 1H, JZ
15.8 Hz), 3.83 (d, 1H, JZ15.8 Hz), 3.66 (dd, 1H, JZ3.2,
11.9 Hz), 3.09 (dd, 1H, JZ3.2, 11.9 Hz), 2.42 (s, 3H). 13C
NMR (CDCl3, 100 MHz) d 144.2, 138.2, 132.9, 132.2,
131.3, 130.0, 128.7, 128.3, 128.0, 127.1, 121.8, 66.1, 50.8,
50.1, 21.5. EIMS m/z (%) 381 [M]C(5), 226 (53), 198 (51),
184 (100), 155 (94), 91 (62). Anal. Calcd for C16H16NO3-
SBr: C, 50.27; H, 4.22; N, 3.66. Found: C, 50.38; H, 4.17; N,
3.58.
3.2.5. 8-Bromo-2-[(4-methylphenyl)sulfonyl]-2,3-dihydro-
1H-isoquinolin-4-one (6). AlCl3 (560 mg, 4.20 mmol) was
added in portions with stirring to a solution of the acid
chloride 5 (500 mg) in anhydrous CH2Cl2 (15 mL)
previously pre-cooled to K78 8C and under N2 atmosphere.
The reaction mixture was allowed to warm to K10 8C over
4 h. Then, a 10% aq HCl solution–ice mixture was added
dropwise at K10 8C and stirred for 30 min. The layers were
separated and the aqueous layer was extracted with CH2Cl2.
The organic layers were combined, washed with H2O, brine,
dried over MgSO4, filtered, evaporated and concentrated
under reduced pressure. The residue was purified by silica
gel column chromatography (cycloxenane/EtOAc, 90:10) to
give 8-bromoTHIQ-4-one 6 as a white solid (291 mg, 64%).
IR: 3387, 2926, 2863, 1706, 1586, 1431, 1349, 1286, 1162,
3.2.8. 8-Bromo-2-[(4-methylphenyl)sulfonyl]-1,2,3,4-
tetrahydroisoquinoline (9). A mixture of 0.07% InCl3
(82 mg, 0.37 mmol) and Me2SiHCl (2.34 g, 24.8 mmol) in
anhydrous CH2Cl2 (6 mL) at room temperature was treated
with 8-BrTHIQ-4-one (6, 2.0 g, 5.27 mmol) in anhydrous
CH2Cl2 (10 mL). The reaction mixture was stirred and
refluxed overnight, cooled at room temperature, diluted with
H2O and extracted with CH2Cl2. The organic layers were
washed with 5% aq HCl, satd NaHCO3, brine, dried over
MgSO4, partially evaporated and precipitated with MeOH
to obtain a white solid (8, 1.5 g, 4.11 mmol, 78%). Mp: 112–
1091, 1028, 961, 860, 814, 699, 544 cmK1 1H NMR
.
(CDCl3, 400 MHz) d 7.76 (d, 1H, JZ7.8 Hz), 7.71 (d, 1H,
JZ7.9 Hz), 7.60 (d, 2H, JZ8.2 Hz), 7.19–7.24 (m, 3H),
4.57 (s, 2H), 4.04 (s, 2H), 2.36 (s, 3H). 13C NMR (100 MHz,
CDCl3) d 189.7, 144.2, 137.8, 137.6, 132.9, 131.7, 129.8,
129.4, 128.7, 125.9, 121.5, 53.3, 48.0, 21.3. EIMS m/z (%)
379 [M]C(5), 224 (100), 148 (23), 105 (54), 91 (49). HRMS
(EI) (MC) calcd for C16H14NO3SBr 378.9877, found
378.9888. Anal. Calcd for C16H14NO3SBr: C, 50.54; H,
3.71; N, 3.68. Found: C, 50.45; H, 3.68; N, 3.70.
114 8C. IR: 2963, 2361, 1598, 1261, 1093, 1024, 800 cmK1
.
1H NMR (CDCl3, 400 MHz) d 7.62 (d, JZ8.3 Hz, 2H), 7.23
(m, 3H), 6.93–6.98 (m, 2H), 4.12 (s, 2H), 3.26 (t, JZ5.7 Hz,
2H), 2.87 (t, JZ5.7 Hz, 2H), 2.36 (s, 3H). 13C NMR
(CDCl3, 100 MHz) d 143.8, 135.9, 133.3, 131.3, 130.4,
129.8, 128.0, 127.9, 122.5, 48.5, 43.2, 29.3, 21.5. EIMS m/z
(%) 365 [M]C(10), 210 (100), 184 (24), 130 (15), 91 (40).).
HRMS (EI) (MC) calcd for C16H16NO2SBr 365.0085,
found 365.0145. Anal. Calcd for C16H16NO2SBr: C, 52.47;
H, 4.40; N, 3.82. Found: C, 52.29; H, 4.31; N, 3.91.
3.2.6. 8-Bromoisoquinolin-4-ol (7). A solution of 8-bromo-
THIQ-4-one 6 (770 mg, 2.03 mmol) and satd aq NaHCO3
solution (50 mL) in EtOH (10 mL) was refluxed overnight.
The solvent was partially evaporated and the mixture was
extracted with EtOAc. The organic layer was washed with
H2O, brine, dried over MgSO4, filtered, evaporated and
concentrated under reduced pressure. The residue was
purified by silica gel column chromatography (cyclohexane/
EtOAc, 80:20) to yield 7 as a brown powder (350 mg,
1.56 mmol, 77%). Mp: 230 8C. IR: 3438, 2925, 2854, 1585,
3.3. General procedure for the synthesis of 8-(Het)-
aryltetrahydroisoquinolines 10–16
A degassed (Ar) solution of 8-BrTHIQ (9), (350 mg,
0.96 mmol) or 8-BrTHIQ-4-ol (8, 350 mg, 0.92 mmol) in
a mixture of toluene/EtOH (20:1, v/v), (42 mL) and 0.05%
Pd(PPh3)4 (80 mg, 0.07 mmol) was treated with the
aryllboronic acid (1.5 equiv), and 2 M Na2CO3 (3 equiv).
The reaction mixture was refluxed overnight under nitrogen.
The mixture was then hydrolysed with H2O and extracted
with EtOAc. The organic layers were washed with brine and
water, dried over MgSO4, filtered and concentrated under
vacuum. The crude material was purified through silica gel
column chromatography yielding the 8-(Het)aryltetra-
hydroisoquinolines 10–16.
1
1458, 1402, 1364, 1304, 1145, 850, 802 cmK1. H NMR
(DMSO, 400 MHz) d 10.78 (br s, 1H), 8.95 (s, 1H), 8.17 (s,
1H), 8.15 (d, 1H, JZ8.2 Hz), 7.96 (d, 1H, JZ7.6 Hz), 7.61
(t, 1H, JZ7.9 Hz). 13C NMR (DMSO, 100 MHz) d 148.1,
141.1, 131.7, 129.7, 128.0, 126.8, 126.5, 121.3, 120.5.
EIMS m/z (%) 223 [M]C(33), 184 (34), 116 (59), 91 (100).).
HRMS (EI) (MC) calcd for C9H6NOBr 222.9632, found
222.9617. Anal. Calcd for C9H6NOBr: C, 48.25; H, 2.70; N,
6.25. Found: C, 48.37; H, 2.64; N, 6.33.
3.2.7. 8-Bromo-2-[(4-methylphenyl)sulfonyl]-1,2,3,4-
tetrahydroisoquinolin-4-ol (8). Over an ice-bath, NaBH4
(600 mg, 15.79 mmol) was added to a solution of 8-bromo-
THIQ-4-one 6 (2 g, 5.27 mmol) in EtOH (50 mL). The
reaction mixture was stirred at room temperature for 3 h.
After this time, the suspension was basified with saturated
NaHCO3 saturated and extracted with EtOAc. The
combined organic layers were washed with brine, dried
over MgSO4, filtered and evaporated under reduced
pressure. The residue was purified by silica gel column
chromatography (hexane/EtOAc, 70:30) to afford the
3.3.1. 8-Phenyl-2-[(4-methylphenyl)sulfonyl]-1,2,3,4-tet-
rahydroisoquinoline (10). Column chromatography
(petroleum ether/EtOAc, 96:4) yielded a white solid (10,
199 mg, 0.55 mmol, 57%). Mp: 150–152 8C. IR: 3428,
2920, 2360, 2326, 1597, 1495, 1452, 1338, 1165, 1090, 954,
814, 705 cmK1. 1H NMR (CDCl3, 400 MHz) d 7.48 (d, 2H,
JZ8.3 Hz), 7.34–7.29 (m, 3H), 7.17 (d, 2H, JZ8.3 Hz),
7.12–7.10 (m, 3H), 7.0–6.95 (m, 2H), 4.01 (s, 2H), 3.28 (t,
2H, JZ5.9 Hz), 2.91 (t, 2H, JZ5.9 Hz), 2.32 (s, 3H). 13C
NMR (CDCl3, 100 MHz) d 143.5, 140.6, 140.0, 133.6,

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133.5, 129.6, 129.4, 128.8, 128.4, 127.9, 127.6, 127.5,
126.6, 46.6, 43.5, 29.2, 21.4. EIMS m/z (%) 363 [M]C(17),
208 (100), 165 (32), 133 (25), 91 (56). HRMS (EI) (MC)
calcd for C22H21NO2S 363.1293, found 363.1273. Anal.
Calcd for C22H21NO2S: C, 72.70; H, 5.82; N, 3.85. Found:
C, 72.83; H, 5.77; N, 3.87.
3.3.5. 8-(Pyridin-3-yl)-2-[(4-methylphenyl)sulfonyl]-1,2,
3,4-tetrahydroisoquinoline (14). Column chromatography
(cyclohexane/EtOAc, 80:20) yielded a beige solid (95 mg,
0.26 mmol, 27%). Mp: 104–106 8C. IR: 3457, 2924, 2850,
2360, 1597, 1457, 1338, 1163, 1019, 950, 815, 785, 751,
1
661 cmK1. H NMR (CDCl3, 400 MHz) d 8.68 (br s, 1H),
8.50 (br s, 1H), 7.57 (d, 2H, JZ8.0 Hz), 7.30–7.23 (m, 5H),
7.14 (d, 1H, JZ7.6 Hz), 7.03 (d, 1H, JZ7.6 Hz), 4.07 (s,
2H), 3.37 (t, 2H, JZ5.9 Hz), 3.03 (t, 2H, JZ5.9 Hz), 2.41
(s, 3H). 13C NMR (CDCl3, 100 MHz) d 149.5, 149.0, 143.7,
136.7, 136.3, 134.0, 133.3, 129.7, 128.9, 128.2, 127.6,
126.9, 46.6, 43.5, 29.2, 21.5. EIMS m/z (%) 364.[M]C(36),
209 (100), 180 (49), 155 (23), 91 (73). HRMS (EI) (MC)
calcd for C21H20N2O2S 364.1245, found 364.1221. Anal.
Calcd for C21H20N2O2S: C, 69.21; H, 5.53; N, 7.69. Found:
C, 69.44; H, 5.58; N, 7.73.
3.3.2. 8-(4-Methylphenyl)-2-[(4-methylphenyl)sulfonyl]-
1,2,3,4-tetrahydroisoquinoline (11). Column chromato-
graphy (petroleum ether/EtOAc, 96:4) yielded a white solid
(180 mg, 0.48 mmol, 50%). Mp: 178–180 8C. IR: 3424,
2919, 2855, 2360, 1592, 1515, 1458, 1358, 1338, 1168, 952,
940, 789, 750 cmK1. 1H NMR (CDCl3, 400 MHz) d 7.57 (d,
2H, JZ8.3 Hz), 7.27 (d, 2H, JZ8.0 Hz), 7.23–7.16 (m, 3H),
7.08 (d, 2H, JZ8.0 Hz), 7.06–7.02 (m, 2H), 4.12 (s, 2H),
3.35 (t, 2H, JZ6.0 Hz), 2.97 (t, 2H, JZ6.0 Hz), 2.42 (s,
3H), 2.40 (s, 3H). 13C NMR (CDCl3, 100 MHz) d 143.5,
140.6, 137.1, 137.0, 133.6, 133.5, 129.6, 129.5, 129.1,
128.6, 128.0, 127.7, 127.6, 126.5, 46.7, 43.6, 29.2, 21.5,
21.2. EIMS m/z (%) 377 [M]C(10), 221 (74), 178 (37), 132
(66), 104 (51), 91 (100), 77 (37). HRMS (EI) (MC) calcd for
C23H23NO2S 377.1449, found 377.1391. Anal. Calcd for
C23H23NO2S: C, 73.18; H, 6.14; N, 3.71. Found: C, 73.09;
H, 6.22; N, 3.84.
3.3.6. 8-Phenyl-2-[(4-methylphenyl)sulfonyl]-1,2,3,4-
tetrahydroisoquinolin-4-ol (15). Column chromatography
(petroleum ether/CH2Cl2/EtOAc, 90:4:6) yielded a white
solid (188 mg, 0.50 mmol, 54%). Mp: 122–124 8C. IR:
3517, 3065, 3029, 2920, 2855, 1595, 1497, 1458, 1340,
1252, 1219, 1161, 1089, 952, 811, 762, 703 cmK1. 1H NMR
(CDCl3, 400 MHz) d 7.57 (d, 2H, JZ8.3 Hz), 7.43–7.36 (m,
4H), 7.29–7.26 (m, 3H), 7.18–7.16 (m, 2H), 7.12–7.10 (m,
1H), 4.80 (br s, 1H), 4.26 (d, 1H, JZ15.5 Hz), 3.83 (d, 1H,
JZ15.5 Hz), 3.58 (dd, 1H, JZ12.0, 3.8 Hz), 3.16 (dd, 1H,
JZ12.0, 3.8 Hz), 3.10 (br s, 1H), 2.38 (s, 3H). 13C NMR
(CDCl3, 100 MHz) d 144.0, 140.3, 139.7, 135.8, 133.0,
133.5, 129.9, 129.8, 129.3, 128.7, 128.6, 128.5, 127.7,
127.3, 66.4, 50.8, 47.1, 21.5. EIMS m/z (%) 379 [M]C(8),
224 (48), 206 (34), 196 (100), 167 (57), 155 (24), 91 (38).
HRMS (EI) (MC) calcd for C22H21NO3S 379.1242, found
379.1266. Anal. Calcd for C22H21NO3S: C, 69.63; H, 5.58;
N, 3.69. Found: C, 69.57; H, 5.52; N, 3.81.
3.3.3. 8-(2-Acetylphenyl)-2-[(4-methylphenyl)sulfonyl]-
1,2,3,4-tetrahydroisoquinoline (12). Column chromato-
graphy (cyclohexane/EtOAc, 80:20) yielded a beige syrup
(225 mg, 0.56 mmol, 58%). Mp: !50 8C. IR: 3430, 2920,
2840, 2360, 2342, 1684, 1596, 1457, 1337, 1164, 1090, 953,
815, 668 cmK1. 1H NMR (CDCl3, 400 MHz) d 7.63 (d, 1H,
JZ7.3 Hz), 7.46–7.37 (m, 4H), 7.16 (d, 2H, JZ7.8 Hz),
7.05 (dd, 2H, JZ7.3, 1.2 Hz), 6.99 (d, 1H, JZ7.6 Hz), 6.79
(d, 1H, JZ7.3 Hz), 3.96 (d, 1H, JZ15.6 Hz), 3.72 (d, 1H,
JZ15.6 Hz), 3.30 (m, 1H), 3.17 (m, 1H), 2.86 (m, 2H), 2.28
(s, 3H), 1.97 (s, 3H). 13C NMR (CDCl3, 100 MHz) d 201.4,
143.5, 139.3, 139.2, 138.5, 133.5, 131.3, 130.4, 129.5,
129.4, 128.6, 128.3 127.9, 127.4, 127.3, 126.4, 46.3, 43.3,
29.3, 28.9, 21.3. LC–MS (ES positive mode) m/z 405 [MC
1]C. EIMS m/z (%) 250 (100), 91 (26). HRMS (EI) (MC)
calcd for C24H23NO3S 405.1398, found 405.1352. Anal.
Calcd for C24H23NO3S: C, 71.09; H, 5.72; N, 3.45. Found:
C, 70.88; H, 5.64; N, 3.39.
3.3.7. 8-(4-Methylphenyl)-2-[(4-methylphenyl)sulfonyl]-
1,2,3,4-tetrahydroisoquinolin-4-ol (16). Column chroma-
tography (petroleum ether/EtOAc/CH2Cl2, 90:4:6) yielded
a yellow solid (240 mg, 0.61 mmol, 66%). Mp: 190–192 8C.
IR: 3550, 3025, 2894, 2361, 2319, 1594, 1514, 1448, 1352,
1
1336, 1168, 955, 815, 730, 698 cmK1. H NMR (CDCl3,
400 MHz) d 7.61 (d, 2H, JZ8.2 Hz), 7.43 (d, 1H, JZ
7.6 Hz), 7.33–7.30 (m, 3H), 7.23 (d, 2H, JZ7.8 Hz), 7.15
(d, 1H, JZ7.6 Hz), 7.08 (d, 2H, JZ7.8 Hz), 4.80 (br s, 1H),
4.36 (d, 1H, JZ15.4 Hz), 3.75 (m, 2H), 3.06 (dd, 1H, JZ
12.0, 2.9 Hz), 2.70 (br s, 1H), 2.43 (s, 6H). 13C NMR
(CDCl3, 100 MHz) d 143.9, 140.3, 137.4, 136.6, 135.7,
132.9, 129.0, 129.7, 129.3, 129.2, 128.5, 128.3, 127.7,
127.3, 66.4, 50.8, 47.1, 21.5, 21.2. EIMS m/z (%) 393
[M]C(9), 238 (31), 210 (77), 165 (41), 91 (100). HRMS (EI)
(MC) calcd for C23H23NO3S 393.1398, found 393.1386.
Anal. Calcd for C23H23NO3S: C, 70.20; H, 5.89; N, 3.56.
Found: C, 70.01; H, 5.97; N, 3.44.
3.3.4. 8-(3,4-Dimethoxyphenyl)-2-[(4methylphenyl)-sul-
fonyl]-1,2,3,4-tetrahydroisoquinoline (13). Column
chromatography (cyclohexane/EtOAc, 80:20) yielded a
brown syrup (200 mg, 0.47 mmol, 49%). Mp: !50 8C. IR:
3433, 2923, 2832, 2357, 2255, 1598, 1516, 1464, 1337,
1
1164, 1025, 952, 814, 749, 660 cmK1. H NMR (CDCl3,
400 MHz) d 7.44 (d, 2H, JZ8.2 Hz), 7.12 (d, 2H, JZ
8.2 Hz), 7.03 (t, 1H, JZ7.4 Hz), 6.92 (m, 2H), 6.78 (d, 1H,
JZ8.1 Hz), 6.62 (dd, 1H, JZ8.1, 1.9 Hz), 6.57 (d, 1H, JZ
1.9 Hz), 3.97 (s, 2H), 3.80 (s, 3H), 3.72 (s, 3H), 3.21 (t, 2H,
JZ6.1 Hz), 2.84 (t, 2H, JZ6.1 Hz), 2.25 (s, 3H). 13C NMR
(CDCl3, 100 MHz) d 148.4, 148.1, 140.0, 134.0, 133.1,
132.4, 129.3, 127.7, 127.5, 127.3, 126.3, 120.8, 111.8,
111.0, 55.6, 55.5, 46.4, 43.3, 28.9, 21.1. EIMS m/z (%) 423
[M]C(12), 274 (100), 268 (44), 149 (28), 137 (18), 106 (59),
98 (11). HRMS (EI) (MC) calcd for C24H25NO4S 423.1504,
found 423.1504. Anal. Calcd for C24H25NO4S: C, 68.06; H,
5.95; N, 3.31. Found: C, 68.04; H, 5.91; N, 3.28.
3.3.8. Synthesis of 8-phenylisoquinolin-4-ol (17). The
synthesis was done using the same procedure as for
compounds 10–14, using the corresponding starting
material, 8-BrIQ-4-ol (7, 250 mg, 1.12 mmol). After usual
workup the crude material was purified through silica gel
column chromatography (cyclohexane/EtOAc, 70:30)
yielded a brown solid (127 mg, 0.57 mmol, 51%). Mp:
174–176 8C. IR: 3438, 2360, 2326, 1613, 1577, 1409, 1297,

I. Andreu et al. / Tetrahedron 61 (2005) 8282–8287
8287
1280, 1133, 1069, 860, 819, 760, 700 cmK1 1H NMR
.
(f) Neumeyer, J. L. In The Chemistry and Biology of
Isoquinoline Alkaloids; Phillipson, J. D., Roberts, M. F.,
Zenk, M. H., Eds.; Springer: Berlin, 1985; pp 146–169. (g)
Cannon, J. G. Progress in Drug Research 1985, 29, 303–314.
2. (a) Shamma, M. The Isoquinoline Alkaloids.; Academic:
London, 1972; pp 194–228. (b) Kametani, T.; Honda, T. In
Brossi, A., Ed.; The Alkaloids; Academic: New York, 1985;
Vol. 24, pp 153–251. (c) Guinaudeau, H.; Leboeuf, M.; Cave,
A. J. Nat. Prod. 1988, 51, 389–474. (d) Guinaudeau, H. J. Nat.
Prod. 1994, 57, 1033–1035.
(CDCl3Cthree drops CD3OD, 400 MHz) d 10.60 (br s, 1H)
8.71 (br s, 1H), 8.28 (d, 1H, JZ8.0 Hz), 7.99 (br s, 1H), 7.74
(t, 1H, JZ8.0 Hz), 7.50 (br s, 6H). 13C NMR (CDCl3Cthree
drops CD3OD, 100 MHz) d 149.5, 140.9, 140.3, 138.9,
129.8, 128.8, 128.6, 128.2, 127.6, 125.0, 120.7. EIMS m/z
(%) 221 [M]C(100), 165 (82), 139 (14), 84 (32). HRMS (EI)
(MC) calcd for C15H11NO 221.0841, found 221.0826. Anal.
Calcd for C15H11NO: C, 81.43; H, 5.01; N, 6.33. Found: C,
81.31; H, 4.87; N, 6.21.
3. (a) Whaley, W. M.; Govindachari, T. R. Org. React. 1951, 6,
151–190. (b) Gensler, W. J. Org. React. 1951, 6, 191–206. (c)
Jones, G. In Katritzky, A., Rees, C. W., Eds.; Comprehensive
Heterocyclic Chemistry; Pergamon: Oxford, 1984; Vol. 2A,
pp 395–524. (d) Kametani, T.; Fukumoto, K. In Grethe, G.,
Ed.; The Chemistry of Heterocyclic Compounds: Isoquino-
lines, Part 1; Wiley: New York, 1981; Vol. 38, p 139.
3.4. Deprotection of N-tosyl group
3.4.1. 8-(3,4-Dimethoxyphenyl)-1,2,3,4-tetrahydro-
isoquinoline5e (18). The N-tosyl group was removed
according to the literature12, from 8-(3,4-dimethoxy-
phenyl)-2-[(4-methyl-phenyl)sulphonyl]-1,2,3,4 THIQ (13,
140 mg, 0.33 mmol) with sodium (31 mg, 1.33 mmol) in
liquid ammonia (15 mL). After usual workup, the crude of
the reaction was purified through silica gel column
chromatography (CH2Cl2/MeOH, 90:10) to yield the
deprotected tetrahydro-isoquinoline 18 (55 mg, 0.2 mmol,
62%). 1H NMR (CD3OD, 400 MHz) d 7.35 (m, 2H), 7.27 (d,
1H, JZ7.8 Hz), 7.16 (d, 1H, JZ7.3 Hz), 6.85 (m, 2H), 4.18
(s, 2H), 3.86 (s, 3H), 3.84 (s, 3H), 3.49 (t, 2H, JZ6.0 Hz),
3.20 (t, 2H, JZ6.0 Hz), 2.79 (br s, 1H). 13C NMR (CD3OD,
100 MHz) d 161.3, 142.1, 133.3, 130.9, 129.4, 129.3, 122.2,
115.7, 114.3, 56.7, 56.6, 44.9, 42.5, 26.4. EIMS m/z (%) 269
[M]C(9), 268 (64), 238 (100), 195 (30), 131 (35), 91 (19).
4. (a) Cannon, J. G.; Mohan, P.; Bojarski, J. P.; Bhatnagar, R. K.;
Leonard, P. A.; Flynn, J. R.; Chatterjee, T. K. J. Med. Chem.
1988, 31, 313–318. (b) Cannon, J. G.; Moe, S. T.; Long, J. P.
Chirality 1991, 3, 19–23. (c) Hedberg, M. H.; Johansson, A.
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M.; Nordvall, G.; Yliniemela, A.; Li, B. H.; Martin, A. R.;
Hjorth, S.; Unelius, L.; Sundell, S.; Hacksell, U. J. Med. Chem.
1995, 38, 647–658. (d) Hedberg, M. H.; Linnanen, T.; Jansen,
J. M.; Nordvall, G.; Hjorth, S.; Unelius, L.; Johansson, A. M.
J. Med. Chem. 1996, 39, 3503–3513.
5. (a) Ellefson, C. R. J. Org. Chem. 1979, 44, 1533–1536. (b)
Ellefson, C. R.; Prodan, K. A.; Brougham, L. R.; Miller, A. J.
Med. Chem. 1980, 23, 977–980. (c) Hara, H.; Murakata, M.;
Hoshino, O.; Umezawa, B.; Iitaka, Y. Chem. Pharm. Bull.
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Acknowledgements
We wish to thank the ‘Conseil Regional de Basse-
Normandie’ for the award of postdoctoral fellowships to
N.C. and I.A. and Mr. Yves Dat for mass spectroscopy.
6. (a) Mendelson, W. L.; Spainhour, C. B., Jr.; Jones, S. S.; Lam,
B. L.; Wert, K. L. Tetrahedron Lett. 1980, 21, 1393–1396. (b)
Hara, H.; Hoshino, O.; Umezawa, B. Chem. Pharm. Bull.
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