Synthesis of 7-anilino-5,8-dimethylisoquinolines having electron-attracting group on anilino moiety

Article abstract of DOI:10.3987/COM-08-S(F)110

7-Amino-5,8-dimethylisoquinoline gave various 7-anilino-5,8- dimethylisoquinolines via a palladium-catalyzed coupling reaction with bromobenzenes having electron-attracting groups (NO₂, F).

Full text of DOI:10.3987/COM-08-S(F)110

HETEROCYCLES, Vol. 77, No. 2, 2009
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HETEROCYCLES, Vol. 77, No. 2, 2009, pp. 1403 - 1408. © The Japan Institute of Heterocyclic Chemistry
Received, 8th September, 2008, Accepted, 15th October, 2008, Published online, 16th October, 2008
DOI: 10.3987/COM-08-S(F)110
SYNTHESIS OF 7-ANILINO-5,8-DIMETHYLISOQUINOLINES HAVING
ELECTRON-ATTRACTING GROUP ON ANILINO MOIETY
Yukinori Nagao,* Ryosuke Endo, Mizuho Tokumaru, and Koji Arimitsu
Department of Pure and Applied Chemistry, Fuculty of Science and Technology,
Tokyo University of Science, Noda, Chiba 278-8510
Abstract − 7-Amino-5,8-dimethylisoquinoline gave various 7-anilino-5,8-
dimethylisoquinolines via a palladium-catalyzed coupling reaction with
bromobenzenes having electron-attracting groups (NO2, F).
INTRODUCTION
Isoquinoline alkaloids and variously substituted isoquinolines have been reported to have special
bioactives. For example, halide substituted isoquinoline has been reported to know an insecticide effect as
to 6-bromoisoquinoline1 and carbazole derivatives containing isoquinoline ring have been reported to
show anticancer and antitumor effects as to ellipticine.2 Therefore, such new isoquinoline derivatives also
are expected to have biological activities.
Previously, synthesis of several isoquinoline derivatives has been investigated to obtain carbazole
derivatives containing isoquinoline ring.3 5,8-Dimethylisoquinoline(1) is synthesized in high yield via
five steps from p-xylene.4 Therefore this compound is expected as good intermediate for new isoquinoline
derivatives. Recently, 7-nitro- and 6-bromo-7-nitro-5,8-dimethylisoquinolines are obtained by similar
steps.5 In our previous work, substitution reactions of
1
was investigated and
7-bromo-5,8-dimethylisoquinoline (2) was selectively synthesized by the bromination of
5,8-dimethylisoquinoline (1) (Scheme 1). Then the substitution reactions of these isoquinolines were
investigated and the catalytic amination of bromoisoquinoline 2 gave 7-amino-5,8-dimethylisoquinoline
(3) and anilinoisoquinoline derivatives having electron-donating or weak attracting groups, however, in
this reaction anilinoisoquinoline derivatives having strong electron attracting groups was not obtained.6
In this work, 7-amino-5,8-dimethyl isoquinoline (3) was reacted with bromobenzenes to give new
7-anilino-5,8-dimethylisoquinolines having electron attracting groups. In this starting step,
5,8-dimethylisoquinoline (1) was prepared by the osmium oxidation of 4,7-dimethylindene instead of
previous ozonation oxidation.
≠ Dedicate to Professor Emeritus Keiichiro Fukumoto on the occasion of his 75th birthday.

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HETEROCYCLES, Vol. 77, No. 2, 2009
Me
Me
Me
1. Os IC-I, NaIO4
rt, 3 h
N
2. NH4OH, rt, 16 h
Me
1
Me
Me
Me
Br
H2N
NH3 (25%aq)
N
N
NBS
Cu2Cl2, Cu
conc.H2SO4
60 °C, 6 h
Me
2
3
Scheme 1
RESULTS AND DISCUSSION
Amiation of 7-bromo-5,8-dimethylisoquinoline. 4,7-Dimethylindene was synthesized via four steps
from p-xylene as a starting material by previous reported method.4 5,8-Dimethylisoquinoline (1) was
synthesized by the method including osmiume oxidation instead of previous ozonation. The high yield
was not yet obtained, but it was obtainable by more safety method than ozonation.
Bromo substituted isoquinolines (2) was synthesized and the catalytic amination of 2 with ammonia in the
presence of copper gave 7-amino-5,8-dimethylisoquinoline(3) according to the previous method in
Scheme 1.6
Coupling reaction of 7-amino-5,8-dimethylisoquinoline with bromobenzenes. The coupling reactions
of 3 with bromobenzenes were investigated as in Scheme 2. Various 7-anilino-5,8-dimethylisoquinolines
(4a ～ f) were synthesized by the palladium-catalyzed coupling reaction of 7-amino-5,8-
dimethylisoquinoline (3) with bromobenzenes. The yields in the palladium-catalyzed coupling reaction
are shown in Table 1.
Non-substituted bromobenzene provided 7-anilino-5,8-dimethylisoquinolines (4f) only in lower yield.
Bromobenzenes having poor electron-attracting substituents (R1= F) on benzene ring gave
7-anilino-5,8-dimethylisoqinoline (4e) in low yield, but bromobenzenes having strong electron-attracting
o-substituent (R1= NO2) gave new 7-anilino-5,8-dimethylisoqinolines (4a~d) in moderate yields.
R1
Br
Me
Me
R1
Me
Me
H
H2N
N
N
R2
N
a: R1= NO2, R2= NO2
b: R1= NO2, R2=Me
c: R1= NO2, R2= F
d: R1=NO2, R2=H
e: R1=F, R2=H
Pd(OAc)2/DPEphos
R2
NaOt-Bu, toluene
100 °C, 24h
3
4a-f
f: R1=H, R2=H
Scheme 2

HETEROCYCLES, Vol. 77, No. 2, 2009
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Table 1 Palladium-catalyzed coupling reaction of aminoisoquinoline (3) with bromobenzenes
Yield
(%)
Bromobenzene
Product
Mp (℃)
Me
NO2
Br
O2N
32
181～182
N
N
H
O2N
NO2
Me
Me
4a
NO2
Br
H3C
45
158～159
N
N
H
H3C
NO2
Me
4b
Me
NO2
Br
F
N
37
36
198～199
174～175
N
H
F
NO2
Me
4c
Me
NO2
Br
N
N
H
NO2
Me
Me
4d
4e
F
Br
N
153～155
11
N
H
(152.3～153.0)6
F
Me
Me
Br
150～151
N
N
H
(152.2～153.5)6
0.1
Me
4f
Further, bromobenzenes having another m-substituents (R2= NO2, Me, F) gave 7-anilino-5,8-
dimethylisoquinolines 4a~c in similar yields. It can be considered that reaction occurs mainly by the
effect of electron-attracting R1= NO2. In the previous paper,6 the palladium-catallyzed coupling reaction
of 7-brom-5,8-dimethylisoquinoline (2) with anilines on the same reaction condition is investigated and
aniline give high yield of non-substituted compound 4f, but o-nitroaniline is no reaction. Therefore, in
this reaction, electron-attracting o-substituent on bromobenzene is effective, but moderate yields is
considered that lower steric hindrance by the substituents has also influenced.

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HETEROCYCLES, Vol. 77, No. 2, 2009
CONCLUSION
Various 7-anilino-5,8-dimethylisoquinolines were synthesized via a palladium-catalyzed coupling
reaction of 7-amino-5,8-dimethylisoquinolines with bromobenzenes having electron-attracting groups
(NO2, F).
EXPERIMENTAL
Instruments Melting points were determined by using a MRK MP-MG. IR spectra were recorded on a
JASCO FT/IR-410 by using potassium bromide pellet or carbon tetrachloride solution. 1H-NMR and
13C-NMR spectra were acquired on a JEOL JNM-ECP500 at 500 and 125 MHz in deuteriochloroform.
1H-NMR coupling constants are given in Hz and all chemical shifts are relative to an internal standard of
trtramethylsilane. Low-resolution electron impact mass spectra were obtained on a JEOL MS station.
Thin layer chromatography was performed on Merck Silica gel 60F254.
Materials.
4,7-Dimethylindene was prepared in four steps from p-xylene by previous method.6 Osmium oxide
catalyst (Wako, Os Ic-I), all solvents, and other reagents were purchased.
5,8-Dimethylisoquinoline (1) was prepared as follows: To a 100 mL, 3-necked flask was charged
4,7-dimethylindene (0.10 g, 0.69 mmol), OsO4 (0.03 mmol), and THF-H2O (1:1) (300 mL). The solution
was stirred at rt and NaIO4 (1.38 mmol) was added, and stirred at rt for 3 h. After filtration, 25% NH4OH
(150 mL) was added to the organic layer and stirred at rt for 16 h. When the reaction was complete, water
(500 mL) was added and the solution was extracted organic layer with AcOEt. The organic layer was
dried (MgSO4), and evaporated under reduced pressure to give yellow liquid. The residual liquid was
purified by distillation under reduced pressure to give 5,8-dimethylisoquinoline (1) as a yellow liquid
(0.04 g, 39%), bp 88～94 ℃/1.0 mmHg (107.2～109.5 ℃/2.5 mmHg).4 1H-NMR (500 MHz,
CDCl3): δ 9.44 (1H, s, CH arom.), 8.58 (1H, d, CH arom., J = 6.5 Hz), 7.75 (1H, d, CH arom., J = 6.5 Hz),
7.39 (1H, d, CH arom., J = 7.5 Hz), 7.27 (1H, d, CH arom., J = 7.5 Hz), 2.75 (3H, s, CH3), 2.62 (3H, s,
13
CH3); C-NMR (125 MHz, CDCl3): δ 149.7 (C-1), 142.8 (C-3), 135.5 (C-4a), 133.1 (C-8), 131.4 (C-6),
130.4 (C-5), 127.6 (C-7), 127.6 (C-8a), 117.3 (C-4), 18.36, 18.31 (CH3); MS (FAB) (m/z): 157[M+1]+
7-Bromo-5,8-dimethylisoquinoline (2) was prepared by the bromination of 1 and the catalytic amination
of 2 with ammonia in the presence of copper gave 7-amino-5,8-dimethylisoquinoline (3) according to
the previous method.6
Synthesis of 7-Anilino-5,8-dimethylisoquinolines
7-(2,4-Dinitroanilino)-5,8-dimethylisoquinoline (4a)
To a 100 mL, 4-necked flask equipped with a condenser, 100 mL separtory funnel and 200 ℃

HETEROCYCLES, Vol. 77, No. 2, 2009
1407
thermometer
was
charged
palladium
acetate
(4.89
mg,
0.022
mmol)
and
bis[2-(diphenylphosphino)phenyl] ether (DPEphos) (17.6 mg, 0.033 mmol) under the nitrogen
atmosphere. Anhydrous toluene (25 mL) was added portionwise over 5 min. After the addition, the
solution was stirred for 5 min at rt under the nitrogen current. 7-Amino-5,8-dimethylisoquinoline (3) (75
mg, 0.436 mmol), 2,4-dinitro-1-bromobenzene (0.90 g, 0.65 mmol) and solid NaOt-Bu (0.064 g, 0.65
mmol) was added. Then, the flask was purged for 5 min with nitrogen, and the mixture was stirred at
100 ℃ for 24 h. When the reaction was complete, the solution was extracted organic layer with CHCl3
and water. The organic layer was washed by aq. NaCl, dried (MgSO4) and evaporated under reduced
pressure to give yellow solid. The crude product was purified by chromatography on silica gel using
AcOEt as the eluant, affording the product as a yellow solid. The solid was recrystallised from
methylcyclohexane to afford a yellow crystal of 7-(2,4-dinitroanilino)-5,8-dimethylisoquinoline (4a)
1
(1.71 g, 32%), mp 181～182 ℃, IR (KBr, cm-1) 3334, 1269 (NH), 1590, 1325 (N = O); H-NMR (500
MHz, CDCl3): δ 9.96 (1H, s, CH arom.), 9.95 (1H, s, CH arom.), 9.22 (1H, s, CH arom.), 8.71 (1H, d, CH
arom., J = 5.7 Hz), 8.18 (1H, d, CH arom., J = 9.5 Hz), 7.83 (1H, d, CH arom., J = 5.7 Hz), 7.38 (1H, s,
CH arom.), 6.77 (1H, s, NH), 2.68 (3H, s, CH3), 2.64 (3H, s, CH3); 13C-NMR (CDCl3, 125 MHz): 149.9,
147.3, 143.9, 137.5, 135.2, 134.4, 131.0, 129.8, 129.4, 128.3, 124.1, 117.2, 116.0, 18.5, 12.7.
HRMS (FAB) (m/z): Calcd for C17H14N4O4: 339.1094. Found M+: 339.1100.
7-(4-Methyl-2-nitroanilino)-5,8-dimethylisoquinoline (4b) The same palladium-catalyzed coupling
above was used as for compound (4a), such that 45% of 4b was isolated. mp 158～159 ℃, IR (KBr,
1
cm-1): 3339, 1262, (NH), 1522, 1344 (N = O); H-NMR (500 MHz, CDCl3): δ 9.51 (1H, s, CH arom.),
9.35 (1H, s, CH arom.), 8.63 (1H, d, CH arom., J = 5.9 Hz), 8.05 (1H, s, CH arom.), 7.78 (1H, d, CH
arom., J = 5.9 Hz), 7.42 (1H, s, CH arom.), 7.18 (1H, d, CH arom., J = 8.7 Hz), 6.68 (1H, s, NH), 2.65
13
(3H, s, CH3), 2.64 (3H, s, CH3), 2.31(3H, s, CH3); C-NMR (CDCl3, 125 MHz): 149.7, 143.0, 141.6,
137.3, 134.7, 134.4, 133.2, 132.7, 129.9, 128.6, 128.2, 127.2, 126.0, 117.2, 116.0, 20.1, 18.4, 12.5
HRMS (FAB) (m/z): Calcd for C18H17N3 O2: 308.1399. Found M+: 308.1398.
7-(4-Fluoro-2-nitroanilino)-5,8-dimethylisoquinoline (4c) The same palladium-catalyzed coupling
above was used as for compound (4a), such that 37% of 4c was isolated. mp 198～199 ℃, IR (KBr, cm-1)
1
3280, 1257 (NH), 1512, 1345 (N = O), 1258 (C-F); H-NMR (500 MHz, CDCl3): δ 9.52 (1H, s, CH
arom.), 9.34 (1H, s, CH arom.), 8.65 (1H, d, CH arom., J = 5.5 Hz), 7.98 (1H, d, CH arom.), 7.78 (1H, d,
CH arom., J = 6.0 Hz), 7.39 (1H, t, CH arom.), 7.15 (1H, s, CH arom.), 6.73 (1H, s, NH), 2.66 (3H×2, s,
CH3); 13C-NMR (CDCl3, 125 MHz): 149.8, 143.3, 140.7, 134.6, 134.3, 133.6, 129.8, 128.7, 124.7, 124.5,
117.4, 117.3, 117.2, 112.2, 112.0, 18.4, 12.5.
HRMS (FAB) (m/z): Calcd for C17H14FN3 O2: 312.1148. Found M+: 312.1150.
7-(2-Nitroanilino)-5,8-dimethylisoquinoline (4d) The same palladium-catalyzed coupling above was

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HETEROCYCLES, Vol. 77, No. 2, 2009
1
used as for compound (4a), such that 52% of 4d was isolated. mp 174～175 ℃, H-NMR (500 MHz,
CDCl3): δ 9.32 (1H, s, CH arom.), 8.34 (1H, d, CH arom., J = 5.5 Hz), 7.83 (1H, d, CH arom., J = 5.5 Hz),
7.53 (1H, s, CH arom.), 6.89 (2H, d, CH arom. J = 8.5 Hz), 6.83 (1H, t, CH arom., J = 8.5 Hz), 6.20 (1H,
s, NH), 2.59(3H×2, s, CH3), MS (FAB)(m/z) 294[M+1]+
7-(2-Fluoroanilino)-5,8-dimethylisoquinoline (4e) The same palladium-catalyzed coupling above
was used as for compound (4a), such that 11% of 4e was isolated. mp 153～155 ℃ ( 152.3～153.0),6
1H-NMR (500 MHz, CDCl3): δ 9.39 (1H, s, CH arom.), 8.40 (1H, d, CH arom., J = 6.0 Hz), 7.72 (1H, d,
CH arom., J = 6.0 Hz), 7.42 (1H, s, CH arom.), 7.16 (1H, t, CH arom., J = 7.5 Hz), 6.82(1H, t, CH arom.,
J = 7.5 Hz), 6.81～6.80 (２H, ｍ, CH arom.), 5.73 (1H, s, NH), 2.63 (3H, s, CH3), 2.57 (3H, s, CH3), MS
(FAB)(m/z) 236[M+1], 238[M+3]
7-Anilino-5,8-dimethylisoquinoline (4f) The same palladium-catalyzed coupling above was used as
for compound (4a), such that 0.1% of 4f was isolated. mp 150～151 ℃ (152.3～153.0℃).6 1H-NMR
(500 MHz, CDCl3): δ 9.26 (1H, s, CH arom.), 8.74 (1H, d, CH arom., J = 6.0 Hz), 7.87 (1H, d, CH arom.,
J = 6.0 Hz), 7.38 (1H, s, CH arom.), 6.89 (2H, t, CH arom., J = 7.5 Hz), 6.80 (1H, d, CH arom., J = 7.5
Hz), 4.86 (1H,s, NH), 2.30 (3H×2, s, CH3), MS (FAB)(m/z) 249[M+1]+
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