Synthesis of 7-substituted derivatives of 5, 8-dimethylisoquinoline

Article abstract of DOI:10.3987/COM-07-S(U)38

7-Bromo-5,8-dimethylisoquinoline was selectively synthesized by the bromination of 5,8-dimethylisoquinoline obtained in five steps from p-xylene as a starting material. Further,7-bromo-5,8-dimethylisoquinolinegave 7-amino-5,8-dimethylisoquinoline by the reaction with ammonia and various 7-anilino-5,8-dimethylisoquinolines via a palladium-catalyzed coupling reaction with anilines.

Full text of DOI:10.3987/COM-07-S(U)38

HETEROCYCLES, Vol. 73, 2007
593
HETEROCYCLES, Vol. 73, 2007, pp. 593 - 602. © The Japan Institute of Heterocyclic Chemistry
Received, 29th June, 2007, Accepted, 20th August, 2007, Published online, 20th August, 2007. COM-07-S(U)38
SYNTHESIS OF 7-SUBSTITUTED DERIVATIVES OF
5, 8-DIMETHYLISOQUINOLINE
Yukinori Nagao,* Katsuaki Hirota, Mizuho Tokumaru, and Kozo Kozawa
Department of Industrial Chemistry, Fuculty of Science and Technology, Tokyo
University of Science, Noda, Chiba 278-8510
Abstract － 7-Bromo-5,8-dimethylisoquinoline was selectively synthesized by
the bromination of 5,8-dimethylisoquinoline obtained in five steps from p-xylene
as a starting material. Further, 7-bromo-5,8-dimethylisoquinoline gave
7-amino-5,8-dimethylisoquinoline by the reaction with ammonia and various
7-anilino-5,8-dimethylisoquinolines via a palladium-catalyzed coupling reaction
with anilines.
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 (6) is synthesized in high yield via
five steps from p-xylene as shown in Scheme 1.4 Therefore this compound is expected as good
intermediate for new isoquinoline derivatives. Recently, 7-nitro- and 6-bromo-7-nitro-5,8-dimethyl-
isoquinolines are obtained by similar steps.5 In this work, substitution reactions of 6 was investigated and
7-bromo-5,8-dimethylisoquinoline (7a), which is expected as intermediate for new isoquinoline
derivatives, was selectively synthesized by the bromination of 5,8-dimethylisoquinoline (6) (Scheme 2).
Then the substitution reactions of these isoquinolines were investigated and the catalytic amination of
bromoisoquinoline 7a gave new anilinoisoquinoline derivatives (Scheme 3).
RESULTS AND DISCUSSION
≠ Dedicate to the memory of departed Professor Ivar Ugi.

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HETEROCYCLES, Vol. 73, 2007
Me
Me
Me
Me
Me
O
3
O
OH
CH2Cl
ClCH2CH2COCl
AlCl3 , CS2
LiAlH4
Et2O
conc.H2SO4
Me
Me
1
Me
Me
3
4
2
Me
1) O3 , MeOH , -780C
(i) or (ii)
N
2) Me2S , NaHCO3
3) NH4OH
(i) MgSO4 , 130oC
(ii) p-toluenesulfonic acid,
Me
Me
anhydrous benzene
5
6
Scheme 1
Bromination and nitration of 5,8-dimethylisoquinoline.
5,8-Dimethylisoquinoline (6) was
synthesized via five steps from p-xylene as a starting material by improving each reported method.4
Yields of each steps were 2’,5’-dimethyl-3-chloropropiophenone (2): 76%, 4,7-dimethylindan-1-one (3):
98%, 4,7-dimethylindan-1-ol (4): 95%, 4,7-dimethylindene (5): 65%(MgSO4), 78% (p-toluenesulfonic
acid), and 5,8-dimethylisoquinoline (6): 92%. On the preparation of indene 5, high yield was obtained
6
by dehydration with p-toluenesulfonic acid than with MgSO4 .
Me
N
O2N
Me
7b
fuming HNO3
Me
Me
Me
Me
Me
Me
NH3
NBS
conc. H2SO4
Cu2Cl2, Cu
N
N
N
H2N
Br
7c
7a
6
Scheme 2
The substitution reactions of 6 were investigated as in Scheme 2. Bromo substituted isoquinolines (7a)
was synthesized in 77% yield according to the method in Scheme 2. Single crystal of 7a was created by
the crystallization from methylcyclohexane, and crystal data is shown in Table 1. The substituted position

HETEROCYCLES, Vol. 73, 2007
595
of bromine was confirmed to be the 7-position of isoquinoline ring as shown by X-ray crystal structure
analysis in Figure 1. It was shown that the bromination gave selectively 7-bromo compound. The
nitration of 6 with fuming nitric acid gave only low yield(1%) of 7-nitro-5,8-dimethylisoquinoline (7b)
because of many side reactions.
Table 1 Crystal data for 7a
Formula
C11H10NBr
293(2)
Temperature (K)
3
0.50×0.30×0.10
Monoclinic
P21/c
Crystal size (mm )
Crystal system
Space group
Unit cell dimension
a (Å)
b (Å)
3.9984(4)
29.463(3)
8.0883(8)
90.845(2)
952.73(17)
c (Å)
β(°)
Volume (Å3)
Z
4
Ref.used(|Fo|≧2σ(Fo))
R factor
1763
0.038
0.091
wR factor
Figure 1 ORTEP drawing of 7a

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HETEROCYCLES, Vol. 73, 2007
Amination and coupling reaction of 7-bromo-5,8-dimethylisoquinoline. The substitution reactions
of 7a were investigated as in Scheme 2 and Scheme 3. The catalytic amination of 7a with ammonia in the
presence of copper gave 7-amino-5,8-dimethylisoquinoline(7c) in 20% yield.
Me
Me
(1), (2)
N
N
N
Br
X2
H
Me
X1
Me
8a~e
(1) : Ullmann reaction
(2) : Pd(OAc)2/ DPEphos
NaOt-Bu, anilines
a : X1=H, X2=H d : X1=Me, X2=H
b : X1=F, X2=H e : X1=H, X2= Me
c : X1=Cl, X2=H
Scheme 3
Table 2 Palladium-catalyzed coupling reaction of bromoisoquinoline 7a with anilines
Yield
(%)
Anilines
Products
Mp (℃)
Me
NH2
80
152.2～153.5
N
N
N
H
Me
8a
8b
Me
NH2
F
67
52
34
52
152.3～153.0
165.8～166.3
164.0～165.0
146.9～147.3
N
H
F
Me
Me
NH2
Cl
N
N
N
H
Cl
Me
8c
Me
NH2
Me
N
H
CH3
Me
8d
Me
NH2
N
H3C
N
Me
H
Me
8e
NH2
Br
no reaction
no reaction
no reaction
NH2
I
NH2
NO2

HETEROCYCLES, Vol. 73, 2007
597
7-Anilino-5,8-dimethylisoquinoline (8a) was obtained in 40% yield by the Ullman reaction of 7a with
acetanilide. The coupling reaction was improved by palladium catalyzed metod7 and various
7-anilino-5,8-dimethylisoquinolines 8a ～e were synthesized by the palladium-catalyzed coupling
reaction of 7-bromo-5,8-dimethylisoquinoline (7a) with anilines. The yields in the palladium-catalyzed
coupling
reaction
are
shown
in
Table
2.
Non-substituted
aniline
provided
7-anilino-5,8-dimethylisoquinolines(8a) in higher yield than Ullman reaction. Anilines having
electron-donating substituent (X1= CH3) or poor electron-attracting substituents (X1= F, Cl) on benzene
ring reacted, but anilines having strong electron-attracting substituent (X1= NO2) did not react. Further,
anilines having halogen substituents (X1= Br, I) did not react. It can be considered that another reaction
occurs mainly, since the electron-attracting of X1= Br, I is poor than X1=F, Cl. Moreover, on the reaction
of methyl substituted anilines, m-position product was provided in higher yield than o-position. The high
yield of non-substituted compound 8a is considered that lower steric hindrance by the substituents has
also influenced.
CONCLUSION
7-Bromo-5,8-dimethylisoquinoline was selectively synthesized in high yield by the bromination of
5,8-dimethylisoquinoline. Then various 7-anilino-5,8-dimethylisoquinolines were synthesized via a
palladium-catalyzed coupling reaction of 7-bromo-5,8-dimethylisoquinolines with anilines.
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 or
deuteriomethanol. 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. X-ray crystal structure analysis was determined by using a Bruker-AXS smart-APEX
and analyzed on a SHELXS-97. Thin layer chromatography was performed on Merck Silica gel 60F254.
Materials
5,8-Dimethylisoquinoline (6)4 was prepared in five steps from p-xylene. All solvents and other reagents
were purchased. 2’,5’-Dimethyl-3-chloropropiophenone (2) was prepared from p-xylene and
4,7-dimethylindan-1-one (3) was prepared from 2.8 Then 4,7-dimethylindan-1-ol (4)9 was prepared by the
reduction of 3 with lithium aluminum hydride.
4,7-Dimethylindene (5) was prepared as follow: To a 500 mL, 4-necked flask equipped with a condenser
and 200 ℃ thermometer was charged 4,7-dimethylindan-1-ol (4) (20.53 g, 0.126 mol) and anhydrous

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benzene (400 mL). The solution was refluxed for 5 min. Further, p-toluenesulfonic acid was added and
refluxed for 30 min. When the reaction was complete, 1 M aq.NaOH was added. The solution was
extracted organic layer with benzene and washed by aq.sodium chloride. 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 the 4,7-dimethylindene (5) as a light yellow liquid (32.32 g,
78.0%), bp 61.0～62.0 ℃/1 mmHg (lit.,6: bp 63.0～65.0 ℃/1 mmHg). 1H-NMR (500 MHz, CDCl3): δ
6.91 (1H, d, CH arom. J=7.5 Hz), 6.89 (1H, d, CH, J=5.5 Hz), 6.82 (1H, d, CH arom. J=7.5 Hz), 6.45
(1H, d, CH, J=5.5 Hz), 3.18 (2H, d, CH2, J=5.5 Hz), 2.32 (3H, s, CH3), 2.23 (3H, s, CH3), MS (m/z): 144
[M]+
5,8-Dimethylisoquinoline (6)4 was prepared as follows: To a 500 mL, 4-necked flask equipped with
ozone debouchments and –100 ℃ thermometer was charged 4,7-dimethylindene (5) (11.45 g, 0.0793
mol) and MeOH (300 mL). The solution was stirred at –78 ℃ and flowed ozone at same temp. for 2 h.
When the reaction was complete, the flask was light shielding by aluminum sheet and left to rt. And after,
dimethyl sulfide (16.0 mL) and NaHCO3 (16.0 g, 0.190 mol) were added and stirred at rt for 4 h. Further,
25% NH4OH (150 mL) was added and stirred at rt for 17 h. When the reaction was complete, water (500
mL) was added and the solution was extracted organic layer with CH2Cl2. 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 (6) as a yellow liquid (11.42 g,
92 %), bp107.5～110.2 ℃/ 2.5mmHg (107.2～109.5 ℃/2.5 mmHg).4 1H-NMR (500 MHz, CD3OD):
δ9.19 (1H, s, CH arom.), 8.37 (1H, d, CH arom. J=6.0 Hz), 7.68 (1H, d, CH arom. J=6.0 Hz), 7.30 (1H,
d, CH arom. J=7.0 Hz), 7.17 (1H, d, CH arom. J=7.0 Hz), 2.59 (3H, s, CH3), 2.49 (3H, s, CH3); 13C-NMR
(125 MHz, CD3OD): δ149.8 (C-1), 142.3 (C-3), 136.7 (C-4a), 134.3 (C-8), 132.6 (C-6), 132.0(C-5),
129.0 (C-7), 128.6 (C-8a), 118.9 (C-4), 18.28, 18.18 (CH3); MS (EI) (m/z): 157 [M]+
Synthesis of 7-substituted 5,8-dimethyisoquinolines
7-Bromo-5, 8-dimethylisoquinoline (7a) To a 100 mL, 4-necked flask equipped with a condenser,
100 mL separtory funnel and 200 ℃ thermometer was charged 5,8-dimethylisoquinoline (6) (3.32 g,
0.0211 mol) and stirred in ice bath under the nitrogen atmosphere. 97% conc. H2SO4 (30 mL) was added
portionwise over 30 min. After portionwise, the solution was added N-bromosuccinimide (4.55 g, 0.0255
mol) and stirred at 60 ℃ for 7 h. When the reaction was complete, the reacted solution was filled with
10 % aq.NaNO2 (100 mL) and was neutralized with 45% aq.NaOH. The solution was filtered off under
reduced pressure. The filtrate was extracted organic layer with CHCl3. The organic layer was dried
(MgSO4). The filtered solid was refluxed in CHCl3, filtered off under reduced pressure and dried

HETEROCYCLES, Vol. 73, 2007
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(MgSO4). The dried solution was evaporated under reduced pressure to give a brown solid. The residual
solid was purified by distillation under reduced pressure to give a white solid. Further, the solid was
recrystallised from mixed hexane and benzene to afford
a
white powder of
7-bromo-5,8-dimethylisoquinoline (7a) (3.87 g, 77 %), bp 162.2～164.4 ℃/4.0 mmHg, mp 93.2～
94.8 ℃, 1H-NMR (500 MHz, CD3OD):δ9.32 (1H, s, CH arom.), 8.48 (1H, d, CH arom. J=6.0 Hz), 7.80
(1H, d, CH arom. J=6.0 Hz), 7.64 (1H, s, CH arom.), 2.59(3H, s, CH3), 2.49(3H, s, CH3); 13C-NMR
(125MHz, CD3OD):δ150.2 (C-1), 143.0 (C-3), 136.4 (C-4a), 136.1 (C-6), 135.0 (C-8), 133.7 (C-5),
129.6 (C-8a), 124.6 (C-7), 119.2 (C-4), 18.0, 17.7 (CH3); MS (EI) (m/z): 235 [M]+, 237 [M+2]+; HRMS
Calcd for C11H10BrN : 234.9997, found M+: 234.9995.
7-Nitro-5,8-dimethylisoquinoline (7b) To a 100 mL 4-necked flask equipped with a condenser, 100 mL
separtory funnel and -100 ℃ thermometer was charged 5,8-dimethylisoquinoline (6) (3.00 g, 0.0191
mol) and 97% conc. H2SO4 (30 mL) was added portionwise over 30 min. After portionwise, the solution
was stirred at -40 ℃ for 1.5 h. When the reaction was complete, the reacted solution was neutralized
with 45% aq.NaOH The solution was filtered off under reduced pressure. The filtrate was extracted
organic layer with CHCl3. The organic layer was dried (MgSO4). The filtered solid was refluxed in CHCl3,
filtered off under reduced pressure and dried (MgSO4). The dried solution was evaporated under reduced
pressure to give a brown solid. The crude product was purified by chromatography on silica gel using
petroleum ether and toluene(1:1) as the eluant, affording the product as a yellow solid. The solid was
recrystallised from methylcyclohexane to afford a yellow crystal of 7-nitro-5,8-dimethylisoquinoline (7c)
1
(0.05 g, 0.8 %), mp 159.0～163.0 ℃ (161.0~162.0 ℃) 5, H-NMR (500 MHz, CD3OD):δ9.56 (1H, s,
CH arom.), 8.67 (1H, d, CH arom. J=10.0 Hz), 7.93 (1H, d, CH arom. J=10.0 Hz), 7.77 (1H, d, CH arom.
J=10.0 Hz), 2.84 (3H, s, CH arom.), 2.63 (3H, s, CH3); MS (EI) (m/z): 203 [M]+
7-Amino-5,8-dimethylisoquinoline (7c) In a steel reaction vessel, (1.14 g, 5.0 mmol) of
7-bromo-5,8-dimethylisoquinoline (7a) are placed, 0.13 g copper, and 60 mL (1.0 mol) of 25 % ammonia
containing 0.11 g of cuprous chloride. The steel reaction vessel is rocked and heated at 195 ℃ for 24 h.
After cooling, the bomb is emptied and the two layers are separated; 2 mL of 40 % NaOH is added to the
mixture, and the mixture was extracted with CHCl3. The organic layer was washed with aq.NaCl, and
dried (MgSO4) and evaporated under reduced pressure to give yellow solid. The crude product was
purified by chromatography on silica gel using CHCl3 as eluent, affording the product as a yellow solid.
The solid was recrystallised from methylcyclohexane to afford
a
yellow crystal of
7-amino-5,8-dimethylisoquinoline (7c) (1.07 g, 44 %) mp 210.0~212.0 ℃ (lit.,5 201.5~202.5 ℃),
1H-NMR (500 MHz, CD3OD):δ9.23 (1H, s, CH arom.), 8.26 (1H, d, CH arom., J=6.0 Hz), 7.54 (1H, d,
CH arom. J=6.0 Hz), 6.92 (1H, s, CH arom.), 3.69 (2H, bs, NH2), 2.53 (3H, s, CH3), 2.26 (3H, s, CH3);

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MS (EI) (m/z): 173 [M]+.
Synthesis of anilino-5,8-dimethylisoquinolines
7-Anilino-5, 8-dimethylisoquinoline (8a)
(Ullmann reaction): To a 50 mL, 3-necked flask equipped with a condenser was charged
7-bromo-5,8-dimethylisoquinoline (7a) (3.63 g, 0.0154 mol), acetanilide (5.00 g, 0.037 mol), K2CO3
(3.00 g, 0.0217 mol) and copper powder (1.50 g, 0.0236 mol), which were crushed and mixed by mortar.
Further, ten spatula of iodide was added. After heating to 100 ℃, the mixture was strongly stirred at
130 ℃ for 24 h. When the reaction was complete, the reacted mixture was melted by CH2Cl2 and filtered
off under reduced pressure. The solution was extracted organic layer with CH2Cl2 and water. The organic
layer was dried (MgSO4), and evaporated under reduced pressure to give brown oil. Then, to a 200 mL,
2-necked flask equipped with a condenser and 200 ℃ thermometer was charged the oil and conc.
hydrochloric acid. The solution was refluxed for 20 h. When the reaction was complete, the reacted
solution was neutralized with 45% aq.NaOH and was filtered off under reduced pressure. The filtrate was
extracted organic layer with CH2Cl2. The organic layer was dried (MgSO4), and evaporated under
reduced pressure to give brown oil. 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-anilino-5,8-dimethylisoquinoline (8a) (1.56 g, 40.9%)
(Palladium-catalyzed coupling reaction): To a 100 mL, 4-necked flask equipped with a condenser,
100 mL separtory funnel and 200 ℃ thermometer was charged palladium acetate (9.7 mg, 0.050 mmol)
and bis[2-(diphenylphosphino)phenyl] ether (DPEphos) (0.035 g, 0.075 mmol)7 under the nitrogen
atmosphere. Anhydrous toluene (22 mL) was added portionwise over 5 min. After the addition, the
solution was stirred for 5 min at rt under the nitrogen current. 7-bromo-5,8-dimethylisoquinoline (7a)
(2.05 g, 8.68 mmol), aniline (0.90 g, 9.72 mmol) and solid NaO t-Bu (1.18 g, 0.012 mol) 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 ether 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 hexane: AcOEt (8:2) as the eluant,
affording the product as a yellow solid. The solid was recrystallised from methylcyclohexane to afford a
yellow crystal of 7-anilino-5,8-dimethylisoquinoline (8a) (1.71 g, 80 %), mp 152.2～153.5 ℃, 1H-NMR
(500 MHz, CD3OD):δ9.32 (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.), 7.20 (2H, t, CH arom. J=7.5 Hz), 6.89 (2H, d, CH arom. J=7.5 Hz),
6.83 (1H, t, CH arom. J=7.5 Hz), 2.59 (3H×2, s, CH3); MS (FAB) (m/z): 249 [M+1]+

HETEROCYCLES, Vol. 73, 2007
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Anal. Calcd for C17H16N2: C, 82.22; H, 6.49 ; N, 11.28 . Found: C, 81.44 ; H, 6.42 ; N, 11.27.
7-(o-Fluoroanilino)-5,8-dimethylisoquinoline (8b) The same palladium-catalyzed coupling above p
was used as for compound (8a), such that 67 % of 8b was isolated. mp 152.3～153.0 ℃, 1H-NMR (500
MHz, CDCl3):δ9.38 (1H, s, CH arom.), 8.46 (1H, d, CH arom. J=6.0 Hz), 7.64 (1H, d, CH arom. J=6.0
Hz), 7.38 (1H, s, CH arom.), 7.05 (1H, t, CH arom. J=7.5 Hz), 6.91 (1H, t, CH arom. J=7.5 Hz), 6.78～
6.73 (2H, m, CH arom.), 5.66 (1H, s, NH), 2.56 (3H, s, CH3), 2.54(3H, s, CH3); MS (FAB) (m/z): 267
[M+1]+
Anal. Calcd for C17H15FN2: C, 76.67 ; H, 5.68 ; N, 10.52. Found: C, 76.43 ; H, 5.72 ; N, 10.60 .
7-(o-Chloroanilino)-5,8-dimethylisoquinoline (8c) The same palladium-catalyzed coupling above
was used as for compound (8a), such that 52 % of 8c was isolated. mp 165.8～166.3 ℃, 1H-NMR (500
MHz, CDCl3):δ9.48 (1H, s, CH arom.), 8.54 (1H, d, CH arom. J=5.5 Hz), 7.76 (1H, d, CH arom. J=5.5
Hz), 7.47 (1H, s, CH arom.), 7.39 (1H, d, CH arom. J=8.5 Hz), 7.09 (1H, t, CH arom. J=8.5 Hz), 6.82
(1H, t, CH arom. J=8.5 Hz), 6.75 (1H, d, CH arom. J=8.5 Hz), 6.07 (1H, s, NH), 2.64 (3H×2, s, CH3);
MS (FAB) (m/z): 283 [M+1]+
Anal. Calcd for C17H15ClN2: C, 72.21; H, 5.35 ; N,9.91. Found: C, 72.04 ; H, 5.32 ; N, 9.59 .
7-(o-Methylanilino)-5,8-dimethylisoquinoline (8d) The same palladium-catalyzed coupling above
1
was used as for compound (8a), such that 34% of 8e was isolated. mp 164.0～165.0 ℃, H-NMR (500
MHz, CDCl3):δ9.41 (1H, s, CH arom.), 8.36 (1H, d, CH arom. J=6.0 Hz), 7.72 (1H, d, CH arom. J=6.0
Hz), 7.26 (1H, s, CH arom.), 7.18 (1H, d, CH arom. J=7.5 Hz), 7.08 (1H, t, CH arom. J=7.5 Hz), 6.92
(1H, t, CH arom. J=7.5 Hz), 6.85 (1H, d, CH arom. J=7.5 Hz), 5.41 (1H, s, NH), 2.53 (3H, s, CH3), 2.51
(3H, s, CH3), 2.24(3H, s, CH3); MS (FAB) (m/z): 263 [M+1]+
Anal. Calcd for C18H18N2: C, 82.41; H, 6.92 ; N, 10.68. Found: C, 82.11 ; H, 6.67 ; N, 10.58 .
7-(m-Methylanilino)-5,8-dimethylisoquinoline (8e)
The same palladium-catalyzed coupling
procedure above was used as for compound (8a), such that 52% of 8f was isolated. mp 152.3～153.0 ℃,
1H-NMR (500 MHz, CDCl3):δ9.43 (1H, s, CH arom.), 8.49 (1H, d, CH arom. J=6.0 Hz), 7.69 (1H, d,
CH arom. J=6.0 Hz), 7.47 (1H, s, CH arom.), 7.15 (1H, t, CH arom. J=7.5 Hz), 6.75 (1H, d, CH arom.
J=7.5 Hz), 6.72～6.71 (2H, m, CH arom.), 5.62 (1H, s, NH), 2.59 (3H×2, s, CH3), 2.31 (3H, s, CH); MS
(FAB) (m/z): 263 [M+1]+
Anal. Calcd for C18H18N2: C, 82.41; H, 6.92 ; N, 10.68. Found : C, 82.09 ; H, 6.59 ; N, 10.82.
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