Synthesis of 8,9-dialkoxybenzodiazepines and 7,8-dialkoxyisoquinolines

Article abstract of DOI:10.1002/jhet.5570430617

o-Aroylarylacetone type 1,5-diketone derivatives (5, 6) were synthesised from arylacetones (1) protected as 1,3-dioxolanes (4) through directed ortho lithiation followed by acylation with aroyl chlorides. 8,9-Dialkoxy-2,3- benzodiazepines 9 were obtained

Full text of DOI:10.1002/jhet.5570430617

Nov-Dec 2006
1539
Synthesis of 8,9-Dialkoxybenzodiazepines and
7,8-Dialkoxyisoquinolines
László Pongó*1, Béla Ágai2, Ferenc Faigl2, József Reiter1 and Gyula Simig1
1Egis Pharmaceuticals Ltd., Chemical Research Division, P.O.Box 100, H-1475 Budapest, Hungary
2Department of Organic Chemical Technology, Budapest University of Technology and Economics, H-1521
Budapest, Hungary
Received January 25, 2006
H2N-NH2, EtOH
4h reflux, or 20h rt
aq. NH3, MeOH
rt, 24h
Me
R3
N
O
R2O
R2O
N
O
N
R2O
R1O
R1O
R1O
R3
R3
H2SO4, CH2Cl2
Kieselgel
Me
Me
O-
O
O
H2N-OH . HCl
EtOH, 4h reflux
H2N-NH2 . HCl
EtOH, 4h reflux
Cl-
NH2
N+
N+
R2O
R2O
O
R2O
R1O
R1O
R1O
R3
R3
R3
1. BuLi
hexane, ether
2. ArCOCl
O
O
R2O
R1O
o-Aroylarylacetone type 1,5-diketone derivatives (5, 6) were synthesised from arylacetones (1) protected
as 1,3-dioxolanes (4) through directed ortho lithiation followed by acylation with aroyl chlorides. 8,9-
Dialkoxy-2,3-benzodiazepines 9 were obtained by cyclisation of diketones 6 with hydrazine. The reaction
of diketones 6 with ammonia gave 7,8-dialkoxyisoquinolines 11. Reaction of ketals 5 with hydrazine
hydrochloride and hydroxylamine hydrochloride afforded N-amino-7,8-dialkoxyisoquinolinium chlorides
(10) and 7,8-dialkoxyisoquinolinium oxides (12), respectively.
J. Heterocyclic Chem., 43, 1539 (2006).
The synthesis of 7,8-dialkoxy-2,3-benzodiazepines 3 has
been reviewed recently [6]. The o-aroylarylacetone type 1,5-
diketone key intermediates 2 were prepared from arylacetones
1 by different procedures using electrophilic aromatic
substitution reaction for the introduction of the new substituent
to the benzene ring (Scheme 2). Cyclisation of diketones 2
with hydrazine hydrate afforded 2,3-benzodiazepines 3.
7,8-Dialkoxy-2,3-benzodiazepines possess strong CNS
activity [1-2]. Thus tofisopam (GrandaxinR, Scheme 1)
was introduced into market in 1975 as a psychovegetative
regulator [3]. Follow-up compounds girisopam and neri-
sopam showed anxiolytic and atypical neuroleptic
properties, respectively [4,5].
Scheme 1
Scheme 2
R1O
R2O
R1O
R2O
R1O
R2O
MeO
MeO
MeO
MeO
MeO
MeO
O
N
O
N
N
N
O
N
N
N
N
Ar
Ar
1
2
3
R1,R2: CH3, -CH2- Ar: phenyl, substituted phenyl
OMe
Cl
MeO
H2N
nerisopam
In a continuation of the structure-activity relationship
studies of 2,3-benzodiazepines and related isoquinoline
tofisopam
Grandaxin
girisopam

1540
L. Pongó, B. Ágai, F. Faigl, J.Reiter and G. Simig
Vol 43
derivatives we decided to synthesize new 8,9-dialkoxy-
2,3-benzodiazepines (9) and related 7,8-dialkoxyiso-
quinolines (10-12).
The synthesis of isomeric 1,5-diketones 6 required for
the ring closure to derivatives 9-12 has been accomplished
starting from arylacetones 1 by directed ortho lithiation
reaction of ethylene ketals 4 at the doubly activated site
and subsequent aroylation with aroyl chlorides to
benzophenone ketals 5 which can be easily transformed to
the required diketones 6 (Scheme 3).
hydrochloride gave the isomeric N-amino-7,8-dialkoxy-
isoquinolinium chlorides (10a-k).
The distinction between compounds 9 and 10 was
achieved by pmr spectroscopy [8,9]. The pmr spectrum of
compounds 9 shows two doublets in the range of 2.98 and
3.45 ppm with coupling constants of J = 12.2–13.3 Hz
characteristic for the non-equivalent protons of the CH2
group of the 5H-2,3-benzodiazepine ring. The resonances
of the 4-H protons of isoquinolines 10 are readily
identified as singlets in the range of 8.40-8.61 ppm.
Scheme 3
1. BuLi
hexane,ether
O
R1O
OH
HO
O
O
O
H+, toluene
R2O
R2O
O
2. ArCOCl
O
R2O
R1O
R1O
1
4
R3
5
H2SO4, CH2Cl2
Kieselgel
1-4ꢀ R1ꢀ
R2
65-70 %
aꢀ
bꢀ
CH3ꢀ CH3
-CH2
-
O
O
R2O
R1O
5, 6: for R1, R2, R3 see Scheme 5
R3
6
Aroylation of aryllithium compounds has been
frequently achieved by reaction with benzonitriles as
electrophiles and subsequent hydrolysis of the primarily
formed ketimines. However, it is described in the
literature that ketimine 7, obtained by lithiation of 4a
followed by treatment with benzonitrile led to
isoquinoline 8 upon hydrolysis, instead of diketone 6a
(Scheme 4) [7].Quenching of aryllithium compounds -
obtained by lithiation of ketals 4 with aroyl chlorides
instead of arylnitriles afforded benzophenone ketals 5,
which could be easily transformed to the required
diketones 6 with acceptable to good yields.
1-Aryl-3-methylisoquinolinium N-oxides 12a-h were
obtained when the 2-aroyldioxolanes 5a-h were reacted
with hydroxylamine hydrochloride (Scheme 5). On the
other hand, diketones 6 are suitable starting materials also
for the synthesis of new 1-aryl-3-methyl-8,9-dialkoxyiso-
quinolines as demonstrated by the preparation of
compounds 11b,e,f by the treatment of o-aroylaryl-
acetones 6b,e,f with aqueous ammonia.
EXPERIMENTAL
Melting points were determined on a Kofler Boëtius micro
apparatus and were not corrected. The ir spectra were recorded
on an Aspect 2000 computer controlled Bruker IFS-113v
vacuum optic FT spectrometer, using KBr pellets of solids or
films of liquids. The pmr and cmr spectra were taken on a
Bruker WM 250 FT, or a Varian Gemini-200, or a Varian Unity
Inova 500 spectrometer, in deuteriochloroform and DMSO-d6 as
solvents. Chemical shifts were reported as ꢀ values (ppm)
downfield from internal tetramethylsilane.
Scheme 4
Me
HH+, H2O
1. BuLi
O
4a
N
2. PhCN
NH
MeO
MeO
OMe
Ph
OMe
Ph
7
8
2-[(3,4-Dimethoxyphenyl)methyl]-2-methyl-1,3-dioxolane (4a).
The reaction of 2-aroylarylacetones 6a-l with hydrazine
To a solution of 1a (97.1 g, 0.5 mol) in toluene (700 ml)
ethylene glycol (100 ml, 1.82 mol) and p-toluenesulfonic acid
monohydrate (3 g) were added and the mixture was refluxed in a
Dean-Stark apparatus for 12 h. After cooling the reaction mixture
affords 8,9-dialkoxy-2,3-benzodiazepines 9a-l in good
yields (Scheme 5). However, treatment of the corre-
sponding benzophenone ketals 5a-k with hydrazine

Nov-Dec 2006
Synthesis of 8,9-Dialkoxybenzodiazepines and 7,8-Dialkoxyisoquinolines
1541
Scheme 5
H2N-NH2, EtOH
4h reflux, or 20h rt
aq. NH3, MeOH
rt, 24h
Me
R3
N
6
R2O
N
N
R2O
53-88 %
58-63 %
R1O
R1O
R3
11
9
Me
+Cl-
Me
O-
H2N-NH2 . HCl
EtOH, 4h reflux
H2N-OH . HCl
EtOH, 4h reflux
N+
N
R2O
NH2
5
R2O
R1O
R1O
65-92 %
67-85 %
R3
R3
10
12
5,6,9-12
R1
R2
R3
a
b
c
d
e
f
g
h
i
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
H
2-F
4-F
2-Cl
3-Cl
4-Cl
2,4-di-Cl
H
2-F
-CH2-
-CH2-
-CH2-
-CH2-
-CH2-
j
k
l
4-F
4-MeO
4-NO2
was made alkaline with an aqueous solution of sodium bicarbonate
(10 %), extracted with water (3 x 200 ml) and dried (Na2SO4).
After evaporation of the volatiles the residue was purified by bulb-
to-bulb vacuum distillation to yield the title compound (89.5 g, 75
%) as colourless oil, bp 110-112 °C/0.15 mmHg. This compound
was described as starting material in ref. [7] without giving any
information about its synthesis and physical data; pmr
(deuteriochloroform, 500 MHz): 6.84 (d, J=1.3 Hz, 1H), 6.79 (m,
2H), 3.89 (m, 2H), 3.87 (s, 3H), 3.85 (s, 3H), 3.74 (m, 2H), 2.87 (s,
2H), 1.31 (s, 3H); cmr (deuteriochloroform, 125 MHz): 148.2,
147.5, 129.4, 122.4, 113.6, 110.7, 109.6, 64.7, 55.7, 44.8, 24.2.
Anal. Calcd. for C13H18O4 (238.29): C, 65.53; H, 7.61. Found:
C, 65.57; H, 7.83.
in ether (120 ml) under argon. The temperature of the reaction
mixture was kept below 5 °C during the addition of butyl lithium
and it was then stirred for further 3 h at 0 °C. The appropriate
aroyl chloride (0.063 mol) was added at 0-5 °C to the resulting
suspension and the mixture was stirred for additional 2.5 hours
at ambient temperature. Water (100 ml) was added under
cooling with an ice–water bath, the pH of the mixture was
adjusted to 7 with aqueous hydrochloric acid solution (1 %). The
resulting layers were separated and the aqueous layer was
extracted with ether (50 ml). The combined organic phases were
washed with water, dried (Na2SO4) and evaporated to dryness to
give o-aroylarylacetone ketals 5. Compounds 5b and 5l were
isolated in crystalline form and characterised. The oily products
5a and 5c-h were characterised by spectra (ir, pmr, cmr) and
elemental analysis before transformation to derivatives 6, 10 and
12 without further purification. Ketals 5i-k were transformed
directly to the corresponding diketons 6i-k and N-amino-7,8-
dialkoxyisoquinolinium chlorides 10i-k without characterisation.
2-Methyl-2-[(3,4-methylenedioxyphenyl)methyl]-1,3-dioxolane (4b).
This compound was prepared analogously to 4a starting from
1b (35.6 g, 0.2 mol) to give 4b (39.5 g, 89 %) as colourless oil,
bp 108 °C/0.4 mmHg; pmr (deuteriochloroform, 500 MHz): 6.79
(m, 1H), 6.72 (m, 1H), 6.70 (m, 1H), 5.91 (s, 2H), 3.90 (m, 2H),
3.79 (m, 2H), 2.82 (s, 2H), 1.29 (s, 3H); cmr (deuteriochloro-
form, 125 MHz): 147.1, 146.0, 130.5, 123.3, 110.7, 109.6,
107.7, 100.6, 64.7, 44.9, 24.1.
2-[(2-Benzoyl-3,4-dimethoxyphenyl)methyl]-2-methyl-1,3-
dioxolane (5a).
This compound was obtained as an oil. Yield: 67 %; ir
(potassium bromide): ꢀ 1669 cm-1; pmr (deuteriochloroform,
250 MHz): 1.21 (s, 3H), 2.79 (s, 2H), 3.5-3.7 (m, 4H), 3.61 (s,
3H), 3.88 (s, 3H), 6.96 (d, J=8.5 Hz, 1H), 7.16 (d, J=8.5 Hz,
1H), 7.4-7.8 (m, 4H); cmr (deuteriochloroform, 62.5 MHz):
24.2, 40.5, 55.7, 61.2, 64.4, 109.5, 112.8, 127.0, 127.3, 128.1,
129.4, 132.9, 135.2, 138.0, 145.8, 150.9, 196.9.
Anal. Calcd. for C12H14O4 (222.24): C, 64.85; H, 6.36. Found:
C, 64.89; H, 6.44.
General Method for the Synthesis of o-Aroylarylacetone Ketals 5.
Butyl lithium (29 ml of a 2.5 M solution in hexane, 0.072
mol) was added to a solution of the corresponding 4 (0.06 mol)

1542
L. Pongó, B. Ágai, F. Faigl, J.Reiter and G. Simig
Vol 43
(deuteriochloroform, 62.5 MHz): 24.3, 40.5, 55.7, 61.1, 64.4,
109.7, 113.1, 122.6, 127.2, 127.7, 128.2, 130.9, 136.7, 139.1,
150.9, 195.6.
Anal. Calcd. for C20H21ClO5 (376.84): C, 63.75; H, 5.62; Cl,
9.41. Found: C, 63.82; H, 5.67; Cl, 9.38.
Anal. Calcd. for C20H22O5 (342.39): C, 70.16; H, 6.48. Found:
C, 70.21; H, 6.53.
2-{[3,4-Dimethoxy-2-(2-fluorobenzoyl)phenyl]methyl}-2-
methyl-1,3-dioxolane (5b)
This compound was obtained as colourless crystals, mp 60-61
°C (ether). Yield: 72 %; ir (potassium bromide): ꢀ 1657 cm-1;
pmr (deuteriochloroform, 250 MHz): 1.23 (s, 3H), 2.91 (s, 2H),
3.5-3.7 (m, 4H), 3.59 (s, 3H), 3.86 (s, 3H), 6.93 (d, J=8.5 Hz,
1H), 7.08 (d, J=8.5 Hz, 1H), 7.2-7.8 (m, 4H); cmr (deuterio-
chloroform, 62.5 MHz): 24.1, 40.1, 55.6, 60.9, 64.3, 109.5,
113.0, 116.3 (d, JC-F=22.5 Hz), 123.6 (d, JC-F= 3.9 Hz), 126.7,
127.4, 131.0, 134.0 (d, 3JC-F=9.0 Hz), 136.3, 146.2, 150.7, 161.1
(d, 1JC-F=258 Hz), 193.0.
2-{[3,4-Dimethoxy-2-(2,4-dichlorobenzoyl)phenyl]methyl}-2-
methyl-1,3-dioxolane (5g).
This compound was obtained as an oil. Yield: 74 %; ir
(potassium bromide): ꢀ 1680 cm-1; pmr (deuteriochloroform,
250 MHz): 1.27 (s, 3H), 2.95 (s, 2H), 3.6-3.8 (m, 4H), 3.55 (s,
3H), 3.85 (s, 3H), 6.94 (d, J=8.5 Hz, 1H), 7.10 (d, J=8.5 Hz,
1H), 7.2-7.5 (m, 4H); (deuteriochloroform, 62.5 MHz): 24.1,
40.0, 55.6, 61.0, 64.3, 109.5, 113.6, 126.3, 127.7, 130.6, 132.5,
133.6, 136.7, 137.1, 146.7, 151.0, 194.1.
2
3
Anal. Calcd. for C20H21FO5 (360.38): C, 66.66; H, 5.87, F,
5.27. Found: C, 66.83; H, 5.91, F, 5.13.
Anal. Calcd. for C20H20Cl2O5 (411.28): C, 58.41; H, 4.90; Cl,
17.24. Found: C, 58.47; H, 4.95; Cl, 17.17.
2-{[3,4-Dimethoxy-2-(4-fluorobenzoyl)phenyl]methyl}-2-methyl-
1,3-dioxolane (5c)
2-[(2-Benzoyl-3,4-methylenedioxyphenyl)methyl]-2-methyl-
1,3-dioxolane (5h).
This compound was obtained as an oil. Yield: 74 %; ir
(potassium bromide): ꢀ 1670 cm-1; pmr (deuteriochloroform,
250 MHz): 1.20 (s, 3H), 2.80 (s, 2H), 3.6-3.9 (m, 4H,), 3.62 (s,
3H), 3.88 (s, 3H), 6.95 (d, J=8.5 Hz, 1H), 7.10 (d, J=8.5 Hz,
1H), 7.2-7.9 (m, 4H); cmr (deuteriochloroform, 62.5 MHz):
This compound was obtained as an oil. Yield: 85 %; ir
(potassium bromide): ꢀ 1676 cm-1; pmr (deuteriochloroform,
250 MHz): 1.21 (s, 3H), 2.90 (s, 2H), 3.4-3.6 (m, 4H), 3.55 (s,
3H), 3.90 (s, 2H), 6.99 (d, J=8.4 Hz, 1H), 7.13 (d, J = 8.4 Hz),
1H), 7.36 (d, J=8.9 Hz, 2H), 8.26 (d, J=8.9 Hz, 2H);
(deuteriochloroform, 62.5 MHz): 24.3, 40.4, 55.7, 61.0, 64.2,
109.3, 113.5, 123.2, 127.4, 128.0, 130.1, 133.5, 143.1, 146.2,
149.8, 150.9, 195.2.
2
24.1, 40.7, 55.7, 61.5, 64.8, 111.2, 113.3, 115.8 (d, JC-F=22.0
3
Hz), 123.0, 127.9, 129.4, 133.0 (d, JC-F=9.1 Hz), 135.8, 146.4,
151.8, 165.9 (d, 1JC-F=258 Hz), 196.4.
Anal. Calcd. for C20H21FO5 (360.38): C, 66.66; H, 5.87; F,
5.27. Found: C, 66.91; H, 5.95; F, 5.20.
Anal. Calcd. for C19H18O5 (326.35): C, 69.93; H, 5.56. Found:
C, 69.71; H, 5.48.
2-{[3,4-Dimethoxy-2-(2-chlorobenzoyl)phenyl]methyl}-2-methyl-
1,3-dioxolane (5d).
2-[3,4-Methylenedioxy-2-(4-nitrobenzoyl)phenylmethyl}-2-
methyl-1,3-dioxolane (5l).
This compound was obtained as an oil. Yield: 68 %; ir
(potassium bromide): ꢀ 1679 cm-1; pmr (deuteriochloroform,
250 MHz): 1.28 (s, 3H), 2.93 (s, 2H), 3.6-3.8 (m, 4H), 3.54 s,
3H), 3.85 (s, 3H), 6.94 (d, J = 8.5 Hz), 1H), 7.12 (d, J=8.5 Hz,
1H), 7.2-7.8 (m, 4H); cmr (deuteriochloroform, 62.5 MHz):
24.3, 40.1, 55.7, 61.0, 64.4, 109.6, 113.5, 126.0, 127.5, 127.6,
130.9, 131.7, 131.8, 132.6, 138.3, 151.0, 195.3.
This compound was obtained as pale yellow crystals, mp 145-
146°C (ether). Yield: 64 %; ir (potassium bromide): ꢀ 1667 cm-1;
pmr (deuteriochloroform, 250 MHz): 1.21 (s, 3H), 3.08 (s, 2H),
3.45-3.61 (m, 4H), 5.84 (s, 2H), 6.86 (d, J = 8.1 Hz, 1H), 6.88 (d,
J=8.1 Hz, 1H), 8.00 (d, J=8.9 Hz, 2H), 8.29 (d, J=8.9 Hz, 2H).
Anal. Calcd. for C19H17NO7 (371.35): C, 61.45; H, 4.61; N,
3.77. Found: C, 61.43; H, 4.65; N, 3.81.
Anal. Calcd. for C20H21ClO5 (376.84): C, 63.75; H, 5.62; Cl,
9.41. Found: C, 63.84, H, 5.79; Cl, 9.35.
General Method for the Synthesis of 2-Aroylphenylacetones 6.
2-{[3,4-Dimethoxy-2-(3-chlorobenzoyl)phenyl]methyl}-2-methyl-
1,3-dioxolane (5e).
To a suspension of silica gel (15 g, Kieselgel 60 for column
chromatography, 0.063 – 0.2 mm) in dichloromethane (30 ml)
aqueous sulphuric acid (15 %, 1.5 ml) was added at room
temperature and it was stirred until the aqueous phase
disappeared due to its adsorption on the silica gel surface (5
min). The corresponding o-aroylarylacetone ketal 5 (0.001 mol)
was added to the mixture and the stirring was continued at room
temperature for further 5 hours. The reaction mixture was then
neutralised with sodium hydrogen carbonate (1 g), the silica gel
was filtered off and washed with dichloromethane (2 x 15 ml).
Evaporation of volatiles from the organic solutions yielded
practically pure 2-aroylphenylacetones 6 that were recrystallised
from an appropriate solvent or used directly to the synthesis of
derivatives 9 and 11.
This compound was obtained as an oil. Yield: 67 %; ir
(potassium bromide): ꢀ 1675 cm-1; pmr (deuteriochloroform,
250 MHz): 1.21 (s, 3H), 2.82 (s, 2H), 3.5-3.7 (m, 4H), 3.60 (s,
3H), 3.88 (s, 3H), 6.97 (d, J=8.5 Hz, 1H), 7.15 (d, J=8.5 Hz,
1H), 7.3-7.8 (m, 4H);(deuteriochloroform, 62.5 MHz): 24.2,
40.4, 55.6, 61.0, 64.3, 109.3, 113.0, 127.0, 127.5, 127.6, 129.1,
129.3, 132.6, 134.1, 134.3, 139.7, 145.8, 150.8, 195.5.
Anal. Calcd. for C20H21ClO5 (376.84): C, 63.75; H, 5.62; Cl,
9.41. Found: C, 63.85; H, 5.65; Cl, 9.36.
2-{[3,4-Dimethoxy-2-(4-chlorobenzoyl)phenyl]methyl}-2-methyl-
1,3-dioxolane (5f).
This compound was obtained as an oil. Yield: 75 %; ir
(potassium bromide): ꢀ 1671 cm-1; pmr (deuteriochloroform,
250 MHz): 1.22 (s, 3H), 2.82 (s, 2H), 3.6-3.8 (m, 4H), 3.63 (s,
3H), 3.89 (s, 3H), 6.96 (d, J=8.5 Hz, 1H), 7.14 (d, J=8.5 Hz),
1H), 7.39 (d, J=9.1 Hz, 2H), 7.77 (d, J=9.1 Hz, 2H);
1-(2-Benzoyl-3,4-dimethoxyphenyl)propan-2-one (6a).
This compound was obtained as an oil. Yield: 71 %; ir
(potassium bromide): ꢀ 1720, 1670 cm-1; pmr (deuteriochloro-
form, 250 MHz): 1.91 (s, 3H), 3.43 (s, 3H), 3.52 (s, 2H, CH2)

Nov-Dec 2006
Synthesis of 8,9-Dialkoxybenzodiazepines and 7,8-Dialkoxyisoquinolines
1543
3.78 (s, 3H), 6.88 (d, J=8.4 Hz, 1H), 6.92 (d, J=8.4 Hz, 1H), 6.8-
7.7 (m, 5H); cmr (deuteriochloroform, 62.5 MHz): 29.4, 46.5,
55.7, 61.1, 113.3, 124.2, 126.4, 128.3, 129.3, 133.4, 134.2,
137.5, 146.0, 151.3, 197.0, 205.6.
Anal. Calcd. for C18H18O4 (298.34): C, 72.47; H, 6.08. Found:
C, 72.55; H, 6.12.
Anal. Calcd. for C18H17ClO4 (332.78): C, 64.97; H, 5.15; Cl,
10.65. Found: C, 65.08; H, 5.18; Cl, 10.51.
1-[2-(2,4-Dichlorobenzoyl)-3,4-dimethoxyphenyl]propan-2-one
(6g).
This compound was obtained as an oil. Yield: 65 %, not
purified, used directly to the synthesis of 9g; ir (potassium
bromide): ꢀ 1719, 1678 cm-1; pmr (deuteriochloroform, 250
MHz): 2.17 (s, 3H), 3.48 (s, 3H), 3.80 (s, 2H) 3.85 (s, 3H), 6.91
(d, J=8.4 Hz, 1H), 6.99 (d, J=8.4 Hz, 1H), 7.2-7.5 (m, 3H); cmr
(deuteriochloroform, 62.5 MHz): 29.4, 46.8, 55.5, 60.6, 114.5,
121.3, 125.8, 126.5, 126.7, 130.1, 131.4, 133.0, 136.9, 137.6,
147.5, 151.4, 195.0, 205.8.
1-[3,4-Dimethoxyphenyl-2-(2-fluorobenzoyl)]propan-2-one (6b).
This compound was obtained as an oil. Yield: 65 %; ir
(potassium bromide): ꢀ 1720, 1675 cm-1; pmr (deuteriochloro-
form, 250 MHz): 2.10 (s, 3H), 3.55 (s, 3H), 3.66 (s, 2H), 3.86 (s,
3H), 6.94 (d, J=8.4 Hz, 1), 6.99 (d, J=8.4 Hz, 1H), 7.1-7.7 (m,
4H); cmr (deuteriochloroform, 62.5 MHz): 29.3, 46.7, 55.6,
2
4
60.7, 113.8, 116.3 (d, JC-F= 22 Hz), 123.8 [d, JC-F=3.8 Hz),
Anal. Calcd. for C18H16Cl2O4 (367.23): C, 58.87; H, 4.39; Cl,
19.31. Found: C, 58.65; H, 4.33; Cl, 19.22.
3
3
124.5, 126.5, 127.3 (d, JC-F=9.6 Hz,), 131.0, 134.2 (d, JC-F=9.0
Hz), 134.8, 146.6, 151.2, 161.1 (d, 1JC-F=262 Hz), 193.8, 205.7.
Anal. Calcd. for C18H17FO4 (316.33): C, 68.35; H, 5.42; F,
6.01. Found: C, 68.42; H, 5.48; F, 5.97.
1-(2-Benzoyl-3,4-methylenedioxyphenyl)propan-2-one (6h).
This compound was obtained as colourless crystals, mp. 112-
113 °C (2-propanol). Yield: 38 %; ir (potassium bromide): ꢀ
1722, 1652 cm-1; pmr (deuteriochloroform, 250 MHz): 2.11 (s,
3H), 3.78 (s, 2H), 5.84 (s, 2H), 6.71 (d, J=8.1 Hz, 1H), 6.89 (d, J
= 7.7 Hz), 1H), 7.45-7.9 (m, 5H); cmr (deuteriochloroform, 62.5
MHz): 29.5, 47.3, 101.6, 110.0, 120.8, 124.6, 127.0, 128.4,
129.7, 133.4, 137.5, 146.2, 146.8, 194.2, 205.7.
1-[3,4-Dimethoxyphenyl-2-(4-fluorobenzoyl)]propan-2-one (6c).
This compound was obtained as an oil. Yield: 52 %; ir
(potassium bromide): ꢀ 1717, 1671 cm-1; pmr (deuterio-
chloroform, 500 MHz): 2.03 (s, 3H), 3.55 (s, 3H), 3.63 (s, 2H),
3.89 (s, 3H), 6.95 (d, J=8.4 Hz, 1), 6.99 (d, J=8.4 Hz, 1H), 7.1-
7.8 (m, 4H); cmr (deuteriochloroform, 125 MHz): 29.5, 46.7,
55.8, 61.2, 113.5, 115.6 (d, 2JC-F= 22 Hz), 124.4, 126.6, 132.2 (d,
Anal. Calcd. for C17H14O4 (282.30): C, 72.33; H, 5.00. Found:
C, 72.45; H, 5.13.
1
3JC-F=9.8 Hz,), 134.0, 134.1, 146.1, 151.5, 165.9 (d, JC-F=255,4
1-[2-(2-Fluorobenzoyl)-3,4-methylenedioxyphenyl]propan-2-
one (6i).
Hz), 195.5, 205.6.
Anal. Calcd. for C18H17FO4 (316.33): C, 68.35; H, 5.42; F,
6.01. Found: C, 68.51; H, 5.47; F, 5.95.
This compound was obtained as colourless crystals, mp. 107-
108 °C (2-propanol). Yield: 59 %; ir (potassium bromide): ꢀ
1724, 1654 cm-1; pmr (deuteriochloroform, 250 MHz): 2.21 (s,
3H), 3.89 (s, 2H), 5.81 (s, 2H), 6.69 (d, J=7.7 Hz, 1H), 6.88 (d, J
=8.1 Hz), 1H), 7.2-7.7 (m, 4H); cmr (deuteriochloroform, 62.5
1-[2-(2-Chlorobenzoyl)-3,4-dimethoxyphenyl]propan-2-one (6d).
This compound was obtained as an oil. Yield: 65 %; ir
(potassium bromide): ꢀ 1720, 1675 cm-1; pmr (deuteriochloro-
form, 250 MHz): 2.16 (s, 3H), 3.43 (s, 3H), 3.76 (s, 2H) 3.84 (s,
3H), 6.91 (d, J=8.4 Hz, 1H), 6.99 (d, J=8.4 Hz, 1H), 7.3-7.7 (m,
4H); cmr (deuteriochloroform, 62.5 MHz): 29.5, 46.9, 55.6,
60.5, 114.4, 125.8, 126.3, 126.7, 130.4, 130.5, 131.7, 133.7,
139.2, 147.5, 151.5, 196.2, 205.9.
2
MHz): 29.6, 47.8, 101.7, 110.8, 116.2 (d, JC-F=22.5 Hz), 121.1,
124.1 (d, 4JC-F=3.8 Hz), 124.8, 127.6 (d, 3JC-F=15.2 Hz), 131.2 (d,
3
4JC-F=1.9 Hz), 134.1 (d, JC-F=8.8 Hz), 147.1, 147.5, 161.1 (d,
1JC-F=256.4 Hz), 190.3, 205.9.
Anal. Calcd. for C17H13FO4 (300.29): C, 68.00; H, 4.36; F,
6.33. Found: C, 67.91; H, 4.45; F, 6.28.
Anal. Calcd. for C18H17ClO4 (332.78): C, 64.97; H, 5.15; Cl,
10.65. Found: C, 65.13; H, 5.21; Cl, 10.53.
1-[2-(4-Fluorobenzoyl)-3,4-methylenedioxyphenyl]propan-2-
one (6j).
1-[2-(3-Chlorobenzoyl)-3,4-dimethoxyphenyl]propan-2-one (6e).
This compound was obtained as colourless crystals, mp. 106-
108 °C (2-propanol). Yield: 77 %; ir (potassium bromide): ꢀ
1712, 1652 cm-1; pmr (deuteriochloroform, 250 MHz): 2.12 (s,
3H), 3.82 (s, 2H), 5.86 (s, 2H), 6.70 (d, J=8.1 Hz, 1H), 6.89 (d,
J=8.1 Hz, 1H), 7.13 (t, J=8.6 Hz, 2H,), 7.90 (dd, J=8.4 and 5.5
Hz, 2H); cmr (deuteriochloroform, 62.5 MHz): 29.6, 47.3,
101.6, 110.1, 115.4, 115.8, 120.6, 124.6, 127.0, 132.3, 132.5,
133.9, 146.1, 146.8, 168.5, 192.7, 205.7.
This compound was obtained as an oil.Yield: 70 %; ir
(potassium bromide): ꢀ 1721, 1674 cm-1; pmr (deuteriochloro-
form, 250 MHz): 2.04 (s, 3H), 3.60 (s, 3H), 3.86 (s, 2H) 3.88 (s,
3H), 6.96 (d, J=8.4 Hz, 1H), 7.02 (d, J=8.4 Hz, 1H), 7.4-7.8 (m,
4H); cmr (deuteriochloroform, 62.5 MHz): 29.3, 46.5, 55.6,
60.9, 112.1, 113.6, 124.3, 126.5, 127.6, 128.7, 129.6, 133.0,
133.2, 134.4, 139.1, 146.1, 151.2, 195.7, 205.3.
Anal. Calcd. for C18H17ClO4 (332.78): C, 64.97; H, 5.15; Cl,
10.65. Found: C, 65.11; H, 5.19; Cl, 10.54.
Anal. Calcd. for C17H13FO4 (300.29): C, 68.00; H, 4.36; F,
6.33. Found: C, 68.22; H, 4.35; F, 6.35.
1-[2-(4-Chlorobenzoyl)-3,4-dimethoxyphenyl]propan-2-one (6f).
1-[2-(4-Methoxybenzoyl)-3,4-methylenedioxyphenyl]propan-2-
one (6k).
This compound was obtained as colourless crystals, mp 74-76
°C (2-propanol). Yield: 71 %; ir (potassium bromide): ꢀ 1722,
1668 cm-1; pmr (deuteriochloroform, 250 MHz): 2.03 (s, 3H),
3.56 (s, 3H), 3.61 (s, 2H) 3.89 (s, 3H), 6.94 (d, J=8.4 Hz, 1H),
7.01 (d, J=8.4 Hz, 1H), 7.4-7.8 (m, 4H; cmr (deuteriochloro-
form, 62.5 MHz): 29.3, 46.5, 55.7, 61.0, 113.5, 124.3, 126.5,
128.6, 130.7, 133.6, 135.9, 139.6, 146.1, 151.3, 195.8, 205.4.
This compound was obtained as colourless crystals, mp. 102-
103 °C (2-propanol). Yield: 56 %; ir (potassium bromide): ꢀ
1712, 1650 cm-1; pmr (deuteriochloroform, 250 MHz): 2.10 (s,
3H), 3.75 (s, 2H), 3.87 (s, 3H), 5.88 (s, 2H), 6.71 (d, J=7.9 Hz,
1H), 6.88 (d, J = 7.9 Hz, 1H, 6.94 (d, J=8.4 Hz, 2H), 7.86 (d,

1544
L. Pongó, B. Ágai, F. Faigl, J.Reiter and G. Simig
Vol 43
J=8.4 Hz, 2H); cmr (deuteriochloroform, 62.5 MHz): 29.6, 47.3,
55.5, 101.5, 109.7, 113.8, 121.4, 124.5, 126.8, 130.3, 132.2,
145.7, 146.7, 164.0, 192.6, 205.9.
Anal. Calcd. for C18H16O5 (312.33): C, 69.22; H, 5.16. Found:
C, 69.15; H, 5.22.
Anal. Calcd. for C18H17FN2O2 (312.34): C, 69.22; H, 5.49; N,
8.97; F, 6.08. Found: C, 69.36; H, 5.54; N, 8.89; F, 6.01.
1-(2-Chlorophenyl)-8,9-dimethoxy-4-methyl-5H-2,3-benzo-
diazepine (9d).
This compound was obtained as colourless crystals, mp. 123-
125 °C (2-propanol). Yield: 78 %; pmr (deuteriochloroform,
250 MHz): 2.13 (s, 3H), 3.20 (d, J=12.4 Hz, 1H), 3.24 (d,
J=12.4 Hz, 1H), 3.40 (d, J=12.4 Hz, 1H), 3.80 (s, 3H), 6.92 (d,
J=8.4 Hz, 1H), 7.04 (d, J=8.4 Hz, 1H), 7.3-7.8 (m, 4H); cmr
(deuteriochloroform, 62.5 MHz): 22.9, 37.4, 55.8, 60.0, 115.4,
121.0, 124.9, 126.5, 129.2, 129.4, 130.7, 132.2, 133.8, 139.6,
147.2, 151.7, 156.0, 156.4.
1-[3,4-Methylenedioxy-2-(4-nitrobenzoyl)phenyl]propan-2-one
(6l).
This compound was obtained as yellow crystals, mp. 112-113
°C (ether). Yield: 78 %; ir (potassium bromide): ꢀ 1723, 1666
cm-1; pmr (deuteriochloroform, 250 MHz): 2.16 (s, 3H), 3.98 (s,
2H), 5.83 (s, 2H), 6.71 (d, J=7.9 Hz, 1H), 6.92 (d, J=7.9 Hz, 1H),
8.02 (d, J=9.0 Hz, 2H), 8.30 (d, J=9.0 Hz, 2H); cmr (deuterio-
chloroform, 62.5 MHz): 29.8, 47.3, 101.7, 110.9, 119.7, 123.5,
124.8, 127.3, 130.5, 142.8, 146.7, 147.1, 150.2, 192.9, 205.7.
Anal. Calcd. for C17H13NO6 (327.30): C, 62.39; H, 4.00; N,
4.28. Found: C, 62.44; H, 4.12; N, 4.35.
Anal. Calcd. for C18H17ClN2O2 (328.80): C, 65.75; H, 5.21; N,
8.52; Cl, 10.78. Found: C, 65.84; H, 5.28; N, 8.48; Cl, 10.71.
1-(3-Chlorophenyl)-8,9-dimethoxy-4-methyl-5H-2,3-benzo-
diazepine (9e).
General Method for the Synthesis of Benzodiazepines (9).
This compound was obtained as colourless crystals, mp. 108-
110 °C (2-propanol). Yield: 76 %; pmr (deuteriochloroform,
250 MHz): 2.10 (s, 3H), 3.00 (d, J=12.4 Hz, 1H), 3.18 (d,
J=12.4 Hz, 1H), 3.00 (d, J=12.4 Hz, 1H), 3.18 (d, J=12.4 Hz,
1H), 3.45 (s, 3H), 3.85 (s, 3H), 6.95 (d, J=8.4 Hz, 1H), 7.08 (d,
J=8.4 Hz, 1H), 7.3-7.6 (m, 4H); cmr (deuteriochloroform, 62.5
MHz): 22.8, 37.4, 55.9, 60.8, 115.5, 121.1, 122.8, 125.8, 127.3,
128.9, 129.1, 133.8, 134.1, 141.1, 147.7, 151.8, 155.9, 156.2;
Anal. Calcd. For C18H17ClN2O2 (328.80): C, 65.75; H, 5.21;
N, 8.52; Cl, 10.78. Found: C, 65.81; H, 5.26; N, 8.46; Cl, 10.70.
To a solution of 2-aroylphenylacetone (6, 0.01 mol) in ethanol
(30 ml) hydrazine (95 %, 0.5 ml, 0.015 mol) was added and the
mixture was refluxed for 30 min. After evaporation of the
solvent in vacuo the residue was triturated with diethyl ether and
the crystalline benzodiazepine (9) was collected by filtration and
dried.
8,9-Dimethoxy-4-methyl-1-phenyl-5H-2,3-benzodiazepine (9a).
This compound was obtained as colourless crystals, mp. 127-
129 °C (2-propanol). Yield: 75 %; pmr (deuteriochloroform, 250
MHz): 2.11 (s, 3H), 3.04 (d, J=12.4 Hz, 1H), 3.16 (d, J=12.4 Hz,
1H), 3.42 (s, 3H), 3.85 (s, 3H), 6.95 (d, J=8.4 Hz, 1H), 7.06 (d,
J=8.4 Hz), 1H), 7.3-7.6 (m, 5H); cmr (deuteriochloroform, 62.5
MHz): 22.7, 37.4, 55.9, 60.9, 115.2, 121.0, 123.4, 127.6, 128.0,
129.1, 134.5, 139.3, 148.2, 152.0, 156.4, 157.4.
1-(4-Chlorophenyl)-8,9-dimethoxy-4-methyl-5H-2,3-benzo-
diazepine (9f).
This compound was obtained as colourless crystals, mp. 129-
130.5 °C (2-propanol). Yield: 87 %; pmr (deuteriochloroform,
250 MHz): 2.10 (s, 3H), 2.99 (d, J=12.4 Hz, 1H), 3.16 d, J=12.4
Hz, 1H), 3.44 (s, 3H), 3.85 (s, 3H), 6.96 (d, J=8.4 Hz), 1H), 7.07
(d, J=8.4 Hz, 1H), 7.3-7.5 (m, 4H); cmr (deuteriochloroform,
62.5 MHz): 22.8, 37.4, 55.9, 60.1, 115.3, 121.1, 122.8, 128.0,
134.1, 137.6, 147.8, 151.8, 156.0, 156.5.
Anal. Calcd. for C18H18N2O2 (294.35): C, 73.45; H, 6.16; N,
9.52. Found: C, 73.54; H, 6.21; N, 9.45.
8,9-Dimethoxy-1-(2-fluorophenyl)-4-methyl-5H-2,3-benzo-
diazepine (9b).
Anal. Calcd. For C18H17ClN2O2 (328.80): C, 65.75; H, 5.21;
N, 8.52; Cl, 10.78. Found: C, 65.80; H, 5.27; N, 8.49; Cl, 10.72.
This compound was obtained as colouirless crystals, mp. 94-
96 °C (2-propanol). Yield: 84 %; pmr (deuteriochloroform, 250
MHz): 2.12 (s, 3H), 3.08 (d, J=12.4 Hz, 1H), 3.20 (d, J=12.4 Hz,
1H), 3.36 (s, 3H), 3.81 (s, 3H), 6.93 (d, J=8.4 Hz, 1H), 7.04 (d,
J=8.4 Hz, 1H), 6.9-7.8 (m, 4H); cmr (deuteriochloroform, 62.5
1-(2,4-Dichlorophenyl)-8,9-dimethoxy-4-methyl-5H-2,3-benzo-
diazepine (9g).
This compound was obtained as colourless crystals, mp. 125-
127 °C (2-propanol). Yield: 88 %; pmr (deuteriochloroform,
250 MHz): 2.13 (s, 3H), 3.13 [d, J=12.4 Hz, 1H), 3.22 (d,
J=12.4 Hz, 1H), 3.32 (s, 3H), 3.81 (s, 3H), 6.92 (d, J=8.4 Hz,
1H), 7.05 (d, J=8.4 Hz, 1H), 7.3-7.7 (m, 3H); cmr
(deuteriochloroform, 62.5 MHz): 22.9, 37.4, 55.8, 60.8, 115.6,
121.1, 124.5, 126.9, 129.0, 131.5, 132.9, 133.7, 134.6, 138.2,
147.2, 151.7, 155.3, 156.0.
2
MHz): 22.8, 37.4, 55.8, 60.5, 115.1 (d, JC-F=18.6 Hz), 121.0,
3
2
123.8 (d, JC-F=4.2 Hz,), 124.8, 128.3 (d, JC-F=11.3 Hz), 129.7
4
3
(d, JC-F = 3.0 Hz), 130.2 (d, JC-F=8.5 Hz), 133.1, 147.5, 151.6,
153.3, 156.1, 160.2 (d, 1JC-F=251 Hz).
Anal. Calcd. for C18H17FN2O2 (312.34): C, 69.22; H, 5.49; N,
8.97; F, 6.08. Found: C, 69.40; H, 5.52; N, 8.91; F, 6.02.
8,9-Dimethoxy-1-(4-fluorophenyl)-4-methyl-5H-2,3-benzo-
diazepine (9c).
Anal. Calcd. For C18H16Cl2N2O2 (363.24): C, 59.52; H, 4.44;
N, 7.71; Cl, 19.52. Found: C, 59.58; H, 4.47; N, 7.68; Cl, 19.50.
This compound was obtained as colourless crystals, mp. 138-
140 °C (2-propanol). Yield: 81 %; pmr (deuteriochloroform,
250 MHz): 2.10 (s, 3H), 3.02 (d, J=12.4 Hz, 1H), 3.16 (d,
J=12.4 Hz, 1H), 3.44 (s, 3H), 3.85 (s, 3H), 6.95 (d, J=8.4 Hz,
1H), 7.08 (d, J=8.4 Hz, 1H), 7.5-7.6 (m, 4H); cmr (deuterio-
4-Methyl-8,9-methylenedioxy-1-phenyl-5H-2,3-benzodiazepine
(9h).
This compound was obtained as colourless crystals, mp. 214-
216 °C (MeOH). Yield: 58 %; pmr (deuteriochloroform, 250
MHz): 2.12 (s, 3H), 3.05 (d, J=12.2 Hz, 1H), 3.23 (d, J=12.2 Hz,
1H, 5.74 (d, J=1.0 Hz, 1H), 5.83 (d, J=1.0 Hz, 1H), 6.72 (d,
J=8.2 Hz, 1H), 6.95 (d, J=8.2 Hz, 1H), 7.4-7.7 (m, 5H); cmr
2
chloroform, 62.5 MHz): 22.7, 37.4, 55.8, 60.9, 114.8 (d, JC-
F=20.8 Hz), 115.2, 121.1, 122.9, 129.3 (d, 3JC-F= 9.1 Hz), 134.1,
135.2, 147.8, 151.8, 156.0, 156.3, 163.3 (d, 1JC-F = 247 Hz).

Nov-Dec 2006
Synthesis of 8,9-Dialkoxybenzodiazepines and 7,8-Dialkoxyisoquinolines
1545
(deuteriochloroform, 62.5 MHz): 22.7, 38.0, 101.4, 110.8, 111.9,
118.5, 128.0, 129.6, 133.9, 137.2, 145.6, 147.2, 154.4, 155.8.
Anal. Calcd. for C17H14N2O2 (278.31): C, 73.37; H, 5.07; N,
10.07. Found: C, 73.42; H, 5.23; N, 9.97.
N-Amino-7,8-dimethoxy-3-methyl-1-phenyl-isoquinolinium
chloride (10a).
This compound was obtained as yellow crystals, mp. 132-134
°C (CH3CN). Yield: 65 %; pmr (DMSO-d6, 250 MHz): 2.88 (s,
3H), 3.13 (s, 3H), 3.96 (s, 3H), 7.24 (bs, 2H), 7.5-7.6 (m, 5H),
8.00 (d, J = 9.1 Hz, 1H), 8.11 (d, J = 9.1 Hz, 1H), 8.50 (s, 1H);
cmr (DMSO-d6, 62.5 MHz): 19.3, 57.0, 60.4, 122.4, 123.3,
124.5, 125.6, 128.1, 128.5, 129.8, 131.0, 132.7, 141.2, 142.9,
151.4, 152.2.
1-(2-Fluorophenyl)-4-methyl-8,9-methylenedioxy-5H-2,3-benzo-
diazepine (9i).
This compound was obtained as colourless crystals, mp. 183-
184 °C (2-propanol). Yield: 70 %; pmr (deuteriochloroform,
250 MHz): 2.13 (s, 3H), 3.07 (d, J=13.3 Hz, 1H), 3.27 (d,
J=13.3 Hz, 1H), 5.72 (d, J=2.2 Hz, 2H) 6.70 (d, J=8.0 Hz, 1H),
6.91 (d, J= 8.0 Hz, 1H), 6.94-7.89 (m, 4H).
Anal. Calcd. for C18H19ClN2O2 (330.81): C, 65.35; H, 5.79; N,
8.47; Cl, 10.72. Found: C, 65.43; H, 5.82; N, 8.38; Cl, 10.58.
N-Amino-7,8-dimethoxy-1-(2-fluorophenyl)-3-methyl-isoquino-
linium chloride (10b).
Anal. Calcd. for C17H13FN2O2 (296.30): C, 68.91; H, 4.42; N,
9.45; F, 6.41. Found: C, 69.03; H, 4.53; N, 9.38; F, 6.34.
This compound was obtained as yellow crystals, mp. 184-186
°C (2-propanol). Yield: 68 %; pmr (DMSO-d6, 250 MHz): 2.95
(s, 3H), 3.20 (s, 3H), 3.99 (s, 3H), 7.49 (bs, 2H), 7.5-7.7 (m,
4H), 8.05 (d, J = 9.1 Hz, 1H), 8.17 (d, J = 9.1 Hz, 1H), 8.59 (s,
1H); cmr (DMSO-d6, 62.5 MHz): 19.4, 57.0, 60.5, 115.3 (d, 2JC-F
= 21 Hz), 121.2, 121.4, 122.4, 123.6, 124.4, 125.1, 126.4, 130.5,
131.3, 132.2 (d, 3JC-F = 8.9 Hz), 143.2 (d, 3JC-F = 13.4 Hz), 147.8,
152.1, 158.9 (d, 1JC-F = 244 Hz).
1-(4-Fluorophenyl)-4-methyl-8,9-methylenedioxy-5H-2,3-benzo-
diazepine (9j).
This compound was obtained as colourless crystals, mp. 230-
232 °C (MeOH). Yield: 53 %; pmr (deuteriochloroform, 250
MHz): 2.12 (s, 3H), 3.04 (d, J=12.2 Hz, 1H), 3.24 d, J=12.2 Hz,
1H), 5.77 (d, J=1.2 Hz, 1H), 5.86 (d, J=1.2 Hz, 1H), 6.74 (d,
J=7.8 Hz), 1H), 6.97 (d, J=7.8 Hz, 1H,), 7.08 (t, J=8.7 Hz, 2H),
7.66 (dd, J=8.7 and 5.4 Hz), 2H).
Anal. Calcd. for C18H18ClFN2O2 (348.80): C, 61.68; H, 5.20;
N, 8.03; F, 5.45; Cl, 10.16. Found: C, 61.79; H, 5.28; N, 7.93; F,
5.41; Cl, 10.20.
Anal. Calcd. for C17H13FN2O2 (296.30): C, 68.91; H, 4.42; N,
9.45; F, 6.41. Found: C, 68.88; H, 4.40; N, 9.49; F, 6.39.
1-(4-Methoxyphenyl)-4-methyl-8,9-methylenedioxy-5H-2,3-
benzodiazepine (9k).
N-Amino-7,8-dimethoxy-1-(4-fluorophenyl)-3-methyl-isoquino-
linium chloride (10c).
This compound was obtained as colourless crystals, mp. 234-
236 °C (EtOH). Yield: 72 %; pmr (deuteriochloroform, 250
MHz): 2.11 (s, 3H), 3.06 (d, J=12.3 Hz, 1H), 3.21 (d, J=12.3 Hz,
1H), 3.83 (s, 3H), 5.76 (d, J=1.2 Hz, 1H), 5.87 (d, J=1.2 Hz,
1H), 6.73 (d, J=7.9 Hz, 1H, 6.92 (d, J=7.9 Hz, 1H), 6.94 (d,
J=9.1 Hz, 2H), 7.62 (dd, J=9.1 and 2.3 Hz), 2H).
This compound was obtained as yellow crystals, mp. 205-208
°C (2-propanol). Yield: 69 %; pmr (DMSO-d6, 250 MHz): 2.89
(s, 3H), 3.18 (s, 3H), 3.97 (s, 3H), 7.43 (bs, 2H), 7.5-7.7 (m,
4H), 8.00 (d, J = 9.1 Hz, 1H), 8.11 (d, J = 9.1 Hz, 1H), 8.51 (s,
1H); cmr (DMSO-d6, 62.5 MHz): 19.4, 57.0, 60.5, 115.6 (d, 2JC-F
3
= 22.5 Hz), 122.6, 123.4, 124.5, 125.7, 129.1, 130.9 (d, JC-F
=
Anal. Calcd. for C18H16N2O2 (308.34): C, 70.12; H, 5.23; N,
9.09. Found: C, 70.20; H, 5.28; N, 9.06.
1
8.8 Hz), 131.0, 141.4, 143.8, 150.7, 152.2, 162.0 (d, JC-F = 246
Hz).
Anal. Calcd. for C18H18ClFN2O2 (348.80): C, 61.68; H, 5.20;
N, 8.03; F, 5.45; Cl, 10.16. Found: C, 61.81; H, 5.25; N, 7.91; F,
5.37; Cl, 10.21.
4-Methyl-8,9-methylenedioxy-1-(4-nitrophenyl)-5H-2,3-benzo-
diazepine (9l).
This compound was obtained as colourless crystals, mp. 226-
228 °C (MeOH). Yield: 77 %; pmr (deuteriochloroform, 250
MHz): 2.16 (s, 3H), 3.02 (d, J=12.3 Hz, 1H), 3.31 (d, J=12.3 Hz,
1H), 5.80 (d, J=1.1 Hz, 1H), 5.89 (d, J=1.1 Hz, 1H), 6.79 (d,
J=7.9 Hz, 1H), 7.02 (d, J=7.9 Hz, 1H), 7.83 (d, J=9.0 Hz, 2H),
8.24 (d, J=9.0 Hz, 2H).
N-Amino-1-(2-chlorophenyl)-7,8-dimethoxy-3-methyl-isoquino-
linium chloride (10d).
This compound was obtained as yellow crystals, mp. 203-206
°C (2-propanol). Yield: 68 %; pmr (DMSO-d6, 250 MHz): 2.94
(s, 3H), 3.23 (s, 3H), 3.99 (s, 3H), 7.43 (bs, 2H), 7.6-7.7 (m,
4H), 8.05 (d, J = 9.1 Hz, 1H), 8.16 (d, J = 9.1 Hz, 1H), 8.58 (s,
1H); cmr (DMSO-d6, 62.5 MHz): 19.0, 57.0, 60.6, 122.2, 123.5,
125.0, 126.3, 127.4, 129.2, 130.0, 131.1, 131.4, 131.6, 132.4,
149.4, 152.1.
Anal. Calcd. for C17H13N3O4 (323.31): C, 63.16; H, 4.05; N,
13.00. Found: C, 63.04; H, 4.21; N, 12.91.
General Method for the Synthesis of N-Aminoisoquinolinium
chlorides (10).
Anal. Calcd. for C18H18Cl2N2O2 (365.26): C, 59.19; H, 4.97;
N, 7.67; Cl, 19.41. Found: C, 59.28; H, 5.03; N, 7.51; Cl, 19.29.
To a solution of a corresponding o-aroylarylacetone ketal (5,
0.06 mol) in methanol (100 ml) and water (12 ml) hydrazine
hydrochloride (8.2 g, 0.12 mol) was added and the reaction
mixture refluxed with stirring for 1 hour. The methanol was
evaporated in vacuo, water (300 ml) was added to the residue
and the mixture extracted with dichloromethane (2 x 150 ml).
The combined organic layers were evaporated in vacuo to
dryness and the residue was recrystallised from an appropriate
solvent to give N-aminoisoquinolinium chlorides (10).
N-Amino-1-(3-chlorophenyl)-7,8-dimethoxy-3-methyl-isoquino-
linium chloride monohydrate (10e).
This compound was obtained as yellow crystals, mp. 195-198
°C (H2O). Yield: 71 %; pmr (DMSO-d6, 250 MHz): 2.86 (s,
3H), 3.20 (s, 3H), 3.97 (s, 3H), 7.00 (bs, 2H), 7.5-7.7 (m, 4H),
8.02 (d, J = 9.1 Hz, 1H), 8.13 (d, J = 9.1 Hz, 1H), 8.51 (s, 1H);
cmr (DMSO-d6, 62.5 MHz): 19.2, 57.0, 60.4, 122.5, 123.4,

1546
L. Pongó, B. Ágai, F. Faigl, J.Reiter and G. Simig
Vol 43
124.7, 125.8, 126.9, 128.1, 129.6, 130.1, 131.2, 133.1, 135.0,
141.7, 143.7, 150.6.
N-Amino-1-(4-methoxyphenyl)-3-methyl-7,8-methylenedioxy-
isoquinolinium chloride hydrochloride (10k).
Anal. Calcd. for C18H18Cl2N2O2.H2O (383.28): C, 56.41; H,
5.26; N, 7.31; Cl, 18.50. Found: C, 56.63; H, 5.38; N, 7.50; Cl,
18.45.
This compound was obtained as pale yellow crystals, mp.
220-222 °C (AcOH/EtOH). Yield: 65 %; pmr (DMSO-d6, 250
MHz): 2.84 (s, 3H), 3.87 (s, 3H) 6.04 (s, 2H), 7.18 (d, J = 8.7
Hz, 2H), 7.32 (bs, 2H), 7.59 (d, J = 8.7 Hz, 2H), 7.78 (d, J = 8.7
Hz, 1H), 7.89 (d, J = 8.7 Hz, 1H), 8.40 (s, 1H).
N-Amino-1-(4-chlorophenyl)-7,8-dimethoxy-3-methyl-isoquino-
linium chloride monohydrate (10f).
Anal. Calcd. for C18H17ClN2O3.HCl (381.25): C, 56.70; H,
4.76; N, 7.35; Cl, 18.60. Found: C, 56.63; H, 4.85; N, 7.33; Cl,
18.53.
This compound was obtained as yellow crystals, mp. 194-196
°C (H2O). Yield: 75 %; pmr (DMSO-d6, 250 MHz): 2.87 (s,
3H), 3.19 (s, 3H), 3.97 (s, 3H), 7.26 (bs, 2H), 7.6-7.7 (m, 4H),
8.01 (d, J = 9.1 Hz, 1H), 8.12 (d, J = 9.1 Hz, 1H), 8.50 (s, 1H);
cmr (DMSO-d6, 62.5 MHz): 19.3, 57.0, 60.5, 122.5, 123.4,
124.6, 125.8, 128.6, 130.3, 131.1, 131.8, 134.5, 141.6, 143.7,
150.8, 152.2.
Anal. Calcd. for C18H18Cl2N2O2.H2O (383.28): C, 56.41; H,
5.26; N, 7.31; Cl, 18.50. Found: C, 56.58; H, 5.35; N, 7.48; Cl,
18.36.
General Method for the Synthesis of Isoquinolines 11.
To a mixture of a 2-aroylphenylacetone (6, 0.033 mol) in
methanol (40 ml) aqueous ammonium hydroxide (25 %, 20 ml,
0.15 mol) was added and refluxed with stirring for 1 hour. The
solution obtained was evaporated in vacuo to dryness and the
residue was chromatographed on a silica gel column (eluents:
different mixtures of hexane and ether). After evaporation the
solvents from the appropriate fractions the residue was triturated
with hexane and the crystalline isoquinoline (11) was collected
by filtration and dried.
N-Amino-1-(2,4-dichlorophenyl)-7,8-dimethoxy-3-methyl-
isoquinolinium chloride monohydrate (10g).
This compound was obtained as yellow crystals, mp. 193-196
°C (H2O). Yield: 78 %; pmr (DMSO-d6, 250 MHz): 2.95 (s,
3H), 3.29 (s, 3H), 4.00 (s, 3H), 7.56 (bs, 2H), 7.7-7.9 (m, 3H),
8.05 (d, J = 9.1 Hz, 1H), 8.61 (s, 1H), 9.17 (d, J = 9.1 Hz, 1H);
cmr (DMSO-d6, 62.5 MHz): 19.3, 57.0, 60.7, 122.2, 123.6,
125.1, 126.6, 127.7, 128.8, 131.2, 131.5, 131.7, 132.7, 135.3,
142.5, 143.2, 148.5, 152.1.
Anal. Calcd. for C18H17Cl3N2O2.H2O (417.72): C, 51.75; H,
4.58; N, 4.58; Cl, 25.46. Found: C, 51.93; H, 4.62; N, 4.44; Cl,
25.32.
7,8-Dimethoxy-1-(2-fluorophenyl)-3-methyl-isoquinoline (11b).
This compound was obtained as colourless crystals, mp. 80-82
°C. Yield: 58 %; pmr (deuteriochloroform, 250 MHz): 2.68 (s,
3H), 3.28 (s, 3H), 3.92 (s, 3H), 7.41 (s, 1H), 7.44 (d, J = 9.0 Hz,
1H), 7.0-7.5 (m, 4H), 7.53 (d, J = 9.0 Hz, 1H); cmr (deuterio-
2
chloroform, 62.5 MHz): 23.9, 56.7, 60.5, 114.4 (d, JC-F = 21.5
Hz), 118.3, 119.4, 121.6, 122.7, 123.2 (d, 4JC-F = 3.3 Hz), 129.0 (d,
3JC-F = 8.0 Hz), 130.1 (d, 3JC-F = 3.6 Hz), 131.8 (d, 2JC-F = 16.5 Hz),
133.6, 144.2, 148.5, 149.4, 152.0, 160.3 (d, 1JC-F = 252.5 Hz).
Anal. Calcd. for C18H16FNO2 (297.33): C, 72.71; H, 5.42; N,
4.71; F, 6.39. Found: C, 72.85; H, 5.51; N, 4.68; F, 6.35.
N-Amino-3-methyl-7,8-methylenedioxy-1-phenyl-isoquino-
linium chloride (10h).
This compound was obtained as yellow crystals, mp. 240-242 °C
(EtOH). Yield: 92 %; pmr (DMSO-d6, 250 MHz): 2.85 (s, 3H),
6.05 (dd, J = 5.8 and 0.8 Hz, 2H), 6.7 (b, 2H), 7.43-7.76 (m, 5H),
7.80 (d, J = 8.7 Hz, 1H), 7.91 (d, J = 8.7 Hz, 1H), 8.52 (s, 1H).
Anal. Calcd. for C17H15ClN2O2 (314.77): C, 64.87; H, 4.80; N,
8.90; Cl, 11.26. Found: C, 64.95; H, 5.01; N, 8.87; Cl, 11.26.
1-(3-Chlorophenyl)-7,8-dimethoxy-3-methyl-isoquinoline (11e).
This compound was obtained as colourless crystals, mp. 89-
91 °C. Yield: 61 %; pmr (deuteriochloroform, 250 MHz): 2.68
(s, 3H), 3.27 (s, 3H), 3.94 (s, 3H), 7.41 (s, 1H), 7.47 (d, J = 9.0
Hz, 1H), 7.3-7.5 (m, 4H), 7.55 (d, J = 9.0 Hz, 1H); cmr
(deuteriochloroform, 62.5 MHz): 23.8, 56.7, 60.4, 118.0, 119.3,
120.5, 122.7, 127.0, 127.1, 128.2, 128.6, 132.8, 133.9, 144.0,
145.2, 148.2, 149.5, 156.0.
N-Amino-1-(2-fluorophenyl)-3-methyl-7,8-methylenedioxy-
isoquinolinium chloride (10i).
Anal. Calcd. for C18H16ClNO2 (313.78): C, 68.90; H, 5.14; N,
4.46; Cl, 11.30. Found: C, 69.03; H, 5.21; N, 4.47; Cl, 11.25.
This compound was obtained as yellow crystals, mp. 238-240 °C
(2-propanol). Yield: 70 %; pmr (DMSO-d6, 250 MHz): 2.92 (s,
3H), 6.08 (dd, J = 5.8 and 0.8 Hz, 2H), 6.5 (b, 2H), 7.43-7.76 (m,
4H), 7.86 (d, J = 8.7 Hz, 1H), 7.97 (d, J = 8.7 Hz, 1H), 8.57 (s, 1H).
Anal. Calcd. for C17H14ClFN2O2 (332.76): C, 61.36; H, 4.24;
N, 8.42; F, 5.71; Cl, 10.65. Found: C, 61.44; H, 4.33; N, 8.30; F,
5.67; Cl, 10.69.
1-(4-Chlorophenyl)-7,8-dimethoxy-3-methyl-isoquinoline (11f).
This compound was obtained as colourless crystals, mp. 92-
94 °C. Yield: 63 %; pmr (deuteriochloroform, 250 MHz): 2.67
(s, 3H), 3.24 (s, 3H), 3.95 (s, 3H), 7.42 (s, 1H), 7.46 (d, J = 9.0
Hz, 1H), 7.3-7.5 (m, 4H), 7.56 (d, J = 9.0 Hz, 1H); cmr
(deuteriochloroform, 62.5 MHz): 23.7, 56.7, 60.3, 117.7, 119.3,
120.3, 122.7, 125.4, 127.0, 130.1, 132.9, 133.9, 141.8, 144.0,
148.3, 149.4, 156.1.
N-Amino-1-(4-fluorophenyl)-3-methyl-7,8-methylenedioxy-
isoquinolinium chloride (10j).
This compound was obtained as yellow crystals, mp. 247-248
°C (2-propanol). Yield: 73 %; pmr (DMSO-d6, 250 MHz): 2.85
(s, 3H), 6.03 (s, 2H), 7.36 (bs, 2H), 7.47 (d, J = 9.0 Hz, 2H),
7.73 (dd, J = 5.4 and 3.5 Hz, 2H), 7.80 (d, J = 8.7 Hz, 1H), 7.91
(d, J = 8.7 Hz, 1H), 8.45 (s, 1H).
Anal. Calcd. for C17H14ClFN2O2 (332.76): C, 61.36; H, 4.24;
N, 8.42; F, 5.71; Cl, 10.65. Found: C, 61.32; H, 4.41; N, 8.38; F,
5.74; Cl, 10.61.
Anal. Calcd. for C18H16ClNO2 (313.78): C, 68.90; H, 5.14; N,
4.46; Cl, 11.30. Found: C, 68.97; H, 5.12; N, 4.50; Cl, 11.26.
General Method for the Synthesis of Isoquinolinium N-oxides
(12).
To a solution of a corresponding o-aroylarylacetone ketal (5,
0.022 mol) in methanol (40 ml) hydroxylamine hydrochloride

Nov-Dec 2006
Synthesis of 8,9-Dialkoxybenzodiazepines and 7,8-Dialkoxyisoquinolines
1547
(3.2 g, 0.05 mol) was added and the mixture was refluxed with
stirring for 1 hour. The methanol was evaporated in vacuo,
aqueous sodium hydrogen carbonate solution (10 %, 30 ml) was
added to the residue and the mixture was stirred at room
temperature for 2 h. The crystalline product was collected by
filtration, washed with water and dried to give the corresponding
isoquinolinium N-oxides (12).
This compound was obtained as colourless crystals, mp. 203-
205 °C (EtOH). Yield: 67 %; pmr (DMSO-d6, 250 MHz): 2.60 (s,
3H), 3.24 (s, 3H), 3.93 (s, 3H), 7.33 d, J = 8.9 Hz, 1H), 7.50 (d, J
= 8.9 Hz, 1H), 7.3-7.5 (m, 5H), 7.61 (s, 1H); cmr (DMSO-d6, 62.5
MHz): 17.8, 56.5, 60.3, 116.7, 122.7, 123.8, 124.9, 126.9, 127.8,
128.7, 129.1, 133.7, 137.4, 141.3, 142.3, 143.8, 151.3.
Anal. Calcd. for C18H16ClNO3 (329.78): C, 65.56; H, 4.89; N,
4.25; Cl, 10.75. Found: C, 65.59; H, 4.93; N, 4.19; Cl, 10.61.
7,8-Dimethoxy-3-methyl-1-phenyl-isoquinolinium-N-oxide (12a).
1-(4-Chlorophenyl)-7,8-dimethoxy-3-methyl-isoquinolinium-N-
oxide (12f).
This compound was obtained as colourless crystals, mp. 149-
151 °C (EtOH). Yield: 68 %; pmr (DMSO-d6, 250 MHz): 2.60
(s, 3H), 3.17 (s, 3H), 3.91 (s, 3H), 7.32 (d, J = 8.9 Hz, 1H), 7.48
(d, J = 8.9 Hz, 1H), 7.4-7.5 (m, 5H), 7.60 (s, 1H); cmr (DMSO-
d6, 62.5 MHz): 17.7, 56.3, 60.2, 116.4, 122.2, 122.5, 123.7,
124.7, 127.2, 127.6, 128.3, 135.5, 141.4, 143.5, 143.6, 151.1.
Anal. Calcd. for C18H17NO3 (295.34): C, 73.20; H, 5.80; N,
4.74. Found: C, 73.38; H, 5.85; N, 4.68.
This compound was obtained as colourless crystals, mp. 230-
232 °C (EtOH). Yield: 75 %; pmr (DMSO-d6, 250 MHz): 2.60
(s, 3H), 3.21 (s, 3H), 3.93 (s, 3H), 7.34 (d, J = 8.9 Hz, 1H), 7.46
(d, J = 8.9 Hz, 1H), 7.3-7.5 (m, 5H), 7.61 (s, 1H); cmr (DMSO-
d6, 62.5 MHz): 17.9, 56.5, 60.3, 116.6, 122.6, 122.7, 123.8,
124.9, 128.0, 130.2, 133.4, 134.1, 141.3, 142.5, 143.7, 151.3.
Anal. Calcd. for C18H16ClNO3 (329.78): C, 65.56; H, 4.89; N,
4.25; Cl, 10.75. Found: C, 65.61; H, 4.94; N, 4.14; Cl, 10.57.
7,8-Dimethoxy-1-(2-fluorophenyl)-3-methyl-isoquinolinium-N-
oxide (12b).
3-Methyl-7,8-methylenedioxy-1-phenyl-isoquinolinium-N-oxide
(12h).
This compound was obtained as colourless crystals, mp. 170-
173 °C (EtOH). Yield: 71 %; pmr (DMSO-d6, 250 MHz): 2.60
(s, 3H), 3.25 (s, 3H), 3.92 (s, 3H), 7.31 (d, J = 8.9 Hz, 1H), 7.49
(d, J = 8.9 Hz, 1H), 7.2-7.4 (m, 5H), 7.61 (s, 1H); cmr (DMSO-
d6, 62.5 MHz): 17.5, 56.1, 60.1, 114.6 (d, 2JC-F = 22.1 Hz), 116.3,
This compound was obtained as colourless crystals, mp. 228-
230 °C (AcOH). Yield: 85 %; pmr (DMSO-d6, 250 MHz): 2.60
(s, 3H,), 5.80 (s, 2H), 7.17 (d, J = 8.6 Hz), 7.29 (d, J = 8.6 Hz,
1H), 7.47 (s, 5H), 7.58 (s, 1H).
Anal. Calcd. for C17H13NO3 (279.30): C, 73.11; H, 4.69; N,
5.01. Found: C, 73.07; H, 4.83; N, 4.89.
3
2
122.7 (d, JC-F = 16 Hz), 123.2 (d, JC-F = 7 Hz), 123.4, 123.8,
3
4
124.4, 129.5 (d, JC-F = 9 Hz), 130.4 (d, JC-F = 3 Hz), 138.2,
140.8, 143.3, 151.0, 159.7 (d, 1JC-F = 240 Hz).
Anal. Calcd. for C18H16FNO3 (313.33): C, 69.00; H, 5.15; N,
4.47; F, 6.06. Found: C, 69.17; H, 5.23; N, 4.35; F, 6.10.
Acknowledgement.
7,8-Dimethoxy-1-(4-fluorophenyl)-3-methyl-isoquinolinium-N-
oxide (12c).
The authors wish to express their thanks to Mrs. Dr. Sándorné
Sólyom for recording the ir spectra, to Mrs. Magdolna Nagy and
dr. István Kövesdi for recording the nmr spectra, to the late Mrs.
Hirkóné Magdolna Csík for performing the elemental analyses
and to Mrs. Éva Jóljárt, Mrs. Ildikó Szebelédi, Mrs. Tünde Jenei,
Mrs. Birkásné Gyöngyi Mester and Mrs. Zsófia Vincze for
technical help.
This compound was obtained as colourless crystals, mp. 205-
208 °C (CH3CN). Yield: 73 %; pmr (DMSO-d6, 250 MHz):
2.60 (s, 3H), 3.21 (s, 3H), 3.93 (s, 3H), 7.34 (d, J = 8.9 Hz, 1H),
7.50 (d, J = 8.9 Hz, 1H), 7.1-7.4 (m, 5H), 7.61 (s, 1H); cmr
2
(DMSO-d6, 62.5 MHz): 17.6, 56.2, 60.1, 114.5 (d, JC-F = 20.6
3
Hz), 116.3, 122.4, 122.6, 123.7, 124.7, 130.4, (d, JC-F = 9.0
1
REFERENCES
Hz), 131.2, 131.3, 141.1, 142.5, 143.5, 151.1, 162.0 (d, JC-F
246 Hz).
=
Anal. Calcd. for C18H16FNO3 (313.33): C, 69.00; H, 5.15; N,
4.47; F, 6.06. Found: C, 69.15; H, 5.21; N, 4.31; F, 6.13.
[1] Belgian Pat. BE 621,917, Chem. Abstr., 59, P 8713g (1963).
[2] J. Kꢀrösi,, and T. Láng, Hung. Pat. 155.572, Chem. Abstr.,
70, 115026 (1969).
1-(2-Chlorophenyl)-7,8-dimethoxy-3-methyl-isoquinolinium-N-
oxide (12d).
[3] L. Petꢀcz and I Kosóczky, Ther. Hung., 23, 134 (1975).
[4] F. Andrási, P. Berzsenyi, J. Borsy, T. Hámori, K. Horváth, Á.
Kenessey, J. Körösi, T. Láng, E. Sineger, M. Tarr, Arzneim.-Forsch.
Drug Res., 37, 1119 (1987).
[5] K. Horváth, F. Andrási, P. Berzsenyi,, M. Pátfalusi, M.
Patthy, G. Szabó, L. Sebestyén, E. Bagdy, J. Körösi, P. Botka, T.
Hámori, T. Láng, Arzneim.-Forsch. Drug Res., 39, 894 (1989).
[6] S. Sólyom, I. Tarnawa, Current Pharmaceutical Design, 8,
913 (2002).
[7] Brovchenko, V. G., Paidak, B. B., Kuznetsov, E. V., Khim.
Geterotsikl. Soedin., 1988, 134; Chem. Heterocycl. Comp., (Eng.
Transl.), 1988, 114.
[8] J. Kꢀrösi, T. Láng, Chem. Ber., 107, 3883 (1974).
[9] J. Kꢀrösi, T. Láng, A. Neszmélyi, Gy. Horváth, Acta Chim.
Acad. Sci. Hung., 114, 301 (1983).
This compound was obtained as colourless crystals, mp. 187-
189 °C (CH3CN). Yield: 71 %; pmr (DMSO-d6, 250 MHz):
2.61 (s, 3H), 3.29 (s, 3H), 3.92 (s, 3H), 7.32 (d, J = 8.9 Hz, 1H),
7.50 (d, J = 8.9 Hz, 1H), 7.4-7.5 (m, 5H), 7.62 (s, 1H); cmr
(DMSO-d6, 62.5 MHz): 17.6, 56.4, 60.5, 116.5, 122.5, 122.7,
123.8, 124.7, 126.4, 128.7, 129.0, 133.0, 135.0, 141.3, 141.4,
143.7, 151.1.
Anal. Calcd. for C18H16ClNO3 (329.78): C, 65.56; H, 4.89; N,
4.25; Cl, 10.75. Found: C, 65.48; H, 4.91; N, 4.27; Cl, 10.83.
1-(3-Chlorophenyl)-7,8-dimethoxy-3-methyl-isoquinolinium-N-
oxide (12e).