Preparation of 1-methyl-3-phenylisoquinoline derivatives from oximes using polyphosphoric esters

Article abstract of DOI:10.1039/c4nj02075h

We show a beneficial new approach to the preparation of 1-methyl-3-phenylisoquinoline derivatives. This method involves heating polyphosphate ester and the appropriate oximes obtained from 3,4-diphenylbut-3-en-2-one derivatives. The isoquinolines were syn

Full text of DOI:10.1039/c4nj02075h

NJC
PAPER
Preparation of 1-methyl-3-phenylisoquinoline
derivatives from oximes using polyphosphoric
esters
Cite this: New J. Chem., 2015,
39, 1868
Michał Niemczak,* Kamil Czerniak and Tomasz Kopczynski
´
We show a beneficial new approach to the preparation of 1-methyl-3-phenylisoquinoline derivatives. This
method involves heating polyphosphate ester and the appropriate oximes obtained from 3,4-diphenylbut-
3-en-2-one derivatives. The isoquinolines were synthesised in yields mainly ranging from about 50 to 70%,
and their structures were confirmed by proton and carbon nuclear magnetic resonance spectroscopy and
elemental analysis. This newly developed procedure is particularly suitable for the synthesis of 1-methyl-3-
phenylisoquinoline derivatives with chlorine, methyl, and methoxy substituents on the aromatic ring.
Received (in Montpellier, France)
18th November 2014,
Accepted 16th December 2014
DOI: 10.1039/c4nj02075h
www.rsc.org/njc
The yield of the reaction depends on both the presence and the
amount of electron donating groups in the aromatic ring
Introduction
Plants containing various alkaloids based on the isoquinoline containing the nitrogen atom.18,19 From 1936–1941, Krabbe and
structure have been known for many hundreds of years and have co-workers studied a cyclisation reaction of N-styrylamide.20–22
´
´
been successfully used in medicine as drugs for different afflic- Later, Goszczynski and Zielinski investigated the effect of the
tions. Because of the high intensity and diversity of physiological N-styrylamide structure on their cyclisation ability in isoquinoline
activities, the syntheses of these compounds have become a very systems.23 Subsequent research demonstrated that 1-methyl-3-
important aim in chemical science.1–4 Among the many alka- phenylisoquinoline derivatives could not be obtained via the
loids containing isoquinoline structures, the most important of Pictet and Gams method. The cyclisation of 2-acetamido-1,2-
them belong to the opium group of compounds, including diphenylethan-1-ol derivatives in boiling decalin with phosphorus
papaverine, an antispasmodic agent commonly used in medicine pentoxide or chlorophosphoric acid at 150 1C resulted in the
to decrease tension as well as the activity of smooth muscles.5,6 formation of 1-methyl-4-phenylisoquinoline derivatives instead
Moreover, also used are some benzophenanthridine derivatives, of the expected products substituted with a phenyl group on the
e.g., sangwinaryna or chelidonine.7–12 Many alkaloids, particularly third carbon atom.24
3-phenylisoquinoline and its derivatives, demonstrate anticancer or
Likewise, isoquinoline derivatives can be obtained from the
antirheumatic activities and can prevent the symptoms of hyper- unsaturated oximes of ketones and aldehydes without the need
tension and neuralgia. It has been demonstrated that 1-(4-methyl- to isolate intermediate products. Thomas and coworkers
piperazinyl)-3-phenylisoquinoline hydrochloride works as an described a synthesis of isoquinoline starting from an oxime
anticarcinogenic agent against various types of cancer cells. of the cinnamic aldehyde in the presence of rare-earth metal
Furthermore, the natural alkaloid known as Decumbenine b ions implanted in zeolites. However, small quantities of bypro-
has been applied in medicine as a very effective drug against ducts (cinnamonitrile and cinnamaldehyde) were formed in the
hypertension and neuralgia for many decades.13–16
process and contaminated the reaction product.25,26 The synth-
In 1893, Bischler and Napieralski described a synthetic esis of isoquinoline derivatives can be performed in common
method for isoquinoline derivatives based on the cyclisation solvents as well as in ionic liquids.27–30
of phenylethylamides in the presence of phosphorus pentoxide
The ethyl ester of polyphosphoric acid (polyphosphate ester,
as a dehydrogenation agent.17 The Bischler–Napieralski reaction PPE) is a dehydrogenation agent containing cyclic esters and may
occurs according to a mechanism involving an intramolecular be obtained from the reaction between phosphorus pentoxide and
electrophilic substitution reaction between an aromatic ring and a diethyl ether in the presence of chloroform. PPE is often used as a
nitrilium ion that is generated in situ from a reacting amide. substitute for polyphosphoric acid (PPA) due to its better solubility
in organic solvents and higher safety when used as a reagent in
organic syntheses. Moreover, the reaction can be conducted under
Department of Chemical Technology, Poznan University of Technology,
milder conditions; thus, PPE improves the economic viability of
the synthesis.31–33 PPE was successfully applied as a reagent in the
60-965 Poznan, Poland. E-mail: michal.m.niemczak@doctorate.put.poznan.pl;
Tel: +48-61-6653541
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Beckmann rearrangement31 and in the Bischer–Napieralski reac-
tion.18,19 Likewise, PPE can be applied in the Biginelli cyclocon-
densation reaction,33 the Fischer indole synthesis,34 alkylation or
N-alkylation reactions,35 and a bioparticle condensation.36 In the
presence of PPE, amino acids and peptides undergo conversions
into macromolecular peptides.36
Scheme 2 The synthesis of oximes from ketones.
Results and discussion
The aim of this work was to develop a simple method to synthesise
1-methyl-3-phenylisoquinoline derivatives from the oximes of unsa-
turated ketones without separating N-styrylamides as intermediates.
The structures of all synthesised compounds were confirmed by
proton and carbon nuclear magnetic resonance spectroscopy, and
product purity was determined by elemental analysis (CHN) and
thin layer chromatography (TLC). 3,4-Diphenylbut-3-en-2-one
derivatives were obtained via the condensation reactions of
benzaldehyde derivatives with 1-phenylpropan-2-one followed
by the dehydration of the formed hydroxy ketones (Scheme 1).
A solution of the benzaldehyde derivative and 1-phenylpropan-2-
one in toluene was heated in the presence of catalytic amounts of
hexanoic acid and piperidine for 12 h.
Scheme 3 A proposed mechanism of isoquinoline synthesis, where A is a
fragment of the PPE molecule.
Afterwards, all the required oximes were formed by the
reaction of the 3,4-diphenylbut-3-en-2-one derivatives and
hydroxylamine hydrochloride in an alkaline environment using
methanol as solvent. Table 1 lists the yields and melting points
of the oximes synthesised according to the reaction presented
in Scheme 2. The oximes of unsaturated ketones were obtained
in the form of crystals during the slow cooling of the post-
reaction mixture with yields ranging from 51 to 90%.
polyphosphate ester at 120 1C leads to a formation of 1-methyl-
3-phenylisoquinoline derivatives. This observation proves
that three different reactions occur in the reaction mixture:
Beckmann rearrangement, isomerisation of intermediates, and
finally condensation. The proposed mechanism of this process
is shown in Scheme 3.
As a result of these studies, we found that heating the
obtained oximes of 3,4-diphenylbut-3-en-2-one derivatives with
An |E| isomer of the amide should be formed in the
rearrangement reaction of the selected oxime. However, this
compound is not able to cyclise to an isoquinoline derivative
due to the presence of the double bond, which is unable to
rotate freely. In the presence of PPE as reaction medium, the
isomerisation of the |E| isomer of the amide to the |Z| isomer
occurs. However, all amides exist in the form of nitrylium
cations in the reaction mixture, which strongly facilitates the
cyclisation reaction. In order to confirm the assumed reaction
mechanism, oximes 2a and 11a were heated with PPE at 70 1C
for 5 min, and water was then slowly added to the post-reaction
mixture. Thus, the mixture of isoquinoline and both amides
was obtained, as confirmed by IR spectroscopy. In the spectrum
of the resulting mixture, we identified the absorption bands
Scheme 1 The synthesis of 3,4-diphenylobut-3-en-2-one derivatives.
Table 1 Prepared oximes
Oxime
R1
R2
R3
R4
Yield (%)
Mp (1C)
1a
2a
3a
4a
5a
6a
7a
8a
H
CH3
H
H
Cl
H
H
OCH3
H
H
OCH3
H
OCH3
OCH3
H
H
H
CH3
H
H
Cl
H
H
OCH3
H
OCH3
OCH3
H
H
OCH3
H
H
H
CH3
H
H
Cl
H
H
OCH3
H
OCH3
OCH3
H
H
H
H
H
H
H
H
H
H
H
H
H
H
OCH3
OCH3
77
81
57
90
87
85
80
89
74
63
81
51
55
71
51
157–158
142–144
132–134
178–180
138–140
145–149
193–194
147–150
132–136
185–188
182–187
184–186
194–196
185–187
166–168
from N–H (3200–3300 cmÀ1) and CQO (1650–1700 cmÀ1
)
stretching vibrations of an amide group.
Moreover, TLC analysis clearly proved that the post-reaction
mixture consists of an isoquinoline structure and two isomers
of the amide.
The oxime 4a was used to determine the influence of reaction
temperature on the efficiency of the synthesis. The mixture of the
substrate and PPE was heated for 3 h at temperatures ranging from
100 to 140 1C (Table 2). The highest yield of isoquinoline was
observed at 120 1C, and this temperature was selected to perform all
syntheses. The deterioration of the reaction yield at temperatures
9a
10a
11a
12a
13a
14a
15a
H
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Table 2 PPE-catalysed synthesis of 1,7-dimethyl-3-phenylisoquinoline
(4b) at various temperatures
11b (5,6-dimethoxy-1-methyl-3-phenylisoquinoline) and 12b
(6,7-dimethoxy-1-methyl-3-phenylisoquinoline) were obtained in
yields of 71% and 74%, respectively. The exception was the
synthesis of compound 13b, which also contained two methoxy
groups. The low yield of this reaction (13%) was caused by the
formation of by-products (e.g., 7-hydroxy-5-methoxy-1-methyl-3-
phenylisoquinoline (17b)) during the reaction. A similar effi-
ciency was observed for the cyclisation of oxime 6a, wherein
6-chloro-1-methyl-3-phenylisoquinoline (6b) was obtained in only
19% yield. This also implies that the presence of a substituent
that reduces the total electron density of the aromatic ring
adversely affects the efficiency of the entire process. This pheno-
menon also confirms the yields of isoquinolines substituted with
a chlorine in the ortho (5b) or para (7b) position, which reached
similar values (slightly less than 50%).
No.
Temperature (1C)
Yield (%)
1
2
3
4
5
100
110
120
130
140
58
60
67
61
56
Table 3 Prepared isoquinoline derivatives
Product
R1
R2
R3
R4
Yield (%)
Mp (1C)
1b
2b
3b
4b
5b
6b
7b
8b
H
CH3
H
H
Cl
H
H
OCH3
H
H
OCH3
H
OCH3
OCH3
H
H
OCH3
H
H
CH3
H
H
Cl
H
H
OCH3
H
OCH3
OCH3
H
H
OCH3
H
H
H
H
CH3
H
H
Cl
H
H
OCH3
H
OCH3
OCH3
H
H
OH
OH
H
H
H
H
H
H
H
H
H
H
H
H
68
48
76
67
45
19
47
61
72
36
71
74
13
53
77
5
47–48a
73–75
47–49
64–65
60–61
The oximes 3a, 6a, 9a, 12a and 15a may theoretically be
converted into two different products, which are structural
isomers. Scheme 3 shows that during the cyclisation of these
five amides, the carbon of the carbonyl group can attack the
95–98
99–100
116–118
132–134
121–122
109–112
144–145
154–156
80–81
9b
carbon C1 as well as the carbon C2. The analysis of 1H and 13
C
10b
11b
12b
13b
14b
15b
16b
17b
NMR spectra revealed that only one of these reaction products
was obtained. By comparing the location and multiplicity of the
signals of the formed isoquinoline with the theoretical spectra
of the two isomers, we discovered that the obtained products
were formed by attack on the C1 carbon.
H
OCH3
OCH3
H
116–118
275–278
151–154
H
H
10
Further research proved that the use of other reagents such
as phosphoryl chloride, phosphorus pentoxide, or chloro-
phosphoric acid instead of PPE does not result in the formation
a
Mp 48 1C, ref. 37.
above 120 1C may be related to the decomposition of PPE, which of isoquinoline structures from oximes. Moreover, the PPE is
is unstable at high temperatures. Table 3 shows that the yield an effective condensing reagent only for oximes of ketones
depends on the type and position of the substituent on the containing the aryl group on the third carbon atom in their
phenyl group of the starting oxime. The unsubstituted 1-methyl-3- structure. The reaction does not occur when this group is
phenylisoquinoline 1b (where R1, R2, R3, R4 = H) is known in the replaced with a hydrogen or alkyl group.
literature23,37 and was obtained with a 65% yield from N-(1,2-
diphenylvinyl)acetamide.23 The location of a methyl group in the
para position causes the cyclisation of the oxime to the isoquinoline
Conclusions
4b with a similar yield (67%). However, when the methyl group was
The ethyl ester of polyphosphoric acid (PPE) applied in our
located in the ortho position, the isoquinoline 2b was obtained with
study proved to be an efficient reagent for the cyclisation of
a lower efficiency (48%). This indicates that steric hindrance occurs
oximes to isoquinolines substituted by one or two functional
during the cyclisation of oxime 2b to this isoquinoline. The highest
groups. PPE allowed 1-methyl-3-phenylisoquinoline derivatives
yield was observed for isoquinoline 3b, in which the methyl group is
to be obtained with high efficiency and purity. Moreover, three
substituted in the meta position (76%).
different reactions, all of which are promoted by only one
The yields of isoquinoline syntheses from oximes containing
reagent, occur in the reaction mixture: Beckmann rearrange-
one methoxy group also depend on the location of this group
ment, isomerisation and condensation. As a result, we elimi-
on the phenyl substituent of the substrate. The oxime 8a with
nate the necessity of isolating the reaction intermediates as well
the methoxy group in the ortho position undergoes transforma-
as the use of various catalysts suitably selected for each reac-
tion to the isoquinoline with a yield lower by about 11% than
tion. The studied cyclocondensation reaction turned out to be a
the oxime 9a containing the methoxy group in the meta position,
selective process; only one isomer of isoquinoline was formed
which was obtained in 72% yield. However, when the methoxy
as the result of all syntheses.
group was located in para position, isoquinoline 10b was synthe-
sised with the lowest yield – only 36%. Moreover, it was found that
in addition to the expected main product, small amounts (5%) of
7-hydroxy-1-methyl-3-phenylisoquinoline (16b) were formed.
Experimental
General
On the other hand, the presence of two methoxy groups in the
oxime generally does not negatively affect the synthetic efficiency. Melting points were measured with a Bu¨chi melting point B-540
As a result of transformation of oximes 11a and 12a, compounds apparatus. The IR spectra were collected using a Bruker FT-IR
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EQUINOX 55 spectrophotometer. H NMR and 13C NMR ana-
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1-Methyl-3-phenylisoquinoline (1b). White cryst. solid. 1H NMR
1
lyses were performed on a Gemini Varian 300 VT spectrometer (300 MHz, CDCl3): d 8.15–6.74 (10H, m), 2.88 (3H, s); 13C NMR
with tetramethylsilane as an internal standard. CHN elemental (75 MHz, CDCl3): d 158.4, 150.0, 139.8, 136.5, 129.6, 128.6, 128.2,
analyses were performed at the Adam Mickiewicz University, 127.5, 126.9, 126.6, 125.5, 115.1, 22.5; Anal. calcd for C16H13N: C,
Poznan (Poland). The TLC chromatograms were obtained using 87.64; H, 5.98; N, 6.39. Found: C, 87.44; H, 6.21; N, 6.12.
KIESEGEL 60 GF254 plates and a mixture of toluene–ethyl
acetate (1 : 1) as the mobile phase.
1,5-Dimethyl-3-phenylisoquinoline (2b). White cryst. solid.
1H NMR (300 MHz, CDCl3): d 8.18 (2H, m), 8.04 (1H, s), 7.42
(6H, m), 3.05 (3H, s) 2.73 (3H, s); 13C NMR (75 MHz, CDCl3):
d 158.9, 149.9, 140.3, 136.1, 134.3, 130.4, 128.7, 128.2, 127.1,
Synthesis of PPE
The reagent was prepared by refluxing a mixture of 150 g of 126.5, 126.2, 111.7, 23.0, 19.0; Anal. calcd for C17H15N: C, 87.52;
phosphorus pentoxide (P4010), 150 mL of diethyl ether and H, 6.48; N, 6.00. Found: C, 87.71; H, 6.33; N, 5.89.
300 mL of chloroform until the solution was clear (15–30 h).
1,6-Dimethyl-3-phenylisoquinoline (3b). White cryst. solid.
The mixture was then filtered through glass wool and concen- 1H NMR (300 MHz, CDCl3): d 8.18 (2H, m), 7.97 (1H, s), 7.43
trated on a rotary evaporator. The obtained PPE was diluted with (6H, m), 3.02 (3H, s) 2.36 (3H, s); 13C NMR (75 MHz, CDCl3):
anhydrous chloroform to a density of 2.7 g mLÀ1 before use.
d 158.4, 149.9, 140.1, 137.0, 130.1, 129.9, 129.3, 127.0, 125.9,
126.8, 125.9, 115.9, 22.5, 21.7; Anal. calcd for C17H15N: C, 87.52;
H, 6.48; N, 6.00. Found: C, 87.64; H, 6.55; N, 6.09.
Condensation of 1-phenylprop-2-one with benzaldehyde
derivatives
1,7-Dimethyl-3-phenylisoquinoline (4b). White cryst. solid.
The appropriate benzaldehyde derivative (0.1 mol), 1-phenylprop- 1H NMR (300 MHz, CDCl3): d 8.16 (2H, m), 7.88 (1H, s), 7.38
2-one (0.11 mol), toluene (100 mL) as a solvent and catalytic (6H, m), 3.03 (3H, s) 2.57 (3H, s); 13C NMR (75 MHz, CDCl3):
amounts of hexanoic acid and piperidine were added to a d 157.7, 149.2, 140.0, 137.0, 134.9, 132.1, 128.6, 128.1, 127.4,
reaction flask. Next, the solution was heated in a Dean Stark 126.8, 126.7, 124.5, 115.0, 22.6, 22.0; Anal. calcd for C17H15N: C,
apparatus for 12 h at 110 1C. The reaction mixture was cooled to 87.52; H, 6.48; N, 6.00. Found: C, 87.45; H, 6.59; N, 6.14.
room temperature, and toluene was evaporated under reduced
5-Chloro-1-methyl-3-phenylisoquinoline (5b). White cryst.
pressure. The obtained raw product was recrystallised from solid. 1H NMR (300 MHz, CDCl3): d 8.29 (1H, s), 8.18–7.39
ethanol.
(8H, m), 3.04 (3H, s); 13C NMR (75 MHz, CDCl3): d 158.9, 151.1,
139.5, 134.7, 132.0, 130.0, 128.8, 128.7, 127.5, 127.2, 126.4,
124.6, 111.4, 22.9; Anal. calcd for C16H12ClN: C, 75.74; H,
Oximation of 3,4-diphenylbut-3-en-2-one derivatives
In a round-bottom flask, a selected ketone (0.05 mol) and hydro- 4.77; N, 5.52. Found: C, 75.61; H, 4.83; N, 5.59.
xylamine hydrochloride (0.08 mol) were dissolved in 50 mL of
6-Chloro-1-methyl-3-phenylisoquinoline (6b). White cryst.
methanol. Afterwards, sodium hydroxide (0.06 mol) dissolved in solid. 1H NMR (300 MHz, CDCl3): d 8.14–7.39 (9H, m), 2.99
aqueous–methanolic solution (1 : 1) was added into the reaction (3H, s); 13C NMR (75 MHz, CDCl3): d 158.5, 151.1, 139.3, 137.6,
mixture. The solution was heated in a round-bottom flask equipped 136.1, 128.7, 128.6, 127.5, 127.3, 127.0, 126.2, 124.7, 114.1, 22.6;
with a reflux condenser for 1 h. The obtained precipitate was Anal. calcd for C16H12ClN: C, 75.74; H, 4.77; N, 5.52. Found: C,
filtered off under reduced pressure and recrystallised from ethanol. 75.58; H, 4.64; N, 5.62.
7-Chloro-1-methyl-3-phenylisoquinoline (7b). White cryst.
solid. 1H NMR (300 MHz, CDCl3): d 8.15–7.36 (9H, m), 3.00
General procedure for the synthesis of 3-phenylisoquinoline
derivatives
(3H, s); 13C NMR (75 MHz, CDCl3): d 157.7, 150.3, 139.3, 135.0,
The cyclisation of a selected oxime (0.02 mol) was carried out in a 132.2, 130.9, 129.2, 128.7, 128.5, 127.0, 126.9, 124.7, 114.5, 22.5;
solution of PPE (0.035 mol) in chloroform at 120 1C for 3 h. The Anal. calcd for C16H12ClN: C, 75.74; H, 4.77; N, 5.52. Found: C,
post-reaction mixture was acidified with hydrochloric acid, and 75.80; H, 4.71; N, 5.67.
both chloroform and contaminants were separated by steam
5-Methoxy-1-methyl-3-phenylisoquinoline (8b). White cryst.
1
distillation. Then, an excess of sodium hydroxide was added to solid. H NMR (300 MHz, CDCl3): 8.36 (1H, s), 8.22–8.20 (2H,
the flask containing the isoquinoline hydrochloride in order to m), 7.65 (1H, m), 7.54–7.26 (4H, m), 6.97 (1H, m), 4.01 (3H, s),
isolate of the reaction product. Next, the mixture was extracted 3.03 (3H, s); 13C NMR (75 MHz, CDCl3): d 157.8, 155.2, 149.5,
three times with diethyl ether, and the organic phase was dried 140.1, 129.3, 128.6, 128.1, 127.2, 126.9, 126.5, 117.4, 109.4,
over sodium sulphate. Afterwards, the solvent was removed, and 107.2, 55.6, 23.0; Anal. calcd for C17H15NO: C, 81.90; H, 6.06;
the crude product was recrystallised from ethanol.
N, 5.62. Found: C, 81.79; H, 6.01; N, 5.74.
In the synthesis of 7-methoxy-1-methyl-3-phenylisoquinoline
6-Methoxy-1-methyl-3-phenylisoquinoline (9b). White cryst.
(10b) and 5,7-dimethoxy-1-methyl-3-phenylisoquinoline (13b), solid. 1H NMR (400 MHz, CDCl3): d 8.15–6.74 (9H, m), 3.91
the separated aqueous phase was acidified with a 10% solution (3H, s), 2.95 (3H, s); 13C NMR (100 MHz, CDCl3): d 160.6, 157.9,
of hydrochloric acid; as a result, by-products containing hydro- 150.6, 140.0, 138.8, 136.1, 128.6, 128.2, 127.8, 127.0, 122.2,
xyl substituents (16b, 17b) precipitated. The aqueous mixture 119.3, 114.7, 105.1, 55.4 22.5; Anal. calcd for C17H15NO: C,
was then extracted three times with diethyl ether, and the 81.90; H, 6.06; N, 5.62. Found: C, 81.97; H, 6.14; N, 5.53.
organic phase was dried over sodium sulphate. Afterwards,
the solvent was removed.
7-Methoxy-1-methyl-3-phenylisoquinoline (10b). White cryst.
solid. 1H NMR (300 MHz, CDCl3): d 8.12–8.09 (2H, m), 7.84 (1H, s),
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7.50–7.24 (5H, m), 6.97 (1H, m), 3.95 (3H, s), 2.99 (3H, s); 13C NMR
(75 MHz, CDCl3): d 158.2, 156.8, 148.1, 139.7, 132.2, 129.2, 128.7,
128.0, 127.5, 126.7, 122.8, 115.1, 103.6, 55.4 22.6; Anal. calcd for
C17H15NO: C, 81.90; H, 6.06; N, 5.62. Found: C, 81.81; H, 6.23; N, 5.49.
5,6-Dimethoxy-1-methyl-3-phenylisoquinoline (11b). White
cryst. solid. 1H NMR (300 MHz, CDCl3): d 8.19–8.16 (3H, m),
7.90 (1H, d, J = 9.0 Hz), 7.86 (1H, m), 7.53–7.26 (3H, m), 4.02
(6H, m), 2.99 (3H, s); 13C NMR (75 MHz, CDCl3): d 158.3, 151.2,
150.1, 142.2, 140.1, 132.8, 128.6, 128.2, 127.1, 122.5, 114.5,
108.8, 61.2, 56.5, 22.7; Anal. calcd for C18H17NO2: C, 77.40; H,
6.13; N, 5.01. Found: C, 77.29; H, 6.23; N, 5.10.
¨
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6,7-Dimethoxy-1-methyl-3-phenylisoquinoline (12b). White
cryst. solid. 1H NMR (400 MHz, CDCl3): d 8.10–7.10 (8H, m),
4.04 (6H, m), 2.96 (3H, s); 13C NMR (100 MHz, CDCl3): d 155.8,
152.5, 149.7, 149.1, 133.4, 128.6, 127.6, 126.7, 122.2, 114.3,
105.6, 103.8, 55.9, 22.7; Anal. calcd for C18H17NO2: C, 77.40;
H, 6.13; N, 5.01. Found: C, 77.52; H, 6.15; N, 4.97.
´
´
ˇ
´
´
´
9 J. Malıkova, A. Zdarilova, A. Hlobilkova and J. Ulrichova, Cell
Biol. Toxicol., 2006, 22, 439.
10 M. J. Fleming, H. A. McManus, A. Rudolph, W. H. Chan,
J. Ruiz, C. Dockendorff and M. Lautens, Chem. – Eur. J.,
2008, 14, 2112.
5,7-Dimethoxy-1-methyl-3-phenylisoquinoline (13b). Brown
1
cryst. solid. H NMR (300 MHz, CDCl3): d 8.23 (1H, s), 7.65–7.21
(7H, m), 3.99 (3H, s), 3.96 (3H, s), 2.95 (3H, s); 13C NMR (75 MHz,
CDCl3): d 158.7, 156.5, 156.2, 147.8, 140.0, 128.6, 127.9, 127.7, 126.8,
125.6, 109.8, 101.0, 95.2, 55.7, 55.4, 22.9; Anal. calcd for C18H17NO2:
C, 77.40; H, 6.13; N, 5.01. Found: C, 77.64; H, 6.01; N, 4.85.
5,8-Dimethoxy-1-methyl-3-phenylisoquinoline (14b). White
cryst. solid. 1H NMR (300 MHz, CDCl3): d 8.22–6.71 (8H, m),
3.96 (3H, s), 3.91 (3H, s), 3.19 (3H, s); 13C NMR (75 MHz, CDCl3):
d 157.9, 151.8, 149.6, 148.7, 139.7, 131.4, 128.6, 128.2, 126.9, 119.5,
108.8, 107.4, 105.2, 55.8, 55.6, 28.9; Anal. calcd for C18H17NO2: C,
77.40; H, 6.13; N, 5.01. Found: C, 77.23; H, 6.28; N, 5.30.
6,8-Dimethoxy-1-methyl-3-phenylisoquinoline (15b). White
cryst. solid. 1H NMR (300 MHz, acetone-d6): d 8.15–8.12 (3H,
m), 7.71 (1H, s), 7.52–7.37 (4H, m), 3.92 (6H, m), 3.12 (3H, s);
13C NMR (75 MHz, CDCl3): d 160.9, 159.4, 157.8, 150.3, 140.1,
139.7, 128.5, 128.2, 126.8, 115.6, 114.3, 98.9, 97.8, 55.4, 55.3,
28.6; Anal. calcd for C18H17NO2: C, 77.40; H, 6.13; N, 5.01.
Found: C, 77.11; H, 5.87; N, 5.14.
11 P. Krajewski, L. Kozerski, G. Grynkiewicz, E. Bednarek and
J. Sitkowski, Magn. Reson. Chem., 2000, 38, 757.
12 A. R. Jalilian, P. Seyfi, H. Afarideh and A. Shafiee, Appl.
Radiat. Isot., 2001, 54, 407.
13 W.-J. Cho, E.-K. Kim, M.-J. Park, S.-U. Choi, C.-O. Lee,
S. H. Cheon, B.-G. Choi and B.-H. Chung, Bioorg. Med.
Chem., 1998, 6, 2449.
14 Y. Wada, N. Nishida, N. Kurono, T. Ohkuma and K. Orito,
Eur. J. Org. Chem., 2007, 4320.
15 W.-J. Cho, E.-K. Kim, I. Y. Park, E. Y. Jeong, T. S. Kim,
T. N. Le, D.-D. Kim and E.-S. Lee, Bioorg. Med. Chem., 2002,
10, 2953.
16 K.-E. Kim, W.-J. Cho, S.-J. Chang, C.-S. Yong, C.-H. Lee and
D.-D. Kim, Int. J. Pharm., 2001, 217, 101.
17 J. J. Li, Name Reactions in Heterocyclic Chemistry, John Wiley
& Sons, Inc, New Jersey, United States Of America, 2005,
p. 381.
18 A. Ishida, T. Nakamura, K. Irie and T. Oh-Ishi, Chem. Pharm.
Bull., 1985, 33, 3237.
7-Hydroxy-1-methyl-3-phenylisoquinoline (16b). Yellow
cryst. solid. 1H NMR (300 MHz, acetone-d6): d 11.40 (1H, s),
7.59–7.37 (9H, m), 2.54 (3H, s); 13C NMR (75 MHz, CDCl3): 19 Y. Kanaoka, E. Sato, O. Yonemitsu and Y. Ban, Tetrahedron
d 178.4, 177.1, 159.5, 139.0, 133.3, 132.3, 129.3, 129.2, 128.7,
Lett., 1964, 35, 2419.
127.6, 121.0, 119.9, 111.2, 19.0; Anal. calcd for C16H13NO: C, 20 W. Krabbe, Ber. Dtsch. Chem. Ges., 1936, 69, 1569.
¨
21 W. Krabbe, H. H. Bohlk and K. H. Schmidt, Ber. Dtsch.
81.68; H, 5.57; N, 5.95. Found: C, 81.79; H, 5.21; N, 5.75.
7-Hydroxy-5-methoxy-1-methyl-3-phenylisoquinoline (17b).
Chem. Ges., 1938, 71, 64.
Yellow cryst. solid. 1H NMR (300 MHz, acetone-d6): d 11.33 22 W. Krabbe, K. H. Schmidt and W. Eisenlohr, Ber. Dtsch.
(1H, s), 7.67–7.28 (6H, m), 6.17 (2H, m), 4.07 (3H, s), 2.51 (3H, s);
Chem. Ges., 1941, 74, 1905.
13C NMR (75 MHz, CDCl3): d 179.5, 178.5, 168.9, 166.4, 136.9, 23 W. Zielinski and S. Goszczynski, Ann. Soc. Chim. Pol., 1970,
´
´
134.5, 132.0, 130.8, 128.1, 127.8, 119.0, 117.7, 112.4, 57.7, 18.8;
44, 109.
´
Anal. calcd for C17H15NO2: C, 76.96; H, 5.70; N, 5.28. Found: C, 24 T. Kopczynski and A. Voelkel, Pol. J. Chem., 2001, 75, 1317.
77.23; H, 5.99; N, 4.94.
25 B. Thomas, S. Prathapan and S. Sugunan, Microporous
Mesoporous Mater., 2005, 84, 137.
26 B. Thomas, U. R. Prabhu, S. Prathapan and S. Sugunan,
Microporous Mesoporous Mater., 2007, 102, 138.
27 Z. M. A. Judeh, C. B. Ching, J. Bu and A. McCluskey,
Tetrahedron Lett., 2002, 43, 5089.
Notes and references
1 J. Szawkalo and Z. Czarnocki, Monatsh. Chem., 2005, 136, 1619.
2 L. F. Tietze, N. Rackelmann and I. Mu¨ller, Chem. – Eur. J., 28 R.-S. Hou, H.-M. Wang, H.-Y. Huang and L.-C. Chen, Org.
2004, 10, 2722.
Prep. Proced. Int., 2004, 36, 491.
1872 | New J. Chem., 2015, 39, 1868--1873
This journal is © The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2015

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