One-step synthesis of 1,4-bis(het)arylisoquinolines by the reaction of 1,2,4-triazines with arynes

Article abstract of DOI:10.1007/s10593-019-02565-8

[Figure not available: see fulltext.] The reaction of 3,6-bis(het)aryl-1,2,4-triazines (hetaryl ≠ 2-pyridyl) with aryne intermediates generated in situ was studied. As a result, novel 1,4-bis(het)arylisoquinolines were synthesized with yields of up to 45%. The main rules of the reactions were studied, and the obtained experimental data were compared with those described in the literature.

Full text of DOI:10.1007/s10593-019-02565-8

DOI 10.1007/s10593-019-02565-8
Chemistry of Heterocyclic Compounds 2019, 55(10), 978–984
One-step synthesis of 1,4-bis(het)arylisoquinolines
by the reaction of 1,2,4-triazines with arynes
Dmitry S. Kopchuk1,2, Igor L. Nikonov1,2, Albert F. Khasanov1,2, Sravya Gundala1,
Alexey P. Krinochkin1,2, Pavel А. Slepukhin1,2, Grigory V. Zyryanov1,2*,
Padmavathi Venkatapuram3, Oleg N. Chupakhin1,2, Valery N. Charushin1,2
1 Ural Federal University named after the first President of Russia B. N. Yeltsin,
19 Mira St., Yekaterinburg 620002, Russia; e-mail: gvzyryanov@gmail.com
2 Postovsky Institute of Organic Synthesis, Ural Branch of the Russian Academy of Sciences,
22 S. Kovalevskoi / 20 Akademicheskaya St., Yekaterinburg 620990, Russia
3 Sri Venkateswara University,
Tirupati-517502, Andhra Pradesh, India
Submitted April 15, 2019
Accepted after revision June 9, 2019
Translated from Khimiya Geterotsiklicheskikh Soedinenii,
2019, 55(10), 978–984
The reaction of 3,6-bis(het)aryl-1,2,4-triazines (hetaryl ≠ 2-pyridyl) with aryne intermediates generated in situ was studied. As a result,
novel 1,4-bis(het)arylisoquinolines were synthesized with yields of up to 45%. The main rules of the reactions were studied, and the
obtained experimental data were compared with those described in the literature.
Keywords: anthranilic acids, aryne intermediates, 1,2,4-triazines, aza-Diels–Alder reaction.
The isoquinoline system is a common component of
naturally occurring compounds, in particular alkaloids.1,2
Compounds of this class have various types of biological
activity,3 including antiHIV4 and antitumor5 activity. In
addition, (benzo)(iso)quinolines are widely found in the
composition of fluorescent chemosensors/ligands of
transition metal cations,6 explosives,7 as well as
fluorophores or fluorescent labels/(bio)probes for various
purposes.8 The introduction of conjugated or annulated
aromatic fragments into the (iso)quinoline ring improves
the photophysical properties of these compounds.9
Till to date, a number of methods for the synthesis of
derivatives of isoquinolines have been described,10 of
which the ''1,2,4-triazine'' approach should be noted.
Within its framework, isoquinolines can be obtained in two
stages via intermediate 5,6,7,8-tetrahydro derivatives11 or
in a single step as a result of the reaction of 1,2,4-triazines
with aryne intermediates.
domino transformation products were unexpectedly obtained
as main products.12 At the same time, 5-cyano-
3-(2-pyridyl)-1,2,4-triazines in the reaction with arynes
mainly formed isoquinolines,13 (benz)isoquinolines, or 2-aza-
anthracenes, which represent push-pull fluorophores with
promising physicochemical properties.14 Finally, only the
domino transformation products were observed in the
reaction of 3-(2-pyridyl)-1,2,4-triazines or 5-cyano-3-(2-py-
ridyl)-1,2,4-triazines with di- or tetrafluorinated arynes
instead of isoquinolines.15,16
The object of the investigation within the framework of
this work are isoquinolines containing a fragment different
from 2-pyridyl or its analogs in the C-1 position. The
synthesis of isoquinolines based on 1,2,4-triazines is
currently mainly limited by examples of the preparation of
compounds with electron-withdrawing substituents at the
position C-1, such as ester or cyano groups.17–19 In
particular, isoquinolines containing (hetero)aromatic
substituents in positions C-1 and C-4, despite the promising
applications of these compounds (in particular, the
possibility of using isoquinolines as fluorophores20), have
not been previously obtained by the "aryne" method. It is
Earlier, our research group studied in detail the reaction
of 1,2,4-triazines containing a fragment of 2-pyridyl or its
analogs in the C-3 position with arynes. Moreover, in
reactions with aryne or its 4,5-dimethoxy derivative,
0009-3122/19/55(10)-0978©2019 Springer Science+Business Media, LLC
978

Chemistry of Heterocyclic Compounds 2019, 55(10), 978–984
Scheme 1
also necessary to note the wide possibilities for pre-
functionalization of the C-5 position of the precursor 1,2,4-
triazines, in particular when using nucleophilic hydrogen
substitution reactions.21 In this article, we present the
results of a study of the possibilities of using 3,6-di(het)-
aryl-1,2,4-triazines containing various substituents at posi-
tion C-5 in reactions with aryl intermediates (both 1,2-de-
hydrobenzene and its 4,5-difluoro and 4,5-dimethoxy
derivatives).
competitive transformations initiated by the nucleophilic
attack of the pyridine nitrogen atom carrying an unshared
electron pair at the formal triple bond of the aryne
intermediate. The possible mechanism of aryne-initiated
domino transformations in the series of 3-(2-pyridyl)-1,2,4-
triazines in the reaction with arynes was previously
discussed.13,15
Scheme 2
The methods shown in Scheme 1 can be used to obtain
5-functionalized 3,6-di(het)aryl-1,2,4-triazines. In parti-
cular, 5-methyl-1,2,4-triazines 1 can be obtained by several
methods, for example, as a result of the reaction of 3,6-di-
phenyl-1,2,4-triazine (2) with methylmagnesium iodide
followed by oxidative aromatization of the σН-adduct.22 In
addition, a methyl group at position C-5 can be formed as a
result of alkaline hydrolysis of 1,2,4-triazine 3, substituted
in this position by a fragment of acetophenone,23 which, in
turn, forms as a result of direct CH functionalization of
5H-1,2,4-triazine 4-oxide 4a.24 The reaction of 1,2,4-tri-
azine 4-oxide 4a with lithium phenylacetylenide followed
by deoxygenative aromatization of the σН-adduct allows to
obtain 5-phenylethynyl-1,2,4-triazine 5.25 1,2,4-Triazine-
5-carbonitriles 6a–g are formed as a result of the reaction
of 1,2,4-triazine 4-oxides 4a–g with acetone cyanohydrin
in the presence of Et3N.26 Cyano group at position C-5 is
very labile, and its subsequent ipso substitution in com-
pound 6a by the action of KOH, for example, leads to
5-methoxy-1,2,4-triazine 7.26 The remaining triazines –
3,5,6-triphenyl-1,2,4-triazine (8),27 as well as unsubstituted
at position 5 1,2,4-triazines 2 and 9a,b28,29 – were prepared
by the procedures described above using various hetero-
cyclization methods.
Next, we investigated the reactivity of the obtained 1,2,4-tri-
azines with unsubstituted aryne, 1,2-dehydrobenzene, and
with its difluoro and dimethoxy derivatives (Scheme 2,
Table 1). We showed that 1,2,4-triazines unsubstituted at
position C-5 (as exemplified by compound 2) or containing
electron-donating substituents at position C-5, for example,
a methyl or methoxy group (triazines 1 and 7) do not react
with unsubstituted aryne. During the reaction of 1,2,4-tri-
azines 9a,b containing a 3- or 4-pyridyl fragment at the C-3
position with 1,2-dehydrobenzene, a complex unidentifi-
able mixture of products forms. This is probably due to
Table 1. The results of the reaction of 1,2,4-triazines
1, 2, 5, 6a–g, 7, 8, 9a,b with aryne intermediates
Product
Triazine
R1
R2
R3
X
(yield, %)
Ph
Ph
Me
Me
Ph
H
OMe
H
–*
1
1
Ph
–
–
Ph
H
Ph
2
Ph
H
Ph
OMe
H
–
2
Ph
PhC≡C
PhC≡C
CN
Ph
Ph
10k (27)
–
5
Ph
ОМе
H
5
Ph
Ph
10b (42)
10c (39)
10d (37)
6a
6b
6c
2-FC6H4
4-FC6H4
CN
Ph
H
CN
4-MeC6H4
H
Thiophen-2-yl
CN
Ph
H
10e (45)
6d
Me
H
CN
CN
CN
CN
CN
OMe
OMe
Ph
4-MeC6H4
4-FC6H4
H
H
10f (40)
10g (40)
6e
6f
6c
6b
6g
7
4-FC6H4
2-FC6H4
3-O2NC6H4
Ph
4-MeC6H4 OMe 10h (25)
Ph
OMe 10i (27)
4-MeC6H4
H
H
10j (39)
Ph
Ph
Ph
Ph
Ph
Ph
–
–
Ph
ОМе
H
7
Ph
10а (45)
–
Mixture
Mixture
8
Ph
3-Py
4-Py
Ph
H
H
OMe
H
H
8
9a
9b
* No reaction.
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Chemistry of Heterocyclic Compounds 2019, 55(10), 978–984
The introduction of an aromatic substituent in the C-5
position of 1,2,4-triazine changes the situation. Thus, the
reaction of 3,5,6-triphenyl-1,2,4-triazine (8) with 1,2-de-
hydrobenzene results in the formation of the corresponding
isoquinoline 10a. The reaction of 1,2,4-triazines having
electron-withdrawing substituents at position C-5 (triazines
5 and 6a–g) with 1,2-dehydrobenzene also proceeds
successfully and leads to the formation of isoquinolines
10b-j,k, although in the former case the yield of the
product is somewhat lower. Moreover, the nature of the
substituent at position C-3 in 1,2,4-triazine-5-carbonitriles
((hetero)aromatic substituent, methyl group, or hydrogen
atom) does not affect the result. As for the possibilities of
using 4,5-dimethoxy-1,2-dehydrobenzene, in reactions with
1,2,4-triazines, its reactivity as a dienophile turned out to
be significantly lower compared to unsubstituted aryne. In
particular, the reaction successfully proceeded only in the
presence of the strongly electron-withdrawing cyano group
at the C-5 position of 1,2,4-triazines, the yields of the
resulting 6,7-dimethoxyisoquinolines were lower. If there
are substituents of a different nature at the C-5 atom, the
reaction with this aryne does not proceed even with the use
of higher boiling solvents (for example, o-xylene).
Figure 1. Molecular structure of isoquinoline 10c with atoms
represented as thermal vibration ellipsoids of 50% probability.
All attempts to conduct the reactions of the most
electron-deficient 4,5-difluoro-1,2-dehydrobenzene with
1,2,4-triazines 1, 2, 5–9 discussed above in no case led to
the formation of the expected 6,7-difluoroisoquinolines: the
starting 1,2,4-triazines were recovered from the reaction
mixture unchanged even under the conditions of using
higher boiling solvents (o-xylene, 1,2-dichlorobenzene).
These results correlate with the conclusions presented
earlier,15 namely, with the fact that in all cases of using
fluorinated arynes in reactions with 3-(2-pyridyl)-1,2,4-
triazines or their aza analogs, the reaction only proceeds as
a domino transformation, but not the classic aza-Diels–
Alder reaction.
Figure 2. Molecular structure of isoquinoline 10d with atoms
represented as thermal vibration ellipsoids of 50% probability.
aromatic substituents at positions C-3 and C-6 of the
triazine ring and additionally functionalized by various
groups, such as phenyl, cyano, and phenylethynyl at the
C-5 position, for a one-step synthesis of 1,4-bis(het)-
arylisoquinolines with yields of up to 45%. Moreover, the
reactivity of unsubstituted 1,2-dehydrobenzene in these
reactions was higher than its 4,5-dimethoxy derivative,
while 4,5-difluoroaryne did not react with triazines, and the
corresponding isoquinolines were not formed.
The structures of products 10a–k were confirmed by 1H,
13C NMR spectroscopy, mass spectrometry, and elemental
1
analysis. In particular, H NMR spectra showed resonance
signals of protons of the isoquinoline fragment (for
example, two singlets in the spectra of 6,7-di-
methoxyisoquinolines; in the case of compound 10i, one of
the signals appears as a doublet due to the interaction of a
proton with a fluorine atom at position 2 of the adjacent
aromatic substituent). Notably, the proton signals of all
substituents of the starting 1,2,4-triazine are preserved
upon a change in chemical shifts; no transformations of
these fragments during the reaction with arynes have been
observed. In this aspect, it should be noted that earlier,
when enamines were used as dienophiles, along with the
expected aza-Diels–Alder reaction, chemical transfor-
mations involving the nitro or cyano group in the 1,2,4-tri-
azine ring or its substituents were noted.30
Experimental
1H, 13C, and 19F NMR spectra were acquired on a Bruker
Avance II (400, 100, 376 MHz, respectively), with TMS
1
(for Н and 13С nuclei) or CFСl3 (for 19F nuclei, δ 0 ppm)
as internal standard. Mass spectra were recorded on a
Bruker Daltonics MicrOTOF-Q II mass spectrometer,
electrospray ionization. Monitoring of the reaction progress
and assessment of the purity of synthesized compounds
were done by TLC on Sigma-Aldrich 91835 plates.
Products were purified by column chromatography on
silica gel supplied by Sigma-Aldrich (230–400 mesh).
The starting 3,6-diphenyl-1,2,4-triazine (2),28 2-(3,6-di-
phenyl-1,2,4-triazin-5-yl)-1-phenylethanol (3),24 3,6-diphenyl-
5-phenylethynyl-1,2,4-triazine (5),25 1,2,4-triazine-5-carbo-
nitriles 6a,e,26c,d,14 5-methoxy-3,6-diphenyl-1,2,4-triazine
(7),26 3,5,6-triphenyl-1,2,4-triazine (8),27 6-phenyl-3-(3-py-
ridyl)-1,2,4-triazine (9a),29 and 6-phenyl-3-(4-pyridyl)-1,2,4-
triazine (9b)29 were synthesized by literature methods.
The structures of the two obtained isoquinoline-3-carbo-
nitriles 10c,d were also confirmed by X-ray structural
analysis (Figs. 1, 2).
To conclude, we have shown the possibility of using
aryne intermediates as dienophiles in the aza-Diels–Alder
reactions with 1,2,4-triazines (azadienes) containing (hetero)-
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Chemistry of Heterocyclic Compounds 2019, 55(10), 978–984
1,3,4-Triphenylisoquinoline (10a). Yield 241 mg (45%),
3-(2-Fluorophenyl)-6-phenyl-1,2,4-triazine-5-carbo-
nitrile (6b) was prepared by a published procedure.26
Yield 103 mg (76%), yellow crystals, mp >250°C. 1H NMR
spectrum (DMSO-d6), δ, ppm (J, Hz): 7.26–7.30 (1H, m,
H fluorophenyl); 7.35 (1H, t, J = 7.6, H fluorophenyl);
7.52–7.55 (1H, m, H fluorophenyl); 7.63–7.70 (3H, m, Н Ph);
8.15–8.20 (2H, m, Н Ph); 8.23–8.28 (1H, m, H fluoro-
phenyl). Mass spectrum, m/z (Irel, %): 277 [M+H]+ (100).
Found, %: С 69.69; Н 3.15; N 20.12. С16Н9FN4. Calculated,
%: С 69.56; Н 3.28; N 20.28.
6-(4-Fluorophenyl)-1,2,4-triazine-5-carbonitrile (6f) was
prepared by a published procedure.26 Yield 99 mg (74%),
yellow crystals, mp >250°C. 1H NMR spectrum (DMSO-d6),
δ, ppm (J, Hz): 7.40–7.44 (2H, m, H fluorophenyl); 8.17–
8.21 (2H, m, H fluorophenyl); 10.07–10.11 (1Н, m, H-3).
Mass spectrum, m/z (Irel, %): 201 [M+H]+ (100). Found, %:
С 60.16; Н 2.63; N 27.85. С10Н5FN4. Calculated, %:
С 60.00; Н 2.52; N 27.99.
6-(4-Methylphenyl)-3-(3-nitrophenyl)-1,2,4-triazine-
5-carbonitrile (6g) was prepared by a published proce-
dure.26 Yield 106 mg (80%), yellow crystals, mp >250°C.
1H NMR spectrum (DMSO-d6), δ, ppm (J, Hz): 2.51 (3Н, s,
CH3); 7.50 (2Н, d, J = 7.6, H methylphenyl); 7.97 (1Н, t,
J = 8.0, Н-5 nitrophenyl); 8.03 (2Н, d, J = 8.0, H methyl-
phenyl); 8.49–8.51 (1Н, m, J = 8.4, Н-6 nitrophenyl); 8.92–
8.94 (1Н, m, J = 8.4, Н-4 nitrophenyl); 9.25–9.26 (1Н, m,
Н-2 nitrophenyl). Mass spectrum, m/z (Irel, %): 318 [M+H]+
(100). Found, %: С 64.24; Н 3.38; N 22.18. С17Н11N5O2.
Calculated, %: С 64.35; Н 3.49; N 22.07.
5-Methyl-3,6-diphenyl-1,2,4-triazine (1). 2-(3,6-Diphenyl-
1,2,4-triazin-5-yl)-1-phenylethanol (3) (210 mg, 0.60 mmol)
was dissolved in a mixture of EtOH (45 ml) and H2O
(5 ml), KOH (101 mg, 1.80 mmol) was added, and the
resulting mixture was heated under reflux for 2 h. The
product was extracted with CH2Cl2 (3×25 ml). The
combined organics were dried over anhydrous Na2SO4, the
solvent was evaporated under reduced pressure, and the
residue was recrystallized from EtOH. Yield 123 mg
(83%), light-yellow crystals, mp 129–131°C (mp 122–
124°C22). 1H NMR spectrum (CDCl3), δ, ppm: 2.71 (3H, s,
CH3); 7.51–7.59 (6H, m, H Ph); 7.70–7.74 (2H, m, H Ph);
8.58–8.62 (2H, m, H Ph). Mass spectrum, m/z (Irel, %): 248
[M+H]+ (100). Found, %: С 77.58; Н 5.21; N 17.20.
C26H16N3. Calculated, %: С 77.71; Н 5.30; N 16.99.
colorless crystals, mp 178–180°C (mp 178–180°C12d).
1H NMR spectrum (CDCl3), δ, ppm (J, Hz): 7.15–7.19 (3Н,
m, H Ph); 7.28–7.32 (2Н, m, H Ph); 7.34–7.45 (5Н, m,
H Ph); 7.48–7.62 (5Н, m, H Ph); 7.72 (1Н, dd, J = 8.0,
J = 1.2, Н-8); 7.81–7.83 (2Н, m, Н-6,7); 8.18 (1Н, dd,
J = 8.0, J = 1.2, Н-5). 13C NMR spectrum (CDCl3),
δ, ppm : 125.5; 126.1; 126.6; 127.0; 127.3; 127.5; 127.6;
128.3; 128.4; 128.6; 129.8; 130.0; 130.3; 130.5; 131.4;
137.0; 137.6; 139.9; 141.0; 149.7; 159.8. Mass spectrum,
m/z (Irel, %): 358 [M+H]+ (100). Found: С 90.52; Н 5.25;
N 3.66. С27Н19N. Calculated, %: С 90.72; Н 5.36; N 3.92.
1,4-Diphenylisoquinoline-3-carbonitrile (10b). Yield
1
193 mg (42%), colorless crystals, mp >250°C. H NMR
spectrum (DMSO-d6), δ, ppm (J, Hz): 7.52–7.57 (2Н, m,
H Ph); 7.58–7.69 (6Н, m, H Ph); 7.69–7.77 (3Н, m, H Ph,
Н-5); 7.78–7.87 (2Н, m, Н-6,7); 8.21 (1Н, dd, J = 7.6,
J = 1.5, Н-8). 13C NMR spectrum (CDCl3), δ, ppm: 117.7;
125.7; 126.7; 127.6; 128.1; 128.6; 129.0; 129.4 (2C);
129.8; 130.1; 130.3; 131.4; 133.8; 135.5; 138.1; 139.4;
161.7. Mass spectrum, m/z (Irel, %): 307 [M+H]+ (100).
Found, %: С 86.08; H 4.53; N 9.00. C22H14N2. Calculated,
%: С 86.25; H 4.61; N 9.14.
1-(2-Fluorophenyl)-4-phenylisoquinoline-3-carbonitrile
(10c). Yield 190 mg (39%), colorless crystals, mp 165–
1
167°C. H NMR spectrum (CDCl3), δ, ppm (J, Hz): 7.27–
7.29 (1H, m, Н fluorophenyl); 7.39 (1H, dd, J = 7.6,
J = 7.3, J = 1.0, Н fluorophenyl); 7.51–7.58 (3H, m,
Н Ar); 7.59–7.68 (4H, m, Н Ar); 7.69–7.78 (2H, m, Н Ar);
7.80–7.82 (1H, m, Н fluorophenyl); 7.92–7.94 (1H, m,
Н isoquinoline). 13C NMR spectrum (CDCl3), δ, ppm
(J, Hz): 116.0 (d, J = 22.5); 117.5; 124.7 (d, J = 4.0);
126.6; 127.8 (d, J = 2.7); 128.2; 128.8; 128.9; 129.5;
130.0; 130.2; 130.9; 131.5 (d, J = 8.6); 131.6; 132.0 (d,
J = 2.7); 132.5; 133.6; 135.0; 140.1; 157.2; 160.0 (d,
J = 249.1). Mass spectrum, m/z (Irel, %): 325 [M+H]+
(100). Found, %: С 81.55; H 3.89; N 8.29. C22H13FN2.
Calculated, %: С 81.47; H 4.04; N 8.64.
1-(4-Fluorophenyl)-4-(4-methylphenyl)isoquinoline-
3-carbonitrile (10d). Yield 186 mg (37%), colorless
crystals, mp 158–160°C. 1H NMR spectrum (CDCl3),
δ, ppm (J, Hz): 2.50 (3H, s, CH3); 7.24–7.31 (3H, m,
Н fluorophenyl, Н isoquinoline); 7.39–7.45 (4H, m,
H methylphenyl); 7.69–7.77 (3H, m, Н fluorophenyl,
Н isoquinoline); 7.84–7.86 (1H, m, Н isoquinoline) 8.17–
8.19 (1H, m, Н isoquinoline). 13C NMR spectrum (CDCl3),
δ, ppm (J, Hz): 21.4; 115.6; 115.8; 117.7; 125.7; 126.9;
127.5; 127.7; 129.1; 129.7; 130.1; 130.6; 132.0; 132.1;
134.2 (d, J = 3.0); 135.7; 139.5 (d, J = 10.5); 160.3; 163.6
(d, J = 249.5). Mass spectrum, m/z (Irel, %): 339 [M+H]+
(100). Found, %: С 81.47; H 4.31; N 8.02. C23H15FN2.
Calculated, %: С 81.64; H 4.47; N 8.28.
Synthesis of isoquinolines 10а–k (General method).
The corresponding triazine 1, 2, 5, 6a–g, 7, 8, 9a,b
(1.5 mmol) was suspended in dry PhMe (50 ml), and
isoamyl nitrite (0.8 ml, 6 mmol) was added. The resulting
mixture was stirred under reflux under an argon
atmosphere, and a solution of the respective anthranilic acid
(6 mmol) in dry 1,4-dioxane (15 ml) was added dropwise
over 30 min. The mixture was heated under reflux for 1 h
and cooled to room temperature. The reaction mixture was
washed with 3 M aqueous NaOH (3×75 ml), the organic
layer was dried over anhydrous Na2SO4, the solvent was
evaporated under reduced pressure. The products were
isolated by column chromatography on silica gel, eluent
CH2Cl2, Rf 0.5. Analytical samples of products were
obtained by recrystallization from MeCN.
4-Phenyl-1-(thiophen-2-yl)isoquinoline-3-carbonitrile
(10e). Yield 211 mg (45%), colorless crystals, mp 169–
1
171°C (mp 169–171°C13b). H NMR spectrum (DMSO-d6),
δ, ppm (J, Hz): 7.31 (1H, dd, J = 4.8, J = 3.6, H-4 thiophene);
7.51–7.55 (2H, m, H Ph); 7.60–7.68 (3H, m, H Ph); 7.71–
7.73 (1H, m, H isoquinoline); 7.79 (1H, dd, J = 3.6,
J = 0.8, H-3 thiophene); 7.82 (1H, dd, J = 4.8, J = 0.8, H-5
981

Chemistry of Heterocyclic Compounds 2019, 55(10), 978–984
thiophene); 7.85–7.94 (2H, m, H isoquinoline); 8.66–8.68
crystals, mp >250°C. 1H NMR spectrum (DMSO-d6),
δ, ppm (J, Hz): 2.54 (3Н, s, CH3); 7.43–7.51 (4Н, m, H Ar);
7.81–7.97 (4Н, m, Н-5,6 nitrophenyl, Н-6,7); 8.17–8.21 (2Н,
m, Н-5,8); 8.45–8.47 (1Н, m, Н-4 nitrophenyl); 8.55 (1Н,
dd, J = 1.8, J = 1.8, Н-2 nitrophenyl). 13C NMR spectrum
(CDCl3), δ, ppm: 21.5; 117.6; 124.2; 125.1; 125.7; 127.0;
127.2; 129.8; 129.9; 130.1 (2C); 130.3; 130.6; 131.9;
135.8; 136.1; 139.6; 139.7; 140.5; 148.3; 158.6. Mass
spectrum, m/z (Irel., %): 366 [M+H]+ (100). Found, %:
С 75.77; H 4.21; N 11.42. C23H15N3О2. Calculated, %:
С 75.60; H 4.14; N 11.50.
(1H, m, H isoquinoline). 13C NMR spectrum (CDCl3),
δ, ppm: 117.5; 125.6; 126.9 (2C); 127.4; 127.8; 129.0;
129.3; 129.4; 130.0; 130.3; 131.5; 133.7; 135.8; 139.0;
141.0; 154.5. Mass spectrum, m/z (Irel, %): 313 [M+H]+
(100). Found, %: C 76.72; H 3.78; N 8.81. С20Н12N2S.
Calculated, %: C 76.90; H 3.87; N 8.97.
1-Methyl-4-(4-methylphenyl)isoquinoline-3-carbonitrile
(10f). Yield 155 mg (40%), colorless crystals, mp 115–117°C.
1H NMR spectrum (CDCl3), δ, ppm (J, Hz): 2.48 (3Н, s,
C6H4CH3); 3.03 (3H, s, CH3); 7.33–7.40 (4H, m, H Ar);
7.69–7.79 (3H, m, H-6,7,8); 8.20–8.25 (1H, m, H-5).
13C NMR spectrum (CDCl3), δ, ppm: 21.4; 22.5; 118.0;
125.2; 125.9; 127.0; 128.3; 129.6; 129.7; 130.1; 130.8; 131.2;
134.5; 139.1; 139.2; 159.7. Mass spectrum, m/z (Irel, %):
259 [M+H]+ (100). Found, %: С 83.56; Н 5.34; N 10.99.
C18H14N2. Calculated, %: С 83.69; Н 5.46; N 10.84.
4-(4-Fluorophenyl)isoquinoline-3-carbonitrile (10g).
Yield 145 mg (40%), colorless crystals, mp 111–113°C.
1H NMR spectrum (DMSO-d6), δ, ppm (J, Hz): 7.25–7.32
(2H, m, H Ar); 7.45–7.50 (2H, m, H Ar); 7.70–7.74 (1H,
m, H-8); 7.76–7.84 (2H, m, H-6,7); 8.10–8.14 (1H, m,
H-5); 9.05 (1H, s, H-1). 13C NMR spectrum (CDCl3), δ, ppm
(J, Hz): 115.2 (d, J = 21.0); 124.9; 127.1; 128.1; 128.3 (d,
J = 3.8); 129.1; 129.9; 131.0; 131.1; 133.3; 138.3; 152.2;
162.4 (d, J = 250.0). 19F NMR spectrum (DMSO-d6),
δ, ppm: –111.32 (1F, s). Mass spectrum, m/z (Irel, %): 249
[M+H]+ (100). Found, %: С 77.29; Н 3.52; N 11.13.
C16H9FN2. Calculated, %: С 77.41; Н 3.65; N 11.28.
1,4-Diphenyl-3-(phenylethynyl)isoquinoline (10k).
Yield 154 mg (27%), colorless crystals, mp 129–131°C.
1H NMR spectrum (DMSO-d6), δ, ppm (J, Hz): 7.20–7.25
(5H, m, H Ph); 7.48–7.63 (10H, m, H Ph); 7.69–7.72 (1H,
m, H-8); 7.74–7.77 (2H, m, H-6,7); 8.08–8.12 (1H, m,
H-5). 13C NMR spectrum (CDCl3), δ, ppm: 89.8; 92.5;
122.9; 125.9; 127.4; 128.0; 128.2; 128.3; 128.4; 128.8;
129.7; 129.9; 130.1; 130.4; 130.5; 130.9; 131.8; 133.0;
134.8; 135.9; 136.0; 136.8; 139.2; 160.8. Mass spectrum, m/z
(Irel, %): 382 [M+H]+ (100). Found, %: С 91.22; Н 5.17;
N 3.81. C29H19N. Calculated, %: С 91.31; Н 5.02; N 3.67.
Scale-up of isoquinoline 10а synthesis method.
Isoamyl nitrite (3.45 ml, 25.88 mmol) was added to a
suspension of triazine 8 (2.00 g, 6.47 mmol) in dry PhMe
(250 ml). A solution of anthranilic acid (3.55 g, 25.88 mmol)
in dry 1,4-dioxane (60 ml) was added dropwise over 30 min
with stirring and heating under reflux under an argon
atmosphere. The mixture was heated under reflux for 1 h
and cooled to room temperature. The reaction mixture was
washed with 3 M aqueous NaOH (3×250 ml), the organic
layer was dried over anhydrous Na2SO4, the solvent was
evaporated under reduced pressure. The product was
isolated by recrystallization from MeCN. Yield 1.00 g
(43%).
1-(4-Fluorophenyl)-6,7-dimethoxy-4-(4-methylphenyl)-
isoquinoline-3-carbonitrile (10h). Yield 149 mg (25%),
colorless crystals, mp 155–157°C. 1H NMR spectrum
(DMSO-d6), δ, ppm (J, Hz): 2.47 (3Н, s, C6H4CH3); 3.35
(3Н, s, OCH3); 3.85 (3Н, s, OCH3); 7.00 (1H, s, H-8); 7.41
(1H, s, H-5); 7.41–7.53 (6H, m, H Ar); 7.81–7.87 (2H, m,
H Ar). 13C NMR spectrum (CDCl3), δ, ppm (J, Hz): 21.5;
56.1 (2C); 105.0; 105.8; 115.6; 115.9; 118.1; 123.9; 124.8;
129.8; 129.9; 131.1; 131.6 (d, J = 8.1); 132.4; 134.7 (d,
J = 3.9); 138.1; 139.3; 151.1; 154.1; 157.7, 163.4 (d,
J = 249.0). Mass spectrum, m/z (Irel, %): 399 [M+H]+
(100). Found, %: С 75.46; Н 4.89; N 7.13. C25H19FN2O2.
Calculated, %: С 75.36; Н 4.81; N 7.03.
X-ray structural analysis of compounds 10c,d was
performed on an Xcalibur
3 (Oxford Diffraction)
diffractometer. Solving and refinement of structures was
carried out using the SHELXTL software package.31 The
structures were solved with the direct method and refined
against F2 by the least-squares technique in the full-matrix
anisotropic (isotropic for hydrogen atoms) approximation.
Main crystallographic parameters of compound 10с
(empirical formula C22H13FN2, Mr 324.36): monoclinic
crystal system; space symmetry group P21/c; a 10.860(7),
b 16.074(3), c 9.681(6) Å; β 104.51(5)°; V 1635.9(15) Å3;
Z 4; μ 0.086 mm–1. 9930 reflections were collected at
scattering angles 5.64 < 2Θ < 52.8°, of which 3339 were
independent (Rint 0.0399). The final refinement parameters:
R1 0.0497 (I > 2σ(I)), R1 0.1212, wR2 0.0963 (all
reflections) with the quality factor GOOF 1.002. Residual
electron density peaks 0.28/–0.31 eÅ–3. Main
crystallographic parameters of compound 10d (empirical
formula C23H15FN2, Mr 338.37): rhombic crystal system;
space symmetry group Pbca; a 17.1411(16), b 9.8087(10),
c 20.2589(17) Å; V 3406.2(5) Å3; Z 8; μ 0.086 mm–1.
12538 reflections were collected at scattering angles
4.68 < 2Θ < 61.66°, of which 4711 were independent
(Rint 0.0684). The final refinement parameters: R1 0.0604,
1-(2-Fluorophenyl)-6,7-dimethoxy-4-phenylisoquinoline-
3-carbonitrile (10i). Yield 156 mg (27%), colorless
1
crystals, mp 160–162°C. H NMR spectrum (DMSO-d6),
δ, ppm (J, Hz): 3.78 (3H, s, OCH3); 3.83 (3H, s, OCH3);
6.94 (1H, s, Н-5); 7.04 (1H, d, J = 3.8, Н-8); 7.33–7.35
(1H, m, Н fluorophenyl); 7.41–7.43 (1H, m, Н fluoro-
phenyl); 7.48–7.69 (6H, m, Н Ph, Н fluorophenyl).
13C NMR spectrum (CDCl3), δ, ppm (J, Hz): 56.1 (2С);
104.6; 105.7 (d, J = 2.9); 115.9 (d, J = 21.7); 117.8; 124.8
(2C); 124.9; 126.3 (d, J = 16.2); 129.0; 129.4; 130.0; 131.3
(d, J = 8.6); 131.8; 132.0 (d, J = 3.7); 134.2; 138.5; 152.1;
153.6; 154.3; 159.9 (d, J = 247.8). Mass spectrum, m/z
(Irel, %): 385 [M+H]+ (100). Found, %: С 74.76; H 4.31;
N 7.09. C24H17FN2O2. Calculated, %: С 74.99; H 4.46;
N 7.29.
4-(4-Methylphenyl)-1-(3-nitrophenyl)isoquinoline-
3-carbonitrile (10j). Yield 213 mg (39%), colorless
982

Chemistry of Heterocyclic Compounds 2019, 55(10), 978–984
Nosova, E. V.; Zyryanov, G. V.; Kovalev, I. S.; Rusinov, V. L.;
wR2 0.0949 (I > 2σ(I)), R1 0.1893, wR2 0.1375 (all
reflections) with the quality factor GOOF 0.974. Residual
electron density peaks 0.23/–0.19 eÅ–3. The full set of X-ray
structural data for compounds 12c,d were deposited at the
Cambridge Crystallographic Data Center (deposits CCDC
1921341 and CCDC 1921342, respectively).
Chupakhin, O. N. Russ. Chem. Bull., Int. Ed. 2015, 64, 872.
[Izv. Akad. Nauk, Ser. Khim. 2015, 872.] (e) Moni, L.; Gers-
Panther, C. F.; Anselmo, M.; Müller, T. J. J.; Riva, R. Chem.–
Eur. J. 2016, 22, 2020.
10. (a) Pomeranz, C. Monatsh. Chem. 1893, 14, 116. (b) Bischler, A.;
Napieralski, B. Ber. Dtsch. Chem. Ges. 1893, 26, 190.
(c) Comprehensive Organic Name Reactions and Reagents;
Wang, Z., Ed.; Wiley-Interscience: New Jersey, 2010,
p. 2206. (d) Doi, S.; Shirai, N.; Sato, Y. J. Chem. Soc., Perkin
Trans. 1997, 1, 2217. (e) Comprehensive Organic Name
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This work was supported by the Russian Science
Foundation (grant 18-13-00365).
Elemental analysis was performed by the elemental
analysis group of the Postovsky Institute of Organic
Synthesis.
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