An Efficient Cyanide-Free Approach towards 1-(2-Pyridyl)isoquinoline-3-carbonitriles via the Reaction of 5-Phenacyl-1,2,4-triazines with 1,2-Dehydrobenzene in the Presence of Alkyl Nitrites

Article abstract of DOI:10.1055/s-0036-1590961

A cyanide-free method for the preparation of 1-(2-pyridyl)isoquinoline-3-carbonitriles (3-cyanoisoquinolines) was developed. The interaction of 5-phenacyl-3-(2-pyridyl)-1,2,4-triazines with 1,2-dehydrobenzene generated in situ from anthranilic acid and an

Full text of DOI:10.1055/s-0036-1590961

SYNLETT
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©
Georg Thieme Verlag Stuttgart · New York
2018, 29, 483–488
letter
483
en
Synlett
D. S. Kopchuk et al.
Letter
An Efficient Cyanide-Free Approach towards 1-(2-Pyridyl)isoquin-
oline-3-carbonitriles via the Reaction of 5-Phenacyl-1,2,4-tri-
azines with 1,2-Dehydrobenzene in the Presence of Alkyl Nitrites
Dmitry S. Kopchuka,b
Alexey P. Krinochkina
Albert F. Khasanova
Igor S. Kovaleva
Pavel A. Slepukhina,b
Ekaterina S. Starnovskayaa
Ar
N
N
Ar
C
OH
N
N
R
N
+
O
N
Ph
O
N
toluene/1,4-dioxane
reflux, 1.5 h
N
Ar = Ph, 4-MeOC6H4, 4-ClC6H4
73–75% yield
Anindita Mukherjeea
Matiur Rahmana
R = iso-amyl, n-amyl
Grigory V. Zyryanova,b
Adinath Majeec
Vladimir L. Rusinova,b
Oleg N. Chupakhina,b
Sougata Santra*a
0
0
0
0
0-
0
0
2
4-
1
8
6
6-
1
0
5
a
Department of Organic & Biomolecular Chemistry, Chemical Engineering Institute, Ural Federal University, 19 Mira Str., Yekaterinburg, 620002, Russian Federation
sougatasantra85@gmail.com
ssantra@urfu.ru
b
c
I. Ya. Postovskiy Institute of Organic Synthesis, Ural Division of the Russian Academy of Sciences, 22 S. Kovalevskoy Str., Yekaterinburg, 620219,
Russian Federation
Department of Chemistry, Visva-Bharati (A Central University),
Santiniketan-731235, India
Received: 16.10.2017
Accepted: 24.10.2017
Published online: 28.11.2017
1,2,4,5-tetrazines afforded (benzo)isoquinolines3 or their
aza analogues in one-pot. Recently, it was reported that in
4
DOI: 10.1055/s-0036-1590961; Art ID: st-2017-b0768-l
case of 1,2,4-triazines, depending on the type of the sub-
stituents in both the 1,2,4-triazine ring and the aryne core
along with ‘classical’ Diels–Alder products, namely (aza)iso-
quinolines,3 the reaction may afford the 1,2,4-triazine core
rearrangement products, such as triazolopyrido[1,2-a]in-
doles5 or triazolopyrimido[1,2-a]indoles.6 For instance,
Diels–Alder products, namely isoquinolin-3-carbonitriles,
were mostly formed if the strong electron-withdrawing cy-
ano group was present at the C5 position of the 1,2,4-tri-
Abstract A cyanide-free method for the preparation of 1-(2-pyr-
idyl)isoquinoline-3-carbonitriles (3-cyanoisoquinolines) was developed.
The interaction of 5-phenacyl-3-(2-pyridyl)-1,2,4-triazines with 1,2-de-
hydrobenzene generated in situ from anthranilic acid and an excess of
amyl nitrites afforded the target compounds in good yields. The pro-
posed mechanism involves the in situ transformation of the 5-phenacyl
group into the 5-cyano group under the action of alkyl nitrite and the
following inverse demand aza-Diels–Alder reaction of thus formed 5-cy-
ano-1,2,4-triazines with 1,2-dehydrobenzene affording the target prod-
ucts. The presence of the 5-phenacyl substituent is a key for the reac-
tion, as in case of 5-styryl- or 5-phenylethynyl-3-(2-pyridyl)-1,2,4-
triazines the formation of the 1,2,4-triazine ring-transformation prod-
ucts was observed
,4
[
3с]
azine core, and this cyano group is commonly introduced
7
,8
into 1,2,4-triazines or their 4-oxides via ipso substitution,
H
9,10
or, less commonly, SN processes
by the reaction of dif-
–
ferent sources of CN . Most of the cyanides are known as
fast-acting poisons; therefore alternative methods for cya-
no-group introduction are in high demand. In literature, a
few transformations of other functional groups into cyano
groups in 1,2,4-triazines have been described, such as 6-
carbamoyl-11 or 5-ketoxyme groups. The direct cyanida-
tion of isoquinoline N-oxides afforded the isoquinoline-3-
Key words 1-(2-pyridyl)isoquinoline-3-carbonitriles,
aryne, inverse demand aza-Diels–Alder reaction, alkyl nitrites
cyanide-free,
12
Aryne-mediated transformations have become a versa-
tile tool for the one-pot synthesis of various organic com-
1
a,b
13
pounds and materials: from natural products
to chemo-
carbonitriles in low yields, and only few approaches were
1c–f
1g–i
14,15
sensors
and organic electronics components.
Addi-
reported based on ipso cyanation,
transformation of
tionally, various
types of Diels–Alder substrates are
other functional groups into the cyano one,16 as well as the
direct heterocyclization of cyano-substituted synthons.
17
commonly used for the synthesis of aza-heterocyclic li-
gands and their annelated derivatives involving (hete-
ro)arynes and various heterocyclic substrates. However,
2
reaction between arynes and substituted 1,2,4-triazines or
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4
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Synlett
D. S. Kopchuk et al.
Letter
F
thy to mention that in our experiments neither 5-styryl-
nor 5-phenylethynyl-1,2,4-triazines afforded the desired
cyanoisoquinolines 6, and in all cases the 1,2,4-triazine
ring-transformation products, i.e., triazolopyrido[1,2-a]in-
doles 7 and 8 were isolated as the only products. The struc-
tures of the compounds 7 and 8 were confirmed based on
the same set of methods as for compound 6. For instance, in
NC
H
N
CN
Ar
N
O
N
H
N
OH
O
O
O
O
ΔF508-CFTR corrector and
potentiator activity
antiasthmatic and
anti-inflammatory
activities
13
the C NMR spectra of compound 7 two resonance peaks
Figure 1 Representative examples of biologically active cyanoquino-
lines
were observed in the region of δ = 76.7 and 102.4 ppm for
the sp-hybridized carbon atoms of the phenylacetylene
moiety.
Additionally, single-crystal X-ray data were collected for
the rearrangement product 8 (Figure 2).26 According to the
XRD data two independent molecules are crystallized in the
centrosymmetric space group (see Figure S1, Supporting
Information).
Cyano-substituted (iso)quinolines exhibit important bi-
ological activities, such as antiasthmatic and anti-inflam-
16
matory, corrector–potentiator activity in ΔF508 cystic fi-
1
8,19
brosis transmembrane conductance regulator protein,
antidiabetic activity,2 etc. (Figure 1). In addition, the cyano
0
group in (benzo)pyridines could be easily converted into
19
other functionalities, such as aminomethyl or carboxylic
17
groups. Herein, we wish to report a convenient cyanide-
free approach for the synthesis of 1-(2-pyridyl)-isoquino-
lin-3-carbonitriles (3-cyanoisoquinolines) by the reactions
of 5-phenacyl-3-(2-pyridyl)-1,2,4-triazines with arynes in
the presence of n-amyl nitrite or iso-amyl nitrite (Scheme 1).
Ar
N
N
OH
N
Ar
N
+ R O
N
Ph
O
N
toluene/1,4-dioxane
reflux, 1.5 h
C
N
N
R = iso-amyl, n-amyl
Figure 2 Crystal structure of the 1,2,4-triazine ring rearrangement
product 8
Scheme 1 Synthesis of 1-(2-pyridyl)isoquinoline-3-carbonitriles
For the initial step, the starting materials 1,2,4-triazines
(Scheme 2, R = OH) were prepared according to the previ-
Scheme 3 represents a possible mechanism for the for-
mation of cyanoisoquinolines 6. According to a commonly
accepted mechanism for the nitrosation of ketones,2 on the
first stage, nitrosation takes place at the double bond of the
enol form of triazine 1 to afford the nitroso-substituted in-
termediate A, followed by the elimination of proton that af-
fords nitroso derivative B. The isomerization of B followed
by protonation affords the unstable intermediate D, and its
Beckmann-type rearrangement with the elimination of
benzoic acid molecule led to the cyano-1,2,4-triazine 9. At
the final step, due to the presence of the electron-with-
drawing cyano group at the C5-position, the classical aza-
Diels–Alder reaction is preferably realized to afford the de-
sired 3-cyanoisoquinolines 6.25
To support the proposed mechanism, the starting 5-
phenacyl-1,2,4-triazines 1b–f were treated with iso-amyl
nitrite in the presence of 0.1–1.0 equiv of benzoic acid in-
stead of anthranilic acid (o-aminobenzoic acid) under the
similar reaction conditions (Scheme 4). Quite expectedly,
the corresponding 5-cyano-1,2,4-triazines 9b–f were iso-
lated in 60–65% yield (Scheme 4). It is worthy to mention
1
3
ously described procedures starting from 5-phenylethynyl-
1
1
2
,2,4-triazines 2 by boiling in aqueous acetic acid2 (Scheme
, path ii) or by the reaction between 5-H-1,2,4-triazine-4-
22
oxides 3 and acetophenone (Scheme 2, path iii). 1,2,4-Tri-
azine 4a (R = H) was also synthesized according to the pre-
23
viously reported method starting from 6-phenyl-3-(2-
1
pyridyl)-1,2,4-triazine 5. Based on the Н NMR data, the
compounds 1а–с and 1e exist in one tautomeric form, as in-
dicated in Scheme 3, while the compound 1d bearing the 2-
thienyl moiety in the C3 position of the 1,2,4-triazine moi-
ety exists in two tautomeric forms (see Supporting Infor-
mation for details). Finally, interaction with 1,2-dehydro-
benzene afforded the corresponding 1-(2-pyridyl)isoquino-
24
line-3-carbonitriles 6 in up to 75% yield (Scheme 2, path
5
v). The structures of the products 6 were confirmed based
1
13
on H NMR and C NMR spectroscopy and mass spectrom-
etry. Finally, all the spectral characteristics of product 6a
fully correspond to those previously published data for this
25
compound obtained by the alternative method. It is wor-
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D. S. Kopchuk et al.
Letter
N
Ar
N
N
N
Ar
N
i
v
N
N
N
N
N
N
N+
O–
Ph
2
a–c
Ph
Ph
for R = OH
Ar
ii
7, 28%
3a–c
iii
for R = OH
N
N
N
Ph
N
N
N
iv
N
v
N
N
R = H
N
Ph
for R = H
Ph
R
N
N
1
4
a–c
a
5
Ph
8, 31%
v
R = OH
1a, Ar = Ph, R = OH, 53%
1b, Ar = 4-MeOC6H4, R = OH, 52%
1c, Ar = 4-ClC6H4, R = OH, 48%
4a, Ar = Ph, R = H, 90%
Ar
R = OH (1), H (4)
6
6
6
a, Ar = Ph, 75%
N
N
b, Ar = 4-MeOC6H4, 73%
c, Ar = 4-ClC6H4, 74%
N
6
a–c
Scheme 2 The general scheme for the cyanide-free synthesis of 1-(2-pyridyl)isoquinoline-3-carbonitriles 6. Reagents and conditions: i) Ph-acetylene,
n-BuLi, –78 °C, 20 min, then MeCOCl; ii) AcOH/H O, reflux, 24 h; iii) acetophenone, NaH, THF, –20 °C, 3.5 h, then AcOH; iv) n-BuLi, phenylacetylene,
2
THF/toluene (1:9), –78 °C, 5 min, then 20 °C, overnight, then MeOH, 20 °C; v) iso-amyl nitrite, anthranilic acid, toluene/1,4-dioxane (5:1), reflux, 1.5 h.
Ar
OH
Ar
N
N
Ar
N
N
N
N
Ar
N
N
N
N
N
+
+
N
–H+
NO /H
H
N
ON
Ph
H
ON
Ph
Py
Py
Py
Py
O
Ph
O
Ph
OH
OH
1
A
B
C
Ar
OH2
N
N
Ar
N
+
H+
2
–H O
N
N
+
PhCOOH
N
Py
N
Py
N
Ph
O
D
9
N
N
Ar
–N2
6
N
NC
N
E
Scheme 3 Plausible reaction pathways
that replacing the substituents at the C3 position of the
,2,4-triazine moiety by the thiophen-2-yl or p-tolyl resi-
corresponding cyanotriazine was much lower (30%). The
1
1
structure of the products 9 were confirmed based on H
due (1d and 1f), as well as the introduction of the other cy-
ano-group precursors, for instance, 4-chlorosubstituted
phenacyl- (1c) or trifluoromethyl-substituted acetonyl
groups (1e) at the C5 position did not change the course of
the reaction. However, in a last case, the conversion into the
NMR, 13C NMR spectroscopy, mass spectrometry, and ele-
27
25
mental analysis. For compounds 9b, 9e, and 9d the spec-
tral data were compared with previously reported data
(where the syntheses were carried out using other ap-
proaches).
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D. S. Kopchuk et al.
Letter
Ar
N
N
Ar
N
N
Ar
N
N
N
i
N
N
ii
H
R
R
N
R
N
9b–f
R1
OH
b–f
10
very low
yield
1
iii
10c, Ar = 4-ClC H , R = 2-Py, 95%
6
4
iii
10d, Ar = Ph, R = thiophen-2-yl, 96%
Ph
9b, Ar = 4-MeOC6H4, R = 2-Py, 65%
S
Ar = 4-MeOC6H4 (b), 4-ClC6H4 (c), Ph (d, e),
Tol (f)
9c, Ar = 4-ClC H , R = 2-Py, 63%
N
6 4
N
9
d, Ar = Ph, R = thiophen-2-yl, 65%
9e, Ar = Ph, R = 2-Py, 30%
f, Ar = p-Tol, R = p-Tol, 60%
R = 2-Py (b, c, e), thiophen-2-yl (d), Tol (f)
1
R
= Ph (b, c, f), 4-ClC6H4 (d), CF3 (e)
6d, 45%
9
Scheme 4 The control experiments. Reagents and conditions: i) AmONO (2 equiv), C H CO H (0.1–1.0 equiv), toluene, reflux, 2 h; ii) pyrrolidine (1.25
6
5
2
equiv), reflux, 2 h; iii) iso-amyl nitrite, anthranilic acid, toluene/1,4-dioxane (5:1), reflux, 1.5 h.
Additionally, the structure of the product 9f was con-
firmed based on the single-crystal X-ray data (Figure 3).28
According to received data, this compound is crystallized in
the chiral space group of the orthorhombic system. The chi-
rality is ensured by the rotation of the p-tolyl substituents
toward the heterocycle (the p-tolyl substituent at C6 is
turned toward triazine at an angle of 45°) and by crystal
packing of the obtained rotamers. The measured С≡N bond
line 6d in low yield (45%). Therefore, the reaction was car-
ried out in two steps via the conversion of the C5-phenacyl
group into the cyano one and followed by inverse demand
aza-Diels–Alder reaction between the 5-cyano-1,2,4-tri-
azine and benzyne. This reaction sequence was successfully
demonstrated for compound 6d.
In conclusion, we have developed a cyanide-free syn-
thetic approach towards 1-(2-pyridyl)-substituted 3-cy-
anoisoquinolines starting from 5-phenacyl-1,2,4-triazines
by the reaction with in situ generated 1,2-dehydrobenzene
in the presence of alkyl nitrites. The reaction proceeds via
nitrosation of the 5-phenacyl substituent followed by
Beckmann-type rearrangement into the 5-cyano function-
ality, and the inverse demand aza-Diels-Alder reaction be-
tween the 5-cyano-1,2,4-triazine and 1,2-dehydrobenzene.
The presence of the 5-phenacyl substituent is crucial for
the reaction, as in case of 5-styryl- or 5-phenylethynyl-3-
length is 1.144 Å, which is longer than in 3,6-diphenyl-
0
1
,2,4-triazin-5-carbonitrile (1.129 Å).1 In the crystal the
molecules of 9f form the stacked molecular architectures,
presumably due to the π–π interactions. The average dis-
tances between the molecular planes in the crystals of 9f
vary from 3.5 to 3.6 Å, which is a typical distance for the π–π
interactions (see Figure S3, Supporting Information).
(2-pyridyl)-1,2,4-triazines the formation of the 1,2,4-tri-
azine ring-transformation products was observed.
Funding Information
We are pleased to acknowledge the Russian Science Foundation (Ref.
#
16-43-02020) for funding. A. Majee acknowledges financial support
from the DST-RSF Major Research Project (Ref. No. INT/RUS/RSF/P-08).
R
u
asni
Secince
F
o
u
n
d
oaitn
1(6-43-0
2
0
2
0)
Figure 3 Crystal structure of product 9f
Acknowledgment
Finally, the compounds 9c and 9d were converted into
the corresponding 5-pyrrolidino-1,2,4-triazines 10 accord-
We express our sincere thanks to Professor Valery N. Charushin, I. Ya.
Postovskiy Institute of Organic Synthesis, Ural Division of the Russian
Academy of Sciences for his advice and constant encouragement.
ing to the previously reported procedure (Scheme 4).29 This
transformation indirectly confirms the presence of the C5-
cyano group in the molecules of 1,2,4-triazines 9, as the C5-
cyano group is reported to be a good leaving group in ipso-
Supporting Information
10–12
substitution reactions with various nucleophiles.
Supporting information for this article is available online at
It is worthy to mention that for the 3-(2-thiphenyl)-
https://doi.org/10.1055/s-0036-1590961.
S
u
p
p
ortioIgnfrm oaitn
S
u
p
p
o
nrtogI
i
f
rm oaitn
1,2,4-triazine 1d the one-pot reaction with anthranilic acid
and iso-amyl nitrite afforded the target 3-cyanoisoquino-
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Letter
References and Notes
(14) Alam, M.; Hawley, R. C.; Lynch, S. M.; Narayanan, A.
WO201486701, 2014.
(
1) (a) Tadross, P. M.; Stoltz, B. M. Chem. Rev. 2012, 112, 3550.
b) Pellissier, H.; Santelli, M. Tetrahedron 2003, 59, 701. (c) Lee,
J.-J.; Noll, B. C.; Smith, B. D. Org. Lett. 2008, 10, 1735.
d) Zyryanov, G. V.; Palacios, M. A.; Anzenbacher, P. Jr. Org. Lett.
008, 10, 3681. (e) Anzenbacher, P. Jr.; Mosca, L.; Palacios, M.
A.; Zyryanov, G. V.; Koutnik, P. Chem. Eur. J. 2012, 18, 12712.
f) Khasanov, A. F.; Kopchuk, D. S.; Kovalev, I. S.; Taniya, O. S.;
(
15) Grande-Carmona, F.; Iglesias-Sigüenza, J.; Álvarez, E.; Díez, E.;
Fernández, R.; Lassaletta, J. M. Organometallics 2015, 34, 5073.
16) Dubé, D.; Blouin, M.; Brideau, C.; Chan, C.-C.; Desmarais, S.;
Ethier, D.; Falgueyret, J.-P.; Friesen, R. W.; Girard, M.; Girard, Y.;
Guay, J.; Riendeau, D.; Tagari, P.; Young, R. N. Bioorg. Med. Chem.
Lett. 1998, 8, 1255.
(
(
(
2
(
(17) Mataka, S.; Takahashi, K.; Tsuda, Y.; Tashiro, M. Heterocycles
Giri, K.; Slepukhin, P. A.; Santra, S.; Rahman, M.; Majee, A.;
Charushin, V. N.; Chupakhin, O. N. New J. Chem. 2017, 41, 2309.
1980, 14, 789.
(18) (a) Phuan, P.-W.; Yang, B.; Knapp, J. M.; Wood, A. B.; Lukacs, G.
(g) Wu, D.; Ge, H.; Liu, S. H.; Yin, J. RSC Adv. 2013, 3, 22727.
L.; Kurth, M. J.; Verkman, A. S. Mol. Pharmacol. 2011, 80, 683.
(h) García, D.; Rodríguez-Pérez, L.; Herranz, M. A.; Peña, D.;
(
b) Knapp, J. M.; Wood, A. B.; Phuan, P.-W.; Lodewyk, M. W.;
Tantillo, D. J.; Verkman, A. S.; Kurth, M. J. J. Med. Chem. 2012, 55,
242.
19) Sahu, R.; Fulwa, V. K.; Jena, H. S.; Manivannan, V. Polyhedron
012, 33, 9.
20) Wu, S. C.; Yoon, D.; Chin, J.; van Kirk, K.; Seethala, R.; Golla, R.;
He, B.; Harrity, T.; Kunselman, L. K.; Morgan, N. N.; Ponticiello,
R. P.; Taylor, J. R.; Zebo, R.; Harper, T. W.; Li, W.; Wang, M.;
Zhang, L.; Sleczk, B. G.; Nayeem, A.; Sheriff, S.; Camac, D. M.;
Morin, P. E.; Everlof, J. G.; Li, Y.-X.; Ferraro, C. A.; Kieltyka, K.;
Shou, W.; Vath, M. B.; Zvyaga, T. A.; Gordon, D. A.; Robl, J. A.
Bioorg. Med. Chem. Lett. 2011, 21, 6693.
Guitián, E.; Bailey, S.; Al-Galiby, Q.; Noori, M.; Lambert, C. J.;
Pérez, D.; Martín, N. Chem. Commun. 2016, 52, 6677. (i) Criado,
A.; Vizuete, M.; Gómez-Escalonilla, M. J.; García-Rodriguez, S.;
Fierro, J. L. G.; Cobas, A.; Peña, D.; Guitián, E.; Langa, F. Carbon
1
(
(
2
2013, 63, 140.
(
2) (a) Castillo, J.-C.; Quiroga, J.; Abonia, R.; Rodriguez, J.; Coquerel,
Y. Org. Lett. 2015, 17, 3374. (b) Castillo, J.-C.; Quiroga, J.; Abonia,
R.; Rodriguez, J.; Coquere, Y. J. Org. Chem. 2015, 80, 9767.
(
(
c) Spiteri, C.; Keeling, S.; Moses, J. E. Org. Lett. 2010, 12, 3368.
d) Shi, F.; Waldo, J. P.; Chen, Y.; Larock, R. C. Org. Lett. 2008, 10,
2
409. (e) McMahon, T. C.; Medina, J. M.; Yang, Y.-F.; Simmons, B.
J.; Houk, K. N.; Garg, N. K. J. Am. Chem. Soc. 2015, 137, 4082.
f) Chakrabarty, S.; Chatterjee, I.; Tebben, L.; Studer, A. Angew.
(21) Prokhorov, A. M.; Slepukhin, P. A.; Kozhevnikov, D. N.
J. Organomet. Chem. 2008, 693, 1886.
(
Chem. Int. Ed. 2013, 52, 2968. (g) Kovalev, I. S.; Kopchuk, D. S.;
Zyryanov, G. V.; Slepukhin, P. A.; Rusinov, V. L.; Chupakhin, O. N.
Chem. Heterocycl. Compd. 2012, 48, 536.
(
22) Prokhorov, A. M.; Kozhevnikov, D. N.; Rusinov, V. L.; Matern, A.
I.; Nikitin, M. M.; Chupakhin, O. N.; Eremenko, I. L.;
Aleksandrov, G. G. Russ. J. Org. Chem. 2005, 41, 1702.
(
3) (a) d’a Rocha Gonsalves, A. M.; Pinho e Melo, T. M. V. D.;
Gilchrist, T. L. Tetrahedron 1992, 48, 6821. (b) Dhar, R.;
Hiihnermann, W.; Kampchen, T.; Overheu, W.; Seitz, G. Chem.
Ber. 1983, 116, 97. (c) Kopchuk, D. S.; Chepchugov, N. V.; Taniya,
O. S.; Khasanov, A. F.; Giri, K.; Kovalev, I. S.; Santra, S.; Zyryanov,
G. V.; Majee, A.; Rusinov, V. L.; Chupakhin, O. N. Tetrahedron
Lett. 2016, 57, 5639.
(
(
23) Iglesias, E.; Brandariz, I. Org. Biomol. Chem. 2013, 11, 1059.
24) Representative Synthetic Procedure for 4-Arylisoquinoline-
3-carbonitriles 6
Corresponding 1,2,4-triazines 1, 4, or 9d (1.0 mmol) were sus-
pended in dry toluene (60 mL). iso-Amyl nitrite or n-amyl
nitrite (0.47 mL, 3.5 mmol) was added at once. The resulting
mixture was stirred under reflux while the solution of anthra-
nilic acid (3.5 mmol) in dry 1,4-dioxane (15 mL) was added
dropwise for 30 min. The reaction mixture was heated under
reflux for an additional hour and then cooled to room tempera-
ture. After that the reaction mixture was washed with 3 M aq
KOH solution (3 × 50 mL), dried with anhydrous Na SO . After
(4) (a) Suh, S.-E.; Barros, S. A.; Chenoweth, D. M. Chem. Sci. 2015, 6,
5128. (b) Li, J.; Li, P.; Wu, J.; Gao, J.; Xiong, W.-W.; Zhang, G.;
Zhao, Y.; Zhang, Q. J. Org. Chem. 2014, 79, 4438. (c) Suh, S.-E.;
Chenoweth, D. M. Org. Lett. 2016, 18, 4080.
(
5) (a) Kopchuk, D. S.; Nikonov, I. L.; Zyryanov, G. V.; Nosova, E. V.;
Kovalev, I. S.; Slepukhin, P. A.; Rusinov, V. L.; Chupakhin, O. N.
Mendeleev Commun. 2015, 25, 13. (b) Nikonov, I. L.; Kopchuk, D.
S.; Kovalev, I. S.; Zyryanov, G. V.; Khasanov, A. F.; Slepukhin, P.
A.; Rusinov, V. L.; Chupakhin, O. N. Tetrahedron Lett. 2013, 54,
2
4
the filtration and evaporation of the solvents under reduced
pressure the obtained residue was purified by column chroma-
tography (silica gel) using the corresponding eluent.
1-(Pyridin-2-yl)-4-phenylisoquinoline-3-carbonitrile (6a)
6427.
Eluent: DCM/EtOAc (3:1); R = 0.4; yield 230 mg (75%); mp 171–
f
(
6) Kopchuk, D. S.; Chepchugov, N. V.; Khasanov, A. F.; Kovalev, I. S.;
Santra, S.; Nosova, E. V.; Zyryanov, G. V.; Majee, A.; Rusinov, V.
L.; Chupakhin, O. N. Tetrahedron Lett. 2016, 57, 3862.
7) Konno, S.; Ohba, S.; Agata, M.; Aizawa, Y.; Sagi, M.; Yamanaka,
H. Heterocycles 1987, 26, 3259.
1
1
73 °С. Н NMR (400 MHz, DMSO-d ): δ = 7.53–7.60 (m, 3 H,
6
Ph), 7.62–7.69 (m, 3 H, Ph, H-5 (py)), 7.72–7.76 (m, 1 H, iso-
quin.), 7.82–7.87 (m, 2 H, isoquin.), 8.06 (ddd, 1 Н, J = 7.8, 7.8,
(
(
(
2.0 Hz, Н-4 (py)), 8.12 (dd, 1 Н, J = 7.8, 0.8 Hz, Н-3 (py)), 8.80
(
dd, 1 Н, J = 4.8, 2.0 Hz, Н-6 (py)), 8.90–8.94 (m, 1 H, isoquin.).
8) Konno, S.; Ohba, S.; Sagi, M.; Yamanaka, H. Chem. Pharm. Bull.
13
C NMR (100 MHz, CDCl ): δ = 117.6, 123.9, 125.4, 125.6, 126.5,
3
1
987, 35, 1378.
9) Konno, S.; Ohba, S.; Sagi, M.; Yamanaka, H. Heterocycles 1986,
4, 1243.
1
27.5, 128.6, 128.9, 129.4, 130.1, 130.2, 131.4, 133.8, 135.9,
–1
137.3, 140.5, 148.7, 157.0. IR (neat): 2227 cm (CN). MS (ESI):
2
m/z [M + H] calcd for С21Н14N3+: 308.12; found: 308.12. Anal.
+
(
10) Kozhevnikov, D. N.; Kozhevnikov, V. N.; Kovalev, I. S.; Rusinov, V.
Calcd (%) for C21H13N : C, 82.07; H, 4.26; N, 13.67. Found: C,
3
L.; Chupakhin, O. N.; Aleksandrov, G. G. Russ. J. Org. Chem. 2002,
81.88; H, 4.03; N, 13.32.
38, 744.
4-(4-Methoxyphenyl)-1-(pyridine-2-yl)isoquinoline-3-car-
(
(
11) Huang, J. J. J. Org. Chem. 1985, 50, 2293.
12) Rykowski, A.; Branowska, D.; Makosza, M.; Van Ly, P. J. Hetero-
cycl. Chem. 1996, 33, 1567.
bonitrile (6b)
Eluent: DCM/EtOAc (3:1); R = 0.5; yield 246 mg (73%); mp 175–
f
1
1
77 °С. Н NMR (400 MHz, CDCl ): δ = 3.93 (s, 3 Н, ОМе), 7.13
3
(
13) Kirby, G. W.; Tan, S. L.; Uff, B. C. J. Chem. Soc. D. 1969, 18, 1075.
(m, 2 Н, 4-MeOPh), 7.48 (m, 3 Н, 4-MeOPh, Н-5 (pу)), 7.75 (m, 2
Н, isoquin.), 7.85 (m, 1 Н, isoquin.), 7.97 (ddd, 1 Н, J = 7.8, 7.8,
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, 483–488

4
88
Synlett
D. S. Kopchuk et al.
Letter
2
2
.0 Hz, Н-4 (pу)), 8.13 (dd, 1 Н, J = 7.8, 0.8 Hz, Н-3 (pу)), 8.82 (m,
(26) Further information can be found in the CIF file. CCDC 1558492
contains the supplementary crystallographic data for com-
pound 8. The data can be obtained free of charge from
–1
Н, Н-6 (pу), isoquin.). IR (neat): 2228 cm (CN). MS (ESI): m/z
+
+
[
M + H] calcd for С22Н16N O : 387.10; found: 387.10. Anal.
3
Calcd (%) for C22H15N O: C, 78.32; H, 4.48; N, 12.46. Found: C,
The Cambridge
Crystallographic
Data
Centre
via
3
78.08; H, 4.24; N, 12.16.
www.ccdc.cam.ac.uk/getstructures.
4
-(4-Chlorophenyl)-1-(pyridine-2-yl)isoquinoline-3-carbo-
(27) Kozhevnikov, D. N.; Kozhevnikov, V. N.; Prokhorov, A. M.;
Ustinova, M. M.; Rusinov, V. L.; Chupakhin, O. N.; Aleksandrov,
G. G.; König, B. Tetrahedron Lett. 2006, 47, 869.
(28) Further information can be found in the CIF file. CCDC 1577518
contains the supplementary crystallographic data for com-
pound 9f. The data can be obtained free of charge from
nitrile (6c)
Eluent: DCM/EtOAc (3:1); R = 0.4; yield 252 mg (74%); mp 180–
f
1
182 °С. Н NMR (400 MHz, CDCl ): δ = 7.45–7.51 (m, 3 H, H-5
3
(
(
8
py), 4-chlorophenyl), 7.59 (m, 2 H, 4-chlorophenyl), 7.72–7.82
m, 3 H, isoquin.), 7.97 (ddd, 1 Н, J = 7.8, 7.8, 2.0 Hz, Н-4 (py)),
.13 (dd, 1 Н, J = 7.8, 0.8 Hz, Н-3 (py)), 8.81 (dd, 1 Н, J = 4.8, 2.0
The Cambridge
Crystallographic
Data
Centre
via
–1
Hz, Н-6 (py)), 8.87 (m, 1 H, isoquin.). IR (neat): 2226 cm (CN).
www.ccdc.cam.ac.uk/getstructures.
MS (ESI): m/z [M + H] calcd for С21Н13ClN3+: 342.08; found:
+
(29) Kopchuk, D. S.; Chepchugov, N. V.; Kovalev, I. S.; Santra, S.;
Rahman, M.; Giri, K.; Zyryanov, G. V.; Majee, A.; Charushin, V.
N.; Chupakhin, O. N. RSC Adv. 2017, 7, 9610.
342.08. Anal. Calcd (%) for C21H12ClN : C, 73.79; H, 3.54; N,
3
12.29. Found: C, 73.62; H, 3.38; N, 12.38.
(25) Kopchuk, D. S.; Nikonov, I. L.; Zyryanov, G. V.; Kovalev, I. S.;
Rusinov, V. L.; Chupakhin, O. N. Chem. Heterocycl. Compd. 2014,
50, 907.
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, 483–488