Solvent-free reaction of 1,2,4-triazine-5-carbonitriles with 4-(cyclohex-1-en-1-yl)morpholine. Unexpected decyanation in addition to classical aza-Diels–Alder reaction

Article abstract of DOI:10.1134/S1070428017010183

The reaction of 1,2,4-triazine-5-carbonitriles with 4-(cyclohex-1-en-1-yl)morpholine under solventfree conditions has been found to follow two pathways: aza-Diels–Alder reaction and unexpected decyanation of the initial nitriles. The scope of the revealed

Full text of DOI:10.1134/S1070428017010183

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2017, Vol. 53, No. 1, pp. 99–102. © Pleiades Publishing, Ltd., 2017.
Original Russian Text © D.S. Kopchuk, A.F. Khasanov, N.V. Chepchugov, I.S. Kovalev, G.V. Zyryanov, V.L. Rusinov, O.N. Chupakhin, 2017, published in
Zhurnal Organicheskoi Khimii, 2017, Vol. 53, No. 1, pp. 103–106.
Solvent-Free Reaction of 1,2,4-Triazine-5-carbonitriles
with 4-(Cyclohex-1-en-1-yl)morpholine. Unexpected Decyanation
in Addition to Classical Aza-Diels‒Alder Reaction
a, b
a
a
a
a, b
D. S. Kopchuk , A. F. Khasanov , N. V. Chepchugov , I. S. Kovalev , G. V. Zyryanov ,*
a, b
a, b
V. L. Rusinov , and O. N. Chupakhin
a
Ural Federal University, ul. Mira 19, Yekaterinburg, 620002 Russia
e-mail: gvzyryanov@gmail.com
*
b
Postovskii Institute of Organic Synthesis, Ural Branch, Russian Academy of Sciences,
ul. S. Kovalevskoi/Akademicheskaya 22/20, Yekaterinburg, 620990 Russia
Received May 3, 2016
Abstract—The reaction of 1,2,4-triazine-5-carbonitriles with 4-(cyclohex-1-en-1-yl)morpholine under solvent-
free conditions has been found to follow two pathways: aza-Diels–Alder reaction and unexpected decyanation
of the initial nitriles. The scope of the revealed decyanation reaction has been roughly estimated.
DOI: 10.1134/S1070428017010183
1
Aza-Diels–Alder reactions of substituted 1,2,4-tri-
azines with enamines are known to underlie a con-
venient method of synthesis of cycloalkane-fused pyr-
idines that are difficult to obtain in other ways [1–3].
These reactions have been successfully accomplished
with 1,2,4-triazinecarbonitriles, in particular with
a view to subsequent synthesis of bipyridine-2-carbox-
ylic acid derivatives [4]; herein, fusion of an aliphatic
carbocycle improved the solubility of the products.
Aromatization of the aliphatic ring in cyclohexane-
fused pyridines leads to substituted isoquinolines [5].
With a few exceptions [6], no reactions of 1,2,4-tri-
azinecarbonitriles with cyclohexenamines have been
reported. We previously noted that 4-(cyclohex-1-en-
[7]. Surprisingly, H NMR analysis of the reaction
mixture showed the presence of expected tetrahydro-
isoquinoline 2, unreacted 1,2,4-triazine-5-carbonitrile,
and unexpected decyanation product, 3,5-diaryl-5H-
1,2,4-triazine 3 (Scheme 1). The products were sepa-
rated by column chromatography.
We then carried out a series of experiments to study
the reaction of 3,6-diaryl-1,2,4-triazine-5-carbonitriles
a and 1b with 4-(cyclohex-1-en-1-yl)morpholine
under solvent-free conditions at different temperatures
in an inert atmosphere (in each case, 5 equiv of the
enamine was added, and an additional 2.5 equiv of the
enamine was added after 2 h; see table). According to
1
1
the H NMR data, reduction of the temperature was
1
4
-yl)morpholine is a less reactive dienophile than
-(cyclopent-1-en-1-yl)morpholine [5]. We failed to
accompanied by decrease of the fraction of 2 (until
complete disappearance at 125°C) and increase of the
fraction of decyanation product 3.
Due to the lack of electron-withdrawing cyano
group, compound 3 becomes a less reactive diene
which is incapable of undergoing subsequent aza-
Diels–Alder reaction with 4-(cyclohex-1-en-1-yl)-
morpholine whose reactivity as dienophile is not
high as well.
react 4-(cyclohex-1-en-1-yl)morpholine with 1,2,4-tri-
azinecarbonitriles in a solvent even on prolonged heat-
ing in boiling o-xylene. With the goal of improving the
the conversion of the initial triazine to pyridine, the
reactions were carried out using 5 equiv of enamine at
elevated temperature (200°C) in an inert atmosphere in
the absence of a solvent [7].
Initial 1,2,4-triazine-5-carbonitriles 1a–1c were
synthesized according to an efficient procedure
reported previously [8] and were brought into reaction
with 4-(cyclohex-1-en-1-yl)morpholine as described in
When more reactive 4-(cyclopent-1-en-1-yl)mor-
pholine was used as dienophile in the aza-Diels–Alder
reaction under analogous conditions (200°C), the con-
version of 1a to pyridinecarbonitrile 2d was almost
9
9

1
00
KOPCHUK et al.
Scheme 1.
(
)n
R
N
R
N
N
R
N
N
(
)n
+
+
N
NC
N
R'
R'
NC
N
R'
O
1
a–1c
3a, 3b
2a–2d
6 4 6 4
R = R′ = Ph (a); R = 4-MeC H , R′ = 4-FC H (b); R = Ph, R′ = pyridin-2-yl (c); 2d, n = 1 (R = R′ = Ph); 2a–2c, n = 2.
1
complete. According to the H NMR and MS data,
compound 2d was the only product, while no
decyanation product like 3 was detected in the reaction
mixture.
of the fused cyclohexene ring resonated as three
signals in the region δ 1.73‒2.77 ppm with intensities
1
3
corresponding to 2H, 2H, and 4H. The C NMR spec-
3
trum of 2c showed signals of four sp -carbon atoms in
the region δ 21.7‒28.5 ppm.
C
The reaction of 4-(cyclohex-1-en-1-yl)morpholine
with triazine-5-carbonitrile 1c additionally activated by
pyridin-2-yl substituent in the 3-position [9] afforded
no decyanation product 3 under analogous conditions,
and compound 2c could be isolated by crystallization
from acetonitrile at reduced temperature without re-
sorting to column chromatography.
According to published data on decyanation of
aromatic and heteroaromatic nitriles, such reactions
generally involve hydrolysis of the cyano group and
subsequent decarboxylation in acid medium [10], in
some cases under microwave irradiation [11, 12], in
basic medium [13], or in D O at elevated temperature
2
(
in a sealed ampule) [14]. Photoinduced decyanation in
Thus, we can presume that only 1,2,4-triazine-5-
carbonitrile 1 but not cyclohexane-fused pyridine 2
undergoes elimination of the cyano group. This
follows from the result of the reaction of 4-(cyclohex-
the presence of triethylamine [15], decyanation by the
action of pyrophosphoric acid at elevated temperature
[16], and reductive decyanation in a hydrogen atmo-
sphere in the presence of a catalyst [17, 18] or with
titanium trichloride [19] have also been reported. In
this respect, examples of the use of enamines as
reducing agents should be taken into account; in
particular, nitro group was reduced to amino [20, 21].
Presumably, in our case we observe analogous reduc-
tive decyanation of 1,2,4-triazinecarbonitrile. In ad-
dition, easy replacement of the cyano group in
1
-en-1-yl)morpholine with triazinecarbonitrile 1c.
Presumably, the aza-Diels–Alder reaction with 1c
proceeds at a considerably higher rate, whereas
elimination of the cyano group from compound 2c
does not occur. Likewise, heating of a mixture of
1
,4-diphenyl-6,7-dihydro-5H-cyclopenta[c]pyridine-3-
carbonitrile (2d) and 4-(cyclohex-1-en-1-yl)morpho-
line for 4 h at 200°C in an inert atmosphere gave no
decyanation product (1,4-diphenyl-6,7-dihydro-5H-
cyclopenta[c]pyridine).
1
,2,4-triazinecarbonitriles by different nucleophiles
should be noted [22, 23]; no analogous substitution in
pyridinecarbonitriles has been observed.
The structure of 2 and 3 was determined on the
1
13
basis of their H and C NMR and mass spectra and
elemental analyses. Decyanation products 3a and 3b
displayed in the H NMR spectra a downfield signal at
δ 9.02‒9.07 ppm due to proton in position 5 of the
Thus, 3,6-diaryl-1,2,4-triazine-5-carbonitriles are
capable of reacting with 4-(cyclohex-1-en-1-yl)mor-
pholine under solvent-free conditions in an inert atmo-
sphere via two competing pathways: aza-Diels–Alder
reaction or substitution of the 5-cyano group by
1
1
triazine ring. In the H NMR spectra of 2a–2c, protons
Reaction of 1,2,4-triazine-5-carbonitriles 1a and 1b with 4-(cyclohex-1-en-1-yl)morpholine
Mole fraction, %
Initial triazine-
Reaction conditions
carbonitrile no.
decyanation product
unreacted 1
aza-Diels–Alder product
1
a
200°C, 3 h
11.5
05.3
15.0
12.5
10.0
36.5
34.7
85.0
57.0
33.0
52.0
60.0
00.0
30.5
57.0
2
1
1
00°C, 6 h
25°C, 4 h
50°C, 4 h
1
b
200°C, 3 h
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 53 No. 1 2017

SOLVENT-FREE REACTION OF 1,2,4-TRIAZINE-5-CARBONITRILES
101
hydrogen. The presence of additional electron-with-
drawing substituents in the 1,2,4-triazinecarbonitrile
molecule, as well as replacement of dienophile by more
reactive 4-(cyclopent-1-en-1-yl)morpholine, favors the
cycloaddition process and inhibits decyanation.
spectrum (CDCl ), δ, ppm: 7.61–7.50 m (6H, Ph),
3
8.16 m (2H, Ph), 8.58 m (2H, Ph), 9.07 s (1H, 5-H).
+
Mass spectrum: m/z 234.10 (Irel 100%) [M + H] .
Found, %: C 77.10; H 4.61; N 17.90. C H N . Cal-
1
5
11
3
culated, %: C 77.23; H 4.75; N 18.01.
-(4-Fluorophenyl)-4-(4-methylphenyl)-5,6,7,8-
tetrahydroisoquinoline-3-carbonitrile (2b). Yield
144 mg (0.42 mmol, 42%), mp 143–145°C, R 0.35.
H NMR spectrum (CDCl ), δ, ppm: 1.74 m (4H, 6-H,
1
EXPERIMENTAL
1
13
f
The H and C NMR spectra were recorded on
a Bruker Avance-400 spectrometer at 400 and
1
3
7
-H), 2.46 s (3H, Me), 2.56 m (2H, 8-H), 2.74 m (2H,
1
00 MHz, respectively, using tetramethylsilane as
5
7
-H), 7.13‒7.22 m (4H, Harom), 7.32 m (2H, MeC H ),
6
4
internal standard. The melting points were measured
on a Boetius melting point apparatus. The mass spectra
.50 m (2H, 4-FC H ). Mass spectrum: m/z 343.16
6
4
+
(
Irel 100%) [M + H] . Found, %: C 80.47; H 5.41;
(
electrospray ionization) were obtained on a Bruker
N 7.94. C H FN . Calculated, %: C 80.68; H 5.59;
2
3
19
2
Daltonics MicrOTOF-Q II mass spectrometer (Bremen,
Germany). The elemental compositions were deter-
mined on a Perkin Elmer PE 2400 Series II CHN
analyzer. 1,2,4-Triazine-5-carbonitriles 1a [8] and 1c
N 8.18.
6-(4-Fluorophenyl)-3-(4-methylphenyl)-1,2,4-tri-
azine (3b). Yield 17 mg (0.06 mmol, 6%), mp 173–
1
[9] were synthesized as described previously.
175°C, R 0.5. H NMR spectrum (CDCl ), δ, ppm:
f
3
2
.49 s (3H, Me), 7.22 m and 7.39 m (2H each,
6
-(4-Fluorophenyl)-3-(4-methylphenyl)-1,2,4-tri-
MeC H ), 8.05 m and 8.59 m (2H each, 4-FC H ), 9.02 s
6
4
6
4
azine-5-carbonitrile (1b) was synthesized as de-
scribed in [8]. Yield 80%, mp 175‒177°C. H NMR
spectrum (DMSO-d ), δ, ppm: 2.50 s (3H, Me), 7.36 m
2H, 4-FC H ), 7.46 m (2H, MeC H ), 7.98 m (2H,
1
(
[
1H, 5-H). Mass spectrum: m/z 257.04 (I 100%)
M + H] . Found, %: C 72.51; H 4.42; N 15.66.
rel
+
6
C H FN . Calculated, %: C 72.44; H 4.56; N 15.84.
(
21 17
5
6
4
6
4
MeC H ), 8.58 m (2H, 4-FC H ). Mass spectrum:
6
4
6
4
4-Phenyl-1-(pyridin-2-yl)-5,6,7,8-tetrahydroiso-
+
m/z 291.10 (I 100%): [M + H] . Found, %: C 70.25;
rel
quinoline-3-carbonitrile (2c). Yield 180 mg
1
H 3.73; N 19.14. C H FN . Calculated, %: C 70.34;
1
7
11
4
(0.58 mmol, 58%), mp 168–170°C. H NMR spectrum
H 3.82; N 19.30.
(
CDCl ), δ, ppm: 1.71–1.77 m (4H, 6-H, 7-H), 2.52‒
3
2
7
.58 m (2H, 8-H), 2.99‒3.05 m (2H, 5-H), 7.29‒
.33 m (2H, Ph), 7.33‒7.39 m (1H, 5′-H), 7.45–7.55 m
Reaction of 1,2,4-triazine-5-carbonitriles with
enamines (general procedure). A mixture of 1 mmol
of triazinecarbonitrile 1a–1c and 5 mmol of the corre-
sponding enamine was stirred for 2 h at 200°C under
argon. An additional portion of the enamine, 2.5 mmol,
was added, and the mixture was stirred for 2 h more
under the same conditions. The products were isolated
by column chromatography using methylene chloride
as eluent. In the reaction with 1c, the mixture was
treated with 10 mL of acetonitrile and kept for 15 h at
(3H, Ph), 7.78 d.d (1H, 3′-H, J = 7.8, 0.8 Hz),
7.86 d.d.d (1H, 4′-H, J = 7.8, 7.8, 2.0 Hz), 8.69 d (1H,
6′-H, J = 4.8, 2.0 Hz). C NMR spectrum (CDCl ), δ ,
ppm: 21.7, 22.0, 27.7, 28.5, 117.0, 123.3, 124.6, 129.0,
129.0, 129.8, 134.8, 136.6, 137.0, 141.7, 147.5, 148.6,
157.1, 157.6. Mass spectrum, m/z 312.15 (Irel 100%)
13
3 C
+
[M + H] . Found, %: C 80.78; H 5.42; N 13.22.
C
H
17
N
3
. Calculated, %: C 81.00; H 5.50; N 13.49.
21
–
18°C, and the precipitate was filtered off, washed
with acetonitrile, and dried.
,4-Diphenyl-5,6,7,8-tetrahydroisoquinoline-3-
1
,4-Diphenyl-6,7-dihydro-5H-cyclopenta[c]pyri-
dine-3-carbonitrile (2d). Yield 163 mg (0.55 mmol,
55%), mp 151–153°C, R 0.4. H NMR spectrum
1
1
f
carbonitrile (2a). Yield 140 mg (0.45 mmol, 45%),
(DMSO-d ), δ, ppm: 2.09 m (2H, 6-H), 2.92 t (2H,
7-H, J = 7.2 Hz), 3.26 t (2H, 5-H, J = 7.2 Hz), 7.42‒
6
1
mp 139‒141°C, R 0.4. H NMR spectrum (CDCl ), δ,
f
3
ppm: 1.73 m (4H, 6-H, 7-H), 2.55 m (2H, 8-H), 2.77 m
2H, 5-H), 7.33 m (2H, Ph), 7.42‒7.59 m (8H, Ph).
Mass spectrum: m/z 311.15 (Irel 100%) [M + H] .
7.60 m (8H, Ph), 7.81 m (2H, Ph). Mass spectrum:
m/z 297.14 (Irel 100%) [M + H] . Found, %: C 84.97;
+
(
+
H 5.39; N 9.31. C H N . Calculated, %: C 85.11;
21
17
2
Found, %: C 85.01; H 5.69; N 8.92. C H N . Cal-
H 5.44; N 9.45.
2
2
18
2
culated, %: C 85.13; H 5.85; N 9.03.
This study was performed under financial support
by the Russian Science Foundation (project no. 16-43-
02020), by the Council for Grants at the President of
5
,6-Diphenyl-1,2,4-triazine (3a). Yield 16 mg
1
(
0.07 mmol, 7%), mp 160–162°C, R 0.5. H NMR
f
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 53 No. 1 2017

1
02
KOPCHUK et al.
the Russian Federation (project no. MK-644.2017.3),
and by the Government of the Russian Federation
11. Hédou, D., Guillon, R., Lecointe, C., Logé, C.,
Chosson, E., and Besson, T., Tetrahedron, 2013, vol. 69,
p. 3182.
(
program no. 211, contract no. 02.A03.21.0006).
1
1
1
1
1
2. Alexandre, F.-R., Berecibar, A., Wrigglesworth, R., and
REFERENCES
Besson, T., Tetrahedron Lett., 2003, vol. 44, p. 4455.
3. Nakamura, A., Ono, M., Segawa, H., and Takematsu, T.,
1
. Ławecka, J., Karczmarzyk, Z., Woliñska, E.,
Olender, E., Branowska, D., and Rykowski, A., Tetra-
hedron, 2011, vol. 67, p. 3098.
Agric. Biol. Chem., 1984, vol. 48, p. 1009.
4. Werstiuk, H.N. and Ju, C., Can. J. Chem., 1989,
vol. 67, p. 5.
2
. Catozzi, N., Bromley, W.J., Wasnaire, P., Gibson, M.,
5. Tada, M., Hamazaki, H., and Hirano, H., Chem. Lett.,
and Taylor, R.J.K., Synlett, 2007, p. 2217.
1
980, vol. 9, p. 921.
3
. Kopchuk, D.S., Zyryanov, G.V., Kovalev, I.S., Khasa-
nov, A.F., Medvedevskikh, A.S., Rusinov, V.L., and
Chupakhin, O.N., Chem. Heterocycl. Compd., 2013,
vol. 49, p. 500.
6. Beauchard, A., Chabane, H., Sinbandhit, S., Guenot, P.,
Thiéry, V., and Besson, T., Tetrahedron, 2006, vol. 62,
p. 1895.
17. Albaneze-Walker, J., Zhao, M., Baker, M.D.,
4. Krinochkin, A.P., Kopchuk, D.S., and Kozhevni-
Dormer, P.G., and McNamara, J., Tetrahedron Lett.,
kov, D.N., Polyhedron, 2015, vol. 102, p. 556.
2
002, vol. 43, p. 6747.
5
. Kopchuk, D.S., Kovalev, I.S., Khasanov, A.F., Zyrya-
nov, G.V., Slepukhin, P.A., Rusinov, V.L., and Chupa-
khin, O.N., Mendeleev Commun., 2013, vol. 23, p. 142.
1
8. Diaz, F., Farouz, F.S., Holcomb, R., Kesicki, E.A., Ooi
Hua, C., Rudolph, A., Stappenbeck, F., Thorsett, E.,
Gaudino, J.J., Fisher, K.L., and Cook, A.W., WO Patent
no. 2006/105262 A1, 2006.
6
. Seitz, G., Dhar, R., and Kampchen, T., Arch. Pharm.,
1
982, vol. 315, p. 697.
19. Clerici, A. and Porta, O., Tetrahedron, 1982, vol. 38,
7
. Kozhevnikov, V.N., Ustinova, M.M., Slepukhin, P.A.,
Santoro, A., Bruce, D.W., and Kozhevnikov, D.N.,
Tetrahedron Lett., 2008, vol. 49, p. 4096.
p. 1293.
2
0. Kopchuk, D.S., Khasanov, A.F., Kovalev, I.S., Zyrya-
nov, G.V., Rusinov, V.L., and Chupakhin, O.N.,
Mendeleev Commun., 2013, vol. 23, p. 209.
8
. Kozhevnikov, D.N., Kozhevnikov, V.N., Nikitina, T.V.,
Rusinov, V.L., Chupakhin, O.N., and Neunhoeffer, H.,
Mendeleev Commun., 2002, vol. 12, p. 30.
2
1. Danishefsky, S. and Cavanaugh, R., Chem. Ind.
(
London), 1967, vol. 52, p. 2171.
9
. Kozhevnikov, V.N., Kozhevnikov, D.N., Nikitina, T.V.,
Rusinov, V.L., Chupakhin, O.N., Zabel, M., and
König, B., J. Org. Chem., 2003, vol. 68, p. 2882.
22. Huang, J.J., J. Org. Chem., 1985, vol. 50, p. 2293.
23. Kozhevnikov, D.N., Kozhevnikov, V.N., Kovalev, I.S.,
Rusinov, V.L., Chupakhin, O.N., and Aleksandrov, G.G.,
Russ. J. Org. Chem., 2002, vol. 38, p. 744.
1
0. Almeida, L., Ioannidis, S., Lamb, M., and Su, M.,
WO Patent no. 2008/117050, 2008.
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