A novel approach to fused 1,2,4-triazines by intramolecular cyclization of 1,2-diaza-1,3-butadienes bearing allyl(propargyl)sulfanyl and cyclic tert-amino groups

Article abstract of DOI:10.1016/j.tetlet.2007.10.140

3-Allyl- and 3-prop-1-ynylsulfanyl-2-arylazo-3-cycloalkylamino-acrylonitriles undergo cyclization under mild conditions to afford the novel heterocyclic systems 1,4,6,7,8,8a-hexahydropyrrolo[2,1-c][1,2,4]-triazine-4-thione, 1,4,6,7,9,9a-hexahydro-[1,4]oxa

Full text of DOI:10.1016/j.tetlet.2007.10.140

Available online at www.sciencedirect.com
Tetrahedron Letters 48 (2007) 9128–9131
A novel approach to fused 1,2,4-triazines by
intramolecular cyclization of 1,2-diaza-1,3-butadienes
bearing allyl(propargyl)sulfanyl and cyclic tert-amino groups
Natalia P. Belskaia,a,* Tatyana G. Deryabina,a Alexandr V. Koksharov,a
Mikhail I. Kodess,b Wim Dehaen,c Albert T. Lebedevd and Vasiliy A. Bakuleva
aLaboratory of Technology for Organic Synthesis, The Urals State Technical University, 620002 Ekaterinburg, Russia
bI. Ya. Postovsky Institute of Organic Synthesis of the Ural Branch of Russian Academy of Sciences, 620041 Ekaterinburg, Russia
cDepartment of Chemistry, K.U. Leuven, Celestijnenlaan 200F, B-3001 Leuven, Belgium
dOrganic Chemistry Department, Moscow State University, Moscow 119992, Russia
Received 21 August 2007; revised 17 October 2007; accepted 25 October 2007
Available online 30 October 2007
Abstract—3-Allyl- and 3-prop-1-ynylsulfanyl-2-arylazo-3-cycloalkylamino-acrylonitriles undergo cyclization under mild conditions
to afford the novel heterocyclic systems 1,4,6,7,8,8a-hexahydropyrrolo[2,1-c][1,2,4]-triazine-4-thione, 1,4,6,7,9,9a-hexahydro-
[1,4]oxazino[3,4-c][1,2,4]triazine and 1,6,7,8,9,9a-hexahydro-4H-pyrido[2,1-c][1,2,4]triazine via a number of consecutive pericyclic
reactions.
Ó 2007 Elsevier Ltd. All rights reserved.
R
Recently, we have shown that 3-methylsulfanyl-2-
CN
CN
N
O
N
N
N
Ar
arylazo-3-pyrrolidine-1-yl)acrylonitriles 1a–c generated
azomethine ylides under mild conditions.1 The latter
reacted by a 1,3-dipolar cycloaddition mechanism with
N-substituted maleimides to form 4-methylene pyrroliz-
idines 3 and 4 (Scheme 1).
Ar
N
N
O
SMe
H
N
O
2a-b
N
H
H
-MeSH
R
O
1a-c
3,4a-c
1a Ar = 4-NO2C6H4; 1b Ar = 4-MeC6H4; 1c Ar = 4-MeOC6H4
2a R = Me; 2b R =Ph
3a R = Me, Ar = 4-NO2C6H4; 3b R = Me, Ar = 4MeC6H4, 3c R = Me, Ar = 4-MeOC6H4
4a R = Ph, Ar = 4-NO2C6H4; 4b R = Ph, Ar = 4-MeC6H4; 4c R = Ph, Ar = 4-MeOC6H4
Herein, we report a novel intramolecular reaction of 3-
alkylsulfanyl-2-arylazo-3-cycloalkylamino-acrylonitriles
leading to 2,3,4,5-tetrahydro-[1,2,4]-triazines fused to
pyrrolidine, piperidine, and morpholine rings. The start-
ing allyl- and propargylsulfanyl-2-arylazo-3-(pyrrolidin-
1-yl, piperidin-1-yl and morpholin-4-yl)acrylonitriles 5
and 6 were prepared by the alkylation of 2-arylhydr-
azono-3-cycloalkylamino-3-thioxopropionitriles with an
excess of allyl- and propargyl bromides in the presence
of KOH in 85–95% yields.
Scheme 1.
tone and acetonitrile at room and higher temperatures
while optimal conditions involved heating of com-
pounds 5 or 6 in acetonitrile at 40 °C.2 Column
chromatography of the final reaction mixtures allowed
us to isolate pure 1-aryl-4-thioxo-[1,2,4]-triazine-3-
carbonitriles 7a–f as the main products in moderate
yields (Scheme 2, Table 1).
Surprisingly, it was found that on standing in CHCl3
compounds 5 and 6 were gradually transformed into
new products. We observed this process in benzene, ace-
The structural determination of compounds 7 was
achieved from their analytical and spectral data. 1H
NMR spectra of products 7a–f were considerably differ-
ent in comparison to those of starting materials 5 and 6.3
There were no signals of protons due to the SR groups
in the spectra of 7. The number of protons of the
Keywords: 1,2-Diaza-1,3-butadiene; Thioamide; Alkylation; tert-Amino
effect; Electrocyclization;Pyrrolotriazine;Oxazinotriazine;Pyridotriazine.
*
Corresponding author. Tel./fax: +7 343 375 41 35; e-mail: belska@
mail.ustu.ru
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.10.140

N. P. Belskaia et al. / Tetrahedron Letters 48 (2007) 9128–9131
9129
CN
CN
CN
N
Ar
40 o
acetonitrile
C
N
S
S
SR
N
N
N
+
N
X
N
NH
N
Ar
Ar
X
X
7a-f
8a-f
5a-d, 6a-f
7,8
a
b
c
d
e
f
Ar 4-EtO2CC6H4 4-ClC6H4 Ph 4-MeOC6H4 Ph
Ph
X
CH2
CH2
CH2
CH2
OCH2 (CH2)2
Scheme 2.
cycloalkylamine had decreased by one. The signals of
the two protons of the cycloalkylamine were shifted
downfield significantly in comparison with the starting
materials. A doublet of doublets at d 5.58 ppm
(J = 8.2, 5.3 Hz) for 7a–d and d 6.40 (J = 10.4, 2.9 Hz)
for 7e–f corresponding to the proton on the bridging
carbon of the heterocyclic system and a complex multi-
plet due to the remaining protons of the cyclic amino
ring were registered in the spectra of compounds 7. A
strong shift (around 20 ppm) of the signal of the carbon
connected to the sulfur atom, the small shifts of the sig-
nals of the aromatic carbon atoms (2–3 ppm), and
strong downfield shifts for the signals of the a- and b-
carbons of the cycloalkylamine were the main features
of the 13C NMR spectra of compounds 7 in comparison
with 5 and 6. Confirmation of the structures of com-
pounds 7 was made on the basis of 2D HMBC and
HSQC experiments. The assigned structures were fur-
ther validated by single-crystal X-ray analysis (Fig. 1).4
Figure 1. X-ray structures of 7d and 7e.
The cyclization according to this mechanism (Scheme 3)
is accomplished by dealkylation of intermediate prod-
ucts 9 to form the final compounds 7. As dry solvents
were used and because the yields of the final products
did not diminish when the reaction was carried out un-
der argon (entries 8 and 12, Table 1) we conclude that
the last step of the reaction may involve elimination of
propene (for compounds 5) or propyne (for compounds
6) from intermediate 9 (formed via thio-Claisen rear-
rangement) rather than an oxidative reaction with the
formation of propen(propyn)ols. Moreover, the use of
sulfur as an oxidant did not lead to a change in the yield
of the reaction (entry 10, Table 1). The formation of
It is worth noting that thioamides 8a–f were isolated as
minor products of side chain dealkylation in all the
transformations of thioimidates 5 and 6 to 7. The mech-
anism of the transformation of 3-allyl- and 3-prop-1-
ynylsulfanyl-2-arylazo-3-cycloalkylamino-acrylonitriles
5 or 6 to fused 1,2,4-triazines 7 can be described in anal-
ogy to cyclizations relying on the so-called ‘tert-amino
effect’ (Scheme 3) as compounds 5 and 6 contain both
tert-amino functions and a conjugated system.5
Table 1. Investigation of the transformation of 3-allyl- and 3-prop-1-ynylsulfanyl-2-arylazo-3-cycloalkylamino-1-yl-acrylonitriles 5 and 6
Entry
Substrate
Ar
X
R
Time (h)
Yielda 7 (%)
Yielda 8 (%)
1
2
3
4
5
5a
6a
5b
6b
5c
6c
5d
5d
5d
5d
6d
6d
6e
6f
4-EtO2CC6H4
4-EtO2CC6H4
4-ClC6H4
4-ClC6H4
C6H5
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
OCH2
(CH2)2
Allyl
Propargyl
Allyl
Propargyl
Allyl
Propargyl
Allyl
Allyl
Allyl
Allyl
40
15
40
9
51
47
68
60
55
65
55
70
55
53
60
53
40
37
3
6
5
12
6
7
60
10
40
40
40
40
10
10
25
20
6
7
C6H5
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
C6H5
17
7
8b
9c
10d
11
12b
13
14
17
11
11
15
10
10
Propargyl
Propargyl
Propargyl
Propargyl
C6H5
a Isolated yields.
b Reaction carried out under argon.
c Reaction carried out with toluene-4-thiol.
d Reaction carried out with sulfur.

9130
N. P. Belskaia et al. / Tetrahedron Letters 48 (2007) 9128–9131
range of cancer cells.10 Some pyrrazolo[5,1-c][1,2,4]tri-
CN
N
CN
CN
azines have acquired considerable importance because of
their remarkable antitumor and antifungal activities.11
Certain synthetic derivatives of imidazo[2,1-c][1,2,4]tri-
azin-4(1H)-ones have revealed a strong affinity for
tumor cells and have demonstrated antiproliferative
properties and anticancer and antibacterial activities.12
N
SR
SR
SR
N
N
[1,5]-H
Ar
HN
N
N
Ar
N
N
Ar
X
X
X
5,6
CN
SR
HN
O2
-ROH
In conclusion, we have discovered a novel reaction,
which represents a new approach for the synthesis of
bicyclic tetrahydro-1,2,4-triazines.
N
N
7
7
Ar
-RH
9
X
Scheme 3. The mechanism of triazine ring construction from 5 and 6
according to the tert-amino effect.
Supplementary data
propene as the principal gas phase product of the reac-
tion was confirmed by a GC-MS experiment.6
1
Supplementary data (copies of H and 13C spectra for
compounds 7). Supplementary data associated with this
article can be found, in the online version, at doi:
10.1016/j.tetlet.2007.10.140.
However, thio-Claisen rearrangements normally take
place under more vigorous conditions and the rear-
rangement of 5-alkylsulfanyl-1,2,4-triazine-3-carboni-
trile 9 should be hampered by the presence of a cyano
group at position 3.7
References and notes
An alternative mechanism involves the elimination of
propene (propyne in the case of compounds 6) to afford
intermediate A, containing a conjugated hetero-hexatri-
ene system (Scheme 4). The latter undergoes a 6p-elec-
trocyclic reaction to furnish final product 7. The
allyl(propargyl)thio group along with active a-protons
makes 5 and 6 well suited for the pericyclic group trans-
fer reactions 8 to final products 7 by elimination of pro-
pene(propyne) or via intermediate allyl(propargyl)
amination (via structure A). A radical mechanism was
excluded because there were no new products detected
when the reaction was carried out in the presence of
toluene-4-thiol (entry 9, Table 1).
1. Deryabina, T. G.; Belskaia, N. P.; Kodess, M. I.; Dehaen,
W.; Toppet, S.; Bakulev, V. Tetrahedron Lett. 2006, 47,
1853.
2. General procedure for the transformation of 5 and 6: A
solution of 0.5 mmol of 5 or 6 in 5 ml of acetonitrile was
kept at 40 °C. The reaction progress was monitored by
TLC (3:2:1;chloroform:hexane:acetone). The solvent
was evaporated and the oily residue purified by column
chromatography (5:4:1;chloroform:hexane:acetone, sil-
ica gel 0.075–0.035 mm).
3. 1-(4-Methoxyphenyl)-4-thioxo-1,4,6,7,8,8a-hexahydropyr-
rolo[2,1-c][1,2,4]triazine-3-carbonitrile (7d): mp 125–
127 °C; IR (KBr, cmꢀ1) 3440, 2960, 2930, 2880, 2840,
2220, 1605, 1500; 1H NMR (DMSO-d6, 400 MHz): d 1.90–
2.03 (m, 3H, CH2), 2.58–2.65 (m, 1H, CH2), 3.79 (s, 3H,
OMe), 3.68–3.87 (m, 2H, CH2) 5.47 (dd, 1H, J = 8.2,
4.8 Hz, CH), 7.03 and 7.40 (AA0XX0, 4H, J = 8.7 Hz, Ar);
13C NMR (DMSO-d6, 100 MHz): d 20.3 (t, J = 133.4 Hz,
CH2), 31.0 (ddm, J = 138.6, 134.1 Hz, CH2), 50.6 (tm,
J = 145.7 Hz, CH2), 55.5 (q, J = 144.7 Hz, OMe), 72.2
(dm, J = 164.5 Hz, CH), 114.3 (dd, J = 161.0, 5.3 Hz,
2CH–Ar), 115.1 (d, J = 1.2 Hz, CN), 120.6 (d, J = 0.9 Hz,
C–CN), 125.0 (dd, J = 162.3, 5.4 Hz, 2CH–Ar), 134.9 (tt,
J = 9.2, 2.5 Hz, C-Ar), 158.7 (C-Ar), 172.5 (t, J = 1.8 Hz,
CS); MS (70 eV) m/z (%) 286 (M+, 40.8); Anal. Calcd for
C14H14N4OS: C, 58.72; H, 4.93; N, 20.57%. Found: C,
57.19; H, 4.36; N, 20.39%.
The main feature of the reported reaction is elimination
of propene (propyne in the case of propargyl derivatives
6) and the formation of a new C–N bond leading to
novel 2,3,4,5-tetrahydro-[1,2,4]-triazine-5-thiones 7a–f.
Piperidine and morpholine derivatives 7e and f are novel
heterocyclic systems.
It is worth mentioning that annulated 1,2,4-triazines are
present as important core structures in many biologi-
cally active compounds, both naturally occurring and
synthetic.9 Various condensed 1,2,4-triazines have found
applications as pharmaceuticals, herbicides, pesticides,
and dyes. For example, pyrrolo[2,1-f][1,2,4]triazines
demonstrate inhibitory effects on the growth of a wide
1-Phenyl-4-thioxo-1,4,6,7,9,9a-hexahydro-[1,4]oxazino[3,4-c]-
[1,2,4]triazine-3-carbonitrile (7e): mp 165–167 °C; IR
(KBr, cmꢀ1) 3440, 2980, 2960, 2840, 2220, 1600, 1540;
1H NMR (400 MHz, DMSO-d6): d 3.59 (ddd, 1H,
J = 12.9, 11.9, 3.1 Hz, CH2), 3.67 (ddd, 1H, J = 11.9,
11.5, 1.8 Hz, CH2), 3.78 (dd, 1H, J = 11.2, 2.9 Hz, CH2),
3.90 (dd, 1H, J = 11.5, 3.1 Hz, CH2), 3.99 (dd, 1H,
J = 11.2, 10.4 Hz, CH2), 5.02 (dd, 1H, J = 12.9, 1.8 Hz,
CH2), 6.45 (dd, 1H, J = 10.4, 2.9 Hz, CH), 7.32 (tt, 1H,
J = 6.6, 1.8 Hz, Ph), 7.54-7.45 (4H, m, Ph). 13C NMR
(100 MHz, DMSO-d6): d 50.5 (ddd, J = 146.0, 143.1,
3.8 Hz, CH2). 64.0 (tm, J = 147.7 Hz, CH2), 65.0 (ddm,
J = 149.4, 145.4 Hz, CH2), 69.7 (dt, J = 160.4, 4.5 Hz,
CH), 114.9 (s, CN), 117.1 (s, C–CN), 117.8 (dm,
J = 163.1 Hz, 2CH–Ph), 126.4 (dt, J = 165.2, 7.5 Hz,
CN
CN
CN
N
N
N
S
H
S
Ar
N
N
Ar
Ar
[1,6]-EC
N
S
R
N
N
N
7
X
X
-RH
X
A
5,6
Scheme 4. The mechanism of triazine ring construction via 6p-
electrocyclization.

N. P. Belskaia et al. / Tetrahedron Letters 48 (2007) 9128–9131
9131
CH–Ph), 129.7 (dd, J = 164.4, 6.6 Hz, 2CH–Ph), 140.9 (t,
J = 6.9 Hz, C–Ph), 174.4 (ddd, J = 5.5, 6.7, 3.1 Hz, CS);
MS (70 eV) m/z (%) 272 (M+, 10.5); Anal. Calcd for
C13H12N4OS: C, 57.34; H, 4.44; N, 20.57%. Found: C,
57.19; H, 4.36; N, 20.39%.
Janousek, Z.; Viehe, H. G. Tetrahedron 1994, 50, 7075;
(e) Kirschke, K.; Moller, A.; Schmitz, E.; Kuban, R. J.;
Schulz, B. Tetrahedron Lett. 1986, 27, 4281; (f) Schmitz,
E.; Lutze, G.; Kirschke, K.; Hubner, P. Bull. Soc. Chim.
Belg. 1992, 101, 61.
4. Crystal data for 7d were measured with an Xcalibur 3 CCD
(graphite monochromator, MoKa): C14H14N4OS, FW =
286.35, orthorhombic, a = 14.840(3), b = 11.2764(9),
6. The presence of volatile organic compounds in the
reaction mixture was monitored using an Agilent 5973
mass spectrometer using electron ionization (70 eV). A
sample (0.5 ml) of the gas phase over the reaction mixture
from the transformation of 5d in benzene in a sealed vial
was taken with a syringe and introduced into the GC-MS
system. A VOC column (# 60 m) was used for the
separation.
7. Castro, A. M. M. Chem. Rev. 2004, 104, 2939.
8. Woodward, R. B.; Hoffmann, R. The Conservation of
Orbital Symmetry; Verlag Chemie: Weinheim, Germany,
1970.
9. El Ashry, E. S. H.; Rashed, N.; Taha, E.; Ramadam, E.
Adv. Heterocycl. Chem. 1994, 59, 39.
10. Hunt, J. T.; Mitt, T.; Borzilleri, R.; Gullo-Brown, J.;
Fargnoli, J.; Fink, B.; Han, W.-C.; Mortillo, S.; Vite, G.;
Wautlet, B.; Wong, T.; Yu, C.; Zheng, X.; Bhide, R. J.
Med. Chem. 2004, 47, 4054.
˚
c = 8.3820(12) A, a = 90.00°, b = 90.00°, c = 90.00 °,
3
˚
V = 1402.7(4) A , T = 295(2) K, space group Pna2(1),
Z = 4 reflections were used in all calculations. R =
0.0367.
Crystal data for 7e were measured with an Xcalibur 3 CCD
(graphite monochromator, MoKa): C13H12N4OS,
FW = 272.33, triclinic, a = 7.9097(8), b = 8.1071(7),
˚
c = 11.3649(7) A, a = 100.870(6)°, b = 106.054(7)°, c =
3
˚
108.337(9)°, V = 633.72(9) A , T = 293(2) K, space group
P1, Z = 2 reflections were used in all calculations.
R = 0.0367. Crystallographic data for the structures in this
Letter have been deposited with the Cambridge Crystallo-
graphic Data Centre as supplementary publications
CCDC-649110 and CCDC-649111. Copies of the data
can be obtained, free of charge, on application to CCDC, 12
Union Road, Cambridge CB2 1EZ, UK [fax:+44(0)-1223-
336033 or e-mail: deposit@ccdc.cam.ac.uk].
11. Singh, S.; Husain, K.; Athar, F.; Azam, A. Eur. J. Pharm.
Sci. 2005, 25, 255.
5. (a) Verboom, W.; Reinhoudt, D. N. Recl. Trav. Chim.
Pays-Bas 1990, 109, 311; (b) Meth-Cohn, O. Adv.
Heterocycl. Chem. 1996, 65, 1; (c) Matyus, P.; Elias, O.;
Tapolcsanyi, P.; Polonka-Balint, A.; Halasz-Dajka, B.
Synthesis 2006, 2625; (d) De Boeck, B.; Jiang, S.;
12. (a) Sztanke, K.; Fidecka, S.; Kedzierska, E.; Kar-
czmarzyk, Z.; Pihlaja, K.; Matosiuk, D. Eur. J. Med.
Chem. 2005, 40, 127; (b) Sztanke, K.; Rzymowska, J.;
Niemczyk, M.; Dybala, I.; Koziol, A. E. Eur. J. Med.
Chem. 2005, 40, 127.