A convenient method of preparation of 3,3′-dichloro-5,5′-bi-1,2,4-triazine and its sythetic applications

Article abstract of DOI:10.3987/COM-08-11535

A convenient method for preparing of 3,3′-dichloro-5,5′-1,2,4-triazine (4) and its application to the synthesis of 3,3′-diamino-5,5′-bi-1,2,4-triazines 6a-i by the nucleophilic aromatic substitution are described. An attempt to synthesis of cyclophanes co

Full text of DOI:10.3987/COM-08-11535

HETEROCYCLES, Vol. 78, No. 3, 2009
623
HETEROCYCLES, Vol. 78, No. 3, 2009, pp. 623 - 633. © The Japan Institute of Heterocyclic Chemistry
Received, 28th August, 2008, Accepted, 15th October, 2008, Published online, 20th October, 2008
DOI: 10.3987/COM-08-11535
A CONVENIENT METHOD OF PREPARATION OF 3,3’-DICHLORO-
5,5’-BI-1,2,4-TRIAZINE AND ITS SYTHETIC APPLICATIONS1
Ewa Wolińska*
Department of Chemistry, Faculty of Sciences, University of Podlasie, 3 Maja 54,
08-110 Siedlce, Poland
e-mail: ewol@ap.siedlce.pl
Abstract – A convenient method for preparing of 3,3'-dichloro-5,5'-1,2,4-triazine
(4) and its application to the synthesis of 3,3'-diamino-5,5'-bi-1,2,4-triazines 6a-i
by the nucleophilic aromatic substitution are described. An attempt to synthesis of
cyclophanes containing 5,5'-bi-1,2,4-triazine subunit by ring-closing metathesis of
the alkenyl ethers 7a,b have been unsuccessful. A crossover experiment clearly
shows that nitrogen atoms of the 1,2,4-triazine ring coordinate to the ruthenium
catalyst and deactivate it.
Substituted 1,2,4-triazines are important class of compounds due to their biological activity and
importance in organic synthesis.2 The presence of three nitrogen atoms makes the 1,2,4-triazine ring one
of the most π-deficient nitrogen-containing heterocycles. Every position of 3, 5 and 6 in 1,2,4-triazine is
susceptible to nucleophilic attack, however their reactivity depends on the kind of substituents and nature
of the leaving group in the ring.3 Furthermore, nucleophilic addition at 1,2,4-triazine ring carbon carrying
hydrogen, SNH reaction, produces stable σ-adducts, which can be converted into aromatic compounds on
several ways.4
In contrast to well known 1,2,4-triazine chemistry only a limited number of reports have appeared
regarding synthesis and chemical properties of its dimeric analogue, namely 5,5'-bi-1,2,4-triazine and its
derivatives. These compounds have been easily prepared by homocoupling reactions of monocyclic
1,2,4-trazine derivatives unsubstituted at C-5 in the presence of cyanide.5 The direct functionalization of

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HETEROCYCLES, Vol. 78, No. 3, 2009
such obtained 5,5'-bi-1,2,4-triazines by nucleophilic displacement of substituents present in the 1,2,4-
triazine ring is still undeveloped area and have not been studied in details. According to literature there
are only two reports concerning nucleophilic displacement of methylsulfinate from readily available 3,3'-
bis(methylsulfanyl)-5,5'-bi-1,2,4-triazine (2) with aqueous dimethylamine6 and ethoxide.5a However, in
some cases a serious limitation for the above approach is rather difficult access to suitable substrates.7a
Also oxidation of methylsulfanyl group in 2 to methylsulfonyl one being more reactive toward
nucleophilic displacements, cannot be completed due to the instability of 3,3'-bis(methylsulfonyl)-5,5'-bi-
1,2,4-triazine (2a) (Scheme 1).7b
In searching for more effective nucleophugal group for nucleophilic displacements we undertook study on
the preparation of 3,3'-dichloro-5,5'-bi-1,2,4-triazine (4) and its application in organic synthesis. Since
some amino and diamino derivatives of 1,2,4-triazine are biologically active and have medicinal value8
reaction of 4 with various amines leading to new diamino 5,5'-bi-1,2,4-triazines have been investigated.9
We also describe in this paper an attempt to synthesis of 5,5'-bi-1,2,4-triazine - based macrocycles by ring
closing metathesis (RCM).
RESULTS AND DISCUSSION
Synthetic approach to 3,3'-dichloro-5,5'-bi-1,2,4-triazine (4) starts with 3-(methylsulfanyl)-1,2,4-triazine
(1) easily prepared using literature procedure10 (Scheme 1). Compound 1 was smoothly converted into
disodium salt of 3,3'-dihydroksy-5,5'-bi-1,2,4-triazine (3a), via a two-step one-pot procedure which
involved the homocoupling of 1 in the presence of 1.5 equivalents of potassium cyanide to give 3,3'-
bis(methylsulfanyl)-5,5'-bi-1,2,4-triazine11 (2), followed by nucleophilic displacement of methylsulfinate
from the latter with sodium hydroxide. This route is practical for a large scale operation and avoids the
use of time and solvent consuming isolation of bitriazine 2 from the reaction mixture. After 24 hours of
stirring at rt disodium salt 3a was isolated as precipitated solid in 86 % yield. When instead of sodium
hydroxide, potassium hydroxide is applied under the identical reaction conditions a better soluble
dipotassium salt 3b is obtained in 80 % yield, after partial evaporation of solvent. Subsequent
chlorination of salts 3a or 3b with an excess of phosphoryl chloride afforded 3,3'-dichloro-5,5'-bi-1,2,4-
triazine (4) in 65 and 70 % yield respectively (Scheme 1). The resulted dichloro compound 4 exhibits
1
13
good air and moisture stability. Evidence for its structure is obtained from H, C NMR and elemental
analysis (see EXPERIMENTAL).

HETEROCYCLES, Vol. 78, No. 3, 2009
625
N
N
N
N
N
N
N
N
iii
N
N
i
N
N
N
N
N
N
MetO
Met = Na, K
OMet
MeS
SMe
SMe
3a,b
1
2
iv
ii
N
N
N
N
N
N
N
N
N
v
N
N
N
N
N
N
N
N
1
1
R N
R
N
R
Cl
Cl
MeO S
2
SO Me
2
2
2
4
R
2a
6a-j
Scheme 1. Reagent and conditions: (i) KCN, H2O, rt; (ii) KMnO4, benzene/H2O, Bu4N+Br-, AcOH, rt;
(iii) NaOH or KOH, H2O/EtOH, rt; (iv) POCl3, 105 °C; (v) 5a-j, dioxane, rt.
With 3,3'-dichloro-5,5'-bi-1,2,4-triazine (4) in hand we next evaluated its reactivity toward nucleophilic
substitution of chlorine atoms with a variety of amines 5a-j. To optimize an amination conditions the
reaction of 4 with n-butylamine 5a was first investigated. Compound 4 was treated with n-butylamine 5a
in dioxane at ambient temperature. To avoid monosubstitution process five equivalents of amine were
necessary to use. The same conditions were applied for reactions of 4 with other amines (Scheme 1). The
reactions were completed within hours and appropriate diamino derivatives of 5,5'-bi-1,2,4-triazine 6a-f
were precipitated from the reaction mixture as yellow solids or oils in the case of 6g-i. The latter, after
evaporation of solvent were turned to solids by treatment with methanol. The yields of the prepared
diamino compounds were good or excellent (Table 1). Only diisopropylamine 5j did not undergo reaction
with 4 due to steric effect of two diisopropyl groups.
Continuing our research on diamino bitriazines we decided to explore their derivatives 6h and 6i as
potential intermediates for the synthesis of 5,5'-bi-1,2,4-triazine containing cyclophanes. The sulfur
analogues of such systems and their application in Diels-Alder/retro Diels-Alder reactions were recently
reported.12 The approach presented in Scheme 2 is focused on the construction of the alkenyl ethers 7a,b
which may be converted into the target molecules by ring-closing metathesis.

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HETEROCYCLES, Vol. 78, No. 3, 2009
Table 1. Yields, reaction times and melting points of compounds 6a-j.
N
N
N
N
2
N
N
N
N
R
dioxane
rt
+
NH
1
N
N
1
1
N
N
R N
R
N
R
2
R
Cl
Cl
2
R
6a-j
5a-j
4
Compound
R1
R2
Reaction Time (h)
21
Yield (%)
84
Mp (°C)
264-265
6a
H
H
H
H
Bu
6b
6c
6d
6e
6f
t-Bu
7
0.5
3
52
86
84
80
65
80
82
84
0
310
248-250
219
Bn
OMe
a
1
255
Et
H
Et
24
181
H2N
6g
6h
6i
0.25
0.25
0.5
24
221-222
278
HO
HO
H
Me
i-Pr
172-173
-
6j
i-Pr
a pyrrolidine ring
Reactions of 6h and 6i with allyl bromide in the presence of sodium hydride afforded 7a,b in good yield.
However, treatment of the olefin substrates 7a,b with rutenium benzylidene complex (Grubbs’ catalyst I)
(10 mol%) in 0.01 M solution of dichloromethane at reflux for 5 hours did not result in the formation of

HETEROCYCLES, Vol. 78, No. 3, 2009
627
desired products; only starting 7a,b were recovered unchanged. It is well documented that amino group
being present in the olefin containing substrate can coordinate to ruthenium catalyst and deactivated it. To
overcome these difficulties conversion of amine to the corresponding amide or the addition of Lewis
acids into the reaction mixture is recommended.13 The latter, binding nitrogen prior to its reaction with
ruthenium catalyst may improve olefin metathesis. Therefore, RCM of compounds 7a,b were repeated in
the presence of equivalent amounts of Ti(Oi-Pr)4 and B(Et2O)4, however, no expected products 8a,b
could be isolated (Scheme 2).
iii
N
N
N
N
N
N
N
N
ii
N
N
N
N
i
6h,i
RN
NR
RN
NR
O
O
O
O
8a-c
7a,b
iv
ii
7c
R = Ac
Scheme 2. Reagents and conditions: (i) allyl bromide, NaH, DMF, 50 °C; (ii) Cl2(PCy3)2Ru=CHPh
(Grubbs’ cat. I), 10 mol%, 0.01 M solution in CH2Cl2, reflux; (iii) Ti(Oi-Pr)4 or B(Et2O)3,
Cl2(PCy3)2Ru=CHPh (Grubbs’ cat. I), 10 mol%, 0.01 M solution in CH2Cl2, reflux; (iv) Ac2O, rt.
Also acetylation of the exocyclic amine group in 7a into amide 7c and RCM reaction of the latter did not
result in the formation of 8c (Scheme 2). On the other hand, 1,2,4-triazines are known to form stable
complexes with transition metals including ruthenium.14 It seems likely that ring nitrogen atoms of
compounds 7a,b are able to coordinate to ruthenium catalyst and prevent its RCM reaction. The colour of
the RCM reaction mixture is deeply green what indicates that Grubbs' catalyst can be destroyed under
these reaction conditions. In order to explain which nitrogen atoms in 7a and 7b are responsible for
coordination to the ruthenium catalyst, pyridotriazine derivative 10 without the exocyclic amino group
was prepared (Scheme 3) and subjected to RCM reaction under conditions described above. When the
compound 10 containing 1,2,4-triazine ring was treated with first generation Grubbs’ catalyst, no reaction
occurred (Scheme 3). This result clearly shows that nitrogen atoms of the 1,2,4-triazine part of 10 must

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HETEROCYCLES, Vol. 78, No. 3, 2009
deactivate ruthenium benzylidene complex, since its 2,2'-bipyridine analogue 12 easily undergoes RCM
to give cyclophane 13 in high yield15 (Scheme 4).
N
N
N
N
N
N
i
ii
N
N
N
N
N
N
O
O
O
O
MeO S
2
SO Me
2
9
10
11
Scheme 3. Reagents and conditions: (i) 4-penten-1-ol, NaH, DMF, 0 °C to rt; (ii) Cl2(PCy3)2Ru=CHPh
(Grubbs’ cat. I), 10 mol%, 0.01 M solution in CH2Cl2, reflux.
This conclusion is supported by a crossover experiment. When compound 12 was treated with Grubbs’
catalyst in the presence of equivalent amount of 7a, 7b or 4 cyclophane 13 was not formed (Scheme 4).
The deep green colour of the reactions mixtures again indicates that the catalyst is destroyed by the
compounds 7a, 7b or 4.
i
N
N
N
N
(ref. 15)
O
O
O
O
13
12
ii
Scheme 4. Reagents and conditions: (i) Cl2(PCy3)2Ru=CHPh (Grubbs’ cat. I), 10 mol%, 0.01 M solution
in CH2Cl2, reflux; (ii) 7a, 7b or 4, Cl2(PCy3)2Ru=CHPh (Grubbs’ cat. I), 10 mol%, 0.01 M solution in
CH2Cl2, reflux.
Thus, in marked contrast to the 2,2'-bipyridine containing alkenyl ethers, their bi-1,2,4-triazine 7a-c or 5-
(pyridyl-2-yl)-1,2,4-triazine 10 analogues do not undergo ring – closing metathesis by treatment with
ruthenium benzylidene complex (Grubbs catalyst I). We suppose that the 1,2,4-triazine ring nitrogen
atoms are responsible for deactivation of the catalyst. However, an influence of the nitrogen atoms of the
exocyclic amine groups in compounds 7a,b on the catalyst is also possible.

HETEROCYCLES, Vol. 78, No. 3, 2009
629
EXPERIMENTAL
All reagents were purchased from Sigma-Aldrich Company. Solvents were purchased from commercial
sources or purified and dried according to standard procedures. Compounds 3-(methylsulfanyl)-1,2,4-
triazine (1),5a 1-methylsulfonyl-3-(3-methylsulfonyl-1,2,4-triazin-5-yl)-6,7,8,9-tetrahydro-5H-cyclohepta-
[c]pyridine (9)16 and 1,1'-bis-pent-4-enyloxy-6,7,6',7'-tetrahydro-5H,5'H-3,3'-bicyclopenta[c]pyridine
(12)14 were synthesized according to procedures described in literature. Melting points are uncorrected.
1
IR spectra were measured with a Magna IR-760 spectrophotometer in KBr pellets. The H NMR spectra
were recorded in varied deuterated solvents on a Varian-Gemini 200 MHz spectrometer. Mass spectra
were measured with an AMD 604 (AMD Intectra GmbH, Germany) and GC/MS QP 5050 Shimadzu (30
m × 0.25 mm ID-BPX 5 0.25 mm). Column chromatography was performed on silica gel (230-400 mesh,
60 Merck). Analytical thin layer chromatography (TLC) was performed on 0.25 mm Merck silica gel 60
F254 plates. The plates were inspected under UV light (254 nm). Elemental analyses were recorded on
Perkin-Elmer 2400-CHN analyzer and the results for indicated elements were within 0.3 % of the
calculated values.
Synthesis of 3,3'-dihydroxy-5,5'-bi-1,2,4-triazine disodium and dipotassium salts 3a and 3b.
3-Methylsulfanyl-1,2,4-triazine (1) (1 g, 7.9 mmol) was dissolved in water (50 mL). The excess of KCN
(0.8 g, 12.3 mmol) was added as a solid. After 3 h of stirring at rt EtOH (80 mL) and a solution of NaOH
or KOH (81.2 mmol) in water (30 mL) were added. The mixture was stirring at rt for 24 h. The
precipitated product 3a or 3b was filtered, washed with EtOH/water (5:1) solvent system and dried at
105 °C in vacuum. The compounds were used to the next step without further purification.
Synthesis of 3,3'-dichloro-5,5'-bi-1,2,4-triazine (4).
Dissodium salt 3a (0.6 g, 2.54 mmol) was placed in round bottom flask and phosphorus (V) oxychloride
(10 mL) was added. The mixture was heated at 105 °C for 0.5 h. An excess of phosphorus oxychloride
was evaporated under reduced pressure to dryness. The product was purified by column chromatography
o
1
using CH2Cl2/acetone (50 : 1) and recrystalized from EtOH. Yield 65 % (0.44 g). Mp 185 C. H NMR
(DMSO-d6) δ: 10.23 (s, 1H). 13C NMR (DMSO-d6) δ: 146.30, 152.95, 163.51. MS (EI m/z) 229 [M+].
Anal. Calcd for C6H2N6Cl2: C, 31.46; H, 0.88; N, 36.69. Found: C, 31.50; H, 1.00; N, 36.70.
General procedure for the nucleophilic substitution of 4 with amines 5a-j.
To a mixture of 4 (0.229 g, 1 mmol) in dry dioxane (2 mL) a solution of 5a-j (5 mmol) in dry dioxane (1
mL) was added. The mixture was stirred at rt until starting compound 4 was consumed (TLC) (Table 1).
The precipitates of 6a-f were filtered off and washed with dioxane. For 6g-i the solvent was evaporated
under reduced pressure. The oily residues were stirred with MeOH and the formed precipitate were

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HETEROCYCLES, Vol. 78, No. 3, 2009
filtered off. The products were recrystalized from MeOH.
3,3'-bis(n-butylamino)-5,5'-bi-1,2,4-triazine (6a). IR (KBr) cm -1: 3222 (NH). 1H NMR (TFA - C6D6) δ:
13
0.95 (t, J = 7, 6H), 1.40–1.48 (m, 4H), 1.51–1.68 (m, 4H), 3.50-3.65 (m, 4H), 8.25 (s, 2H). C NMR
(TFA-C6D6) δ: 12.60, 19.92, 30.75, 43.00, 134.80, 157.86. MS (EI m/z) 302 [M+]. Anal. Cald for
C14H22N8: C, 55.61; H, 7.33; N, 37.06. Found: C, 55.52; H, 7.29; N, 36.86.
3,3'-bis(t-butylamino)-5,5'-bi-1,2,4-triazine (6b). IR (KBr) cm -1: 3247 (NH). 1H NMR (CDCl3) δ: 1.55
(s, 18H), 5.71 (br.s, 2H), 9.41 (s, 2H). MS (EI m/z) 302 [M+]. Anal. Cald for C14H22N8: C, 55.61; H, 7.33;
N, 37.06. Found: C, 55.58; H, 7.20; N, 37.06.
-1
1
3,3'-bis(benzylamino)-5,5'-bi-1,2,4-triazine (6c). IR (KBr) cm : 3224 (NH). H NMR (TFA-C6H6) δ:
4.59 (s, 4H), 7.19–7.30 (m, 10H), 8.50 (s, 2H). Anal. Cald for C20H18N8 × ½H2O: C, 63.31; H, 5.04; N,
29.53. Found: C, 63.57; H, 4.99; N, 29.03.
1
3,3'-bis(2-methoxybenzylamino)-5,5'-bi-1,2,4-triazine (6d). IR (KBr) cm -1: 3233 (NH). H NMR
(CDCl3) δ: 3.91 (s, 6H), 4.77 (s, 4H), 6.35 (br.s, 4H), 6.81–6.96 (m, 4H), 7.26–7.40 (m, 4H), 9.45 (s, 2H).
Anal. Cald for C22H22N8O2: C, 61.38; H, 5.15; N, 26.03. Found: C, 61.26; H, 5.13; N, 25.98.
3,3'-bis(1-pyrrolidino)-5,5'-bi-1,2,4-triazine (6e). 1H NMR (CDCl3) δ: 2.05–2.11 (m, 8H), 3.69–3.79 (m,
4H), 9.42 (s, 2H). Anal. Cald for C14H18N8: C, 56.36; H, 6.08; N, 37.56. Found: C, 56.37; H, 6.07; N,
37.60.
1
3,3'-bis(N, N-diethylamino)-5,5'-bi-1,2,4-triazine (6f). H NMR (CDCl3) δ: 1.28 (t, J = 7.2 12H), 3.77
(m, 8H), 9.39 (s, 2H). Anal. Cald for C14H22N8: C, 55.61; H, 7.33; N, 37.06. Found: C, 55.60; H, 7.32; N,
37.09.
3,3'-bis[(2-aminoethyl)amino]-5,5'-bi-1,2,4-triazine (6g). 1H NMR (TFA–CD2Cl2) δ: 3.80-3.84 (m, 4H),
4.46-4.49 (m, 4H), 9.63 (s, 2H). HR–EI: calcd for C10H16N10 276.15594. Found 276.15518.
3,3'-bis[(2-hydroxyethyl)amino]-5,5'-bi-1,2,4-triazine (6h). IR (KBr) cm -1: 3251 (NH), 3383 (OH). 1H
NMR (TFA–C6D6) δ: 3.62–3.85 (m, 8H), 8.98 (s, 2H). HR–EI: calcd for C10H14N8O2 278.12397. Found
278.12511.
3,3'-bis[N-(2-hydroxyethyl)-N-methylamino]-5,5'-bi-1,2,4-triazine (6i). IR (KBr) cm -1: 3293 (OH). 1H
NMR (DMSO-d6) δ: 3.27 (s, 6H), 3.60–3.85 (m, 8H), 4.81 (t, J = 5.2, 2H), 9.38 (s, 2H). 13C NMR
(DMSO-d6) δ: 37.01, 52.19, 59.08, 136.59, 151.95 161.43. Anal. Cald for C12H18N8O2: C, 47.05; H, 5.92;
N, 36.60. Found: C, 47.11; H, 5.90, N, 36.47.
General procedure for synthesis of compounds 7a,b. To a mixture of NaH (10 mmol, 60 % in oil) and
the substrate 6h,i (1 mmol) in dry DMF (7 mL) a solution of allyl bromide (10 mmol) in dry DMF (2 mL)
was added. The mixture was stirred at 50 °C for 4 h. The solvent was evaporated under reduced pressure.
The residue was poured into ice/water and acidified with HCl (10 % solution). The products 7a,b were

HETEROCYCLES, Vol. 78, No. 3, 2009
631
isolated from the water layer by extraction with EtOAc and purified by column chromatography using
CH2Cl2/MeOH as eluent.
-1
3,3'-bis[(2-allyloxyethyl)amino]-5,5'-bi-1,2,4-triazine (7a). Yield 45 %. Mp 150 °C. IR (KBr) cm :
1
3359 (NH) . H NMR (DMSO-d6) δ: 3.64-3.69 (m, 8H), 4.39-4.42 (m, 4H), 4.84 (t, J = 5.2, 2H), 5.12–
5.24 (m, 4H), 5.81–6.01 (m, 2H), 9.39 (s, 2H). MS (EI m/z) 358 [M+]. HR–EI: calcd for C16H22N8O2
358.18657. Found 358.18781.
3,3'-bis[N-(2-allyloxyethyl)-N-methylamino]-5,5'-bi-1,2,4-triazine (7b). Yield 77 %. Mp 58-59 °C. 1H
NMR (CDCl3) δ: 3.41 (s, 6H), 3.74 (t, J = 5.3, 4H), 3.98–4.01 (m, 8H), 5.12-5.29 (m, 4H), 5.78-5.97 (m,
2H), 9.41 (s, 2H). MS (EI m/z) 386 [M+]. HR–EI: calcd for C18H26N8O2 386.21787. Found 386.21878.
Acetylation of compound 7a.
To a mixture of 7a (0.36 g, 1 mmol) and acetic anhydride (8 mL), sodium acetate (0.33 g, 4 mmol) was
added and the mixture was stirred at rt for 2 hours. The remained acetic anhydride was hydrolyzed by
heating with water at 45 °C. The mixture was neutralized with NaHCO3 and extracted with EtOAc.
Product was purified by column chromatography CH2Cl2/MeOH (50:1) as eluent.
3,3'-bis[N-acetyl-N-(2-allyloxyethyl)amino]-5,5'-bi-1,2,4-triazine (7c): oil, yield 89 %. IR (KBr) cm -1:
1741 (C=O). 1H NMR (CDCl3) δ: 2.04 (s, 6H), 3.95-4.03 (m, 4H), 4.36–4.41 (m, 8H), 5.19-5.29 (m, 4H),
5.89-6.01 (m. 2H), 9.46 (s, 2H). MS (EI m/z) 442 [M+]. HR–EI: calcd for C20H26N8O4 442.20770. Found
442.20863.
Synthesis of 1-(pent-4-enyloxy)-3-[3-(pent-4-enyloxy)-1,2,4-triazin-5-yl]-6,7,8,9-tetrahydro-5H-
cyclohepta[c]pyridine (10).
To a mixture of sodium hydride (0.038 g, 0.95 mmol, 60 % in oil), and 4-penten-1-ol (0.086 g, 1 mmol),
in dry DMF (4 mL) a solution of the substrate 9 (0.38 g, 1 mmol) in dry DMF (10 mL) was added. After
stirring at 0 °C for 2.5 h the mixture was transferred to a flask containing a solution of sodium hydride
(0.26 g, 6.55 mmol) and 4-penten-1-ol (0.48g, 5.62 mmol) in dry DMF (15 mL). The reaction mixture
was stirred for additional 2.5 h at ambient temperature and than poured into ice/water and acidified with
acetic acid. The precipitate was filtered off and washed with water. The product was purified by column
chromatography using CH2Cl2/acetone mixture. Yield 14 % 1H NMR (CDCl3) δ: 1.60-1.75 (m, 2H), 1.86-
2.06 (m, 8H), 2.21-2.32 (m, 4H), 2.82-2.94 (m, 4H), 4.44 (t, J = 6.4, 2H), 4.63 (t, J = 6.4, 2H), 4.99-5.13
(m, 4H), 5.79-6.00 (m, 2H). MS (EI m/z) 394 [M+]. HR–EI: calcd for C23H30N4O2 394.23688. Found
394.23518.
General procedure of ring closing metathesis reaction. To a solution (0.01 M) of substrate in dry and

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HETEROCYCLES, Vol. 78, No. 3, 2009
degassed CH2Cl2 Grubbs’ catalyst I (10 % mol) was added and the mixture was refluxed for 5 h.
ACKNOWLEDGEMENTS
We thank Professor Andrzej Rykowski from the University of Podlasie for fruitful discussions.
REFERENCES AND NOTES
1.
Part 45 in "1,2,4-triazines in organic synthesis". For Part 44, see D. Branowska, J. Ławecka, W.
Wysocki, and A. Rykowski, Arkivoc, 2008 (in print).
2.
a) C. W. Lindley and M. E. Layton, 'Science of Synthesis: 1,2,4-Triazines,' Vol. 17, ed. by S. M.
Weinreb, Thieme Verlag, Stuttgard, New York, 2004, pp. 357-447. b) H. Neunhoeffer,
'Comprehensive Heterocyclic Chemistry: 1,2,4-Triazines and their benzo derivatives,' Vol. 6, ed by
A. R. Katritzky, Pergamon Press, Oxford, 1996, pp. 507-573. c) H. Neunhoeffer, 'Houben –Weyl:
1,2,4-Triazines,' 4th edition, Vol. E9c, ed. by E. Schaumann, Thieme Verlag, Stuttgard, New York,
1988, pp. 582-666.
3.
4.
a) V. N. Charushin, S. G. Alexeev, O. N. Chupahkin, and H. C. van der Plas, in 'Advances in
Heterocyclic Chemistry: Behavior of Monocyclic 1,2,4-triazines in reactions with C-, N-, O-, and S-
nucleophiles,' Vol. 46, ed. by A. R. Katritzky, Academic Press, Inc., London, 1986, pp. 73-142.
a) A. Rykowski and M. Mąkosza, Liebigs Ann. Chem., 1988, 36, 627. b) D. N. Kozhevnikov, V. L.
Rusinov, O. N. Chupakhin, M. Mąkosza, A. Rykowski, and E. Wolińska, Eur. J. Org. Chem., 2002,
1412. c) A. Rykowski and E. Wolińska, Tetrahedron Lett., 1996, 37, 5795. d) A. Rykowski, E.
Wolińska, and H. C. Van der Plas, J. Heterocycl. Chem., 2000, 37, 879. e) A. Rykowski, E.
Wolińska, and D. Branowska, and H. C. Van der Plas, Arkivoc, 2004, MM-942G, 74. f) A.
Rykowski, E. Guzik, M. Mąkosza, and W. Holzer, J. Heterocyclic Chem., 1993, 30, 413. g) A.
Rykowski, D. Branowska, M. Mąkosza, and P. Van Ly, J. Heterocycl. Chem., 1996, 33, 1567.
a) D. K. Krass and W. W. Paudler, J. Heterocycl. Chem., 1974, 11, 43. b) D. K. Krass and W. W.
Paudler, J. Heterocycl. Chem., 1973, 10, 343. c) A. Rykowski and H. C. Van der Plas, Recl. Trav.
Chim. Pays-Bas, 1975, 94, 204. d) D. Shamroc, US patent 4105434, 1978. e) D. Branowska and J.
Kielak, Polish J. Chem., 2003, 77, 1149 and references cited therein.
5.
6.
7.
8.
D. Branowska and B. Iwańska, Molbank, 2004, M372.
a) J. Daunis and C. Pigiere, Bull., Soc., Chim., Fr., 1973, 2493, b) A. Rykowski, to be published.
For monoamino 1,2,4-triazine drugs: 3-amino-1,2,4-benzotriazine 1,4-dioxide (Tirapazamine), 3-
amino-6-[(5-nitro-2-furyl)vinyl]-1,2,4-triazine (Panfuran), and diamino 1,2,4-triazine drug 3,5-
diamino-6-(2,3-dichlorophenyl)-1,2,4-triazine (Lomatrigine) see ref. 1b.
9.
Biological evaluation of the compounds will be published elsewhere.
10. W. W. Paudler and T.-K. Chen, J. Heterocycl. Chem., 1970, 7, 767.

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11. D. Branowska, Molecules, 2005, 10, 265.
12. J. Ławecka, E. Olender, P. Piszcz, and A. Rykowski, Tetrahedron Lett., 2008, 49, 723.
13. Q. Yang, W.-J. Xiao, and Z. Yu, Org. Lett., 2005, 7, 871, and references cited therein.
14. X.-L. Hong, H. Chao, L.-J. Lin, K.-Ch. Zeng, H. Li, X.-L. Wang, F.-C. Yun, and L.-N. Ji, Helv.
Chim. Acta, 2004, 87, 1180.
15. D. Branowska and A. Rykowski, Tetrahedron, 2005, 61, 10713.
16. D. Branowska, Tetrahedron, 2004, 60, 6021.