Chichibabin-type condensation of cyclic ketones with 3-R-1,2,4-triazin-5(4 H)-ones

Article abstract of DOI:10.1021/jo300697v

Reactions between substituted 1,2,4-triazines and ketones were investigated. General procedures for one-pot synthesis of hydrogenated derivatives of such polycyclic systems as benzo[c][1,2,4]triazino[1,6-a][2] azecine, [1,2,4]triazino[1,6-f]phenantridine, and dicyclopenta[b,d]pyrido[1,2-f] [1,2,4]triazine are described.

Full text of DOI:10.1021/jo300697v

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Article
Chichibabin-type condensation of cyclic
ketones with 3-R-1,2,4-triazin-5(4H)-ones
Ilya Nikolaevich Egorov, Tatyana A. Tseitler, Igor S. Kovalev, Pavel
A. Slepukhin, Vladimir L. Rusinov, and Oleg Nikolaevich Chupakhin
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo300697v • Publication Date (Web): 21 Jun 2012
Downloaded from http://pubs.acs.org on June 29, 2012
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Chichibabin-type condensation of cyclic ketones with 3-R-1,2,4-
triazin-5(4H)-ones
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Ilya N. Egorov,a,* Tatyana A. Tseitler,a Igor S. Kovalev,a Pavel A. Slepukhin,b Vladimir L.
Rusinova,b and Oleg N. Chupakhina,b
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a Ural Federal University, Department of Organic Chemistry,
Mira St. 19, Ekaterinburg, 620 002, Russia, e-mail: i.n.egorov@gmail.com
b Institute of Organic Synthesis Ural Branch of Russian Academy of Sciences,
S. Kovalevskoy St. 22, Ekaterinburg, 620 041, Russia
Abstract Graphic
Abstract
Reactions between substituted 1,2,4-triazines and ketones were investigated. General procedures
for one-pot synthesis of hydrogenated derivatives of such polycyclic systems as
benzo[c][1,2,4]triazino[1,6-a][2]azecine,
[1,2,4]triazino[1,6-f]phenantridine
and
dicyclopenta[b,d]pyrido[1,2-f][1,2,4]triazine are described.
Keywords: 1,2,4-triazines, azecines, cyclic ketones, cycloaddition, fused pyridines, cyclic
lactames
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Introduction
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Fused pyridines are widespread among natural organic compounds,1 they are of great importance
for medicine.2 Pyridines, fused with two aliphatic rings draw considerable attention of
researchers, as 1,2,3,4,7,8,9,10-octahydrophenantrene shows pesticide activity.3 Triazine-fused
pyridines are known to exhibit antidepressant activity.4 The most popular synthetic route to bis-
fused angular pyridines is Chichibabin’s synthesis from cyclic ketones, ammonia and aldehydes.
The reaction requires high pressure,3,5 or hydrothermal conditions in aqueous ammonium
chloride.6 Procedures that utilize activated forms of cyclic ketones, such as the product of
dimerization of cyclohexanone – 1,1’-bi(cyclohexilidene)-2-one,7 enamines of cyclic ketones2b,8
are noteworthy. Syntheses from pyrilium salts9 and cyclobutadienes10 are also known. The
source of nitrogen in the molecule of fused pyridine in most cases is ammonia,5,6,9 while
amides,7a urea,7b,8d 2-azadienes,8a enamines,8b carbodiimides,8c ethylcyanoacetate,10 dienamides11
are also used.
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Results and Discussion
In this paper we describe a detailed study of synthetic methods for synthesis of 1,2,4-triazine
derivatives of angular bis-fused pyridines in the reactions of cyclic ketones with 1,2,4-triazines.
Compounds containing fragments of 1,2,4-triazine (6-azauridine) arouse interest because some
of them show anticancer,12 antivirus13 and antibacterial activity14. It is known, that 3-R-1,2,4-
triazin-5(4H)-ones react with C-nucleophiles such as indoles,15 pyrroles,15 phenols,16 anilines16.
We investigated the reaction between 3-R-1,2,4-triazin-5(4H)-ones and ketones. It was shown
that the reaction of 3-R-1,2,4-triazin-5(4H)-ones (1a,b) with acetophenone (2) in the presence of
acids leads to the formation of the expected products of nucleophilic addition to the double C=N
bond of 3a,b (Scheme 1). When acetone was used, resinification of the reaction mixture was
observed, while butanone-2 and hexanone-2 did not react.
Scheme 1.
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Earlier we had demonstrated that cycloaddition of 3-R-1,2,4-triazin-5(4H)-ones and
cyclohexanone (4) or cyclopentanone (5) in the presence of trifluoroacetic acid leads to the
formation of fused pyridines of Chichibabin’s type.17 In the course of our research we
investigated the process of formation of fused pyridines. The search for proper conditions of the
reaction of 3-R-1,2,4-triazin-5(4H)-one (1a) with cyclohexanone (4) under the action of bases
showed only methanolic solution of NaOCH3 to be a suitable reaction medium. This reaction
gives product 6a with low yield (7%). So our studies were then switched to acidic conditions.
The following conditions were modified to find an optimal combination: temperature, acid
strength, addition of some oxidative and dehydrating agents (Tables 1,2).
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Table 1. Reaction of 3-Ph-1,2,4-triazin-5(4H)-one (1a) with cyclohexanone 4 under different
conditions.
Acid
Solvent
DMF
T, 0C
153
153
82
Time
0.5 h
12 h
1 h
Yield of 6a, %
p-TsOH
p-TsOH
p-TsOH
CF3COOH
CF3SO3H
AlCl3
29
DMF
49
CH3CN
DMF
34
100
100
20
6 h
30
22 *
DMF
6 h
DMF
1 day
3 h
36
p-TsOH, DDQ
CH3CN
82
28
p-TsOH, DDQ, P2O5 CH3CN
82
3 h
21
CF3COOH, CAN
CF3COOH
H3PO4
DMF
DMF
H3PO4
20
3 days
7 days
3 h
19
44 17
20
50
12
CH3COOH
CH3COOH
CF3SO3H
CF3SO3H
CF3SO3H
HCl
CH3COOH 20
CH3COOH 118
3 days
3 h
0
31
CH3CN
CH3OH
DMF
82
6 h
31 *
19 *
10 *
40 **
65
6 h
153
20
0.5 h
1 day
EtOH
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*yield of 6a triflate (6aa); **yield of the 6a chloride (6ab).
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Irrespective of the mechanism, Chichibabin synthesis of pyridines includes an oxidative stage, it
is known that such oxidative agents as copper (II) acetate, nitrobenzene or air oxygen have no
effect on the reaction.18 We demonstrated the same to be true for DDQ and CAN
((NH4)2Ce(NO3)6). It turned out that if protic acids in the reaction are replaced by Lewis acids,
such as AlCl3, the same product 6a is formed. Our results indicate that the most efficient route to
cycloaddition products 6,7 in zwitter-ionic form is performing the reaction of 3-R-1,2,4-triazin-
5(4H)-ones (1a-d) with ketones 4,5 in the presence of p-TsOH either in refluxing DMF or in
refluxing acetonitrile (Tables 1,2). The addition of P2O5 in the reaction mixture as a dehydrating
agent leads to increase in the yield of 6a,c-d.
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Table 2. Reaction of 3-R-1,2,4-triazin-5(4H)-ones (1a-d) with ketones 4,5 in the presence of
p-TsOH (1 equiv).
Starting
R
n
Conditions
Time, h Product Yield, %
material
1a
Ph
2
2
2
2
2
2
2
2
2
2
1
1
DMF
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3
3
1
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3
1
3
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3
1
1
44
66
21
11
0
6a
6a
6a
6b
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6b
6c
6c
6d
6d
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7b
Ph
CH3CN, P2O5
CH3CN, mol. sieves (3Å)
DMF
1a
Ph
1a
SMe
SMe
SMe
4-MePh
4-MePh
4-ClPh
4-ClPh
Ph
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CH3CN, P2O5
CH3CN, P2O5
DMF
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0
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42
15
18
30
21
1c
CH3CN, P2O5
DMF
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1d
CH3CN, P2O5
DMF
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1a
SMe
DMF
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Starting
material
1c
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n
Conditions
Time, h Product Yield, %
4-MePh
4-ClPh
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1
DMF
DMF
1
1
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22
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If strong acids were used in the reaction, salts of 6a-d were formed. There was no noticed
influence of acid strength on the reaction yield. The reaction of 3-R-1,2,4-triazin-5(4H)-ones
(1a-d) with ketones 4,5 in the presence of trifluoromethanesulfonic acid leads to the salts 6aa-da
(Table 3). Reducing the amount of cyclohexanone in the reaction mixture from 2 equiv. to 1
equiv. leads to significant decrease of 6aa yield. Increasing cyclohexanone or CF3SO3H
concentrations does not have visible effects. Compounds 6ab-db are soluble in acidic solutions
and neutralization of reaction mixture leads to increased yield of products 6. Triazines with
aliphatic substituents in position 3 (1e, R = CH2Ph) do not react with cyclic ketones either in the
presence of CF3SO3H, or in ethanolic HCl solution. 1,2,4-Triazines without an oxo group in
position 5 of the triazine ring (3-Ph-1,2,4-triazine, 3-SMe-1,2,4-triazine) also have no reactivity
under such conditions.
Table 3. Reaction of 3-R-1,2,4-triazin-5(4H)-ones (1a-e) with cyclohexanone (4) in the presence
-
of 1 equiv. of CF3SO3H (X- = CF3SO3 ).
Starting
material
1a
Time,
days
7
R
n
Product Yield, %
Ph
2
2
2
2
2
2
2
2
2
8
6aa
6aa
6aa
6aa
6aa
6aa
6ba
6ca
6da
Ph
17
18
26
21
3
1a
Ph
35
1a
Ph
35 *
35 **
35 ***
35
1a
Ph
1a
Ph
25
24
26
26
1a
SMe
4-MePh
4-ClPh
1b
35
1c
35
1d
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Starting
material
1e
Time,
R
n
2
Product Yield, %
days
CH2Ph
35
0
-
*3 equiv. triflic acid; **1 equiv. cyclohexanone; ***4 equiv. cyclohexanone.
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It is known cyclohexanone 4 gives condensation product 9 in the presence of acids, for example
in the presence of trifluoromethanesulfonic acid (Scheme 2).19 It was logical to expect the
formation of products 6a-d in the reaction of 3-R-1,2,4-triazin-5(4H)-one (1) with 1,1’-
bi(cyclohexilidene)-2-one (9) and we obtained them in refluxing DMF with addition of
CF3SO3H (15% yield), but at ambient temperature in the presence of CF3COOH the reaction
leads to lactams 10a-c,e (Table 4).
Scheme 2
Table 4. Reaction of 3-R-1,2,4-triazin-5(4H)-ones (1a-c,e) with 9a in the presence of
CF3COOH.
Starting
R
Product Yield, %
material
1a
Ph
58
71
68
53
10a
10b
10c
10e
SMe
1b
4-MePh
CH2Ph
1c
1e
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Our next step was to study the reaction of 1'-hydroxybi(cyclohexan)-2-one (8) with 3-Ph-1,2,4-
triazin-5(4H)-one (1a). When the reaction was carried out at ambient temperature in the presence
of CF3COOH/CF3SO3H the formation of 6a was not observed. Reaction in refluxing CH3CN in
the presence of P2O5 resulted in the formation of 6a (54% yield) (Scheme 3).
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Scheme 3.
When we tried to use 1,1’-bi(cyclopentilidene)-2-one (11) instead of 1,1’- bi(cyclohexilidene)-2-
one (9) in the reaction with 3-R-1,2,4-triazin-5(4H)-ones, only product 12c (R = 4-MePh) could
be isolated and identified. In all other cases we could not obtain pure products (Scheme 4). The
structure of compound 12c was assigned by analogy with compounds 10a-c, and confirmed by
1
13
mass-spectrometry data, Н and C NMR spectra. When we attempted to carry out the reaction
under other conditions, we observed no reaction in refluxing acetonitrile in the presence of
CF3COOH. The reaction was carried out in refluxing DMF in the presence of CF3SO3H and
resulted in the formation of 7aa (19% yield) after 1 hour.
Scheme 4.
To prove the assumption that compounds 10 are intermediate compounds in the reactions leading
to 6 we investigated their behavior in different conditions. It appears that 10a does not undergo
transformations in refluxing DMF or in DMF at ambient temperature in the presence of
CF3COOH or p-TsOH. Refluxing of 10a in DMF in the presence of CF3SO3H results in the
formation of triflate of triazinone 1a and the condensation product 6aa in low yields (Scheme 5).
The salt of 1a is a decomposition product of 10a and could be used as starting material for
reaction with cyclohexanone residue from the reaction mixture resulting in the formation of 6aa.
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Scheme 5.
Liquid chromatography-mass spectrometry analysis of the reaction mixtures of 3-Ph-1,2,4-
triazin-5(4H)-one (1a) with cyclohexanone in DMSO solutions in the presence of CF3SO3H after
24 hours shows intensive peaks of some molecular ions. There were observed peaks of 6ab (ESI-
MS, m/z = 332.1798 (calcld. 332.1757 for [C21H22N3O]+, [M+H]+)), 10a (ESI-MS, m/z =
352.2032 (calcld. 352.2020 for [C21H26N3O2]+, [M+H]+)), and peak of unidentified compound
(ESI-MS, m/z = 258.1610 (calcld. 258.1601 for [C15H20N3O]+, [M+H]+)). In the reaction of 3-
Ph-1,2,4-triazin-5(4H)-one (1a) with cyclopentanone intensive peaks of 7ab were observed
(ESI-MS, m/z = 304.1488 (calcld. 304.1444 for [C19H18N3O]+, [M+H]+)), 12a (ESI-MS, m/z =
324.1729 (calcld. 324.1706 for [C19H22N3O2]+, [M+H]+)), benzonitrile (ESI-MS, m/z = 104.0520
(calcld. 104.0494 for [C7H6N]+, [M+H]+)), peak of unidentified compound (ESI-MS, m/z =
244.1470 (calcld. 244.1444 for [C14H18N3O]+, [M+H]+)), its dimer (ESI-MS, m/z = 477.2034
(calcld. 477.2033 for [C28H25N6O2]+, [M+H]+)), and peak of unidentified compound (ESI-MS,
m/z = 545.2625 (calcld. 545.2619 for [C28H33N8O4]+, [M+H]+)).
Absence of the formation of lactam products 10,12 in quantities sufficient for identification in
the reactions of triazines 1 with cyclic ketones probably means that there are two different ways
of formation of tetracyclic compounds 6,7 and lactam compounds 10,12. We suggested two
different routes for the reactions of triazines 1 with free cyclic ketones and their dimerization
products.
The high activity of 3-R-1,2,4-triazin-5(4H)-ones in the reactions with C-nucleophiles suppose
initial nucleophilic addition of cyclic ketones to 1,2,4-triazine ring with formation of high
reactive compounds 1A or 1B. The attack of the cyclic ketone on 1A leads to the series of
transformations with the final product 6. We suppose that the product 1B after intermolecular
addition gives 1D. Compound 1D at ambient temperature gives 10-membered lactame 10, the
high temperature of refluxing DMF and the presence of triflic acid lead to the loss of a water
molecule and formation of 6 (Scheme 6).
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O
, H+
O
, H+
O
HO
N
+
H
N
+
N
O
N
4
O
N
H
R
H
N
O
N
H
R
N
1
1A
O
N
H
R
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, H+
+
H+
O
9
HO
O
O
OH
N
H
N
OH
N
N
N
N
O
N
H
R
N
H
R
O
N
H
1D
R
1C
1B
- 2 H2O
r.t.
- H2O, 2H
autoaroma-
tisation
O
N
N+
N
N
N
- 2H
N
-O
O
N
H
R
N
R
O
N
R
H
6
10
Scheme 6.
Conclusions
In the course of the present study new heterocyclic systems of benzo[c][1,2,4]triazino[1,6-
a][2]azecine and cyclopenta[c][1,2,4] triazino[1,6-a]azonine were obtained, optimal reaction
conditions were found for the condensation between 1,2,4-triazine-5(4H)-ones and cyclic
ketones. It was shown that benzo[c][1,2,4]triazino[1,6-a][2]azecines 10 are not intermediates in
the reaction of formation of [1,2,4]triazino[1,6-f]phenantridine derivatives 6.
It should be noted that C-C coupling reactions between azines and cyclic ketones had been
described earlier,20 but intramolecular condensation was observed and investigated for the first
time.
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Experimental Section
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(1a),21
3-SMe-1,2,4-triazin-5(4H)-one
(1b),22
1'-
5
6
7
8
3-Ph-1,2,4-triazin-5(4Н)-one
hydroxybi(cyclohexan)-2-one (8),23 1,1’-bi(cyclohexilidene)-2-one (9)24 and 1,1’-
bi(cyclopentilidene)-2-one (11)25 were synthesized by known methods, others starting materials
9
1
are commercially available. H, 13C NMR spectra were recorded using 400MHz spectrometer;
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tetramethylsilane (TMS) was used as an internal standard. TOF mass analyzer was used for the
HRMS.
3-(4-Tolyl)-1,2,4-triazin-5(4H)-one (1c). Methanol (10.1 ml, 0.170 mole) was added to the
solution of 4-methylbenzonitrile (10.0 g, 0.085 mole) in ether (50 ml), resulting solution was
chilled to T = 0÷-5 °C and then dry HCl was bubbled through the solution for 2-3h. The reaction
mixture was stirred for 16h at room temperature. The sediment of methyl ether of 4-
methylbenzimidate hydrochloride was filtered out, washed with ether and dried. The
hydrochloride was dissolved in water and 50 ml of aqueous NaOH (5N) was added to the
solution. Then the product was extracted with ether, the ether solution was dried over Na2SO4
and ether was evaporated.
On the next stage hydrazine hydrate (2.35 g, 0.047 mole) was added to solution of 4-
methylbenzimidate (7.0 g, 0.047 mole) in 10 ml of methanol. The reaction mixture was stirred
for 16 h, after that it was cooled to T = 5°C and glyoxylic acid monohydrate (4.32 g, 0.047
mmol) was added by portions to the solution. The temperature has to be lower 10°C. The
reaction mixture was stirred 1 h at 5°C, then it was stayed in refrigerator for 16 h at 5°C. The
formed yellow sediment was filtered, washed with cold methanol and dried. The yellow solid
was dissolved in DMF (50ml) and refluxed for 30 min. After cooling of the solution to room
temperature crystals formed. They were filtered and crystallized from ethanol. Yield 41 % (6.5
g), light brown crystals, mp 255 °C; 1H NMR (400 MHz, DMSO-d6) δ: 2.43 (s, 3H), 7.35 (d, J =
8.1 Hz, 2H), 7.63 (s, 1H), 7.98 (d, J = 8.2 Hz, 2H), 14.0 (br.s, 1H, NH); 13C NMR (100MHz,
DMSO-d6) δ: 21.0, 127.5, 127.6, 129.5, 143.0, 143.4, 158.1, 162.2; ESI-MS, m/z = 188.0819
(calcld. 188.0818 for [C10H10N3O]+, [M+H]+).
3-(4-Chlorophenyl)-1,2,4-triazin-5(4H)-one (1d). The procedure is the same as for 1c. Yield 31
% (5.4 g), yellow crystals, mp 282-283 °C; 1H NMR (400 MHz, DMSO-d6) δ: 7.68 (d, 2H), 7.86
(s, 1H), 8.07 (d, 2H), 14.12 (br.s, 1H); 13C NMR (100MHz, DMSO-d6) δ: 129.6, 129.8, 130.1,
138.1, 144.3, 157.8, 162.5; ESI-MS, m/z = 208.0283 (calcld. 208.0272 for [C9H7ClN3O]+,
[M+H]+).
3-Benzyl-1,2,4-triazin-5(4H)-one (1e). The procedure is the same as for 1c. Yield 39 % (6.2 g),
1
yellow crystals, mp 165-166 °C. H NMR (400 MHz, DMSO-d6) δ: 3.11 (s, 2H), 6.43-6.54 (m,
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5H), 6.92 (s, 1H), 13.68 (br.s, 1H); 13C NMR (100MHz, CD3OD) δ: 41.0, 128.7, 130.0, 130.1,
135.9, 144.7, 165.3, 165.4; ESI-MS, m/z = 188.0812 (calcld. 188.0818 for [C10H10N3O]+,
[M+H]+).
6-(2-Oxo-2-phenylethyl)-3-phenyl-1,6-dihydro-1,2,4-triazin-5(4H)-one (3a). Acetophenone
(270 µl, 2.310 mmol) and CF3SO3H (100 µl) were added to the suspension of 3-Ph-1,2,4-triazin-
5(4H)-one (200 mg, 1.155 mmol) in 10 ml CH3CN. The solution was refluxed for 3 h, then it
was cooled, neutralized with NEt3 and after 16 h formed sediment was filtered and crystallized
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from CH3CN. Yield 35% (119 mg); yellow crystals; mp 194-195 °C; H NMR (400 MHz,
CDCl3) δ: 3.30 (dd, J = 18.5, 10.1Hz, 1H), 3.92 (dd, J = 18.5, 2.4 Hz, 1H), 4.29 (dd, J = 10.1,
2.3 Hz, 1H), 6.39 (br.s, 1H), 7.41-7.45 (m, 3H), 7.48-7.52 (m, 2H), 7.60-7.64 (m, 1H), 7.67-7.70
(m, 2H), 8.00-8.02 (m, 2H), 8.37 (br.s, 1H); 13C NMR (100MHz, CDCl3) δ: 37.1, 52.3, 124.9,
128.2, 128.8, 129.0, 130.1, 131.2, 133.9, 136.0, 139.4, 167.7, 197.6; ESI-MS, m/z = 294.1291
(calcld. 294.1237 for [C17H16N3O2]+, [M+H]+).
3-(Methylthio)-6-(2-oxo-2-phenylethyl)-1,6-dihydro-1,2,4-triazin-5(4H)-one
(3b).
Acetophenone (326 µl, 2.794 mmol) and CF3SO3H (100 µl) were added to the suspension of 3-
SMe-1,2,4-triazin-5(4H)-one (200 mg, 1.397 mmol) in 10 ml CH3CN. The solution was refluxed
for 3 h (emission of CH3SH !), then it was cooled, neutralized with NEt3 and evaporated. The
residue was chromatographed by column using EtOAc as an eluent. Yield 13% (40 mg); yellow
crystals; mp 132-133 °C; Rf = 0.3 (EtOAc); 1H NMR (400 MHz, DMSO-d6) δ: 2.33 (s, 3H), 3.10
(dd, J = 17.8, 6.0 Hz, 1H), 3.57 (dd, J = 17.8, 5.8 Hz, 1H), 3.86-3.89 (m, 1H), 6.56 (d, J = 3.0
Hz, 1H), 7.48-7.52 (m, 2H), 7.58-7.62 (m, 1H), 7.98-7.99 (m, 2H), 10.64 (s, 1H); 13C NMR
(100MHz, DMSO-d6) δ: 12.8, 36.4, 52.2, 128.0, 128.7, 133.3, 136.3, 139.3, 167.3, 196.6; ESI-
MS, m/z = 264.0791 (calcld. 264.0801 for [C12H14N3O2S]+, [M+H]+).
Procedures for synthesis of 6a.
Method A. Cyclohexanone 4 (239 ꢀL, 2.310 mmol) and 1 equiv. of acid (CF3COOH or AlCl3,
see Table 1) were added to the solution of 3-Ph-1,2,4-triazin-5(4H)-one (200 mg, 1.155 mmol) in
the corresponding solvent (see Table 1). The solution was stirred or refluxed for the time
mentioned in the Table 1. Formed sediment was filtered and crystallized from DMF. Otherwise
the reaction mixture was poured to the water (50 ml) and extracted with CH2Cl2. The organic
layer was separated, washed with water, brine and dried over Na2SO4. The solution in CH2Cl2
was evaporated and the residue was crystallized from DMF.
Method B. Cyclohexanone 4 (239 ꢀL, 2.310 mmol) was added to the solution of 3-Ph-1,2,4-
triazin-5(4H)-one (200 mg, 1.155 mmol) in the phosphoric acid (5 ml). The solution was stirred
for 3 h at 50 °C then it was cooled and poured in water (50 ml). Formed sediment was filtered
and chromatographed by column using EtOAc as an eluent.
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Method C. Cyclohexanone 4 (239 ꢀL, 2.310 mmol) was added to the solution of 3-Ph-1,2,4-
triazin-5(4H)-one (200 mg, 1.155 mmol) in the acetic acid (5 ml). The reaction mixture was
refluxed for 1 h and then it was evaporated. The residue was refluxed in CHCl3 for 5 min and
filtered. The chloroform solution was evaporated and the residue was crystallized from DMF.
Method D. 1,1’-Bi(cyclohexilidene)-2-one (9) (206 ꢀL, 1.155 mmol) and CF3SO3H (1.155
mmol, 102 ꢀL) were added to the solution of 3-Ph-1,2,4-triazin-5(4H)-one (200 mg, 1.155
mmol) in DMF (3 ml). The reaction mixture was refluxed for 1 h, neutralized with NEt3 and then
it was evaporated. The residue was crystallized from DMF.
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Method E. 1'-Hydroxybi(cyclohexan)-2-one (8) (227 ꢀL, 1.155 mmol), p-TsOH (203 mg, 1.155
mmol) and P2O5 (492 mg, 1.155 mmol) were added to the mixture of 3-R-1,2,4-triazin-5(4H)-
one (200 mg, 1.155 mmol) and CH3CN (10 ml). Then it was divided on two parts. The solution
in CH3CN was decanted and evaporated to the half volume. NEt3 (100 µl) was added to the
solution and after 2 h the sediment was filtered. Solid part of the reaction mixture was dissolved
in water and neutralized with concentrated solution of NaHCO3, the resulting sediment was
filtered. Combined sediments were dried and crystallized from DMF.
Method F. Cyclohexanone 4 (239 ꢀL, 2.310 mmol) was added to the solution of 3-Ph-1,2,4-
triazin-5(4H)-one (200 mg, 1.155 mmol) in methanolic MeONa (1M) (4 ml). The reaction
mixture was stirred for 24 h, then it was poured in water (50 ml) neutralized with HCl (2M), the
product extracted with CH2Cl2. Solution in CH2Cl2 was washed with water, brine and dried over
Na2SO4. Then it was evaporated and the residue was crystallized from DMF.
Procedures for synthesis of 6a-d, 7a-d.
Method A. Ketone 4 or 5 (2 equiv.), p-TsOH (1 equiv) and P2O5 (3 equiv.) (or 1 g of molecular
sieves 3Å) were added to the mixture of 3-R-1,2,4-triazin-5(4H)-one (150 mg) and CH3CN (10
ml). The reaction mixture was refluxed for 3 h. Then it was divided on two parts. The solution in
CH3CN was decanted and evaporated to the half volume. NEt3 (100 µl) was added to the solution
and after 2 h the sediment was filtered. Solid part of the reaction mixture was dissolved in water
and neutralized with concentrated solution of NaHCO3, the resulting sediment was filtered.
Combined sediments were dried and crystallized from DMF.
Method B. Ketone 4 or 5 (2 equiv.) and p-TsOH (1 equiv) were added to the solution of 3-R-
1,2,4-triazin-5(4H)-one (200 mg) in DMF (3 ml). The solution was refluxed for 1 h. After 16 h
sediment was filtered. If there was no sediment the reaction mixture was poured in water, the
product extracted with CH2Cl2. The organic layer was separated, washed with water, brine and
dried over Na2SO4. The solution in CH2Cl2 was evaporated and the residue was crystallized from
DMF.
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2-Phenyl-5,6,7,8,9,10,11,12-octahydro[1,2,4]triazino[1,6-f]phenanthridin-13-ium-4-olate
(6a). Yield 44% (169 mg), cream crystals, mp > 300 °C; 1H NMR (400 MHz, CDCl3) δ: 1.77-
1.81 (m, 4Н), 1.90-1.99 (m, 4Н), 2.67 (t, J = 6.1 Hz, 2Н), 2.71 (t, J = 6.2 Hz, 2H), 3.35 (t, J =
6.2 Hz, 2H), 3.61 (t, J = 6.2 Hz, 2H), 7.38-7.46 (m, 3Н), 8.36-8.38 (m, 2Н). The spectral data of
the compound are identical to literature values.17
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2-(Methylthio)-5,6,7,8,9,10,11,12-octahydro-[1,2,4]triazino[1,6-f]phenanthridin-13-ium-4-
olate (6b). Yield 21% (73 mg), cream crystals, mp 249 °C; 1H NMR (400 MHz, CDCl3) δ: 1.76-
1.97 (m, 8H), 2.54 (s, 3H), 2.74 (dd, J = 13.3, 6.8Hz, 4H), 3.19 (t, J = 6.2Hz, 2H), 3.59 (t, J =
6.2Hz, 2H); 13C NMR (100MHz, DMSO-d6) δ: 13.5, 21.0, 21.2, 21.4, 21.9, 26.3, 27.1, 27.7,
28.8, 131.4, 136.1, 136.4, 142.4, 146.6, 163.8, 170.9; ESI-MS, m/z = 302.1355 (calcld. 302.1322
for [C16H20N3OS]+, [M+H]+).
2-(p-Tolyl)-5,6,7,8,9,10,11,12-octahydro-[1,2,4]triazino[1,6-f]phenanthridin-13-ium-4-olate
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(6c). Yield 24% (96 mg), grey crystals, mp 304-305 °C; H NMR (400 MHz, CDCl3) δ: 1.77-
1.79 (m, 4H), 1.90-1.99 (m, 4H), 2.38 (s, 3H), 2.72-2.78 (m, 4H), 3.39 (t, J = 6.3Hz, 2H), 3.66
13
(t, J = 6.1Hz, 2H), 7.19 (d, J = 8.0 Hz, 2H), 8.22 (d, J = 8.2 Hz, 2H); C NMR (100MHz,
DMSO-d6) δ: 21.0, 21.3, 21.5, 21.9, 26.3, 27.1, 27.6, 28.8, 128.0, 128.7, 132.1, 132.9, 135.7,
136.3, 141.1, 143.3, 146.6, 161.5, 166.5; ESI-MS, m/z = 346.1903 (calcld. 346.1914 for
[C22H24N3O]+, [M+H]+). Crystallographic data have been deposited with the Cambridge
Crystallographic Data Centre (deposition number CCDC 859049). These data can be obtained
via: www.ccdc.cam.ac.uk/data_request/cif
2-(4-Chlorophenyl)-5,6,7,8,9,10,11,12-octahydro-[1,2,4]triazino[1,6-f]phenanthridin-13-
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ium-4-olate (6d). Yield 15% (63 mg), yellow crystals, mp 257-258 °C; H NMR (400 MHz,
CDCl3) δ: 1.76-1.96 (m, 8H), 2.76-2.77 (m, 4H), 3.30 (t, J = 5.7Hz, 2H), 3.45 (t, J = 5.9Hz, 2H),
7.44 (d, J = 8.5Hz, 2H), 8.23 (d, J = 8.5Hz, 2H); 13C NMR (100MHz, CDCl3) δ: 21.0, 21.3,
21.5, 21.9, 26.4, 27.1, 27.7, 28.9, 128.0, 129.2, 132.0, 134.1, 135.9, 136.7, 136.9, 143.6, 147.5,
160.2, 166.5; ESI-MS, m/z = 366.1354 (calcld. 366.1368 for [C21H21ClN3O]+, [M+H]+).
2-Phenyl-5,6,7,8,9,10-hexahydrodicyclopenta[3,4:5,6]pyrido[2,1-f][1,2,4]triazin-11-ium-4-
olate (7a). Yield 30% (105 mg), light green crystals, mp > 300 °C; 1H NMR (400 MHz, CDCl3)
δ: 2.25-2.33 (m, 2H), 2.37-2.45 (m, 2H), 3.01 (t, J = 7.7Hz, 2H), 3.09-3.18 (m, 2H), 3.55 (t, J =
7.9Hz, 2H), 3.79 (t, J = 7.9Hz, 2H), 7.40-7.47 (m, 3H), 8.42-8.44 (m, 2H). The spectral data of
the compound are identical to literature values.17
2-(Methylthio)-5,6,7,8,9,10-hexahydrodicyclopenta[3,4:5,6]pyrido[2,1-f][1,2,4]triazin-11-
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ium-4-olate (7b). Yield 21% (66 mg), grey crystals, mp 258-259 °C; H NMR (400 MHz,
CDCl3) δ: 2.21-2.30 (m, 2H), 2.31-2.42 (m, 2H), 2.53 (s, 3Н), 2.98 (t, J = 7.8 Hz, 2H), 3.10 (t, J
= 7.6 Hz, 2H), 3.37 (t, J = 7.8 Hz, 2H), 3.70 (t, J = 7.6 Hz, 2H); 13C NMR (100MHz, CDCl3) δ:
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13.5, 22.1, 24.7, 30.5, 31.2, 31.5, 34.0, 129.4, 139.2, 143.2, 149.4, 152.5, 162.8, 172.3. The
spectral data of the compound are identical to literature values.17
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2-(p-Tolyl)-5,6,7,8,9,10-hexahydrodicyclopenta[3,4:5,6]pyrido[2,1-f][1,2,4]triazin-11-ium-4-
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olate (7c). Yield 24% (88 mg), brown crystals, mp 236-237 °C; H NMR (400 MHz, CDCl3) δ:
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2.20-2.27 (m, 2H), 2.34-2.42 (m, 5H), 2.88-2.96 (m, 2H), 3.08 (t, J = 7.6 Hz, 2H), 3.51 (t, J = 7.7
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Hz, 2H), 3.74 (t, J = 7.6 Hz, 2H), 7.23 (d, J = 8.0 Hz, 2H), 8.28 (d, J = 8.1 Hz, 2H); C NMR
(100MHz, CDCl3) δ: 21.4, 22.1, 24.5, 30.4, 31.3, 31.3, 34.1, 128.0, 128.7, 130.2, 133.0, 139.0,
141.1, 142.8, 150.4, 152.5, 162.8, 165.6; ESI-MS, m/z = 318.1620 (calcld. 318.1601 for
[C20H20N3O]+, [M+H]+).
2-(4-Chlorophenyl)-5,6,7,8,9,10-hexahydrodicyclopenta[3,4:5,6]pyrido[2,1-f][1,2,4]triazin-
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11-ium-4-olate (7d). Yield 22% (86 mg), yellow green crystals, mp > 300 °C; H NMR (400
MHz, CDCl3) δ: 2.21-2.28 (m, 2H), 2.34-2.41 (m, 2H), 2.94 (t, J = 7.7 Hz, 2H), 3.07 (t, J = 7.6
Hz, 2H), 3.47 (t, J = 7.7 Hz, 2H), 3.70 (t, J = 7.6 Hz, 2H), 7.34 (d, J = 8.6Hz, 2H), 8.26 (d, J =
8.6Hz, 2H). The spectral data of the compound are identical to literature values.17
Procedures for synthesis of 6aa-da.
Method A. Cyclohexanone (2 equiv.) and CF3SO3H (1 equiv.) were added to the solution of 3-
R-1,2,4-triazin-5(4H)-one (200 mg) in DMF (3 ml). The reaction mixture was stirred at room
temperature for the period of time specified in Table 3. The sediment was filtered and
crystallized from DMF.
Method B. Cyclohexanone (2 equiv.) and CF3SO3H (1 equiv.) were added to the solution of 3-
R-1,2,4-triazin-5(4H)-one (200 mg) in DMF (3 ml). The reaction mixture was refluxed for the
time in Table 1 and cooled, after 12 h formed sediment was filtered and crystallized from DMF.
4-Oxo-2-phenyl-3,4,5,6,7,8,9,10,11,12-decahydro-[1,2,4]triazino[1,6-f]phenanthridin-13-
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ium trifluoromethanesulfonate (6aa). Yield 25% (138 mg), green crystals, mp 252-253 °C; H
NMR (400 MHz, CDCl3) δ: 1.78-2.04 (m, 8H), 2.85-2.66 (m, 4H), 3.40 (t, J = 6.4Hz, 2H), 3.67
(t, J = 6.1Hz, 2H), 7.42-7.50 (m, 3H), 8.41-8.44 (m, 2H); 13C NMR (100MHz, CDCl3) δ: 21.1,
21.3, 21.6, 22.0, 26.3, 27.2, 27.6, 28.8, 128.0, 128.1, 130.8, 135.9, 136.0, 136.3, 143.4, 146.9,
161.7, 166.4; 19F NMR (100MHz, CDCl3) δ: -78.2; ESI-MS, m/z = 332.1762 (calcld. 332.1757
for [C21H22N3O]+, [M+H]+). Crystallographic data have been deposited with the Cambridge
Crystallographic Data Centre (deposition number CCDC 820437). These data can be obtained
via: www.ccdc.cam.ac.uk/data_request/cif
2-(Methylthio)-4-oxo-3,4,5,6,7,8,9,10,11,12-decahydro-[1,2,4]triazino[1,6-f]phenanthridin-
13-ium trifluoromethanesulfonate (6ba). Yield 24% (150 mg), light yellow crystals, mp 215-
216 °C; 1Н NMR (400MHz, CDCl3) δ: 1.74-1.80 (m, 2H), 1.84-1.95 (m, 6H), 2.52 (s, 3H), 2.72-
2.77 (m, 4H), 3.16-3.19 (m, 2H), 3.54-3.57 (m, 2H); 13C NMR (100MHz, CDCl3) δ: 13.6, 21.1,
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21.3, 21.4, 22.0, 26.3, 27.2, 27.7, 28.9, 131.4, 136.2, 136.6, 146.2, 146.8, 163.8, 170.9; 19F NMR
(100MHz, CDCl3) δ: -78.3; ESI-MS, m/z = 302.1318 (calcld. 302.1322 for [C16H20N3OS]+,
[M+H]+).
2-(4-Methylphenyl)-4-oxo-3,4,5,6,7,8,9,10,11,12-decahydro-[1,2,4]triazino[1,6-
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f]phenanthridin-13-ium trifluoromethanesulfonate (6ca). Yield 26% (140 mg), light yellow
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crystals, mp 277-278 °C; Н NMR (400MHz, CDCl3) δ: 1.72-1.83 (m, 4H), 1.87-2.01 (m, 4H),
2.38 (s, 3H), 2.62-2.65 (m, 2H), 2.68-2.71 (m, 2H), 3.31-3.34 (m, 2H), 3.57-3.60 (m, 2H), 7.19
(d, J = 7.6 Hz, 2H), 8.22 (d, J = 8.0 Hz, 2H); NMR 13C (100MHz, CDCl3) δ: 21.0, 21.3, 21.5,
22.0, 26.3, 27.2, 27.7, 28.9, 128.0, 128.8, 132.1, 132.9, 135.8, 136.4, 141.2, 143.5, 146.8, 161.4,
166.5; 19F NMR (100MHz, CDCl3) δ: -78.3; ESI-MS, m/z = 346.1914 (calcld. 346.1914 for
[C22H24N3O]+, [M+H]+).
2-(4-Chlorophenyl)-4-oxo-3,4,5,6,7,8,9,10,11,12-decahydro-[1,2,4]triazino[1,6-
f]phenanthridin-13-ium trifluoromethanesulfonate (6da). Yield 26% (131 mg), wine red
1
crystals, mp 252-253 °C; H NMR (400MHz, CDCl3) δ: 1.75-1.98 (m, 8H), 2.65-2.71 (m, 4H),
3.25 (t, J = 6.0 Hz, 2H), 3.54-3.57 (m, 2H), 7.30 (d, J = 8.4 Hz, 2H), 8.22 (d, J = 8.8 Hz, 2H);
13C NMR (100MHz, CDCl3) δ: 21.0, 21.3, 21.5, 21.9, 26.4, 27.1, 27.7, 28.9, 128.0, 129.2, 132.0,
134.1, 135.9, 136.7, 136.9, 143.6, 147.5, 160.2, 166.5; 19F NMR (100MHz, CDCl3) δ: -77.3;
ESI-MS, m/z = 366.1372 (calcld. 366.1368 for [C21H21ClN3O]+, [M+H]+).
Procedure
for
synthesis
of
4-Oxo-2-phenyl-3,4,5,6,7,8,9,10,11,12-decahydro-
chloride 6ab. Cyclohexanone (239ꢀL,
[1,2,4]triazino[1,6-f]phenanthridin-13-ium
2.310mmol) was added to the solution of 3-Ph-1,2,4-triazin-5(4H)-one (200 mg, 1.155mmol) in
conc. ethanol solution of HCl (5 ml). The reaction mixture was stirred at room temperature for 1
day. The sediment was filtered washed with ethanol, crystallized from DMF and dried. Yield
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40% (172 mg), dark yellow crystals, mp 270-271 °C; H NMR (400MHz, DMSO-d6) δ: 1.86-
2.01 (m, 8H), 2.92-2.98 (m, 4H), 3.42-3.45 (m, 2H), 3.49-3.51 (m, 2H), 7.59-7.63 (m, 2H), 7.69-
7.73 (m, 1H), 8.17 (d, J = 7.2 Hz, 2H); 13C NMR (100MHz, DMSO-d6) δ: 20.6, 20.8, 21.1, 21.5,
26.4, 27.8, 28.0, 28.5, 128.7, 129.1, 129.1, 129.6, 132.7, 133.8, 137.2, 140.7, 147.7, 152.7,
154.1, 157.4, 157.5; ESI-MS, m/z = 332.1769 (calcld. 332.1757 for [C21H22N3O]+, [M+H]+).
Procedure for synthesis of 10a-c,e. 1,1’-Bi(cyclohexilidene)-2-one (9) (1 equiv) and CF3COOH
(1 equiv) were added to the solution of 3-R-1,2,4-triazin-5(4H)-one (200 mg, 1.155 mmol) in
DMF (3 ml). The reaction mixture was stirred at room temperature for 5 days, poured in Petri
dish; residue from flask was washed off with ethanol (5 ml) to the same Petri dish. After 2 h
formed sediment was filtered and crystallized from CH3CN.
3-Phenyl-7,8,9,10,12,13,14,15,15a,15b-decahydro-1H-benzo[c][1,2,4]triazino[1,6-a]azecine-
1
1,6(2H)-dione (10a). Yield 57% (232 mg), colorless crystals, mp 210-211 °C; H NMR (400
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MHz, CDCl3) δ: 1.15-1.27 (m, 1H), 1.41-2.14 (m, 14H), 2.28-2.32 (m, 1H), 3.56 (dd, J = 14.3,
10.1, 1.5 Hz, 1H), 4.90 (d, J = 10.1 Hz, 1H), 5.12 (d, J = 11.4 Hz, 1H), 7.41-7.47 (m, 3H), 7.88-
7.90 (m, 2H), 11.30 (s, 1H); 13C NMR (100MHz, CDCl3) δ: 21.6, 24.7, 25.5, 25.8, 26.3, 27.6,
29.0, 32.4, 43.1, 57.0, 125.9, 129.0, 130.3, 130.4, 131.0, 135.1, 139.2, 167.8, 176.0; ESI-MS,
m/z = 352.1996 (calcld. 352.2020 for [C21H26N3O2]+, [M+H]+). Crystallographic data have been
deposited with the Cambridge Crystallographic Data Centre (deposition number CCDC 859113).
These data can be obtained via: www.ccdc.cam.ac.uk/data_request/cif
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3-(Methylthio)-7,8,9,10,12,13,14,15,15a,15b-decahydro-1H-benzo[c][1,2,4]triazino[1,6-
1
a]azecine-1,6(2H)-dione (10b). Yield 70% (315 mg), colorless crystals, mp 244-245 °C; H
NMR (400 MHz, DMSO-d6) δ: 1.11-1.21 (m, 1H), 1.33-1.41 (m, 1H), 1.46-2.12 (m, 13H), 2.28
(d, J = 15.0 Hz, 1H), 2.46 (s, 3H), 3.33 (dd, J = 14.0, 9.6 Hz, 1H), 4.90 (d, J = 10.4 Hz, 1H),
5.01 (d, J = 11.4 Hz, 1H), 11.30 (br.s, 1H); 13C NMR (100MHz, DMSO-d6) δ: 13.6, 21.6, 24.5,
25.5, 25.7, 26.0, 27.4, 28.9, 32.2, 42.8, 57.5, 129.9, 135.2, 141.3, 166.1, 175.0; ESI-MS, m/z =
322.1580 (calcld. 322.1584 for [C16H24N3O2S]+, [M+H]+). Crystallographic data have been
deposited with the Cambridge Crystallographic Data Centre (deposition number CCDC 820598).
These data can be obtained via: www.ccdc.cam.ac.uk/data_request/cif
3-p-Tolyl-7,8,9,10,12,13,14,15,15a,15b-decahydro-1H-benzo[c][1,2,4]triazino[1,6-a]azecine-
1,6(2H)-dione (10c). Yield 67% (262 mg), colorless crystals, mp 205-206 °C; [α]D = 0 (c = 0.6,
MeOH); 1H NMR (400 MHz, DMSO-d6) δ: 1.11-1.28 (m, 1H), 1.39-2.15 (m, 14H), 2.30 (d, J =
14.5 Hz, 1H), 2.40 (s, 3H), 3.55 (dd, J = 14.1, 10.0 Hz, 1H), 4.89 (d, J = 10.3 Hz, 1H), 5.11 (d, J
= 11.4 Hz, 1H), 7.22 (d, J = 8.1 Hz, 2H), 7.77 (d, J = 8.1 Hz, 2H), 11.24 (s, 1H); 13C NMR
(100MHz, DMSO-d6) δ: 20.6, 21.1, 23.9, 24.9, 25.1, 25.4, 26.9, 28.3, 31.5, 41.8, 56.3, 126.2,
127.5, 129.1, 129.2, 134.4, 140.4, 140.5, 165.9, 174.7; ESI-MS, m/z = 366.2143 (calcld.
366.2176 for [C22H28N3O2]+, [M+H]+).
3-Benzyl-7,8,9,10,12,13,14,15,15a,15b-decahydro-1H-benzo[c][1,2,4]triazino[1,6-a]azecine-
1,6(2H)-dione (10e). Yield 52% (203 mg), light brown crystals, mp 211-212 °C; 1H NMR (400
MHz, DMSO-d6) δ: 1.03-1.15 (m, 1H), 1.27-2.09 (m, 14H), 2.23-2.27 (m, 1H), 3.61 (s, 2H), 4.85
(d, J = 10.1 Hz, 1H), 4.96 (d, J = 11.4 Hz, 1H), 7.24-7.29 (m, 1H), 7.34-7.35 (m, 4H), 11.1 (s,
1H); 13C NMR (100MHz, DMSO-d6) δ: 21.0, 23.9, 24.8, 25.0, 25.2, 26.9, 28.2, 31.3, 37.5, 41.7,
55.8, 126.8, 128.3, 128.7, 129.1, 134.3, 135.8, 142.9, 165.6, 174.4; ESI-MS, m/z = 366.2142
(calcld. 366.2176 for [C22H28N3O2]+, [M+H]+).
3-(p-Tolyl)-7,8,9,11,12,13,13a,13b-octahydro-1H-cyclopenta[c][1,2,4]triazino[1,6-a]azonine-
1,6(2H)-dione (12c). 1,1’-bi(cyclopentilidene)-2-one (11) (162 ꢀL, 1.068 mmol) and CF3COOH
(100 ꢀL) were added to the solution of 3-(4-Tol)-1,2,4-triazin-5(4H)-one (1c) (200 mg, 1.068
mmol) in DMF (3 ml). The reaction mixture was stirred at room temperature for 5 days and
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evaporated. The residue was chromatographed by column using EtOAc as an eluent. Yield 9%
3
4
1
(32 mg), yellow crystals, mp 229-230 °C, Rf = 0.6 (EtOAc); H NMR (400 MHz, DMSO-d6) δ:
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1.64-1.75 (m, 4H), 1.77-1.85 (m, 1H), 2.08-2.15 (m, 1H), 2.23-2.44 (m, 7H), 2.58-2.64 (m, 1H),
2.71 (br.s, 2H), 3.71 (dd, J = 5.5, 2.1 Hz, 1H), 6.99 (d, J = 2.1 Hz, 1H), 7.14 (d, J = 8.1 Hz, 2H),
7.61 (d, J = 8.2 Hz, 2H), 10.56 (s, 1H); 13C NMR (100MHz, DMSO-d6) δ: 20.5, 22.1, 24.4, 26.1,
26.7, 31.7, 33.3, 47.4, 51.7, 56.5, 99.2, 124.9, 127.3, 128.5, 129.2, 138.3, 138.9, 157.3, 165.7,
203.7; ESI-MS, m/z = 338.1849 (calcld. 338.1863 for [C20H24N3O2]+, [M+H]+).
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Acknowledgements
This work was carried out with the assistance of laboratory of complex investigation and expert
valuation of organic materials (Ural Federal University). This work was supported by Ministry
of Science and Education of Russian Federation (State Contract # 14.740.11.1020)
1
Supporting Information Available: H, 13C NMR spectra of products and other data. This
material is available free of charge via the Internet at http://pubs.acs.org.
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