Reaction of 3-phenyl-1,2,4-triazin-5(4H)-one under acylating conditions with natural alcohols containing an asymmetric carbon atom

Article abstract of DOI:10.1007/s10593-012-1036-9

This study describes the reactions of natural chiral alcohols such as borneol, isoborneol, cholesterol, and dihydrocholesterol with 3-phenyl-1,2,4-triazin-5(4H)-one in the presence of carboxylic acid anhydrides.

Full text of DOI:10.1007/s10593-012-1036-9

Chemistry of Heterocyclic Compounds, Vol. 48, No. 4, July, 2012 (Russian Original Vol. 48, No. 4, April, 2012)
REACTION OF 3-PHENYL-1,2,4-TRIAZIN-5(4H)-ONE UNDER
ACYLATING CONDITIONS WITH NATURAL ALCOHOLS
CONTAINING AN ASYMMETRIC CARBON ATOM
I. N. Egorov1*, G. V. Zyryanov1,2, P. A. Slepukhin2, T. A. Tseitler1,
V. L. Rusinov1, and O. N. Chupakhin1,2
This study describes the reactions of natural chiral alcohols such as borneol, isoborneol, cholesterol,
and dihydrocholesterol with 3-phenyl-1,2,4-triazin-5(4H)-one in the presence of carboxylic acid
anhydrides.
Keywords: borneol, cholesterol, dihydrocholesterol, 1,2,4-triazines, nucleophilic addition reactions.
Chiral azines have recently attracted a close attention. Studies have been carried out on the synthesis of
bornyl derivatives of bipyridines [1, 2], terpyridines [3-5], and also bispyridylamine [6] as catalysts for
asymmetric synthesis. In addition, examples are known of bornyl and isobornyl derivatives of azines exhibiting
antiviral activity [7]. It was also of interest to modify azines introducing cholesterol residues since
functionalization of the A ring of the polycyclic cholesterol system can lead to compounds which modify the
properties of cell membranes [8].
In this work, we have studied the possible asymmetric synthesis of the products of addition of
O-nucleophiles to the C=N bond of the aromatic azine [9] using readily available natural alcohols. Employing
nucleophiles which contain an optically active center could lead to formation of diastereomerically enriched
products. There is example in the literature of the stereoselective addition of nucleophiles to the C=N double
bond of azirines involving an isobornyl residue [10]. It has been shown previously that in the reaction of
3-phenyl-1,2,4-triazin-5(4H)-one (1) with (-)-menthol, addition products were obtained with diastereoselectivity
de 20-70% depending on the type of anhydride used [11].
We have used the readily available racemic isoborneol (2) and borneol (3b) and also the optically pure
borneol (3a), dihydrocholesterol (4), and cholesterol (5) as nucleophiles in an addition reaction to the C=N
double bond of the 3-phenyl-1,2,4-triazin-5(4H)-one 1. The non-activated triazinone 1 is unreactive towards
nucleophiles. There are two routes for converting it to an active azinium salt which involve either carrying out
reactions in the presence of acids (route A) or in the presence of acid anhydrides (route B) [12, 13] where it
_______
*To whom correspondence should be addressed, e-mail: i.n.egorov@gmail.com.
1
Ural Federal University named after the First President of Russia B. N. Yeltsin, 19 Mira St., Yekaterinburg
620002, Russia.
2I. Ya. Postovsky Institute of Organic Synthesis, Ural Branch of the Russian Academy of Sciences, 22 S.
Kovalevska St./20 Academic St., Yekaterinburg 620219, Russia; e-mail: chupakhin@ios.uran.ru.
_________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 4, pp. 670-679, April, 2012. Original
article submitted February 1, 2012.
0009-3122/12/4804-0625©2012 Springer Science+Business Media, Inc.
625

presumably exists either in the azinium form 1a or the acylazinium salt 1b, respectively. The use of a chiral
nucleophile in the case of acid activation must lead to the mixture of diastereomers 1A but when activated by
acid anhydrides containing bulky substituents could give a diastereomerically enriched product 1B.
H
H
N
COR
N+
R1O
O
1O
O
N
N
R
R1OH
N
(RCO)2O
N
O
N
H
1a
Ph
N
H
Ph
N
H
1A
Ph
Route A
H+
COR
COR
Route B
(RCO)2O
N+
N
1O
O
N
N
R
R1OH
N
N
O
N
H
Ph
O
N
H
Ph
N
H
Ph
1
1b
1B
In order to prepare diastereomerically enriched products, we have studied the possible use of different
carboxylic acid anhydrides in the given reaction. A problem is in that, in the reaction of triazinone 1 with
O-nucleophiles, the acid anhydride can interact both with the triazine substrate and with the O-nucleophile. It is
known that a high activity of anhydride, like trifluoroacetic anhydride, can give a quantitative yield of borneol
[14] or cholesterol [15] trifluoroacetates at room temperature. In order to minimize side reactions we have
selected the low activity acetic, isobutyric, and pivalic anhydrides which differ only in their steric hindrance
towards nucleophilic attack.
It was found that triazine 1 does not react at room temperature in pure acid anhydrides with the said
O-nucleophiles, nor was a result obtained when the reactions were carried out in a mixture of the acid and its
anhydride. Success was achieved by two routes. Firstly, we have found that the addition of trifluoroacetic acid
to a suspension of the triazinone 1 in the anhydride leads to formation of the products of addition of the
O-nucleophiles. Secondly, a preliminary reprecipitation of triazinone 1 when heating in the acid anhydride with
subsequent addition of a nucleophile also gives the products of O-nucleophile addition.
O
R
N
O
R
N
1O
O
HO
O
N
N
R
(RCO)2O
H+
R1OH
1
+
+
2, 3a,b, 4, 5
N
H
Ph
N
H
Ph
7a,b
6a,b, 8a–c, 9a,b, 10a,b
6–10 a, 8c R = Me; 6–10 b R = i-Pr
Me
Me
H
Me
Me
Me
Me
; 3a, 8a,b R1 =
; 3b, 8c R1 =
2, 6a,b R1 =
H
H
Me
Me
Me
(rac-)
(–)
(rac-)
Me
Me
Me
Me
H
Me
4, 9a,b R1 =
; 5, 10a,b R1 =
Me
H
Me
Me
Me
H
H
Me
H
H
H
626

Hence a reaction of the 3-phenyl-1,2,4-triazin-5(4H)-one (1) with a series of O-nucleophiles in acetic or
isobutyric anhydride medium in the presence of CF3COOH at room temperature gave the addition products 6-
10. It should be noted that no reaction was observed in a pivalic anhydride medium in the presence of
CF3COOH.
The 1H and 13C NMR spectra of the products obtained as a result of addition of the chiral nucleophiles 3a,
4, 5 to the C=N bond of the 3-phenyl-1,2,4-triazin-5(4H)-one (1) showed a double set of signals corresponding in
intensities to the formation of a 1:1 mixture of diastereomers. The HPLC analysis of the products 9-10a,b also
showed that they are formed as a 1:1 pair of diastereomers. It should be noted that the 1H and 13C NMR spectra of
compound 6b show a single set of signals even though the angle of rotation for this compound is zero. X-ray
structural analysis shows that this compound also is an equimolar mixture of diastereomers (the molecular structure
of one of the diastereomers is given in Fig. 1). The absence of stereoselectivity in the studied reaction series allows
to assume that the 3-phenyl-1,2,4-triazin-5(4H)-one (1) in this case enters the reaction as the protonated salt 1a.
Besides the addition products of the alcohols to triazinone 1 and esters of the alcohols used in this work
there were also compounds 7a,b isolated in 10-15% yields as the products of water addition. Formation of these
compounds can be explained by existence of the water traces in the air and in solvents in the process of the
reaction products isolation [16]. To explain the formation of the products 7a,b, we have carried out the same
reaction but without addition of the O-nucleophiles. As a result, compounds 7a,b were obtained in good yields.
In order to test the assumption that the products 7a,b can exchange the hydroxyl group for other O-nucleophiles
we have studied their reactivity towards (-)-borneol and cholesterol. The products 8a,b and 10a,b were obtained
as a result.
O
R
N
O
R
N
R1OH
3a, 5
H+
RCOOH
(RCO)2O
1O
O
N
N
HO
O
R
1
CF3COOH
N
H
7a,b
Ph
N
H
Ph
8,10 a,b
In the reaction between 3-phenyl-1,2,4-triazin-5(4H)-one (1) with O-nucleophiles (first dissolving the
triazinone 1 in the carboxylic acid anhydride with heating and then continuing the reaction at room temperature)
the addition products 8a,b, 10a were also formed. However, when the pivalic acid anhydride was used as a
carboxylic acid anhydride the single reaction product was compound 11c as a result of O-acylation. The
structure of the compound obtained was proved by X-ray structural analysis (Fig. 2).
R1OH
3a, 5
N
H+
(RCO)2O
(RCO)2O
H2O
O
N
7a,b
8a,b, 10a
1
1a
R
O
N
11a,b
Ph
(t-BuCO)2O
N
N
O
N
t-Bu
O
Ph
11c
11 a R = Me, b R = i-Pr
It can be suggested that triazinone 1 in the carboxylic acid anhydride initially forms the product of
O-acylation which, in the case of R =Me, i-Pr can dissociate to the starting triazine under the reaction
conditions. Hence compounds 11a,b are not observed under these conditions. When R = t-Bu, the position 6 of
the triazine ring becomes non-reactive due to steric hindrance and only compound 11c is formed.
627

Fig. 1. Overall view of compound 6b with 50% probability thermal ellipsoids.
Fig. 2. Overall view of compound 11c with 50% probability thermal ellipsoids.
There are two ways to explain the absence of stereoselectivity in the reactions yielding compounds
8-10a,b. The first is proceeding of the reaction via the intermediate azinium salt 1a which does not create
sufficient steric hindrance upon reaction with the chiral nucleophiles 3-5. The second is proceeding of the
reaction via the intermediate formation of the racemic N(1)-acylated hydroxytriazines 7a,b.
Hence we have, for the first time, obtained the products of addition of cholesterol, dihydrocholesterol,
borneol, and isoborneol as O-nucleophiles to the azine ring. It was shown that addition of the said alcohols to
3-phenyl-1,2,4-triazin-5(4H)-one in acetic and isobutyric anhydrides occurs nondiastereoselectively.
EXPERIMENTAL
1H and 13C NMR spectra were recorded on a Bruker DRX-400 spectrometer (400 and 100 MHz
respectively) with TMS as internal standard. UV spectra were recorded on a PerkinElmer Lambda 45
spectrometer using 2-propanol. Mass spectra were recorded on a Bruker Daltonics MicroTOF-Q II mass
spectrometer with electrospray ionization. The optical rotation was measured on a PerkinElmer polarimeter.
628

TABLE 1. Basic Crystallographic Parameters for Compounds 6b and 11c
Parameters
Compound 6b
Compound 11c
Empirical formula
М
C23H31N3O3
397.51
C14H15N3O2
257.29
Crystal size, mm
Temperature, K
Crystal system
Space group
A,Å
0.45  0.36  0.21
295(2)
0.25  0.20  0.15
295(2)
Monoclinic
P21/c
Monoclinic
P21/c
16.575(3)
6.5340(9)
21.338(5)
109.579(18)
2177.3(7)
4
5.8524(7)
18.848(3)
12.0716(15)
97.817(10)
1319.2(3)
4
b, Å
c, Å
β, deg
V, Å3
Z
ρcalc, g·cm–3
μ/mm–1
1.213
1.295
0.081
0.089
θ/deg
2.71–26.38
9605 / 4436
0.0413
2.75–26.37
5610 / 2780
0.0208
Overall number of reflections measured /independent
Rint
Number of observed reflections with I > 2σ(I)
Completeness (for θ, deg)
R1, I > 2σ(I)
1696
1915
99.6 % (26.38)
0.0368
99.6 % (26.37)
0.0382
wR2, I > 2σ(I)
0.0464
0.0974
R1, I > 2σ(I)
0.1100
0.0595
wR2, I > 2σ(I)
Residual electron density/e Å–3, ρmax/ρmin
0.0487
0.1037
0.125 / –0.159
0.206 / -0.148
Melting points were determined on a Boetius hot stage apparatus. The HPLC analysis of compounds 9-10a,b was
performed on a Knauer Smartline-1100 chromatograph with Reprosil 100 column (2504.6 mm). TLC analysis
was carried out using Merck silica gel 60 F254 and visualized by UV radiation. Column chromatography was
performed using Merck silica gel 60 with EtOAc–CH2Cl2 (1:1) as eluent. Commercially available starting materials
were used in the study, and the 3-phenyl-1,2,4-triazin-5(4H)-one (1) was prepared by a known method [17].
X-ray structural analysis was performed on an Oxford Diffraction Xcalibur S CCD diffractometer using
the software package CrysAlisPro [18]. The structures were solved by direct methods using the SHELXS-97
software package and refined in F2 full-matrix least-squares analysis using SHELXL-97 [19]. The
crystallographic data for compounds 6b and 11c is presented in Table 1 and has been deposited to the
Cambridge Crystallographic Data Center as CCDC 768207 and 815379.
Synthesis of Compounds 6a,b, 8a-c, 9-10a,b (General Method). A. CF3COOH (0.2 ml) was added to
a suspension of the triazinone 1 (200 mg, 1.15 mmol) and the corresponding O-nucleophile 2-5 (1.73 mmol) in
a mixture of Ac2O (2 ml), AcOH (5 ml), and CHCl3 (3 ml). The obtained mixture was stirred for 1 day at room
temperature and evaporated to dryness. The residue was separated on a chromatographic column.
B. A suspension of the triazinone 1 (200 mg, 1.15 mmol) in the corresponding anhydride (3 ml) was
heated to dissolution, and treated with the O-nucleophile (1.15 mmol) while cooling. The reaction mixture was
stirred for 1 day at room temperature. The obtained solution was evaporated in a Petri dish to dryness and the
residue was separated on a chromatographic column.
C. A suspension of triazinone 1 (200 mg, 1.15 mmol) and the corresponding O-nucleophile (1.15 mmol)
in a mixture of the corresponding anhydride (2 ml) and CF3COOH (0.2 ml) was stirred for 1 day at room
temperature. The solution obtained was evaporated to dryness and the residue was separated on a
chromatographic column.
D. CF3COOH (0.2 ml) was added to a suspension of the triazinone 1 (200 mg, 1.15 mmol) and the
corresponding O-nucleophile (1.73 mmol) in a mixture of Ac2O (2 ml) and AcOH (5 ml). The solution obtained
629

was stirred for 1 day at room temperature. The precipitate formed was filtered off, recrystallized from ethanol,
and purified on a chromatographic column if needed.
E. The O-nucleophile (0.7 mmol) and CF3COOH (0.2 ml) were added to a suspension of compound
7a,b (0.7 mmol) in AcOH (5 ml) and the mixture was stirred for 1 day at room temperature. The precipitate
obtained was filtered off and recrystallized from alcohol (compounds 10a,b). In the absence of a precipitate
(compounds 8a,b) the reaction mixture was evaporated and the residue was separated on a chromatographic
column.
1-Acetyl-3-phenyl-6-((1S/R,2R/S,4R/S)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yloxy)-1,6-dihydro-
1,2,4-triazin-5(4H)-one (6a). Yield 20% (method A). Colorless crystalline powder; mp 182-183ºC, Rf 0.8
(EtOAc–CH2Cl2, 1:1). 1H NMR spectrum (DMSO-d6), , ppm (J, Hz): 0.65 (1.5Н, s) and 0.74 (4.5H, s, 2CH3);
0.85 (1.5H, s) and 0.86 (1.5H, s, CH3); 0.94-1.06 (2H, m, CH2); 1.41-1.73 (4.5H, m) and 1.85-1.91 (0.5H, m,
2СН2, СН); 2.36 (1.5H, s) and 2.38 (1.5H, s, COCH3); 3.49-3.51 (0.5H, m) and 3.57-3.60 (0.5H, m, Н-2'); 5.85
13
(0.5H, s) and 5.86 (0.5H, s, H-6); 7.42-7.50 (3H, m, Н Ph); 7.85-7.88 (2H, m, Н Ph); 11.56 (1H, s, NH). C
NMR spectrum (DMSO-d6), , ppm: 11.1; 11.4; 19.6; 19.8; 19.9; 21.0; 21.2; 33.6; 33.7; 37.9; 38.0; 44.3; 44.4;
46.2; 48.6; 48.8; 73.4; 74.9; 84.6; 86.1; 126.4; 126.5; 128.6; 130.3 (2С); 130.7 (2С); 141.0; 141.3; 161.4; 161.8;
172.7; 172.9. Found, m/z: 370.2110 [M+H]+. C21H28N3O3. Calculated, m/z: 370.2125.
1-Isobutyryl-3-phenyl-6-((1S/R,2R/S,4R/S)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yloxy)-1,6-dihyd-
ro-1,2,4-triazin-5(4H)-one (6b). Yield 25% (method C). Colorless crystalline powder; mp 204-205ºC, Rf 0.8
20
1
(EtOAc–CH2Cl2, 1:1). []D = 0 (c = 0.5, MeOH). H NMR spectrum (DMSO-d6), , ppm: 0.64-0.74 (6H, m,
2СН3); 0.85-0.91 (3H, m, СН3); 0.93-1.06 (2H, m, СН2); 1.12-1.14 (3H, m) and 1.19-1.25 (3H, m, СН(СН3)2);
1.40-1.92 (5H, m, 2СН2, СН); 3.46-3.61 (2H, m, Н-2', CH(СН3)2); 5.84 (1H, s, H-6); 7.41-7.49 (3H, m, Н Ph);
13
7.84-7.86 (2H, m, Н Ph); 11.53 (1H, s, NH); C NMR spectrum (DMSO-d6), , ppm: 12.0; 18.8; 19.3; 20.1;
20.4; 27.1; 30.6; 34.1; 38.8; 44.9; 46.7; 49.4; 75.7; 86.8; 126.9; 129.2; 130.9; 131.3; 141.7; 162.0; 179.1.
Found, m/z: 398.2414 [M+H]+. C23H32N3O3. Calculated, m/z: 398.2438.
1-Acetyl-3-phenyl-6-((1S,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yloxy)-1,6-dihydro-1,2,4-tria-
zin-5(4H)-one (8a). Yield 53% (method A), 31% (method B), 17% (method E). Colorless crystalline powder;
20
1
mp 183-184ºC, Rf 0.65 (EtOAc–CH2Cl2, 1:1). []D = -18.7 (c = 1.0, CHCl3). H NMR spectrum (CDCl3), ,
ppm (J, Hz): 0.71 (1.5H, s), 0.80-0.83 (6H, s), and 0.89 (1.5H, s, 3CH3); 0.97-1.01 (0.5H, m), 1.05-1.22 (2.5H,
m, СН2); 1.57-1.67 (2H, m, СН2); 1.74-1.82 (1H, m); 2.06-2.15 (0.5H, m) and 2.21-2.29 (0.5H, m, СН); 2.46
(1.5Н, s) and 2.47 (1.5H, s, COCH3); 4.06 (0.5H, ddd, J = 9.6, J = 3.2, J = 1.9) and 3.98 (0.5H, ddd, J = 9.5,
J = 3.2, J =1.9, Н-2'); 6.21 (1H, s, H-6); 7.48-7.56 (3H, m, Н Ph); 7.81-7.86 (2H, m, Н Ph); 9.08 (0.5Н, s) and
13
9.13 (0.5H, s, NH). C NMR spectrum (CDCl3), , ppm: 13.3; 13.5; 18.9 (2С); 19.6; 19.7; 21.5; 21.7; 26.3;
28.0; 36.0; 36.1; 44.9; 45.0; 47.5; 47.7; 49.3; 49.6; 74.9; 76.1; 84.5; 86.5; 125.9; 129.0; 130.2; 131.1; 139.6;
139.7; 162.8; 163.1; 173.7; 173.9. Found, m/z: 370.2115 [M+H]+ C21H28N3O3. Calculated, m/z: 370.2125.
1-Isobutyryl-3-phenyl-6-(1S,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yloxy)-1,6-dihydro-1,2,4-tria-
zin-5(4H)-one (8b). Yield 8% (method B), 17% (method C), 13% (method E). Colorless crystalline powder; mp
20
1
158ºC, Rf 0.8 (EtOAc–CH2Cl2, 1:1). []D = -14.9 (c = 1.0, CHCl3). H NMR spectrum (CDCl3), , ppm (J,
Hz): 0.69-1.31 (17H, m, 3СН3, СН2, СН(CH3)2); 1.55-1.67 (2H, m, СН2); 1.75-1.82 (2H, m, СН2); 2.04-2.13
(0.5H, m, CH); 2.20-2.28 (0.5H, m, CH); 3.60-3.69 (1H, m, CH(CH3)2); 3.92-3.96 (0.5H, m) and 4.07-4.10
(0.5H, m, H-2'); 6.19 (0.5H, s) and 6.22 (0.5H, s, H-6); 7.48-7.55 (3H, m, Н Ph); 7.87-7.91 (2H, m, Н Ph); 9.93
(0.5H, s) and 9.99 (0.5H, s, NH). 13C NMR spectrum (CDCl3), , ppm: 13.3; 13.5; 18.5; 18.8 (2С); 18.9; 19.1;
19.6; 26.2; 28.0 (2С); 30.9; 31.0; 35.7; 36.3; 44.9; 45.0; 47.5; 47.6; 49.1; 49.6; 74.8; 76.4; 77.0; 77.3; 83.7;
86.6; 125.8; 129.0; 130.4; 131.0; 139.1; 139.4; 162.4; 162.8; 179.8; 180.2. Found, m/z: 398.2434 [M+H]+.
C23H31N3O3. Calculated, m/z: 398.2438.
1-Acetyl-3-phenyl-6-((1S/R,2S/R,4R/S)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yloxy)-1,6-dihyd-
ro-1,2,4-triazin-5(4H)-one (8c). Yield 12% (method A), 20% (method C). Colorless crystalline powder; mp
1
189-190ºC, Rf 0.65 (EtOAc–CH2Cl2, 1:1). H NMR spectrum (DMSO-d6), , ppm (J, Hz): 0.67 (1.5H, s),
0.80-0.83 (6H, s) and 0.87 (1.5H, s, 3CH3); 0.91-0.95 (0.5H, m), 1.00-1.20 (2.5H, m), 1.56-1.67 (2H, m) and
630

1.72-1.79 (1H, m, 3СН2); 2.00-2.08 (0.5H, m) and 2.16-2.24 (0.5H, m, CH); 2.36 (1.5Н, s) and 2.37 (1.5Н, s,
COCH3); 3.84-3.88 (0.5H, m) and 3.93-3.97 (0.5H, m, H-2'); 5.87 (1H, s, H-6); 7.42-7.50 (3H, m, Н Ph);
13
7.88-7.91 (2H, m, Н Ph); 11.61 (1H, s, NH). C NMR spectrum (DMSO-d6), , ppm: 13.0; 13.3; 18.4; 19.3;
19.4; 21.0; 21.2; 25.7; 25.8; 27.7; 35.6; 44.1; 44.2; 46.9; 47.2; 48.7; 49.0; 74.3; 75.4; 82.5; 84.4; 126.5; 128.6;
130.2; 130.3; 130.8; 140.7; 141.0; 161.5; 161.7; 172.7; 173.0. Found, m/z: 370.2113 [M+H]+. C21H28N3O3.
Calculated, m/z: 370.2125.
1-Acetyl-6-[(3S,5S,8R,9S,10S,13R,14S,17R)-10,13-dimethyl-17-((R)-6-methylheptan-2-yl)hexadeca-
hydro-1H-cyclopenta[a]phenanthren-3-yloxy]-3-phenyl-1,6-dihydro-1,2,4-triazin-5(4H)-one (9a). Yield
20
51% (method D). Colorless crystalline powder; mp 199-200ºC, Rf 0.9 (EtOAc–CH2Cl2, 1:1). []D = +13.7
(c = 1.0, CHCl3). UV spectrum, max, nm: 228, 292. 1H NMR spectrum (CDCl3), , ppm (J, Hz): 0.57-0.64 (4H,
m); 0.74 (3H, s, СН3); 0.84-0.87 (10H, m); 0.95-2.03 (20H, m); 1.42-2.03 (9H, m); 2.37 (3H, s, COCH3);
3.49-3.59 (1H, m, H-3'); 5.92 (1H, s, H-6); 7.40-7.49 (3H, m, Н Ph); 7.89-7.90 (2H, m, Н Ph); 11.58 (1H, s,
NH). 13C NMR spectrum (CDCl3), , ppm: 12.1; 12.2; 18.7; 21.2; 21.6; 22.6; 22.8; 23.8; 24.2; 28.0; 28.1; 28.3;
28.5; 28.7; 28.8; 32.0; 34.6; 35.0; 35.5 (2С); 35.8; 36.2; 36.9; 37.0; 39.5; 40.0; 42.6; 44.6; 44.9; 54.3; 56.2;
56.4; 73.5; 73.7; 77.2; 79.2; 79.4; 125.9; 129.0; 130.1; 131.1; 139.4; 139.5; 163.1 (2С); 173.7. Found, m/z:
610.4523 [M+Li]+. C38H57N3O3Li. Calculated m/z: 610.4555.
6-[(3S,5S,8R,9S,10S,13R,14S,17R)-10,13-Dimethyl-17-((R)-6-methylheptan-2-yl)hexadecahydro-
1H-cyclopenta[a]phenanthren-3-yloxy]-1-isobutyryl-3-phenyl-1,6-dihydro-1,2,4-triazin-5(4H)-one (9b).
Yield 6% (method C). Colorless crystalline powder; mp 191-192ºC, Rf 0.9 (EtOAc–CH2Cl2, 1:1). []D20 = +15.4
(c = 0.5, CHCl3). 1H NMR spectrum (CDCl3), , ppm (J, Hz): 0.56-0.63 (4Н, m); 0.74 (3Н, s); 0.85-1.84 (43.5Н,
m); 1.92-1.97 (1Н, m); 2.01-2.09 (0.5Н, m); 3.59-3.74 (2H, m, СH(СH3)2, Н-3'); 6.27 (0.5H, s) and 6.28 (0.5Н, s,
Н-6); 7.47-7.54 (3H, m, Н Ph); 7.81-7.83 (2H, m, Н Ph); 8.95 (1Н, s, NH). 13C NMR spectrum (CDCl3), , ppm:
12.1; 12.2; 18.6; 18.7; 19.1 (2С); 21.2; 22.6; 22.8 (2С); 24.2; 28.0; 28.2; 28.6; 28.7; 28.8; 31.0; 32.0; 34.7; 35.2;
35.5; 35.8; 36.2; 36.9; 37.0; 39.5; 40.0; 42.6; 44.7; 44.9; 54.3; 56.3; 56.5; 74.0; 74.1; 79.3; 79.5; 125.9; 129.0;
130.3; 131.0; 139.1; 163.1; 180.0 (2С). Found, m/z: 632.4743 [M+H]+. C40H62N3O3. Calculated, m/z: 632.4786.
1-Acetyl-6-[(3S,8S,9S,10R,13R,14S,17R)-10,13-dimethyl-17-((R)-6-methylheptan-2-yl)-2,3,4,7,8,9,
10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yloxy]-3-phenyl-1,6-dihyd-ro-
1,2,4-triazin-5(4H)-one (10a). Yield 8% (method B); 35% (method C), 50% (method D), 44% (method E).
20
Colorless crystalline powder; mp 182-183ºC, Rf 0.9 (EtOAc–CH2Cl2, 1:1). []D = -6.5 (c = 1.0, CHCl3). UV
spectrum, max, nm: 229, 292. 1H NMR spectrum (CDCl3), , ppm: 0.66 (3H, s, СH3); 0.85-1.61 (34H, m); 1.78-
2.03 (4.5H, m); 2.08-2.36 (2H, m); 2.48 (1.5Н, s) and 2.49 (1.5H, s, СОCH3); 2.53-2.58 (0.5H, m); 3.60-3.71
(1H, m, H-3'); 5.31-5.33 (0.5H, m) and 5.38-5.40 (0.5H, m, =СН); 6.28 (0.5Н, s) and 6.29 (0.5H, s, Н-6); 7.47-
7.54 (3H, m, Н Ph); 7.83-7.85 (2H, m, Н Ph); 9.31 (0.5Н, s) and 9.38 (0.5Н, s, NH). 13C NMR spectrum
(CDCl3), , ppm: 11.9; 18.7; 19.3; 21.1; 21.6; 22.6; 22.9; 23.8; 24.3; 28.0; 28.3; 28.7; 31.9 (2С); 32.0; 35.8;
36.2; 36.6; 37.0; 37.1; 39.0; 39.2; 39.5; 39.8; 42.3; 50.0; 50.1; 56.1; 56.7; 73.4; 73.7; 79.3; 79.6; 122.1; 122.4;
126.0; 129.0; 130.1; 131.2; 139.4; 140.1; 140.3; 163.1; 163.2; 173.7 (2С). Found, m/z: 602.4296 [M+H]+.
C38H56N3O3. Calculated, m/z: 602.4316.
1-Isobutyryl-6-[(3S,8S,9S,10R,13R,14S,17R)-10,13-dimethyl-17-((R)-6-methylheptan-2-yl)-2,3,4,7,
8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yloxy]-3-phenyl-1,6-dihydro-
1,2,4-triazin-5(4H)-one (10b). Yield 28% (method C), 60% (method E). Colorless crystalline powder; mp
20
1
209-210ºC, Rf 0.85 (EtOAc–CH2Cl2, 1:1). []D = -4.7 (c = 1.0, CHCl3). H NMR spectrum (CDCl3), , ppm:
0.68 (3H, s, СH3); 0.88-1.70 (39H, m); 1.80-2.04 (4.5H, m); 2.04-2.28 (2H, m); 2.50-2.55 (0.5H, m); 3.62-3.74
(2H, m, СH(CH3)2, Н-3'); 5.31-5.33 (0.5H, m) and 5.40-5.41 (0.5H, m, =СН); 6.29 (0.5H, s) and 6.31 (0.5H, s,
Н-6); 7.49-7.56 (3H, m, Н Ph); 7.89-7.92 (2H, m, Н Ph); 9.85 (0.5H, s) and 9.92 (0.5H, s, NH). 13C NMR
spectrum (CDCl3), , ppm: 11.8; 18.5; 18.6; 18.7; 19.1 (2С); 19.3; 21.0; 22.6; 22.8; 23.8; 24.3; 28.0; 28.2; 28.3;
28.8; 31.0 (2С); 31.8; 31.9 (2С); 35.8; 36.2; 36.6; 37.0; 37.1; 39.1; 39.3; 39.5; 39.7; 42.3; 49.9; 50.0; 56.1; 56.7;
73.9; 74.1; 77.2; 79.5; 79.8; 122.0; 122.3; 125.9; 129.0; 130.2; 131.0; 139.1; 139.2; 140.1; 140.3; 163.1; 179.9
(2С). Found, m/z: 630.4632 [M+H]+. C40H60N3O3. Calculated, %: m/z 630.4629.
631

1-Acetyl-6-hydroxy-3-phenyl-1,6-dihydro-1,2,4-triazin-5(4H)-one (7a). A suspension of the
3-phenyl-1,2,4-triazin-5(4H)-one (1) (1.0 g, 5.77 mmol) in a mixture of AcOH (10 ml), Ac2O (3 ml), and
CF3COOH (0.5 ml) was stirred for 1 day at room temperature. The triazine 1 was gradually dissolved and after
some time a precipitate was formed. The precipitate was filtered off, washed with a small amount of AcOH and
ether, and dried. The product was quite pure, but could be separated on a chromatographic column if needed.
Yield 0.93 g (69%). Colorless crystalline powder; mp 185-186ºC, Rf 0.4 (EtOAc–CH2Cl2, 1:1). 1H NMR spectrum
(DMSO-d6), , ppm (J, Hz): 2.36 (3H, s, COCH3); 5.92 (1H, d, J = 6.3, H-6); 7.20 (1H, d, J = 6.3, OH);
7.39-7.48 (3H, m, H Ph); 7.89-7.92 (2H, m, H Ph); 11.43 (1H, s, NH). 13C NMR spectrum (DMSO-d6), , ppm:
21.2; 69.2; 126.4; 128.5; 130.4; 130.6; 140.1; 163.5; 172.3. Found, m/z: 232.0710 [M-H]-. C11H10N3O3.
Calculated, m/z: 232.0728.
6-Hydroxy-1-isobutyryl-3-phenyl-1,6-dihydro-1,2,4-triazin-5(4H)-one (7b).
A
suspension of
3-phenyl-1,2,4-triazin-5(4H)-one (1) (200 mg, 1.15 mmol) in a mixture of isobutyric acid (3 ml), isobutyric
anhydride (1 ml), and CF3COOH (0.2 ml) was stirred for 1 day at room temperature. The solution obtained was
evaporated in a Petri dish and the residue was separated on a chromatographic column. Yield 195 mg (65%).
Yellow crystalline powder; mp 225-226ºC, Rf 0.4 (EtOAc–CH2Cl2, 1:1). 1H NMR spectrum (DMSO-d6), , ppm
(J, Hz): 1.17 (6H, dd, J = 21.9, J = 6.9, CH(CH3)2); 3.52-3.62 (1H, m, J = 7.0, CH(CH3)2); 5.91 (1H, d, J = 6.3,
13
H-6); 7.20 (1H, d, J = 6.3, OH); 7.38-7.50 (3H, m, H Ph); 7.89-7.92 (2H, m, H Ph); 11.44 (1H, s, NH). C
NMR spectrum (DMSO-d6), , ppm: 18.2; 19.0; 30.0; 69.4; 126.4; 128.6; 130.5; 130.6; 140.0; 163.6; 178.2.
Found, m/z: 260.1026 [M-H]-. C13H15N3O3. Calculated, m/z: 260.1041.
3-Phenyl-1,2,4-triazin-5-ylpivalate (11c). A suspension of the 3-phenyl-1,2,4-triazin-5(4H)-one (1)
(150 mg, 0.87 mmol) was heated in pivalic anhydride (3 ml) to dissolution and then stirred for 1 day at room
temperature. The reaction mixture was separated on a chromatographic column. Yield 46%. Colorless
1
crystalline powder; mp 77-78ºC, Rf 0.6 (EtOAc–CH2Cl2, 1:1). H NMR spectrum, , ppm (J, Hz): 1.44 (9H, s,
13
3CH3); 7.51-7.59 (3H, m, H Ph); 8.51-8.54 (2H, m, H Ph); 9.13 (1H, s, H-6). C NMR spectrum (CDCl3), ,
ppm: 26.8; 39.7; 128.6; 128.8; 132.1; 133.9; 142.2; 159.1; 164.3; 174.7.
This work was carried out with the financial support Ministry of Education and Science of the Russian
Federation State Contract No. 14.740.11.1020.
This work was carried out with the assistance of the Laboratory of Complex Investigation and Expert
Valuation of Organic Materials (Ural Federation University).
The authors thank A. N. Grishakov for help with carrying out the HPLC analysis and I. S. Kovalev for
help with recording the mass spectra.
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