Synthesis of isobornylphenol-containing 3-aryl-1,2,4-triazin-5(4H)-ones

Article abstract of DOI:10.1007/s11172-011-0143-6

A method for modification of 3-aryl-1,2,4-triazin-5(4H)-ones with isobornylphenols was proposed. The influence of various acylating agents on the reaction pathway was studied.

Full text of DOI:10.1007/s11172-011-0143-6

Russian Chemical Bulletin, International Edition, Vol. 60, No. 5, pp. 914—918, May, 2011
914
Synthesis of isobornylphenolꢀcontaining 3ꢀarylꢀ1,2,4ꢀtriazinꢀ5(4H)ꢀones*
I. N. Egorov,a O. N. Chupakhin,a,b M. V. Berezin,b G. L. Rusinov,b V. L. Rusinov,a
E. V. Buravlev,c I. Yu. Chukicheva,c and A. V. Kuchinc
aUral Federal University named after the First President of Russia B. N. El´tsin,
19 ul. Mira, 620002 Ekaterinburg, Russian Federation.
Phone: +7 (343) 375 4501. Eꢀmail: i.n.egorov@gmail.com
bI. Ya. Postovsky Institute of Organic Synthesis, Ural Branch of the Russian Academy of Sciences,
20 ul. S. Kovalevskoi, 620219 Ekaterinburg, Russian Federation.
Phone: +7 (343) 374 1189. Eꢀmail: chupakhin@ios.uran.ru
cInstitute of Chemistry, Komi Research Center, Ural Branch of the Russian Academy of Sciences,
48 ul. Pervomaiskaya, 167982 Syktyvkar, Komi Republic, Russian Federation.
Fax: +7 (821 2) 43 6677. Eꢀmail: chukichevaꢀiy@chemi.komisc.ru
A method for modification of 3ꢀarylꢀ1,2,4ꢀtriazinꢀ5(4H)ꢀones with isobornylphenols was
proposed. The influence of various acylating agents on the reaction pathway was studied.
Key words: 1,2,4ꢀtriazinꢀ5(4H)ꢀones, isobornylphenols, nucleophilic addition, arylation,
valine.
Terpenophenols are physiologically active broadꢀspecꢀ
quantitative decomposition into the starting reagents. Acyꢀ
lation provides a possible way of stabilizing such adducts.9
In the present work, we studied reactions of 3ꢀarylꢀ
1,2,4ꢀtriazinꢀ5(4H)ꢀones 1a,b with racemic 2ꢀisobornylꢀ
6ꢀmethylphenol (2) and 2ꢀisobornylꢀ4ꢀmethylphenol (3)
as Cꢀnucleophiles. We found that compound 2 forms adꢀ
ducts in both pure acid anhydride and its mixture with
a carboxylic acid (Scheme 1, Table 1). The reactions gave
N(1)ꢀacetyl (4a, 4c) and N(1)ꢀisobutyroyl derivatives (4b)
in moderate yields. Reflux of 3ꢀ(2ꢀpyridyl)ꢀ1,2,4ꢀtriꢀ
azinꢀ5(4H)ꢀone 1b with compound 2 in trifluoroacetic
acid—trifluoroacetic anhydride for 1.5 h afforded adduct
4d containing the trifluoroacetyl residue (see Scheme 1).
Xꢀray diffraction study of a crystal of compound 4a
isolated from the reaction mixture revealed the presence
of two pairs of diastereomers in a ratio of ~1 : 3 (Fig. 1).
However, the specific rotation of a solution of compound
4a is zero, which suggests that each of the diastereomers is
a racemate.
Attempted addition of compound 3 as a Cꢀnucleophile
to the 1,2,4ꢀtriazine ring in acetic anhydride or its mixture
with acetic acid failed. In the case of AcOH—Ac2O, the
reaction gave compound 5 in 37% yield via the addition of
water to the imine fragment followed by Nꢀacylation
(Scheme 2). The source of water molecules in this reacꢀ
tion may be acetic acid.
When analyzing possible causes behind the different
reactivities of two isomeric isobornylphenols 2 and 3, we
noticed that reflux of compound 5 in acetic acid—acetic
anhydride in the presence of 2ꢀisobornylꢀ6ꢀmethylphenol (2)
trum compounds produced in plant biosynthesis.1,2 Alkylꢀ
phenols are well known for their antioxidant3,4 and antiꢀ
bacterial properties;5 they also exhibit antiatherosclerosis
activity.6 These compounds have found use in diverse areas:
e.g., 2,6ꢀdi(tertꢀbutyl)ꢀ4ꢀmethylphenol (ionol) is employed
as a stabilizer and an antioxidant in the production of
foods, lubricating oils, etc.4 A search for new active comꢀ
pounds among alkylphenols is of great practical interest.
Some azine derivatives of borneol and isoborneol are
known to exhibit antiviral properties.7 Modification of
terpenophenols with a 1,2,4ꢀtriazine fragment is imporꢀ
tant for further target synthesis of products combining
antioxidant and/or antiviral properties.
Previously, we have reported on successful introducꢀ
tion of a number of Cꢀnucleophiles8,9 (in particular, alkylꢀ
phenols10 and crown ethers10,11) into the 1,2,4ꢀtriazine
ring under acylation conditions. For instance, dissolution
of 1,2,4ꢀtriazinꢀ5(4H)ꢀones in trifluoroacetic or acetic acid
results in the formation of triazinium salts, which readily
react with 2,6ꢀdimethylphenol and resorcinol at room temꢀ
perature.9 This reversible reaction produces C(6)ꢀadducts
that are stable only in strongly acidic solutions and detectꢀ
ed by 1H NMR spectroscopy (the presence of a resonance
signal for the methine proton at the sp3ꢀhybridized C atom
in the spectrum of the reaction mixture). Any attempts to
isolate these adducts in the individual state result in their
* Dedicated to Academician V. N. Charushin on the occasion of
his 60th birthday.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 5, pp. 893—897, May, 2011.
1066ꢀ5285/11/6005ꢀ914 © 2011 Springer Science+Business Media, Inc.

1,2,4ꢀTriazineꢀcontaining phenols
Russ.Chem.Bull., Int.Ed., Vol. 60, No. 5, May, 2011
915
Scheme 1
C(10)
a
O(1)
C(5)
C(4)
C(6)
C(2)
N(3)
C(7)
C(3)
N(1)
O(2)
C(8)
C(1)
C(9)
C(20)
C(11)
C(26)
C(27)
C(19)
C(15)
N(2)
C(21)
C(25)
C(24)
C(16)
C(12)
C(14)
C(28)
C(22)
C(18)
C(17)
C(13)
C(23)
O(1)
b
C(10)
C(2)
C(5)
N(3)
C(26)
C(25)
C(4)
C(6)
C(1)
C(7)
C(8)
1: Ar = Ph (a), 2ꢀpyridyl (b)
4: R = Me, Ar = Ph (a); R = CHMe2, Ar = Ph (b);
R = Me, Ar = 2ꢀpyridyl (c); R = CF3, Ar = 2ꢀpyridyl (d)
C(3)
C(9)
N(1)
C(24)
O(3)
C(15A)
C(11)
C(21)
O(2)
N(2)
C(27)
C(14)
C(22)
C(23)
results in replacement of the OH group at the sp3ꢀhybridꢀ
ized C atom by the isobornylphenol residue, giving comꢀ
pound 4a (see Scheme 2). However, a similar reaction
C(14A)
C(16A)
C(20A)
C(28)
C(18A)
C(13A)
C(12A)
Scheme 2
Fig. 1. Crystal structures of the major (a) and minor diastereoꢀ
mers (b) of compound 4a (Xꢀray diffraction data).
with 2ꢀisobornylꢀ4ꢀmethylphenol (3) failed. This is eviꢀ
dence that isobornylphenol 2 is a more reactive Cꢀnucleoꢀ
phile than its isomer 3.
On further optimization of the reaction conditions,
we found that a reaction of triazinone 1a with compound 3
i. AcOH, Ac2O, reflux.
Table 1. Reaction conditions for the synthesis of compounds 4a—d
Starting
compound
Acylating
agent
T/°C
Product
Yield (%)
1a
1a
1a
1a
1b
1b
1b
1b
Ac2O
AcOH, Ac2O
140
Reflux
25
100
Reflux
25
4a
4a
4a
4b
4c
4c
4c
4d
32
30
27
8
45
30
55
85
CF3COOH, Ac2O, CH2Cl2
(Me2CHCO)2O
CF3COOH, Ac2O
CF3COOH, Ac2O
AcOH, Ac2O
Reflux
Reflux
CF3COOH, (CF3CO)2O

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Egorov et al.
in CH2Cl2 in the presence of trifluoroacetic acid—aceꢀ
tic anhydride affords compound 6 as a sole product
(Scheme 3).
isobornylphenols and testing of the products for antioxiꢀ
dant properties.
Experimental
Scheme 3
The starting compounds 3ꢀphenylꢀ1,2,4ꢀtriazinꢀ5(4H)ꢀone
(1a), 3ꢀ(4ꢀmethylphenyl)ꢀ1,2,4ꢀtriazinꢀ5(4H)ꢀone (1c) (see
Ref. 13), 2ꢀisobornylꢀ6ꢀmethylphenol (2), and 2ꢀisobornylꢀ4ꢀ
methylphenol (3) (see Ref. 14) were prepared according to known
procedures. The other starting materials are commercially availꢀ
able. The course of the reaction was monitored, and the purity of
the products was checked, by TLC on Merck Silica Gel 60 F254
plates; spots were visualized under UV light. Column chromaꢀ
1
tography was carried out on Silica Gel 60 (Merck). H NMR
spectra were recorded on a Bruker DRXꢀ400 instrument. Meltꢀ
ing points were determined on a Boetius instrument. Specific
rotation was measured on a Perkin—Elmer 341 polarimeter. An
Xꢀray diffraction study of compound 4a was carried out on an
Oxford Diffraction Xcalibur S CCD diffractometer with the Crysꢀ
AlisPro software.15 The structure was solved by direct methods
with the SHELXSꢀ97 program and refined by the fullꢀmatrix
leastꢀsquares method on F2 with the SHELXLꢀ97 program.16
Selected crystallographic parameters and the data collection
and refinement statistics are summarized in Table 2. The
atomic coordinates and the comprehensive Xꢀray diffraction
data have been deposited with the Cambridge Crystalloꢀ
graphic Data Center (CCDC 763851) and available on
www.ccdc.cam.ac.uk/data_request/cif.
3ꢀ(2ꢀPyridyl)ꢀ1,2,4ꢀtriazinꢀ5(4H)ꢀone (1b). Hydrazine hyꢀ
drate (15 mL, 0.3 mol) was added to a solution of 2ꢀcyanopyriꢀ
dine (5.2 g, 0.05 mol) in methanol (9 mL). The reaction mixture
was stirred at room temperature for 2 h and diluted with an equal
amount of water. The product was extracted with diethyl ether
(8×20 mL). The combined organic extracts were dried with CaCl2
and concentrated to a colorless precipitate. The yield of pyriꢀ
dineꢀ2ꢀcarboxamidrazone was 1.5 g (22%). In subsequent exꢀ
periments, this compound was used without further purification.
Pyridineꢀ2ꢀcarboxamidrazone (1.5 g, 0.011 mol) was dissolved
in ethanol (50 mL). Then glyoxylic acid monohydrate (1.2 g,
0.013 mol) in cooled ethanol (10 mL) was added at –20 °C. The
reaction mixture was kept at this temperature for 18 h and conꢀ
i. CF3COOH, Ac2O, CH2Cl2
We also studied the possibility of a diastereoselective
synthesis similar to documented12 reactions of compound
1a with indoles. For this purpose, we used NꢀTsꢀLꢀvaline
acid chloride 7 instead of acetic anhydride as an acylating
agent. However, in contrast to the earlier employed inꢀ
doles, phenols 2 and 8a,b proved to be inert under these
conditions and the reaction gave compounds 9a,b in low
yields (14—16%; Scheme 4), following much the same
pattern as described for compound 5 (see Scheme 2). In
this case, the water source is incompletely dehydrated
THF. The 1H NMR spectra of compounds 9a,b show one
set of signals, which is indicative of the formation of only
one of two possible diastereomers. It should be noted that
compound 1a reacts with acid chloride 7 alone (without
phenols) to give compound 9b in 13% yield.
To sum up, we demonstrated the fundamental possiꢀ
bility of modifying isobornylphenols with azines. The next
steps will include reactions of enantiomerically pure
Scheme 4
i. AlCl3, THF, 0 °С.
Ar = Ph (1a, 9a), 4ꢀMePh (1c, 9b)
2: R1 = Me, R2 = R3 = H, R4 = isobornyl
8: R1 = R2 = R3 = R4 = H (a); R1 = R4 = H, R2 = R3 = Me (b)

1,2,4ꢀTriazineꢀcontaining phenols
Russ.Chem.Bull., Int.Ed., Vol. 60, No. 5, May, 2011
917
Table 2. Crystallographic parameters and the data collection and
refinement statistics for structure 4a
C. A solution of compound 5 (150 mg, 0.64 mmol) (see beꢀ
low) in a mixture of acetic acid (3 mL) and acetic anhydride
(1 mL) was refluxed for 2 h. The solution was concentrated and
the residue was chromatographed on silica gel with ethyl acetate
as an eluent. The yield was 25%. The crystals obtained were
examined by Xꢀray diffraction.
Parameter
Value
Molecular formula
Molecular mass
C28H33N3O3
459.57
D. Trifluoroacetic acid (0.1 mL) and acetic anhydride (0.5 mL)
were added to a suspension of triazinone 1a (1.2 mmol) and
phenol 2 (1.2 mmol) in CH2Cl2 (8 mL). The resulting solution was
stirred at room temperature for 24 h. The precipitate that formed
was filtered off and washed with CH2Cl2. The yield was 27%.
6ꢀ[4ꢀHydroxyꢀ3ꢀmethylꢀ5ꢀ(1,7,7ꢀtrimethylbicyclo[2.2.1]ꢀ
heptꢀ2ꢀyl)phenyl]ꢀ1ꢀisobutyroylꢀ3ꢀphenylꢀ1,6ꢀdihydroꢀ1,2,4ꢀtriꢀ
azinꢀ5(4H)ꢀone (4b). Isobutyric anhydride (2 mL) was added to
triazinone 1a (1.2 mmol) and phenol 2 (1.2 mmol). The reaction
mixture was stirred at 100 °C for 3 h and kept at room temperaꢀ
ture for 24 h. The colorless crystals that formed were filtered off
and washed with diethyl ether. The product was chromatoꢀ
graphed on silica gel with ethyl acetate as an eluent. The yield
was 8%, m.p. > 260 °C, Rf 0.8 (ethyl acetate). 1H NMR (DMSOꢀd6),
δ: 11.41—11.43 (m, 1 H, OH); 7.93 (s, 1 H, NH); 7.84—7.88
(m, 2 H, Ph); 7.40—7.43 (m, 3 H, Ph); 6.87—6.91 (m, 1 H);
6.75—6.76 (m, 1 H); 6.87—6.88 (m, 1 H, C(6)H); 3.54—3.64
(m, 1 H, CH); 3.15—3.20 (m, 1 H); 2.14—2.15 (m, 3 H); 1.85—1.90
(m, 1 H); 1.68—1.78 (m, 2 H); 1.39—1.52 (m, 3 H); 1.22—1.31
(m, 1 H); 1.12—1.17 (m, 6 H); 0.55—0.74 (m, 8 H). Found (%):
C, 73.72; H, 7.32; N, 8.67. C30H37N3O3. Calculated (%):
C, 73.89; H, 7.65; N, 8.62.
Crystal system
Space group
a/Å
b/Å
c/Å
α/deg
β/deg
Triclinic
Pꢀ1
10.6821(17)
10.697(2)
11.225(3)
74.656(18)
89.429(16)
88.641(14)
1236.5(4)
2
γ/deg
V/Å3
Z
dcalc/g cm–3
1.234
0.081
492
μ/mm–1
F(000)
Crystal dimensions/mm
θ/deg
Number of measured reflections
Number of independent reflections
Rint
Number of reflections with I > 2σ(I)
R1 (I > 2σ(I))
0.34×0.29×0.21
2.72—26.42
11970
5008
0.0381
1894
0.0503
wR2 (I > 2σ(I))
0.1208
Residual electron
1ꢀAcetylꢀ6ꢀ[4ꢀhydroxyꢀ3ꢀmethylꢀ5ꢀ(1,7,7ꢀtrimethylbicycloꢀ
[2.2.1]heptꢀ2ꢀyl)phenyl]ꢀ3ꢀ(2ꢀpyridyl)ꢀ1,6ꢀdihydroꢀ1,2,4ꢀtriꢀ
azinꢀ5(4H)ꢀone (4c). A. Triazinone 1b (0.574 mmol) and phenol 2
(0.631 mmol) were refluxed in a mixture of AcOH (1 mL) and
Ac2O (1 mL) for 1.5 h. The solvents were removed and the oily
residue was triturated with a small amount of water. The resultꢀ
ing colorless powder was crystallized from methanol. The yield
was 55%, m.p. 239—241 °C. 1H NMR (DMSOꢀd6), δ: 11.16 (s, 1 H,
OH); 8.66 (s, 1 H, NH); 8.21—8.22 (m, 1 H, Py); 8.11—8.14
(m, 1 H, Py); 7.96—8.00 (m, 1 H, Py); 7.58 (s, 1 H, Py); 6.83—6.89
(m, 2 H, Ph); 5.91 (s, 1 H, C(6)H); 2.35 (s, 3 H, MeCO); 2.22
(s, 3 H, Me); 1.90—1.91 (m, 3 H); 1.09—1.11 (m, 3 H); 1.07—1.08
(m, 1 H); 0.69 (s, 3 H); 0.57 (s, 3 H); 0.54 (s, 3 H). Found (%):
C, 70.33; H, 7.00; N, 12.01. C27H32N4O3. Calculated (%): C, 70.41;
H, 7.00; N, 12.16.
B. Triazinone 1b (0.287 mmol) and phenol 2 (0.319 mmol)
were refluxed in a mixture of CF3COOH (1 mL) and Ac2O
(1 mL) for 1.5 h. The solvents were removed and the oily residue
was triturated with a small amount of water. The resulting colorꢀ
less powder was crystallized from methanol. The yield was 45%.
C. Triazinone 1b (0.287 mmol) and phenol 2 (0.319 mmol)
were stirred in CF3COOH (1 mL) at room temperature for 12 h.
Then Ac2O (1 mL) was added and stirring was continued for an
additional 12 h. The solvents were removed and the oily residue
was triturated with a small amount of water. The resulting colorꢀ
less powder was crystallized from methanol. The yield was 30%.
6ꢀ[4ꢀHydroxyꢀ3ꢀmethylꢀ5ꢀ(1,7,7ꢀtrimethylbicyclo[2.2.1]ꢀ
heptꢀ2ꢀyl)phenyl]ꢀ3ꢀ(2ꢀpyridyl)ꢀ1ꢀtrifluoroacetylꢀ1,6ꢀdihydroꢀ
1,2,4ꢀtriazinꢀ5(4H)ꢀone (4d). Triazinone 1b (0.287 mmol) and
phenol 2 (0.319 mmol) were refluxed in a mixture of CF3COOH
(1 mL) and trifluoroacetic anhydride (1 mL) for 1.5 h. The solꢀ
vents were removed and the oily residue was triturated with
a small amount of water. The resulting colorless powder was
density (ρmin/ρmax)/e Å–3
–0.173/0.165
centrated. The resulting oily residue was dissolved in DMF
(7 mL) and refluxed for 1 h. The precipitate that formed was
crystallized from ethanol. The yield was 86%, gray crystalline
powder, m.p. 244 °C. 1H NMR (DMSOꢀd6), δ: 14.37 (br.s, 1 H,
NH); 8.80—8.82 (m, 1 H, C(6)H); 8.30—8.32 (m, 1 H, Py);
8.12—8.13 (m, 1 H, Py); 8.10—8.11 (m, 1 H, Py); 7.73—7.75
(m, 1 H, Py). Found (%): C, 55.10; H, 3.38; N, 31.95. C8H6N4O.
Calculated (%): C, 55.17; H, 3.47; N, 32.17.
1ꢀAcetylꢀ6ꢀ[4ꢀhydroxyꢀ3ꢀmethylꢀ5ꢀ(1,7,7ꢀtrimethylbicycloꢀ
[2.2.1]heptꢀ2ꢀyl)phenyl]ꢀ3ꢀphenylꢀ1,6ꢀdihydroꢀ1,2,4ꢀtriazinꢀ
5(4H)ꢀone (4a). A. Acetic anhydride (3 mL) was added to triazinꢀ
one 1a (1.2 mmol) and phenol 2 (1.2 mmol). The reaction mixꢀ
ture was refluxed for 1 h and kept at room temperature for 24 h.
The resulting colorless crystals were filtered off and washed with
a small amount of acetic anhydride and diethyl ether. The yield
20
was 32%, m.p. > 260 °C, Rf 0.8 (ethyl acetate), [α]D 0 (c 1.0,
DMF). 1H NMR (DMSOꢀd6), δ: 11.44 (s, 1 H, OH); 7.95 (s, 1 H,
NH); 7.84—7.89 (m, 2 H, Ph); 7.38—7.47 (m, 3 H, Ph);
6.88—6.90 (m, 1 H); 6.76—6.78 (m, 1 H); 5.89 (s, 1 H, C(6)H);
3.15—3.20 (m, 1 H, CH); 2.34—2.35 (m, 3 H); 2.15 (s, 3 H);
1.68—1.88 (m, 3 H); 1.43—1.52 (m, 3 H); 1.23—1.30 (m, 1 H);
0.72—0.75 (m, 3 H); 0.62—0.68 (m, 6 H). Found (%): C, 73.34;
H, 7.52; N, 9.35. C28H33N3O3. Calculated (%): C, 73.18;
H, 7.24; N, 9.14.
B. Acetic acid (3 mL) and acetic anhydride (1 mL) were
added to triazinone 1a (1.2 mmol) and phenol 2 (1.2 mmol). The
reaction mixture was refluxed for 1 h and kept at room temperaꢀ
ture for 24 h. The resulting colorless crystals were filtered off and
washed with acetic acid and diethyl ether. The yield was 30%.

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Egorov et al.
crystallized from methanol. The yield was 85%, m.p. 189—191 °C.
1H NMR (DMSOꢀd6), δ: 11.50 (br.s, 1 H, OH); 8.70—8.71
(m, 1 H, NH); 8.36—8.37 (m, 1 H, Py); 8.02—8.07 (m, 2 H, Py);
7.62—7.64 (m, 1 H, Py); 6.93—6.94 (m, 2 H, Ph); 5.80 (s, 1 H,
C(6)H); 3.17—3.33 (m, 1 H); 2.16 (s, 3 H, Me); 1.65—1.73 (m, 3 H);
1.49.—1.52 (m, 3 H); 1.40—1.47 (m, 1 H); 0.71 (s, 1 H); 0.66
(s, 2 H); 0.63 (s, 2 H); 0.59 (s, 1 H); 0.57 (s, 2 H); 0.50 (s, 1 H).
Found (%): C, 63.21; H, 5.74; N, 10.68; F, 10.55. C28H33N4O3F3.
Calculated (%): C, 63.38; H, 6.27; N, 10.56; F, 10.74.
crystalline powder, m.p. 225 °C, Rf 0.8 (ethyl acetate). 1H NMR
(DMSOꢀd6), δ: 11.28 (s, 1 H, NH); 7.77 (d, 1 H, 4ꢀMeC6H4,
J = 8.2 Hz); 7.43 (d, 2 H, 4ꢀMeC6H4, J = 8.2 Hz); 7.31 (d, 2 H,
Ts, J = 8.1 Hz); 7.16 (d, 1 H, OH, J = 6.8 Hz); 7.04 (d, 2 H, Ts,
J = 8.1 Hz); 5.35 (d, 1 H, C(6)H, J = 6.8 Hz); 4.65 (dd, 1 H, CH,
J1 = 7.8 Hz, J2 = 10.4 Hz); 2.43 (s, 3 H, Me); 2.33 (s, 3 H, Me);
2.02 (m, 1 H, CH); 1.01 (d, 3 H, Me, J = 6.7 Hz); 0.92 (d, 3 H,
Me, J = 6.7 Hz). Found (%): C, 57.80; H, 5.90; N, 11.97.
C22H26N4O5S. Calculated (%): C, 57.63; H, 5.72; N, 12.22.
1ꢀAcetylꢀ6ꢀhydroxyꢀ3ꢀphenylꢀ1,6ꢀdihydroꢀ4Hꢀ[1,2,4]triꢀ
azinꢀ5ꢀone (5). Acetic acid (3 mL) and acetic anhydride (1 mL)
were added to 3ꢀphenylꢀ1,2,4ꢀtriazinꢀ5ꢀone (1a) (1.2 mmol).
The reaction mixture was refluxed for 1 h and concentrated
in vacuo. The residue was chromatographed on silica gel with
ethyl acetate—chloroform (1 : 1) as an eluent. The yield was 42%,
colorless crystalline powder, m.p. 195 °C, Rf 0.4 (AcOEt—CHCl3,
This work was financially supported by the Council on
Grants at the President of the Russian Federation (State
Support Program for Leading Scientific Schools of the
Russian Federation, Grant NShꢀ65261.2010.3) and the
Ministry of Education and Science of the Russian Federaꢀ
tion (State Contract No. 02.740.11.0260).
1
1 : 1). H NMR (DMSOꢀd6), δ: 11.44 (s, 1 H, NH); 7.89—7.91
(m, 2 H, Ph); 7.41—7.46 (m, 3 H, Ph); 7.20 (d, 1 H, OH, J = 6.3 Hz);
5.92 (d, 1 H, C(6)H, J = 6.3 Hz); 2.36 (s, 3 H, MeCO).
Found (%): C, 56.61; H, 4.72; N, 18.04. C11H11N3O3. Calculatꢀ
ed (%): C, 56.65; H, 4.75; N, 18.02.
References
1. E. V. Kuzakov, E. N. Shmidt, Khim. Prir. Soedin., 2000, 198
[Chem. Nat. Compd. (Engl. Transl.), 2000, 36, 245].
2. A. A. Semenov, Ocherk khimii prirodnykh soedinenii [Essay
on the Chemistry of Naturally Occurring Compounds], Nauka,
Novosibirsk, 2000, 664 pp. (in Russian).
3. V. V. Plemenkov, Vvedenie v khimiyu prirodnykh soedinenii
[Introduction to the Chemistry of Naturally Occurring Comꢀ
pounds], Kazan, 2001, 376 pp. (in Russian).
4. V. V. Ershov, G. A. Nikiforov, A. A. Volod´kin, Prostranꢀ
stvennoꢀzatrudnennye fenoly [Sterically Hindered Phenols],
Khimiya, Moscow, 1972, 352 pp. (in Russian).
5. Z. M. Petrykina, A. N. Polin, I. S. Belostotskaya, N. L.
Komissarova, V. B. Vol´eva, L. G. Plekhanova, V. V. Erꢀ
shov, Antibiot. Khimioter. [Antibiotics and Chemotherapy],
1998, 43, No. 8, 11 (in Russian).
1ꢀAcetylꢀ6ꢀ[2ꢀhydroxyꢀ5ꢀmethylꢀ3ꢀ(1,7,7ꢀtrimethylbicycloꢀ
[2.2.1]heptꢀ2ꢀyl)phenyl]ꢀ3ꢀphenylꢀ1,6ꢀdihydroꢀ1,2,4ꢀtriazinꢀ
5(4H)ꢀone (6). Trifluoroacetic acid (0.1 mL) and acetic anꢀ
hydride (0.5 mL) were added to a suspension of triazinone 1a
(1.2 mmol) and phenol 3 (1.2 mmol) in CH2Cl2 (8 mL). The
resulting solution was stirred at room temperature for 24 h. The
precipitate that formed was filtered off. The yield was 24%, colorꢀ
less crystalline powder, m.p. > 260 °C, Rf 0.8 (AcOEt). 1H NMR
(DMSOꢀd6), δ: 11.92—11.95 (m, 1 H, OH); 8.76—8.79 (m, 1 H,
NH); 7.93—7.96 (m, 2 H, Ph); 7.45—7.51 (m, 3 H, Ph); 6.98
(s, 1 H); 6.42 (s, 1 H); 6.10—6.11 (m, 1 H, C(6)H); 3.27—3.33
(m, 1 H, CH); 2.38—2.39 (m, 3 H); 2.06—2.14 (m, 4 H);
1.79—1.85 (m, 2 H); 1.47—1.55 (m, 3 H); 1.29—1.36 (m, 1 H);
0.81—0.83 (m, 6 H); 0.70—0.73 (m, 3 H). Found (%): C, 73.12;
H, 7.28; N, 9.09. C28H33N3O3. Calculated (%): C, 73.18;
H, 7.24; N, 9.14.
6. P. K. Witting, B. J. Wu, M. Raftery, P. SouthwellꢀKeely,
R. Stocker, J. Biol. Chem., 2005, 280, 15612.
Triazine derivatives of valine (9). Aluminum trichloride
(0.01 mmol) and NꢀTsꢀLꢀvaline acid chloride 7 (1.2 mmol) were
added at –5 to 0 °C to THF (3 mL). The solution was stirred for
5 min. Then triazinone 1 (1.2 mmol) and, after 5 min, an approꢀ
priate phenol 8a,b or 2 (1.2 mmol) were added. The reaction
mixture was stirred at 0—5 °C for 1 h and then at room temperature
for 1 h and poured into cooled water (50 mL). The product was
extracted with ethyl acetate (2×30 mL). The combined extracts
were dried with Na2SO4, concentrated on a rotary evaporator,
and chromatographed on silica gel with ethyl acetate as an eluent.
6ꢀHydroxyꢀ1ꢀ(3ꢀmethylꢀ2(S)ꢀtosylaminobutanoyl)ꢀ3ꢀphenylꢀ
5,6ꢀdihydroꢀ1,2,4ꢀtriazinꢀ5(4H)ꢀone (9a). Colorless crystalline
7. US Pat. 5 166 348A; Chem. Abstr., 1993, 115, 183354.
8. V. L. Rusinov, G. V. Zyryanov, T. L. Pilitcheva, O. N.
Chupakhin, H. Neunhoeffer, J. Heterocycl. Chem., 1997,
34, 1013.
9. O. N. Chupakhin, G. L. Rusinov, D. G. Beresnev, H. Neunꢀ
hoeffer, J. Heterocycl. Chem., 1997, 34, 573.
10. G. L. Rusinov, D. G. Beresnev, N. A. Itsikson, O. N. Chuꢀ
pakhin, Heterocycles, 2001, 12, 2349.
11. N. A. Itsikson, D. G. Beresnev, G. L. Rusinov, O. N. Chupaꢀ
khin, ARKIVOC, 2004, 12, 6.
12. I. N. Egorov, G. V. Zyryanov, E. N. Ulomsky, V. L. Rusiꢀ
nov, O. N. Chupakhin, Tetrahedron Lett., 2006, 47, 7485.
13. V. Uchutilova, P. Fiedler, M. Prystas, J. Gut, Collect. Czech.
Chem. Commun., 1971, 36, 1955.
20
powder, m.p. 229—230 °C, Rf 0.8 (ethyl acetate), [α]D –29.7
1
(c 1.0, DMF). H NMR (DMSOꢀd6), δ: 11.32 (s, 1 H, NH);
7.87—7.89 (m, 2 H, Ph); 7.64 (d, 1 H, NH, J = 10.4 Hz); 7.45
(d, 2 H, Ts, J = 8.2 Hz); 7.48—7.51 (m, 3 H, Ph); 7.14 (d, 1 H,
OH, J = 6.9 Hz); 7.05 (d, 2 H, Ts, J = 8.2 Hz); 5.38 (d, 1 H,
C(6)H, J = 6.8 Hz); 4.66 (dd, 1 H, CH, J1 = 7.7 Hz, J2 = 10.4 Hz);
2.32 (s, 3 H, Me); 1.99—2.07 (m, 3 H, CH); 1.01 (d, 3 H, Me,
J = 6.8 Hz); 0.93 (d, 1 H, Me, J = 6.8 Hz). Found (%): C, 56.88;
H, 5.63; N, 12.40. C21H24N4O5S. Calculated (%): C, 56.74;
H, 5.44; N, 12.60.
14. I. Yu. Chukicheva, A. V. Kuchin, Ross. Khim. Zh., 2004, 48,
21 [Mendeleev Chem. J. (Engl. Transl.), 2004, 48, No. 3].
15. CrysAlisPro (Version 171.31.8), CrysAlisRed (Version
1.171.31.8), Oxford Diffraction, Ltd., Abingdon, Oxfordꢀ
shire, England, 2007.
16. G. M. Sheldrick, Acta Crystallogr. A: Found. Crystallogr., 2008,
64, 112.
6ꢀHydroxyꢀ3ꢀ(4ꢀmethylphenyl)ꢀ1ꢀ(3ꢀmethylꢀ2(S)ꢀtosylamiꢀ
nobutanoyl)ꢀ5,6ꢀdihydroꢀ1,2,4ꢀtriazinꢀ5(4H)ꢀone (9b). Colorless
Received October 13, 2010