Synthesis of some 1-(Flavon-7-yl)-4,5-dihydro-1,2,4-triazin-6(1H)-ones and related congeners

Article abstract of DOI:10.2174/157017812802139573

Herein, a selected set of chiral N1-(4-oxochromen-7-yl)-4,5-dihydro-1,2,4- triazin-6(1H)-ones (7a-k/8a-k) were prepared via direct interaction of L-α-amino esters with N1-(4-oxochromen-7-yl) nitrile imines (generated in situ from their hydrazonoyl chloride precursors 5a,b by the action of triethylamine). These novel dihydrotriazinone-flavone hybrid compounds (7), their 2-methylchromenone analogs (8) and the L-proline homologs (9,10) were characterized by microanalytical and spectral (HRMS and NMR) data. Compounds 7a and 7i displayed good activity against (MCF-7) breast cancer.

Full text of DOI:10.2174/157017812802139573

Letters in Organic Chemistry, 2012, 9, 465-473
465
Synthesis of Some 1-(Flavon-7-yl)-4,5-dihydro-1,2,4-triazin-6(1H)-ones and
Related Congeners
Marwa N. Abu-Aisheha, Mohammad S. Mustafaa, Mohammad S. Mubaraka, Mustafa M.
El-Abadelah*,a and Wolfgang Voelter*,b
aDepartment of Chemistry, Faculty of Science, The University of Jordan, Amman 11942, Jordan
bInterfakultäres Institut für Biochemie, Universität Tübingen, Hoppe-Seyler-Straße 4, 72076 Tübingen, Germany
Received April 09, 2012: Revised June 29, 2012: Accepted July 03, 2012
Abstract: Herein, a selected set of chiral N1-(4-oxochromen-7-yl)-4,5-dihydro-1,2,4-triazin-6(1H)-ones (7a-k / 8a-k)
were prepared via direct interaction of L-ꢀ-amino esters with N1-(4-oxochromen-7-yl) nitrile imines (generated in situ
from their hydrazonoyl chloride precursors 5a,b by the action of triethylamine). These novel dihydrotriazinone-flavone
hybrid compounds (7), their 2- methylchromenone analogs (8) and the L-proline homologs (9,10) were characterized by
microanalytical and spectral (HRMS and NMR) data. Compounds 7a and 7i displayed good activity against (MCF-7)
breast cancer.
Keywords: 7-Aminoflavone, 7-amino-2-methylchromen-4-one, 4-oxo-N-(chromen-7-yl)hydrazonoyl chlorides, antitumor ac-
tivity L-ꢀ-amino esters, nitrileimine, substituted dihydro-1,2,4-triazin-6-ones.
INTRODUCTION
free radical processes [21]. They also possess low mammal-
ian toxicity and are present in large amounts in the diet of
humans due to their origin in plants [22], especially in fruits
and vegetables [23]. Flavonoids, a group of benzopyrone
derivatives [24], have been recognized as one of the largest
and most widespread classes of plant constituents occurring
throughout the plant kingdom [25]. A great number of bio-
logical aspects were reported for flavones [26], such as bio-
cidal [27], immune-stimulatory [28], anti-ulcer [29], anti-
estrogenic [30], anti-tumor [31], anti-allergic [32], anti-
inflammatory [33], anti-viral [34], and anti-HIV [35], activi-
ties.
The chemistry of triazinone derivatives has been the sub-
ject of much interest in recent years due to use of such ring
system as the core structure in many heterocyclic com-
pounds covering a wide range of pharmacological applica-
tions. A number of 1,2,4-triazinone derivatives possess sig-
nificant biological activities, such as 5-lipoxygenase (5-LO)
inhibitory [1], bactericidal [2], fungicidal [3], antimicrobials
[4], antiproliferative [5], antiviral [6], CRF1 receptor antago-
nist [7], pesticidal [8], herbicidal [9], as well as blood plate-
let aggregation-inhibitory [10], while some others exhibit
anti-HIV [11], antitumoral activity against leukemia [12],
lymphoma [13], ovarian, lung, and breast cancer [14]. Re-
cently, 1,2,4-triazinone derivatives have gained great atten-
tion as ligands to transition metals [15].
RESULTS AND DISCUSSION
Synthesis
Among the different 1,2,4-triazinones described in the
literature, only a few are 4,5-dihydro-1,2,4-triazin-6-ones.
These compounds are best prepared via cyclocondesation
reactions of various nitrileimines with the respective ꢀ-
amino esters [16, 17], or with ꢀ-hydrazino esters [18].
The
2-oxo-N-(4-oxo-2-phenyl-4H-chromen-7-yl)pro-
panehydrazonoyl chloride synthon (5), required in this study,
was prepared via direct coupling of 7-flavone diazonium
chloride or 7-(2-methylchromen-4-one) diazonium chloride
with 3-chloropentane-2,4-dione (Japp-Klingemann reaction)
[36] (Scheme 1).
On the other hand, chromones occur widely in nature,
and have attracted much synthetic interest because of their
reactivity and biological activity of their naturally-occurring
representatives [19]. Chromones are well-known for their
antioxidant activity [20], a property that stems from their
ability to neutralize active forms of oxygen, and to cut off
The former intermediate arenediazonium chloride solu-
tion was freshly prepared by diazotization of 7-aminoflavone
(or 7-amino-2-methylchromen-4-one). ꢀ-Amino esters (6a-
k), acting as nitrogen nucleophiles, are expected to add onto
nitrile imine, generated in situ from the corresponding hy-
drazonoyl chloride (5) by the action of triethyl amine, to give
initially the corresponding Z-amidrazone esters as the kineti-
cally-controlled product; the latter transient acyclic adducts
undergo spontaneous intramolecular condensation, involving
the amidrazone nitrogen and the ester carbonyl group, to
* Address correspondence to this author at the Interfakultäres Institut für
Biochemie, Universität Tübingen, Hoppe-Seyler Str. 4, D-72076 Tübingen,
Germany, The University of Jordan, Amman-Jordan; Tel: 070717-2973041;
Fax: 07071-650016;
E-mails: wolfgang.voelter@uni-tuebingen.de; mustelab@ju.edu.jo
1875-6255/12 $58.00+.00
© 2012 Bentham Science Publishers

466 Letters in Organic Chemistry, 2012, Vol. 9, No. 7
Wolfgang et al.
O
O
O
6N HCl /
NaNO2
(Ac)2CHCl
0 - 5 °C
aq. NaOAc, EtOH /
-5 to 0 °C
X
H2N
O
X
ClN2
4a (X = Ph)
(X = Me)
4b
O
O
5
4
4a
3
6
Cl
Cl
-AcOH
N
Ac
N
7
2
8a
X
N
O
X
N
O
Ac
8
H
1
Ac
(X = Ph)
(X = Me)
5a
5b
Scheme 1. Synthesis of N-((2-substituted)-4-oxo-2H-chromen-7-yl)-2-oxopropanehydrazonoyl chloride (5).
O
5'
4'
4'a
8'a
O
3'
2'
6'
Ac
C
N
N
2
NEt3 / EtOH
-5 to 0 °C
1
N
Ac
N
(5)
7'
O
O
1'
X
3
O
8'
O
6
N
4
OMe
X
R'
5
HN
R'
H
R
R
7a-k ( X = Ph)
7a-j (R' = H)
7k (R' = Me)
8a-k (X = Me)
8a-j (R' = H)
8k (R' = Me)
6a-j (R' = H)
6k (R' = Me)
R
entry
R
R
H
entry
entry
CH2CH2CO2Me
CH2
a
i
e
CH2OH
Me
CH(OH)Me
CH2CH2SMe
b
f
j
g
N
H
CH2CHMe2
CH2Ph
c
H
h
k
CH2CO2Me
d
Scheme 2. Synthesis of compounds (7a-k and 8a-k).
O
5'
4'a
4'
6'
3'
2'
O
OMe
3
2
N
Ac
6
N
4
NEt3 / EtOH
-5 to 0 °C
7'
O
8'a
O
X
(5)
8'
1'
1
5
HN
N
8a
8
7
9 (X = Ph)
10 (X = Me)
Scheme 3. Synthesis of pyrrolo[1,2-d][1,2,4]triazin-1-one (9 and 10).
yield the respective targeted heterocycles (7a-k / 8a-k)
(Scheme 2).
via reacting ꢀ-amino esters with N-arylhydrazonoyl chlo-
rides [16].
Proline methyl ester reacted with (5) in a similar fashion
to give the corresponding bicyclic triazinones (9/10)
(Scheme 3).
The newly synthesized compounds 7a-k, 8a-k, 9, and 10
were characterized by elemental analyses, MS and NMR
spectral data. These data, detailed in the experimental part,
are consistent with the suggested structures. Thus, the mass
spectra display the correct molecular ion peaks for which the
This methodology was modeled on previously reported
synthesis of related N-aryl 4,5-dihydro-1,2,4-triazin-2-ones

Synthesis of Some 1-(Flavon-7-yl)-4,5-dihydro-1,2,4-triazin-6(1H)-ones
Letters in Organic Chemistry, 2012, Vol. 9, No. 7
467
Table 1. Percentage Cell Survival of MCF-7 Following 72
Table 2. Effects of Compounds 7a and 7i on MCF-7 and K562
Hours Exposure to 50 ꢀM of all Compounds
Compound
IC50 MCF-7 (μM)
IC50 K562 (μM)
Standard
Deviation
Compound a
% Survival at 50 ꢀM
7a
7i
42.58 ± 9.79
30.52 ± 1.02
>100
>100
7a
7b
7d
7f
48.80
58.33
36.93
86.55
92.50
79.49
61.63
77.51
96.12
85.19
91.07
62.63
87.65
95.65
0.79
0.31
0.51
0.35
0.31
2.45
0.26
2.39
1.80
0.93
1.32
0.51
3.16
2.33
drochlorides of aspartic and glutamic acids. Silica gel for
column chromatography was purchased from Macherey-
Nagel GmbH & Co (Germany). Melting points (uncorrected)
were determined on a Stuart scientific melting point appara-
tus in open capillary tubes. Optical rotations were taken on a
Perkin Elmer 141 photoelectric spectropolariometer in di-
7g
7i
methylformamide (c ~ 1), at 20 ± 1 °C. H- and 13C-NMR
1
7k
8a
8b
8d
8f
spectra were recorded on a 300 MHz spectrometer (Bruker
DPX-300) with TMS as the internal standard. Chemical
shifts are expressed in ꢁ units, J-values for H-1H coupling
1
constants are given in Hertz. Elemental analyses were per-
formed on a Euro Vector elemental analyzer, model EA
3000. High resolution mass spectra (HRMS) were acquired
(in positive or negative mode) using electrospray ion trap
(ESI) technique by collision-induced dissociation on a
Bruker APEX-4 (7-Tesla) instrument. The samples were
dissolved in acetonitrile, diluted in spray solution (metha-
nol/water 1:1 v/v + 0.1% formic acid) and infused using a
syringe pump with a flow rate of 2 μL/min. External calibra-
tion was conducted using arginine cluster in a mass range
m/z 175-871.
8g
8k
10
a The remaining 10 compounds were inactive at 50 ꢀM
measured high resolution (HRMS) data are in good agree-
ment with the calculated values. DEPT and 2D (COSY,
HMQC, HMBC) experiments showed correlations that
General procedure for preparation of N-([2-substituted]-4-
oxo-4H-chromen-7-yl)-2-oxo-propanehydrazonoyl
rides (5a,b)
helped in the H and 13C- signal assignments to the different
1
chlo-
carbons and their attached, and/or neighboring hydrogens.
The Title Compounds were Prepared by the Following
Procedure
Antitumor Activity Results
The antitumor activity of the 24 compounds (7a-k, 8a-k,
9 and 10 / Scheme 2 and 3) was evaluated by conducting cell
viability assay using tetrazolium dye 3-(4,5-dimethylthiazol-
2-yl)-2,5-diphenyltetrazolium bromide (MTT). The tests
were performed on cultures of MCF-7 breast cancer at two
concentrations of 10 and 50 ꢀM and the results are shown in
Table 1.
Step (i): 7-Aminoflavone 4a or 7-Amino-2-methyl-
chromen-4-one 4b (0.10 mol) was dissolved in 17% aqueous
hydrochloric acid (160 mL). To this a solution was added,
dropwise, a solution of sodium nitrite (7.6 g, 0.11 mol) in
water (15 mL) with efficient stirring at 0-5°C. Stirring was
continued for 20-30 min, and the resulting fresh cold, fla-
vone-7-diazonium chloride
/ 2-methylchromen-4-one-7-
diazonium chloride solution was used immediately as such
for the following coupling reaction.
At 50 ꢀM concentration, compounds 7a and 7i showed a
potential anti–MCF-7 activity. These two compounds were
able to reduce the viability after 72 hours to less than 50%.
However, none of the compounds retained the activity at 10
ꢀM. The IC50 values were determined for the potential com-
pounds 7a and 7i against MCF-7 (Table 2). Moreover, the
anti-leukemic effects of these two potential compounds were
tested against K526 cell line, yet neither has shown any po-
tential activity.
Step (ii): A cold (–5 °C) freshly prepared solution of fla-
vone-7-diazonium chloride
/ 2-methylchromen-4-one-7-
diazonium chloride (0.1 mol) was poured onto cold solution
(–10 to 0 °C, ice-salt bath) of 3-chloropentan-2,4-dione (13.5
g, 0.1 mol) in ethanol/water (160 mL, 1:1 v/v) containing
30.0 g of sodium acetate with vigorous stirring. The resulting
orange-colored mixture was further stirred until a solid pre-
cipitate was formed (5-10 min). The reaction mixture was
then diluted with cold water (200 mL), the solid product was
collected by suction filtration, washed several times with
cold water, dried, and recrystallized from the appropriate
solvent.
EXPERIMENTAL
MATERIALS AND EQUIPMENTS
The following chemicals used, in this study, were pur-
chased from Acros and were used as received: (L)-ꢀ-Amino
acid methyl ester hydrochlorides of alanine, leucine, pheny-
lalnine, glycine, tryptophane, serine, threonine, methionine,
sarcosine, and proline, (L)-ꢀ-amnio acid dimethyl ester hy-
2-Oxo-N-(4-oxo-2-phenyl-4H-chromen-7-yl) Propanehy-
drazonoyl Chloride (5a)
Yield: 95 %; mp: 271-272 °C (recryst. from ethanol). 1H
NMR (300 MHz, CDCl3): ꢁ 2.64 (s, 3H, CH3), 6.79 (s, 1H,

468 Letters in Organic Chemistry, 2012, Vol. 9, No. 7
Wolfgang et al.
H-3), 7.20 (m, 1H, H-6), 7.39 (d, J = 1.8 Hz, 1H, H-8), 7.52-
7.54 (m, 3H, H-3' + H-4' + H-5'), 7.90- 7.93 (m, 2H, H-2' +
H-6'), 8.22 (d, J = 8.5 Hz, 1H, H-5), 8.64 (s, 1H, N-H). 13C
NMR (75 MHz, CDCl3): ꢀ 26.1 (CH3), 102.6 (C-8), 107.4
(C-3), 113.8 (C-6), 118.8 (C-4a), 126.2 (C-1'), 126.8 (C-2' /
C-6'), 127.0 (C-4'), 129.6 (C-3' / C-5'), 131.7 (C-7), 132.2
(C-5), 148.0 (-C=N), 157.5 (C-8a), 162.6 (C-2), 176.8 (C-4),
188.7 (O=C-Me). HRMS (ESI) m/z: Calcd for
C18H13ClN2O3Na [M + Na]+ 363.05124; found 363.05069.
Anal. Calcd for C18H13ClN2O3 (340.76): C, 63.44; H, 3.85;
N, 8.22, found: C, 63.18; H, 3.74; N, 8.04.
1H, H-6'), 7.91-7.94 (m, 2H, H-2'' + H-6''), 8.02 (d, J = 1.8
Hz, 1H, H-8'), 8.24 (d, J = 8.8 Hz, 1H, H-5'). 13C-NMR (75
MHz, CDCl3): ꢀ 19.6 (CH3(CH)-5), 24.0 (O=C-CH3), 49.6
(C-5), 107.8 (C-8'), 112.9 (C-3'), 120.6 (C-6'), 121.8 (C-4'a),
125.9 (C-4''), 126.4 (C-2'' / C-6''), 129.1 (C-3'' / C-5''), 131.7
( C-1''), 132.3 (C-5'), 143.6 (C-7'), 145.6 (C-3), 156.1 (C-
8'a), 163.4 (C-2'), 163.9 (C-6), 177.0 (C-4'), 193.2 (O=C-
Me). HRMS (ESI) m/z: Calcd for C21H18N3O4 [M + H]+
376.12973; found 376.12918. Anal. Calcd for C21H18N3O4
(375.38): C, 67.19; H, 4.56; N, 11.19; found: C, 67.11; H,
4.48; N, 11.07.
N-(2-Methyl-4-oxo-4H-chromen-7-yl)-2-
oxopropanehydrazonoyl Chloride (5b)
(S)-3-Acetyl-5-isobutyl-1-(4-oxo-2-phenyl-4H-chromen-7-
yl)-4,5-dihydro-1,2,4-triazin-6(1H)-one (7c)
o
o
Yield: 91 %; mp: 274-276 C (recryst. from acetonitrile).
Yield: 20 %, mp = 135-136 C. [ꢁ] = – 120 o (c ~ 1,
D
1H NMR (300 MHz, DMSO-d6): ꢀ 2.38 (s, 3H, CH3-2), 2.40
(s, 3H, O=C-CH3), 6.11 (s, 1H, H-3), 7.27 (d, J = 1.8 Hz,
1H, H-8), 7.40 (dd, J = 8.7, 1.8 Hz, 1H, H-6), 8.19 (d, J =
8.7 Hz, 1H, H-5), 9.56 (s, 1H, N-H). 13C NMR (75 MHz,
DMSO-d6): ꢀ 20.7 (CH3-2), 26.1 (O=C-CH3), 100.9 (C-8),
110.1 (C-3), 112.5 (C-6), 118.1 (C-4a), 127.5 (C-5), 145.4
(C-7), 147.8 (-C=N), 158.0 (C-8a), 165.5 (C-2), 177.8 (C-4),
189.1 (O=C-Me). HRMS (ESI) m/z: Calcd for C13H12ClN2O3
[M + H]+ 279.05364; found 279.05310. Anal. Calcd for
C13H11ClN2O3 (278.69): C 56.03, H 3.98, N 10.05, found: C,
56.14; H, 4.02; N, 9.88.
DMF). 1H-NMR (300 MHz, CDCl3): ꢀ 0.98 (dd, J = 7.6, 6.2
Hz, 6H, (CH3)2CH), 1.67 (m, 1H, CHMe2), 1.80 (m, 2H,
CH2-5), 2.54 (s, 3H, O=C-CH3), 4.23 (m, 1H, H-5), 5.99 (s,
1H, NH-4), 6.81 (s, 1H, H-3'), 7.51-7.52 (m, 3H, H-3'' + H-
4'' + H-5''), 7.78 (dd, J = 8.8, 1.8 Hz, 1H, H-6'), 7.90-7.93
(m, 2H, H-2'' + H-6''), 8.01 (d, J = 1.8 Hz, 1H, H-8'), 8.23 (d,
J = 8.8 Hz, 1H, H-5'). 13C-NMR (75 MHz, CDCl3): ꢀ 21.6
((CH3)2CH), 23.1 (CHMe2), 24.1 (O=C-CH3), 42.0 (CH2-5),
52.2 (C-5), 107.7 (C-8'), 112.8 (C-3'), 120.7 (C-6'), 121.7
(C-4'a), 126.0 (C-4''), 126.4 (C-2'' / C-6''), 129.1 (C-3'' / C-
5''), 131.7 ( C-1''), 131.8 (C-5'), 142.2 (C-7'), 145.0 (C-3),
156.0 (C-8'a), 162.8 (C-2'), 163.8 (C-6), 178.0 (C-4'), 192.9
(O=C-Me). HRMS (ESI) m/z: Calcd for C24H22N3O4 [M –
H]– 416.16103; found 416.16158. Anal. Calcd for
C24H23N3O4 (417.46): C, 69.05; H, 5.55; N, 10.07; found: C,
69.16; H, 5.44; N, 9.92.
General Procedure for the Syntheses of Compounds (7-10)
To a cold suspension (0 to -10 °C) of 2.0 mmol of com-
pound (5) in 20.0 mL of ethanol was added, with stirring, a
cold solution of the appropriate L-(ꢁ)-amino acid methyl
ester hydrochloride (2.1 mmol) and triethylamine (3 mL) in
10 mL of ethanol. Stirring was continued at 0 to 5 °C for 2-4
h, and then at ambient temperature for 24 h. The solvent was
evaporated and the residue was treated with water (15 mL).
The resulting crude solid product was collected by suction
filtration, washed with water, dried and purified on prepara-
tive silica gel TLC plates.
(S)-3-Acetyl-5-benzyl-1-(4-oxo-2-phenyl-4H-chromen-7-
yl)-4,5-dihydro-1,2,4-triazin-6(1H)-one (7d)
o
Yield: 44 %, mp = 151-152 C. [ꢁ] = – 350 o (c ~ 1,
D
1
DMF). H-NMR (300 MHz, CDCl3): ꢀ 2.41 (s, 3H, CH3),
2.63 (m, 2H, CH2Ph), 4.48 (m, 1H, H-5), 5.92 (s, 1H, NH-4),
6.82 (s, 1H, H-3'), 7.13 -7.16 (m, 2H, H-2''' + H-6'''), 7.28 -
7.32 (m, 3H, H-3''' + H-4''' + H-5'''), 7.50 – 7.54 (m, 3H, H-
3'' + H-4'' + H-5''), 7.66 (dd, J = 8.8, 2.0 Hz, 1H, H-6'), 7.91
– 7.93 (m, 2H, H-2'' + H-6''), 7.94 (d, J = 2.0 Hz, 1H, H-8'),
8.23 (d, J = 8.8 Hz, 1H, H-5'). 13C-NMR (75 MHz, CDCl3):
ꢀ 23.9 (O=C-CH3), 40.3 (CH2-Ph), 55.2 (C-5), 107.8 (C-8'),
113.0 (C-3'), 120.8 (C-6'), 121.9 (C-4'a), 125.9 (C-4''), 126.4
(C-2''/C-6''), 127.7 (C-4'''), 129.0 (C-2''' / C-6'''), 129.1 (C-3''
/ C-5''), 129.6 (C-3''' / C-5'''), 131.7 ( C-1''), 131.8 (C-5'),
134.9 (C-1'''), 141.9 (C-7'), 144.7 (C-3), 156.2 (C-8'a), 161.9
(C-2'), 163.8 (C-6), 177.9 (C-4'), 192.6 (O=C-Me). HRMS
(ESI) m/z: Calcd for C27H20N3O4 [M – H]– 450.14538; found
450.14593. Anal. Calcd for C27H21N3O4 (451.47): C, 71.83;
H, 4.69; N, 9.31; found: C, 71.58; H, 4.58; N, 9.16.
3-Acetyl-1-(4-oxo-2-phenyl-4H-chromen-7-yl)-4,5-dihydro-
1,2,4-triazin-6(1H)-one (7a)
o
1
Yield: 97 %, mp = 275-276 C. H-NMR (300 MHz,
DMSO-d6): ꢀ 2.46 (s, 3H, CH3), 4.04 (s, 2H, H2-5), 7.02 (s,
1H, H-3'), 7.56-7.58 (m, 3H, H-3'' + H-4'' + H-5''), 7.72 (br.
s, 1H, NH-4), 7.85 (dd, J = 8.8, 1.7 Hz, 1H, H-6'), 8.04-8.12
(m, 4H, H-5' + H-8' + H-2'' + H-6''). 13C-NMR (75 MHz,
DMSO-d6): ꢀ 24.9 (CH3), 43.8 (C-5), 107.6 (C-8'), 112.8 (C-
3'), 121.2 (C-6'), 121.3 (C-4'a), 125.4 (C-4''), 126.9 (C-2'' /
C-6''), 129.7 (C-3'' / C-5''), 131.6 (C-1''), 132.4 (C-5'), 143.7
(C-7'), 145.4 (C-3), 156.1 (C-8'a), 160.8 (C-2'), 163.3 (C-6),
177.0 (C-4'), 193.1 (O=C-Me). HRMS (ESI) m/z: Calcd for
C20H16N3O4 [M + H]+ 362.11408; found 362.11353. Anal.
Calcd for C20H15N3O4 (361.35): C, 66.48; H, 4.18; N, 11.63;
found: C, 66.25; H, 4.12; N, 11.42.
(S)-3-Acetyl-5-(hydroxymethyl)-1-(4-oxo-2-phenyl-4H-
chromen-7-yl)-4,5-dihydro-1,2,4-triazin-6(1H)-one (7e)
o
Yield: 96 %, mp = 271-272 C. [ꢁ] = – 226 o (c ~ 1,
D
(S)-3-Acetyl-5-methyl-1-(4-oxo-2-phenyl-4H-chromen-7-
yl)-4,5-dihydro-1,2,4-triazin-6(1H)-one (7b)
DMF). 1H-NMR (300 MHz, DMSO-d6): ꢀ 2.43 (s, 3H, CH3),
3.57-3.85 (m, 2H, CH2-5), 4.17 (br s, 2H, H-5), 5.18 (t, J =
5.7 Hz, 1H, OH), 7.02 (s, 1H, H-3'), 7.55-7.57 (m, 3H, H-3''
+ H-4'' + H-5''), 7.70 (br. s, 1H, NH-4), 7.83 (dd, J = 8.7, 1.7
Hz, 1H, H-6'), 8.05(d, J = 8.7 Hz, 1H, H-5'), 8.09 (d, J = 1.7
Hz, 1H, H-8'), 8.11(m, 2H, H-2'' + H-6''). 13C-NMR (75
MHz, DMSO-d6): ꢀ 24.8 (CH3), 56.7 (C-5), 64.0 (CH2-5),
o
Yield: 75 %, mp = 277-278 C. [ꢁ] = – 99 o (c ~ 1,
D
1
DMF). H-NMR (300 MHz, CDCl3): ꢀ 1.55 (d, J = 6.7 Hz,
3H, CH3(CH)-5), 2.54 (s, 3H, O=C-CH3), 4.30 (q, J = 6.6
Hz, 1H, H-5), 5.93 (s, 1H, NH-4), 6.82 (s, 1H, H-3'), 7.49-
7.53 (m, 3H, H-3'' + H-4'' + H-5''), 7.79 (dd, J = 8.8, 1.8 Hz,

Synthesis of Some 1-(Flavon-7-yl)-4,5-dihydro-1,2,4-triazin-6(1H)-ones
Letters in Organic Chemistry, 2012, Vol. 9, No. 7
469
107.5 (C-8'), 112.9 (C-3'), 121.2 (C-6'), 121.3 (C-4'a), 125.4
(C-4''), 126.9 (C-2'' / C-6''), 129.6 (C-3'' / C-5''), 131.6 ( C-
1''), 132.4 (C-5'), 143.4 (C-7'), 145.6 (C-3), 156.1 (C-8'a),
162.1 (C-2'), 163.3 (C-6), 177.0 (C-4'), 193.3 (O=C-Me).
HRMS (ESI) m/z: Calcd for C21H17N3O5Na [M + Na]+
414.10659; found 414.10604. Anal. Calcd for C21H17N3O5
(391.38): C, 64.45; H, 4.38; N, 10.74; found: C, 64.16; H,
4.28; N, 10.65.
193.2 (O=C-Me). HRMS (ESI) m/z: Calcd for C23H20N3O6
[M + H]+ 434.13521; found 434.13466. Anal. Calcd for
C23H19N3O6 (433.41): C, 63.74; H, 4.42; N, 9.70; found: C,
63.55; H, 4.36; N, 9.62.
(S)-Methyl
3-(3-acetyl-6-oxo-1-(4-oxo-2-phenyl-4H-
chromen-7-yl)-1,4,5,6-tetrahydro-1,2,4-triazin-5-
yl)propanoate (7i)
o
Yield: 45 %, mp = 134-135 C. [ꢀ] = – 140 o (c ~ 1,
D
(5S)-3-Acetyl-5-((R)-1-hydroxyethyl)-1-(4-oxo-2-
phenyl-4H-chromen-7-yl)-4,5-dihydro-1,2,4-triazin-6(1H)-
one (7f)
DMF). 1H-NMR (300 MHz, CDCl3): ꢁ 2.23 (m, 2H,
CH2CH), 2.54 (m, 2H, CH2CO2Me), 2.53 (s, 3H, O=C-CH3),
3.67(s, 3H, CO2CH3), 4.32 (m, 1H, H-5), 6.25 (s, 1H, NH-4),
6.82 (s, 1H, H-3'), 7.48 – 7.52 (m, 3H, H-3''+ H-4''+ H-5''),
7.77 (dd, J = 8.8, 1.8 Hz, 1H, H-6'), 7.90 – 7.93 (m, 2H, H-
2'' + H-6''), 8.00 (d, J = 1.8 Hz, 1H, H-8'), 8.22 (d, J = 8.8
Hz, 1H, H-5'). 13C-NMR (75 MHz, CDCl3): ꢁ 24.1 (O=C-
CH3), 28.6 (CH2CH), 29.7 (CH2CO2Me), 52.1 (CO2CH3),
53.1 (C-5), 107.7 (C-8'), 112.9 (C-3'), 120.7 (C-6'), 121.9
(C-4'a), 125.9 (C-4'') , 126.4 (C-2'' / C-6''), 129.1 (C-3'' / C-
5''), 131.7 ( C-1''), 131.8 (C-5'), 142.3 (C-7'), 144.8 (C-3),
156.2 (C-8'a), 161.8 (C-2'), 163.8 (C-6), 173.2 (CO2Me),
177.9 (C-4'), 192.6 (O=C-Me). HRMS (ESI) m/z: Calcd for
C24H22N3O6 [M + H]+ 448.15086; found 448.15031. Anal.
Calcd for C24H21N3O6 (447.44): C, 64.42; H, 4.73; N, 9.39;
found: C, 64.18; H, 4.62; N, 9.28.
o
Yield: 80 %, mp = 267-268 C. [ꢀ] = – 150 o (c ~ 1,
D
1
DMF). H-NMR (300 MHz, DMSO-d6): ꢁ 1.09 (d, J = 6.4
Hz, 3H, CH3-CH), 2.44 (s, 3H, O=C-CH3), 3.92 (br s, 1H, H-
5), 4.04 (br s,1H, CH-5), 5.02 (d, J = 5.5 Hz, 1H, OH), 7.02
(s, 1H, H-3'), 7.55-7.58 (m, 3H, H-3'' + H-4''+ H-5''), 7.62
(br. s, 1H, NH-4), 7.83 (dd, J = 8.7, 1.7 Hz, 1H, H-6'), 8.05
(d, J = 8.7 Hz, 1H, H-5'), 8.09-8.12 (m, 2H, H-8' + H-2'' + H-
6''). 13C-NMR (75 MHz, DMSO-d6): ꢁ 19.6 (CH3-CH), 24.9
(O=C-CH3), 59.5 (CH-5), 68.8 (C-5), 107.6 (C-8'), 113.0 (C-
3'), 121.2 (C-6'), 121.4 (C-4'a), 125.4 (C-4''), 126.9 (C-2'' /
C-6''), 129.7 (C-3'' / C-5''), 131.6 ( C-1''), 132.4 (C-5'), 143.5
(C-7'), 145.7 (C-3), 156.1 (C-8'a), 162.6 (C-2'), 163.3 (C-6),
177.0 (C-4'), 193.3 (O=C-Me). HRMS (ESI) m/z: Calcd for
C22H20N3O5 [M + H]+ 406.14030; found 406.13975. Anal.
Calcd for C22H19N3O5 (405.40): C, 65.18; H, 4.72; N, 10.37;
found: C, 65.02; H, 4.62; N, 10.24.
(S)-5-((1H-Indol-3-yl)methyl)-3-acetyl-1-(4-oxo-2-phenyl-
4H-chromen-7-yl)-4,5-dihydro-1,2,4-triazin-6(1H)-one (7j)
o
Yield: 28 %, mp = 136-137 C. [ꢀ] = – 260 o (c ~ 1,
D
(S)-3-Acetyl-5-(2-(methylthio)ethyl)-1-(4-oxo-2-phenyl-
4H-chromen-7-yl)-4,5-dihydro-1,2,4-triazin-6(1H)-one (7g)
1
DMF). H-NMR (300 MHz, CDCl3): ꢁ 2.29 (s, 3H, O=C-
CH3), 3.31 (m, 2H, CH2-5), 4.51 (d, J = 3.8 Hz, 1H, H-5),
6.04 (s, 1H, NH-4), 6.80 (s, 1H, H-3'), 7.02 (s, 1H, H-2'''),
7.07 (t, J = 7.4Hz, 1H, H-6'''), 7.19 (t, J = 7.5 Hz, 1H, H-5'''),
7.39 (d, J = 8.1 Hz, 1H, H-7'''), 7.51 – 7.57 (m, 5H, H-3'' +
H-4'' + H-5'' + H-6' + H-4'''), 7.81 (s, 1H, H-8'), 7.85-7.95
(m, 2H, H-2'' + H-6''), 8.17 (d, J = 8.7 Hz, 1H, H-5'), 8.63 (
s, 1H, NH-1''). 13C-NMR (75 MHz, CDCl3): ꢁ 23.9 (CH3),
30.4 (CH2-5), 54.4 (C-5), 107.6 (C-8'), 108.9 (C-3'''), 111.5
(C-3'), 113.1 (C-7'''), 118.6 (C-4'''), 119.9 (C-5'''), 120.9 (C-
6'), 121.7 (C-4'a), 122.5 (C-6'''), 123.7 (C-2'''), 125.7 (C-4''),
126.4 (C-2'' / C-6''), 127.1 (C-3'''a), 129.1 (C-3'' / C-5''),
131.6 (C-1''), 131.8 (C-5'), 136.5 (C-7'''a), 142.2 (C-7'),
144.9 (C-3), 156.1 (C-8'a), 162.6 (C-2'), 163.8 (C-6), 178.1
(C-4'), 192.7 (O=C-Me). HRMS (ESI) m/z: Calcd for
C29H21N4O4 [M – H]– 489.15628; found 489.15683. Anal.
Calcd for C29H22N4O4 (490.51): C, 71.01; H, 4.52; N, 11.42;
found: C, 71.08; H, 4.46; N, 11.35.
o
Yield: 38 %, mp = 189-190 C. [ꢀ] = – 110 o ( c ~ 1,
D
1
DMF). H-NMR (300 MHz, CDCl3): ꢁ 2.10 (s, 3H, CH3S),
2.17 (m, 2H, CH2-5), 2.54 (s, 3H, O=C-CH3), 2.67 (t, J = 7.1
Hz, 2H, CH2S), 4.40 (t, J = 5.1 Hz, 1H, H-5), 6.25 (s, 1H,
NH-4), 6.81 (s, 1H, H-3'), 7.50- 7.52 (m, 3H, H-3''+ H-4'' +
H-5''), 7.77 (dd, J = 8.8, 2.0 Hz, 1H, H-6'), 7.90 – 7.93 (m,
2H, H-2'' + H-6''), 8.00 (d, J = 2.0 Hz, 1H, H-8'), 8.23 (d, J =
8.8 Hz, 1H, H-5'). 13C-NMR (75 MHz, CDCl3): ꢀ 15.4
(CH3S), 24.1 (O=CCH3), 29.7 (CH2S), 32.0 (CH2CH), 53.0
(C-5), 107.7 (C-8'), 112.9 (C-3'), 120.7 (C-6'), 121.8 (C-4'a),
125.9 (C-4''), 126.4 (C-2'' / C-6''), 129.1 (C-3'' / C-5''),
131.67 (C-1''), 131.74 (C-5'), 142.1 (C-7'), 144.9 (C-3),
156.2 (C-8'a), 162.1 (C-2'), 163.8 (C-6), 177.9 (C-4'), 192.7
(O=C-Me). HRMS (ESI) m/z: Calcd for C23H22N3O4S [M +
H]+ 436.13310; found 436.13255. Anal. Calcd for
C23H21N3O4S (435.50): C, 63.43; H, 4.86; N, 9.65; found: C,
63.18; H, 4.81; N, 9.54.
3-Acetyl-4-methyl-1-(4-oxo-2-phenyl-4H-chromen-7-yl)-
4,5-dihydro-1,2,4-triazin-6(1H)-one (7k)
(S)-Methyl2-(3-acetyl-1,4,5,6-tetrahydro-6-oxo-1-(4-oxo-2-
phenyl-4H-chromen-7-yl)-1,2,4-triazin-5-yl)acetate (7h)
o
1
Yield: 89 %, mp = 181-182 C. H-NMR (300 MHz,
CDCl3): ꢁ 2.53 (s, 3H, O=C-CH3), 3.16 (s, 3H, CH3-(N)4),
4.00 (s, 2H, H2-5), 6.78 (s, 1H, H-3'), 7.47-7.51 (m, 3H, H-3''
+ H-4'' + H-5''), 7.80 (dd, J = 8.8, 2.0 Hz, 1H, H-6'), 7.88-
7.91 (m, 2H, H-2'' + H-6''), 8.04 (d, J = 2.00 Hz, 1H, H-8'),
8.20 (d, J = 8.8 Hz, 1H, H-5'). 13C-NMR (75 MHz, DMSO-
d6): ꢁ 28.3 (O=C-CH3), 38.0 (CH3-(N)4), 51.8 (C-5), 107.7
(C-8'), 112.3 (C-3'), 120.7 (C-6'), 121.3 (C-4'a), 125.5 (C-
4''), 126.9 (C-2'' / C-6''), 129.6 (C-3'' / C-5''), 131.6 ( C-1''),
132.3 (C-5'), 144.9 (C-7'), 145.3 (C-3), 156.1 (C-8'a), 160.5
(C-2'), 163.4 (C-6), 177.8 (C-4'), 194.2 (O=C-Me). HRMS
(ESI) m/z: Calcd for C21H18N3O4 [M + H]+ 376.12973; found
Yield: 18 %, mp = 222-224 oC. [ꢀ] = – 60 o ( c ~ 1,
D
1
DMF). H-NMR (300 MHz, CDCl3): ꢁ 2.43(s, 3H, CH3),
2.84-3.05 (m, 2H, H2-5), 3.37 (s, 1H, CO2CH3), 4.55 (m, 1H,
H-5), 7.02 (s, 1H, H-3'), 7.52-7.57 (m, 3H, H-3'' + H-4'' + H-
5''), 7.78-7.82 (m, 2H, NH-4 + H-6'), 8.04-8.11 (m, 4H, H-5'
+ H-8' + H-2'' + H-6''). 13C-NMR (75 MHz, DMSO-d6): ꢁ
24.8 (O=C-CH3), 37.5 (CH2-5), 50.6 (CO2CH3), 52.2 (C-5),
107.6 (C-8'), 113.0 (C-3'), 121.3 (C-6'), 121.4 (C-4'a), 125.4
(C-4''), 126.9 (C-2'' / C-6''), 129.6 (C-3'' / C-5''), 131.6 (C-
1''), 132.3 (C-5'), 142.6 (C-7'), 145.5 (C-3), 156.1 (C-8'a),
162.5 (C-2'), 163.3 (C-6), 171.0 (CO2Me),177.0 (C-4'),

470 Letters in Organic Chemistry, 2012, Vol. 9, No. 7
Wolfgang et al.
376.12918. Anal. Calcd for C21H17N3O4 (375.38): C, 67.19;
H, 4.56; N, 11.19; found: C, 67.02; H, 4.48; N, 11.12.
CDCl3): ꢀ 23.1 (CH3-2'), 24.0 (O=C-CH3), 40.2 (CH2-Ph),
55.3 (C-5), 110.7 (C-8'), 112.8 (C-3'), 120.5 (C-6'), 122.0
(C-4'a), 125.7 (C-5'), 126.0 (C-4'''), 127.4 (C-2''' / C-6'''),
129.1 (C-3''' / C-5'''), 134.8 (C-1'''), 142.3 (C-7'), 144.9 (C-3),
156.7 (C-8'a), 162.8 (C-2'), 165.7 (C-6), 177.9 (C-4'), 193.0
(O=C-Me). HRMS (ESI) m/z: Calcd for C22H19N3O4Na [M +
Na]+ 412.12733; found 412.12785. Anal. Calcd for
C22H19N3O4 (389.40): C, 67.86; H, 4.92; N, 10.79; found: C,
67.58; H, 4.82; N, 10.63.
3-Acetyl-1-(2-methyl-4-oxo-4H-chromen-7-yl)-4,5-dihydro-
1,2,4-triazin-6(1H)-one (8a)
o
1
Yield: 83 %, mp = 282-285 C. H-NMR (300 MHz,
DMSO-d6): ꢀ 2.36 (s, 3H, CH3-2'), 2.46 (s, 3H, O=C-CH3),
3.98 (s, 2H, H2-5), 6.22 (s, 1H, H-3'), 7.73 (br. s, 1H, NH-4),
7.80 (dd, J = 8.8, 1.7 Hz, 1H, H-6'), 7.87 (d, J = 1.7 Hz, 1H,
H-8'), 8.16 (d, J = 8.8 Hz, 1H, H-5'). 13C-NMR (75 MHz,
DMSO-d6): ꢀ 23.1 (CH3-2'), 24.3 (O=C-CH3), 44.8 (C-5),
110.8 (C-8'), 112.5 (C-3'), 120.2 (C-6'), 121.3 (C-4'a), 125.7
(C-5'), 143.1 (C-7'), 144.9 (C-3), 156.6 (C-8'a), 161.8 (C-2'),
165.3 (C-6), 177.2 (C-4'), 193.1 (O=C-Me). HRMS (ESI)
m/z: Calcd for C15H14N3O4 [M + H]+ 300.09843; found
300.09496. Anal. Calcd for C15H13N3O4 (299.28): C, 60.20;
H, 4.38; N, 14.04; found: C, 60.03; H, 4.26; N, 13.92.
(S)-3-acetyl-5-(hydroxymethyl)-1-(2-methyl-4-oxo-4H-
chromen-7-yl)-4,5-dihydro-1,2,4-triazin-6(1H)-one (8e)
o
Yield: 86 %, mp = 257-260 C. [ꢁ] = – 170 o (c ~ 1,
D
DMF). 1H-NMR (300 MHz, DMSO-d6): ꢀ 2.33 (s, 3H, CH3-
2'), 2.49 (s, 3H, O=C-CH3), 3.80 (m, 2H, CH2-5), 4.10 (s,
2H, H-5), 5.20 (t, J = 5.7 Hz, 1H, OH), 6.23 (s, 1H, H-3'),
7.70 (br. s, 1H, NH-4), 7.76 (dd, J = 8.7, 1.7 Hz, 1H, H-6'),
7.89 (d, J = 8.7 Hz, 1H, H-5'), 8.25 (d, J = 1.7 Hz, 1H, H-8').
13C-NMR (75 MHz, DMSO-d6): ꢀ 23.4 (CH3-2'), 24.3 (O=C-
CH3), 54.7 (C-5), 64.5 (CH2-5), 110.7 (C-8'), 112.5 (C-3'),
120.2 (C-6'), 121.5 (C-4'a), 125.9 (C-5'), 142.4 (C-7'), 144.6
(C-3), 156.2 (C-8'a), 162.5 (C-2'), 166.3 (C-6), 177.6 (C-4'),
192.7 (O=C-Me). HRMS (ESI) m/z: Calcd for C16H16N3O5
[M + H]+ 330.10900; found 330.10868. Anal. Calcd for
C16H15N3O5 (329.31): C, 58.36; H, 4.59; N, 12.76; found: C,
58.45; H, 4.52; N, 12.63.
(S)-3-Acetyl-5-methyl-1-(2-methyl-4-oxo-4H-chromen-7-
yl)-4,5-dihydro-1,2,4-triazin-6(1H)-one (8b)
o
Yield: 69 %, mp = 272-273 C. [ꢁ] = – 90 o (c ~ 1,
D
1
DMF). H-NMR (300 MHz, CDCl3): ꢀ 1.53 (d, J = 6.8 Hz,
3H, CH3(CH)-5), 2.38 (s, 3H, CH3-2'), 2.52 (s, 3H, O=C-
CH3), 4.28 (m, 1H, H-5), 5.91 (s, 1H, NH-4), 6.16 (s, 1H, H-
3'), 7.76 (dd, J = 8.7, 1.8 Hz, 1H, H-6'), 7.84 (d, J = 1.8 Hz,
1H, H-8'), 8.18 (d, J = 8.7 Hz, 1H, H-5'). 13C-NMR (75
MHz, CDCl3): ꢀ 19.6 (CH3(CH)-5), 20.6 (CH3-2'), 24.0
(O=C-CH3), 49.6 (C-5), 110.7 (C-8'), 112.6 (C-3'), 120.4 (C-
6'), 121.4 (C-4'a), 125.9 (C-5'), 142.3 (C-7'), 144.7 (C-3),
156.4 (C-8'a), 163.0 (C-2'), 166.6 (C-6), 177.7 (C-4'), 192.8
(O=C-Me). HRMS (ESI) m/z: Calcd for C16H16N3O4 [M +
H]+ 314.11408; found 314.11369. Anal. Calcd for
C16H15N3O4 (313.31): C, 61.34; H, 4.83; N, 13.41; found: C,
61.16; H, 4.71; N, 13.24.
(5S)-3-acetyl-5-((R)-1-hydroxyethyl)-1-(2-methyl-4-oxo-
4H-chromen-7-yl)-4,5-dihydro-1,2,4-triazin-6(1H)-one (8f)
o
Yield: 71 %, mp = 230-233 C. [ꢁ] = – 120 o (c ~ 1,
D
1
DMF). H-NMR (300 MHz, DMSO-d6): ꢀ 1.04 (d, J = 6.4
Hz, 3H, CH3-CH), 2.39 (s, 3H, CH3-2'), 2.51 (s, 3H, O=C-
CH3), 3.90 (br s, 1H, H-5), 4.02 (d, J = 6.4 Hz, 1H, CH-5),
5.00 (m, 1H, OH), 6.21 (s, 1H, H-3'), 7.63 (br. s, 1H, NH-4),
7.79 (dd, J = 8.7, 1.7 Hz, 1H, H-6'), 7.86 (d, J = 1.7 Hz, 1H,
H-8'), 8.16 (d, J = 8.7 Hz, 1H, H-5'). 13C-NMR (75 MHz,
DMSO-d6): ꢀ 20.1 (CH3-CH), 23.0 (CH3-2'), 24.1 (O=C-
CH3), 58.6 (CH-5), 68.7 (C-5), 110.4 (C-8'), 112.7 (C-3'),
120.4 (C-6'), 121.5 (C-4'a), 126.0 (C-5'), 142.5 (C-7'), 144.7
(C-3), 155.8 (C-8'a), 162.6 (C-2'), 166.7 (C-6), 177.7 (C-4'),
192.8 (O=C-Me). HRMS (ESI) m/z: Calcd for C17H18N3O5
[M + H]+ 344.12465; found 344.12411. Anal. Calcd for
C17H17N3O5 (343.33): C, 59.47; H, 4.99; N, 12.24; found: C,
59.31; H, 4.86; N, 12.08.
(S)-3-Acetyl-5-isobutyl-1-(2-methyl-4-oxo-4H-chromen-7-
yl)-4,5-dihydro-1,2,4-triazin-6(1H)-one (8c)
o
Yield: 56 %, mp = 177-179 C. [ꢁ] = – 100 o (c ~ 1,
D
DMF). 1H-NMR (300 MHz, CDCl3): ꢀ 1.01 (dd, J = 6.5, 6.0
Hz, 6H, (CH3)2CH), 1.68 (m, 1H, CHMe2), 1.80 (m, 2H,
CH2-5), 2.40 (s, 3H, CH3-2'), 2.56 (s, 3H, O=C-CH3), 4.24
(m, 1H, H-5), 6.03 (s, 1H, NH-4), 6.18 (s, 1H, H-3'), 7.77
(dd, J = 8.7, 2.0 Hz, 1H, H-6'), 7.86 (d, J = 2.0 Hz, 1H, H-
8'), 8.20 (d, J = 8.7 Hz, 1H, H-5').13C-NMR (75 MHz,
CDCl3): ꢀ 20.6 ((CH3)2CH), 21.6 (CHMe2), 23.0 (CH3-2'),
24.1 (O=C-CH3), 41.9 (CH2-5), 52.2 (C-5), 110.7 (C-8'),
112.5 (C-3'), 120.3 (C-6'), 121.3 (C-4'a), 125.8 (C-5'), 142.1
(C-7'), 144.7 (C-3), 156.4 (C-8'a), 162.7 (C-2'), 166.4 (C-6),
177.6 (C-4'), 192.7 (O=C-Me). HRMS (ESI) m/z: Calcd for
C19H21N3O4Na [M + Na]+ 378.14298; found 378.14257.
Anal. Calcd for C19H21N3O4 (355.39): C, 64.21; H, 5.96; N,
11.82; found: C, 64.14; H, 5.85; N, 11.66.
(S)-3-Acetyl-1-(2-methyl-4-oxo-4H-chromen-7-yl)-5-(2-
(methylthio)ethyl)-4,5-dihydro-1,2,4-triazin-6(1H)-one (8g)
o
Yield: 65 %, mp = 165-167 C. [ꢁ] = – 100 o ( c ~ 1,
D
1
DMF). H-NMR (300 MHz, CDCl3): ꢀ 2.11 (s, 3H, CH3S),
2.20 (m, 2H, CH2-5), 2.39 (s, 3H, CH3-2'), 2.53 (s, 3H, O=C-
CH3), 2.63 (t, J = 7.0 Hz, 2H, CH2S), 4.38 (m, 1H, H-5),
6.19 (s, 1H, H-3'), 6.28 (s, 1H, NH-4), 7.78 (dd, J = 8.7, 2.0
Hz, 1H, H-6'), 7.86 (d, J = 2.0 Hz, 1H, H-8'), 8.22 (d, J = 8.7
Hz, 1H, H-5'). 13C-NMR (75 MHz, CDCl3): ꢀ 15.6 (CH3S),
23.2 (CH3-2'), 24.1 (O=C-CH3), 30.0 (CH2S), 32.1 (CH2CH),
52.8 (C-5), 110.5 (C-8'), 112.9 (C-3'), 120.4 (C-6'), 121.3
(C-4'a), 126.0 (C-5'), 142.3 (C-7'), 144.7 (C-3), 156.6 (C-
8'a), 162.9 (C-2'), 165.8 (C-6), 177.9 (C-4'), 192.7 (O=C-
Me). HRMS (ESI) m/z: Calcd for C18H20N3O4S [M + H]+
374.11745; found 374.11702. Anal. Calcd for C18H19N3O4S
(373.43): C, 57.89; H, 5.13; N, 11.25; found: C, 57.72; H,
5.03; N, 11.14.
(S)-3-Acetyl-5-benzyl-4,5-dihydro-1-(2-methyl-4-oxo-4H-
chromen-7-yl)-1,2,4-triazin-6(1H)-one (8d)
o
Yield: 58 %, mp = 164-166 C. [ꢁ] = – 345 o (c ~ 1,
D
DMF). 1H-NMR (300 MHz, CDCl3): ꢀ 2.39 (s, 3H, CH3-2'),
2.50 (s, 3H, O=C-CH3), 3.08 (m, 2H, -CH2Ph), 4.45 (m, 1H,
H-5), 5.84 (s, 1H, NH-4), 6.17 (s, 1H, H-3'), 7.46-7.54 (m,
3H, H-3'' + H-4'' + H-5''), 7.64 (dd, J = 8.2, 1.7 Hz, 1H, H-
6'), 7.74 (d, J = 1.7 Hz, 1H, H-8'), 7.88 – 7.96 (m, 2H, H-2''
+ H-6''), 8.17 (d, J = 8.2, Hz, 1H, H-5'). 13C-NMR (75 MHz,

Synthesis of Some 1-(Flavon-7-yl)-4,5-dihydro-1,2,4-triazin-6(1H)-ones
Letters in Organic Chemistry, 2012, Vol. 9, No. 7
471
(S)-Methyl2-(3-acetyl-1,4,5,6-tetrahydro-6-oxo-1--(2-
methyl-4-oxo-4H-chromen-7-yl)-1,2,4-triazin-5-yl)acetate
(8h)
(s, 3H, CH3-(N)4), 4.02 (s, 2H, H2-5), 6.17 (s, 1H, H-3'),
7.79 (dd, J = 8.7, 2.0 Hz, 1H, H-6'), 7.85 (d, J = 2.0 Hz, 1H,
H-8'), 8.21 (d, J = 8.7 Hz, 1H, H-5'). 13C-NMR (75 MHz,
CDCl3): ꢁ 23.1 (CH3-2'), 24.3 (O=C-CH3), 38.4 (CH3-(N)4),
51.9 (C-5), 110.7 (C-8'), 112.3 (C-3'), 120.8 (C-6'), 121.3
(C-4'a), 125.7 (C-5'), 142.0 (C-7'), 144.6 (C-3), 156.2 (C-
8'a), 162.6 (C-2'), 166.3 (C-6), 177.7 (C-4'), 192.7 (O=C-
Me). HRMS (ESI) m/z: Calcd for C16H16N3O4 [M + H]+
314.11408; found 314.11369. Anal. Calcd for C16H15N3O4
(313.31): C, 61.34; H, 4.83; N, 13.41; found: C, 61.23; H,
4.72; N, 13.28.
o
Yield: 35 %, mp = 234-236 C. [ꢀ] = – 80 o ( c ~ 1,
D
DMF). 1H-NMR (300 MHz, CDCl3): ꢁ 2.39 (s, 3H, CH3-2'),
2.51 (s, 3H, O=C-CH3), 2.92 (m, 2H, CH2-5), 3.67 (s, 3H,
CO2CH3), 4.57 (m, 1H, H-5), 6.24 (s, 1H, H-3'), 6.48 (s, 1H,
NH-4), 7.78 (m, 1H, H-6'), 7.86 (m, 1H, H-5'), 8.24 (d, J =
1.7 Hz, 1H, H-8'). 13C-NMR (75 MHz, CDCl3): ꢁ 23.4 (CH3-
2'), 24.8 (O=C-CH3), 38.4 (CH2-5), 51.6 (CO2CH3), 53.2 (C-
5), 110.7 (C-8'), 112.5 (C-3'), 120.8 (C-6'), 121.7 (C-4'a),
125.9 (C-5'), 142.8 (C-7'), 145.2 (C-3), 156.4 (C-8'a), 162.5
(C-2'), 166.4 (C-6), 171.2 (CO2Me), 177.2 (C-4'), 192.5
(O=C-Me). HRMS (ESI) m/z: Calcd for C18H18N3O6 [M +
H]+ 372.11956; found 372.11956. Anal. Calcd for
C18H17N3O6 (371.34): C, 58.22; H, 4.61; N, 11.32; found: C,
58.28; H, 4.62; N, 11.24.
(S)-4-Acetyl-6,7,8,8a-tetrahydro-2-(4-oxo-2-phenyl-4H-
chromen-7-yl)pyrrolo[1,2-d][1,2,4]triazin-1(2H)-one (9)
o
Yield: 67 %, mp = 210-211 C. [ꢀ] = + 404 o (c ~ 1,
D
1
DMF). H-NMR (300 MHz, CDCl3): ꢁ 1.96 (m, 2H, H2-7),
2.33 (m, 2H, H2-8), 2.53 (s, 3H, CH3), 3.83 (m, 1H, H-8a),
4.00 (m, 2H, H2-6), 6.79 (s, 1H, H-3'), 7.49 (m, 3H, H-3'' +
H-4'' + H-5''), 7.81 (dd, J = 8.8, 1.8 Hz, 1H, H-6'), 7.90 (m,
2H, H-2'' + H-6''), 8.04 (d, J = 1.8 Hz, 1H, H-8'), 8.21 (d, J =
8.8 Hz, 1H, H-5'). 13C-NMR (75 MHz, CDCl3): 24.3 (CH3),
26.4 (C-7), 27.5 (C-8), 50.1 (C-6), 58.0 (C-8a), 107.7 (C-8'),
112.3 (C-3'), 120.3 (C-6'), 121.5 (C-4'a), 125.9 (C-4''), 126.3
(C-2'' / C-6''), 129.1 (C-3'' / C-5''), 131.6 (C-1''), 131.7 (C-5'),
143.9 (C-7'), 144.8 (C-3), 156.2 (C-8'a), 162.1 (C-2'), 163.7
(C-1), 177.9 (C-4'), 194.3 (O=C-Me). HRMS (ESI) m/z:
(S)-Methyl 3-(3-acetyl-1-(2-methyl-4-oxo-4H-chromen-7-
yl)-6-oxo-1,4,5,6-tetrahydro-1,2,4-triazin-5-yl)propanoate
(8i)
o
Yield: 72 %, mp = 147-149 C. [ꢀ] = – 130 o (c ~ 1,
D
DMF). 1H-NMR (300 MHz, CDCl3): ꢁ 2.25 (m, 2H,
CH2CH), 2.40 (s, 3H, CH3-2'), 2.53 (s, 3H, O=C-CH3), 2.55
(m, 2H, CH2CO2Me), 3.68 (s, 3H, CO2CH3), 4.30 (m, 1H, H-
5), 6.21 (s, 1H, H-3'), 6.24 (s, 1H, NH-4), 7.73 (dd, J = 8.7,
1.8 Hz, 1H, H-6'), 7.89 (d, J = 1.8 Hz, 1H, H-8'), 8.25 (d, J =
8.7 Hz, 1H, H-5'). 13C-NMR (75 MHz, CDCl3): ꢁ 23.4 (CH3-
2'), 24.3 (O=C-CH3), 28.9 (CH2CH), 30.0 (CH2 CO2Me),
52.2 (CO2CH3), 53.0 (C-5), 111.0 (C-8'), 112.6 (C-3'), 120.3
(C-6'), 121.4 (C-4'a), 125.8 (C-5'), 142.6 (C-7'), 144.7 (C-3),
156.2 (C-8'a), 161.9 (C-2'), 165.8 (C-6), 173.0 (CO2Me),
177.8 (C-4'), 192.6 (O=C-Me). HRMS (ESI) m/z: Calcd for
C19H20N3O6 [M + H]+ 386.13521; found 386.13558. Anal.
Calcd for C19H19N3O6 (385.37): C, 59.22; H, 4.97; N, 10.90;
found: C, 58.98; H, 4.85; N, 10.76.
Calcd for C23H20N3O4 [M
+
H]+ 402.14538; found
402.14483. Anal. Calcd for C23H19N3O4 (401.41): C, 68.82;
H, 4.77; N, 10.47; found: C, 68.64; H, 4.82; N, 10.41.
(S)-4-Acetyl-6,7,8,8a-tetrahydro-2-(2-methyl-4-oxo-4H-
chromen-7-yl)pyrrolo[1,2-d][1,2,4]triazin-1(2H)-one (10)
o
Yield: 58 %, mp = 179-182 C. [ꢀ] = + 460 o (c ~ 1,
D
1
DMF). H-NMR (300 MHz, CDCl3): ꢁ 1.95 (m, 2H, H2-7),
2.33 (m, 2H, H2-8), 2.39 (s, 3H, CH3-2'), 2.53 (s, 3H, O=C-
CH3), 3.85 (m, 1H, H-8a), 4.01 (m, 2H, H2-6), 6.18 (s, 1H,
H-3'), 7.79 (dd, J = 8.7, 1.8 Hz, 1H, H-6'), 7.86 (d, J = 1.8
Hz, 1H, H-8'), 8.20 (d, J = 8.8 Hz, 1H, H-5'). 13C-NMR (75
MHz, CDCl3): 23.0 (CH3-2'), 24.4 (O=C-CH3), 26.7 (C-7),
27.6 (C-8), 51.1 (C-6), 58.7 (C-8a), 110.4 (C-8'), 112.5 (C-
3'), 120.3 (C-6'), 121.5 (C-4'a), 126.0 (C-5'), 142.9 (C-7'),
144.8 (C-3), 156.9 (C-8'a), 162.9 (C-2'), 166.4 (C-1), 177.7
(C-4'), 193.1 (O=C-Me). HRMS (ESI) m/z: Calcd for
C18H18N3O4 [M + H]+ 340.12973; found 340.12941. Anal.
Calcd for C18H17N3O4 (339.35): C, 63.71; H, 5.05; N, 12.38;
found: C, 63.58; H, 4.96; N, 12.30.
(S)-5-((1H-Indol-3-yl)methyl)-3-acetyl-1-(2-methyl-4-oxo-
4H-chromen-7-yl)-4,5-dihydro-1,2,4-triazin-6(1H)-one (8j)
o
Yield: 35 %, mp = 178-181 C. [ꢀ] = – 290 o (c ~ 1,
D
1
DMF). H-NMR (300 MHz, CDCl3): ꢁ 2.30 (s, 3H, O=C-
CH3), 2.38 (s, 3H, CH3-2'), 3.33 (m, 1H, H-4), 3.65 (m, 2H,
CH2-5), 4.55 (m, 1H, H-5), 6.18 (s, 1H, H-3'), 7.03 (s, 1H,
H-2'''), 7.08 (t, J = 7.3 Hz, 1H, H-6'''), 7.21 (t, J = 7.9 Hz,
1H, H-5'''), 7.37 (d, J = 8.4 Hz, 1H, H-7'''), 7.55 (m, 1H, H-
4'''), 7.76 (m, 1H, H-6'), 7.86 (d, J = 2.0 Hz, 1H, H-8'), 8.20
(d, J = 8.7 Hz, 1H, H-5'), 8.66 (s, 1H, NH-1'''). 13C-NMR (75
MHz, CDCl3): ꢁ 23.1 (CH3-2'), 24.3 (O=C-CH3), 31.0 (CH2-
5), 54.5 (C-5), 109.0 (C-3'''), 110.6 (C-8'), 112.5 (C-3'),
113.2 (C-7'''), 119.0 (C-4'''), 119.8 (C-5'''), 120.6 (C-6'),
121.4 (C-4'a), 122.4 (C-6'''), 123.8 (C-2'''), 127.7 (C-3'''a),
125.8 (C-5'), 136.6 (C-7'''a), 142.3 (C-7'), 144.7 (C-3), 156.4
(C-8'a), 162.7 (C-2'), 166.4 (C-6), 178.1 (C-4'), 192.7 (O=C-
Me). HRMS (ESI) m/z: Calcd for C24H21N4O4 [M + H]+
429.15628; found 429.15582. Anal. Calcd for C24H20N4O4
(428.44): C, 67.28; H, 4.71; N, 13.08; found: C, 67.12; H,
4.69; N, 12.96.
Cell Lines and Cell Culture / Materials and Methods
MCF-7 breast cancer cells were obtained from ATCC
and were cultured in DMEM. The media was supplemented
with 2 mM glutamine and 10% Fetal Bovine Serum (FBS,
Gibco Life Technologies) and cells were maintained under
standard cell culture conditions at 37 °C in a water-saturated
atmosphere of 5% CO2 in air.
Cell Proliferation Assay
MCF-7 cells were seeded at a density of 5 ꢀ 103 per well
in 96-well plates in appropriate medium. The cells were
treated with 10 and 50 μM concentrations of the tested com-
pounds. The drugs were dissolved in DMSO immediately
3-Acetyl-4-methyl-1-(2-methyl-4-oxo-4H-chromen-7-yl)-
4,5-dihydro-1,2,4-triazin-6(1H)-one (8k)
o
1
Yield: 75 %, mp = 175-177 C. H-NMR (300 MHz,
CDCl3): ꢁ 2.38 (s, 3H, CH3-2'), 2.55 (s, 3H, O=C-CH3), 3.20

472 Letters in Organic Chemistry, 2012, Vol. 9, No. 7
Wolfgang et al.
before the addition to cell cultures and equal amounts of the
solvent were added to control cells. Cell viability was as-
sessed, after 3 days of treatment, with tetrazolium dye 3-
(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide
(MTT), obtained from Sigma (Dorset, UK). For the IC50
determination, the cells were treated with increasing concen-
trations of the tested compound (1.56–100 ꢀM). IC50 con-
centrations were obtained from the dose–response curves
using Graph Pad Prism Software 5 (San Diego, California
USA, www.graphpad.com).
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ACKNOWLEDGEMENTS
We wish to thank the Deanship of Scientific Research at
the University of Jordan, Amman, Jordan, for financial sup-
port. We are grateful to Malik Zihlif and Randa G. Naffa
(The University of Jordan) for performing antitumor testing.
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CONFLICT OF INTEREST
[13]
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Abdel-Rahman, R.M. Synthesis and anti human immune virus
activity of some new fluorine containing substituted-3-thioxo-
1,2,4-triazin-5-ones. Farmaco, 1991, 46, 379-389.
The author(s) confirm this article content has no conflicts
of interest.
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of some 1,6-dihydro-3-heteroaryl-1,2,4-triazin-5-(4H)-ones. Indian
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a) Abushamleh, A.S.; El-Abadelah, M.M.; Moessmer, C.M. Transi-
tion metal complexes of derivatized chiral dihydro-1,2,4-triazin-6-
ones. Part I. Nickel(II) complex of (D)-3-acetyl-5-benzyl-1-phenyl-
4,5-dihydro-1,2,4-triazin-6-one oxime. An instance of a carbon-
carbon coupling reaction. Heterocycles, 2000, 53, 1155-1165; b)
Abushamleh, A.S.; El-Abadelah, M.M.; Moessmer, C.M. Part II.
Synthesis and structural characterization of palladium(II) complex
with (L)-3-acetyl-5-benzyl-1-phenyl-4,5-dihydro-1,2,4-triazin-6-
one oxime. Heterocycles 2000, 53, 1737-1744; c) Abushamleh,
A.S.; El-Abadelah, M.M.; Voelter, W. Transition metal complexes
of derivatized chiral dihydro-1,2,4-triazin-6-ones. Part III. X-ray
crystal structure analysis of N,N'-bis[(1-phenyl-5-isopropyl-4,5-
dihydro-6-oxo-1,2,4-triazin-3-yl)ethylidene]propane-1,3-diamine
nickel(II). Z. Naturforsch., 2000, 55b, 1074-1078; d) El-Abadelah,
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metal complexes of derivatized chiral dihydro-1,2,4-triazin-6-ones,
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DISCLOSURE
Part of information in the introduction of this article has
been previously published in International Journal of Chem-
istry ISSN 1916-9698 (Print) 1916-9701.
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