Synthesis of new (trifluoromethyl)-1H-benzo[e][1,2,4]triazolo[1,2-a][1,2,4]triazine-1,3(2H)-diones and (trifluoromethyl)benzo[5,6][1,2,4]triazino [1,2-b]phthalazine-8,13-diones

Article abstract of DOI:10.1016/j.jfluchem.2016.12.004

In this paper we investigated reactions of urazole and phthalazine with N-(aryl)-2,2,2-trifluoroacetimidoyl chloride derivatives. Results showed that when imidoyl chloride derivative has a fluorine atom at ortho position (3a–c), in two steps under a S

Full text of DOI:10.1016/j.jfluchem.2016.12.004

Accepted Manuscript
Title: Synthesis of new (trifluoromethyl)-1H-
benzo[e][1,2,4]triazolo[1,2-a][1,2,4]triazine-1,3(2H)-diones
and (trifluoromethyl)benzo[5,6][1,2,4]triazino
[1,2-b]phthalazine-8,13-diones
Author: Mahin Ramezani Ali Darehkordi
PII:
S0022-1139(16)30431-6
DOI:
Reference:
http://dx.doi.org/doi:10.1016/j.jfluchem.2016.12.004
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2-11-2016
5-12-2016
6-12-2016
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<AT>Synthesis of new (trifluoromethyl)-1H-benzo[e][1,2,4]triazolo[1,2-a][1,2,4]triazine-
1,3(2H)-diones and (trifluoromethyl)benzo[5,6][1,2,4]triazino [1,2-b]phthalazine-8,13-diones
<AU>Mahin Ramezani, Ali Darehkordi* ##Email##darehkordi@vru.ac.ir ##/Email##
##Email##adarehkordi@yahoo.com##/Email##
<AFF>Department of Chemistry, Faculty of Science, Vali-e-Asr University of Rafsanjan,
Rafsanjan 77176, Iran
<ABS-Head><ABS-HEAD>Graphical abstract
<ABS-P>
<ABS-P><xps:span class="xps_Image">fx1</xps:span>
<ABS-HEAD>Highlights► ● new (trifluoromethyl)-1H-benzo[e][1,2,4]triazolo[1,2-
a][1,2,4]triazine-1,3(2H)-diones and (trifluoromethyl)benzo[5,6][1,2,4]triazino [1,2-
b]phthalazine-8,13-diones were prepared ●Simple procedure● High reaction yields. ●New
bioactive Trifluoromethyl heterocyclic compounds
<ABS-HEAD>Abstract
<ABS-P>In this paper we investigated reactions of urazole and phthalazine with N-(aryl)-2,2,2-
trifluoroacetimidoyl chloride derivatives.
<ABS-P><ST>Results</ST> showed that when imidoyl chloride derivative has a fluorine atom
at ortho position (3a-c), in two steps under a SNi mechanism and then SNAr reaction mechanism
produce ayl-5-(trifluoromethyl)-1H-benzo[e][1,2,4]triazolo[1,2-a][1,2,4]triazine-1,3(2H)-diones
(4a-c) and 6-(trifluoromethyl)benzo[5,6][1,2,4]triazino[1,2-b]phthalazine-8,13-diones (4i,4j) in
good to excellent yields. In the other imidoyl derivatives (3d-h and 3i,3j) under these conditions
cyclization reaction does not occur and therefore produce 1-aryl-2,2,2-trifluoromethyl)-4-phenyl-
1,2,4-triazolidine-3,5-diones (4d-h) and 2-(2,2,2-trifluoro-1-(arylimino)ethyl)-2,3-
dihydrophthalazine-1,4-diones(4k,4l) (non-cyclic products) in good to excellent yields.
<KWD>Keywords: N-(aryl)-2,2,2-trifluoroacetimidoyl chloride; urazoe; phthalazine;
(trifluoromethyl)-1H-benzo[e][1,2,4]triazolo[1,2-a][1,2,4]triazine-1,3(2H)-dione;
(trifluoromethyl)benzo[5,6] [1,2,4]triazino[1,2-b]phthalazine-8,13-diones
Introduction
The preparation of novel heterocyclic compounds has always been important and interesting
because of their wide applications. Among these compounds, nitrogen-containing heterocyclic
compounds occur very widely in natural products and are essential to life, and their applications
in biochemical, agrochemicals, and functional materials are very important.1, 2a-d Heterocycles
containing a urazole nucleus and a hydrazine moiety are of interest because they have showed
useful biological activities and use in clinical process (Fig. 1).3,4a-c Also urazole derivatives and
fused phthalazines exhibit various biological activity such as anticonvulsant,5 fungicidal 6, 7
antimicrobial,8 anticonvulsant,9 anticancer,10 and anti-inflammatory activities.11 Therefore,
synthesis and development of new synthetic methods for preparing heterocycles containing
urazole or phthalazine ring moiety have attracted much interest in organic and medicinal
chemistry recently. 4a–c, 12, 13
1

The synthesis of biologically active organofluorine heterocyclics has received more attention in
the medicinal chemistry and materials sciences. Among these derivatives synthesis and
development of new methods for preparation of CF3 containing heterocylic compounds are more
attention, because of their physical and pharmaceutical properties and using in industry,
medicinal and agriculture.14, 15
Combination of organofluorine compounds with urazole or phthalazine ring can be improve
biological properties and influences the electron density distribution in organic and bioorganic
molecules. The electron-withdrawing properties of CF3 group enhanced the electrophilicity in
functional of molecule16a-d and therefore makes some partially fluorinated compounds valuable
precursor for synthesis of new heterocyclic containing fluorine atom.17-20
Due to the important of urazole and phthalazide derivatives and organofluorine compounds
especially trifluoromethylated heterocyclics, in chemistry, drug and medicinal chemistry and in
continuation of our research on the synthesis of trifluoromethylated compounds from imidoyl
halides 21-25, the present work aimed at the synthesis of fused trifluoromethylated
heteropolycyclic nitrogen systems containing a fused urazole or phthalazide moiety starting from
imidoyle chlorides.
Result and discussion
Imidoyl chlorides (1a-j) have been prepared by refluxing a mixture of trifluoroacetic acid (TFA),
primary amines, in carbon tetrachloride in the presence of triethylamine and triphenylphosphine
in one pot reaction. Work-up and distillation provided the desired imidoyl chlorides from good to
excellent yields.26, 27
In our initial studies, urazole (1) and N-(2,6-difluorophenyl)-2,2,2-trifluoroacetimidoyl chloride
3a were chosen as model substrates to optimize the reaction parameters. Firstly the reaction was
carried out with 1 mmol urazole (1) and 1 mmol N-(2,6-difluorophenyl)-2,2,2-
trifluoroacetimidoyl chloride (3a) in DMF as solvent and potassium carbonate (K2CO3) as a
base. After 24 h at the room temperature and 18 h under reflux conditions did not give the
desired product and N-(2,6-difluorophenyl)-2,2,2-trifluoroacetimidoyl chloride was hydrolyzed
to N-(2,6-difluorophenyl)-2,2,2-trifluoroacetamide based on analytical and spectral data (Table
1, entry 1,2). Also reaction was performed in THF as solvent in present of sodium hydride (NaH)
as the base at room temperature or under reflux conditions. After 18 h at the room temperature
and 12 h under reflux hydrolyzed product was obtained (Table 1, entry 3,4). Therefore this
reaction was repeated with 1 mmol of N-(2,6-difluorophenyl)-2,2,2-trifluoroacetimidoyl chloride
(3a), 1 mmol of urazole (2) in acetonitrile as solvent in the presence of sodium hydride (NaH) as
the base at room temperature and under reflux conditions. The results are summarized in table 1.
It was observed that, NaH as base and acetonitrile as solvent under reflux conditions shown
excellent product yield (Table 1, entry 6).
Prompted by this success, we extended the reaction of urazole with a wide range of other
substituted imidoyl chloride compounds under similar conditions, furnishing the corresponding
product in good to excellent yields (Table 2).
A as a mentioned in table 1 (entry 6), optimized conditions for synthesis of 4-phenyl-1-(2,2,2-
trifluoro-1-(arylimino)ethyl)-1,2,4-triazolidine-3,5-diones (4d-c) and 2-phenyl-5-
(trifluoromethyl)-1H-benzo[e][1,2,4]triazolo[1,2-a][1,2,4]triazine-1,3(2H)-diones (4a-c) by
treatment of N-(aryl)-2,2,2-trifluoroacetimidoyl chlorides with urazole (1) is refluxing in dry
acetonitrile in present of sodium hydride as base. This promoted us to a similar strategy on
utilizing 2,3-dihydrophthalazine-1,4-dione instead of urazole. Thus we carried out a reaction
utilizing equimolar quantities of 2,2,2-trifluoro-N-(2-fluorophenyl)acetimidoyl chloride (3c),
2

2,3-dihydrophthalazine-1,4-dione (2) in 10 mL dry acetonitrile in the same conditions. The
product 4i was not detected in this conditions (Table 3, entry 1). However, the products obtained
was identified as the 2,2,2-trifluoro-N-(2-fluorophenyl)acetamide (hydrolysis product) based on
analytical and spectral data. In an attempt to produce and improve the yield of 4i, the above
reactions were carried out in a variety of solvents such as tetrahydrofuran, dimethylformamide,
tetrahydrofuran-dimethylformamide, and different bases such as NaH, K2CO3, and Et3N at reflux
conditions. The results are summarized in table 3. Therefore, the optimal reaction conditions
were identified as follows: dry tetrahydrofuran as a solvent, triethylamine as a base and reflux
conditions (Table 3, entry 6).
After the optimal reaction conditions were established, we continued to explore the generality of
the protocol. The outcome was listed in Table 4.
All of the products were characterized by FT-IR, 1H- 13C-NMR, 19F-NMR spectra and elemental
analysis. Also some of the structure compounds were confirmed with use of MS and 2-D-NMR
(HSQC technique).
In the 1HNMR spectrum of 8-fluoro-2-phenyl-5-(trifluoromethyl)-1H
benzo[e][1,2,4]triazolo[1,2-a][1,2,4]triazine-1,3(2H)-dione (4a) the aromatic protons of phenyl
urazol appear in the region of δ 7.50-7.62 ppm. All of these protons (C1, C2, C6, C3, and C5) are
correlating to each other in their corresponding correlation spectroscopy (Fig. 2, and Fig 4).
The 1H-NMR spectrum of compound 4a (Fig 2) exhibited three signals, a triplet of doublets at
7.29 for the proton 19 (J= 8.7, 2.9 Hz), a doublet of doublets at 7.36 for the proton 21 (J= 8.8,
2.9 Hz) and a doublet of doublets at 7.59 for the proton 18 (J= 9.0, 5.2 Hz) that the match with
chemical structure of compound 4a.
The chemical shifts of para-substituted fluorobenzenes have a reasonable correlation with the σp
values of the substituents for carbons in 13C-NMR spectrum; the more electron-withdrawing
substituents leading to greater deshielding of the p-fluorine and rough correlation for ortho-
substituted and meta-substituted.28
A fluorine substituent on benzene has a characteristic effect upon the 13C-NMR spectrum of
benzene, and it couples in a distinctive and highly consistent manner with the ipso, ortho, meta,
and para carbons. The F coupling to carbon can be vary considerably for the carbon directly
substituted (ipso), depending on its substitution environment, but it is always very large.29 In the
13C-NMR spectrum (Fig. 3) the C20 providing the largest observed effect, deshielding carbon at
δ 159.59 with coupling constant of 243.4 Hz and carbons in ortho position observed effects at
117.71 (2JC-F= 23.0 Hz, C19) and δ 115.51 (2JC-F= 16.2 Hz, C21), meta position observed effects
at δ 115.92 (3JC-F= 7.8 Hz, C18) and δ 130.44 (C15) ppm and para position observed effects at δ
125.78 (4JC-F= 3.2 Hz, C14) ppm. Also the aromatic carbons of phenyl urazol appear between
127.51-130.55 ppm. The 13C-NMR spectrum (Fig. 3) shows that the amide carbonyl carbons
appear at high frequency region at δ 145.35 and 142.28 ppm. The aromatic carbons and its
corresponding protons are in correlation in their heteronuclear single quantum correlation
(HSQC) spectrum (Fig. 4). Also all of the protons are correlating with corresponding carbons in
their single quantum correlation spectrum. The carbons, which have no protons, are not
correlating with any other proton nuclei.
The carbon signals deriving from CF3 groups are often difficult to discern and thus sometimes
are unfortunately not even reported. Trifluoromethyl exhibited a very little variation quartet at
116.73 ppm with coupling constant of 275.9 Hz and C17-CF3 exhibited a quartet at 136.72 ppm
3

with coupling constant of 41 Hz (Fig 3). Also 19F-NMR in figure 5 exhibited the CF3 group at -
68.16 and the F group attached to the benzene ring at -113.60 ppm.
Due to the ambident nature of the nucleophile formed in the reaction, nitrogen nucleophile can
perform the SNAr reaction, and the reaction course is very dependent on the X substituents on the
aromatic ring and its position that showed in scheme1. In the other hand compounds 4d-4h and
4j, 4l are different. These compounds cannot undergo SNAr reaction. For example the IR
spectrum of compound 4d exhibit an absorption bands at 3336 cm-1 which is related to NH group
and also chemical shift data and coupling constant in NMR showed which in these compounds,
cyclocondensation reaction don’t occurred. Also Mass spectra were indicated this results.
A suggested mechanism for cyclization reaction is shown in scheme 2. We assume that initially
immino group of imidoyl is attacked by nucleophilic urazole in present of sodium hydride as a
base to replace of chlorine atom by nitrogen under SNi mechanism. Subsequent attack of the
another nitrogen atom of urazole on the fluoro atom on the aromatic ring under SNAr reaction
mechanism gives the 8-fluoro-2-phenyl-5-(trifluoromethyl)-1H-benzo[e][1,2,4]triazolo[1,2-
a][1,2,4]triazine-1,3(2H)-dione (4a) (Scheme 2).
Conclusion
We have synthesis a novel series of (trifluoromethyl)-1H-benzo[e][1,2,4]triazolo[1,2-
a][1,2,4]triazine-1,3(2H)-diones and (trifluoromethyl)benzo[5,6][1,2,4]triazino[1,2-
b]phthalazine-8,13-diones by reaction of urazole and phthalzine with N-(aryl)-2,2,2-
trifluoroacetimidoyl chlorides in good to excellent yields. By this reaction we have developed a
new method for synthesis of trifluoromethylated heterocyclic compounds using imidoyl
chlorides and 1,2-N,N bi-nucleophile. I hope the presented synthesis provides access to
preparation of bioactive fluoroheterocycli compounds.
Experimental
General
1H-NMR spectra were recorded in CDCl3 and DMSO-d6 on a Bruker model DRX-400 AVANCE
spectrometer (400 MHz) with TMS as internal standard. 19F-NMR spectra were taken on a
Bruker AM-400 (376.27 MHz) spectrometer using CFCl3 as external standard. 13C-NMR spectra
were taken a Bruker model DRX-400 AVANCE (100 MHz) spectrometer. Only compound 4h
were recorded on a Bruker model DRX-300 AVANCE (1H: 300, 13C: 75, F: 282.20 MHz) NMR
spectrometer. Chemical shifts are given in d relative to TMS, the coupling constants J are given
in Hz and spectra were recorded in parts per million (ppm). Melting points were determined on a
Melt-Tem II melting point apparatus and are uncorrected. IR spectra were obtained on a Thermo
scientific, Nicolet is10 FT-IR spectrometer. Peaks are reported in wave numbers (cm-1). Mass
spectra were recorded on an Agillent, 6410 QQQ, LC mass spectrometer (direct injection).
Element analyses (CHN) were performed with a EUROVECTOR EuroEA3000 CHNSO
analyzer.
General procedure for the synthesis of 4a-g, from urazole (1) with aceteimidoyle chloride
derivatives (3).
A mixture of urazole 1 (1 mmol), sodium hydride (2 mmol) in dry acetonitrile (5 mL) was stirred
at the ambient temperature for 10 min. Then a solution of aceteimidoyl chloride derivative 3 (1
mmol) in dry acetonitrile (5 mL) was added dropwise and the reaction mixture was heated under
reflux conditions. After completion of the reaction, as indicated by TLC, the solvent was
evaporated at reduced pressure; a precipitate formed was washed with n-hexane and was
4

recrystallized from 95% ethanol for compounds 4a-c or was purified by plate chromatography on
silica gel (n-hexane/ethyl acetate 6:2) for compounds 4d-h.
8-fluoro-2-phenyl-5-(trifluoromethyl)-1H-benzo[e][1,2,4]triazolo[1,2-a][1,2,4]triazine-
1,3(2H)-dione (4a).
Yellow solid. mp 176-178 °C. IR (KBr, cm-1): 2924, 1796, 1784, 1732, 1649. 1H NMR (400
MHz, DMSO-d6): δ 7.95 (dd, J = 9.0, 5.2 Hz, 1H), 7.67–7.47 (m, 5H), 7.36 (dd, J = 8.8, 2.9 Hz,
1H), 7.29 (td, J = 8.7, 2.9 Hz, 1H). 13C-NMR (100 MHz, DMSO-d6) δ 159.42 (d, JC-F = 243.4
Hz, C20, C-F), 145.35 (C=O), 142.27 (C=O), 136.72 (q, JC-C-F = 41.1 Hz, C17, C-CF3), 130.55,
130.44, 129.77 (C1, C2, C6), 127.51(C3, C5), 125.78 (d, J = 3.2 Hz, C14), 117.71 (d, J = 23.0
Hz, C19), 116.73 (q, JC-F = 275.9 Hz, C23, C-CF3), 115.92 (d, J = 7.8 Hz, C18), 115.51 (d, J =
16.2 Hz, C21). 19F NMR (376.27 MHz, DMSO-d6): δ -68.16 (s, 3F, CF3), -113.60 (m, 1F). Anal.
Calcd for C16H8F4N4O2 (364.26): C, 52.76; H, 2.21; N, 15.38; Found: C, 52.70; H, 2.02; N,
15.29 %.
9-fluoro-2-phenyl-5-(trifluoromethyl)-1H-benzo[e][1,2,4]triazolo[1,2-a][1,2,4]triazine-
1,3(2H)-dione (4b).
Yellow solid. mp 158-160 °C. IR (KBr, cm-1): 2923, 1796, 1784, 1737, 1645. 1H-NMR (400
MHz, CDCl3): δ 7.92 (dd, J = 9.2, 2.7 Hz, 1H), 7.63-7.47 (m, 5H), 7.39 (dd, J = 8.7, 5.5 Hz, 1H),
13
6.89 (ddd, J = 8.7, 7.9, 2.7 Hz, 1H). C-NMR (100 MHz, CDCl3): δ 163.35 (d, JC-F = 253.6 Hz,
C-F), 154.40 (q, JC-C-F = 31.2 Hz, C-CF3), 151.40 (C=O), 150.64 (C=O), 144.09, 137.93 (d, J =
8.1 Hz), 135.94, 134.58, 130.36 (d, J = 9.7 Hz), 129.52(3C), 125.97(2C), 117.61 (q, JC-F = 277.4
Hz, C-CF3), 113.09 (d, J = 22.9 Hz), 103.50 (d, J = 31.2 Hz). 19F-NMR (376.27 MHz, CDCl3): δ
-68.06 (s, 3F, CF3), -103.82 (m, 1F). Anal. Calcd for C16H8F4N4O2 (364.26): C, 52.76; H, 2.21;
N, 15.38. Found: C, 52.73; H, 2.16; N, 15.34%.
2-phenyl-5-(trifluoromethyl)-1H-benzo[e][1,2,4]triazolo[1,2-a][1,2,4]triazine-1,3(2H)-dione
(4c).
Yellow solid. mp 162-165 °C. IR (KBr, cm-1): 2925, 1784, 1731, 1646. 1H-NMR (400 MHz,
CDCl3): δ 8.14 (dd, J = 8.1, 1.3 Hz, 1H), 7.65–7.46 (m, 4H), 7.41 (dd, J = 7.8, 1.5 Hz, 1H), 7.35
(td, J = 7.9, 1.5 Hz, 1H), 7.21 (td, J = 7.7, 1.3 Hz, 1H). 13C-NMR (100 MHz, CDCl3): δ 144.12
(C=O), 141.03(C=O), 134.96 (q, JC-C-F = 42.4 Hz, C-CF3), 132.49, 131.48, 129.77, 129.47 (2C),
129.33, 128.68, 128.26, 126.66, 126.03 (2C), 117.82 (q, JC-F = 276.4 Hz, C-CF3), 114.71. 19F-
NMR (376.27 MHz, CDCl3): δ -68.10 (s, 3F, CF3). MS (m/z): calcd for C16H9F3N4O2 [M+]
346.0736, found: 346.2030.
1-(1-(2-bromophenylimino)-2,2,2-trifluoromethyl)-4-phenyl-1,2,4-triazolidine-3,5-dione
(4d).
White solid. mp 210-215 °C. IR (KBr, cm-1): 3336, 3071, 1790, 1758, 1696, 1610. 1H-NMR
(400 MHz, DMSO-d6): δ 7.27-7.55 (m, 9H, Ar), 10.02 (s, 1H, NH). 13C-NMR (100 MHz,
DMSO-d6): δ 158.53 (q, JC-F = 30.7 Hz, C-CF3), 154.30 (C=O), 151.99 (C=O), 138.53, 134.46,
134.28, 129.34, 128.81 (2C), 128.57, 126.16, 125.84 (2C), 125.78, 123.62 (q, JC-C-F = 274.0 Hz,
C-CF3), 119.28. 19F NMR (376.27 MHz, DMSO-d6): δ -73.54 (s, 3F, CF3). MS (m/z): calcd for
C20H12N4O6 (M+H+) 404.0736, found: 404.0734.
1-(1-(4-chlorophenylimino)-2,2,2-trifluoromethyl)-4-phenyl-1,2,4-triazolidine-3,5-dione
(4e).
5

Yellow solid. mp 287-292 °C. IR (KBr, cm-1): 3400, 1789, 1757, 1705, 1649. 1H-NMR (400
MHz, DMSO-d6): δ 7.25-7.66 (m, 9H), 9.98 (s, 1H, NH). 13C-NMR (100 MHz, DMSO-d6): δ
154.06 (q, JC-C-F = 29.0 Hz, C-CF3), 151.85 (C=O), 150.73 (C=O), 145.93, 134.44, 129.97 (2C),
129.03, 128.79 (2C), 127.27 (2C), 126.79, 126.19 (2C), 123.59 (q, JC-F = 261.0 Hz, C-CF3). 19F
NMR (376.27 MHz, DMSO-d6): δ -73.52 (s, 3F, CF3). Anal. Calcd for C16H10ClF3N4O2
(382.73): C, 50.21; H, 2.63; N, 14.64. Found: C, 50.15; H, 2.60; N, 14.60%.
4-phenyl-1-(2,2,2-trifluoro-1-((3-(trifluoromethyl)phenyl)imino)ethyl)-1,2,4-triazolidine-3,5-
dione (4f).
Cream solid. IR (KBr, cm-1): 3374, 3000, 1706, 1708, 1609. 1H-NMR (400 MHz, DMSO-d6): δ
8.25 (s, 1H, NH), 8.08 (s, 1H), 7.95 (d, J = 8.3 Hz, 2H), 7.67–7.60 (m, 3H), 7.59–7.52 (m, 3H).
13C-NMR (101 MHz, DMSO-d6): δ 155.36 (q, JC-C-F= 37.0 Hz, C-CF3), 154.81 (C=O), 149.36
(C, C=O), 137.96, 131.96, 131.48, 131.38, 130.16, 129.54 (q, JC-C-F = 33.2 Hz, C-CF3), 128.74,
128.63, 124.81, 122.48 (q, JC-F = 271.8 Hz, C-CF3), 121.65, 117.37, 114.29 (q, JC-F = 279.0 Hz,
C-CF3). 19F NMR (376.27 MHz, DMSO-d6): δ -59.26 (s, 3F, CF3), -71.41 (s, 3F, CF3). Anal.
Calcd for C17H10F6N4O2 (416.28): C, 49.05; H, 2.42; N, 13.46. Found: C, 49.03; H, 2.49; N,
13.36%.
4-phenyl-1-(2,2,2-trifluoro-1-(p-tolylimino)ethyl)-1,2,4-triazolidine-3,5-dione (4g).
Cream solid. mp 281-287 °C. IR (KBr, cm-1): 3401, 1790, 1758, 1701, 1623. 1H NMR (400
MHz, DMSO-d6): δ 9.98 (s, 1H, NH), 7.62–7.22 (m, 9H), 2.10 (s, 3H, CH3). 13C NMR (100
MHz, DMSO-d6): δ 154.22 (C=O), 153.34 (C=O), 147.88 (q, JC-C-F = 42.7 Hz, C-CF3), 144.82,
134.26, 129.34, 129.26, 128.82, 126.68, 126.12, 126.06, 125.88 (2C), 121.51, 119.77, 114.20 (q,
JC-F = 271.1 Hz, C-CF3), 21.00 (CH3). 19F NMR (376.27 MHz, DMSO-d6): δ -74.01 (s, 3F, CF3).
Anal. Calcd for C17H13F3N4O2 (362.31): C, 56.36; H, 3.62; N, 15.46. Found: C, 56.31; H, 3.45;
N, 15.05%.
1-(1-(2,4-dimethylphenylimino)-2,2,2-trifluoroethyl)-4-phenyl-1,2,4-triazolidine-3,5-dione
(4h).
White solid. mp 110 °C. IR (KBr, cm-1): 3374, 3000, 1703, 1700, 1609. 1H-NMR (300 MHz,
DMSO-d6): δ 10.09 (s, 1H, NH), 7.90–6.47 (m, 8H), 2.39–1.99 (s, 6H, 2CH3). 13C-NMR (75
MHz, DMSO-d6): δ 151.81 (C=O), 151.50 (q, JC-C-F = 32.4 Hz, C-CF3), 150.03 (C=O), 144.52,
132.98, 131.83, 129.51, 128.70, 128.09, 127.83 (2C), 126.63 (3C), 122.03, 120.62 (q, JC-F
=
268.1 Hz, C-CF3), 20.70 (CH3), 18.72 (CH3). 19F NMR (282.20 MHz, DMSO-d6): δ -74.08(s, 3F,
CF3). Anal. Calcd for C18H15F3N4O2 (376.34): C, 57.45; H, 4.02; N, 14.89. Found: C, 56.65; H,
4.05; N, 14.83%.
General procedure for the synthesis of (4i-4l) from 2, 3-dihydrophthalazine-1, 4-dione (2)
A mixture of 2, 3-dihydrophthalazine-1, 4-dione 2 (1 mmol), Et3N (3 mmol) and THF (5 mL)
were stirred at r.t for 10 min and then a solution of aceteimidoyle chloride derivatives 3 (1 mmol)
in THF (5 mL) was added dropwise. The reaction mixture was stirred at reflux. The progress of
the reaction was monitored by TLC. After completion of the reaction, the solvent was evaporated
under reduced pressure and the resulting crude product was purified by plate chromatography on
silica gel using hexane-ethyl acetate (6:2), producing the desired products 4i-l, in 76-90% yield.
6-(trifluoromethyl)benzo[5,6][1,2,4]triazino[1,2-b]phthalazine-8,13-dione (4i).
White solid. mp 128-134 °C. IR (KBr, cm-1): 3022, 2877, 1714, 1667, 1624, 1600. 1H-NMR
(400 MHz, DMSO-d6): δ 7.19–6.87 (m, 4H), 8.24–7.87 (m, 4H). 13C-NMR (100 MHz, DMSO-
d6): δ 166.58 (C=O), 164.97 (C=O), 154.27 (q, JC-C-F = 31.8 Hz, C-CF3), 135.63, 133.85 (3C),
129.09 (2C), 126.95 (2C), 125.00, 124.97, 123.45, 116.47, 115.47 (q, JC-F = 283.2 Hz, C-CF3).
6

19F NMR (376.27 MHz, DMSO-d6): δ -67.36 (s, 3F, CF3). Anal. Calcd for C16H8F3N3O2
(331.25): C, 58.01; H, 2.43; N, 12.69. Found: C, 57.87; H, 2.43; N, 12.58%.
2-fluoro-6-(trifluoromethyl)benzo[5,6][1,2,4]triazino[1,2-b]phthalazine-8,13-dione (4j).
White solid. mp 146-147 °C. IR (KBr, cm-1): 3020, 1701, 1654, 1611, 1586. 1H NMR (400 MHz,
DMSO-d6): δ 8.25–8.17 (m, 1H), 8.09–7.93 (m, 3H), 7.30–7.20 (m, 2H), 6.94–6.85 (m, 1H). 13C-
NMR (100 MHz, DMSO-d6): δ = 160.29(C=O), 159.29(C=O), 160.64 (d, JC-F = 251.8 Hz, C-F),
157.42 (q, JC-C-F = 31.8 Hz, C-CF3), 134.75 (2C), 133.97 (2C), 131.64, 129.33(2C), 127.02 (2C),
123.53, 118.37 (q, JC-F = 269.9 Hz, CF3), 112.14 (d, JC-C-F = 25.8 Hz), 105.29 (d, JC-C-F = 23.8
Hz). 19F NMR (376.27 MHz, DMSO-d6): δ -67.23 (s, 3F, CF3), -111.46 (m, 1F). Anal. Calcd for
C16H7F4N3O2 (349.24): C, 55.03; H, 2.02; N, 12.03. Found: C, 54.56; H, 2.34; N, 11.62%.
2-(2,2,2-trifluoro-1-(4-nitrophenylimino)ethyl)-2,3-dihydrophthalazine-1,4-dione (4k).
White solid. mp 215-218 °C. IR (KBr, cm-1): 3176, 3029, 2910, 1716, 1673, 1601. 1H-NMR
(400 MHz, DMSO-d6): δ 12.41 (s, 1H, NH), 8.15 (d, J = 7.8 Hz, 1H), 8.07–7.89 (m, 5H), 7.28–
7.17 (m, 2H). 13C-NMR (100 MHz, DMSO-d6): δ 166.49 (C=O), 155.28 (C=O), 145.87 (q, JC-C-F
= 32.5 Hz, C-CF3), 144.48, 142.88, 132.00 (2C), 131.26, 127.74, 126.87, 125.36 (2C), 125.27,
121.52(2C), 120.23 (q, JC-F= 287 Hz, C-CF3). 19F NMR (376.27 MHz, DMSO-d6): δ -71.94 (s,
3F, CF3). MS (m/z): Calcd for C16H9F3N4O4 [M+] 377.0756, Found: 376.7000.
2-(2,2,2-trifluoro-1-((2,4,6-tribromophenyl)imino)ethyl)-2,3-dihydrophthalazine-1,4-dione (4l).
Bright brown solid. mp 220-226 °C. IR (KBr, cm-1): 3029, 2909, 1733, 1666, 1600.1H-NMR
(400 MHz, DMSO-d6): δ 12.54 (s, 1H, NH), 8.20 (d, J = 7.9 Hz, 1H), 8.05–7.79 (m, 5H). 13C-
NMR (100 MHz, DMSO-d6): δ 159.33 (C=O), 148.01 (C=O), 145.08, 144.46, 135.72, 134.72,
133.94, 129.07, 126.92, 125.55, 125.34, 124.89, 123.66, 121.70, 121.51, 116.70 (q, JC-F= 278
Hz, C-CF3). 19F NMR (376.27 MHz, DMSO-d6): δ -71.45 (s, 3F, CF3). Anal. Calcd for
C16H7Br3F3N3O2 (569.96): C, 33.72; H, 1.24; N, 7.37. Found: C, 33.66; H, 0.87; N, 7.14%.
Acknowledgments
We gratefully acknowledge, the Vail-e-Asr University of Rafsanjan Faculty Research Grant for
financial support.
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<Figure>Scheme 1: Reactions of imidoyl chloride derivatives with urazole and phthalazine
<Figure>Scheme 2. Schematic presentation of the possible mechanism for products 4a-c and
4i.4l formation.
<Figure>Fig. 1: Biological active compounds base on urazole derivatives
<Figure>Figure 2. 1H-NMR spectrum of compound 4a
<Figure>Figure 3. 13C-NMR spectrum of compound 4a
<Figure>Figure 4. HSQC spectrum of compound.4a
<Figure>Figure 5. 19FNMR spectrum of compound 4a
Tables
<Table>Table 1: Optimization of the solvent, temperature and base for reaction of urazole 1 with
imidoyl chloride 2a
Entry
Base
solvent
Condition
Time (h)
Yields (%)
1
2
3
4
5
6
K2CO3
K2CO3
NaH
DMF
DMF
r.t
reflux
r.t
24
18
24
18
24
8
0
0
THF
0
NaH
THF
60 °C
r.t
0
NaH
CH3CN
CH3CN
40
92
NaH
reflux
<Table>Table 2: Synthesis of products 4a-h
9

Entry
1
imidoyle
products
Time (h) Yield (%)
8
92
92
2
8
3
4
9
88
78
12
5
12
80
10

6
7
12
14
85
80
8
13
80
<Table>Table 3: Optimization of the solvent, temperature and base for reaction of phthalazine 2
with imidoyl chloride 3c
Time
(h)
Yields
(%)
entry
Base
Solvent
Condition
1
2
3
4
5
6
NaH
CH3CN
THF
reflux
reflux
reflux
reflux
r.t
18
16
16
16
14
10
0
K2CO3
K2CO3
10
48
56
60
88
DMF
K2CO3 THF.DMF
Et3N
Et3N
THF
THF
reflux
<Table>Table 4: Synthesis of products 4i-l
11

Entry
1
imidoyle
Products
Time (h) Yield (%)
10
9
88
90
2
3
4
12
12
76
80
TDENDOFDOCTD
12