Synthesis and biological activity of fluorinated 2-amino-4-aryl-3,4- dihydro[1,3,5]triazino[1,2-a]benzimidazoles

Article abstract of DOI:10.1016/j.jfluchem.2005.02.009

The heterocyclic nucleus s-triazino[1,2-a]benzimidazole has been reported to exhibit antibacterial activity. In this study, seven new 3,4-dihydro[1,3,5] triazino[1,2-a]benzimidazole derivatives were prepared via cyclocondensation between 2-guanidinobenzimidazole and fluorine substituted (including trifluoromethyl) benzaldehydes. The structures of all the compounds were confirmed by ¹H, ¹³C NMR and IR spectral data. Spectral data also suggested the existence of various tautomeric forms of the fluorine-containing s-triazino[1,2-a]benzimidazole compounds. The synthesized compounds were also screened for antibacterial and bovine dihydrofolate reductase (DHFR) inhibitory activities. The compound 3g substituted with a 3′,5′-bis(trifluoromethyl)phenyl moiety demonstrated the best antibacterial activity in the series. None of the tested compounds significantly inhibited bovine DHFR.

Full text of DOI:10.1016/j.jfluchem.2005.02.009

Journal of Fluorine Chemistry 126 (2005) 759–763
www.elsevier.com/locate/fluor
Synthesis and biological activity of fluorinated 2-amino-4-aryl-3,
4-dihydro[1,3,5]triazino[1,2-a]benzimidazoles§
b
Anton V. Dolzhenko a, Wai-Keung Chui a, , Anna V. Dolzhenko ,
*
Lai-Wah Chan a
a Department of Pharmacy, Faculty of Science, National University of Singapore,
18 Science Drive 4, Singapore 117543, Singapore
b Perm State Pharmaceutical Academy, 48 Lenin Street, Perm 614990, Russian Federation
Received 27 December 2004; received in revised form 14 February 2005; accepted 17 February 2005
Available online 13 April 2005
Abstract
The heterocyclic nucleus s-triazino[1,2-a]benzimidazole has been reported to exhibit antibacterial activity. In this study, seven new 3,4-
dihydro[1,3,5]triazino[1,2-a]benzimidazole derivatives were prepared via cyclocondensation between 2-guanidinobenzimidazole and
fluorine substituted (including trifluoromethyl) benzaldehydes. The structures of all the compounds were confirmed by 1H, 13C NMR
and IR spectral data. Spectral data also suggested the existence of various tautomeric forms of the fluorine-containing s-triazino[1,2-
a]benzimidazole compounds. The synthesized compounds were also screened for antibacterial and bovine dihydrofolate reductase (DHFR)
inhibitory activities. The compound 3g substituted with a 30,50-bis(trifluoromethyl)phenyl moiety demonstrated the best antibacterial activity
in the series. None of the tested compounds significantly inhibited bovine DHFR.
# 2005 Elsevier B.V. All rights reserved.
Keywords: 2-Guanidinobenzimidazole; Cyclocondensation; s-Triazino[1,2-a]benzimidazole; Antibacterial activity; Dihydrofolate reductase inhibition
1. Introduction
reported to be synthesized; however no spectral data and
elemental analysis results were presented in the article [2].
Our laboratory has been working on the s-triazine DHFR
inhibitors for sometime [18], it is therefore of interest to us
to explore the modification of the s-triazino[1,2-a]benzi-
midazole nucleus in an attempt to search for new potential
inhibitors of DHFR. The objective of this study was to
introduce an aryl group at position 4 of the heterocycle
through condensation of the guanidino intermediate with
benzaldehydes. Fluorinated (including trifluoromethyl)
benzaldehydes were used in the synthesis for the purpose
of investigating whether fluorinated aryl group attached to
the heterocyclic nucleus will give rise to DHFR inhibitory
and antibacterial activity. In our laboratory, it was found
that lipophilic groups attached to the dihydro-s-triazines
appeared to give better DHFR inhibitory activity. There-
fore, for this study we intended to investigate if lipophilic
fluorinated derivatives of 2-amino-3,4-dihydro[1,3,5]tria-
zino[1,2-a]benzimidazoles would exhibit DHFR inhibitory
activity.
A variety of biological effects have been attributed to the
heterocyclic nucleus s-triazino[1,2-a]benzimidazole [2–14].
In particular, 2-amino-3,4-dihydro[1,3,5]triazino[1,2-a]ben-
zimidazoles have been found to possess both antibacterial
[2] and dihydrofolate reductase (DHFR) inhibitory [3,4]
activities.
The synthesis of 2-amino-3,4-dihydro[1,3,5]tria-
zino[1,2-a]benzimidazoles through
a base catalyzed
cyclization of 2-guanidinobenzimidazole (2) with benzal-
dehyde was first reported by Nagarajan et al. in 1970
[15]. To date only a limited number of studies on
the synthesis of the above mentioned 2-amino-3,4-
dihydro[1,3,5]triazino[1,2-a]benzimidazoles have been
reported [1,2,16,17]. Fluorinated compound 3c has been
§
Part 2 in the series ‘Fused heterocyclic systems with s-triazine ring’ [1]
* Corresponding author. Tel.: +65 6874 2933; fax: +65 6779 1554.
E-mail address: phacwk@nus.edu.sg (W.-K. Chui).
0022-1139/$ – see front matter # 2005 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2005.02.009

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A.V. Dolzhenko et al. / Journal of Fluorine Chemistry 126 (2005) 759–763
Scheme 1. The synthesis of fluorinated 2-amino-4-aryl-3,4-dihydro[1,3,5]triazino[1,2-a]benzimidazoles (3a–g).
Table 1
1H and 13C NMR spectral data for the s-triazine ring of fluorinated 2-amino-
2. Results and discussion
4-aryl-3,4-dihydro[1,3,5]triazino[1,2-a]benzimidazoles (3a–g)
2.1. Chemistry
Compound
RF
1H NMR,
13C NMR, d (ppm)
d (ppm)
2-Guanidinobenzimidazole (2) was prepared by the
cyclocondensation of o-phenylenediamine (1) with cyano-
guanidine according to the method reported by King et al.
[19]. The piperidine-catalyzed reaction of 2 with fluorinated
aromatic aldehyde in refluxing ethanol, led to a cyclization
process with the formation of an s-triazine ring (Scheme 1).
This chemical reaction proceeded smoothly and the yields of
the products were generally good, ranging from 64 to 90%.
The structures of the synthesized 2-amino-4-aryl-3,
4-dihydro[1,3,5]triazino[1,2-a]benzimidazoles (3a–g) were
elucidated with the help of IR and NMR spectral data as well
as elemental analyses. The presence of the 2-NH2 group in
the structure was supported with a significant stretching
absorption signal (nN–H) observed at 3224–3474 cmꢀ1 and
the scissoring absorption signal (dN–H) appearing at 1605–
1625 cmꢀ1 in the IR spectra of compounds 3a–g.
H-4
NH
C-2
C-4
C-10a
3a
3b
3c
3d
3e
3f
2-F
7.06
6.80
6.82
7.01
6.97
6.97
7.06
8.30
8.09
8.25
7.90
8.36
8.51
8.26
155.2
155.3
155.2
154.9
155.2
155.3
155.1
61.2
64.9
65.1
62.1
64.9
65.0
64.2
153.3
153.3
153.2
153.7
153.3
153.3
153.1
3-F
4-F
2-CF3
3-CF3
4-CF3
3,5-(CF3)2
3g
dihydro- (B) and 4,10-dihydro- (C) (Fig. 1). The prototropic
interconversion between these tautomeric forms was postu-
lated based on the broadening of the signals of dihydro[1,3,5]-
triazino[1,2-a]benzimidazole heterocyclic system in the 13
C
NMR spectra of the compounds 3a–g, particularly, the
signals of C-2, C-4, C-10a that are in close proximity with the
nitrogen atoms that are involved in the tautomerization.
However, in compound 3c a broad signal in the 13C NMR
spectrum was observed for C-9a. This observation, together
with a large broadening effect of the NH signal in 1H NMR
spectrumofthiscompound3c,mightindicatethepredominant
existenceofthe1,4-dihydro-andthe4,10-dihydro-tautomeric
forms (B and C) during the equilibrium state.
1
The assignment of H and 13C NMR signals was made
based on the data for analogous compounds [1,16,20] and the
electronic effect of the substituents. The formation of the s-
triazineringinthereactionwassuggestedbytheNMRspectral
data (Table 1). The singlet of H-4 observed at 6.80–7.06 ppm
inthe 1H NMRspectra of 3a–g, togetherwith thesignal of C-4
at 61.2–65.1 ppm in the 13C NMR spectra confirmed the
formation of the dihydro-s-triazine ring. This strong evidence
ofthesp3 hybridizationofC-4ruledoutthepossibleformation
of the azomethine carbon of Schiff base-like compounds. At
the same time, the signals of the other two carbon atoms of the
s-triazine ring (C-2 and C-10a), surrounded by three nitrogen
atoms each, were found located at 154.9–155.2 and 153.1–
153.7 ppm, respectively. This provided further evidence for
the formation of the triazine ring.
2.2. Biological activity
For both the antibacterial and DHFR inhibition bioassays,
the compounds were dissolved in Me2SO. In order to ensure
that the solvent per se had no effect on bacterial growth or
enzymatic activity, negative control tests were performed
using Me2SO at the same concentrations.
It should be noted that the compounds 3a–g could exist
in three tautomeric forms, namely, 3,4-dihydro- (A), 1,4-
In the antibacterial bioassay, the minimum inhibitory
concentrations (MIC) were determined using the two-fold

A.V. Dolzhenko et al. / Journal of Fluorine Chemistry 126 (2005) 759–763
761
Fig. 1. The tautomeric forms of fluorinated 2-amino-4-aryl-3,4-dihydro[1,3,5]triazino[1,2-a]benzimidazoles (3a–g).
Table 2
Biological activity of the fluorinated 2-amino-4-aryl-3,4-dihydro[1,3,5]triazino[1,2-a]benzimidazoles (3a-g)
Compound
RF
Antibacterial effect, MIC (mg mlꢀ1
)
Bovine DHFR inhibition
Concentration (mM)
S. aureus
B. subtilis
B. megaterium
K. aerogenes
E. coli
Inhibition (%)
3a
3b
3c
3d
3e
3f
2-F
>200
>200
100
>200
>200
>200
>100
>25
>25
25
>200
>200
>200
>100
>25
>200
>200
>200
>100
>25
>200
>200
>200
>100
>25
0.5
1
3
7
3-F
4-F
1
15.5
11
NDa
6
2-CF3
3-CF3
4-CF3
3,5-(CF3)2
–
100
0.2
–
>25
>25
25
>25
>25
>25
>25
>25
>25
0.1
–
3g
Tetracycline
NDa
0.63
0.63
0.63
1.25
1.25
–
–
a
ND: not determined due to solubility problems.
serial dilution technique [21]. The following bacteria were
used for screening: Staphylococcus aureus, Bacillus subtilis,
Bacillus megaterium, Klebsiella aerogenes, and Escherichia
coli. The compounds did not inhibit the growth of the
bacteria B. megaterium, K. aerogenes, and E. coli at the
concentrations used. However, three of the s-triazino[1,2-
a]benzimidazoles (3c,d and g) did exhibit weak antibacterial
effect against S. aureus and B. subtilis in comparison to the
reference drug tetracycline (Table 2). The most active
compound in the series was found to be compound 3g which
possesses the 30,50-bis(trifluoromethyl)phenyl moiety.
The DHFR inhibition bioassay was carried out using
bovine DHFR (Fluka Chemie) according to the previously
described method [18], the effect of the compounds was
expressed as percentage inhibition (Table 2). The com-
pounds were screened at one of the following concentrations
0.1, 0.2, 0.5 and 1.0 mM depending on solubility. Because of
the poor solubility of the 30-trifluoromethyl substituted
derivatives (3e,g) in the bioassay medium, they could not be
tested in these concentrations. The screening found that none
of the s-triazino[1,2-a]benzimidazoles showed significant
inhibition of bovine DHFR.
cally evaluated for both antibacterial and DHFR inhibitory
activities. The basic 2-NH2 group and its adjacent N atom
are believed to interact with specific amino acids at the
active site of the DHFR enzyme. However, the 4-aryl
substituent may be too large for the compound to fit properly
in the active site; hence a lack of DHFR inhibitory was
observed. Nevertheless, three of the compounds (3c,d and g)
were found to possess some degree of antimicrobial activity.
Therefore they may be used as lead compounds for further
development.
4. Experimental
Melting points (uncorrected) were determined on a
Gallenkamp melting point apparatus. 1H and 13C NMR
spectra were recorded on a Bruker DPX-300 spectrometer,
using Me2SO-d6 as a solvent and TMS as an internal
reference. IR spectra were performed on a Jasco FT-IR-430
spectrophotometer in KBr pellets. The course of the
reactions was monitored by TLC on Silica gel 60 F254
plates (Merck, Germany). 2-Guanidinobenzimidazole (2)
was prepared using reported method [19].
3. Conclusions
4.1. General method for the syntheses of 2-amino-4-aryl-
3,4-dihydro[1,3,5]triazino[1,2-a]benzimidazoles (3a–g)
The present work has demonstrated the use of a simple
cyclocondensation method for the synthesis of fluorinated 2-
amino-4-aryl-3,4-dihydro[1,3,5]triazine[1,2-a]benzimida-
zoles. This method was able to give reasonably good and
clean yields. Seven derivatives were prepared and biologi-
A solution of 2-guanidinobenzimidazole (2, 1.75 g,
0.01 mol), fluorine or trifluoromethyl substituted benzalde-
hyde (0.01 mol) and 0.5 ml piperidine in ethanol (20–50 ml)

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A.V. Dolzhenko et al. / Journal of Fluorine Chemistry 126 (2005) 759–763
was heated under reflux for 1–8 h (vide infra). After cooling,
the product was filtered, washed with ethanol and dried.
H-60), 8.25 (1H, br s, NH). 13C NMR (75 MHz, Me2SO-d6): d
65.1 (s, C-4), 108.2 (s, C-6), 115.7 (s, C-9), 115.8 (d,
J = 21.8 Hz, C-30 and C-50), 119.1 (s, C-8), 121.0 (s, C-7),
128.5 (d, J = 8.7 Hz, C-20 and C-60), 130.9 (s, C-5a), 136.7 (s,
C-10), 142.6 (s, C-9a), 153.2 (s, C-10a), 155.2 (s, C-2), 162.3
(d, J = 245.6 Hz, C-40). Anal. Calcd for C15H12FN5: C, 64.05;
H, 4.30; N, 24.90. Found: C, 64.32; H, 4.36; N, 24.52.
4.2. 2-Amino-4-(20-fluorophenyl)-3,4-
dihydro[1,3,5]triazino[1,2-a]benzimidazole (3a)
Reaction time 1.5 h; yield 90%; mp 276–277 8C; IR
(KBr): n 3474 (NH st), 3323 (NH st), 3251 (NH st), 3109
(CH st), 2968 (CH st), 2757 (CH st), 1659 (C N st), 1625
(NH d), 1590, 1531, 1457, 1433, 1405, 1276, 1252, 1224,
769, 734, 706 cmꢀ1. 1H NMR (300 MHz, Me2SO-d6): d 6.65
(2H, s, NH2), 6.75 (1H, d, J = 7.2 Hz, H-9), 6.81 (1H, t,
J = 7.3 Hz, H-8), 6.95 (1H, t, J = 7.7 Hz, H-7), 7.05 (1H, s,
H-4), 7.15–7.26 (3H, m, H-30, H-50 and H-60), 7.27 (1H, d,
J = 8.4 Hz, H-6), 7.41 (1H, td, J = 7.6 Hz, JHF = 5.3 Hz, H-
40), 8.30 (1H, s, NH). 13C NMR (75 MHz, Me2SO-d6): d
61.2 (s, C-4), 107.5 (s, C-6), 115.9 (s, C-9), 116.0 (d,
J = 19.6 Hz, C-30), 119.0 (s, C-8), 120.9 (s, C-7), 124.9 (d,
J = 3.6 Hz, C-60), 126.9 (d, J = 10.2 Hz, C-40), 128.1 (d,
J = 2.9 Hz, C-50), 131.0 (s, C-5a), 131.3 (d, J = 8.0 Hz, C-
10), 143.2 (s, C-9a), 153.3 (s, C-10a), 155.2 (s, C-2), 159.5
(d, J = 247.8 Hz, C-20). Anal. Calcd. for C15H12FN5: C,
64.05; H, 4.30; N, 24.90. Found: C, 63.86; H, 4.22; N, 24.56.
4.5. 2-Amino-4-[20-(trifluoromethyl)phenyl]-3,4-
dihydro[1,3,5]triazino[1,2-a]benzimidazole (3d)
Reaction time 5 h; yield 64%; mp 274–275 8C; IR (KBr):
n 3403 (NH st), 3327 (NH st), 3133 (CH st), 3064 (CH st),
1656 (C N st), 1618 (NH d), 1591, 1528, 1462, 1425, 1313,
1276, 1248, 1168, 1125, 1106, 1038, 768, 742, 676 cmꢀ1. 1H
NMR (300 MHz, Me2SO-d6): d 6.39 (1H, d, J = 7.5 Hz, H-
9), 6.45 (2H, s, NH2), 6.77 (1H, t, J = 7.5 Hz, H-7), 6.95 (1H,
t, J = 7.5 Hz, H-8), 7.01 (1H, s, H-4), 7.19 (1H, d,
J = 7.5 Hz, H-6), 7.27 (1H, d, J = 7.5 Hz, H-60), 7.61 (1H,
t, J = 7.7 Hz, H-40), 7.67 (1H, t, J = 7.7 Hz, H-50), 7.88 (1H,
d, J = 7.5 Hz, H-30), 7.90 (1H, s, NH). 13C NMR (75 MHz,
Me2SO-d6): d 62.1 (s, C-4), 107.4 (s, C-6), 116.2 (s, C-9),
119.3 (s, C-8), 121.2 (s, C-7), 124.2 (q, J = 272.8 Hz, CF3),
125.9 (q, J = 30.6 Hz, C-20), 125.9 (q, J = 5.3 Hz, C-30),
128.0 (s, C-60), 129.9 (s, C-40), 130.9 (s, C-5a), 134.0 (s, C-
50), 138.3 (q, J = 4.1 Hz, C-10), 143.3 (s, C-9a), 153.7 (s, C-
10a), 154.9 (s, C-2). Anal. Calcd. for C16H12F3N5: C, 58.01;
H, 3.65; N, 21.14. Found: C, 58.35; H, 3.74; N, 20.73.
4.3. 2-Amino-4-(30-fluorophenyl)-3,4-
dihydro[1,3,5]triazino[1,2-a]benzimidazole (3b)
Reaction time 1.5 h; yield 68%; mp 276 8C; IR (KBr): n
3338 (NH st), 3230 (NH st), 3149 (CH st), 3059 (CH st),
1647 (C N st), 1615 (NH d), 1593, 1536, 1457, 1424, 1401,
1276, 1258, 1246, 761, 742, 701 cmꢀ1. 1H NMR (300 MHz,
Me2SO-d6): d 6.81–6.90 (5H, m, H-4, H-8, H-9 and NH2),
6.97 (1H, td, J = 7.2, 2.3 Hz, H-7), 7.14–7.23 (3H, m, H-20,
H-50 and H-60), 7.26 (1H, d, J = 7.9 Hz, H-6), 7.43 (1H, dd,
J = 7.9 Hz, JHF = 10.5 Hz, H-40), 8.47 (1H, s, NH). 13C
NMR (75 MHz, Me2SO-d6): d 64.9 (s, C-4), 108.1 (s, C-6),
113.0 (d, J = 21.8 Hz, C-20), 115.9 (d, J = 21.1 Hz, C-40),
116.0 (s, C-9), 119.1 (s, C-8), 121.0 (s, C-7), 122.0 (d,
J = 2.9 Hz, C-60), 131.0 (s, C-5a), 131.1 (d, J = 8.7 Hz, C-
50), 143.1 (s, C-9a), 143.2 (d, J = 5.1 Hz, C-10), 153.3 (s, C-
10a), 155.3 (s, C-2), 162.1 (d, J = 245.6 Hz, C-30). Anal.
Calcd. for C15H12FN5: C, 64.05; H, 4.30; N, 24.90. Found:
C, 64.36; H, 4.22; N, 24.98.
4.6. 2-Amino-4-[30-(trifluoromethyl)phenyl]-3,4-
dihydro[1,3,5]triazino[1,2-a]benzimidazole (3e)
Reaction time 3 h; yield 75%; mp 262–263 8C; IR (KBr): n
3440 (NH st), 3342 (NH st), 3237 (NH st), 3154 (CH st), 3059
(CH st), 1647 (C N st), 1615 (NH d), 1592, 1537, 1458, 1425,
1401, 1329, 1277, 1246, 1171, 1128, 1095, 1073, 764, 744,
1
704 cmꢀ1. H NMR (300 MHz, Me2SO-d6): d 6.70 (2H, s,
NH2), 6.83 (1H, t, J = 6.8 Hz, H-8), 6.84 (1H, d, J = 7.5 Hz,
H-9), 6.96 (1H, t, J = 8.3 Hz, H-7), 6.97 (1H, s, H-4), 7.25
(1H, d, J = 7.9 Hz, H-60), 7.54 (1H, d, J = 7.9 Hz, H-6), 7.62
(1H, t, J = 7.7 Hz, H-50), 7.74 (1H, d, J = 7.5 Hz, H-40), 7.83
(1H, s, H-20), 8.36 (1H, s, NH). 13C NMR (75 MHz, Me2SO-
d6): d 64.9 (s, C-4), 108.0 (s, C-6), 116.1 (s, C-9), 119.1 (s, C-
8), 120.9 (s, C-7), 122.9 (q, J = 3.6 Hz, C-20), 123.9 (q,
J = 272.5 Hz, CF3), 125.8 (q, J = 3.6 Hz, C-40), 129.4 (q,
J = 32.0 Hz, C-30), 130.0 (s, C-50), 130.2 (s, C-60), 131.0 (s, C-
5a), 141.9 (s, C-10), 143.3 (s, C-9a), 153.3 (s, C-10a), 155.2 (s,
C-2). Anal. Calcd. for C16H12F3N5: C, 58.01; H, 3.65; N,
21.14. Found: C, 57.96; H, 3.75; N, 20.84.
4.4. 2-Amino-4-(40-fluorophenyl)-3,4-
dihydro[1,3,5]triazino[1,2-a]benzimidazole (3c)
Reaction time 2 h; yield 76%; mp 242 8C (lit. 210–212 8C
[2]); IR (KBr): n 3415 (NH st), 3321 (NH st), 3224 (NH st),
3138 (CH st), 1659 (C N st), 1605 (NH d), 1510, 1459, 1401,
1372, 1279, 1244, 1230, 1156, 841, 762, 743 cmꢀ1. 1H NMR
(300 MHz, Me2SO-d6): d 6.65 (2H, s, NH2), 6.76 (1H, d,
J = 7.5 Hz, H-9), 6.82 (1H, t, J = 7.5 Hz, H-8), 6.82 (1H, s, H-
4), 6.96 (1H, t, J = 7.5 Hz, H-7), 7.23 (2H, ddd, J = 7.2,
2.3 Hz, JHF = 7.7 Hz, H-30 and H-50), 7.25 (1H, d, J = 7.5 Hz,
H-6), 7.44 (2H, ddd, J = 7.2, 2.3 Hz, JHF = 5.7 Hz, H-20 and
4.7. 2-Amino-4-[40-(trifluoromethyl)phenyl]-3,4-
dihydro[1,3,5]triazino[1,2-a]benzimidazole (3f)
Reaction time 1 h; yield 72%; mp 267–268 8C; IR (KBr):
n 3464 (NH st), 3354 (NH st), 3237 (NH st), 3101 (CH st),
3058 (CH st), 1645 (C N st), 1615 (NH d), 1590, 1539,

A.V. Dolzhenko et al. / Journal of Fluorine Chemistry 126 (2005) 759–763
763
1459, 1416, 1327, 1277, 1246, 1170, 1121, 1067, 1017, 845,
1
References
764, 745 cmꢀ1. H NMR (300 MHz, Me2SO-d6): d 6.81–
[1] A.V. Dolzhenko, W.K. Chui, J. Heterocyclic Chem., in press.
6.90 (4H, m, J = 7.9 Hz, H-8, H-9 and NH2), 6.97 (1H, t,
J = 8.3 Hz, H-7), 6.98 (1H, s, H-4), 7.25 (1H, d, J = 7.9 Hz,
H-6), 7.58 (2H, d, J = 7.9 Hz, H-20 and H-60), 7.78 (2H, d,
J = 8.3 Hz, H-30 and H-50), 8.51 (1H, s, NH). 13C NMR
(75 MHz, Me2SO-d6): d 65.0 (s, C-4), 108.1 (s, C-6), 116.0
(s, C-9), 119.2 (s, C-8), 121.0 (s, C-7), 123.9 (q,
J = 272.5 Hz, CF3), 125.7 (q, J = 3.6 Hz, C-30 and C-50),
127.0 (s, C-20 and C-60), 129.5 (q, J = 31.2 Hz, C-40), 131.0
(s, C-5a), 143.1 (s, C-9a), 144.9 (s, C-10), 153.3 (s, C-10a),
155.3 (s, C-2). Anal. Calcd. for C16H12F3N5: C, 58.01; H,
3.65; N, 21.14. Found: C, 57.62; H, 3.75; N, 20.48.
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Reaction time 8 h; yield 65%; mp 297–298 8C; IR (KBr): n
3440 (NH st), 3317 (NH st), 3062 (CH st), 1654 (C N st),
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1
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J = 7.5 Hz, H-7), 7.06(1H, s, H-4), 7.28 (1H, d, J = 7.9 Hz, H-
6), 7.97 (2H, s, H-20 and H-60), 8.16 (1H, s, H-40), 8.26 (1H, s,
NH). 13C NMR (75 MHz, Me2SO-d6): d 64.2 (s, C-4), 107.9
(s, C-6), 116.3 (s, C-9), 119.3 (s, C-8), 121.2 (s, C-7), 122.9 (q,
J = 272.8 Hz, 2CF3), 123.0 (q, J = 4.1 Hz, C-40), 126.8 (q,
J = 3.2 Hz, C-20 and C-60), 130.8 (q, J = 32.9 Hz, C-30 and
C-50), 130.9(s, C-5a), 143.8(s, C-10), 143.3(s, C-9a), 153.1(s,
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Acknowledgment
This work is supported by the Academic Research Fund
from the National University of Singapore.