A facile one pot synthesis of 2, 4-diamino-6-substituted s-triazine derivatives

Article abstract of DOI:10.1002/jhet.5570450618

(Chemical Equation Presented) A novel and facile one-pot procedure for the preparation of 2,4-diamino-6-substituted-s-triazine derivatives (IIa-n) was reported. The scope of its application was demonstrated with a number of examples. The new procedure involved treatment of pmguanil or chloroproguanil with acyl chloride or alky chlorooxoacetate in pyridine at ice cold temperature followed by reflux overnight to give good yields of the desired products.

Full text of DOI:10.1002/jhet.5570450618

Nov-Dec 2008
1673
A Facile One Pot Synthesis of 2, 4-Diamino-6-substituted
s-Triazine Derivatives
Ramadas Sathunuru, Victor Melendez, Michael P. Kozar and Ai J. Lin*
Division of Experimental Therapeutics, Walter Reed Army Institute of Research,
Silver Spring, Maryland 20910
Received May 9, 2008
HN
R2
HN
NH
H
N
N
N
H
N
NH
N
1). R2-COCl / C5H5N / 0 oC
Cl
HN
Cl
2). Reflux
R1
R1
Ia (R1 = H) : Proguanil
Ib (R1 = Cl): Chloroproguanil
IIa-j (R1 = H)
IIk-n (R1 = Cl)
A novel and facile one-pot procedure for the preparation of 2,4-diamino-6-substituted-s-triazine
derivatives (IIa-n) was reported. The scope of its application was demonstrated with a number of
examples. The new procedure involved treatment of proguanil or chloroproguanil with acyl chloride or
alky chlorooxoacetate in pyridine at ice cold temperature followed by reflux overnight to give good yields
of the desired products.
J. Heterocyclic Chem., 45, 1673 (2008).
INTRODUCTION
further elaboration. The other route involves the reaction
of substituted isothiocyanates with sodium hydro-
gencyanamide, followed by amidines in the presence of 1-
(3-dimethylaminopropyl)-3-ethylcarbodiimide hydro-
chloride (EDC) [17-18]. This procedure appears more
general. In another study, Insuasty et al. [19] prepared
another series of pyrazolo[1,5-a]-1,3,5-triazines by the
reaction of S,S-diethyl aroyliminodithoicarbonates and
aroyl isothiocyanates with 5-amino-3-methylpyrazole in
As part of our efforts in search of malaria prophylactic
and/or therapeutic agents, a series of imidazolidinedione
(IZ) derivatives were found to possess profound activity
against liver stage malaria in rodent and non-human
primate models [1-4]. Subsequently, the IZ compounds
were found to metabolize to s-triazine derivatives in
microsomal preparations and in animals [4]. Active in
mice tests, the triazines were considered the active
metabolite of the IZ compounds. This finding prompted
us to develop methods to prepare a series of N,N'-
disubstituted s-triazine-2,4-diamine and 6-substituted
dimethylformamide under reflux.
Subsequently,
Montalbetti et al. [20] prepared a series of 4,6-diamino-
1,3,5-triazines by acetone-potassium carbonate catalyzed
reaction of 2,4-dichloro-6-morpholin-1,3,5-triazine and
chloroanilines followed by the Suzuki coupling reaction
to introduce an aryl substituent at the 2-position.
pyrimidine-2,4-diamine
antimalarial agents.
derivatives
as
potential
The 1,3,5-triazine (s-triazine) ring is well represented in
synthetic compounds endowed with biological activities.
Its chemistry continues to draw the attention of many
RESULTS AND DISCUSSION
researchers throughout the world.
Several reviews
The one pot reaction involved the treatment of an
acylchloride or alkyl chlorooxoacetate with proguanil (Ia)
or chloroproguanil (Ib) in anhydrous pyridines at 0 °C,
allowed to warm up to room temperature and then reflux
overnight. The yields of the triazines (IIa-n) ranged from
52% to 77%, which are, for the most part, significantly
higher than any methods previously reported. This simple
method can be applied to prepare a wide variety of 6-
substituted 2,4-diaminotriazine derivatives using various
aliphatic or aromatic acylchlorides and substituted
biguanides Ia,b as starting material to give the
corresponding triazines IIa-n in one step. The starting
materials, reagents, yields and products of the one pot
synthesis are shown in Table 1.
emphasize synthetic approaches and reactivity of this
heterocycle [5-8] and a well documented application of
the pharmacological properties of its derivatives are
widely reported [4,9,10]. 6-Substituted-1,3,5-triazine-2,4-
diamines have often been found to be synthetic targets as
chemotherapeutic agents [11-15]. Previous synthetic
methods for such compounds mainly relied on four routes,
which required two, three or four steps. One route starts
with cyanuric chloride, which can sequentially be reacted
with Grignard reagents [11,16], ammonia, and amines to
give the desired s-triazines. The utility of this procedure
is limited by the fact that Grignard reagents are highly
reactive and therefore prevent versatile functionalities for

1674
R. Sathunuru, V. Melendez, Michael P. Kozar and A. J. Lin
Vol 45
Scheme 1: One Pot Reaction
HN
R2
O
N
N
HN
NH
H
N
H
N
R2
C5H5N
NH
N
Cl
1. at 0 0C
2. reflux
HN
Cl
Cl
R1
R1
Ia (R1 = H) : Proguanil
Ib (R1 = Cl): Chloroproguanil
IIa-j (R1 = H)
IIk-n (R1 = Cl)
Table 1
Yields of s-Triazines from Coupling of Biguanides with Acylchlorides or Alkyl-chlorooxoacetates.
Compound
Biguanide
Acyl Chloride
R2
Yields (%)
IIa
IIb
IIc
IId
IIe
IIf
IIg
IIh
IIi
IIj
IIk
IIl
IIm
IIn
Ia
Ia
Ia
Ia
Ia
Ia
Ia
Ib
Ia
Ib
Ib
Ib
Ib
Ia
CH3COCl
(CH3)2CHCOCl
(CH3)2CHCH2COCl
(CH3CH2)2CHCOCl
PhCOCl
p-Cl-PhCOCl
p-Me-PhCOCl
PhCOCl
CH3CH2CH2COCl
(CH3CH2)2CHCOCl
CH3OCOCOCl
CH3CH2OCOCOCl
PhCH2OCOCOCl
CH3CH2OCOCl
CH3
CH(CH3)2
(CH3)2CHCH2-
(CH3CH2)2CH-
Ph-
52.2
64.4
72.8
56.3
51.2
77.4
49.1
71.1
47.3
60.6
28.7
32.9
76.6
72.5
p-Cl-Ph
p-Me-Ph
-Ph
-CH2CH2CH3
-CH(CH2CH3)2
-COOCH3
-COOCH2CH3
-COOCH2Ph
-OH
The possible mechanism of the one pot reaction is
proposed as shown in Scheme 2. Treating proguanil with
an equal molar amount of acyl chloride at low
temperature, the primary amino group of the proguanil
reacts with acylchlorides to give a mixture of mono-amide
intermediates 1 and 2 which cyclized to form 2-aryl-
amino-4-isopropylamino-6–alkyl/aryl-1,2,5,6-tetrahydro-
[1,3,5]-triazin-6-ol (3), from which a water molecule was
eliminated to give the desired s-triazines (IIa-m). When
ethyl chloroformate was used as an acylating agent,
Scheme 2: Mechanism of One Pot Reaction
O
C
OH
-O
N
H
N
OR
NH
H
NH
NH
N
OR
N
N
N
HN
-OR
HN
N
NH
HN
N
NH
Cl
NH
Cl
NH
Cl
N
C=O
OR
+
NH
IIn
Cl
5
6
4
R
HO
N
H
N
Cl
N
N
H
N
H
RO COCl /
dry pyridine
3
-H2O
heat
NH
O
C
HN
NH
C
R
H
N
H
NH
NH
N
R
N
N
N
N
HN
NH2
Cl
N
H
N
N
H
RCOCl
NH
Cl
NH
N
C=O
+
NH
dry pyridine
0 o
R
C
IIa-m
Cl
proguanil
Cl
1
2

Nov-Dec 2008
A Facile One Pot Synthesis of 2, 4-Diamino-6-substituted s-Triazine Derivatives
1675
2-hydroxy-s-triazine (IIn) was formed, instead of the
2-ethoxy-s-triazine analog, involving elimination of
ethoxy rather than the hydroxy group from the
intermediate 6.
The NMR spectra of the tautomers were provided
separately in the experimental section. The final products
1
13
were characterized by H NMR,
C NMR, MS, and
elemental analysis. The NH protons of the s-triazine IIa-
n at the 2- and the 4-positions were confirmed by
deuterium oxide exchange studies.
1
The H NMR spectra of IIa-d, IIh-i, IIl and IIm in
CDCl3 or DMSO-d6 showed a pure single compound but
the spectra of IIe-g, IIj-l, and IIn in the same solvent
indicated the formation of two tautomers, A and B, as
shown in Scheme 3. The NMR data in CDCl3 indicated
the ratio between the B and A tautomers of the new
triazines is about 6:4 by integration. The ratio is solvent
dependent. The most striking difference in chemical
shifts of the two tautomers is the N-CH proton of the
isopropyl group. The B tautomer N-CH proton (~ 4.2
ppm) is about 0.2 ppm up field to the same proton of the
A tautomer (~ 4.4 ppm). Without NH in the B for
coupling, the N-CH(CH3)2 proton appeared as sharp
multiplets, in contrast to a broad multiplets for the same
proton in the A, a sign of further -NH-CH-coupling. A
single tautomer C formed when a drop of trifluoroacetic
acid or deuterated acetic acid was added to the CDCl3 or
DMSO-d6 solution.
In conclusion, we have described an efficient, one pot,
and versatile method for the preparation of 2,4-diamino-s-
triazine derivatives by treatment of biguanides with acyl
chlorides or alkyl chlorooxoacetates.
EXPERIMENTAL
Melting points were determined on a Mettler FP62 melting
point apparatus and are uncorrected. Analytical thin-layer
chromatography (TLC) was performed using HPTLC-HLF
normal phase 150 micron silica gel plates (Analtech, Newark,
DE). Visualization of the developed chromatogram was
performed by UV absorbance or by staining with iodine vapor.
Liquid chromatography was performed using a Horizon HPFC
System (Biotage, Charlottesville, VA) with Flash 25M or 40M
cartridges (KP-Sil Silica, 32-63 ꢀm, 60 A°). Preparative TLC
was performed using silica gel GF tapered uniplates (Analtech,
1
Newark, DE). H NMR and 13C NMR spectra were recorded in
deuteriochloroform, unless otherwise noted, on a Bruker Avance
300 spectrometer (Bruker Instruments, Inc, Wilmington, DE).
Chemical shifts are reported in parts per million on the ꢁ scale
from an internal standard of tetramethylsilane. When the
compounds formed two tautomers, the chemical shifts with *
indicated the peaks were shared by both tautomers in NMR
spectra. Combustion analyses were performed by Atlantic
Microlab, Inc. (Norcross, GA). Where analyses are indicated by
symbols of the elements, the analytical results obtained were
within ± 0.4% of the theoretical values. Mass analysis based on
electron impact (EI) was done on a Hewlett Packard (Agilent;
Santa Clara, CA) 5973 Mass Selector adapted with a HPP7
Direct Insertion Probe (Scientific Instrument Services; Ringoes,
NJ) using a steep temperature gradient at either low voltage
(5eV) to identify masses present or high voltage (70eV) to
obtain fragmentation data. An LC/UV-VIS/Trap MS was also
Scheme 3: Formation of Tautomers A and B
R2
R2
N
N
N
N
CH3
CH3
CH3
CH3
R1 HN
N
NH CH
R1 HN
N
H
N CH
A
B
H+
H+
R2
N
N
CH3
CH3
R1 HN
N
H
N CH
+
H
C
Table 2
Elemental analysis of alkyltriazines
Molecul.
Calcd
Found
Compd
Formula
Weight
278.21
306.19
320.47
334.68
340.57
374.66
354.20
374.24
306.24
404.76
356.03
370.23
432.07
280.57
C
H
Cl
N
C
H
Cl
N
IIa
IIb
IIc
IId
IIe
IIf
IIg
IIh
IIi
IIj
IIk
IIl
IIm
IIn
C13H16ClN5
C15H20ClN5
C16H22ClN5
C17H24ClN5
C18H18ClN5
C18H17Cl2N5
C19H20ClN5
C18H17Cl2N5
C15H20ClN5
C17H24Cl3N5
C14H15Cl2N5O2
C15H17Cl2N5O2
C20H19Cl2N5O2
C12H14ClN5O
56.22
58.91
60.08
61.16
63.62
57.76
64.49
57.76
58.91
50.44
47.21
48.66
55.57
51.52
5.81
6.59
6.93
7.25
5.34
4.58
5.70
4.58
6.59
5.98
4.24
4.63
4.43
5.04
12.76
11.59
11.08
10.62
10.43
18.95
10.02
18.95
11.59
26.28
19.91
19.15
16.40
12.67
25.21
22.90
21.90
20.98
20.61
18.71
19.79
18.71
22.90
17.30
19.66
18.92
16.20
25.04
56.01
58.77
60.17
61.56
63.77
58.04
64.71
57.70
59.10
50.49
47.20
48.73
55.62
51.78
5.78
6.55
7.07
7.22
5.40
4.58
5.80
4.52
6.63
5.98
4.30
4.70
4.42
5.06
12.98
11.81
11.35
10.75
10.34
18.82
9.84
24.95
22.69
21.84
20.43
20.53
18.69
19.53
18.68
22.85
17.21
19.17
18.69
16.16
24.95
18.87
11.52
26.16
20.23
19.27
16.55
12.49

1676
R. Sathunuru, V. Melendez, Michael P. Kozar and A. J. Lin
Vol 45
employed for purity analysis and chromophore properties. The
system consisted of an Agilent 1100 Series LC-UV/VIS system
online with a ThermoFinnigan (now ThermoFisher; Waltham,
MA) LCQ MS equipped with electrospray ionization (ESI)
source. Samples were analyzed using shallow acetonitrile:buffer
gradients at low flow rate.
J = 6.00 Hz, 6H, CH3 x 2), 0.88 (t, J = 9.00 Hz, 6H, CH3 x 2).
13C NMR (CDCl3): ꢀ 181.59, 165.08, 164.20, 137.86, 128.63,
127.53, 120.86, 51.70, 42.60, 31.56, 26.65, 22.62, 22.58, 14.07,
12.08. MS: (m/z) 334.68 (M+). Anal. Calcd. for C17H24ClN5: C,
61.16; H, 7.25; Cl, 10.62; N, 20.98. Found: C, 61.56; H, 7.22;
Cl, 10.75; N, 20.43.
General procedure for the synthesis of N,N'-(disubsti-
tuted)-6-alkyl or 6-aryl-[1,3,5]-triazine-2,4-diamines (IIa-n).
The solution of Ia or Ib (2.0 g, 7.90 mmol) in dry pyridine (20
mL) was cooled to 0 °C. Acyl chloride (8.69 mmol) was added
drop wise to the solution with stirring. After the addition of acyl
chloride was completed, the mixture was allowed to stir at room
temperature for 2 hours and then heated to reflux overnight with
an oil bath. The pyridine was removed under reduced pressure
and the excess acyl chloride was decomposed with crushed ice.
The resulting crude product was extracted with ethyl acetate
twice (2 x 50 mL). The ethyl acetate extracts were combined,
washed with water, dried over anhydrous Na2SO4 and
concentrated. The residue was purified with a flash silica gel
column to give the s-triazines. All the s-triazines IIa-n were
prepared by the same procedure. The reagents, acyl chlorides,
biguanides, products and the yields of the one pot reaction are
listed in Table 1. The physical properties of the new s-triazines
are described as follows. When the compounds formed two
tautomers, the chemical shifts with * indicated the peaks were
shared by both tautomers in NMR spectra.
N-(4-Chlorophenyl)-N'-isopropyl-6-methyl-[1,3,5]-triazine-
2,4-diamine (IIa). White solid, mp 172 °C {lit. [21] mp 173.5-
174° C}; 1H NMR (CDCl3): ꢀ 7.57 (d, J = 9.00 Hz, 2H,
aromatic), 7.27 (d, J = 9.00 Hz, 2H, aromatic), 7.00 (br, 1H,
NH), 5.09 (br, 1H, NH), 4.16 (m, 1H, CH), 2.30 (s, 3H, CH3),
1.24 (d, J = 6.00 Hz, 6H, CH3 x 2). 13C NMR (DMSO-d6): ꢀ
174.68, 165.08, 164.37, 139.57, 128.65, 125.82, 121.42, 42.14,
25.19, and 22.64. MS: (m/z) 278.21(M+). Anal. Calcd. for
C13H16ClN5: C, 56.22; H, 5.81; Cl, 12.76; N, 25.21. Found: C,
56.01; H, 5.78; Cl, 12.98; N, 24.95.
N-(4-Chlorophenyl)-N'-isopropyl-6-phenyl-[1,3,5]-triazine-
2,4-diamine (IIe). White solid, mp 206.6 °C; Major tautomer
(60%): 1H NMR (CDCl3): ꢀ 8.31 (m, 2H, aromatic)*, 7.63 (m,
2H, aromatic)*, 7.51 (m, 1H, aromatic)*, 7.47 (d, J = 9.00 Hz,
2H, aromatic)*, 7.30 (d, J = 9.00 Hz, 2H, aromatic)*, 7.20 (br,
1H, NH)*, 5.31 (br, 1H, NH)*, 4.21 (m, 1H, CH)*, 1.28 (d, J =
6.00 Hz, 6H, CH3 x 2). 13C NMR (DMSO-d6): ꢀ 170.27*,
165.43*, 164.81*, 139.53*, 137.23*, 131.83*, 128.75*, 128.25*,
126.05*, 121.74, 42.42*, 22.70*. MS: (m/z) 340.57 (M+). Anal.
Calcd. for C18H18ClN5: C, 63.62; H, 5.34; Cl, 10.43; N, 20.61.
Found: C, 63.77; H, 5.40; Cl, 10.34; N, 20.53. Minor tautomer
(40%): 1H NMR (CDCl3): ꢀ 8.35 (m, 1H, aromatic), 7.55 (d, J
= 9.00 Hz, 1H, aromatic), 7.12 (br, 1H, NH), 5.12 (br, 1H, NH),
4.43 (m, 1H, CH). 13C NMR (DMSO-d6): ꢀ 170.40, 165.33,
164.53, 139.58, 137.31, 131.92, 128.34, 125.93, 22.88.
N-(4-Chlorophenyl)-N'-isopropyl-6-p-chlorophenyl-[1,3,5]-
triazine-2,4-diamine (IIf). White solid, mp 194.5 °C; Major
tautomer (65%): 1H NMR (CDCl3), ꢀ 8.27 (d, J = 9.00 Hz, 2H,
aromatic)*, 7.62 (d, J = 9.00 Hz, 2H, aromatic)*, 7.42 (d, J =
9.00 Hz, 2H, aromatic), 7.31 (d, J = 9.00 Hz, 2H, aromatic),
7.12 (br, 1H, NH)*, 5.28 (br, 1H, NH)*, 4.21 (m, 1H, CH)*, 1.29
(d, J = 6.00 Hz, 6H, CH3 x 2)*. 13C NMR: (DMSO-d6): ꢀ
169.27*, 165.34*, 164.74*, 139.39*, 136.65*, 136.09*, 129.96*,
128.91*, 128.77*, 126.14*, 121.78*, 42.43*, 22.66*. MS: (m/z)
374.66 (M+). Anal. Calcd. for C18H17Cl2N5: C, 57.76; H, 4.58;
Cl, 18.95; N, 18.71. Found: C, 58.04; H, 4.58; Cl, 18.82; N,
18.69. Minor tautomer (35%): 1H NMR (CDCl3): ꢀ 8.34 (d, J =
9.00 Hz, 1H, aromatic), 7.55 (d, J = 9.00 Hz, 1H, aromatic),
7.04 (br, 1H, NH), 5.12 (br, 1H, NH), 4.40 (m, 1H, CH), 1.25 (d,
J = 6.00 Hz, CH3 x 2). 13C NMR (DMSO-d6): ꢀ 169.41, 165.26,
164.43, 139.46, 136.77, 136.16, 130.05, 128.69, 126.02, 22.87.
N-(4-Chlorophenyl)-N'-isopropyl-6-p-tolyl-[1,3,5]-triazine-
2,4-diamine (IIg). White solid; mp 224.1 °C; Major tautomer
N-(4-Chlorophenyl)-N'-isopropyl-6-isopropyl-[1,3,5]-tria-
1
zine-2,4-diamine (IIb). White solid, mp 142 °C; H NMR
(CDCl3): ꢀ 7.59 (d, J = 9.00 Hz, 2H, aromatic), 7.27 (d, J = 9.00
Hz, 2H, aromatic), 7.05 (br, 1H, NH), 5.12 (br, 1H, NH), 4.15
(m, 1H, CH), 2.77 (m, 1H, CH), 1.25 (d, J = 6.00 Hz, 12H, CH3
x 4). 13C NMR (CDCl3): ꢀ 177.56, 165.32, 164.34, 137.79,
128.72, 127.68, 121.00, 42.64, 36.96, 22.68, and 20.85. MS:
(m/z) 306.19 (M+). Anal. Calcd. for C15H20ClN5: C, 58.91; H,
6.59; Cl, 11.59; N, 22.90. Found: C, 58.77; H, 6.55; Cl, 11.81;
N, 22.69.
1
(60%): H NMR (DMSO-d6): ꢀ 9.72 (br, 1H, NH)*, 7.91 (d, J =
9.00 Hz, 2H, aromatic)*, 7.86 (d, J = 9.00 Hz, 2H, aromatic)*,
7.61 (br, 1H, NH)*, 7.36 (d, J = 9.00, 2H, aromatic), 7.33 (d, J =
9.00, 2H, aromatic), 4.15 (m, 1H, CH)*, 2.38 (s, 3H, CH3), 1.21
(d, J = 6.00 Hz, 6H, CH3 x 2)*. 13C NMR (DMSO-d6): ꢀ
170.21*, 165.39*, 164.76*, 141.74*, 139.58, 134.50*, 129.38,
128.76*, 128.26*, 125.94*, 121.65, 42.36, 22.72*, 21.53. MS
(m/z): 354.20 (M+). Anal. Calcd. for C19H20ClN5: C, 64.49; H,
5.70; Cl, 10.02; N, 19.79. Found: C, 64.71; H, 5.80; Cl, 9.84; N,
19.53. Minor tautomer (40%), 1H NMR (DMSO-d6): ꢀ 9.60
(br, 1H, NH), 8.24 (d, J = 9.00 Hz, 1H, aromatic), 7.20 (d, J =
9.00 Hz, 1H, aromatic), 7.31 (d, J = 9.00 Hz, 1H, aromatic),
7.45 (br, 1H, NH), 4.31 (m, 1H, CH), 1.22 (d, J = 6.00 Hz, 6H,
CH3 x 2). 13C NMR (DMSO-d6): ꢀ170.35, 165.28, 164.49,
141.86, 134.59, 128.68, 128.36, 125.82, 22.90.
N-(4-Chlorophenyl)-N'-isopropyl-6-isobutyl-[1,3,5]-tria-
1
zine-2,4-diamine (IIc). White solid, mp 153 °C; H NMR
(CDCl3): ꢀ 7.59 (d, J = 9.00 Hz, 2H, aromatic), 7.29 (d, J = 9.00
Hz, 2H, aromatic), 6.99 (br, 1H, NH), 5.10 (br, 1H, NH), 4.17
(m, 1H, CH), 2.39 (d, J = 6.00 Hz, 2H, CH2), 2. 21 (m, 1H, CH),
1.26 (d, J = 6.00 Hz, 6H, CH3 x 2), 1.00 (d, J = 6.00 Hz, 6H,
CH3 x 2). 13C NMR (CDCl3): ꢀ 178.04, 165.05, 164.08, 137.61,
128.73, 127.77, 121.00, 47.85, 42.63, 27.50, 22.65, and 22.54.
MS: (m/z) 320.47 (M+). Anal. Calcd. for C16H22ClN5: C, 60.08;
H, 6.93; Cl, 11.08; N, 21.90. Found: C, 60.17; H, 7.07; Cl,
11.35; N, 21.84.
N-(4-Chlorophenyl)-N'-isopropyl-6-(1-ethylpropyl)-[1,3,5]-
triazine-2,4-diamine (IId). White solid, mp 87.5 °C; 1H NMR
(CDCl3): ꢀ 7.61 (d, J = 9.00 Hz, 2H, aromatic), 7.29 (d, J = 9.00
Hz, 2H, aromatic), 7.04 (br, 1H, NH), 5.14 (br, 1H, NH), 4.17
(m, 1H, CH), 2.23 (m, 1H, CH), 1.64 (m, 4H, CH2 x 2), 1.27 (d,
N-(3,4-Dichlorophenyl)-N'-isopropyl-6-phenyl-[1,3,5]-tria-
zine-2,4-diamine (IIh). White solid, mp 187.7 °C; Major
tautomer (75%): 1H NMR (CDCl3): ꢀ 8.15 (br, 1H, aromatic),
7.91 (d, J = 7.8 Hz, 2H, aromatic), 7.80 (d, J = 7.42 Hz, 1H,
*
aromatic) *, 7.66 (d, J = 7.8 Hz, 2H, aromatic) , 7.56 (d, J =
8.64 Hz, 1H, aromatic), 7.39 (m, 1H, aromatic), 7.19 (br, 1H,
NH) *, 5.35 (br.d, J = 6.0 Hz, NH,)*, 4.19 (m, 1H, CH) *, 1.31 (d,
J = 6.5 Hz, 6H, CH3 x 2). 13C NMR (DMSO-d6): ꢀ 170.36*,

Nov-Dec 2008
A Facile One Pot Synthesis of 2, 4-Diamino-6-substituted s-Triazine Derivatives
1677
165.33*, 164.72*, 140.80*, 137.06*, 131.97*, 131.18*, 130.75*,
128.81, 128.22*, 123.58*, 121.25*, 120.01, 42.50, 22.64*. MS:
(m/z) 374.24 (M+). Anal. Calcd. for C18H17Cl2N5: C, 57.76; H,
4.58;, Cl, 18.95; N, 18.71. Found: C, 57.70; H, 4.52; Cl, 18.87;
N, 18.68. Minor tautomer (25%): 1H NMR (CDCl3): ꢀ 7.83 (br,
1H, aromatic), 7.62 (br, 1H, aromatic), 7.09 (br, 1H, NH), 5.15
2-(3,4-Dichlorophenyl)amino-4-isopropylamino-[1,3,5]-tria-
zine-6-carboxylic acid benzyl ester (IIm). White solid, mp
216.2 °C. Major tautomer (75%): 1H NMR (CDCl3): ꢀ 8.11 (d,
J = 2.0 Hz, 1H, aromatic), 7.46 (m, 3H, aromatic)*, 7.37 (m, 3H,
aromatic) , 7.28 (br, 1H, aromatic)*, 5.64 (d, J = 7.00 Hz, 1H,
NH)*, 5.43 (s, 2H, CH2)*, 4.19 (m, 1H, CH), 1.31 (d, J = 6.51
Hz, 6H, CH3 x 2). 13C NMR (CDCl3): ꢀ 165.1*, 164.1*, 163.4*,
163.0*, 137.5*, 134.9*, 133.0*, 132.7*, 130.3*, 128.7*, 128.6*,
126.7*, 121.7, 119.0, 68.3, 43.4, 22.2. MS: (m/z) 432.07 (M+).
Anal. Calcd. for C20H19Cl2N5O2: C, 55.57, H, 4.43, Cl, 16.40, N,
16.20. Found: C, 55.62; H, 4.42; Cl, 16.55; N, 16.16. Minor
(br, 1H, NH), 4.44 (m, 1H, CH). 13C NMR (DMSO-d6):
ꢀ
170.48, 165.22, 164.46, 140.85, 137.13, 132.08, 131.24, 130.63,
128.34, 123.53, 121.07, 22.86.
N-(4-Chlorophenyl)-N'-isopropyl-6-propyl-[1,3,5]-triazine-
2,4-diamine (IIi). White solid, mp 122.1 °C; 1H NMR (CDCl3):
ꢀ 7.59 (d, J = 9.00 Hz, 2H, aromatic), 7.28 (d, J = 9.00 Hz, 2H,
aromatic), 7.06 (br, 1H, NH), 5.12 (br, 1H, NH), 4.16 (m, 1H,
CH), 2.48 (t, J = 9.00 Hz, CH2), 1.78 (q, J = 9.00 Hz, CH2),
1.25 (d, J = 6.00 Hz, 6H, CH3 x 2), 1.00 (t, J = 6.00 Hz, CH3).
13C NMR (CDCl3): ꢀ 178.54, 165.06, 164.18, 137.64, 128.70,
127.78, 121.12, 42.62, 40.75, 22.60, 20.91, 13.93. MS: (m/z)
306.24 (M+). Anal. Calcd. for C15H20ClN5: C, 58.91; H, 6.59;
Cl, 11.59; N, 22.90. Found: C, 59.10; H, 6.63; Cl, 11.52; N,
22.85.
N-(3,4-Dichlorophenyl)-N'-isopropyl-6-(1-ethylpropyl)-
[1,3,5]-triazine-2,4-diamine(IIj). white solid, mp 142.0 °C.
Major tautomer (85%): 1H NMR (CDCl3): 8.16 (br, 1H,
aromatic), 7.35 (d, J = 8.0Hz, 1H aromatic)*, 7.28 (d, J =
10.0Hz, 1H, aromatic)*, 7.01 (br, 1H, NH)*, 5.18 (br, 1H, NH)*,
4.15 (m, 1H, CH), 2.26 (m, 1H, CH), 1.61 (m, 4H, CH2 x 2)*,
1.28 (d, J = 6.35Hz, 6H, CH3 x 2), 0.87 (t, J = 7.42 Hz, 6H, CH3
x 2)*. 13C NMR (CDCl3): ꢀ 181.77, 164.99*, 164.00, 138.73*,
132.46, 130.14, 125.50, 121.25, 118.53, 51.81, 42.82, 26.69*,
25.75, 22.62, 12.11. MS (m/z): 404.76 (M+). Anal. Calcd. for
C17H24Cl3N5: C, 50.44; H, 5.98; Cl, 26.28; N, 17.30. Found: C,
50.49; H, 5.98; Cl, 26.16; N, 17.21.
1
tautomer (25%): H NMR (CDCl3): ꢀ 7.90 (d, J = 2.0 Hz,
aromatic), 4.36 (m, 1H, CH), 1.26 (d, J = 6.51 Hz, 6H, CH3 x 2).
13C NMR: (CDCl3): ꢀ 119.3, 67.9, 43.2, 22.8.
2-(4-Chlorophenylamino)-4-isopropylamino-[1,3,5]-tria-
zin-6-ol (IIn). White solid, mp 357 °C; 1H NMR (DMSO-d6):
ꢀ 10.68 (br, OH), 9.51 (br, 1H, NH), 7.43 (d, J = 9.00 Hz, 2H,
aromatic), 7.40 (d, J = 9.00 Hz, 2H, aromatic), 7.15 (br, 1H,
NH), 4.17 (m, 1H, CH), 1.17 (d, J = 6.00 Hz, 6H, CH3 x 2). 13
C
NMR (CDCl3+TFA): ꢀ 149.07, 133.47, 132.31, 129.45, 124.38,
119.98, 116.21, 112.44, 108.67, 46.04, 20.91. MS (m/z): 280.57
(M+). Anal. Calcd. for C12H14ClN5O: C, 51.52; H, 5.04; Cl,
12.67; N, 25.04. Found: C, 51.78; H, 5.06; Cl, 12.49; N, 24.95.
Acknowledgement. Material has been reviewed by the
Walter Reed Army Institute of Research. There is no objection
to its presentation and/or publications. The opinions or
assertions contained herein are the private views of the authors,
and are not to be construed as official, or as reflecting true views
of the Department of the Army or the Department of Defense.
This research is supported in part by funding from Military
Infections Diseases Research Program (A40096_06_WR_
CSPP), U. S. Army Medical Research and Material Command,
Department of Defense, USA., Peer Reviewed Medical
Research Program (PRMRP) (Grant # PR054609), and Malaria
and Medicine Venture (MMV), Geneva, Switzerland, (Grant #
MMV04/0013).
Minor tautomer (15%): 1H NMR (CDCl3): ꢀ 7.95 (br, 1H,
aromatic), 7.82 (br, 1H, aromatic), 6.91 (br, 1H, NH), 5.01 (br,
1H, NH), 1.72 (m, 4H, CH2 x 2), 0.95 (t, J = 7.45Hz, 6H, CH3 x
2). 13C NMR (CDCl3): ꢀ 119.31, 53.42, 43.18, 22.80.
2-(3,4-Dichlorophenylamino-4-isopropylamino-[1,3,5]-tria-
zine-6-carboxylic acid methyl ester (IIk). White solid, mp
142.5 °C. Major tautomer (70%): 1H NMR (CDCl3): ꢀ 8.11 (br,
1H, aromatic), 7.53 (br, 1H, NH)*, 7.38 (d, J = 8.70 Hz, 1H,
aromatic)*, 7.28 (br, 1H, aromatic)*, 5.66 (d, J = 7.00 Hz, 1H,
NH), 4.21 (m, 1H, CH), 4.00 (s, 3H, COOMe)*, 1.31 (d, J =
6.51 Hz, 6H, CH3 x 2). 13C NMR (CDCl3): ꢀ 165.28*, 164.40*,
163.68*, 163.36*, 137.66*, 132.71*, 130.35*, 126.77*, 121.78*,
119.03, 53.64, .43.49, 22.29. MS: (m/z) 356.03 (M+). Anal.
Calcd. for C14H15Cl2N5O2: C, 47.21; H, 4.24; Cl, 19.91; N,
19.66. Found: C, 47.20; H, 4.30; Cl, 20.23; N, 19.17. Minor
REFERENCES
* Corresponding author address: e-mail: ai.lin@na.amedd.army.mil;
Division of Experimental Therapeutics, Walter Reed Army Institute of
Research, Silver Spring, Maryland 20910, Tel: 301-319-9084, Fax: 301-
319-9449.
[1] Guan, J.; Zhang, Q.; Gettayacamin, M.; Karle, J. M.; Ditusa,
C. A.; Milhous, W. K.; Skillman, D. R.; and Lin, A. J. Bioorg. Med.
Chem., 2005, 13, 699.
[2] Zhang, Q.; Guan, J.; Sacci, J.; Ager, A.; Ellis, W.; Milhous,
W. K.; Kyle, D.; and Lin, A. J. J. Med. Chem., 2005, 48, 6472.
[3] Lin, A. J.; Zhang, Q.; Guan, J.; and Milhous, W. K. US
Patent Number: 2006, 7, 101, September 5, 902.
1
tautomer (30%): H NMR (CDCl3): ꢀ 7.90 (br, 1H, aromatic),
5.41 (d, J = 7.00 Hz, 1H, NH), 4.41 (m, 1H, CH), 1.27 (d, J =
6.51 Hz, 6H, CH3 x 2). 13C NMR (CDCl3): ꢀ 119.31, 53.42,
43.18, 22.80.
[4] Guan, J.; Wang, X.; Smith, K.; Ager, A.; Gettayacamin, M.;
Kyle, D. E.; Milhous, W. K.; Kozar, M. P.; Magill, A. J.; and Lin, A. J.
J. Med. Chem., 2007, 50, 6226.
[5] Rogers, D. J.; and Randolph, S. E. Science, 2000, 289, 1763.
[6] Wahlgren, M.; and Benjarano, M. T. Nature, 1999, 400, 506.
[7] Rastelli, G.; Sirawaraporn, W.; Sompornpisut, P.; Vilaivan,
T.; Kamchonwongpaisan, S.; Quarrell, R.; Lowe, G.; Thebtaranonth, Y.;
and Yuthavong, Y. Bioorg. Med. Chem, 2000, 8, 1117.
[8] Kumar, A.; Katiyar, S. B.; Agarwal, A.; and Chauhan, P. M.
S. Curr. Med. Chem, 2003, 10, 1137.
2-(3,4-Dichlorophenylamino-4-isopropylamino-[1,3,5]-tria-
zine-6-carboxylic acid ethyl ester (IIl). White solid, mp 178.6
°C, 1H NMR (CDCl3): ꢀ 8.00 (s, 1H, aromatic), 7.52 (d, J = 8.70
Hz, 1H, aromatic), 7.35 (d, J = 8.75Hz, 1H, aromatic), 7.25 (br,
1H, NH), 5.60 (br, 1H, NH), 4.47 (q, J = 6.49Hz, 2H, CH2),
4.15 (m, 1H, CH), 1.42 (t, J = 7.00 Hz, 3H, CH3), 1.29 (d, J =
6.42 Hz, 6H, CH3 x 2). 13C NMR (CDCl3): ꢀ 165.2, 164.4,
163.7, 163.2, 137.7, 132.6, 130.3, 126.6, 121.7, 118.9, 62.8,
43.4, 22.2, 14.1. MS: (m/z) 370.10 (M+). Anal. Calcd. for
C15H17Cl2N5 O2: C, 48.66; H, 4.63; Cl, 19.15; N, 18.92. Found:
C, 48.73; H, 4.70; Cl, 19.27; N, 18.69.
[9] Rathod, P. K.; and Phillips, M. A. Nat. Struct. Biol, 2003,
10, 316.

1678
R. Sathunuru, V. Melendez, Michael P. Kozar and A. J. Lin
Vol 45
[10] Fiddock, D. A.; and Wellems, T. E. Natl. Acad. Sci. USA,
1997, 94, 10931.
[11] Pitts, W. J.; Guo, J.; Dhar, T.G.; Shen, Z.G.; Watterson,
H.S.H.; Bednarz, M. S.; Chen, B. C.; Barrish, J. C.; Hollenbaugh, D. L.;
and Iwanowicz, E. J. Bioorg. Med. Chem. Lett. 2002, 12, 2137.
[12] Hanessian, S.; and Sagarbi, S. P. W. Bioorg. Med. Chem.
Lett. 2000, 10, 433.
Morinaga, F.; Shirai, G.; and Hatae, S. J. Med. Chem. 1970, 13, 1081.
[16] Hirt, R.; Nidecker, H.; and Berchtold, R. Helv. Chim. Acta.
1950, 33, 1365.
[17] Liu, C.; and Iwanowicz, E. J. Tetrahedron Lett, 2003, 44,
1409.
[18] Liu, C.; Lin, E. J.; and Leftheris, K. Tetrahedron Lett, 2007,
48, 435.
[13] Hajiduk, P. J.; Dinges, J.; Schkeryantz, J. M.; Janowick, D.;
Kaminski, M.; Tufano, M.; Augeri, D. J.; Peteros, A.; Nienaber, V.;
Zhong, P.; Hammond, R.; Coen, M.; Beutel, B.; Katz, L.; and Fesik, S.
W. J. Med. Chem. 1999, 42, 3852.
[14] Kosary, J.; Kasztriner, E.; Rabloczky, G.; and Kurthy, M.
Eur. J. Med. Chem. 1989, 24, 97.
[15] Irikura, T.; Abe, Y.; Okamura, K.; Higo, K.; Maeda, A.;
[19] Insuasty, H.; Estrada, M.; Cortes, E.; Quiroga, J.; Insuasty, B.;
Abonia, R.; Nogueras, M.; and Cobo, J. Tetrahedron Lett. 2006, 47, 5441.
[20] Montalbetti, C. A. G. N.; Coulter, T. S.; Uddin, M. K.;
Reignier, S. G.; Magaraci, F.; Granas, C.; Jensen, C. K.; and Felding, J.
Tetrahedron Lett. 2006, 47, 5973.
[21] Fraser, G. P.; and Kermack, W. O. J. Chem. Soc, 1951,
2682.