An efficient synthesis of 1-aryl-4,6-diamino-1,2-dihydro-1,3,5-triazines

Article abstract of DOI:10.1081/SCC-120005415

1-Aryl-4,6-diamino-1,2-dihydro-1,3,5-triazines bearing diverse substituents at C² and on the aromatic ring have been synthesized in good yield from an acid-catalyzed reaction between corresponding arylbiguanide and carbonyl compound in the presence of triethyl orthoacetate as a water scavenger.

Full text of DOI:10.1081/SCC-120005415

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AN EFFICIENT SYNTHESIS OF 1-ARYL-4,6-DIAMINO-1,2-
DIHYDRO- 1,3,5-TRIAZINES
a
a
a
Neungruthai Saesaengseerung , Tirayut Vilaivan & Yodhathai Thebtaranonth
a
Organic Synthesis Research Unit , Department of Chemistry , Faculty of Science ,
Chulalongkorn University , Phayathai Road, Bangkok, 10330, Thailand
b
National Center for Genetic Engineering and Biotechnology , National Science and
Technology Development Agency , Rama VI Road, Bangkok, 10400, Thailand
Published online: 18 Oct 2011.
To cite this article: Neungruthai Saesaengseerung , Tirayut Vilaivan & Yodhathai Thebtaranonth (2002) AN EFFICIENT
SYNTHESIS OF 1-ARYL-4,6-DIAMINO-1,2-DIHYDRO- 1,3,5-TRIAZINES, Synthetic Communications: An International Journal for
Rapid Communication of Synthetic Organic Chemistry, 32:14, 2089-2100, DOI: 10.1081/SCC-120005415
To link to this article: http://dx.doi.org/10.1081/SCC-120005415
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SYNTHETIC COMMUNICATIONS
Vol. 32, No. 14, pp. 2089–2100, 2002
AN EFFICIENT SYNTHESIS OF
-ARYL-4,6-DIAMINO-1,2-DIHYDRO-
1
1,3,5-TRIAZINES
1
1,
Neungruthai Saesaengseerung, Tirayut Vilaivan, *
2
and Yodhathai Thebtaranonth
1
Organic Synthesis Research Unit, Department of
Chemistry, Faculty of Science, Chulalongkorn
University, Phayathai Road, Bangkok 10330, Thailand
2
National Center for Genetic Engineering and
Biotechnology, National Science and Technology
Development Agency, Rama VI Road,
Bangkok 10400, Thailand
ABSTRACT
1
-Aryl-4,6-diamino-1,2-dihydro-1,3,5-triazines bearing diverse
2
substituents at C and on the aromatic ring have been syn-
thesized in good yield from an acid-catalyzed reaction
between corresponding arylbiguanide and carbonyl com-
pound in the presence of triethyl orthoacetate as a water
scavenger.
Key Words: Cycloguanil; Antifolate; Dihydrotriazine
*
Corresponding author. Fax: 66-2-2541309; E-mail: vtirayut@chula.ac.th
2
089
DOI: 10.1081/SCC-120005415
Copyright & 2002 by Marcel Dekker, Inc.
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com

2
090
SAESAENGSEERUNG, VILAIVAN, AND THEBTARANONTH
1
-Aryl-4,6-diamino-1,2-dihydro-1,3,5-triazine (I) is an important class
[
1]
of dihydrofolate reductase (DHFR) inhibitors. Cycloguanil (Ia) is one
representative example previously used as antimalarial drug although it
has lost much of its effectiveness nowadays due to the emergence of drug
resistant malarial parasites. Resistance to cycloguanil of A16V þ S108T
mutant dihydrofolate reductase from Plasmodium falciparum has been
attributed to the non-bonding interaction between the valine-16 side-chain
of the mutant enzyme with the gem-dimethyl group at C position of cyclo-
guanil and between the threonine-108 side chain with the p-chloro substi-
[
tuent on the aromatic ring. During our program to explore the structure
[
2]
2
3]
[
3,4]
activity relationship between the enzyme and inhibitors,
-aryl-4,6-diamino-1,2-dihydro-1,3,5-triazines bearing diverse substituents
a number of
1
at C and on the aromatic ring were required.
2
The three-component synthesis of 1-aryl-4,6-diamino-1,2-dihydro-
,3,5-triazine (I) by an acid-catalyzed cyclo-condensation reaction between
1
an aromatic amine, dicyanodiamide and a carbonyl compound has been
[
5,6]
reported since early 1950.
Later a two-component methodology
has been developed in which the arylbiguanide was formed first by reaction
between an aromatic amine and dicyanodiamide in the presence of acid
[
7]
followed by subsequent reaction with a carbonyl compound. Both
methods work well only with relatively unhindered carbonyl compounds
such as acetone, cyclic ketones and aldehydes. Attempts to extend the
method to carbonyl compounds bearing bulky substituents resulted in
incomplete reaction or no reaction at all.
It is a well-known art in organic synthesis that in situ removal of water
from a condensation reaction very often provides better result since the reac-
tion equilibrium is shifted to the product side. Dehydrating agents success-
fully employed in such reactions include anhydrous calcium sulfate in
[
8]
conjunction with a Dean-Stark trap. Dehydration under homogeneous con-
ditions employing triethyl orthoformate as water scavenger in the synthesis of
[
9]
dihydrotriazines has also been reported. Since triethyl orthoformate and its
hydrolysis products are volatile, it can be directly added to the reaction mix-
ture without interfering with purification of the products. However, in certain
cases, the use of triethyl orthoformate suffers a major drawback in which an
[
9]
s-triazine (II) is formed as a side-product, or even exclusively. After several
experiments employing various water scavengers we have found that triethyl
orthoacetate is very effective for the two component synthesis of 1-aryl-4,6-
diamino-1,3,5-triazine, i.e., it gave clean products with a wide number of
carbonyl compounds and with minimal side reactions.
The reaction between 4-methylphenylbiguanide hydrochloride
and 4-methyl-2-pentanone in the presence of concentrated aqueous HCl
at reflux temperature in ethanol gave only recovered starting material.

1
-ARYL-4,6-DIAMINO-1,2-DIHYDRO-1,3,5-TRIAZINES
2091
After addition of triethyl orthoacetate to this reaction mixture, however, the
starting material was completely consumed within a few hours at reflux
temperature. Evaporation of the solvent followed by trituration of the
0
residue with acetone gave the desired product, 1-(4 -methylphenyl)-4,6-
diamino-2-methyl-2-isobutyl-1,2-dihydro-1,3,5-triazine hydrochloride, as a
white crystalline solid in 62% yield. The crude product gave a clean
1
H-NMR spectrum and provided correct mass (MALDI-TOF).
Reaction parameters including amount of carbonyl compound, water
scavenger, acid, and temperature were optimized in a model reaction
between
Progress of the reaction was followed by reverse phase HPLC technique
C-18 column, gradient elution using acetonitrile/0.1 M triethylammonium
4-chlorophenylbiguanideÁHCl
and
4-methyl-2-pentanone.
(
acetate as eluent). Best result was obtained when 5 eq. of ketone was used in
conjunction with triethyl orthoacetate (0.75 mL/mmol of biguanide) at
room temperature in methanol. Although the reaction rate was faster at
high temperature, formation of substantial amounts of rearranged products
(III) discouraged its use. The amount of conc. HCl higher than the optimal
value (25 mL/mmol of biguanide) also gave poor results, presumably because
it catalyzed further reaction of the product initially formed. Under the
optimal conditions, quantitative yield of the product was routinely obtained
after evaporation and trituration of the residue with ether. HPLC analysis
suggested that the product was more than 85% pure, only contaminants
being the biguanide starting material and a small amount of the rearranged
product (III) whose proportion increased with the size of the substituents at
2
C (Figure 1). Recrystallization from a suitable aqueous or alcoholic solvent
systems gave analytically pure products in fair to good yield.

2
092
SAESAENGSEERUNG, VILAIVAN, AND THEBTARANONTH
Figure 1. Reverse phase HPLC chromatogram of the crude product from
-chlorophenylbiguanide and 4-methyl-2-pentanone under the optimized conditions.
4
HPLC conditions: C-18 column, acetonitrile–0.1 M triethyl ammonium acetate pH
7
.0, linear gradient from 15–60% acetonitrile over 15 min.
A number of arylbiguanides and carbonyl compounds including those
possessing relatively bulky subtituents participate in the reactions equally
well. Exceptions include highly sterically hindered carbonyl compounds
such as diisopropyl ketone and aromatic ketones such as benzophenone
and acetophenone. Reactions involving ortho-substituted arylbiguanides
such as 2,4-dichlorophenyl-biguanides also gave poor results. Nevertheless
the reaction appears to work well with most simple aliphatic ketones as well
as aromatic aldehydes (Table 1).
In conclusion, an efficient method for the synthesis of 1-aryl-4,6-
diamino-1,2-dihydro-1,3,5-triazine has been developed based on an
acid-catalysed two-component cyclocondensation reaction between an
arylbiguanide and a carbonyl compound in the presence of triethyl
orthoacetate as water scavenger. The reaction procedure is straight-
forward and gave good yields of clean products with a variety of
substrates under mild conditions. The method also provides a convenient

1
-ARYL-4,6-DIAMINO-1,2-DIHYDRO-1,3,5-TRIAZINES
2093
Table 1. Example
Synthesized
of
4,6-Diamino-1,2-dihydro-1,3,5-triazines
Successfully
1
2
Entry
Ar
R
R
% Yield
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
4-ClC
C H -
4-MeC
6
H
4
-
Me
Me
n
69
93
82
73
88
61
78
38
59
u 5
u 2
68
75
89
85
90
64
58
93
75
Me
Me
Et
Pr
Pr
6
5
n
6
H
4
-
C
3,4-Cl C H -
6
H
5
-
Et
Et
Et
-(CH ) -
2 4
2
6
3
C H -
6 5
4-MeC
4-ClC
4-EtC H -
6
H
4
-
-(CH
Me
Me
2 4
) -
i
6
H
4
-
Pr
Pr
B
B
Pr
i
6
4
i
1
1
1
1
1
1
1
1
1
1
2
4-MeC
6
H
4
-
Me
Me
7
6
i
4-ClC
4-ClC H -
6
H
4
-
n
Pr
n
6
4
i
3,4-Cl
2
C
6
H
3
-
Me
Me
Me
Me
Et
H
H
H
C
5
H
11
n
C
4-ClC H -
6
H
5
-
C
6
H
13
13
13
n
n
n
C H
6
6
4
4-MeC
6
H
4
-
C
C
6
H
H
4-ClC
4-ClC
6
6
H
H
4
-
-
5
11
4
C
4-BnOC H -
6
H
5
-
4-EtC H -
6
4
6
4
4-BrC
6
H
4
-
4-BnOC
6
4
H -
2
access to dihydrotriazines carrying sterically hindered substituents at C
position which could not be easily synthesized by previously reported
procedures.
EXPERIMENTAL
General
Elemental Analyses were performed on a Perkin Elmer Elemental
Analyzer 2400 CHNS/O at the Research Equipment Centre,
1
Chulalongkorn University. Routine H NMR spectra were obtained on a

2
094
SAESAENGSEERUNG, VILAIVAN, AND THEBTARANONTH
Bruker ACF 200 (Chulalongkorn University, Bangkok) operating at
2
1 13
00 MHz ( H) and 50.28 MHz ( C). Chemical shifts are reported in parts
per million (ppm, ꢀ) downfield relative to the internal standard tetramethyl-
silane. MALDI-TOF mass spectrum was recorded on a Bruker Biflex mass
spectrometer (The Institute of Genetic Engineering and Biotechnology,
Chulalongkorn University, Bangkok) using CCA matrix. Masses are
quoted as m/z unless otherwise stated, only the molecular ions and major
fragments being quoted. Unless otherwise noted, all chemicals and solvents
were obtained from commercial suppliers (Aldrich, Fluka and Merck) and
were used as received.
Typical Procedure for Synthesis of 4,6-Diamino-1,2-dihydro-1,3,5-triazine
by Modified Two Component Method
To a suspension of the arylbiguanideÁHCl (1mmol) in absolute
methanol (5 mL) containing the ketone (5 eq) and triethyl orthoacetate
(
0.75 mL) was added conc. HCl (0.025 mL). The reaction mixture was stirred
at room temperature until a negative biguanide test was obtained
24–120 h). After evaporation of the solvent, the residue was triturated
(
with acetone–ether. The solid was collected by filtration and washed again
with ether and dried under vacuum. All samples were recrystallized from
suitable solvents before analysis. Melting points were not reported because
ꢀ
all compounds have m.p. above 200 C.
0
1-(4 -Chlorophenyl)-2,2-dimethyl-4,6-diamino-1,2-dihydro-1,3,5-triazine
Hydrochloride
Colourless prisms from MeOH/Et O (0.1993 g, 69%, 1.00 mmol scale).
2
Found C, 46.0; H, 5.60; N, 24.20% (C H N Cl requires C, 45.8; H, 5.25;
2
1
1
15
5
N, 24.30%); ꢀ (DMSO-d , 200 MHz) 1.25 (2 Â 3H, s, 2 Â CH -2), 7.18 and
H
6
3
þ
7
.38 (2 Â 2H, 2 Â d, J ¼ 8 Hz, aromatic C-H); m/z 252.0 (M-Cl) .
1-Phenyl-2-propyl-2-methyl-4,6-diamino-1,2-dihydro-1,3,5-triazine
Hydrochloride
Colourless prisms from EtOH/Et O (0.2612 g, 93%, 0.21 mmol scale).
2
Found C, 55.46; H, 7.12; N, 24.75% (C H ClN requires C, 55.41; H, 7.15;
1
3
20
5
N, 24.85%); ꢀH (D O, 200 MHz) 0.74 (3H, t, J ¼ 7.0 Hz, CH CH CH -2),
2
3
2
2
1
.19 (3H, s, CH -2), 1.20 (2H, m, CH CH CH -2), 1.45 and 1.65 (2 Â 1H, m,
3
3
2
2

1
-ARYL-4,6-DIAMINO-1,2-DIHYDRO-1,3,5-TRIAZINES
2095
CH CH CH -2), 7.20 (2H, m, aromatic C-H), 7.60 (3H, m, aromatic C-H);
3
2
2
þ
m/z 246.2 (M-Cl) .
0
1-(4 -Methylphenyl)-2-propyl-2-methyl-4,6-diamino-1,2-dihydro-1,3,5-
triazine Hydrochloride
Colourless prisms from EtOH/Et O (0.2425 g, 82%, 1.00 mmol scale).
2
Found C, 56.80; H, 7.51; N, 23.66% (C H ClN requires C, 56.84; H, 7.50;
1
4
22
5
N, 23.68%); ꢀ (D O, 200 MHz) 0.72 (3H, t, J ¼ 7.0 Hz, CH ), 1.15 (3H, s,
H
2
3
CH -2), 1.22 (2H, m, CH CH CH -2), 1.45 and 1.60 (2 Â 1H, m,
3
3
2
2
0
CH CH CH -2), 2.20 (3H, s, CH -4 ), 7.05 and 7.20 (2 Â 2H, 2 Â d,
3
2
2
3
þ
J ¼ 8.0 Hz, aromatic C-H); m/z 260.5 (M-Cl) .
1-Phenyl-2,2-diethyl-4,6-diamino-1,2-dihydro-1,3,5-triazine Hydrochloride
Pale green crystalline solids from EtOH/Et O (0.2042 g, 73%,
2
1
.00 mmol scale). Found C, 55.41; H, 7.02; N, 24.85% (C H ClN requires
3
1
20
5
C, 55.41; H, 7.15; N, 24.85%); ꢀH (D O, 200 MHz) 1.78 (6H, t, J ¼ 7.2 Hz,
2
2
7
 CH CH -2), 1.50 (4H, m, 2  CH CH -2), 7.23 (2H, m, aromatic C-H),
3
2
3
2
þ
.37 (3H, m, aromatic C-H); m/z 246.2 (M-Cl) .
0 0
-(3 ,4 -Dichlorophenyl)-2,2-diethyl-4,6-diamino-1,2-dihydro-1,3,5-triazine
Hydrochloride
1
Pale yellow crystalline solids from MeOH/Et O (0.3063 g, 88%,
2
1
.00 mmol scale). Found C, 44.66; H, 4.99; N, 19.99% (C H Cl N
1
3
18
3
5
requires C, 44.53; H, 5.17; N, 19.97%); ꢀH (D O, 200 MHz) 0.77 (6H, t,
2
J ¼ 7 Hz, 2 Â CH ), 1.52 (4H, m, 2 Â CH -2), 7.18 (1H, dd, J ¼ 8.5, 2.2 Hz,
3
2
þ
aromatic C-H), 7.48 (2H, m, aromatic C-H); m/z 314.0 (M-Cl) .
1-Phenyl-2-cyclopentylidene-4,6-diamino-1,2-dihydro-1,3,5-triazine
Hydrochloride
Light brown crystalline solids from EtOH/Et O (0.1701 g, 61%,
2
1
.00 mmol scale). Found C, 55.92; H, 6.52; N, 25.16% (C H ClN requires
5
1
3
18
C, 55.81; H, 6.48; N, 25.03%); ꢀH (D O, 200 MHz) 1.45 (2 Â 2H, m,
2
2
 CH ), 1.72 (2  2H, m, 2  CH ), 7.20 (2H, m, aromatic C-H), 7.48
2
2
þ
(
3H, m, aromatic C-H); m/z 244.1 (M-Cl) .

2
096
SAESAENGSEERUNG, VILAIVAN, AND THEBTARANONTH
0
1-(4 -Methylphenyl)-2-cyclopentylidene-4,6-diamino-1,2-dihydro-1,3,5-
triazine Hydrochloride
Light brown crystalline solids from EtOH/Et O (0.2297 g, 78%,
2
1.00 mmol scale). Found C, 57.29; H, 6.86; N, 23.90% (C H ClN requires
14 20 5
C, 57.23; H, 6.86; N, 23.84%); ꢀH (D O, 200 MHz) 1.45 (2 Â 2H, m,
2
0
2
(
 CH ), 1.75 (2  2H, m, 2  CH ), 2.20 (3H, s, CH -4 ), 7.08 and 7.20
2
2
3
þ
2 Â 2H, 2 Â d, J ¼ 8.0 Hz, aromatic C-H); m/z 258.1 (M-Cl) .
0
1-(4 -Chlorophenyl)-2-isopropyl-2-methyl-4,6-diamino-1,2-dihydro-1,3,5-
triazine Hydrochloride
Colourless prisms from EtOH/Et O (0.1185 g, 38%, 1.00 mmol scale).
2
Found C, 49.42; H, 5.93; N, 22.32% (C H Cl N requires C, 49.38;
1
3
19
2
5
H, 6.06; N, 22.15%); ꢀH (D O, 200 MHz) 0.70 and 0.85 (2 Â 3H, 2 Â d,
2
J ¼ 7.0 Hz, (CH ) CH-2), 1.13 (3H, s, CH -2), 2.00 (1H, m, (CH ) CH-2),
3
2
3
3 2
þ
7
.25 and 7.85 (2 Â 2H, 2 Â d, J ¼ 8.0 Hz, aromatic C-H); m/z 281.4 (M-Cl) .
0
1-(4 -Ethylphenyl)-2-isopropyl-2-methyl-4,6-diamino-1,2-dihydro-1,3,5-
triazine Hydrochloride
Colourless plates from EtOH/Et O (0.1816 g, 59%, 1.00 mmol scale).
2
Found C, 58.15; H, 7.78; N, 22.66% (C H ClN requires C, 58.15; H, 7.81;
1
5
24
5
N, 22.60%); ꢀH (D O, 200 MHz) 0.70 and 0.90 (2 Â 3H, 2 Â d, J ¼ 7.0 Hz,
2
0
(
(
CH ) CH-2), 1.02 (3H, t, J ¼ 7.2 Hz, CH CH -4 ), 1.14 (3H, s, CH -2), 2.00
3
2
3
2
3
0
1H, m, (CH ) CH-2), 2.50 (2H, q, J ¼ 7.2 Hz, CH CH -4 ), 7.02 (2H, m,
3
2
3
2
þ
aromatic C-H), 7.22 (2H, d, J ¼ 8.0 Hz, aromatic C-H); m/z 275.5 (M-Cl) .
0
1-(4 -Methylphenyl)-2-isobutyl-2-methyl-4,6-diamino-1,2-dihydro-1,3,5-
triazine Hydrochloride
Colourless prisms from MeOH/Et O (0.2314 g, 75%, 1.00 mmol scale).
2
Found C, 55.18; H, 7.81; N, 21.42% (C H ClN þH O requires C, 54.95;
1
5
24
5
2
H, 7.99; N, 21.36%); ꢀ (D O, 200 MHz) 0.73 (6H, d, J ¼ 7.0 Hz,
H
2
(
CH ) CHCH -2), 1.13 (3H, s, CH -2), 1.45 and 1.86 (2H, 2 Â dd,
3 2 2 3 2 2
3
2
2
3
J ¼ 14.4, 6.0 Hz, (CH ) CHCH -2), 1.60 (1H, m, (CH ) CHCH -2), 2.22
0
(
aromatic C-H); m/z 275.8 (M-Cl) .
3H, s, CH -4 ), 7.05 (2H, m, aromatic C-H), 7.15 (2H, d, J ¼ 8.0 Hz,
3
þ

1
-ARYL-4,6-DIAMINO-1,2-DIHYDRO-1,3,5-TRIAZINES
2097
0
1-(4 -Chlorophenyl)-2-isobutyl-2-methyl-4,6-diamino-1,2-dihydro-1,3,5-
triazine Hydrochloride
Colourless prisms from EtOH/Et O (0.2049 g, 62%, 1.00 mmol scale).
2
Found C, 48.42; H, 6.38; N, 20.04% (C H Cl N þH O requires C, 48.28;
1
4
21
2
5
2
H, 6.66; N, 20.11%); ꢀH (D O, 200 MHz) 0.73 (6H, d, J ¼ 7.0 Hz,
2
(
1
CH ) CHCH -2), 1.13 (3H, s, CH -2), 1.45 and 1.83 (2 Â H, 2 Â dd, J ¼
3
2
2
3
4.4, 6.4 Hz, (CH ) CHCH -2), 1.55 (1H, m, (CH ) CHCH -2), 7.18 (2H, m,
3 2 2 3 2 2
þ
aromatic C-H), 7.38 (2H, d, J ¼ 8.0 Hz, aromatic C-H); m/z 295.6 (M-Cl) .
0
1-(4 -Chlorophenyl)-2,2-dipropyl-4,6-diamino-1,2-dihydro-1,3,5-triazine
Hydrochloride
Colourless prisms from EtOH/Et O (0.2349 g, 68%, 1.00 mmol scale).
2
Found C, 52.24; H, 6.60; N, 20.40% (C H Cl N requires C, 52.33; H, 6.73;
1
5
23
2
5
N, 20.34%); ꢀ (D O, 200 MHz) 0.65 (6H, t, J ¼ 7.0 Hz, 2 Â CH CH CH -2),
H
2
3
2
2
1
7
.25 (4H, m, 2 Â CH CH CH -2), 1.45 (4H, m, 2 Â CH CH CH -2), 7.15 and
3
2
2
3
2
2
þ
.25 (2 Â 2H, 2 Â d, J ¼ 8.0 Hz, aromatic C-H); m/z 308.2 (M-Cl) .
0
0
1
-(3 ,4 -Dichlorophenyl)-2-isopentyl-2-methyl-4,6-diamino-1,2-dihydro-
,3,5-triazine Hydrochloride
1
Colourless prisms from EtOH/Et O (0.2803 g, 75%, 1.00 mmol scale).
2
Found C, 47.51; H, 5.85; N, 18.45% (C H Cl N requires C, 47.57;
3
1
5
22
5
H, 5.86; N, 18.49%); ꢀH (D O, 200 MHz) 1.08 (6H, d, J ¼ 7.2 Hz,
2
0
(
(
(
CH ) CHCH CH -2), 1.00–1.30 (3H, m, (CH ) CHCH CH -2 ), 1.20
2
3
2
2
2
3 2
2
3H, s, CH -2), 1.65 and 1.75 (2H, 2 Â m, (CH ) CHCH CH -2), 7.24
3
3 2
2
2
þ
1H, m, aromatic C-H), 7.55 (2H, m, aromatic C-H); m/z 341.9 (M-Cl) .
1-Phenyl-2-hexyl-2-methyl-4,6-diamino-1,2-dihydro-1,3,5-triazine
Hydrochloride
Light brown crystalline solids from EtOH/Et O (0.2877 g, 89%,
2
1
0
0
.00 mmol scale). Found C, 57.40; H, 8.39; N, 21.64% (C H ClN þ
1
6
26
5
.5H O requires C, 57.73; H, 8.18; N, 21.04%); ꢀ (D O, 200 MHz)
2
H
2
.63 (3H, t, J ¼ 7.2 Hz, CH (CH ) CH -2), 1.05–1.40 (4 Â 2H, m,
3
2 4
2
CH (CH ) CH -2), 1.15 (3H, s, CH -2), 1.50 and 1.70 (2H, 2 Â m,
3
2 4
2
3
CH (CH ) CH -2), 7.18 (2H, m, aromatic C-H), 7.38 (5H, 2 Â m, aromatic
3
2 4
2
þ
C-H); m/z 288.5 (M-Cl) .

2
098
SAESAENGSEERUNG, VILAIVAN, AND THEBTARANONTH
0
1-(4 -Chlorophenyl)-2-hexyl-2-methyl-4,6-diamino-1,2-dihydro-1,3,5-triazine
Hydrochloride
Colourless prisms from MeOH/Et O (0.3046 g, 85%, 1.00 mmol scale).
2
Found C, 53.58; H, 6.99; N, 19.63% (C H Cl N requires C, 53.63;
5
1
6
25
2
H, 7.03; N, 19.55%); ꢀH (D O, 200 MHz) 0.65 (3H, t, J ¼ 7.2 Hz,
2
CH (CH ) CH -2), 1.08–1.30 (4 Â 2H, m, CH (CH ) CH -2), 1.18 (3H, s,
3
2 4
2
3
2 4
2
CH -2), 1.50 and 1.70 (2H, 2 Â m, CH (CH ) CH -2), 7.20 (2H, m, aromatic
3
3
2 4
2
þ
C-H), 7.40 (2H, d, J ¼ 8.0 Hz, aromatic C-H); m/z 322.5 (M-Cl) .
0
1-(4 -Methylphenyl)-2-hexyl-2-methyl-4,6-diamino-1,2-dihydro-1,3,5-triazine
Hydrochloride
Pale yellow crystalline solids from MeOH/Et O (0.3044 g, 90%,
2
1
.00 mmol scale). Found C, 60.18; H, 8.69; N, 20.86% (C H ClN requires
28
1
7
5
C, 60.43; H, 8.35; N, 20.73%); ꢀH (D O, 200 MHz) 0.64 (3H, t, J ¼ 7.2 Hz,
2
CH (CH ) CH -2), 1.05–1.30 (4 Â 2H, m, CH (CH ) CH -2), 1.17 (3H, s,
3
2 4
2
3
2 4
2
0
CH -2), 1.50 and 1.70 (2H, 2 Â m, CH (CH ) CH -2), 2.20 (3H, s, CH -4 ),
3
3
2 4
2
3
7
3
.05 (2H, m, aromatic C-H), 7.20 (2H, d, J ¼ 8.0 Hz, aromatic C-H); m/z
þ
03.7 (M-Cl) .
0
1-(4 -Chlorophenyl)-2-ethyl-2-pentyl-4,6-diamino-1,2-dihydro-1,3,5-triazine
Hydrochloride
Colourless prisms from EtOH/Et O (0.2274 g, 64%, 1.00 mmol scale).
2
Found C, 53.58; H, 6.99; N, 19.63% (C H Cl N requires C, 53.63;
1
6
25
2
5
H, 7.03; N, 19.55%); ꢀH (D O, 200 MHz) 0.65 (3H, t, J ¼ 6.8 Hz,
2
CH (CH ) CH -2), 0.80 (3H, t, J ¼ 7.0 Hz, CH CH -2), 1.04 (6H, m,
3
2 3
2
3
2
CH (CH ) CH -2), 1.20 and 1.40 (2H, 2 Â m, CH (CH ) CH -2), 1.55
3
2 3
2
3
2 3
2
(
aromatic C-H); m/z 324.1 (M-Cl) .
2H, m, CH CH -2), 7.15 (2H, m, aromatic C-H), 7.45 (2H, d, J ¼ 8.0 Hz,
3
2
þ
0
1-(4 -Chlorophenyl)-2-phenyl-4,6-diamino-1,2-dihydro-1,3,5-triazine
Hydrochloride
Colourless prisms from MeOH/Et O (0.1955 g, 58%, 1.00 mmol scale).
2
Found C, 53.4; H, 4.4; N, 20.9% (C H N Cl requires C, 53.58; H, 4.50;
1
5
15
5
2
N, 20.83%); ꢀH (DMSO-d , 200 MHz); 6.06 (1H, s, H-2), 7.16 and 7.43
6

1
-ARYL-4,6-DIAMINO-1,2-DIHYDRO-1,3,5-TRIAZINES
2099
(
m/z 300.0 (M-Cl) .
2 Â 2H, 2 Â d, J ¼ 8.0 Hz, (aromatic C-H)-1), 7.36 (5H, m, aromatic C-H);
þ
0
00
1
1
-(4 -Ethylphenyl)-2-(4 -benzyloxy)phenyl-4,6-diamino-1,2-dihydro-
,3,5-triazine Hydrochloride
Colourless prisms from MeOH/Et O (0.3335 g, 93%, 0.83 mmol scale).
2
Found C, 66.09; H, 6.23; N, 6.00% (C H ClN O requires C, 66.12;
5
2
4
26
H, 6.01; N, 16.06%); ꢀH (DMSO-d , 200 MHz); 1.03 (3H, t, J ¼ 7.2 Hz,
6
0
0
CH CH -4 ), 2.03 (2H, q, J ¼ 7.2 Hz, CH CH -4 ), 5.08 (2H, s, PhCH O),
3
2
3
2
2
5
.92 (1H, s, H-2), 7.00 and 7.40 (9H, 2 Â m, aromatic C-H), 7.24 (4H, m,
þ
aromatic C-H), 9.00 (s, 1H, NH); m/z 400.1 (M.H ).
0
00
1
1
-(4 -Bromophenyl)-2-(4 -benzyloxy)phenyl-4,6-diamino-1,2-dihydro-
,3,5-triazine Hydrochloride
Colourless prisms from MeOH/Et O (0.4393 g, 75%, 1.21 mmol scale).
2
Found C, 54.16; H, 4.53; N, 14.20% (C H ClN O requires C, 54.28; H,
2
2
24
5
4
.35; N, 14.39%); ꢀH (DMSO-d , 200 MHz); 5.08 (2H, s, PhCH O), 6.00
6
2
(
C-H), 7.38 (5H, m, aromatic C-H); 9.00 (1H, s, NH); m/z 449.9 (M-Cl) .
1H, s, H-2), 7.00, 7.08, 7.23 and 7.57 (4 Â 2H, 4 Â d, J ¼ 8.0 Hz, aromatic
þ
ACKNOWLEDGMENTS
We acknowledge financial support from National Science and
Technology Development Agency (NSTDA), The Thailand Research
Funds (PDF/57/2540) and Chulalongkorn University (Development
Grants for New Faculty/Researchers). We also thank Ms. N. Panchan
(Institute for Genetic Engineering and Biotechnology, Chulalongkorn
University) for recording MALDI-TOF mass spectra.
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. Baker, B.R.; Johnson, M.A. Irreversible Enzyme Inhibitors 101.
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2
Received in the UK March 5, 2001