Antiviral activities of some new 2,4,6-trisubstituted 1,3,5-triazines having alkoxy and/or alkylamino groups

Article abstract of DOI:10.3987/COM-17-13735

We report the preparation of C3-and CS-symmetrical 2,4,6-trisubstituted 1,3,5-triazine derivatives having alkoxy and/or alkylamino groups and results of biological evaluation of their anti-herpes simplex virus type 1 (anti-HSV-1) activity and cytotoxic activity against Vero cells. New targeted symmetrical molecules were obtained by using a method starting with 2,4,6-trichloro-1,3,5-triazine (1). Among the synthesized compounds, CS-symmetrical tri-aliphatic alkylamino-substituted compound 6s showed high anti-HSV-1 activity (EC50 = 5.4 μM) and low cytotoxicity (CC50 > 200 μM). The results of an SAR study suggested that the presence of two hydrogen bond donor protons of sec-amine functionality in the molecule is an important structural factor for expression of potential anti-HSV-1 activities.

Full text of DOI:10.3987/COM-17-13735

HETEROCYCLES, Vol. 94, No. 9, 2017
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HETEROCYCLES, Vol. 94, No. 9, 2017, pp. 1653 - 1677. © 2017 The Japan Institute of Heterocyclic Chemistry
Received, 26th April, 2017, Accepted, 23rd June, 2017, Published online, 12th July, 2017
DOI: 10.3987/COM-17-13735
ANTIVIRAL ACTIVITIES OF SOME NEW 2,4,6-TRISUBSTITUTED
1,3,5-TRIAZINES HAVING ALKOXY AND/OR ALKYLAMINO GROUPS
Nobuko Mibu,1 Kazumi Yokomizo,2 Ai Yuzuriha,1 Marie Otsubo,1
Yuna Kawaguchi,1 Marina Sano,1 Izumi Sakai,1 Keita Nakayama,2
Jian-Rong Zhou,2 and Kunihiro Sumoto1*
1Faculty of Pharmaceutical Sciences, Fukuoka University, 8-19-1 Nanakuma,
Jonan-Ku, Fukuoka 814-0180, Japan
2Faculty of Pharmaceutical Sciences, Sojo University, 4-22-1 Ikeda, Kumamoto
862-0082, Japan. *E-mail: kunihiro@adm.fukuoka-u.ac.jp
Abstract – We report the preparation of C3- and CS-symmetrical
2,4,6-trisubstituted 1,3,5-triazine derivatives having alkoxy and/or alkylamino
groups and results of biological evaluation of their anti-herpes simplex virus type
1 (anti-HSV-1) activity and cytotoxic activity against Vero cells. New targeted
symmetrical molecules were obtained by using a method starting with
2,4,6-trichloro-1,3,5-triazine (1). Among the synthesized compounds,
CS-symmetrical tri-aliphatic alkylamino-substituted compound 6s showed high
anti-HSV-1 activity (EC50 = 5.4 μM) and low cytotoxicity (CC50 > 200 μM). The
results of an SAR study suggested that the presence of two hydrogen bond donor
protons of sec-amine functionality in the molecule is an important structural factor
for expression of potential anti-HSV-1 activities.
INTRODUCTION
Specific interactions between carbohydrate-containing glycoproteins, proteoglycans and glicolipids on the
cell surface and various types of lectins (protein receptors) are important biological processes for various
cell-to-cell communications, including the processes of bacterial or viral infection and tumor
metastasis.1-3 Molecular recognition of two-fold (C2) or three-fold (C3) symmetrical geometry
macromolecules is one of the common features in many important biological responses. From the
viewpoint of molecular symmetry, many host receptors that consist of homo-oligometric units
(homo-multiligands) often form symmetric macromolecule architectures such as C2- or C3-symmetrical

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HETEROCYCLES, Vol. 94, No. 9, 2017
geometry receptor systems.4 These phenomena of bio-macromolecules have encouraged us to develop
new multivalent symmetrical synthetic molecules to find new bioactive compounds or leads. Regarding
such geometrical molecules, we have already designed and synthesized a few new symmetrical molecules
and evaluated their bioactivities in order to find new types of bioactive compounds.5-10
In connection with the above projects, we have recently reported some symmetrical 2,4,6-trisubstituted
1,3,5-triazine (TAZ) derivatives and the results of biological evaluation of the synthesized symmetrical
TAZ derivatives.11 Among previously targeted tri-substituted TAZ derivatives, we found that a
C3-symmetrical TAZ derivative with three isopropoxy groups on a TAZ template (compound 4b) showed
a high level of anti-HSV-1 activity and a low level of cytotoxicity. This compound is considered to be a
potential lead in the search for preferred anti-HSV-1 activity with a good selectivity index.5
The results of a few trials for molecular modifications of symmetrical 2,4,6-trialkoxy-TAZ
derivatives12-15 in order to find new bioactive molecules have recently been reported. Our previous works
revealed the importance of three isopropoxy groups including the C3-type TAZ molecule 4b for
expression of anti-HSV-1 activity with a high selectivity index and also the contribution of these
isopropoxy groups to potential diastereoselective sugar-recognition in some monosaccharides probably in
a manner through hydrophobic interaction. It is also thought that the ability to form multiple hydrogen
bonds plays an important role in guest molecule recognition of many artificial receptor-type symmetrical
molecules.7,11
In this paper, we report the results of further preparation of newly targeted 2,4,6-trisubstituted TAZ
derivatives (4-8) together with the results of evaluation of the antiviral activities of synthesized TAZ
derivatives in order to reveal the noncovalent reversible bonds such as hydrogen bonds. We describe the
structure-activity relationships (SARs) of these tri-substituted TAZ derivatives that have branched C3~C4
alkoxy and/or amino groups in the TAZ template.
SYNTHESIS OF NEW TARGETED 2,4,6-TRISUBSTITUTED 1,3,5-TRIAZINES
Target 2,4,6-trisubstituted TAZ derivatives (4-8) were synthesized from 2,4,6-trichloro-1,3,5-triazine
(TCTAZ, 1) as a starting material using stepwise nucleophilic substitution of three active chlorine atoms
of TCTAZ by various alcohols (ROH) and/or alkylamines (RNH2) (as nucleophiles). The overall process
for the preparation of these target molecules is shown in Scheme 1.
Preparation of C3-symmetrical alkoxy- or alkylamino-trisubstituted TAZ derivatives (4 or 6) was
conducted by nucleophilic substitution of TCTAZ (1) in one pot with alcohols (c-e, hH) or alkylamines
(p-tH). As we mentioned previously,6,11 it is well known as Moffatt’s rule16,17 that decreased reactivity of
the final chlorine atom in the TAZ template to nucleophiles requires drastic reaction conditions with
strong bases (such as NaH, t-BuOK) or under microwave irradiation (MW). As can be seen in Tables S1

HETEROCYCLES, Vol. 94, No. 9, 2017
1655
OR1
N
R1OH
i or ii
N
N
R1O
R2O
N
41
OR1
OR1
OR1
OR1
N
R2OH
R1OH
N
N
v, vi, ix,
x or xi
i, ii, iii or
iv
Cl
N
31
OR1
N
521
OR1
R3NH2
x
N
N
R3HN
N
OR1
831
OR1
N
OR1
N
OR1
N
Cl
R2OH
R2OH
R1OH
N
N
N
N
N
N
v, vi, vii,
viii, x or xi
Cl
N
21
Cl
Cl
N
312
OR2
v, vi, vii,
viii, x or xi
i, ii, iii or
iv
R2O
N
512
OR2
Cl
N
Cl
1
OR1
N
OR1
N
R3NH2
x
R3NH2
x
N
NHR3
R3HN
N
NHR3
Cl
N
913
713
NHR3
N
NHR3
N
Cl
R3NH2
R3NH2
N
N
N
N
R3HN
N
NHR3
xii, xiii
or xiv
R3HN
Me
N
103
NHR3
x, xiii or
xiv
Cl
N
Y3
Cl
63
F3C
F3C
OH
OH
O
O
ROH = MeOH
OH
OH
OH
OH
OH
OH
(H2C)6 OH
F3C
cH
m-
p-
aH
bH
dH
eH
NH2
pH
fH
gH
hH
iH jH
kH
F
F
O
R3NH2 =
NH2
NH2
NH2
rH
O
qH
sH
i: R1OH, NaH, rt to ; then 1, rt to , THF (for 4c, 4d, 4h)
iii: collidine, rt, acetone (for 2b, 2d, 2f, 2g, 2j, 3j) or THF (for 2h)
ii: t-BuOK, 0 oC to rt, THF (for 4e)
iv: R1OH, NaH, 0 oC; then 1, -78 oC to rt, THF (for 3b, 3f) or R1OH, NaH, ; then 1, , benzene (for 3d)
v: R2OH, NaH, rt to  or rt; then 21, rt to  or ,THF (for 5ab, 5bh, 5hb, 5jg)
vi: Et3N, rt, THF (for 5ka, 5kb) or , acetone (for 5gj)
vii: collidine, rt and/or , acetone (for 5bi, 5bk, 3bk, 5fi, 5fj·(3fj)2, 5fk, 5gi, 3jg), acetone-THF (for 5ak, 3ak)
viii: collidine, MW, dioxane (for 5bj, 3bj)
x: MW, dioxane (for 7dp, 7dq, 8pb, 8qd)
xii: MW, dioxane (for 6p, 10p)
ix: collidine, rt to , acetone; then MW, dioxane (for 5jb)
xi: DIPEA, , THF (for 7bp, 7bq, 9bq, 7fq, 9fq, 8qb, 8pd)
xiii: 0 oC to rt; then MW, dioxane (6q, 6r, 6s)
xiv: DIPA, , THF (for 6q, 10q, 10r) or DIPA, MW, dioxane (for 6q,10q)
DIPEA = diisopropylethylamine, DIPA = diisopropylamine
Scheme 1. Synthesis of compounds 4-8

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HETEROCYCLES, Vol. 94, No. 9, 2017
and S2, overall yields in the preparation of target C3-symmetrical TAZ derivatives (4, 6) were moderate,
but the reproducibility of the method was variable (see Tables S1 and S2 for Supplementary Materials of
the online version for details).
Preparation of CS-symmetrical alkoxy- and/or alkylamino-trisubstituted TAZ derivatives (5, 7 or 8) was
also achieved from stepwise substitution reactions of TCTAZ (1) by various alcohols (ROH) and
alkylamines (RNH2). Thus, reactions with different ratios of two reagents (1 : ROH = 1 : 1 and 1 : ROH =
1 : 2) afforded intermediate monoalkoxy- or dialkoxy-substituted TAZ derivatives mainly (2 and 3,
respectively), and the intermediate TAZ derivatives 2 and 3 obtained were further used for subsequent
substitution reactions of chlorine atoms on the TAZ template with other needed nucleophiles (ROH or
RNH2) giving target CS-symmetrical trialkoxy-TAZ derivatives (5) or alkoxy-alkylamino-trisubstituted
TAZ derivatives (7, 8). All of the intermediate mono- or dichloro-substituted TAZ derivatives (2, 3) and
target CS-symmetrical tri-substituted TAZ derivatives (5, 7, 8) were obtained in moderate to good yields
(see Tables S3-S5 for Supplementary Materials of the online version for details).
BIOLOGICAL ACTIVITY AND DISCUSSION
It is thought that the ability to form multiple hydrogen bonds plays an important role in guest molecule
recognition of many artificial receptor-type molecules. Title tripodal receptor-type C3- or CS-geometrical
molecules that have donors or acceptors for hydrogen bonds on a symmetrical TAZ template are thought
to offer new biologically active interesting molecules.
EC50 values of the anti-HSV-1 activities of synthesized TAZ derivatives were obtained by plaque
reduction assays,18 and cytotoxicities (CC50) against Vero cells were determined (Tables 1 and 2). Among
the new C3- and CS-symmetrical tri-substituted TAZ derivatives, most of the C3- and CS-symmetrical
compounds (4, 5) that have three alkoxy groups showed no significant anti-HSV-1 (EC50 > 100 μM)
activity or cytotoxic activity (CC50 > 200 μM) as was previously reported for tri-alkoxy substituted TAZ
derivatives.11 Only a few compounds showed anti-HSV-1 activity and moderate cytotoxic activity. Three
CS-symmetrical compounds, 5ab, 5bk and 5kb, showed anti-HSV-1 activity (EC50 = 26.1, 21.8 and 34.3
μM, respectively) and three CS-symmetrical compounds, 5hb, 5bk and 5kb, showed moderate cytotoxic
activity (CC50 = 85.9, 26.4 and 138.0 μM, respectively). Compounds 5hb, 5jb and 5kb have two
isopropoxy groups on the TAZ template, and neither of the prepared TAZ derivatives 5 showed
significantly higher anti-HSV-1 activity than that of the C3-symmetrical prototype 4b. From these
modifications, we reconfirmed the importance of the presence of three isopropoxy groups on the
(C3-symmetrical) TAZ template (4b) for showing high anti-HSV-1 activity (EC50 = 1.87 μM) and low
cytotoxic activity (CC50 = 479.8 μM) (see Table 1).5,11 Calculated log P values for the compounds are
also shown in Table 1. There was no distinct correlation between log P values and EC50 values or

HETEROCYCLES, Vol. 94, No. 9, 2017
1657
between log P values and CC50 values among the compounds listed in Table 1.
Table 1. Anti-HSV-1 Activity (EC50) and Cytotoxicity (CC50) against Vero Cells of Target TAZ
Derivatives (4, 5) and Byproducts (3)
EC50
(μM)
CC50
(μM)
EC50
(μM)
CC50
(μM)
Log Pa
Compound
Log Pa
)
)
Compound
O
O
b
)
4b
1.87
479.8
>200
3.36
21.8
34.3
26.4
4.94
O
O
5bk
5kb
O
O
N
N
N
N
㻌
㻌
O
O
N
O
N
O
㻌
CF3
O
O
O
F3C
CF3
O
>100
7.21
5.06
4.02
133.0
4.15
7.69
5.41
4c
4d
4e
N
N
CF3
N
N
N
N
O
O
CF3
N
O
F3C
O
O
N
O
㻌
㻌
CF3
O
CF3
>100
>100
>200
>200
>100
>100
>200
>200
5fi
N
N
N
㻌
㻌
O
N
N
O
N
O
O
O
N
5fk
O
O
O
N
N
N
N
O
O
O
O
O
O
O
㻌
e
) M
H
(C
O
CF3
CF3
O
N
>100
>200
7.42
>100
>200
9.06
4h
5gi
N
N
N
㻌
N
O
O
O
(CH2)6Me
Me
O
O
N
26.1
>100
>100
>100
>100
>100
>100
>200
>200
>200
85.9
2.71
2.84
6.07
4.72
7.22
7.22
5.29
F3C
>100
>100
>100
>100
>100
>100
>100
>200
>200
>200
>200
>200
>200
132
9.06
8.97
3.97
3.15
3.8
5ab
5ka
5bh
5hb
5bi
CF3 5gj
N
N
N
O
N
㻌
㻌
㻌
㻌
㻌
㻌
㻌
O
N
O
O
O
F3C
O
O
N
5jg
N
N
N
N
Me(H2C)6
(CH2)6Me
O
N
O
MeO
OMe
㻌
Cl
O
N
N
N
3f
N
N
O
N
O
O
O
Cl
N
O
O
O
N
N
3ak
3bk
3bj
N
N
MeO
O
O
N
O
㻌
Cl
F3C
CF3
O
O
N
N
>200
>200
>200
N
N
O
O
N
O
O
N
O
Cl
O
F3C
CF3
N
N
F3C
4.95
6.78
5bj
5jb
N
N
O
N
N
O
N
O
O
N
F3C
Cl
N
O
F3C
N
3jg
(CH2)6Me
N
O
O
O
N
O
a) All log P values were calculated by using ChemDrawUltra 15.1. b) Data were taken from referene 5.

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HETEROCYCLES, Vol. 94, No. 9, 2017
Regarding Cs-symmetrical molecules as shown in Table 2, many alkylamino- and alkyloxy-substituted
TAZ derivatives (7 and 8) that have branched C3~C5 alkoxy (b, d, fH) or alkylamino (p-rH)
functionalities on the TAZ template showed high levels of anti-HSV-1 activity (EC50 = 18.5~47.7 μM)
and relatively high levels of cytotoxic activity (CC50 = 13.8~139.2 μM). Three Cs-symmetrical TAZ
derivatives (8pb, 8qb and 8qd) that have the same two alkoxy and alkylamino functionalities as those of
7bp, 7bq and 7dq, respectively, showed no anti-HSV-1 or cytotoxic activity (EC50 > 100 μM and CC50 >
200 μM, respectively). Compounds 7bp and 7dq showed no anti-HSV-1 activity (EC50 >100 μM) but
showed a low or moderate level of cytotoxic activity (CC50 = 139.2 and 28.3 μM, respectively). All of
these molecules (7 and 8) have calculated log P values below 5.0 (see Table 2). We consider that two
sec-alkylamino groups as donors for hydrogen bonds on a symmetrical TAZ template contribute to the
biological activity. In fact, most of the C3-and CS-symmetrical tri-aliphatic alkylamino-substituted TAZ
derivatives (6p, 6q, 6r, 6s, 7bq and 7dp), except for two compounds (7bp and 7dq) that have the same
alkyl moiety in alkoxy and alkylamino substituents, showed considerably high levels of anti-HSV-1
activity (EC50 = 5.4~45.0 μM). Among these compounds, compound 6s showed decreased levels of
cytotoxic activity (CC50 > 200 μM). In this series, the overall results strongly suggested that at least the
presence of two hydrogen bond donor protons of sec-alkylamine functionality at the 2, 4 and 6 positions
of the TAZ template is an important factor for expression of anti-HSV-1 activity. This consideration is
supported by previous observations that most of the C3-symmetrical TAZ derivatives that have a
tri-aromatic amine and/or tert-amine-substituted TAZ template were almost inactive (both EC50 and CC50
values being over 100 μM).6
Compared with trialkoxy-substituted TAZ series such as prototype 4b, we consider that the
above-described results may indicate a different mode of antiviral action of these new tri-substituted TAZ
series (such as 6, 7 and 8) from that of trialkoxy-substituted TAZ series.
Regarding the isolated intermediates including a chloro-substituent in the TAZ template (3, 9 and 10) that
are listed in Tables 1 and 2, none of these compounds showed anti-HSV-1 activity (EC50 > 100 μM) and
only a few compounds showed a low level of cytotoxic activity (CC50 = 132~249 μM).
On the basis of the information obtained by the above-described structural modifications for biological
activities in these tri-substituted TAZ series together with recent information on the
tris(2-aminoethyl)amine (TAEA) series,8 further molecular modifications of the highest antiviral active
compound 6s and new hybrid TAZ-TAEA-type molecules are now under investigation in order to find
new promising bioactive compounds.

HETEROCYCLES, Vol. 94, No. 9, 2017
1659
Table 2. Anti-HSV-1 Activity (EC50), Cytotoxicity (CC50) against Vero Cells, and Calculated Log P of
Target TAZ Derivatives (6-8) and Byproducts (9, 10)
X
Cl
63
713 831
103
N
N
N
N
X
Y
R3NH R1O R3NH Cl
R3NH R3NH R1O R3NH
R1O
N
NHR3
Y
N
Y
913
6-8, 10
bH
R1OH
R2OH =
OH
OH
OH
dH
fH
F
F
MeO
MeO
O
O
NH2
R3NH2
=
NH2
NH2
pH
NH2
NH2
qH
rH
sH
tH
EC50
(μM)
CC50
(μM)
EC50
(μM)
CC50
(μM)
Log Pa
Compound
Log Pa
)
)
Compound
NH
NH
N
N
27.3
80.4
2.23
>100
>100
>200
>200
2.99
6p
6q
8pb
N
N
HN
HN
N
N
H
O
O
N
O
O
NH
NH
N
N
N
N
29.8
24.4
10.9
3.93
1.23
3.55
4.12
8qb
8pd
N
N
H
N
F
NH
F
F
F
N
F
N
NH
>200
47.7
57.2
6r
6s
HN
N
F
N
H
N
N
O
N
O
O
H2
C
O
NH
NH
O
N
N
CH2
O
N
N
N
5.4
>200
4.8
>100
>200
4.69
N
8qd
HN
H
O
N
O
H2C
O
O
Cl
O
N
N
N
>100
46.3
45.0
139.2
78.3
22.2
2.61
3.74
3.18
>100
>100
>100
249
3.68
2.26
3.4
7bp
7bq
7dp
9fq
10p
10q
N
N
N
N
O
N
H
N
H
H
Cl
O
N
N
N
>200
>200
N
N
N
N
N
H
N
N
N
O
N
H
H
N
H
Cl
N
N
H
N
H
N
Cl
N
N
H
N
N
H
O
N
O
F
F
F
F
N
N
>100
18.5
28.3
13.8
4.31
4.22
>100
1.1
142.4
>444
1.6
7dq
7fq
10r
N
N
N
N
H
N
H
N
H
N
H
b
)
Aciclovir
-0.76
N
N
H
N
N
H
a) All log P values were calculated by using ChemDrawUltra 15.1. b) Data were taken from reference 19.

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EXPERIMENTAL
Melting points were determined using a micro melting point apparatus (Yanaco MP-S3) without
correction. IR spectra were measured by a Shimadzu FTIR-8100 IR spectrophotometer. MicromATR
Vision [an apparatus of attenuated total reflectance (ATR)] was used for a neat sample operation. Low-
and high-resolution mass spectra (LR-MS and HR-MS) were obtained by a JEOL JMS HX-110
double-focusing model equipped with an FAB ion source interfaced with a JEOL JMA-DA 7000 data
system. MS/MS analysis of compound 4c was conducted with an API4000 Qtrap tandem mass
l
13
spectrometer (AB Sciex, Concord, Ontario, Canada) with an ESI interface. H- and C-NMR spectra
were obtained by JEOL JNM A-500 (2b, 2h, 2j, 3f, 3j, 3ak, 3bj, 3bk, 3jg, 4d, 4e, 4h, and 5 except for
5hb) and ECG600R (2d, 2f, 3b, 3d, 4c, 5hb, 6-10). Chemical shifts were expressed in δ ppm downfield
l
from an internal TMS signal for H-NMR and the carbon signal of the corresponding solvent [CDCl3
13
(77.00 ppm), DMSO-d6 (39.50 ppm)] for C-NMR. The abbreviations qu=quintet, dd=double doublets,
l
dt=double triplets, and dm=double multiplets are used for the multiplicity of H-NMR data. The signal
assignments were confirmed by two-dimensional (2D)-NMR analyses: lH-lH 2D correlation spectroscopy
l
l
(COSY), H-l3C heteronuclear multiple-quantum coherence (HMQC), and H-l3C heteronuclear
multiple-bond connectivity (HMBC). Microanalyses were performed with a Yanaco MT-6 CHN corder.
Routine monitoring of reactions was carried out using precoated Kieselgel 60F254 plates (E. Merck).
Microwave irradiation experiments were carried out in a CEM Discover Focused Microwave System.
Visualization was accomplished with UV light, iodine, ninhydrin, or phosphomolybdic acid. Open
column, flash column, and centrifugal chromatography separations of the reaction products were
performed on silica gel (Kanto 60N or Able-Biott) with a UV and/or RI detector. Commercially available
starting materials were used without further purification, and dry solvents were used in all reactions.
General Procedure for C3-Symmetrical Trialkoxy-substituted TAZ derivatives (4) (Table S1):
Example: Synthesis of 2,4,6-Tris[(1,1,1,3,3,3-hexafluoropropan-2-yl)oxy]-1,3,5-triazine (4c):
(Step 1): To a solution of hexafluoroisopropyl alcohol (cH, 2.69 g, 1.60 mmol) in THF (10 mL) was
added NaH (55% in mineral oil, 384 mg, 16.0 mmol) at room temperature under a N2 atmosphere. A
suspension of sodium n-heptyloxide was prepared by stirring at room temperature for 15 min and then
refluxing for 1 h.
(Step 2): After cooling to room temperature, compound 1 (922 mg, 5.00 mmol) was added and stirred for
15 min at room temperature under a N2 atmosphere. Then the reaction mixture was refluxed for 1 h. After
cooling to room temperature, saturated aq. ammonium chloride (10 mL) was added to the resulting
mixture, and the mixture was extracted with CH2Cl2 (3×50 mL). The combined organic layer was washed
with brine (10 mL) and dried over MgSO4. After evaporation of the solvent, the residue was recrystallized

HETEROCYCLES, Vol. 94, No. 9, 2017
1661
by n-hexane to give 4c (2.11 g, 3.65 mmol, 73%) as colorless needles. Mp 87-89 oC (from n-hexane). IR
(KBr) cm-1: 1586 (C=N), 1388 (C-F), 1195, 1141, 1107 (C-O). 1H-NMR (CDCl3) δ: 6.25 (3H, heptet, J =
13
9.2 Hz, H1’). C-NMR (CDCl3) δ: 70.69 (qu, J = 35.4 Hz, C1’), 119.99 (q, J = 282.7 Hz, C2’, 3’),
172.23 (C2, 4, 6). Negative-ion EPI-MS m/z: 578.2. Anal. Calcd for C12H3F18N3O3•0.7H2O: C, 24.36; H,
0.75; N, 7.10. Found: C, 24.28; H, 0.66; N, 7.27. [299929-60-5]
o
2,4,6-Tris(2-methylpropoxy)-1,3,5-triazine (4d): Colorless crystals. Mp 34-38 C (from i-PrOH). IR
(KBr) cm-1: 1559 (C=N), 1147, 1119 (C-O). 1H-NMR (CDCl3) δ: 1.01 (18H, d, J = 6.7 Hz, H1’, 4’), 2.11
13
(3H, qu, J = 6.7 Hz, H2’), 4.16 (6H, d, J = 6.7 Hz, H3’). C-NMR (CDCl3) δ: 19.10 (C3’, 4’), 27.77
(C2’), 74.40 (C1’), 173.25 (C2, 4, 6). Positive-ion FAB-MS m/z: 298 (M+H)+. HR-FAB-MS m/z:
298.2121 (Calcd for C15H28N3O3: 298.2131). Anal. Calcd for C15H27N3O3: C, 60.58; H, 9.15; N, 14.13.
Found: C, 60.53; H, 9.35; N, 13.96. [30895-05-7]
o
2,4,6-Tris(tricyclo[3.3.1.13,7]dec-2-yloxy)-1,3,5-triazine (4h): A white powder. Mp > 300 C (from
1
CH2Cl2). IR (KBr) cm-1: 1567, 1548 (C=N), 1140 (C-O). H-NMR (CDCl3) δ: 1.56 (6H, d, J = 12.8 Hz,
H4’, 9’), 1.76 (6H, br s, H6’), 1.80 (6H, d, J = 12.5 Hz, H8’, 10’), 1.84-1.93 (12H, m, H5’, 7’, 8’, 10’),
13
2.19 (6H, br s, H1’, 3’), 2.20 (6H, d, J = 12.8 Hz, H4’, 9’), 5.16 (3H, br s, H2’). C-NMR (CDCl3) δ:
27.15 (C5’ or 7’), 27.24 (C7’ or 5’), 31.58 (C1’, 3’ or 4’, 9’), 31.79 (C4’, 9’ or 1’, 3’), 36.46 (C8’, 10’),
37.48 (C6’), 80.50 (C2’), 172.80 (C2, 4, 6). Positive-ion FAB-MS m/z: 532 (M+H)+. HR-FAB-MS m/z:
532.3531 (Calcd for C33H46N3O3: 532.3539). Anal. Calcd for C33H45N3O3•1.5H2O: C, 70.94; H, 8.66; N,
7.52. Found: C, 70.91; H, 8.42; N, 7.44.
Synthesis of 2,4,6-Tris(1,1-dimethylethoxy)-1,3,5-triazine (4e): To a solution of TCTAZ (1, 922 mg,
5.0 mmol) in THF (30 mL), potassium t-butoxide (1 M THF solution, 15 mL, 15.0 mmol) was added at 0
o
oC under a N2 atmosphere and the reaction mixture was continuously stirred for 10 min at 0 C and then
for another 1 h at room temperature. After addition of brine (70 mL), the mixture was extracted with
CHCl3 (3×70 mL) and dried over MgSO4. After evaporation of the solvent, the obtained crude product 4e
o
(1.08 g, 3.6 mmol, 72%) was recrystallized from EtOH to give colorless crystals. Mp 130-135 C (from
1
EtOH). IR (KBr) cm-1: 1562 (C=N), 1164, 1130 (C-O of ether). H-NMR (CDCl3) δ: 1.60 (27H, s, H1’,
13
3’, 4’). C-NMR (CDCl3) δ: 28.38 (C1’, 3’, 4’), 81.84 (C2’), 171.87 (C2, 4, 6). Positive-ion FAB-MS
m/z: 298 (M+H)+. HR-FAB-MS m/z: 298.2130 (Calcd for C15H28N3O3: 298.2131). Anal. Calcd for
C15H27N3O3: C, 60.58; H, 9.15; N, 14.13. Found: C, 60.50; H, 9.28; N, 14.09. [500334-23-6]
General Procedure for C3-Symmetrical Trialkyamino-substituted TAZ derivatives (6) (Table S2):
Example: Synthesis of N2,N4,N6-Triisobutyl-1,3,5-triazine-2,4,6-triamine (6q):
(MW Method): To a solution of TCTAZ (1, 277 mg, 1.50 mmol) in dioxane (2 mL), a solution of
o
isobutylamine qH (1.10 g, 15.0 mmol) in dioxane (1 mL) was added dropwise at 0 C, and then the
mixture was continuously stirred for 25 min at room temperature and then for another 1 h at room

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o
temperature. Then the mixture was subjected to microwave irradiation (MW) at 100 C (100 W) for 25
min with stirring. After addition of water (30 mL), the mixture was extracted with EtOAc (2×25 mL). The
combined organic layer was dried over MgSO4. After evaporation of the solvent, the crude compound 6q
(405 mg, 1.50 mmol, 92%) was obtained as a white solid. An analytically pure sample was obtained as
colorless crystals after recrystallization from EtOH.
(Reflux Method): To a solution of 1 (371 mg, 2.00 mmol) in THF (20 mL) was added a mixture of qH
(483 mg, 6.60 mmol) and diisopropylamine (DIPA) to give a white suspension. After reflux for 22 h,
water (25 mL) and EtOAc (40 mL) were added to the mixture. The organic layer was separated and dried
over MgSO4. After evaporation of the solvent, the residue was purified by centrifugal chromatography
(CH2Cl2 : EtOH = 95 : 5) to give compounds 10q (65.3 mg, 0.253 mmol, 13%) and 6q (263 mg, 0.891
mmol, 45%), both as a white solid. An analytically pure sample of 10q was obtained as colorless crystals
after recrystallization from i-PrOH.
o
6q: Mp 59-62 C (from EtOH). IR (KBr) cm-1: 3309 (NH), 1559, 1532, 1508 (C=N), 1351 (C-N).
1H-NMR (CDCl3) δ: 0.93 (18H, d, J = 6.9 Hz, H3’, 4’), 1.82 (3H, br s, H2’), 2.13 (1.5H, br s NH), 3.18
13
(6H, br s, H1’), 4.92 (1.5H, br s, NH). C-NMR (CDCl3) δ: 20.21 (C3’, 4’), 28.63 (C2’), 48.19 (C1’),
166.33 (C2, 4, 6). Positive-ion FAB-MS m/z: 295 (M+H)+. HR-FAB-MS m/z: 295.2610 (Calcd for
C15H31N6: 295.2618). Anal. Calcd for C15H30N6•0.15H2O: C, 60.63; H, 10.28; N, 28.28. Found: C, 60.58;
H, 10.42; N, 28.19. [656822-23-0]
o
6-Chloro-N2,N4-diisobutyl-1,3,5-triazine-2,4-diamine (10q): Mp 208-210 C (from i-PrOH). IR (KBr)
cm-1: 3448 (NH), 1635, 1560 (C=N), 1101 (C-N), 800 (C-Cl). 1H-NMR (DMSO-d6) δ: 0.85 (ca. 4H, d, J
= 6.2 Hz, H3’, 4’), 0.86* (ca. 8H, d, J = 6.2 Hz, H3’, 4’), 1.75-1.85 (2H, m, H2’), 2.99-3.07 (4H, m, H1’),
13
7.52 (0.2H, t, J = 5.5 Hz, NH), 7.71-7.76 (0.8H, m, NH), 7.88* (1H, t, J = 5.5 Hz, NH). C-NMR
(DMSO-d6) δ: 20.04, 20.09* (C3’, 4’), 27.46, 27.75, 27.83* (C2’), 47.69, 47.75* (C1’), 165.17, 165.46*,
165.74 (C2, 4), 167.52*, 168.03 (C6). (The observed signals of the predominant tautomer are asterisked.)
Positive-ion FAB-MS m/z: 258 (M+H)+. HR-FAB-MS m/z: 258.1474 (Calcd for C11H21ClN5: 258.1485).
Anal. Calcd for C11H20ClN5: C, 51.26; H, 7.82; N, 27.17. Found: C, 51.32; H, 8.08; N, 27.19.
o
N2,N4,N6-Triisopropyl-1,3,5-triazine-2,4,6-triamine (6p): Colorless crystals. Mp 129-130 C (from
EtCN). IR (KBr) cm-1: 3445 (NH), 1584, 1506 (C=N), 1192 (C-N). 1H-NMR (CDCl3) δ: 1.17 (18H, d, J =
6.2 Hz, H2’, 3’), 2.23 (1.5H, br s, NH), 4.11 (3H, br s, H1’), 4.67 (1.5H, br s, NH). 13C-NMR (CDCl3) δ:
23.05 (C2’, 3’), 42.02 (C1’), 165.43 (C2, 4, 6). Positive-ion FAB-MS m/z: 253 (M+H)+. HR-FAB-MS
m/z: 253.2139 (Calcd for C12H25N6: 253.2141). Anal. Calcd for C12H24N6: C, 57.11; H, 9.59; N, 33.30.
Found: C, 56.86, H, 9.58; N, 33.14. [5465-03-2]
o
6-Chloro-N2,N4-diisopropyl-1,3,5-triazine-2,4-diamine (10p): Colorless solid. Mp 179-184 C. IR
(KBr) cm-1: 1620, 1579, 1550 (C=N), 1169, 1130 (C-N), 805 (C-Cl). 1H-NMR (CDCl3) δ: 1.09 (ca. 5.3H,

HETEROCYCLES, Vol. 94, No. 9, 2017
1663
d, J = 6.2 Hz, H2’, H3’), 1.12* (ca. 6.7H, d, J = 6.9 Hz, H2’, 3’), 3.95-4.04* (2H, br s, H2’), 7.53 (ca.
13
0.9H, d, J = 8.2 Hz, NH), 7.65* (ca. 0.56H, d, J = 7.5 Hz, NH). C-NMR (CDCl3) δ: 21.89* (C2’, 3’),
22.11 (C2’&3’ or C2”&3”), 22.24 (C2”&3” or C2’&3’), 41.51 (C1’ or C1”), 41.73 (C1” or C1’), 41.94*
(C1’), 164.06 (C2), 164.42* (C2, 4), 164.67 (C4), 167.48* (C6), 168.07 (C6). (In the 13C-NMR spectrum
of compound 10p, signals that appeared are fully consistent with the tautomeric mixture of two isomers
shown below (T1 and T2). The signals assignable to the predominant tautomer T1 are asterisked.)20
Positive-ion FAB-MS m/z: 230 (M+H)+. HR-FAB-MS m/z: 230.1167 (Calcd for C9H17ClN5: 230.1172).
Anal. Calcd for C9H16ClN5: C, 47.06; H, 7.02; N, 30.49. Found: C, 47.15; H, 6.97; N, 30.22. [139-40-2]
o
N2,N4,N6-Tris(2,2-difluoroethyl)-1,3,5-triazine-2,4,6-triamine (6r): Pale yellow solid. Mp 73 C. IR
(KBr) cm-1: 3463 (NH), 1619, 1582, 1542, 1513 (C=N), 1117, 1046 (C-N), 810 (C-Cl). 1H-NMR (CDCl3)
δ: 3.74 (6H, br s, H1’), [5.24 (1H), 5.62 (2H)] (br s, NH), 5.89 (3H, tt, J = 56.5, 4.1 Hz, H2’). 13C-NMR
(CDCl3) δ: 43.06 (t, J = 26.8 Hz, C1’), 114.00 (t, J = 241.3 Hz, C2’), 166.19 (C2, 4, 6). Positive-ion
FAB-MS m/z: 319 (M+H)+. HR-FAB-MS m/z: 319.1104 (Calcd for C9H13F6N6: 319.1106). Anal. Calcd
for C9H12F6N6: C, 33.97; H, 3.80; N, 26.41. Found: C, 33.93; H, 3.70; N, 26.27.
6-Chloro-N2-(2,2-difluoroethyl)-N4-(difluoromethyl)-1,3,5-triazine-2,4-diamine (10r): Colorless
needles. Mp 189-190 oC (from EtCN). IR (KBr) cm-1: 3253, 3115 (NH), 1636, 1557 (C=N), 1111, 1182,
1
1064 (C-N), 801 (C-Cl). H-NMR (DMSO-d6) δ: 3.59-3.71 (4H, m, H1’), [6.86 (tm, J = 56.1 Hz), 6.12
(tm, J = 56.1 Hz), 6.13* (tt, J = 56.1, 4.2 Hz)] (2H, H2’), [8.07 (0.15H, t, J = 6.2 Hz), 8.24* (0.85H, q, J
1
= 6.2 Hz), 8.34 (1H, t, J = 6.2 Hz)] (NH). (The observed H-signals assignable to the predominant
13
tautomer are asterisked.) C-NMR (DMSO-d6) δ: 42.65 (t, J = 27.4 Hz, C1’), 114.33 (t, J = 239.9 Hz,
C2’), 165.79 (C2, 4), 168.20 (C6). (Signals for only the predominant tautomer are shown.) Positive-ion
FAB-MS m/z: 274 (M+H)+. HR-FAB-MS m/z: 274.0487 (Calcd for C7H9ClF4N5: 274.0483). Anal. Calcd
for C7H8ClF4N5: C, 30.73; H, 2.95; N, 25.60. Found: C, 30.86; H, 3.23; N, 25.52.
N2,N4,N6-Tris(benzo[d][1,3]dioxol-5-ylmethyl)-1,3,5-triazine-2,4,6-triamine (6s): Colorless crystals.
Mp 128 oC (from MeCN). IR (ATR) cm-1: 3451, 3355, 3277 (NH), 1522, 1487, 1471 (C=N), 1245, 1215,
1
1036 (C-N and/or C-O). H-NMR (CDCl3) δ: 1.76 (3H, br s, NH), 4.45 (6H, br s, ArCH2), 5.91 (6H, s,
13
H2), 6.69-6.74 (6H, m, H6, 7), 6.78 (3H, br s, H4). C-NMR (CDCl3) δ: 44.43 (ArCH2), 100.92 (C2’),
108.12 (C7’), 108.20 (C4’), 120.63 (C6’), 133.39 (C5’), 146.64 (C3a’), 147.74 (C7a’), 166.14 (C2, 4, 6).
Positive-ion FAB-MS m/z: 529 (M+H)+. HR-FAB-MS m/z: 529.1843 (Calcd for C27H25N6O6: 529.1836).
Anal. Calcd for C27H24N6O6: C, 61.36; H, 4.58; N, 15.90. Found: C, 61.36; H, 4.61; N, 15.94.
General Procedure for Intermediate Monoalkoxy-dichloro-TAZ derivatives (2) (Table S3):
Example: Synthesis of 2,4-Dichloro-6-(tricyclo[3.3.1.13,7]dec-2-yloxy)-1,3,5-triazine (2h): To a
solution of 1 (1.84 g, 10.0 mmol) in THF (25 mL), 2-adamantanol hH (1.83 g, 12.0 mmol) and collidine
(1.45 g, 12.0 mmol) were added at room temperature under an Ar atmosphere. The mixture was stirring

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for 2.5 h to give an orange suspension. After filtration of white solids (collidine•HCl salt) and evaporation
of the solvent, the residue was purified by flash chromatography (CH2Cl2 : n-hexane = 30 : 70 → 40 : 60)
to give compound 2h (1.88 g, 6.26 mmol, 63%) as a white solid. Mp ca. 280 oC (decomp). IR (KBr) cm-1:
1
1556, 1497 (C=N), 1249, 1046 (C-O), 849, 803 (C-Cl). H-NMR (CDCl3) δ: 1.62 (2H, dm, J = 12.8 Hz,
H4’, 9’), 1.78 (2H, br s, H6’), 1.84 (2H, dm, J = 12.5 Hz, H8’, 10’), 1.88-1.96 (4H, m, H5’, 7’, 8’,10’),
13
2.15 (2H, dm, J = 12.8 Hz, H4’, 9’) 2.20 (2H, br s, H1’, 3’), 5.30 (1H, br t, J = 3.4 Hz, H2’). C-NMR
(CDCl3) δ: 26.86 (C5’ or 7’), 27.03 (C7’ or 5’), 31.45 (C1’, 3’), 31.55 (C4’, 9’), 36.23 (C8’, 10’), 37.21
(C6’), 83.95 (C2’), 170.57 (C6), 172.50 (C2, 4). Positive-ion FAB-MS m/z: 300 (M+H)+. HR-FAB-MS
m/z: 300.0697 (Calcd for C13H16Cl2N3O: 300.0670).
2,4-Dichloro-6-(1-methylethoxy)-1,3,5-triazine (2b):5,11 IR (NaCl) cm-1: 2987 (CH), 1542, 1500 (C=N),
1100, 1036 (C-O), 861, 807 (C-Cl). 1H-NMR (CDCl3) δ: 1.44 (6H, d, J = 6.1 Hz, C1’, 3’), 5.41 (1H, qu, J
13
= 6.1 Hz, C2’). C-NMR (CDCl3) δ: 21.42 (C1’, 3’), 74.90 (C2’), 170.51 (C6), 172.47 (C2, 4). The
positive FAB mass spectra of this compound showed no significant molecular ion for the determination
of its chemical formula, indicating instability of the corresponding molecular ion in the mass range as
well as that of compound 2d. [6684-27-1]
2,4-Dichloro-6-isobutoxy-1,3,5-triazine (2d): Pale yellow oil. IR (NaCl) cm-1: 1542, 1509 (C=N), 1047
(C-O), 849 (C-Cl).1H-NMR (CDCl3) δ: 1.05 (6H, d, J = 6.9 Hz, H3’, 4’), 2.16 (1H, qu, J = 6.9 Hz, H2’),
4.28 (2H, d, J = 6.2 Hz, H1’).13C-NMR(CDCl3) δ: 18.71 (C3’, 4’), 27.53 (C2’), 76.29 (C1’), 171.02 (C6),
172.32 (C2, 4). The positive FAB mass spectra of this compound showed no significant molecular ion for
the determination of its chemical formula, indicating instability of the corresponding molecular ion in the
mass range as well as that of compound 2b. [30886-23-8]
2,4-Dichloro-6-(cyclopentyloxy)-1,3,5-triazine (2f): Pale yellow oil. 1H-NMR (CDCl3) δ: 1.63-1.74 (2H,
m, H3’, 4’), 1.80-1.95 (4H, m, H3’, 4’, 2’, 5’), 1.97-2.05 (2H, m, H2’, 5’), 5.56 (1H, heptet, J = 3.1 Hz,
H1’).13C-NMR(CDCl3) δ: 23.57 (C3’, 4’), 32.56 (C2’, 5’), 84.01 (C1’), 170.65 (C6), 172.34 (C2, 4).
Positive-ion FAB-MS m/z: 234 (M+H)+. HR-FAB-MS m/z: 234.0208 (Calcd for C8H10Cl2N3O: 234.0201).
[107392-86-9]
2,4-Dichloro-6-(heptyloxy)-1,3,5-triazine (2g): See reference 6. [107392-85-8]
4,6-Dichloro-2-[4-(trifluoromethyl)phenoxy]-1,3,5-triazine (2j): White solid. IR (KBr) cm-1: 1542,
1
1508 (C=N), 1325 (CF3), 1204, 1174 (C-O), 800 (C-Cl). H-NMR (CDCl3) δ: 7.32 (2H, d, J = 8.4 Hz,
H2’, 6’), 7.75 (2H, d, J = 8.4 Hz, H3’, 5’). 13C-NMR (CDCl3) δ: 121.71 (C2’, 6’), 123.62 (q, J = 272.1 Hz,
CF3), 127.39 (q, J = 4.1 Hz, C3’, 5’), 129.42 (q, J = 33.1 Hz, C4’), 153.30 (C1’), 170.71 (C2), 173.35 (C4,
6). Positive-ion FAB-MS m/z: 310 (M+H)+. HR-FAB-MS m/z: 309.9762 (Calcd for C10H5Cl2F3N3O:
309.9770).
6-Chloro-2,4-bis[4-(trifluoromethyl)phenoxy]-1,3,5-triazine (3j): Colorless needles. IR (KBr) cm-1:

HETEROCYCLES, Vol. 94, No. 9, 2017
1665
1
1552 (C=N), 1320 (CF3), 1122, 1109 (C-O), 836, 812 (C-Cl). H-NMR (CDCl3) δ: 7.27 (4H, d, J = 8.4
13
Hz, H2’, 6’), 7.68 (4H, d, J = 8.4 Hz, H3’, 5’). C-NMR (CDCl3) δ: 121.83 (C2’, 6’), 123.63 (q, J =
272.1 Hz, CF3), 127.13 (q, J = 4.1 Hz, C3’, 5’), 129.12 (q, J = 33.1 Hz, C4’), 153.51 (C1’), 172.04 (C2,
4), 174.20 (C6). Positive-ion FAB-MS m/z: 436 (M+H)+. HR-FAB-MS m/z: 436.0285 (Calcd for
C17H9ClF6N3O2: 436.0287). [112748-53-5]
General Procedure for Intermediate Dialkoxy-monochloro-TAZ derivatives (3) (Table S3):
Example: Synthesis of 2-Chloro-4,6-bis(1-methylethoxy)-1,3,5-triazine (3b):5
(Step 1): To a solution of 2-propanol (bH, 1.80 g, 30.0 mmol) in dry THF (30 mL) was added NaH (55%
in mineral oil, 1.96 g, 45.0 mmol) at 0 oC under an Ar atmosphere. A suspension of sodium i-propyloxide
was prepared by stirring at 0 oC for 1.5 h.
o
(Step 2): After cooling to -77 C, compound 1 (2.77 g, 15.0 mmol) was added and stirred for 10 min at
o
-77 C under an Ar atmosphere. Then the reaction mixture was allowed to stand at room temperature.
Saturated aq. ammonium chloride (30 mL) was added to the resulting mixture, and the mixture was
extracted with EtOAc (3×50 mL). The combined organic layer was washed with brine (30 mL) and dried
over MgSO4. After evaporation of the solvent, the residue was purified by flash chromatography
(n-hexane : EtOAc = 95 : 5) to give compound 3b (2.15 g, 9.28 mmol, 62%) as a colorless oil. IR (NaCl
neat) cm-1: 1558 (C=N), 1096 (C-O), 814 (C-Cl). 1H-NMR (CDCl3) δ: 1.40 (12H, d, J = 6.1 Hz, H1’, 3’),
5.35 (2H, qu, J = 6.1 Hz, H 2’). 13C-NMR (CDCl3) δ: 21.59 (C1’, 3’), 71.94 (C2’), 171.60 (C4, 6), 172.58
(C2). Positive ion FAB-MS m/z: 232 (M+H)+. HR-FAB-MS m/z: 232.0856 (Calcd for C9H15ClN3O2:
232.0853). [30894-76-9]
2-Chloro-4,6-diisobutoxy-1,3,5-triazine (3d): Pale yellow oil. 1H-NMR (CDCl3) δ: 1.01 (12H, d, J = 6.9
13
Hz, C3’, 4’), 2.12 (2H, qu, J = 6.9 Hz, C2’), 4.16 (4H, d, J = 6.9 Hz, C1’). C-NMR (CDCl3) δ: 19.12
(C3’, 4’), 27.73 (C2’), 74.42 (C1’), 172.48 (C2), 173.17 (C4, 6). Positive-ion FAB-MS m/z: 260 (M+H)+.
HR-FAB-MS m/z: 260.1159 (Calcd for C11H19ClN3O2: 260.1166).
2-Chloro-4,6-bis(cyclopentyloxy)-1,3,5-triazine (3f): Pale yellow transparent needles. Mp 46-49 oC. IR
(KBr) cm-1: 1550 (C=N), 1296, 1110 (C-O), 807 (C-Cl). 1H-NMR (CDCl3) δ: 1.60-1.69 (4H, m, H3’, 4’),
1.78-1.92 (8H, m, H2’, 3’, 4’, 5’), 1.93-2.02 (4H, m, H2’, 5’), 5.49 (2H, heptet, J = 3.1 Hz, H1’).
13C-NMR (CDCl3) δ: 23.68 (C3’, 4’), 32.64 (C2’, 5’), 82.17 (C1’), 171.67 (C4, 6), 172.39 (C2).
Positive-ion FAB-MS m/z: 284 (M+H)+. HR-FAB-MS m/z: 284.1147 (Calcd for C13H19ClN3O2:
284.1166). Anal. Calcd for C13H18ClN3O2: C, 55.03; H, 6.39; N, 14.81. Found: C, 55.04; H, 6.42; N,
14.89. [852671-76-2]
General Procedure for CS-Symmetrical Trialkoxy-substituted TAZ derivatives (5) (Table S4):
Example
1
(using NaH): Synthesis of 2,4-Bis(1-methylethoxy)-6-(tricyclo[3.3.1.13,7]dec-
2-yloxy)-1,3,5-triazine (5hb):

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(Step 1): To a solution of 2-propanol (bH, 451 mg, 7.50 mmol) in THF (10 mL) was added NaH (55% in
mineral oil, 275 mg, 6.30 mmol) at room temperature under an Ar atmosphere. A suspension of sodium
2-propyloxide was prepared by stirring at room temperature for 10 min and then refluxing for 30 min.
(Step 2): After cooling to room temperature, a solution of compound 2h (901 mg, 3.00 mmol) in THF (10
mL) was added and stirred for 15 min at room temperature under a N2 atmosphere. Then the reaction
mixture was refluxed for 2 h. After cooling to room temperature, saturated aq. ammonium chloride (10
mL) was added to the resulting mixture, and the mixture was extracted with EtOAc (3×20 mL). The
combined organic layer was washed with brine (10 mL) and dried over MgSO4. After evaporation of the
solvent, the residue was purified by flash chromatography (CH2Cl2 : n-hexane = 20 : 80 → 30 : 70) to
o
give 5hb (589 mg, 1.70 mmol, 57%) as a colorless solid. Mp 119-121 C. IR (KBr) cm-1: 1570 (C=N),
1
1141, 1096 (C-O). H-NMR (CDCl3) δ: 1.38 (12H, d, J = 6.2 Hz, H1’’, 3’’), 1.56 (2H, d, J = 13.1 Hz,
H4’, 9’), 1.75 (2H, br s, H6’), 1.82 (2H, br d, J = 12.4 Hz, H8’, 10), 1.87 (2H, br s, H5’, 7’), 1.88 (2H, br
d, J = 12.4 Hz, H8’, 10’), 2.18 (2H, br s, H1’, 3’), 2.19 (2H, br d, J = 13.1 Hz, H4’, 9’), 5.21 (1H, br s,
H2’), 5.33 (2H, qu, J = 6.2 Hz, H2”). 13C-NMR (CDCl3) δ: 21.78 (C1’’, 3’’), 27.02 (C5’ or 7’), 27.17 (C7’
or 5’), 31.56 (C4’, 9’), 31.68 (C1’, 3’), 36.28 (C8’, 10’), 37.40 (C6’), 71.24 (C2’’), 80.25 (C2’), 172.61
(C4, 6), 172.67 (C2). Positive-ion FAB-MS m/z: 348 (M+H)+. HR-FAB-MS m/z: 348.2291 (Calcd for
C19H30N3O3: 348.2287). Anal. Calcd for C19H29N3O3: C, 65.68; H, 8.41; N, 12.09. Found: C, 65.13; H,
8.58; N, 12.28.
o
2,4-Di(1-methylethoxy)-6-methoxy-1,3,5-triazine (5ab): Colorless solid. Mp 70-71 C. IR (KBr) cm-1:
1
1568 (C=N), 1148, 1096 (C-O). H-NMR (CDCl3) δ: 1.39 (12H, d, J = 6.1 Hz, H1’, 3’), 4.00 (3H, s,
OCH3), 5.36 (2H, qu, J = 6.1 Hz, H2’). 13C-NMR (CDCl3) δ: 21.81 (C1’, 3’), 55.16 (OCH3”), 71.65 (C2’),
172.71 (C2, 4), 173.64 (C6). Positive-ion FAB-MS m/z: 228 (M+H)+. HR-FAB-MS m/z: 228.1346 (Calcd
for C10H18N3O3: 228.1348). Anal. Calcd for C10H17N3O3: C, 52.85; H, 7.54; N, 18.49. Found: C, 52.85; H,
7.67; N, 18.31.
2-(1-Methylethoxy)-4,6-bis(tricyclo[3.3.1.13,7]dec-2-yloxy)-1,3,5-triazine (5bh): Colorless crystals. Mp
233-238 oC (from i-Pr2O-CHCl3). IR (KBr) cm-1: 1568 (C=N), 1139 (C-O). 1H-NMR (CDCl3) δ: 1.37 (6H,
d, J = 6.4 Hz, H1”, 3”), 1.56 (4H, d m, J = 12.5 Hz, H4’, 9’), 1.76 (4H, br s, H6’), 1.81 (4H, br d, J = 12.2
Hz, H8’, 10’), 1.85-1.93 (12H, m, H5’, 7’, 8’, 10’), 2.18 (4H, br s, H1’, 3’), 2.20 (4H, br d, J = 12.5 Hz,
13
H4’, 9’), 5.18 (2H, br s, H2’), 5.30 (1H, qu, J = 6.4 Hz, H2”). C-NMR (CDCl3) δ: 21.80 (C1”, 3”),
27.14 (C5’or 7’), 27.25 (C7’or 5’), 31.60 (C4’, 9’), 31.79 (C1’, 3’), 36.42 (C8’, 10’), 37.48 (C6’), 71.23
(C2”), 80.41 (C2’), 172.75 (C2), 172.77 (C4, 6). Positive-ion FAB-MS m/z: 440 (M+H)+. HR-FAB-MS
m/z: 440.2902 (Calcd for C26H38N3O3: 440.2913). Anal. Calcd for C26H37N3O3•0.3H2O: C, 70.18; H,
8.52; N, 9.44. Found: C, 70.21; H, 8.58; N, 9.20.
4,6-Bis(1-heptyloxy)-2-[4-(trifluoromethyl)phenoxy]-1,3,5-triazine (5jg): Colorless oil. IR (KBr) cm-1:

HETEROCYCLES, Vol. 94, No. 9, 2017
1667
1
1578 (C=N), 1324 (C-F), 1129, 1065 (C-O). H-NMR (CDCl3) δ: 0.88 (6H, t, J = 7.0 Hz, H7’’),
1.24-1.35 (12H, m, H4’’, 5’’, 6’’), 1.35-1.44 (4H, m, H3’’), 1.76 (4H, q, J = 7.1 Hz, H2’’), 4.35 (4H, t, J
= 6.7 Hz, H1’’), 7.31 (2H, d, J = 8.4 Hz, H2’, 6’), 7.67 (2H, d, J = 8.4 Hz, H3’, 5’). 13C-NMR (CDCl3) δ:
13.98 (C7’’), 22.52 (C6’’), 25.69 (C3’’), 28.54 (C2”), 28.87 (C4’’), 31.67 (C5’’), 68.96 (C1’’), 122.13
(C2’, 6’), 123.88 (q, J = 272.1 Hz, CF3), 126.85 (q, J = 4.1 Hz, C3’, 5’), 128.16 (q, J = 32.8 Hz, C4’),
154.30 (C1’), 172.70 (C2), 173.49 (C4, 6). Positive-ion FAB-MS m/z: 470 (M+H)+. HR-FAB-MS m/z:
470.2632 (Calcd for C24H35F3N3O3: 470.2631). Anal. Calcd for C24H34F3N3O3: C, 61.39; H, 7.30; N, 8.95.
Found: C, 61.17; H, 7.45; N, 8.84.
General Procedure for CS-Symmetrical Trialkoxy-substituted TAZ derivatives (5) (Table S4):
Example 2 (using collidine by MW): Synthesis of 2-Isopropoxy-4,6-bis[4-(trifluoromethyl)-
phenoxy]-1,3,5-triazine (5bj): To a solution of compound 2b (624 mg, 2.00 mmol) in dioxane (5 mL),
4-(trifuluoromethyl)phenol (jH, 972 mg, 6.00 mmol) and collidine (727 mg, 6.00 mmol) were added at
o
room temperature. Then the mixture was subjected to MW at 160 C (300 W) for 40 min with stirring.
After removal of white solids (collidine•HCl salt) by filtration, the solvent was evaporated. The residue
was purified by flash chromatography (n-hexane㸸EtOAc = 95㸸5 → 90㸸10) to obtain compound 5bj (461
mg, 1.00 mmol, 50%) and 3bj (140 mg, 0.420 mmol, 21%), both as colorless solids. Mp 125-126 oC. IR
1
(KBr) cm-1: 1577 (C=N of either), 1324 (CF3), 1126, 1065 (C-O). H-NMR (CDCl3) δ: 1.33 (6H, d, J =
6.1 Hz, H1’, 3’), 5.19 (1H, qu, J = 6.1 Hz, H2’), 7.28 (4H, d, J = 8.4 Hz, H2’’, 6’’), 7.65 (4H, d, J = 8.4
Hz, H3’’, 5’’). 13C-NMR (CDCl3) δ: 21.45 (C1’, 3’), 73.26 (C2’), 122.04 (C2’’, 6’’), 123.75 (q, J = 272.1
Hz, CF3), 126.48 (q, J = 4.1 Hz, C3’’, 5’’), 128.41 (q, J = 33.1 Hz, C4’’), 158.01 (C1’’), 173.03 (C4, 6),
173.17 (C2). Positive-ion FAB-MS m/z: 460 (M+H)+. HR-FAB-MS m/z: 460.1115 (Calcd for
C20H16F6N3O3: 460.1096). Anal. Calcd for C20H15F6N3O3: C, 52.30; H, 3.29; N, 9.15. Found: C, 52.30; H,
3.26; N, 9.18.
2-Chloro-4-isopropoxy-6-[4-(trifluoromethyl)phenoxy]-1,3,5-triazine (3bj): Mp 109-110 oC. IR (KBr)
1
cm-1: 1565 (C=N), 1324 (CF3), 1117, 1065 (C-O), 807 (C-Cl). H-NMR (CDCl3) δ: 1.37 (6H, d, J = 6.4
Hz, H1’, 3’), 5.27 (1H, qu, J = 6.4 Hz, H2’), 7.31 (2H, d, J = 8.2 Hz, H2’’, 6’’), 7.71 (2H, d, J = 8.2 Hz,
H3’’, 5’’). 13C-NMR (CDCl3) δ: 21.47 (C1’, 3’), 74.06 (C2’), 121.95 (C2’’, 6’’), 123.77 (q, J = 272.1 Hz,
CF3), 127.10 (q, J = 4.1 Hz, C3’’, 5’’), 128.75 (q, J = 33.1 Hz, C4”), 153.81 (C1’’), 171.77 (C4 or C6),
171.87 (C6 or C4), 173.37 (C2). Positive-ion FAB-MS m/z: 334 (M+H+). HR-FAB-MS m/z: 334.0572
(Calcd for C13H12ClF3N3O2: 334.0570). Anal. Calcd for C13H11ClF3N3O2: C, 46.79; H, 3.32; N, 12.59.
Found: C, 46.79; H, 3.34; N, 12.59.
o
2,4-Diisopropoxy-6-[4-(trifluoromethyl)phenoxy]-1,3,5-triazine (5jb): White solid. Mp 98-99 C
1
(from i-PrOH). IR (KBr) cm-1: 1589 (C=N), 1325 (CF3), 1222, 1134, 1065 (C-O). H-NMR (CDCl3) δ:
1.36 (12H, d, J = 6.1 Hz, H1’, 3’), 5.28 (2H, qu, J = 6.1 Hz, H2’), 7.30 (2H, d, J = 8.4 Hz, H2’’, 6’’), 7.67

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(2H, d, J = 8.4 Hz, H3’, 5’). 13C-NMR (CDCl3) δ: 21.67 (C1’, 3’), 72.28 (C2’), 122.14 (C2’’, 6’’), 123.90
(q, J = 272.1 Hz, CF3), 126.85 (q, J = 4.1 Hz, C3’’, 5’’), 128.08 (q, J = 33.1 Hz, C4’’), 154.34 (C1’’),
172.78 (C6), 172.94 (C2, 4). Positive-ion FAB-MS m/z: 358 (M+H)+. HR-FAB-MS m/z: 358.1372 (Calcd
for C16H19F3N3O3: 358.1379). Anal. Calcd for C16H18F3N3O3: C, 53.78; H, 5.08; N, 11.76. Found: C,
53.78; H, 5.11; N, 11.48.
General Procedure for CS-Symmetrical Trialkoxy-substituted TAZ derivatives (5) (Table S4):
Example
3
(using
collidine
or
Et3N
by
reflux):
Synthesis
of
6-(1-Heptyloxy)-2,4-bis[3-(trifluoromethyl)phenoxy]-1,3,5-triazine (5gi): To a solution of compound
2g (646 mg, 2.45 mmol) in acetone (10 mL), 3-(trifuluoromethyl)phenol (iH, 851 mg, 5.25 mmol) and
collidine (636 mg, 5.25 mmol) were added at room temperature, and the reaction mixture was stirred for
30 min at room temperature and then refluxed for 1 h. After removal of white solids (collidine•HCl salt)
by filtration, the solvent was evaporated. The residue was purified by centrifugal chromatography
(CH2Cl2 : n-hexane = 30 : 70) to obtain compound 5gi (1.17 g, 2.27 mmol, 93%) as a sticky solid. Mp
45-48 oC. IR (KBr) cm-1: 1578 (C=N), 1322 (C-F), 1127, 1092 (C-O). 1H-NMR (CDCl3) δ: 0.88 (3H, t, J
= 7.0 Hz, H7’’), 1.20-1.33 (6H, m, H4’’, 5’’, 6’’), 1.33-1.40 (2H, m, H3’’), 1.72 (2H, qu, J = 7.0 Hz,
H2’’), 4.32 (2H, t, J = 6.7 Hz, H1’’), 7.32-7.35 (2H, m, H6’), 7.42 (2H, br s, H2’), 7.47-7.52 (4H, m,
H4’,5’). 13C-NMR (CDCl3) δ: 13.98 (C7’’), 22.51 (C6’’), 25.61 (C3’’), 28.42 (C2’’), 28.81 (C4’’), 31.65
(C5’’), 69.47 (C1’’), 118.92 (q, J = 4.1 Hz, C2’), 122.91 (q, J = 4.1 Hz, C4’), 123.43 (q, J = 272.1 Hz,
CF3), 132.07 (q, J = 33.1 Hz, C3’), 151.66 (C1’), 173.12 (C2, 4), 173.84 (C6). Positive-ion FAB-MS m/z:
516 (M+H)+. HR-FAB-MS m/z: 516.1729 (Calcd for C24H24F6N3O3: 516.1722). Anal. Calcd for
C24H23F6N3O3: C, 55.92; H, 4.50; N, 8.15. Found: C, 56.15; H, 4.72; N, 8.30.
2-(1,3-Benzodioxol-5-yloxy)-4-chloro-6-methoxy-1,3,5-triazine (3ak): White solid. Mp 140-141 oC. IR
(KBr) cm-1: 1577 (C=N), 1292, 1177, 1011 (C-O), 812 (C-Cl). 1H-NMR (CDCl3) δ: 4.03 (3H, s, OCH3),
6.01 (2H, s, H2’), 6.62 (1H, dd, J = 8.2, 2.4 Hz, H6’), 6.67 (1H, d, J = 2.4 Hz, H4’), 6.80 (1H, d, J = 8.2
13
Hz, H7’). C-NMR (CDCl3) δ: 56.17 (OCH3), 101.91 (C2’), 103.40 (C6’), 108.09 (C7’), 113.72 (C4’),
145.73 (C5’ or 7a’), 145.87 (C7a’ or 5’), 148.23 (C3a’), 172.52, 172.81, 173.28 (C2, 4, 6). Positive-ion
FAB-MS m/z: 282 (M+H)+. HR-FAB-MS m/z: 282.0280 (Calcd for C11H9ClN3O4: 282.0282). Anal.
Calcd for C11H8ClN3O4•0.1H2O: C, 46.61; H, 2.92; N, 14.82. Found: C, 46.76; H, 2.98; N, 14.55.
[1485339-02-3]
6-(2-Propoxy)-2,4-bis[3-(trifluoromethyl)phenoxy]-1,3,5-triazine (5bi): White powder. Mp 132-134
oC (from EtOH). IR (KBr) cm-1: 1577 (C=N), 1211, 1174, 1132 (C-O). 1H-NMR (CDCl3) δ: 1.33 (6H, d,
J = 6.1 Hz, H1”, 3”), 5.16 (1H, qu, J = 6.1 Hz, H2’’), 7.32-7.36 (2H, m, H6’), 7.42 (2H, br s, H2’),
13
7.48-7.51 (4H, m, H4’, 5’). C-NMR (CDCl3) δ: 21.49 (C1”, 3”), 73.25 (C2”), 118.96 (q, J = 4.1 Hz,
C2’), 122.88 (q, J = 4.1 Hz, C4’), 123.45 (q, J = 272.1 Hz, CF3), 124.53 (C6’), 130.09 (C5’), 132.05 (q, J

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1669
= 33.1 Hz, C3’), 151.71 (C1’), 173.17 (C2, 4), 173.22 (C6). Positive-ion FAB-MS m/z: 460 (M+H)+.
HR-FAB-MS m/z: 460.1098 (Calcd for C20H16F6N3O3: 460.1096). Anal. Calcd for C20H15F6N3O3: C,
52.30; H, 3.29; N, 9.15. Found: C, 52.13; H, 3.35; N, 9.16.
2,4-Bis(1,3-benzodioxol-5-yloxy)-6-(1-methylethoxy)-1,3,5-triazine (5bk): White solid. Mp 167-170
oC (from CHCl3). IR (KBr) cm-1: 1570 (C=N), 1174, 1137, 1041 (C-O). 1H-NMR (CDCl3) δ: 1.33 (6H, d,
J = 6.1 Hz, H1”, 3”), 5.20 (1H, qu, J = 6.1 Hz, H2”), 5.98 (4H, s, H2’), 6.60 (2H, dd, J = 8.2, 2.1 Hz,
H6’), 6.66 (2H, d, J = 2.1 Hz, H4’), 6.76 (2H, d, J = 8.2 Hz, H7’). 13C-NMR (CDCl3) δ: 21.59 (C1”, 3”),
72.71 (C2”), 101.75 (C2’), 103.77 (C4’), 107.94 (C7’), 113.93 (C6’), 145.50 (C7a’), 146.15 (C5’), 148.03
(C3a’), 173.16 (C6), 173.79 (C2, 4). Positive-ion FAB-MS m/z: 412 (M+H)+. HR-FAB-MS m/z:
412.1162 (Calcd for C20H18N3O7: 412.1145). Anal. Calcd for C20H17N3O7•0.2H2O: C, 57.89; H, 4.23; N,
10.13. Found: C, 57.81; H, 4.03; N, 10.12.
2-(1,3-Benzodioxol-5-yloxy)-4-chloro-6-(1-methylethoxy)-1,3,5-triazine (3bk): White solid. Mp
o
1
104-106 C. IR (KBr) cm-1: 1561 (C=N), 1177, 1093 (C-O of ether), 809 (C-Cl). H-NMR (CDCl3) δ:
1.37 (6H, d, J = 6.1 Hz, H1”, 3”), 5.27 (1H, qu, J = 6.1 Hz, H2”), 6.01 (2H, s, H2’), 6.61 (1H, dd, J = 8.5,
2.4 Hz, H6’), 6.67 (1H, d, J = 2.4 Hz, H4’), 6.79 (1H, d, J = 8.5, H7’). 13C-NMR (CDCl3) δ: 21.49 (C1”,
3”), 73.71 (C2”), 101.88 (C2’), 103.46 (C4’), 108.07 (C7’), 113.77 (C6’), 145.80 (C5’ or C7a’), 145.82
(C7a’ or C5’), 148.21 (C3a’), 171.84 (C6), 172.51 (C2), 173.17 (C4). Positive-ion FAB-MS m/z: 309
(M)+. HR-FAB-MS m/z: 309.0498 (Calcd for C13H12ClN3O4: 309.0516). Anal. Calcd for C13H12ClN3O4:
C, 50.42; H, 3.91; N, 13.57. Found: C, 50.18; H, 3.87; N, 13.60. [1478568-21-6]
6-(Cyclopentyloxy)-2,4-bis[3-(trifluoromethyl)phenoxy]-1,3,5-triazine (5fi): Pale yellow solid. Mp
o
1
65-70 C. IR (KBr) cm-1: 1577, 1557 (C=N), 1169, 1122 (C-O). H-NMR (CDCl3) δ: 1.55-1.67 (2H, m,
H3”, 4”), 1.74-1.83 (6H, m, H3”, 4”, 2”, 5”), 5.26-5.35 (1H, m, H1”), 7.30-7.36 (2H, m, H6’), 7.42 (2H,
13
br s, H2’), 7.46-7.53 (4H, m, H4’, 5’). C-NMR (CDCl3) δ: 23.62 (C3’’, 4”), 32.48 (C2’’, 5”), 82.39
(C1’’), 118.93 (q, J = 4.1 Hz, C2’), 122.80 (q, J = 4.1 Hz, C4’), 123.42 (q, J = 272.1 Hz, CF3), 125.05
(C6’), 130.03 (C5’), 131.96 (q, J = 33.1 Hz, C3’), 151.68 (C1’), 173.02 (C2, 4), 173.39 (C6). Positive-ion
FAB-MS m/z: 486 (M+H+). HR-FAB-MS m/z: 486.1250 (Calcd for C22H18F6N3O3: 486.1252). Anal.
Calcd for C22H17F6N3O3: C, 54.44; H, 3.53; N, 8.66. Found: C, 53.49; H, 3.64; N, 9.36.
6-(Cyclopentyloxy)-2,4-bis[4-(trifluoromethyl)phenoxy]-1,3,5-triazine
(5fj)
and
6-Chloro-4-(cyclopentyloxy)-2-[4-(trifluoromethyl)phenoxy]-1,3,5-triazine (3fj) (1 : 2) complex: This
complex consisting of two triazine derivatives, 5fj•(3fj)2, was isolated as a colorless solid. Mp 98-101 oC.
Anal. Calcd for C52H43Cl2F12N9O7: C, 51.84; H, 3.60; N, 10.46. Found: C, 51.99; H, 3.58; N, 10.36. This
complex showed no anti-HSV-1 or cytotoxic activity (EC50 > 100 μM and CC50 > 200 μM, respectively).
The obtained spectroscopic data of this complex are shown below.
5fj: 1H-NMR (CDCl3) δ: 1.54-1.67 (2H, m, H3”, 4”), 1.73-1.95 (6H, m, H3”, 4”, 2”, 5”), 5.27-5.32 (1H,

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m, H1”), 7.26 (4H, d, J = 8.5 Hz, H2’, 6’), 7.65 (4H, d, J = 8.5 Hz, H3’, 5’). 13C-NMR (CDCl3) δ: 23.70
(C3’’, 4”), 32.56 (C2’’, 5”), 82.48 (C1’’), 122.08 (C2’, 6’), 123.77 (q, J = 272.1 Hz, CF3), 126.86 (q, J =
4.1 Hz, C3’, 5’), 128.45 (q, J = 33.1 Hz, C4’), 154.05 (C1’), 172.94 (C2, 4), 173.41 (C6). Positive-ion
FAB-MS m/z: 486 (M+H)+. HR-FAB-MS m/z: 486.1245 (Calcd for C22H18F6N3O3: 486.1252).
3fj: 1H-NMR (CDCl3) δ: 1.54-1.67 (2H, m, H3”, 4”), 1.73-1.95 (6H, m, H3”, 4”, 2”, 5”), 5.37-5.42 (1H,
m, H1’’), 7.31 (2H, d, J = 8.5 Hz, H2’, 6’), 7.71 (2H, d, J = 8.5 Hz, H3’, 5’). 13C-NMR (CDCl3) δ: 23.64
(C3’’, 4”), 32.56 (C2’’, 5”), 83.19 (C1’’), 121.96 (C2’, 6’), 123.77 (q, J = 272.1 Hz, CF3), 127.06 (q, J =
4.1 Hz, C3’, 5’), 128.71 (q, J = 33.1 Hz, C4’), 153.84 (C1’), 171.63 (C2 or C6), 172.03 (C4), 173.25 (C6
or C2). Positive-ion FAB-MS m/z: 360 (M+H)+. HR-FAB-MS m/z: 360.0721 (Calcd for C15H14ClF3N3O2:
360.0727).
o
2,4-Bis(1,3-benzodioxol-5-yloxy)-6-cyclopentyloxy-1,3,5-triazine (5fk): White solid. Mp 194-195 C
1
(from CH2Cl2). IR (KBr) cm-1: 1568 (C=N), 1174, 1135 (C-O). H-NMR (CDCl3) δ: 1.54-1.62 (2H, m,
H3”, 4”), 1.73-1.85 (4H, m, H2”, 3”, 4”, 5”), 1.85-1.92 (2H, m, H2”, H5”), 5.31 (1H, qu, J = 3.1 Hz, H1”),
5.98 (4H, s, H2’), 6.60 (2H, dd, J = 8.5, 2.4 Hz, H6’), 6.66 (2H, d, J = 2.4 Hz, H4’), 6.76 (2H, d, J = 8.5
Hz, H7’). 13C-NMR (CDCl3) δ: 23.77 (C3”, 4”), 32.57 (C2”, 5”), 81.92 (C1”), 101.73 (C2’), 103.77 (C4’),
107.90 (C7’), 113.93 (C6’), 145.45 (C5’ or C7a’), 146.15 (C7a’ or C5’), 147.99 (C3a’), 173.36 (C6),
173.64 (C2, 4). Positive-ion FAB-MS m/z: 438 (M+H)+. HR-FAB-MS m/z: 438.1299 (Calcd for
C22H20N3O7: 438.1301). Anal. Calcd for C22H19N3O7: C, 60.41; H, 4.38; N, 9.61. Found: C, 60.20; H,
4.36; N, 9.72.
o
6-(1-Heptyloxy)-2,4-bis[4-(trifluoromethyl)phenoxy]-1,3,5-triazine (5gj): White solid. Mp 66-67 C
1
(from EtOH). IR (KBr) cm-1: 1579 (C=N), 1330 (C-F), 1224, 1123, 1066 (C-O). H-NMR (CDCl3) δ:
0.88 (3H, t, J = 7.0 Hz, H7’’), 1.24-1.32 (6H, m, H4’’, 5’’, 6’’), 1.32-1.37 (2H, m, H3’’), 1.69-1.75 (2H,
m, H2’’), 4.32 (2H, t, J = 6.7 Hz, H1’’), 7.27 (4H, d, J = 8.4 Hz, H2’, 6’), 7.65 (4H, d, J = 8.4 Hz, H3’,
13
5’). C-NMR (CDCl3) δ: 13.98 (C7’’), 22.51 (C6’’), 25.62 (C3’’), 28.42 (C2’’), 28.83 (C4’’), 31.64
(C5’’), 69.53 (C1’’), 122.07 (C2’, 6’), 123.77 (q, J = 272.1 Hz, CF3), 126.90 (q, J = 4.1 Hz, C3’, 5’),
128.53 (q, J = 33.1 Hz, C4’), 154.02 (C1’), 173.04 (C2, 4), 173.82 (C6). Positive-ion FAB-MS m/z: 516
(M+H)+. HR-FAB-MS m/z: 516.1721 (Calcd for C24H24F6N3O3: 516.1722). Anal. Calcd for
C24H23F6N3O3: C, 55.92; H, 4.50; N, 8.15. Found: C, 55.78; H, 4.57; N, 8.21.
2-Chloro-4-heptyloxy-6-[4-(trifluoromethyl)phenoxy]-1,3,5-triazine (3jg): Colorless crystals. Mp
63-66 oC (from n-hexane). IR (KBr) cm-1: 1585, 1527 (C=N), 1337 (C-F), 1129, 1067 (C-O), 808 (C-Cl).
1H-NMR (CDCl3) δ: 0.88 (3H, t, J = 7.0 Hz, H7’’), 1.25-1.35 (6H, m, H4’’, 5’’, 6’’), 1.35-1.45 (2H, m,
H3’’), 1.76 (2H, q, J = 7.0 Hz, H2’’), 4.38 (2H, t, J = 6.7 Hz, H1’’), 7.31 (2H, d, J = 8.9 Hz, H2’, 6’),
13
7.71 (2H, d, J = 8.9 Hz, H3’, 5’). C-NMR (CDCl3) δ: 13.98 (C7’’), 22.51 (C6’’), 25.60 (C3’’), 28.36
(C2”), 28.81 (C4’’), 31.63 (C5’’), 70.05 (C1’’), 121.94 (C2’, 6’), 123.74 (q, J = 273.1 Hz, CF3), 127.10 (q,

HETEROCYCLES, Vol. 94, No. 9, 2017
1671
J = 4.1 Hz, C3’, 5’), 128.78 (q, J = 33.1 Hz, C4’), 153.80 (C1’), 171.73 (C2 or C6), 172.47 (C4), 173.37
(C6 or C2). Positive-ion FAB-MS m/z: 390 (M+H)+. HR-FAB-MS m/z: 390.1194 (Calcd for
C17H20ClF3N3O2: 390.1196). Anal. Calcd for C17H19ClF3N3O2: C, 52.38; H, 4.91; N, 10.78. Found: C,
52.35; H, 4.82; N, 10.80.
o
2-(1,3-Benzodioxol-5-yloxy)-4,6-diisopropoxy-1,3,5-triazine (5kb): Colorless needles. Mp 128-129 C
(from EtOH). IR (ATR) cm-1: 1562 (C=N), 1175, 1098 (C-O). 1H-NMR (CDCl3) δ: 1.36 (12H, d, J = 6.2
Hz, H2’’, 3’’), 5.29 (2H, qu, J = 6.2 Hz, H1’’), 6.00 (2H, s, H2’), 6.62 (1H, dd, J = 8.2, 2.1 Hz, H6’), 6.68
13
(1H, d, J = 2.1 Hz, H4’), 6.78 (1H, d, J = 8.2 Hz, H7’). C-NMR (CDCl3) δ: 21.69 (C2’’, 3’’), 71.98
(C1’’), 101.68 (C2’), 103.81 (C4’), 107.92 (C7’), 113.97 (C6’), 145.33 (C7a’), 146.18 (C5’), 147.95
(C3a’), 172.83 (C4, 6), 173.45 (C2). Positive-ion FAB-MS m/z: 334 (M+H)+. HR-FAB-MS m/z:
334.1399 (Calcd for C16H20N3O5: 334.1403). Anal. Calcd for C16H19N3O5: C, 57.65; H, 5.75; N, 12.61.
Found: C, 57.49; H, 5.75; N, 12.58.
o
2-(1,3–Benzodioxol-5-yloxy)-4,6-dimethoxy-1,3,5-triazine (5ka):6 Colorless crystals. Mp 118-119 C
(from EtOH). IR (KBr) cm-1: 1570 (C=N), 1191, 1170, 1121, 1039 (C-O). 1H-NMR (CDCl3) δ: 4.01 (6H,
s, OCH3), 6.00 (2H, s, H2’), 6.62 (1H, dd, J = 8.2, 2.4 Hz, H6’), 6.68 (1H, d, J = 2.4 Hz, H4’), 6.79 (1H,
13
d, J = 8.2 Hz, H7’). C-NMR (CDCl3) δ: 55.47 (OCH3), 101.75 (C2’), 103.71 (C4’), 107.96 (C7’),
113.91 (C6’), 145.51 (C7a’), 146.05 (C5’), 148.03 (C3a’), 173.55 (C4, 6), 174.00 (C2). Positive-ion
FAB-MS m/z: 278 (M+H+). HR-FAB-MS m/z: 278.0771 (Calcd for C12H12N3O5: 278.0777). Anal. Calcd
for C12H11N3O5: C, 51.99; H, 4.00; N, 15.16. Found: C, 51.96; H, 3.98; N, 15.20.
General Procedure for CS-Symmetrical Alkoxy-Alkylamino-Trisubstituted TAZ derivatives (7, 8)
(Table
S5):
Example
1
(using
DIPEA
by
reflux):
Synthesis
of
6-Isopropoxy-N2,N4-diisopropyl-1,3,5-triazine-2,4-diamine (7bp): To a solution of intermediate 2b
(416 mg, 2.00 mmol) in THF (25 mL), 2-propylamine pH (473 mg, 8.00 mmol) and
diisopropylethylamine (DIPEA, 517 mg, 4.00 mmol) were added at room temperature and the reaction
mixture was refluxed for 17 h. After addition of water (20 mL), the mixture was extracted with EtOAc
(3×30 mL). The combined organic layer was washed with brine (10 mL) and dried over MgSO4. After
evaporation of the solvent, the residue was recrystallized by n-hexane to obtain pure compound 7bp (431
o
mg, 1.70 mmol, 85%) as colorless crystals. Mp 102.0-102.5 C (from n-hexane). IR (ATR) cm-1: 3243,
1
3099 (N-H), 1611, 1578, 1525 (C=N), 1314, 1195, 1099 (C-N and/or C-O). H-NMR (CDCl3) δ: 1.19
(12H, d, J = 5.5 Hz, H2’, 3’), 1.33 (6H, br s, H2”, 3”), 4.17 (2H, br s, H1’), 4.78, 4.87* (2H, br s, NH),
1
5.23 (1H, br s, H1”). (The observed H-signals assignable to the predominant tautomer are asterisked.)
13C-NMR (CDCl3) δ: 21.96 (C2”, 3”), 22.98 (C2’, 3’), 42.22 (C1’), 69.11 (C1”), 166.73 (C2, 4), 170.26
(C6). (Signals for only the predominant tautomer are shown.) Positive-ion FAB-MS m/z: 254 (M+H)+.
HR-FAB-MS m/z: 254.1973 (Calcd for C13H24N5O: 254.1981). Anal. Calcd for C12H23N5O: C, 56.89; H,

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HETEROCYCLES, Vol. 94, No. 9, 2017
9.15; N, 27.64. Found: C, 56.89; H, 9.33; N, 27.53. [30360-64-6]
o
N2,N4-Diisobutyl-6-isopropoxy-1,3,5-triazine-2,4-diamine (7bq): White solid. Mp 131.0-132.5 C
(from n-hexane). IR (ATR) cm-1: 3358, 3254, 3111 (NH), 1738, 1618, 1583, 1522 (C=N), 1281, 1178,
1
1105 (C-N and/or C-O). H-NMR (CDCl3) δ: 0.94 (12H, d, J = 6.9 Hz, H3’, 4’), 1.30, 1.33* (6H, br s,
H2”, 3”), 1.83 (1H, br s, H2’), 3.17, 3.23* (4H, br s, H1’), 5.04*, 5.15 (2H, br s, NH), 5.20 (1H, s, H1”).
1
13
(The observed H-signals assignable to the predominant tautomer are asterisked.) C-NMR (CDCl3) δ:
20.12 (C3’, 4’), 21.95 (C2”, 3”), 28.61 (C2’), 48.20 (C1’), 69.18 (C1”), 167.51 (C2, 4), 170.21 (C6).
(Signals for only the predominant tautomer are shown.) Positive-ion FAB-MS m/z: 282 (M+H)+.
HR-FAB-MS m/z: 282.2297 (Calcd for C14H28N5O: 282.2294). Anal. Calcd for C14H27N5O: C, 59.76; H,
9.67; N, 24.89. Found: C, 59.76; H, 9.85; N, 24.85.
1
4-Chloro-N-isobutyl-6-isopropoxy-1,3,5-triazin-2-amine (9bq): White solid. H-NMR (CDCl3) δ:
0.956*, 0.963 (6H, d, J = 6.9 Hz, H3’, 4’), [1.35 (2H), 1.38* (4H)] (d, J = 6.2 Hz, H2”, 3”), 1.88 (1H,
heptet, J = 6.9 Hz, H2’), 3.28* (0.67H, dd, J = 6.8, 6.2 Hz, H1’), 3.29 (0.33H, dd, J = 6.9, 6.2 Hz, H1’),
[5.25 (0.33H), 5.30* (0.67H)] (qu, J = 6.2 Hz, H1”), [5.55 (0.33H), 5.83* (0.67H)] (br s, NH). (The
1
13
observed H-signals assignable to the predominant tautomer are asterisked.) C-NMR (CDCl3) δ: 19.99
(C3’, 4’), 21.69 (C2”, 3”), 28.31 (C2’), 48.45 (C1’), 71.86 (C1”), 167.22 (C2), 170.34, 173.27 (C4, 6).
(Signals for only the predominant tautomer are shown.) Positive-ion FAB-MS m/z: 245 (M+H)+.
HR-FAB-MS m/z: 245.1160 (Calcd for C10H18N4O: 245.1169).
4-Chloro-6-(cyclohexyloxy)-N-isobutyl-1,3,5-triazin-2-amine (9fq): Colorless crystals. Mp 101-102 oC
1
(from i-Pr2O). IR (KBr) cm-1: 1638, 1572 (C=N), 1295, 1230 (C-O), 806 (C-Cl). H-NMR (CDCl3) δ:
0.96 (6H, d, J = 6.7 Hz, H3’, 4’), 1.57-1.68 (2H, m, H3’’, 4’’), 1.77-2.00 (7H, m, H3’’, 4’’, 2’, 2”, 5”),
3.26-3.31 (2H, m, H1’), 5.36-5.44 (1H, m, H1”), 5.59 (0.35H, br s, NH), 5.81* (0.65H, br s, NH). (The
1
13
observed H-signals assignable to the predominant tautomer are asterisked.) C-NMR (CDCl3) δ: 20.00
(C3’), 23.81 (C3”, 4”), 28.35 (C2’), 32.70 (C2”, 5”), 48.52 (C1’), 81.18 (C1”), 167.21 (C2), 170.29,
170.57 (C4, 6). (Signals for only the predominant tautomer are shown.) Positive-ion FAB-MS m/z: 271
(M+H)+. HR-FAB-MS m/z: 271.1329 (Calcd for C12H20ClN4O: 271.1326). Anal. Calcd for
C12H19ClN4O•0.2H2O: C, 52.53; H, 7.13; N, 20.42. Found: C, 52.57; H, 7.08; N, 20.13.
o
6-(Cyclopentyloxy)-N2,N4-isobutyl-1,3,5-triazine-2,4-diamine (7fq): White solid. Mp 80-81 C. IR
(KBr) cm-1: 3374 (N-H), 1531 (C=N), 1179, 1164, 1122 (C-O). 1H-NMR (CDCl3) δ: 0.93 (12H, d, J = 6.2
Hz, H3’, 4’), 1.54-1.62 (2H, m, H3”, 4”), 1.76-1.97 (8H, m, H2’, 2”, 3”, 4”, 5”), 3.16, 3.23* (4H, br s,
H1’), 5.14*, 5.19 (2H, br s, NH), 5.30, 5.35* (1H, br s, H1”). 13C-NMR (CDCl3) δ: 20.11 (C3’, 4’), 23.67,
23.88* (C3”, 4”), 28.46, 28.58* (C2’), 32.80 (C2”, 5”), 48.14, 48.26* (C1’), 78.27*, 78.71 (C1”), 167.03,
1
167.37*, 167.60 (C2, 4), 169.93, 170.27*, 170.83 (C6). (The observed H- and 13C-siganals assignable to
the predominant tautomer are asterisked.) Positive-ion FAB-MS m/z: 308 (M+H)+. HR-FAB-MS m/z:

HETEROCYCLES, Vol. 94, No. 9, 2017
1673
308.2452 (Calcd for C16H30N5O: 308.2450). Anal. Calcd for C16H29N5O: C, 62.51; H, 9.51; N, 22.78.
Found: C, 62.33; H, 9.73; N, 22.61.
o
N-Isobutyl-4,6-diisopropoxy-1,3,5-triazin-2-amine (8qb): Colorless needles. Mp 113-114 C (from
n-hexane). IR (KBr) cm-1: 3260 (N-H), 1575 (C=N), 1124, 1099 (C-O). 1H-NMR (CDCl3) δ: 0.95 (6H, dd,
J = 6.9, 2.1 Hz, H3’, 4’), 1.34A, 1.37B (12H, d, J = 4.2 Hz, H2”, 3”), 1.81-1.90 (1H, m, H2’), 3.24-3.29
13
(2H, m, H1’), 5.23-ca.5.29A, ca.5.29-5.34B (2H, m, H1”), 5.49 (1H, br s, NH). C-NMR (CDCl3) δ:
20.05 (C3’, 4’), 21.87AorB, 21.93BorA (C2”, 3”), 28.47 (C2’), 48.26 (C1’), 70.01A, 70.41B (C1”), 168.40
1
13
(C2), 171.04A, 171.64B (C4, 6). [Signals that appeared in H- and C-NMR spectra are approximately
consistent with the tautomeric mixture of two isomers (T3 and T4)20 with the ratio of 1 : 1. The signals
assignable to each tautomer are marked with a superscript A or B.] Positive-ion FAB-MS m/z: 269
(M+H)+. HR-FAB-MS m/z: 269.1978 (Calcd for C13H25N4O2: 269.1978). Anal. Calcd for C13H24N4O2: C,
58.18; H, 9.01; N, 20.88. Found: C, 58.29; H, 8.95; N, 20.88.
o
4,6-Diisobutoxy-N-isopropyl-1,3,5-triazin-2-amine (8pd): Colorless crystals. Mp 63-64 C. IR (KBr)
1
cm-1: 3444 (N-H), 1598, 1581 (C=N), 1169, 1095 (C-O). H-NMR (CDCl3) δ: 1.00 (12H, t, J = 6.2 Hz,
H3”, 4”), 1.22 (6H, d, J = 6.2 Hz, H2’, 3’), 2.02-2.16 (1H, m, H2”), 4.05A (1H, d, J = 6.2 Hz, H1”), 4.11B
(1H, d, J = 6.9 Hz, H1”), 4.20-4.24 (1H, m, H1’), 5.08, 5.09 (1H, br s, NH). 13C-NMR (CDCl3) δ: 19.16A,
19.26B (C3”, 4”), 22.80 (C2’, 3’), 27.79 (C2”), 42.67 (C1’), 73.45A, 73.71B (C1”), 167.31 (C2), 172.03A,
1
13
172.33B (C4, 6). [Signals that appeared in H- and C-NMR spectra are approximately consistent with
the tautomeric mixture of two isomers (T3 and T4)20 with the ratio of 1 : 1. The signals assignable to each
tautomer are marked with a superscript A or B.] Positive-ion FAB-MS m/z: 283 (M+H)+. HR-FAB-MS
m/z: 283.2132 (Calcd for C14H27N4O2: 283.2134). Anal. Calcd for C14H26N4O2: C, 59.55; H, 9.28; N,
19.84. Found: C, 59.43; H, 9.51; N, 19.63.
General Procedure for CS-Symmetrical Alkoxy-Alkylamino-Trisubstituted TAZ derivatives (7, 8)
(Table
S5):
Example
2
(No
Base
by
MW):
Synthesis
of
4,6-Diisobutoxy-N-isobutyl-1,3,5-triazin-2-amine (8qd): To a solution of compound 3d (327 mg, 1.26
mmol) in dioxane (5 mL) was added a solution of isobutylamine (qH, 263 mg, 3.60 mmol) at ca. 10 oC.
o
Then the mixture was subjected to MW at 100 C (100 W) for 30 min with stirring. After addition of
water (20 mL), the mixture was extracted with EtOAc (2×25 mL). The combined organic layer was dried
over MgSO4. After evaporation of the solvent, the residue was purified by centrifugal chromatography
(n-hexane : EtOAc = 85 : 15) to obtain compound 8qd (318 mg, 1.07 mmol, 85%) as a white solid. Mp
93.5-94.0 oC. IR (ATR) cm-1: 3266, 3146 (NH), 1631, 1574, 1550 (C=N), 1351, 1332, 1112 (C-N and/or
1
C-O). H-NMR (CDCl3) δ: 0.95 (12H, d, J = 6.2 Hz, H3’, 4’), 0.996AorB (6H, d, J = 6.9 Hz, H3”, 4”),
1.002BorA (6H, d, J = 6.9 Hz, H3”, 4”), 1.86 (1H, heptet, J = 6.9 Hz, H2’), 2.06A (1H, heptet, J = 6.9 Hz,
H2”), 2.11B (1H, heptet, J = 6.9 Hz, H2”), 3.27 (2H, t, J = 6.9 Hz, H1’), 4.07A (2H, d, J = 6.9 Hz, H1”),

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HETEROCYCLES, Vol. 94, No. 9, 2017
13
4.11B (2H, d, J = 6.9 Hz, H1”), 5.40 (1H, br s, NH). C-NMR (CDCl3) δ: 19.15, 19.24 (C3”, 4”), 20.06
(C3’, 4’), 27.79, 27.81 (C2”), 28.49 (C2’), 48.34 (C1’), 73.47A, 73.71B (C1”), 168.34 (C2), 171.73A,
1
13
172.29B (C4, 6). [Signals that appeared in H- and C-NMR spectra are approximately consistent with
the tautomeric mixture of two isomers (T3 and T4)20 with the ratio of 1 : 1. The signals assignable to each
tautomer are marked with a superscript A or B.] Positive-ion FAB-MS m/z: 297 (M+H)+. HR-FAB-MS
m/z: 297.2292 (Calcd for C15H29N4O2: 297.2291). Anal. Calcd for C15H28N4O2: C, 60.78; H, 9.52; N,
18.90. Found: C, 60.85; H, 9.48; N, 18.76.
o
6-Isobutoxy-N2,N4-diisopropyl-1,3,5-triazine-2,4-diamine (7dp): White solid. Mp 85-86 C. IR (KBr)
1
cm-1: 3250 (N-H), 1532 (C=N), 1193 (C-N), 1100 (C-O). H-NMR (CDCl3) δ: 0.98 (6H, d, J = 6.9 Hz,
H3”, 4”), 1.20 (12H, br d, J = 4.8 Hz, H2’, 3’), 2.06 (1H, br s, H2”), 3.97, 4.03* (2H, br s, H1”), 4.17 (2H,
1
br s, H1’), 4.79, 4.89* (2H, br s, NH). (The observed H-signals assignable to the predominant tautomer
13
are asterisked.) C-NMR (CDCl3) δ: 19.25 (C3”, 4”), 22.92 (C2’, 3’), 27.85 (C2”), 42.28 (br s, C1’),
72.82 (br s, C1”), 166.51 (br s, C2, 4), 170.90 (br s, C6). Positive-ion FAB-MS m/z: 268 (M+H)+.
HR-FAB-MS m/z: 268.2141 (Calcd for C13H26N5O: 268.2137). Anal. Calcd for C13H25N5O: C, 58.16; H,
9.42; N, 26.19. Found: C, 58.27; H, 9.53; N, 26.21.
o
6-Isobutoxy-N2,N4-diisobutyl-1,3,5-triazine-2,4-diamine (7dq): Pale yellow solid. Mp 40-41 C. IR
1
(ATR) cm-1: 3264, 3131 (NH), 1575, 1513 (C=N), 1350, 1330, 1168, 1119 (C-N and/or C-O). H-NMR
(CDCl3) δ: 0.94 (12H, d, J = 6.9 Hz, H3’, 4’), 0.99 (6H, d, J = 6.9 Hz, H3”, 4”), 1.84 (2H, br s, H2’), 2.07
(1H, br s, H2”), 3.17, 3.23* (4H, br s, H1’), 3.97, 4.04* (2H, br s, H1”), 5.00 (0.8H, br s, NH), 5.15*
(1.2H, br s, NH). 13C-NMR (CDCl3) δ: 19.27 (C3”, 4”), 20.14 (C3’, 4’), 27.86 (C2”), 28.61 (C2’), 48.05*,
1
48.25 (C1’), 72.63*, 72.82 (C1”), 167.46 (C2, 4), 170.49 (C6). (The observed H- and 13C-signals
assignable to the predominant tautomer are asterisked.) Positive-ion FAB-MS m/z: 296 (M+H)+.
HR-FAB-MS m/z: 296.2457 (Calcd for C15H30N5O: 296.2450). Anal. Calcd for C15H29N5O•0.3H2O: C,
59.89; H, 9.92; N, 23.28. Found: C, 59.91; H, 10.08; N, 23.10.
4,6-Diisopropoxy-N-isopropyl-1,3,5-triazin-2-amine (8pb): White solid. Mp 96-98 oC (from
MeOH-H2O). IR (ATR) cm-1: 3258, 3154 (N-H), 1608, 1573, 1540 (C=N), 1314, 1119, 1092 (C-N and/or
C-O). 1H-NMR (CDCl3) δ: 1.21 (6H, d, J = 6.9 Hz, H2’, 3’), 1.34A (6H, d, J = 6.2 Hz, H2’, 3’), 1.37B (6H,
d, J = 6.2 Hz, H2’, 3’), 4.18-4.27 (1H, m, H1’), 5.10, 5.11 (1H, br s, NH), 5.25A (1H, qu, J = 6.2 Hz, H1”),
13
5.31B (1H, qu, J = 6.2 Hz, H1”). C-NMR (CDCl3) δ: 21.90 (C2”, 3”), 22.86 (C2’, 3’), 42.57 (C1’),
69.98A, 70.37B (C1”), 167.42 (C2), 171.07A, 171.69B (C4, 6). [Signals that appeared in 1H- and 13C-NMR
spectra are approximately consistent with the tautomeric mixture of two isomers (T3 and T4)20 with the
ratio of 1 : 1. The signals assignable to each tautomer are marked with a superscript A or B.] Positive-ion
FAB-MS m/z: 255 (M+H)+. HR-FAB-MS m/z: 255.1820 (Calcd for C12H23N4O2: 255.1821). Anal. Calcd
for C12H22N4O2: C, 56.67; H, 8.72; N, 22.03. Found: C, 56.76; H, 8.82; N, 21.82.

HETEROCYCLES, Vol. 94, No. 9, 2017
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Antiviral Activity and Cytotoxicity of Synthesized Trisubstituted TAZ derivatives
Antiviral Activity Assay: The antiviral activities of the compounds were measured by the plaque
reduction assay.18 Confluent monolayers of Vero cells (ca. 1×106 cells/well) in 6-well plastic plates were
infected with 100 PFU of HSV-1 (KOS). After a 1-h adsorption period at 37 °C, the cultures were
overlaid with 2 mL of Dulbecco’s modified Eagle’s minimum essential medium (DMEM) containing 2%
heat-inactivated fetal calf serum, 2% ɤ-globulin, and various concentrations of the target compounds. The
cultures inoculated with HSV-1 were incubated in a CO2 incubator, fixed with formalin, and stained with
crystal violet in methanol at 3 d postinoculation. After washes with water and drying, the plaques were
enumerated. Calculated EC50 values for the tested compounds are summarized in Tables 1 and 2 together
with data for aciclovir.19
Cytotoxicity Assay: The antiviral activities of the compounds were examined as described below. Vero
cells were seeded in 96-well plastic plates at 1×104 cells per well. After 1 day, the cells were re-fed with
100 μL of DMEM containing 5% fetal calf serum and various concentrations of the target compounds.
After 69 h incubation, 10 μL of AlamarBlue reagent was added to each culture and then the plates were
reincubated for 4 h. The optical density of each culture at 570 nm was determined by a spectrophotometer
using a reference wavelength of 630 nm.18 Calculated cytotoxicity (CC50) values for the tested
compounds are also summarized in Tables 1 and 2. Calculated log P values for the compounds are also
shown in Tables 1 and 2.
ACKNOWLEDGMENTS
The authors thank Dr. Tadashi Hayama for the ESI-MS analyses of compound 4c, and they would also
like to thank Mr. Shunsuke Shimomura, Mr. Kenta Morimoto, and Mr. Ryo Sato for their valuable
technical assistance.
REFERENCES AND NOTES
1. A. Varki, R. D. Cummings, J. D. Esko, H. H. Freeze, P. Stanley, C. R. Bertozzi, G. W. Hart, and M.
E. Etzler, ‘Essentials of Glycobiology’, 2nd ed., Cold Spring Harbor Laboratory Press, Cold Spring
Harbor N. Y., 2009, pp. 537-551 and related references cited therein.
2. F. Sansone and A. Casnati, Chem. Soc. Rev., 2013, 42, 4623.
3. S. Reitsma, D. W. Slaaf, H. Vink, M. A. M. J. van Zandvoort, and M. G. A. oude Egbrink, Pflugers
Arch. Eur. J. Physiol., 2007, 454, 345.
4. A. M. Duran and J. Meiler, Comput. Struct. Biotechnol. J., 2013, 8, e201308004.
5. N. Mibu, K. Yokomizo, A. Koga, M. Honda, K. Mizokami, H. Fujii, N. Ota, A. Yuzuriha, K.
Ishimaru, J. Zhou, T. Miyata, and K. Sumoto, Chem. Pharm. Bull., 2014, 62, 1032.

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HETEROCYCLES, Vol. 94, No. 9, 2017
6. N. Mibu, K. Yokomizo, S. Takemura, N. Ueki, S. Itohara, J. Zhou, T. Miyata, and K. Sumoto, Chem.
Pharm. Bull., 2013, 61, 823.
7. N. Mibu, H. Aki, H. Ikeda, A. Saito, W. Uchida, K. Yokomizo, J. Zhou, T. Miyata, and K. Sumoto,
J. Therm. Anal. Calorim., 2013, 113, 1015.
8. N. Mibu, K. Yokomizo, K. Murakami, Y. Ono, M. Ishimaru, M. Otsubo, H. Inao, Y. Ono, J.-R.
Zhou, and K. Sumoto, Chem. Pharm. Bull., 2016, 64, 1769.
9. M. Furutachi, A. Ejima, R. Tsuru, S. Goto, T. Gondo, K. Ako, S. Fujii, A. Okumura, A. Tozuka, K.
Yokomizo, J.-R. Zhou, H. Inao, Y. Ono, N. Kashige, F. Miake, and K. Sumoto, Heterocycles, 2016,
92, 925.
10. F. Fujisaki, M. Furutachi, R. Fujiwara, M. Okabe, H. Aki, N. Kashige, F. Miake, and K. Sumoto,
Heterocycles, 2015, 91, 1668.
11. N. Mibu, K. Yokomizo, H. Aki, N. Ota, H. Fujii, A. Yuzuriha, S. Saneyoshi, A. Tanaka, A. Koga, J.
Zhou, T. Miyata, and K. Sumoto, Chem. Pharm. Bull., 2015, 63, 935.
12. Many similar 2,4,6-trisubstituted TAZ derivatives have been prepared and tested herbicidal activity
and a few conclusion of structure-activity relation of the 1,3.5-triazine herbicides have been
presented. The mode of action of the triazine herbicides has been extensively reviewed. See,
‘Bioactive Heterocyclic Compound Classes, Agrochemicals’, ed. by C. Lamberth and J. Dinges,
WILEY-VCH, 2012, pp. 23-38.
13. K. Srinivas, U. Srinivas, V. J. Rao, K. Bhanuprakash, K. H. Kishorec, and U. S. N. Murty, Bioorg.
Med. Chem. Lett., 2005, 15, 1121.
14. K. Arya and A. Dandia, Bioorg. Med. Chem. Lett., 2007, 17, 3298.
15. D. Sun, G. Melman, N. J. LeTourneau, A. M. Hays, and A. Melman, Bioorg. Med. Chem. Lett., 2010,
20, 458.
16. W. W. Cuthbertson and J. S. Moffatt, J. Chem. Soc., 1948, 561.
17. R. Banerjee, D. R. Brown, and E. Weerapana, Synlett, 2013, 1599.
18. R. F. Schinazi, J. Peters, C. C. Williams, D. Chance, and A. J. Nahmias, Antimicrob. Agents
Chemother., 1982, 22, 499.
19. T. Ikeda, K. Yokomizo, M. Okawa, R. Tsuchihashi, J. Kinjo, T. Nohara, and M. Uyeda, Biol. Pharm.
Bull., 2005, 28, 1779.
20. Some of the tri-substituted TAZ derivatives described in this paper showed a complicated 13C-NMR
signal pattern because of their keto-enol tautomeric isomers in solutions. Compounds (7bp, 7bq,
7dp, 7dq, 7fq, 8pb, 8pd, 8qb, 8qd, 9bq, 9fq, 10p, 10q, 10r) that have sec-alkylamino groups on a
TAZ template are examples of TAZ derivatives with such a signal pattern. A few compounds
showed the presence of two tautomeric isomers in solution. Thus, signals that appeared in the

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13C-NMR spectrum of compound 10p are fully consistent with the tautomeric mixture of two
isomers shown below (T1 and T2). Signals that appeared in the 13C-NMR spectra of a few
compounds 8 are also consistent with the tautomeric mixture of two isomers shown below (T3 and
T4).
Tautomeric Isomerism of TAZ derivatives 10p and 8