Synthesis and biological evaluation of symmetrical 2,4,6-trisubstituted 1,3,5-triazine derivatives

Article abstract of DOI:10.1248/cpb.c13-00308

We describe the synthesis and biological evaluation of newly designed 2,4,6-trisubstituted symmetrical 1,3,5-triazine (TAZ) derivatives. Among the tested trisubstituted symmetrical TAZ derivatives, various C3- or CS-symmetrical alkoxy-amino-substituted TA

Full text of DOI:10.1248/cpb.c13-00308

August 2013
Regular Article
Chem. Pharm. Bull. 61(8) 823–833 (2013)
823
Synthesis and Biological Evaluation of Symmetrical 2,4,6-Trisubstituted
1,3,5-Triazine Derivatives
Nobuko Mibu,a Kazumi Yokomizo,b Satoshi Takemura,a Nami Ueki,a Saki Itohara,a
,a
Jianrong Zhou,b Takeshi Miyata,b and Kunihiro Sumoto*
a Faculty of Pharmaceutical Sciences, Fukuoka University; 8–19–1 Nanakuma, Jonan-ku, Fukuoka 814–0180,
b
Japan: and Faculty of Pharmaceutical Sciences, Sojo University; 4–22–1 Ikeda, Nishi-ku, Kumamoto 860–0082,
Japan.
Received April 22, 2013; accepted May 21, 2013
We describe the synthesis and biological evaluation of newly designed 2,4,6-trisubstituted symmetrical
1,3,5-triazine (TAZ) derivatives. Among the tested trisubstituted symmetrical TAZ derivatives, various C3-
or CS-symmetrical alkoxy-amino-substituted TAZ derivatives showed significant antiviral activity against
herpes simplex virus type 1 (HSV-1) and/or cytotoxic activity against Vero cells. The structure–activity
relationships for anti-HSV-1 activity of these symmetrical 2,4,6-trisubstituted TAZ derivatives are also
described. Experimental results indicated that a CS-symmetrical TAZ structure with introduction of two
alkoxy groups and one amine moiety seems to be the minimally required structure for anti-HSV-1 activity.
Key words 1,3,5-triazine; anti-herpes simplex virus type 1; cytotoxic activity; C3 symmetry; CS symmetry;
plaque reduction assay
Molecular recognition of two-fold (C2) or three-fold (C3) derivatives in the target molecules together with the results
symmetrical geometry macromolecules is one of the common of anti-herpes simplex virus type 1 (HSV-1) activity and cy-
features in many important biological responses,1,2) and we totoxic activity against Vero cell of the obtained symmetrical
have therefore already designed a few symmetrical target mol- 2,4,6-trisubstituted TAZ derivatives.
ecules for the purpose of finding biologically active new leads
or candidates.3–5) With reference to the molecular symmetry,
Results and Discussion
small molecules having C3-, CS-, or C2-symmetrical geometry
Synthesis To begin with, we carried out a few synthetic
frequently appear in various biologically active compounds.6–8) trials for the preparation of target symmetrical triacylamino-
Such small symmetrical molecules are usually constructed on substituted TAZ (2) derivatives by using 2,4,6-triamino-
a corresponding symmetrical template.
1,3,5-triazine (TATAZ) as a starting material. However, our
From this point of view, we have recently reported some attempts to separate the target products (2x or 2y) after acyla-
molecular modifications of tris(2-aminoethyl)amine (TAEA) tion reactions of TATAZ with acylating agents failed17) (Fig.
derivatives to C3- or CS-symmetrical tripodal receptor type 1).
molecules and the results of biological evaluation of these
We therefore attempted using 2,4,6-trichloro-1,3,5-triazine
symmetrical compounds.3) We have also reported an interest- (TCTAZ; 1) as a starting material to prepare target molecules,
ing lectin-like property for sugar recognition of some of these and we examined substitution reactions by amine or alcohol
tripodal receptor type TAEA molecules.4)
nucleophiles under various reaction conditions shown in a
In order to achieve a suprafacial three-dimensional interac- synthetic review by Blotny.18) As a result, we obtained many
tion of a bioactive symmetrical molecule for its binding site, types of target trisubstituted symmetrical TAZ derivatives.
the nature of substituents in the molecule is thought to be very The obtained results are summarized in Table 1.
important for preferential interactions. Such interactions are
As shown in Table 1, triamino-substituted C3-symmetrical
dictated largely by van der Waals interactions or formation derivatives (2a,19) 2b, and 2d) were obtained predominantly in
of hydrogen bonds. The introduction of amine (basic nitro- good yields from reactions of TCTAZ (1) with the correspond-
gen atom) and/or a bivalent oxygen group such as a hydroxy ing amine nucleophile (Entries 1–3).
or alkoxy group into a C3-symmetrical 1,3,5-triazine (TAZ)
Trials for the preparation of alkoxy-diamino-trisubstituted
template seems to be interesting, because it is well known that TAZ (3) by nucleophilic substitutions of TCTAZ with an
amine functionalities behave as both hydrogen acceptors and aliphatic amine (dH) and an alcohol (qH, rH, or sH) as nu-
hydrogen donors in appropriate circumstances. These facts cleophiles under various reaction conditions (Entries 4–9)
may indicate that molecules with some amine and/or bivalent resulted in the formation of a mixture of a few types of tar-
oxygen functionalities on a heterocyclic C3-symmetrical TAZ
template can produce a property for suprafacial hydrogen-
bonding interaction.
For an extension of our studies, we planned to investi-
gate the synthesis of 2,4,6-trisubstituted symmetrical TAZ
derivatives9–16) as well as to evaluate their biological proper-
ties. In this paper, we report the results of new synthetic
routes for C3- or CS-symmetrical 2,4,6-trisubstituted TAZ
The authors declare no conflict of interest.
Fig. 1. Target Triacylamino-Substituted TAZ
© 2013 The Pharmaceutical Society of Japan
*To whom correspondence should be addressed. e-mail: kunihiro@adm.fukuoka-u.ac.jp

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Vol. 61, No. 8
Table 1. TAZ Derivatives from Reactions of TCTAZ (1) and Amines (XH)
Ratio of
1:amine:(additive)
Entry
Amine XH
Conditionsa)
Reflux 15min
Solvent
AcOH
Products (yield %)
2a (83)
1
1:3.3
2
1:3.3
Reflux 1.5h
AcOH
2b·HCl (82)
3
4
5
6
7
8
9
10
1:6
1:6
1:2
MW 50W, 160°C, 5min
MW 50W, 100°C, 5min
MW 50W, 160°C, 5min
MW 50W, 160°C, 10min
MW 50W, 160°C, 10min
MW 50W, 160°C, 10min
0°C, 1h to rt 17h
Dioxane
EtOH
2d (70)
2d (24), 3dq (36), 4dqq (4)
3dr (2), 5d (12), 6d (11)
2d (8), 3dr (4), 5d (27)
2d (9), 3dr (1), 5d (88)
3ds (3), 5d (26)
i-PrOH
i-PrOH
i-PrOH
n-HepOH
CH2Cl2
1:4:(10 DIPEAb))
1:2.5:(5 DIPEAb))
1:2.5:(5 DIPEAb))
1:2:(2 TEAc))
1:6
5d (57)
2e (29)
180°C, 1h
11
1:2:(2 TEAc))
0°C, 1h to rt 18h
dry CH2Cl2
5f (33)
12
13
1:3
1:3.3d)
rt 1h
dry THF
AcOH
5g·3HCl (20)
Ag (46)
Reflux 1d
a) MW means microwave irradiation. b) N,N-Diisopropylethylamine. c) Triethylamine. d) The target compound could not be isolated.
get trisubstituted TAZ derivatives. Among these entries, the diates TAZs (5g and 2g) occurred in the reaction of TCTAZ
highest yield (88%) of diamino-chloro-trisubstituted TAZ with a nucleophile (gH) at a high reaction temperature, re-
derivative (5d) was obtained from microwave-assisted reaction sulting in the formation of dimeric triazine (Ag), which had
with i-PrOH as a solvent in the presence of N,N-diisopropyl- a bridged structure with two TAZ rings (Entry 13, see Ex-
ethylamine (DIPEA) (Entry 7). Reactions of TCTAZ with an perimental for details). The reaction mechanism for formation
amine nucleophile (dH or fH) under mild conditions (room of the dimerized compound Ag via triamino-TAZ (2g)22) is
temperature) or reactions using an alcohol as a solvent acting shown in Chart 1.
as a nucleophile gave diamino-monochloro-substituted TAZ
In terms of selective formation of targeted symmetrical
derivatives (5d or 5f20)) and monoamino-dichloro-substituted alkoxy-amino-TAZ derivatives, we found that the above-
TAZ product (6d) (Entries 5–9, and 11).
described synthetic strategy for the preparation of alkoxy-
Using the method reported by Azarifar et al.,21) reactions amino-substituted (trisubstituted) TAZ from TCTAZ (1) has
of TCTAZ (1) with a racemic 3-hydroxypiperidine (eH) as an disadvantages as a method for preparation of targeted sym-
amine nucleophile also resulted in the formation of triamino- metrical alkoxy-amino-TAZ derivatives (3 or 4).
substituted TAZ (2e) in 29% yield (Entry 10).
Mono- or diamino-substituted triazines generally showed
The reaction of TCTAZ with N-methylpiperazine (gH) poor reactivity against weak nucleophiles such as alcohols.
proceeded smoothly even at room temperature to afford the On the other hand, alkoxy-substituted chloro-TAZs had higher
corresponding diamino-monochloro-TAZ derivative (5g·HCl) reactivities as substrates in further nucleophic substitutions
in 20% yield (Entry 12). Dimerization between two interme- with amine nucleophiles than those of amine-substituted

August 2013
825
Chart 1. Formation Mechanism of Dimeric TAZ Derivative (Ag)
Chart 2
chloro-TAZ derivatives. Therefore, for the purpose of prepara-
Among the results, it is noteworthy that when using an
tion of designed alkoxy-amino-TAZ derivatives as our target isolated monoalkoxy-dichloro-TAZ derivative (7s),23) reactions
molecules, the synthetic procedure via alkoxy-substituted with amine nucleophiles (Entries 17–20) gave the correspond-
chloro-TAZ is expected to be superior to the procedure via ing target alkoxy-diamino-trisubstituted TAZ derivatives (3ds,
amine-substituted chloro-TAZs.
3es, 3hs, and 3is) in moderate to excellent yields. These facts
Chart 2 shows the strategic point of synthetic pathways via apparently indicate that the strategy is advantageous for the
alkoxy-chloro-TAZ derivatives (7, 8) to alkoxy-amino-TAZ purpose of preparation of designed trisubstituted symmetrical
derivatives (3, 4). Our method via alkoxy-substituted chloro- alkoxy-amino-TAZ derivatives as our target molecules (3 or
TAZ intermediates for target alkoxy-amino-TAZs consisting 4). The results of stepwise one-pot reactions of TCTAZ with
of stepwise nucleophilic substitutions gave moderate to excel- other alcohols and then amine nucleophiles are also shown in
lent results as shown in Table 2.
Table 2 (Entries 21–23).

826
Vol. 61, No. 8
From these reactions with TCTAZ as a starting material, derivatives using a TAZ template.
we could prepare many target symmetrical TAZ derivatives (3
Among the prepared trisubstituted TAZ derivatives, C3-
and 4) including 3dq, 3ds, 3dt, 3du, 3es, 3hs, 3is, 4dpp, 4dpt, symmetrical TAZ derivatives (2a, 2b·HCl, 2d, 2e27)) showed
4dqq, and 4dss. In some runs, we also obtained trialkoxy- no significant anti-HSV-1 activity or cytotoxic activity at a
substituted TAZ derivatives (9ppt, 9ptt, and 9sss24)).
All structures of the synthesized compounds were easily
concentration of less than 100µm.
However, two CS-symmetrical derivatives (3ds and 3es27)),
confirmed by spectroscopic and analytical data. The geom- in which a hydroxylated cyclic amine moiety in the C3-sym-
etries of C3- or CS-symmetrical structures of target TAZ metrical TAZ molecules (2d and 2e) had been substituted with
derivatives in this article were also confirmed by 13C-NMR an alkoxy group (HepO), showed different properties of those
spectroscopic data.
bioactivities. In compound 3ds, both the antiviral activity and
Antiviral Activity and Discussion Synthesized TAZ de- cytotoxicity were increased (EC50 and IC50=25–50µm), but
rivatives were evaluated for anti-HSV-1 activities by plaque compound 3es did not show any significant change in either of
reduction assays25) and were also evaluated for their cytotox- the biological activities at a concentration of less than 200µm.
icities against Vero cells. The results are summarized in Table In the CS-symmetrical derivatives (3dt) substituted with a
3, and aciclovir26) is also shown as a positive control. Calculat- different alkoxy group, similar effects regarding anti-HSV-1
ed logP values for the compounds are also shown in Table 3. activity and cytotoxicity are also observed (EC50=>6.3µm
There were few significant correlations between logP values and IC50=42.2µm). In the CS-symmetrical compounds (3dq
and EC50 values (anti-HSV-1 activity) or between logP values and 3du) having a different alkoxy group, weak anti-HSV-1
and IC50 values (cytotoxicity against Vero cells) among the activity also appeared in both compounds (see Table 3). In
compounds listed in Table 3. However, regarding structural the other CS-symmetrical derivative (3is) in which a hydrox-
features of the evaluated 2,4,6-trisubstituted TAZ derivatives, ylated amine moiety (d) in the CS-symmetrical molecule
we obtained interesting results for bioactivities of symmetrical (3ds) had been replaced with a different amine functionality
Table 2. Synthesis of Alkoxy-amino-TAZ Derivatives (3 and 4) from Reactions of TCTAZ (1) with Various Alcohols (ROH) and Amines (XH)
Entry
Reagents
Ratio of reagents and/or (additive)a)
Conditionsb)
Solvent
Products (yield %)c)
14
i) 1, sH
ii) dH
1:sH:dH:(collidine) =
1:1.3:4:(1)
i) Collidine, 0°C, 1h
ii) MW 50W, 160°C,
10min
Dry acetone
Dry dioxane
3ds (73), 4dss (4), 9sss (1)
15
i) 1, sH
ii) dH
1, sH
7s, dH
7s, eH
7s, hH
7s, iH
i) 1, tH
ii) dH
1:sH:dH:(collidine:DIPEA)=
1:2.6:2:(2:2)
1: sH:(collidine)=1:1.3:(1)
7s:dH=1:6.3
7s:eH:(DIPEA)=1:3:(3)
7s:hH:(DIPEA)=1:2:(3)
7s:iH:(DIPEA)=1:3:(3)
1:tH:dH:(collidine)=
1:1.3:4:(1)
i) Collidine, 0°C, 1h
ii) DIPEA, rt 6h
0°C, 1h
MW 50W, 160°C, 10min
rt 2h
rt 20h
rt 21h
i) Collidine, rt 3h
ii) MW 300W, 160°C,
10min
Dry acetone
Dry acetonitrile
Dry acetone
3ds (1), 4dss (47)
16
17
18
19
20
21
7s (70), 9sss (1)
3ds (85)
3es (92)
3hs (69)
3is (37)
Dry dioxane
Dry acetonitrile
Dry acetonitrile
Dry acetonitrile
Dry acetone
3dt (74)
Dry dioxane
22
23
i) 1, tH
ii) dH
1:tH:dH:(NaOH)=
1.1:1:5:(4)
i) Aq. NaOH, rt 2h
ii) MW 50W, 150°C,
15min
i) Collidine, rt 3h
ii) MW 300W, 160°C,
10min
MeOH
Dry dioxane
4dpp (20), 4dpt (8),
9ppt (21),d) 9ptt (22)d)
i) 1, uH
ii) dH
1:uH:dH:(collidine)=
1:1.3:4:(1)
Dry acetone
Dry dioxane
3du (29), Bdu (9), Cdu (3)
a) DIPEA stands for N,N-diisopropylethylamine. b) MW stands for microwave irradiation. c) Yield obtained from TCTAZ (1). d) Yields of 9ppt and 9ptt based on tH were
23% and 49%, respectively.

August 2013
827
(i) bearing an ether-linked alcohol, both anti-HSV-1 activity both anti-HSV-1 activity and cytotoxicity (EC50=>50µm and
and increased cytotoxicity were observed (EC50=>3.1 µm and IC50=55.3 µm) comparable to those of compound 3ds. These
IC50=21.4 µm). CS-Symmetrical compound 3hs also showed results suggest the importance of the presence of hydroxy
Table 3. Antiviral Activity (EC50), Cytotoxicity (IC50) against HSV-1, and Calculated LogPa)
Compound
EC50 (µm) IC50 (µm)
Log P
Compound
EC50 (µm) IC50 (µm)
Log P
2a
2b·HCl
2d
>100
>100c)
>100
>200
>100d)
>100
6.64
3hs
3is
>50
>3.1
92.1
55.3
21.4
8.43
5.51e)
2.88
1.74
2.43
4dpp
>200
2e
>100
395.6
25–30
>200
>200
25–30
1.96
2.42
4.57
4dss
38.0
247.5
>200
178.7
266.0
>200
6.72
2.39
2.67
3dq
3ds
5d
5f
3dt
3du
3es
>6.3
123.5
>200
42.2
>200
>200
3.52
3.36
4.27
9ptt
Ag
>200
>200
>200
4.28
3.79
112.1
Bdu
>200
>200
>444
5.03f)
Aciclovirb)
1.1
−0.76
a) LogP was calculated by using ChemDraw Ultra 10.0. b) Data were taken from ref. 26. c) Compound (2b·HCl) at a concentration of 100µm reduced plaque formation by
ca. 10%. d) Compound (2b·HCl) showed cytotoxicity at a concentration of 200µm. e) A value of the free amine (2b). f) LogP was calculated by using CAChe 6.1.12.

828
Vol. 61, No. 8
groups and also the importance of the introduction of an recognition properties of some of the highly bioactive sym-
alkoxy group for each biological activity. metrical compounds such as 3ds, 3dt, 3is, and 4dss described
Regarding antiviral activities of these symmetrical de- in this article, we are also planning to carry out calorimetric
rivatives, comparison of the activities of two CS-symmetrical experiments.
compounds (3ds and 4dss) is particularly interesting. CS-Sym-
metrical compound 4dss, modified by additional introduction
of the same alkoxy group (s: HepO) into the TAZ ring of 3ds
Experimental
Melting points were determined using a micro melting point
instead of an amino moiety (d), showed almost the same level apparatus (Yanaco MP-S3) without correction. IR spectra
of antiviral activity (EC50=38.0µm) and decreased cytotoxic- were measured by a Shimadzu FTIR-8100 IR spectropho-
ity (IC50=178.7 µm). The results indicate that this modification tometer. Low- and high-resolution mass spectra (LR-MS and
of 3ds to 4dss gave a better selectivity index (SI=IC50/EC50) HR-MS) were obtained by a JEOL JMS HX-110 double-focus-
for the antiviral compound, though obtained SI value was ing model equipped with an FAB ion source interfaced with a
l
still small, providing an easy way for generating an antivi- JEOL JMA-DA 7000 data system. H- and 13C-NMR spectra
ral lead of this 2,4,6-trisubstituted TAZ series. With respect were obtained by JEOL JNM A-500. Chemical shifts were ex-
to functional groups included in the molecule, the observed pressed in δ ppm downfield from an internal tetramethylsilane
l
anti-HSV-1 activity of this molecule 4dss indicates that the (TMS) signal for H-NMR and the carbon signal of the cor-
distance of one set of two functional groups [an amine moiety responding solvent [CDCl3 (77.00ppm), CD3OD (49.00ppm),
containing a hydroxy group and an alkoxy group] seems to be DMSO-d6 (39.50ppm), and pyridine-d5 (149.80ppm)] for
important for a preferential required structure for anti-HSV-1 13C-NMR. The signal assignments were confirmed by two
1
activity. In fact, compound 4dpp in which two long-chain dimensional (2D)-NMR analyses; H–1H 2D correlation spec-
alkoxy groups of 4dss were replaced by two methoxy groups troscopy (COSY), 1H–13C heteronuclear multiple-quantum
1
still had considerable activity (EC50=92.1 µm) with low cyto- coherence (HMQC), and H–13C heteronuclear multiple-bond
toxicity (IC50=>200µm). In addition, both the observed anti- connectivity (HMBC). Microanalyses were performed with a
HSV-1 and cytotoxic activities of compound 5d were weak Yanaco MT-6 CHN corder. Routine monitoring of reactions
(EC50=247.5 µm and IC50=266.0µm) and neither of the TAZ was carried out using precoated Kieselgel 60F254 plates (E.
derivatives (5f and 9ptt) showed any significant anti-HSV-1 Merck). Microwave irradiation experiments were carried out
or cytotoxic activity at a concentration of less than 200µm. in a CEM Discover Focused Microwave System. Centrifugal
These results suggest the importance of the presence of hy- or flash column chromatography was performed on silica gel
droxy groups and an alkoxy group in these CS-symmetrical (Able-Biott, Fuji Silysia FL-60D, or Kanto 60N) with a UV
TAZ molecular structures for the development of anti-HSV-1 detector. Commercially available starting materials were used
agents.
Concerning the biological activities of dimeric TAZ deriva-
without further purification.
General Procedure for Substitution Reactions of TCTAZ
tives, compound Ag showed only weak anti-HSV-1 activity with Amines TCTAZ (1, 1–10mmol) was added to a stirred
(EC50=112.1 µm) and no cytotoxic activity at a concentration solution of an amine in an appropriate solvent (6–75mL) with
of less than 200µm, but dimeric TAZ derivative Bdu did not or without an additive, and the resulting mixture was refluxed
show any significant biological activities at a concentration of immediately or stirred or was subjected to microwave ir-
less than 200µm. Although there is still some uncertainty, the radiation (MW) under the conditions shown in Table 1. The
results seem to indicate that the tested dimeric symmetrical obtained products were purified by chromatography or recrys-
TAZ derivatives have a different mode of antiviral or cyto- tallization from appropriate solvents, and the yields are also
toxic activity.
summarized in Table 1. Typical protocols for the preparation
Regarding biological activities, the obtained results in this of triamino-TAZ derivatives 2a (Entry 1) and 2d (Entry 3) are
TAZ series provide interesting information for further mo- shown below in detail.
lecular modifications targeting antiviral compounds. Thus, the
4,4′,4″-(1,3,5-Triazine-2,4,6-triyltriimino)trisbenzoic
TAZ template seems to be a preferable template for antiviral Acid 1,1′,1″-Triethylester (2a) [96474-94-1]19) Entry 1:
compounds rather than the TAEA template,3) because antiviral TCTAZ (1; 1.84g, 10mmol) was added to a stirred solution
activities of most of the CS-symmetrical compounds in this of ethyl 4-aminobenzoate (aH, 5.45g, 33mmol) in glacial
study were observed at lower concentrations than those of the acetic acid (AcOH, 75mL) and the resulting solution was re-
corresponding cytotoxicities. In addition, many trisubstituted fluxed immediately for 15min. The precipitated white solids
target CS-symmetrical TAZ derivatives described in this paper were collected by filtration, washed with boiling water (ca.
showed wide ranges of antiviral (anti-HSV-1) activities.
20mL×3), and dried at 90°C in vacuo to afford product 2a
In the search for new antiviral active candidates or new (4.74g, 83% yield) with high purity (>98% confirmed by
leads, the results indicate that this heterocyclic TAZ template NMR). Purification by recrystallization from i-PrOH gave
is a potential new scaffold for designing antiviral active mol- an analytically pure product 2a (3.06g, 54% yield) as color-
ecules. Considering the nature of an introduced substituent less crystals: mp 222–225°C (from i-PrOH) [lit.19) mp 158°C
characterizing the lipophilicity of a molecule, further modifi- (EtOH)]. IR (KBr) cm−1: 3450 (NH of amine), 1720 (C=
1
cations for finding more promising antiviral leads with better O), 1280, 1105 (C–O). H-NMR (DMSO-d6) δ: 1.34 (9H, t,
selectivity indexes are now under investigation. Based on the J=7.0Hz, CH3), 4.31 (6H, q, J=7.0Hz, CH2), 7.92 (6H, dm,
results of our previous studies on a few types of symmetrical J=8.7Hz, H3, 5), 8.00 (6H, t, J=8.7Hz, H2, 6), 9.90 (3H,
compounds,3–5) we speculate that a symmetrical molecule s, NH). 13C-NMR (DMSO-d6) δ: 14.15 (CH3), 60.23 (CH2),
constructed on a symmetric template or with a linker may 119.44 (C2, 6), 123.14 (C4), 129.75 (C3, 5), 144.13 (C1), 163.66
be an efficient structural feature. For the elucidation of sugar (C=N), 165.40 (C=O). Positive-ion FAB-MS m/z: 571(M+H+).

August 2013
829
HR-FAB-MS m/z: 571.2303 (Calcd for C30H31N6O6: 571.2305). 2.3Hz, H2′β, 6′β), 3.41 (4H, d, J=6.1Hz, H1), 4.33 (2H, q,
Anal. Calcd for C30H30N6O6·2.5H2O: C, 58.53; H, 5.73; N, J=7.0Hz, H1‴), 4.71 (4H, brd, J=13Hz, H2′α, 6′α). 13C-NMR
13.65. Found: C, 58.51; H, 5.44; N, 13.67.
(CD3OD) δ: 14.86 (C2‴), 29.79 (C3′, 5′), 40.31 (C4′), 44.54
Hy- (C2′, 6′), 63.28 (C1‴), 67.79 (C1), 166.96 (C2″, 4″), 172.10
N2,N4,N6-Tris(1,3-benzodioxol-5-yl)-1,3,5-triazine
drochloride (2b·HCl) Entry 2: In the same manner as (C6″). Positive-ion FAB-MS m/z: 352 (M+H+). HR-FAB-MS
that for the preparation of 2a (Entry 1), by the reaction of 1 m/z: 352.2347 (Calcd for C17H30N5O3: 352.2349). Anal. Calcd
and 3,4-methylenedioxyaniline (bH), product 2b·HCl (82%) for C17H29N5O3: C, 58.10; H, 8.32; N, 19.93. Found: C, 57.89;
with high purity (>98% confirmed by NMR) was obtained. H, 8.24; N, 19.76.
1
Recrystallization from MeOH gave an analytically pure prod-
4dqq: H-NMR (CD3OD) δ: 1.19 (2H, m, H3′β, 5′β), 1.38
uct 2b·HCl (42%) as a white powder: mp 272–274°C (from (6H, q, J=7.0Hz, H2‴), 1.75 (1H, m, H4′α), 1.80 (2H, m, H3′α,
MeOH). IR (KBr) cm−1: 3410 (NH of amine), 1240 (C–N), 5′α), 2.92 (2H, dt, J=10.8, 2.4Hz, H2′β, 6′β), 3.42 (2H, d,
1
1040 (C–O). H-NMR (DMSO-d6) δ: 6.01 (6H, s, H2), 6.87 J=7.0Hz, H1), 4.36 (4H, q, J=7.0Hz, H1‴), 4.76 (2H, m, H2′α,
(3H, d, J=8.2Hz, H7), 6.99 (3H, d, J=8.2Hz, H6), 7.35 (3H, 6′α). 13C-NMR (CD3OD) δ: 14.67 (C2‴), 29.69 (C3′, 5′), 40.06
br s, H4), 10.14 (3H, brs, NH). 13C-NMR (DMSO-d6) δ: 101.13 (C4′), 44.82 (C2′, 6′), 64.23 (C1‴), 67.55 (C1), 167.40 (C2″),
(C2), 104.12 (C4), 107.85 (C7), 114.92 (C6), 131.72 (C5), 143.82 172.90 (C4″, 6″). Positive-ion FAB-MS m/z: 283 (M+H+). HR-
1
(C7a), 147.20 (C3a). H-NMR (pyridine-d5) δ: 5.95 (6H, s, H2), FAB-MS m/z: 283.1778 (Calcd for C13H23N4O3; 283.1770).
6.88 (3H, d, J=8.2Hz, H7), 7.41 (3H, dd, J=8.2, 1.5Hz, H6),
1-(4,6-Dichloro-1,3,5-triazine-2-yl)-4-piperidinemeth-
7.84 (3H, s, H4), 8.64 (3H, brs, NH or HCl), 10.22 (3H, brs, anol (6d) Entry 5: In the same manner as that for the
HCl or NH). 13C-NMR (pyridine-d5, 149.80ppm) δ: 101.44 preparation of 2d (Entry 3), the reaction of 1 and dH was
(C2), 104.39 (C4), 108.23 (C7), 114.34 (C6), 135.47 (C5), carried out in i-PrOH. After removal of the white precipi-
143.47 (C7a), 148.11 (C3a), 165.46 (C2′). Positive-ion FAB- tated solid (dH·HCl), the residue obtained by evaporation was
MS m/z: 487 (M+H+). HR-FAB-MS m/z: 487.1365 (Calcd purified by flash chromatography (CH2Cl2 :95% EtOH:28%
for C24H19N6O6: 487.1366). Anal. Calcd for C24H18N6O6·HCl· NH3=97:2.7:0.3→93:6.5:0.5) to give products 6d (11%) as a
0.7H2O: C, 53.83; H, 3.84; N, 15.69. Found: C, 53.88; H, 3.83; yellow oil, 5d (12%), and 3dr (2%).
N, 15.49.
6d: Positive-ion FAB-MS m/z: 263 (M+H+). HR-FAB-MS
1
1,1′,1″-(1,3,5-Triazine-2,4,6-trityl)tris[(piperidine-4-yl)- m/z: 263.0460 (Calcd for C9H13Cl2N4O: 263.0466). H-NMR
methanol] (2d) Entry 3: A mixture of 1 (0.74g, 4.0mmol) (CDCl3) δ: 1.26 (2H, m, H3′β, 5′β), 1.44 (0.5H, brs, OH), 1.58
and 4-piperidinemethanol (dH, 2.76g, 24mmol) in dioxane (0.5H, brs, OH), 1.84 (1H, m, H4′α), 1.89 (2H, dm, J=13.4Hz,
(8mL) was subjected to MW at 160°C (50W) for 5min with H3′α, 5′α), 2.97 (2H, dt, J=13.0, 2.7Hz, H2′β, 6′β), 3.55 (2H,
stirring. After evaporation of the solvent, the residue was dis- d, J=6.1Hz, H1), 4.78 (2H, dt, J=6.7, 2.3Hz, H2′α, 6′α).
solved in a mixture of EtOAc (40mL) and aqueous saturated 13C-NMR (CDCl3) δ: 28.40 (C3′, 5′), 38.50 (C4′), 44.26 (C2′,
NaHCO3 (40mL) and then separated. The aqueous layer was 6′), 67.01 (C1), 163.75 (C2″), 170.26 (C4″, 6″).
extracted with EtOAc (40mL×2). The combined organic layer
1,1′-(6-Isopropoxy-1,3,5-triazine-2,4-diyl)bis[(piperidin-
was dried (MgSO4). Evaporation of the solvent gave product 4-yl)methanol] (3dr) Entry 6: In the same manner as that
2d (1.17g, 70%). Recrystallization from propionitrile gave for the preparation of 2d (Entry 3), the reaction of 1 and dH
2d (0.86g, 51%) as colorless crystals: mp 198–201°C (from was carried out with DIPEA in i-PrOH. After evaporation of
EtCN). IR (KBr) cm−1: 3400 (OH of alcohol), 1250 (C–N of the solvent, the resulting residue was purified by centrifugal
1
t-amine), 1040 (C–O of alcohol). H-NMR (DMSO-d6) δ: 0.99 chromatography (CH2Cl2 :95% EtOH:28% NH3=93:6.5:0.5)
(6H, dm, J=12.5Hz, H3′β, 5′β), 1.58 (3H, m, H4′), 1.66 (6H, to give 5d (27%), 2d (8%), and 3dr (4%).
dm, J=12.5Hz, H3′α, 5′α), 2.70 (6H, dt, J=12.5, 2.1Hz, H2′β,
3dr: Positive-ion FAB-MS m/z: 366 (M+H+). HR-FAB-MS
6′β), 3.25 (6H, d, J=5.6Hz, H1), 4.40 (3H, t, J=5.3Hz, OH), m/z: 366.2509 (Calcd for C18H32 N5O3: 366.2505). 13C-NMR
4.60 (6H, brd, J=12.5Hz, H2′α, 6′α). 13C-NMR (DMSO-d6) δ: (CDCl3) δ: 21.93 (Me), 28.47 (C3′, 5′), 39.10 (C4′), 43.22 (C2′,
28.38 (C3′, 5′), 38.74 (C4′), 42.60 (C2′, 6′), 65.74 (C1), 164.68 6′), 67.66 (C1), 69.02 (C1‴), 165.79 (C2″, 4″), 171.03 (C6″).
(C2″). Positive-ion FAB-MS m/z: 421 (M+H+). HR-FAB-MS
1,1′-(6-Chloro-1,3,5-triazine-2,4-diyl)bis[(piperidin-4-
m/z: 421.2929 (Calcd for C21H37N6O3: 421.2927). Anal. Calcd yl)methanol] (5d) Entry 7: In the same manner as that
for C21H36N6O3: C, 59.98; H, 8.63; N, 19.98. Found: C, 59.92; described in Entry 6 except for the ratio of reagents (dH and
H, 8.59; N, 19.98.
DIPEA), the reaction was carried out under the conditions
1,1′-(6-Ethoxy-1,3,5-triazine-2,4-diyl)bis[(piperidin-4- shown in Table 1. Purification by open column chromatog-
yl)methanol] (3dq) and 1-(4,6-Diethoxy-1,3,5-triazine-2-yl)- raphy (n-hexane:EtOAc=20:80→0:100) gave 5d (88%), 2d
(piperidine-4-yl)-methanol (4dqq) Entry 4: In the same (9%), and 3dr (1%). An analytical sample 5d was obtained by
manner as that for the preparation of 2d (Entry 3), the reac- recrystallization from CH2Cl2 as white powder.
tion of 1 and dH was carried out in EtOH. After evapora-
Entry 8: In the same manner as that in Entry 7 except for
tion, the residue was purified by flash chromatography the use of n-heptanol instead of i-PrOH, the reaction was car-
(CH2Cl2 : EtOH=90:10) to give 2d (24%), 3dq (36%), and ried out. Purification of the products by open column chroma-
4dqq (4%) as a colorless oil. An analytical sample 3dq was tography (n-hexane:EtOAc=20:80→0:100) gave 5d (26%)
obtained by recrystallization from AcOEt.
and 3ds (3%).
3dq: Colorless crystals, mp 133–134°C (from AcOEt). IR
Entry 9: To a solution of 1 (10.0mmol) in dry CH2Cl2
(KBr) cm−1: 3345 (OH of alcohol), 1190, 1145 (C–N of t- (20mL) was added a solution of dH (20mmol) and TEA
amine), 1025 (C–O of alcohol). 1H-NMR (CD3OD) δ: 1.13 (20mmol) in dry CH2Cl2 (20mL). After stirring for 1h at
(4H, m, H3′β, 5′β), 1.33 (3H, t, J=7.0Hz, H2‴), 1.73 (2H, m, 0°C, the reaction mixture was allowed to warm up to room
H4′), 1.75 (4H, brt, J=12Hz, H3′α, 5′α), 2.82 (4H, dt, J=12.8, temperature and then stirred for another 17h. After addition of

830
Vol. 61, No. 8
a solution of KOH (100mmol) in water (60mL), the resulting crystals.
1
mixture was extracted with CH2Cl2 (30 mL×2) and then the
5g·3HCl: H-NMR (CDCl3) δ: 2.35 (6H, s, CH3), 2.73 (8H,
organic layer was washed with aqueous NaHCO3 (20mL) and m, H3, 5), 3.22 (8H, m, H2, 6). 13C-NMR (CDCl3) δ: 43.37
brine (20mL×2). The organic layer was dried and the solvent (C2, 6), 45.71 (CH3), 51.50 (C3, 5), 164.34 (C2′, 4′), 169.57
was evaporated to give crude 5d as an oil, which was crystal- (C6′). Positive-ion FAB-MS m/z: 312 (M+H+). HR-FAB-MS
lized by addition of CH2Cl2 to form a white solid. Recrystal- m/z: 312.1710 (Calcd for C13H23N7Cl for 312.1703).
lization of crude 5d from CH2Cl2 gave an analytical pure
sample 5d (57%) as a white powder.
2,2′-(1,4-Piperazinediyl)bis[4,6-di(4-methyl-1-pipera-
zinyl)-1,3,5-triazine] (Ag) Entry 13: To a solution of gH
5d: mp 154–155°C (from CH2Cl2). IR (KBr) cm−1: 3400 (33.0mmol) in AcOH (70mL) was added 1 (1.84g, 10.0mmol),
1
(OH), 1570 (N=C). H-NMR (CDCl3) δ: 1.20 (4H, dq, J=7.3, and the resulting mixture was refluxed for 1d. The pre-
4.3Hz, H3′β, 5′β), 1.45 (2H, brs, OH), 1.76 (2H, m, H4′α), cipitated solids were collected and washed with hot water
1.79 (4H, t, J=11.9Hz, H3′α, 5′α), 2.83 (4H, dt, J=13.1, 2.1Hz, (20mL×2). The obtained precipitate was dissolved in 10%
H2′β, 6′β), 3.52 (4H, d, J=5.8Hz, H1), 4.73 (4H, d, J=13.1Hz, NaOH (20mL) and the resulting solution was extracted with
H2′α, 6′α). 13C-NMR (CDCl3) δ: 28.53 (C3′, 5′), 38.94 (C4′), CH2Cl2 (40 mL×2). The organic layer was washed with brine
43.46 (C2′, 6′), 67.48 (C1), 164.32 (C2″, 4″), 169.61 (C6″). (30mL) and dried over MgSO4. After removal of the solvent,
Positive-ion FAB-MS m/z: 342 (M+H+). HR-FAB-MS m/z: Ag (46%) was obtained as a pale yellow solid. Recrystalliza-
342.1689 (Calcd for C15H25ClN5O2: 342.1697). Anal. Calcd for tion from EtOH–H2O gave the dimeric TAZ derivative Ag as
C15H24 ClN5O2: C, 52.70; H, 7.08; N, 20.49. Found: C, 52.58; a white powder.
H, 7.12; N, 20.20.
Ag: mp 255–257°C decn. (from EtOH–H2O). 1H-NMR
1,1′,1″-(1,3,5-Triazine-2,4,6-triyl)tris-3-piperidinol (2e27)) (CDCl3) δ: 2.31 (12H, s, CH3), 2.40 (16H, t, J=5.0Hz, H3′,
Entry 10: A mixture of 1 (10mmol) and 3-hydroxypiperidine 5′), 3.78a) (8H, s, Ha), 3.80a) (16H, m, H2′, 6′). 13C-NMR
(eH, 60mmol) was heated. After addition of water (100mL) (CDCl3) δ: 43.04 (C2′, 6′), 43.14 (Ca), 46.23 (CH3), 55.00 (C3′,
and then ether (100mL), the insoluble solid material was fil- 5′), 165.39 (C4, 6), 165.53 (C2). Positive-ion FAB-MS m/z: 637
tered and then the obtained product was dissolved in MeOH (M+H+). HR-FAB-MS m/z: 637.4651 (Calcd for C30H53N16Cl
(300mL). After addition of ether (100mL), the resulting pre- for 637.4639).
cipitates were collected. Recrystallization of the crude product
General Procedure for Stepwise Substitution of TCTAZ
from EtOH gave pure product 2e (29%) as colorless crystals: with Alcohols and Amines (Step 1) To a solution of 1
mp 264–265°C (from EtOH). IR (KBr) cm−1: 3340 (OH of (5–20mmol) in dry acetone (7–60mL) were added an alcohol
alcohol), 1230 (C–N of t-amine), 1060 (C–O of alcohol). (ROH) and collidine. After stirring for 1–3h at 0°C or at room
1H-NMR (DMSO-d6) δ: 1.32 (6H, m, H4, 5), 1.67 (3H, m, H5), temperature, the precipitated collidine·HCl was removed by
1.88 (3H, m, H4), 2.68 (3H, m, H2), 2.83 (3H, m, H6), 3.38 filtration. Evaporation of the solvent gave crude alkoxy-chloro-
(3H, m, H3), 4.28 (3H, m, H6), 4.43 (3H, m, H2), 4.79 (3H, m, TAZ (7 or 8). (Step 2) This crude product was dissolved in
OH). 13C-NMR (DMSO-d6) δ: 22.90 (C5), 33.50 (C4), 42.46 dry dioxane (7–60mL), and an amine with or without DIPEA
(C6), 49.91 (C2), 65.27 (C3), 164.72 (C2′). Positive-ion FAB- was added. Then stirring was continued at room temperature,
MS m/z: 379 (M+H+). HR-FAB-MS m/z: 379.2456 (Calcd for or the resulting mixture was subjected to MW at 150–160°C
C18H31N6O3: 379.2458). Anal. Calcd for C18H30N6O3: C, 57.12; (50W) under the conditions shown in Table 2. After evapora-
H, 7.99; N, 22.21. Found: C, 57.03; H, 7.96; N, 22.01.
tion of the solvent, the residue was purified by chromatogra-
3,3′,3″,3‴-[(6-Chloro-1,3,5-triazine-2,4-diyl)-dinitrilo]- phy or recrystallization. A typical protocol for the preparation
tetrakispropanenitrile (5f) [856812-02-7]20) Entry 11: In a of compound 3ds (Entry 14) is shown below in detail.
manner similar to that described in Entry 9, the reaction of
1,1′-(6-Heptoxy-1,3,5-triazine-2,4-diyl)bis[(piperidin-4-
1 with fH was carried out. Evaporation of the solvent gave yl)methanol] (3ds), [1-[4,6-Bis(heptyloxy)-1,3,5-triazin-2-
crude product 5f as a pale yellow solid, which was washed yl]piperidin-4-yl]methanol (4dss), and 2,4,6-Tris(heptyloxy)-
with CH2Cl2 (15mL) to give 5f (33%) as a white solid. An 1,3,5-triazine (9sss) [37068-43-2]24) Entry 14: (Step 1) To a
analytical sample 5f was obtained by recrystallization from solution of 1 (1.02g, 5.5mmol) in dry acetone (7mL) were
CH2Cl2 as colorless needles: mp 156–157°C (from CH2Cl2) added sH (0.843g, 7.25mmol) and collidine (0.69g, 5.7mmol)
[lit.20) mp 149–151°C]. IR (KBr) cm−1: 2250 (CN), 805 (C–Cl). at 0°C. After stirring for 1h at 0°C, the resulting white pre-
1H-NMR (DMSO-d6) δ: 2.84 (4H, t, J=6.7Hz, H2A), 2.88 (4H, cipitated salt (collidine·HCl) was removed by filtration. After
t, J=6.7Hz, H2B), 3.84 (4H, t, J=6.7Hz, H3A), 3.89 (4H, t, evaporation of the solvent, a dark orange solid was obtained.
J=6.7Hz, H3B). 13C-NMR (DMSO-d6) δ: 15.52 (C2B), 15.79 (Step 2) This material was dissolved in dry dioxane (5mL),
(C2A), 42.86 (C3A), 43.06 (C3B), 118.84 (CNA), 119.08 (CNB), and dH (2.53g, 22.0mmol) was added, and then the resulting
164.34 (C2′), 168.58 (C6′). Positive-ion FAB-MS m/z: 358 mixture was subjected to MW at 160°C (50W) for 10min with
(M+H+). HR-FAB-MS m/z: 358.1299 (Calcd for C15H17N9Cl: stirring. After evaporation of the solvent, the residue was puri-
358.1295). Anal. Calcd for C15H16N9Cl·0.5H2O: C, 49.12; H, fied by flash chromatography (CH2Cl2 : 95%EtOH : 28%N H3=
4.67; N, 34.37. Found: C, 48.95; H, 4.47; N, 34.60.
95:4.5:0.5→93:6.5:0.5) to give 3ds (1.69g, 73% yield) as
2-Chloro-4,6-bis(4-methyl-1-piperazinyl)-1,3,5-triazine a white solid, 4dss (93mg, 4% yield), and 9sss (23mg, 1%
Trihydrochloride (5g·3HCl) Entry 12: To a solution of 1 yield).
(1.0mmol) in dry tetrahydrofuran (THF, 6mL) was added
3ds: mp 122–123°C (from CH3CN). IR (KBr) cm−1: 3420
1-methylpiperazine (gH, 3.0mmol) with stirring at room tem- (OH of alcohol), 1355, 1050 (C–N of t-amine). 1H-NMR
perature. After removal of the precipitated solid, 1m HCl/ (CDCl3) δ: 0.88 (3H, t, J=7.0Hz, H7‴), 1.18 (4H, m, H3′β,
EtOH was added to the filtrate, and filtration of the result- 5′β), 1.29 (6H, m, H5‴, 6‴, 4‴), 1.40 (2H, m, H3‴), 1.47
ing material gave product 5g·3HCl in 20% yield as colorless (2H, brs, OH), 1.76 (8H, m, H2‴, 4′α, 3′α, 5′α), 2.80 (4H, dt,

August 2013
831
J=12.8, 2.1Hz, H2′β, 6′β) 3.51 (4H, d, J=5.8Hz, H1) 4.26 3hs (69%), and 3is (37%), respectively (see Entries 17–20). A
(2H, t, J=6.9Hz, H1‴), 4.79 (4H, brd, J=12.8Hz, H2′α, 6′α). typical protocol for the preparation of 3ds is shown below in
13C-NMR (CDCl3) δ: 14.06 (C7‴), 22.58 (C6‴), 25.96 (C3‴), detail. Physical and spectroscopic data of these compounds are
28.57 (C3′, 5′), 28.93, 29.07 (C2‴, 4‴), 31.75 (C5‴), 39.12 (C4′), shown below.
43.24 (C2′, 6′), 66.57 (C1‴), 67.69 (C1), 165.82 (C2″, 4″), 170.91
Entry 17: A solution of 7s (12.0mmol) and dH (75.7mmol)
(C6″). Positive-ion FAB-MS m/z: 422 (M+H+). HR-FAB-MS in dry dioxane (15mL) was subjected to MW with stirring.
m/z: 422.3141 (Calcd for C22H40N5O3: 422.3131). Anal. Calcd The obtained product was separated by flash chromatogra-
for C22H39N5O3: C, 62.68; H, 9.32; N, 16.61. Found: C, 62.45; phy (n-hexane:EtOAc=40:60→20:80) to give 3ds (85%) as
H, 9.15; N, 16.60.
a white solid.
4dss: mp 68–70°C (from CH3CN). IR (KBr) cm−1: 3365
1,1′-[6-(Heptyloxy)-1,3,5-triazine-2,4-diyl]bis(piperidin-
(OH of alcohol), 1250, 1130, 1045 (C–O alcohol and ether). 3-ol) (3es27)) Entry 18: Colorless crystals, mp 126–127°C
1H-NMR (CDCl3) δ: 0.88 (6H, t, J=7.0Hz, H7‴), 1.20 (2H, m, (CH3CN). IR (KBr) cm−1: 3420 (OH of alcohol), 1375, 1510
1
H3′β, 5′β), 1.25–1.35 (12H, m, H4‴, 5‴, 6‴), 1.41 (4H, m, H3‴), (C–N of t-amine), 1105 (C–O). H-NMR (pyridine-d5) δ: 0.83
1.60 (1H, brs, OH), 1.73–1.83 (7H, m, H2‴, 4′α, 3′α, 5′α), 2.86 (3H, t, J=7.0, H7″), 1.15–1.25 (6H, m, H4″, 5″, 6″), 1.38 (2H,
(2H, dt, J=13.1, 2.1Hz, H2′β, 6′β), 3.52 (2H, d, J=6.1Hz, H1), m, H3″), 1.50 (2H, m, H5α or β), 1.65–1.85 (6H, m, H2″, 4α
4.31 (4H, t, J=6.9Hz, H1‴), 4.81 (2H, dm, J=13.1Hz, H2′α, or β, 5β or α), 2.13 (2H, m, H4β or α), 3.19 (2H, m, H6α or β),
6′α). 13C-NMR (CDCl3) δ: 14.04 (C7‴), 22.57 (C6‴), 25.87 3.38 (2H, m, H2α or β), 3.96 (2H, m, H3), 4.36 (2H, brs, H1″),
(C3‴), 28.53, 28.79, 29.00 (C3′, 5′, 2‴, 4‴), 31.73 (C5‴), 38.95 4.50 (2H, brs, H6β or α), 4.87 (2H, brd, J=10.4Hz, H2β or
(C4′), 43.55 (C2′, 6′), 67.49 (C1), 67.49 (C1‴), 166.39 (C2″, α), 4.90 (2H, brs, OH). 13C-NMR (pyridine-d5) δ: 14.11 (C7″),
4″), 171.90 (C6″). Positive-ion FAB-MS m/z: 423 (M+H+). 22.71 (C6″), 23.53 (C5), 26.29 (C3″), 29.20, 29.42 (C2″, 4″),
HR-FAB-MS m/z: 423.3339 (Calcd for C23H43N4O3: 423.3335). 31.88 (C5″), 34.28 (C4), 43.65 (C6), 51.23 (C2), 66.28, 66.36
Anal. Calcd for C23H42N4O3: C, 65.37; H, 10.02; N, 13.26. (C1″, 3), 166.82 (C2′, 4′), 171.63 (C6′). Positive-ion FAB-MS
Found: C, 65.43; H, 10.05; N, 13.08.
m/z: 394 (M+H+). HR-FAB-MS m/z: 394.2822 (Calcd for
9sss: Positive-ion FAB-MS m/z: 424 (M+H+). HR-FAB-MS C20H36N5O3: 394.2818). Anal. Calcd for C20H35N5O3: C, 58.89;
m/z: 424.3538 (Calcd for C24H46N3O3: 424.3539). 1H-NMR H, 9.04; N, 17.17. Found: C, 58.95; H, 9.04; N, 17.11.
(CDCl3) δ: 0.88 (9H, t, J=7.0Hz, H7′), 1.25–1.35 (18H, m,
3,3′-[1,1′-(6-(Heptyloxy)-1,3,5-triazine-2,4-diyl)bis-
H5′, 6′, 4′), 1.43 (6H, m, H3′), 1.78 (6H, m, H2′), 4.38 (6H, t, (piperidine-4,1-diyl)]diphenol (3hs) Entry 19: White solid,
J=6.7Hz, H1′). 13C-NMR (CDCl3) δ: 13.96 (C7′), 22.53 (C6′), mp 79–80°C. IR (KBr) cm−1: 3400 (O–H of ArOH), 1575, 1515
1
25.75 (C3′), 28.64 (C2′), 28.91 (C4′), 31.69 (C5′), 68.43 (C1′), (C–N of t-amine). H-NMR (CDCl3) δ: 0.86 (3H, t, J=6.9Hz,
173.15 (C2, 4, 6).
H7‴), 1.26 (6H, m, H4‴, 5‴, 6‴), 1.39 (2H, m, H3‴), 1.61 (4H,
Entry 15: (Step 1) The reaction was carried out in the same m, H3′, 5′), 1.73 (2H, m, H2‴), 1.85 [6H, brd, J=12.5Hz, H3′,
manner as that described above procedure (Entry 14, Step 1) 5′ (4H), OH (2H)], 2.68 (2H, brt, J=12.5Hz, H4′), 2.86 (4H, t,
except for the ratio of reagents [alcohol (sH) and collidine]. J=12.5Hz, H2′β, 6′β), 4.28 (2H, t, J=6.9Hz, H1‴), 4.90 (4H,
(Step 2) The residue was dissolved in dry acetonitrile, and brd, J=13.1Hz, H2′α, 6′α), 5.74 (1H, brs, H2O), 6.66 (2H, s,
dH and DIPEA were added, and then the resulting mixture H2), 6.67 (2H, d, J=7.6Hz, H4), 6.74 (2H, d, J=7.6Hz, H6),
was stirred at room temperature for 6h. After evaporation of 7.14 (2H, t, J=7.6Hz, H5). 13C-NMR (CDCl3) δ: 14.02 (C7‴),
the solvent, the residue was purified by flash chromatography 22.57 (C6‴), 25.95 (C3‴), 28.95 (C2‴ or C4‴), 29.05 (C4‴
(n-hexane:EtOAc=70:30→60:40) to give 3ds (1%) as a white or C2‴), 31.74 (C5‴), 33.08 (C3′, 5′), 42.96 (C4′), 44.10 (C2′,
solid and 4dss (47%). Analytical samples of 3ds and 4dss 6′), 66.73 (C1‴), 113.37 (C4), 113.81 (C2), 119.07 (C6), 129.58
were obtained by recrystallization from acetonitrile as color- (C5), 147.76 (C1), 156.02 (C3), 165.80 (C2″, 4″), 170.99 (C6″).
less crystals.
Positive-ion FAB-MS m/z: 546 (M+H+). HR-FAB-MS m/z:
2,4-Dichloro-6-(heptyloxy)-1,3,5-triazine (7s) [107392- 546.3441 (Calcd for C32H44N5O3: 546.3444). Anal. Calcd for
85-8]23) Entry 16: In a manner similar to that for prepara- C32H43N5O3·0.5H2O: C, 69.29; H, 7.99; N, 12.62. Found: C,
tion of compound 3ds (Entry 14, Step 1), the reaction of 1 69.16; H, 8.01; N, 12.43.
(22mmol), sH (29mmol) and collidine (23mmol) was carried
4,4′-[6-(Heptyloxy)-1,3,5-triazine-2,4-diyl]bis[2-[2-(1-
at 0°C for 1h. After removal of the salt (collidine·HCl), ice- piperazinyl)-ethoxy]ethanol] (3is) Entry 20: Yellow oil.
water (40mL) was added to the filtrate and the mixture was IR (KBr) cm−1: 3375 (OH of alcohol), 1570, 1525 (C–N
extracted with CH2Cl2 (20mL×3). The organic layer was of t-amine), 1120 (C–O). 1H-NMR (CDCl3) δ: 0.88 (3H, t,
dried, and filtrated. The filtrate was evaporated and the resi- J=7.0Hz, H7‴), 1.29 (6H, m, H4‴, 5‴, 6‴), 1.40 (2H, m, H3‴),
due was purified by open column chromatography (CH2Cl2) to 1.74 (2H, m, H2‴), 2.54 (8H, t, J=5.0Hz, H3′, 5′), 2.62 (4H,
give 7s (70%) as a colorless oil and 9sss (1%) as a white solid. t, J=5.2Hz, H5), 2.93 (2H, brs, OH), 3.61 (4H, t, J=4.6Hz,
1
7s: H-NMR (CDCl3) δ: 0.89 (3H, t, J=7.0Hz, H7′), 1.31 H2), 3.68 (4H, t, J=5.2Hz, H4), 3.71 (4H, t, J=4.6Hz,
(4H, m, H5′, 6′), 1.35 (2H, m, H4′), 1.44 (2H, m, H3′), 1.82 H1), 3.83 (8H, t, J=5.0Hz, H2′, 6′), 4.25 (2H, t, J=6.9Hz,
(2H, m, H2′), 4.49 (2H, t, J=6.6Hz, H1′). 13C-NMR (CDCl3) H1‴). 13C-NMR (CDCl3) δ: 14.00 (C7‴), 22.55 (C6‴), 25.94
δ: 13.99 (C7′), 22.51 (C6′), 25.55 (C3′), 28.27 (C2′), 28.77 (C3‴), 28.90 (C2‴ or C4‴), 29.02 (C4‴ or C2‴), 31.73 (C5‴),
(C4′), 31.60 (C5′), 70.68 (C1′), 171.05 (C1), 172.45 (C3, 5). 42.93 (C2′, 6′), 53.20 (C3′, 5′), 57.99 (C5), 61.91 (C1), 66.69
Positive-ion FAB-MS m/z: 264 (M+H+). HR-FAB-MS m/z: (C1‴), 67.75 (C4), 72.39 (C2), 165.97 (C2″, 4″), 170.95 (C6″).
264.0618 (Calcd for C10H16Cl2N3O: 264.0670).
Positive-ion FAB-MS m/z: 540 (M+H+). HR-FAB-MS m/z:
Reactions of 7s with Amines The reaction of 7s with var- 540.3881 (Calcd for C26H50N7O5: 540.3873). Anal. Calcd for
ious nucleophiles (dH, eH, hH, and iH) under the conditions C26H49N7O5·0.2H2O: C, 57.48; H, 9.16; N, 18.05. Found: C,
shown in Table 2 afforded compound 3ds (85%), 3es (92%), 57.38; H, 9.37; N, 18.15.

832
Vol. 61, No. 8
1,1′-[6-(1,3-Benzodioxol-5-yloxy)-1,3,5-triazine-2,4-diyl]- or C6″), 172.38 (C6″ or C4″). Positive-ion FAB-MS m/z: 361
bis-4-piperidinemethanol (3dt) Entry 21: This compound (M+H+). HR-FAB-MS m/z: 361.1516 (Calcd for C17H21N4O5:
was prepared in a manner similar to that for compound 361.1512).
1
3ds (Entry 14). Purification by flash chromatography
9ppt: H-NMR (CDCl3) δ: 4.01 (6H, s, OCH3), 6.00 (2H, s,
(CH2Cl2 : EtOH=95:5→93:7) gave 3dt (74%) as a yellow H2), 6.62 (1H, dd, J=8.2, 2.4Hz, H6), 6.68 (1H, d, J=2.4Hz,
solid. An analytical sample was obtained by recrystallization H4), 6.79 (1H, d, J=8.2Hz, H7). 13C-NMR (CDCl3) δ: 55.47
from propionitrile as colorless crystals: mp 165–166°C (from (OCH3), 101.75 (C2), 103.71 (C4), 107.96 (C7), 113.91 (C6),
C2H5CN). IR (KBr) cm−1: 1585, 1505 (C–N of t-amine) 1035 145.51 (C7a), 146.05 (C5), 148.03 (C3a), 173.55 (C4′, 6′),
1
(C–O of alcohol). H-NMR (CDCl3) δ: 1.18 (4H, m, H3′β, 5′β), 174.00 (C2′). Positive-ion FAB-MS m/z: 278 (M+H+). HR-
1.52 (2H, brs, OH), 1.75 (6H, m, H4′α, 3′α, 5′α), 2.78 (4H, t, FAB-MS m/z: 278.0775 (Calcd for C12H12N3O5: 278.0777).
J=12.5Hz, H2′β, 6′β), 3.50 (4H, d, J=6.1Hz, H1), 4.68 (4H,
9ptt: mp 156–157°C (from MeOH). IR (KBr) cm−1: 1355,
brs, H2′α, 6′α), 5.97 (2H, s, H2‴), 6.62 (1H, d, J=2.4, 8.5Hz, 1170 (C–N of t-amine). 1H-NMR (CDCl3) δ: 3.96 (3H, s,
H6‴), 6.70 (1H, d, J=2.4Hz, H4‴), 6.74 (1H, d, J=8.5Hz, OCH3), 5.99 (4H, s, H2), 6.61 (2H, dd, J=8.5, 2.4Hz, H6),
H7‴). 13C-NMR (CDCl3) δ: 28.53 (C3′, 5′), 39.06 (C4′), 43.34 6.66 (2H, d, J=2.4Hz, H4), 6.78 (2H, d, J=8.5Hz, H7).
(C2′, 6′), 67.61 (C1), 101.39 (C2‴), 104.28 (C4‴), 107.44 (C7‴), 13C-NMR (CDCl3) δ: 55.63 (OCH3), 101.78 (C2), 103.68 (C4),
114.29 (C6‴), 144.35 (C7a‴), 147.23 (C3a‴ or 5‴), 147.45 (C5‴ 107.98 (C7), 113.88 (C6), 145.58 (C7a), 145.99 (C5), 148.04
or 3a‴), 165.89 (C2″, 4″), 171.20 (C6″). Positive-ion FAB-MS (C3a), 173.81 (C6′) 176.26 (C2′, 4′). Positive-ion FAB-MS
m/z: 444 (M+H+). HR-FAB-MS m/z: 444.2251 (Calcd for m/z: 384 (M+H+). HR-FAB-MS m/z: 384.0829 (Calcd for
C22H30N5O5: 444.2247). Anal. Calcd for C22H29N5O5: C, 59.58; C18H14N3O7: 384.0832). Anal. Calcd for C18H13N3O7: C, 56.40;
H, 6.59; N, 15.79. Found: C, 59.57; H, 6.70; N, 15.95.
H, 3.42; N, 10.96. Found: C, 56.18; H, 3.59; N, 11.09.
1-(4,6-Dimethoxy-1,3,5-triazine-2-yl)-4-piperidinemetha-
[1,1′-[6-(4-Hydroxyphenoxy)-1,3,5-triazine-2,4-diyl]-
nol (4dpp), 1-[4-(1,3-Benzodioxol-5-yloxy)-6-methoxy-1,3,5- bis(piperidine-4,1-diyl)]dimethanol (3du), [1,1′,1″,1‴-[6,6′-
triazine-2-yl]-4-piperidinemethanol (4dpt), 2-(1,3-Benzo- [1,4-Phenylenebis(oxy)]-bis(1,3,5-triazine-6,4,2-triyl)]-
dioxol-5-yloxy)-4,6-dimethoxy-1,3,5-triazine (9ppt), and tetrakis(piperidine-4,1-diyl)]tetramethanol (Bdu) and [1,1′-
2,4-Bis(1,3-benzodioxol-5-yloxy)-6-methoxy-1,3,5-triazine [6-[4-[[4-[4-(Hydroxymethyl)piperidin-1-yl]-6-(4-
(9ptt) Entry 22: (Step 1) To a solution of 1 (4.06g, 22mmol) hydroxyphenoxy)-1,3,5-triazin-2-yl]oxy]phenoxy]-1,3,5-
in MeOH (60mL) were added tH (2.76g, 20mmol) and NaOH triazine-2,4-diyl]-bis(piperidine-4,1-diyl)]dimethanol (Cdu)
(3.20g, 80mmol) in water (40mL) at room temperature, Entry 23: This compound was prepared in a manner similar
and the resulting mixture was stirred for 2h. The separated to that for compound 3ds (Entry 14). Purification of products
solid was filtrated. (Step 2) The mixture of this solid and dH by flash chromatography (CH2Cl2 : EtOH=90:10→85:15→
(1.15g, 100mmol) in dry dioxane (30mL) was subjected to 80:20) gave 3du (29%) as a brown solid, Bdu (9%) as a white
MW with stirring. After evaporation of the solvent, CHCl3 solid, and Cdu (3%) as a brown solid.
and MeOH (both 30mL) were added to the residue and
3du: mp 228–229°C. IR (KBr) cm−1: 3400 (OH of alcohol),
stirred vigorously. The separated solid was removed by filtra- 1580, 1500 (C–N of t-amine), 1200, 1035 (C–O). 1H-NMR
tion and then the solvent was evaporated. Purification of the (DMSO-d6) δ: 1.01 (4H, m, H3′β, 5′β), 1.62 (2H, m, H4′α),
residue by flash chromatography (CH2Cl2 :95% EtOH:28% 1.64 (4H, m, H3′α, 5′α), 2.50 (4H, s, H2′β, 6′β), 3.25 (4H, t,
NH3=997:2.7:0.3→970:27:3) gave 9ppt (1.24g, 21%) as a J=5.6Hz, H1), 4.4 (2H, brs, H2′α, 6′α), 4.41 (2H, t, J=5.3Hz,
white solid, 9ptt (1.86g, 22%) as a white solid, 4dpt (638mg, C1-OH), 4.57 (2H, brs, H2′α, 6′α), 6.73 (2H, d, J=9.0Hz, H3‴,
8% yield) as a pale yellow solid, and 4dpp (1.11g, 20% yield) 5‴), 6.92 (2H, d, J=9.0Hz, H2‴, 6‴), 9.25 (1H, s, ArOH).
as a white solid. An analytical sample 9ppt was obtained by 13C-NMR (DMSO-d6) δ: 28.26 (C3′, 5′), 38.48 (C4′), 42.77
recrystallization from MeOH.
(C2′, 6′), 65.54 (C1), 115.14 (C3‴, 5‴), 122.32 (C2‴, 6‴), 144.52
4dpp: mp 116–118°C. IR (KBr) cm−1: 3335 (OH of alcohol), (C1‴), 154.02 (C4‴), 165.34 (C2″, 4″), 170.83 (C6″). Positive-
1
1360, 1130 (C–N of t-amine). H-NMR (CDCl3) δ: 1.2 (2H, ion FAB-MS m/z: 416 (M+H+). HR-FAB-MS m/z: 416.2303
m, H3′β, 5′β), 1.63 (1H, brs, OH), 1.8 (3H, m, H3′α, 4′α, 5′α), (Calcd for C21H30N5O4: 416.2303). Anal. Calcd for C21H29N5O4:
2.88 (2H, dt, J=13.1, 2.7Hz, H2′β, 6′β), 3.53 (2H, d, J=6.1Hz, C, 60.71; H, 7.04; N, 16.86. Found: C, 60.45; H, 7.27; N, 16.57.
H1), 3.95 (6H, s, MeO), 4.82 (2H, dm, J=13.1Hz, H2′α, 6′α).
Bdu: mp 249–251°C. IR (KBr) cm−1: 3385 (OH of alcohol),
13C-NMR (CDCl3) δ: 28.49 (C3′, 5′), 38.91 (C4′), 43.59 (C2′, 1580, 1490 (C–N of t-amine), 1195, 1040 (C–O).1H-NMR
6′), 54.40 (MeO), 67.40 (C1), 166.32 (C2″), 172.27 (C4″, 6″). (DMSO-d6) δ: 1.01 (8H, brs, H3′β, 5′β), 1.62 (12H, m, H3′α,
Positive-ion FAB-MS m/z: 255 (M+H+). HR-FAB-MS m/z: 4′α, 5′α), 2.77 (8H, brs, H2′β, 6′β), 3.25 (8H, t, J=5.5Hz, H1),
255.1454 (Calcd for C11H19N4O3: 255.1457). Anal. Calcd for 4.42 (4H, t, J=5.5Hz, OH), 4.4 (4H, brs, H2′α, 6′α), 4.59
C11H18N4O3: C, 51.96; H, 7.13; N, 22.03. Found: C, 51.97; H, (4H, brs, H2′α, 6′α), 7.14 (4H, s, H2‴, 3‴, 5‴, 6‴). 13C-NMR
7.17; N, 21.79.
(DMSO-d6) δ: 28.26 (C3′, 5′), 38.45 (C4′), 42.80 (C2′, 6′),
1
4dpt: H-NMR (CDCl3) δ: 1.19 (2H, m, H3′β, 5′β), 1.75–1.85 65.51 (C1), 122.07 (C2‴, 3‴), 148.85 (C1‴, 4‴), 165.29 (C2″,
(3H, m, H3′α, 4′α, 5′α), 2.86 (2H, m, H2′β, 6′β), 3.52 (2H, d, 4″), 170.51 (C6″). Positive-ion FAB-MS m/z: 721 (M+H+). HR-
J=6.1Hz, H1), 3.90 (3H, s, OMe), 4.65 (1H, d, J=13.1Hz, H2′α FAB-MS m/z: 721.4150 (Calcd for C36H53N10O6: 721.4144).
1
or 6′α), 4.81 (1H, d, J=13.1Hz, H6′α or 2′α), 5.98 (2H, s, H2‴),
Cdu: H-NMR (DMSO-d6) δ: 1.0 (6H, m, H3, 5 in A, B),
6.61 (1H, dd, J=8.5, 2.4Hz, H6‴), 6.68 (1H, d, J=2.4Hz, 1.65 (9H, m, H4, 3, 5 in A, B), 2.75 (6H, m, H2, 6 in A, B),
H4‴), 6.76 (1H, d, J=8.5Hz, H7‴). 13C-NMR (CDCl3) δ: 28.42 3.25 (6H, brs, CH2OH), [4.4 (m) and 4.6 (m) (6H, H2, 6 in A,
(C3′, 5′), 38.76 (C4′), 43.64 (C2′, 6′), 54.50 (MeO), 67.25 (C1), B)], 4,43 (3H, brs, CH2OH), 6.76 (2H, d, J=9.0Hz, H3, 5 in
101.53 (C2‴), 103.96 (C4‴), 107.69 (C7‴), 114.08 (C6‴), 144.89 E), 6.98 (2H, d, J=9.0Hz, H2, 6 in E), 7.19 (4H, m, H2, 3, 5,
(C7a‴), 146.50 (C5‴), 147.70 (C3a‴), 166.30 (C2″), 172.22 (C4″ 6 in F), 9.37 (1H, brs, ArOH). 13C-NMR (DMSO-d6) δ: 28.10

August 2013
833
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17) Solubility of TATAZ in most of the common organic solvents (such
as acetonitrile, dioxane, acetone or AcOH) was very poor, and
none of identified TAZ products could be isolated from reactions of
TATAZ with 1-adamantyl isothiocyanate or 3,5-bis(trifluoromethyl)-
(C3, 5 in A), 28.26 (C3, 5 in B), 38.13 (C4 in A), 38.46 (C4 in
B), 43.08, 43.12 (C2, 6 in A, B), 65.30 (CH2OH in A), 65.53
(CH2OH in B),115.37 (C3, 5 in E), 122.02 (C2, 3, 5, 6 in F),
122.23 (C2, 6 in E), 144.04 (C1 in E), 148.36, 149.35 (C1, 4
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C36H46N9O7: 716.3522).
Antiviral Activity Assay and Cytotoxicity of Target
Compounds The antiviral activities of synthesized com-
pounds were measured by using a plaque reduction assay25) as
described in our previous paper.3) Results for antiviral activity
(EC50) and cytotoxicity (IC50) with Vero cells are summarized
in Table 3.
benzoyl chloride under refluxing conditions in THF–CH
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2Cl2 for
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Acknowledgment Appreciation is expressed to Ms. Airi
Koga for skillful technical assistance.
References and Notes
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9) Many synthetic methods for the preparation of trisubstituted TAZ
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have been applied not only in the search for bioactive compounds
but also for the use of TAZ dendrimers as drug delivery systems
aiming cancer or non-viral DNA and RNA delivery systems. It is
also well known that glycosylated TAZ dendrimers interfere with
signal transduction in the Toll-4 receptor pathway (see following
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27) We used a racemic 3-hydroxylated piperizine derivative (eH) as a
starting material in the synthesis of C3- or CS-symmetric type target
TAZ derivatives. The obtained symmetric products (2e, 3es) showed
very simple symmetric 13C-NMR in DMSO-d6 or pyridine-d5, in-
dicating little difference with respect to the signals assignable to
symmetric trisubstituted TAZs. From a stereochemical viewpoint,
however, the obtained C3-type product (2e) can be considered to be
a mixture of four stereoisomers, i.e., two C3-symmetric molecules
that have the same absolute configuration regarding three intro-
duced chiral piperidines (R,R,R or S,S,S) in the molecules and a set
of two enantiomers (R,R,S and S,S,R). The trisubstituted symmetric
TAZ derivative (3es) that has two chiral piperidines in the molecule
is also expected to be a mixture of three stereoisomers, i.e., a CS-
symmetrical meso-compound having different absolute configura-
tions (R and S) with reference to the two chiral carbons and two
enantiomeric molecules that have the same absolute configuration
regarding two introduced piperidine rings in each molecule. The
obtained diastereomeric mixture exhibited very simple symmetrical
13C-NMR in pyridine-d5, showing little difference magnetically
with respect to all of the signals assignable to trisubstituted TAZ.
Since these chiral compounds (2e and 3es) as a mixture of stereo-
isomers showed no significant anti-HSV-1 activity or cytotoxicity
at a concentration of less than 100µm, we did not carry out further
detailed experiments for isolation or determination of the absolute
configurations of these stereoisomers. We have already reported
some examples of the formation of theoretical stereoisomers from
a reaction using a racemic reagent as the starting material for the
construction of similar symmetrical molecules (see ref. 5).