Facile synthesis of 5-aryl-1-[(arylamino)methyl]- 1,3,5-triazinane-2- thiones

Article abstract of DOI:10.1002/jhet.730

A series of 5-aryl-1-arylaminomethyl-1,3,5-triazinane-2-thiones has been prepared in a one-step procedure from condensation of readily available aromatic amines with thiourea and formaldehyde. A mechanism is presented to account for the formation of the p

Full text of DOI:10.1002/jhet.730

March 2012
Facile Synthesis of 5-Aryl-1-[(arylamino)methyl]-
1,3,5-triazinane-2-thiones
433
Zhenfeng Zhang,* Siqian Wang, and Guisheng Zhang*
College of Chemistry and Environmental Science, Henan Normal University,
Xinxiang 453007, People’s Republic of China
*E-mail: zzf5188@sohu.com
Received April 22, 2010
DOI 10.1002/jhet.730
Published online 20 December 2011 in Wiley Online Library (wileyonlinelibrary.com).
A series of 5-aryl-1-arylaminomethyl-1,3,5-triazinane-2-thiones has been prepared in a one-step pro-
cedure from condensation of readily available aromatic amines with thiourea and formaldehyde. A
mechanism is presented to account for the formation of the products. The overall sequence provides a
simple and efficient route to prepare in good to excellent yields and in a short experimental time.
J. Heterocyclic Chem., 49, 433 (2012).
INTRODUCTION
RESULTS AND DISCUSSION
Heterocyclic compounds containing thiourea structural
unit have found some powerful bioactivities, such as
powerful ectoparasiticidal action [1], potent antidiabetic
properties [2], and anti-HIV activity [3,4]. In addition,
some such compounds can serve as calcium channel
blockers, antihypertensive agents, and a-1a-antagonists
[5]. Therefore, it is not surprising that searching for new
methods to synthesize heterocyclic compounds starting
from thiourea has received special attention. Burke and
Petersen have early reported the synthetic studies of 5-
alkyl or 4,6-dialkyl substituted 1,3,5-triazinane-2-thiones
[6a,b]. However, for 5-aryl-1-arylaminomethyl-1,3,5-tri-
azinane-2-thiones, only 5-phenyl-1-[(phenylamino)-
methyl]-1,3,5-triazinane-2-thione (4a, Fig. 1) was
reported as an abnormal product [7]. The facile and
effective approaches to a series of the titled compounds,
and their bioactivities have not been reported so far. In
our efforts to find bioactive 1,3,5-triazinane-2-thione
compounds, we designed a series of diversely substi-
tuted 5-aryl-1-arylaminomethyl-1,3,5-triazinane-2-thio-
nes (Fig. 1) and tried to prepare them following the lit-
erature procedure [7]; however, we did not obtained
such compounds except for 4a. In this article, we
describe a method whereby a wide variety of 5-aryl-1-
arylaminomethyl-1,3,5-triazinane-2-thiones can be pre-
pared rapidly and in excellent yields by a one-step syn-
thesis from readily available materials and their antitu-
mor activities.
Initially, we attempted to prepare 1,5-disubstituted
1,3,5-triazinane-2-thiones (4a–h) following the litera-
ture procedure [7] for 4a, using a three-component
condensation of thiourea with arylamines and aqueous
formaldehyde in a one-pot manner at 1:2:2 ratio in
ethanol at room temperature. However, the desired
compounds were not obtained except for 4a. It was
noted that white precipitates appeared from the reaction
mixtures when the reactions were performed for 4b–h.
The precipitate was N-methylenearylamine or its
trimer, 1,3,5-triaryl-1,3,5-triazacyclohexane, in terms of
1
its H-NMR spectrum. The formation of the precipitate
cumbered the further aminomethylation of thiourea to
produce 4b–h. When the reaction mixture was refluxed
with a catalytic amount of acetic acid, the precipitate
smoothly underwent the aminomethylation of thiourea
to afford the desired compounds. Taking into account
the structural characteristic of these compounds and the
above unexpected finding, the ratio of reactants was
adjusted to thiourea:anilines:formaldehyde ¼ 1:2:3, and
the reaction temperature was elevated to explore a bet-
ter route to 1,5-disubstituted 1,3,5-triazinane-2-thiones.
It turned out that this one-pot three-component proce-
dure worked very well under the optimized conditions
(Scheme 1). Accordingly, thiourea 1, 4-toluidine 2d,
and aqueous formaldehyde 3 were mixed in ethanol
(95%), after the addition of a catalytic amount of ace-
tic acid (5 mol %), the mixture was refluxed with
C
V
2011 HeteroCorporation

434
Z. Zhang, S. Wang, and G. Zhang
Vol 49
tic pathway can be delineated at present time, the fol-
lowing mechanistic concept may be advanced to account
for the formation of the products 4 (Scheme 2).
Although this is likely to be an equilibrium nucleophilic
addition of anilines 2 to formaldehyde 3 leads to N-
hydroxymethylanilines reaction, addition compounds 5
are expected to undergo rapid dehydration in the pres-
ence of acid to a highly reactive carbenium ion which
may be formulated as a resonance-stabilized N-phenyli-
minium species, i.e., 6. In the presence of the thiourea,
each two iminium ions 7 are intercepted by one thiourea
molecule to furnish intermediate 7. It was then reacted
with the third formaldehyde molecule, to give addition
product 8. Finally, the cyclization and dehydration of 9
under generally acetic acid-catalyzed reaction conditions
produced 1,3,5-triazinane-2-thione derivatives 4. This
mechanism is also supported by the fact that reaction
with aryl amines, carrying electron-withdrawing groups,
did not occur. In this situation, the intermediate 6 could
not be stabilized by delocalization to the benzene ring,
and the transformation from intermediate 5–6 does not
seem to happen.
Figure 1. 5-Aryl-1-arylaminomethyl-1,3,5-triazinane-2-thiones.
stirring for about 10 min. Finally, the product 4d was
isolated in high yields.
Encouraged by our initial observation, we further
explored the substrate scope and limitation of this reac-
tion. Various aromatic primary amines with different
substituents were reacted with thiourea and formalde-
hyde under the same reaction conditions (Scheme 1). As
shown in Table 1, all reactions proceeded smoothly to
afford the corresponding 1,5-disubstituted 1,3,5-triazi-
nane-2-thiones 4 in high yields. However, the reactions
of aromatic amines carrying strongly electron-withdraw-
ing substituent(s), such as 3- or 4-nitrobenzenamine,
were not occurred. In addition, we also explored the
reaction of urea, in place of thiourea, with aromatic
amine and formaldehyde under the same conditions;
unfortunately, the corresponding 1,3,5-triazinane-2-ones
were not obtained.
In summary, we have shown that the condensation
reaction of aromatic amines, thiourea, and formaldehyde
occurs efficiently in boiling in 95% ethanol as a solvent,
providing a convenient and rapid synthesis of a series
of 5-aryl-1-arylaminomethyl-1,3,5-triazinane-2-thiones in
high yield, by a simple procedure and short experimental
time. Compound 4c showed inhibitory activity toward
dual-specificity phosphatase Cdc25A (cell division cycle
25A) at a concentration of 20 lg/mL in vitro.
The structures of the products 4a–h were character-
1
ized on the basis of their elemental analysis, H-NMR
and 13C-NMR spectra. Meanwhile, structures of com-
pounds 4a, 4b, and 4g were further confirmed by X-ray
crystal structure analysis [8,9].
Compounds 4a and 4c–f were evaluated for their anti-
tumor activities by cell-culture bioassay. They showed
inhibitory activity toward dual-specificity phosphatase
Cdc25A by 12.99, 46.23, 13.20, 3.06, 0.67%, respec-
tively, at a concentration of 20 lg/mL [10].
Asymmetrically structural feature of these target mol-
ecules suggests an interesting reactive mechanism,
which is different from that for the similar reaction of
urea (thiourea), formaldehyde, and primary aliphatic
amines [6]. Although no definitely accessible mechanis-
EXPERIMENTAL
1H- and 13C-NMR spectra were recorded on Avance 400/
DPX (Bruker) (400 MHz and 100 MHz, respectively) from
DMSO-d6 solutions using the residual solvent signal as refer-
ence. Elemental analysis was carried out on a Heraeus Vari-
oEL-III C, H, and N analyzer. All reagents and solvents were
commercially available and used without further purification.
Chemical shifts are reported in parts per million. All chemical
Scheme 1. The one-pot synthesis of the 5-aryl-1-arylaminomethyl-1,3,5-triazinane-2-thiones.
Journal of Heterocyclic Chemistry
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Facile Synthesis of 5-Aryl-1-[(arylamino)methyl]-1,3,5-triazinane-2-thiones
435
Table 1
One-pot preparation of 1,5-disubstituted 1,3,5-triazinane-2-thiones.
Entry
Product
Yield (%)a,b
Entry
Product
Yield (%)a,b
1
77
5
91
80
85
74
2
3
4
82
73
85
6
7
8
a Isolated yields.
b Reaction time is within 10 min.
shift values are quoted in ppm and coupling constants quoted
in Hz.
5-Phenyl-1-[(phenylamino)methyl]-1,3,5-triazinane-2-thione
(4a). The pure compound 4a was obtained as a white solid by
recrystallization from acetonitrile (77% yield), mp 160–162ꢀC;
1H-NMR: (400 MHz, DMSO-d6): d 8.30 (s, 1H), 7.10–6.58
(m, 10H), 6.45 (t, J ¼ 7.2 Hz, 1H), 5.23 (d, J ¼ 6.8 Hz, 2H),
4.79 (s, 2H), 4.57 (s, 2H); 13C-NMR (100 MHz, DMSO-d6): d
176.0, 146.2, 145.7, 128.2, 128.1, 120.7, 117.2, 116.4, 112.4,
60.7, 59.2, 57.4; m/z ¼ 297.6, 194.5. Anal. Calcd. for
C16H18N4S: C, 64.40; H, 6.08; N, 18.78. Found: C, 64.34; H,
6.22; N, 18.73.
General procedure for the preparation of 4a–h. To a
mixture of thiourea (0.1 mol) and aniline (0.2 mol) in ethanol
(95%), aqueous formaldehyde (0.3 mol) and a catalytic amount
of acetic acid (5 mol %) were added. The resulted mixture
was refluxed with stirring for about 10 min, then allowed to
stand overnight at room temperature to precipitate the product
completely. The precipitate was filtered off, washed with etha-
nol (95%), dried, and recrystallized to give the pure product 4.
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Z. Zhang, S. Wang, and G. Zhang
Vol 49
Scheme 2. Possible mechanism for the formation of products 4a–h.
5-(4-Chlorophenyl)-1-{[(4-chlorophenyl)amino]methyl}-1,3,5-
5-(4-Bromophenyl)-1-{[(4-bromophenyl)amino]methyl}-1,3,5-
triazinane-2-thione (4f) The compound was recrystallized from
anhydrous ethanol (colorless), mp 167–169ꢀC; 1H-NMR: (400
MHz, DMSO-d6) d: 8.42 (s, 1H), 7.23–6.78 (m, 8H), 6.66 (t, J
¼ 6.8 Hz, 1H), 5.22–5.20 (d, J ¼ 6.8, 2H), 4.80 (s, 2H), 4.59
(s, 2H); 13C-NMR (100 MHz, DMSO-d6): d 177.0, 146.4,
145.8, 131.8, 131.6, 120.8, 120.3, 115.5, 113.6, 61.6, 59.7,
57.8; m/z ¼ 302.7, 274.4, 272.4, 186.4. Anal. Calcd. for
C16H16Br2N4S: C, 42.12; H, 3.54; N, 12.28. Found: C, 42.05;
H, 3.69; N, 12.20.
triazinane-2-thione (4b) The compound was recrystallized
from DMSO (slight dark), mp 166–168ꢀC; 1H-NMR: (400
MHz, DMSO-d6): d 8.37 (s, 1H), 6.80–7.08 (m, 8H), 6.59 (t, J
¼ 6.8 Hz, 1H), 5.20–5.19 (d, J ¼ 6.8 Hz, 2H), 4.78 (s, 2H),
4.57 (s, 2H); 13C-NMR (100 MHz, DMSO-d6): d 176.9, 145.8,
145.3, 128.7, 128.6, 125.6, 120.7, 119.8, 114.8, 61.6, 59.8,
57.7; m/z
¼
365.5, 367.5, 228.4. Anal. Calcd. for
C16H16Cl2N4S: C, 52.32; H, 4.39; N, 15.25. Found: C, 52.28;
H, 4.46; N, 15.16.
5-(3-Chlorophenyl)-1-{[(3-chlorophenyl)amino]methyl}-1,3,5-
triazinane-2-thione (4c) The compound was recrystallized
from 95% ethanol (colorless), mp 149–151ꢀC; 1H-NMR (400
MHz), DMSO-d6): 8.41 (s, 1H), 7.08–6.56 (m, 8H), 6.71–6.61
(t, J ¼ 6.4, 1H), 5.22–5.25 (d, J ¼ 6.4, 2H), 4.81 (s, 2H), 4.62
(s, 2H); 13C-NMR (100 MHz, DMSO-d6): d 177.1, 148.7,
148.1, 134.0, 130.6, 130.5, 128.8, 121.6, 117.8, 116.9, 116.7,
112.8, 112.1, 61.5, 59.7, 57.7; m/z ¼ 367.6, 228.5. Anal.
Calcd. for C16H16Cl2N4S: C, 52.32; H, 4.39; N, 15.25. Found:
C, 52.24; H, 4.46; N, 15.21.
5-(4-Methylphenyl)-1-{[(4-methylphenyl)amino]methyl}-1,3,5-
triazinane-2-thione (4d) The precipitate was recrystallized
from ethyl acetate (white), mp 170–172ꢀC; 1H-NMR (400
MHz, DMSO-d6) d 8.23 (s, 1H), 6.91–6.71 (m, 8H), 6.18 (t, J
¼ 7.2 Hz, 1H), 5.17–5.15 (d, J ¼ 7.2 Hz, 2H), 4.71 (s, 2H),
4.50 (s, 2H), 2.14 (s, 3H), 2.13 (s, 3H); 13C-NMR (100 MHz,
DMSO-d6) d 177.6, 145.7, 145.1, 131.5, 130.5, 130.4, 126.6,
119.2, 114.4, 63.1, 61.1, 59.5, 21.2, 21.1; m/z ¼ 326.6. Anal.
Calcd. for C18H22N4S: C, 66.22; H, 6.79; N, 17.16. Found: C,
66.00; H, 6.99; N, 17.01.
5-(4-Methoxyphenyl)-1-{[(4-methoxyphenyl)amino]methyl}-
1,3,5-triazinane-2-thione (4e) The compound was recrystal-
lized from ethyl acetate (white), mp 150–152ꢀC; 1H-NMR:
(400 MHz, DMSO-d6): d 8.24 (s, 1H), 6.85–6.63 (m, 8H),
6.06 (t, J ¼ 6.8 Hz, 1H), 5.16–5.14 (d, J ¼ 6.8 Hz, 2H), 4.67
(s, 2H), 4.45 (s, 2H), 3.62 (s, 3H), 3.61 (s, 3H); 13C-NMR
(100 MHz, DMSO-d6): d 176.9, 154.6, 151.8, 140.8, 140.4,
120.1, 114.8, 114.6, 114.4, 62.8, 60.8, 59.0, 55.4, 55.3; m/z ¼
358.7, 208.5. Anal. Calcd. for C18H22N4O2S: C, 60.31; H,
6.19; N, 15.63. Found: C, 60.23; H, 6.28; N, 15.46.
5-(3-Fluoro-4-methoxyphenyl)-1-{[(3-fluoro-4-methoxyphenyl)
amino]methyl}-1,3,5-triazinane-2-thione (4g) The compound
was recrystallized from ethyl acetate (brown), mp 166–168ꢀC;
1H-NMR: (400 MHz, DMSO-d6) d: 8.36 (s, 1H), 6.52–6.87
(m, 6H), 6.34 (t, J ¼ 6.8 Hz, 1H), 5.16–5.17 (d, J ¼ 6.8, 2H),
4.75 (s, 2H), 4.54 (s, 2H), 3.72 (s, 3H), 3.71 (s, 3H); 13C-
NMR (100 MHz, DMSO-d6): d 177.1, 154.0, 153.1, 151.6,
150.7, 142.4, 141.3, 139.0, 115.9, 114.4, 109.1, 107.7, 102.0,
62.6, 60.3, 58.3, 57.0, 56.4; m/z ¼ 395.8, 394.8, 242.6. Anal.
Calcd. for C18H20F2N4O2S: C, 54.81; H, 5.11; N, 14.20.
Found: C, 54.92; H, 5.28; N, 14.08.
5-(4-Tert-butylphenyl)-1-{[(4-tert-butylphenyl)amino]methyl}-
1,3,5-triazinane-2-thione (4h) The compound was recrystal-
lized from ethanol (white), mp 187–189ꢀC; 1H-NMR: (400
MHz, DMSO-d6): d 8.26 (s, 1H), 7.31–6.82 (m, 8H), 6.35 (t, J
¼ 6.8 Hz, 1H), 5.26 (d, J ¼ 6.8, 1H), 4.79 (s, 2H), 4.60 (s,
2H), 4.56 (s, 1H), 1.26 (s, 9H), 1.20 (s, 9H); 13C-NMR (100
MHz, DMSO-d6): d 176.7, 144.4, 139.7, 126.1, 125.9, 118.7,
118.4, 117.1, 113.4, 61.6, 60.1, 58.5, 34.2, 34.1, 31.9, 31.6; m/
z ¼ 411.7, 409.7, 250.5. Anal. Calcd. for C24H34N4S: C,
70.20; H, 8.35; N, 13.64. Found: C, 70.55; H, 8.57; N, 13.49.
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Facile Synthesis of 5-Aryl-1-[(arylamino)methyl]-1,3,5-triazinane-2-thiones
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