A convenient one-pot synthesis of trisubstituted 1,3,5-triazines through intermediary amidinothioureas

Article abstract of DOI:10.1016/j.tetlet.2010.01.034

A thiophile-promoted one-pot synthesis of trisubstituted 1,3,5-triazines starting from isothiocyanates, N,N-diethylamidines, and carbamidines has been studied. The reaction proceeds through the formation of intermediary amidinothioureas, which react with

Full text of DOI:10.1016/j.tetlet.2010.01.034

Tetrahedron Letters 51 (2010) 1486–1489
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A convenient one-pot synthesis of trisubstituted 1,3,5-triazines through
intermediary amidinothioureas
*
Jitendra C. Kaila, Arshi B. Baraiya, Amit N. Pandya, Hitesh B. Jalani, V. Sudarsanam, Kamala K. Vasu
Department of Medicinal Chemistry, B.V. Patel Pharmaceutical Education and Research Development (PERD) Centre, Thaltej-Gandhinagar Highway, Thaltej,
Ahmedabad 380 054, Gujarat, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A thiophile-promoted one-pot synthesis of trisubstituted 1,3,5-triazines starting from isothiocyanates,
N,N-diethylamidines, and carbamidines has been studied. The reaction proceeds through the formation
of intermediary amidinothioureas, which react with carbamidines in the presence of mercury(II) chloride
to generate the desired 1,3,5-triazines in good to moderate yields (40–70%).
Received 24 October 2009
Revised 30 December 2009
Accepted 10 January 2010
Available online 15 January 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Thiophile
1,3,5-Triazines
Amidinothioureas
Carbamidines
1,3,5-Triazines are one of the oldest classes of organic com-
pounds that continue to be of interest due to their interesting phar-
macological properties. Members of this class have been found to
possess anti-tumor,1 corticotrophin-releasing factor-1 receptor
antagonist,2 leukotriene C4 (LTC4) antagonist,3 inosine monophos-
phate dehydrogenase (IMPDH) inhibitory,4 erm methyltransferase
inhibitory,5 and reticuloendothelial hyperfunction depressive
activities.6 Despite the biological importance of 1,3,5-triazines,
synthetic methods for the preparation of analogs containing differ-
ent substituents at each carbon are limited.
Cyanuric chloride has been used widely for the preparation of tri-
substituted triazines, but stepwise replacement of the three chlo-
rines with Grignard reagents, ammonia, and amines is often
unreliable and leads to mixtures of compounds.4,7 The synthesis of
triazines with alkyl substituents can be problematic using this
methodology due to the highly reactive nature of the Grignard
reagents. More general routes to these compounds involve the
reaction of substitutedbiguanides with acid chlorides,8 anhydrides,9
or carboxylates.5,6 However, the preparation of substituted bigua-
nides requires harsh conditions and isolation of the products are
difficult due to their high water solubility. The cyclizations of
acylamidines with amidines or guanidines gave s-triazines with dif-
ferent substitutents.10 This is a convenient synthetic route to trisub-
stituted 1,3,5-triazines, but it allows only two variations at position
4 of the triazine ring. The recently published procedure involves the
treatment of isothiocyanates with sodium hydrogencyanamide,
followed by amidines in the presence of 1-(3-dimethylaminopro-
pyl)-3-ethylcarbodiimide (EDC) hydrochloride.11 This protocol ap-
pears to be general with isothiocyanates (both aromatic and
aliphatic) and aromatic carbamidines, while less hindered aliphatic
carbamidines lead to undesired N-cyanoguanidines. Therefore, it is
still of continued interest and great importance to explore novel
and efficient synthetic approaches for such heterocycles. Herein,
we report a convenient, one-pot procedure for the preparation of tri-
substituted 1,3,5-triazines through intermediary amidinothioureas
which is applicable for the wide range of substituents at each carbon
of the triazine ring.
During the course of our recent studies on amidinothioureas for
the synthesis of biologically interesting heterocycles, we reported
the synthesis of various amidinoguanides from amidinothioureas
using mercury(II) chloride as a thiophile.12 It was envisaged that
this methodology could be extended to the preparation of trisub-
stituted 1,3,5-triazine by replacing anilines with binucleophilic
carbamidines. Thus, 4-chlorophenyl isothiocyanate
1
(R1 = 4-
ClC6H4) was reacted with readily available N,N-diethyl acetamidine
2 (R2 = CH3) in THF to provide the corresponding intermediary
amidinothiourea 3 (Scheme 1). Without isolation of intermediary
amidinothiourea, it was treated with benzamidine hydrochloride
4 (R3 = C6H5) at room temperature in the presence of triethylamine
and mercury(II) chloride. The desulfurization of the amidinothiou-
rea was monitored visually based on the formation of the black
precipitate of HgS. The formation of 1,3,5-triazine was observed
as a new spot at the uppermost part of the TLC. The reaction mix-
ture was kept under stirring for another 4 h and after column chro-
matographic purification, it was identified as the desired triazine 5
by LC, MS, and 1H NMR (Table 1, entry 1).
* Corresponding author. Tel.: +91 79 27439375; fax: +91 79 27450449.
E-mail addresses: perd@perdcentre.com, kamkva@gmail.com (K.K. Vasu).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.01.034

J. C. Kaila et al. / Tetrahedron Letters 51 (2010) 1486–1489
1487
Scheme 1.
Table 1
Synthesis of trisubstituted 1,3,5-triazines
Entry Isothiocyanates 1
N,N-Diethylamidines or
tetramethylguanidine 2
Carbamidines 4
Products 5
Yielda
(%)
HCl
H2N
Cl
NH
NH
NCS
NCS
N
N
1
2
N
N
70
N
H
N
HN
HN
Cl
F
HCl
H2N
F
F
67
40
65
N
N
N
N
H
N
N
NCS
HCl
H2N
HN
HN
NH
NH
3
N
N
F
N
H
N
HCl
H2N
NCS
4
N
N
N
H
N
HCl
H2N
NH
NH
NCS
N
N
5
6
7
45
40
65
HN
HN
N
N
N
N
H
HCl
H2N
MeO
MeO
NCS
OMe
MeO
MeO
Cl
N
N
OMe
Cl
N
H
N
HCl
H2N
NH
NCS
N
Cl
HN
N
N
Cl
N
H
N
(continued on next page)

1488
J. C. Kaila et al. / Tetrahedron Letters 51 (2010) 1486–1489
Table 1 (continued)
Entry Isothiocyanates 1
N,N-Diethylamidines or
tetramethylguanidine 2
Carbamidines 4
Products 5
Yielda
(%)
HCl
H2N
NH
NH
NH
N
NCS HN
8
45
OMe
N
N
OMe
OMe
N
H
N
HCl
H2N
N
MeO
MeO
NCS
HN
HN
OMe
9
50
MeO
MeO
OMe
N
N
OMe
N
H
N
HCl
H2N
N
N
N
N
O
N
O
10
11
12
62
50
80
O
NCS
O
N
H
N
N
N
HCl
H2N
NCS
N
N
Cl
NH
NH
N
N
HN
HN
Cl
N
H
HCl
H2N
N
N
N
N
NCS
N
N
H
N
HCl
H2N
N
N
NH
NCS
F
OMe
N
N
N
N
13
55
HN
F
Cl
N
H
Cl
OMe
a
Isolated yield.
Copper sulfate–Silica Gel,13 lac sulfur on alumina-triethanola-
be studied to identify the most suitable reagent for this reaction in
one-pot without the isolation of intermediates. We chose to com-
pare these reagents as our thiophiles (Table 2) and monitored the
formation of (4-chlorophenyl)-(4, 6-diphenyl-[1,3,5]triazin-2-yl)-
mine14
and
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
(EDC) hydrochloride15 have been used as thiophiles for the guany-
lation of amines by thioureas. We reasoned that these reagents can
Table 2
Reaction of 4-chlorophenyl isothiocyanate, N,N-diethyl benzamidine, and benzamidine hydrochloride to generate 4-chlorophenyl-(4,6-diphenyl-[1,3,5] triazin-2-yl)-amine
mediated by a thiophile
HCl
NH2
NCS
Cl
Thiophile
N
N
N
HN
HN
Cl
TEA, THF
N
H
N
Thiophile
Reaction time
Yielda (%)
a
b
c
d
e
HgCl2
6 h
75
Hg(OAc)2
CuSO4ÁSiO2
12 h
12 h
12 h
12 h
No reaction
10
No reaction
55
Lac sulfur:Alumina
EDC hydrochloride
a
Isolated yield.

J. C. Kaila et al. / Tetrahedron Letters 51 (2010) 1486–1489
1489
can be found, in the online version, at doi:10.1016/
j.tetlet.2010.01.034.
References and notes
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Scheme 2.
amine in a model reaction. On the basis of the product yield it was
clear that EDC hydrochloride and HgCl2 were the optimal reagents
for this reaction. We studied the generality of both the thiophiles
for the synthesis of desired triazines. EDC hydrochloride failed to
yield triazines when acetamidine hydrochloride was used as a
binucleophile, but HgCl2 gave the desired product. Therefore, HgCl2
was selected as a general thiophile for all other reactions.
All the reactions between isothiocyanates, N,N-diethylamidines,
and carbamidines with systematic variations of R1, R2, and R3 pro-
ceeded smoothly to afford the corresponding 1,3,5-triazines in
good to moderate yields (Scheme 1). The generality of this new
synthetic method for the efficient construction of 1,3,5-triazines
was investigated by employing HgCl2 as a thiophile using THF as
a solvent at room temperature.16 The results are summarized in
Table 1. The generality of this method for the synthesis of 2,5-dia-
mino-1,3,5-triazines was also studied by reacting isothiocyanates
with tetramethylguanidine followed by condensation with carb-
amidines in the presence of HgCl2 (Scheme 2, Table 1, entries
10–13).
In conclusion, we have reported a convenient one-pot synthesis
of biologically important trisubstituted 1,3,5-triazine derivatives
from readily available starting materials under mild conditions.
The reaction is applicable to a wide range of substituted isothiocy-
anates, N,N-diethylamidines, and carbamidines.
15. Linton, B. R.; Carr, A. J.; Orner, B. P.; Hamilton, A. D. J. Org. Chem. 2000, 65,
1566–1568.
16. General experimental procedure for the preparation of trisubstituted 1,3,5-
triazines: To a stirred solution of isothiocyanate 1 (1 mmol) in THF (5 mL),
N,N-diethylamidine 2 (1 mmol) was added at room temperature and allowed
to stir for 2 h. To the stirred reaction mixture triethylamine (15 mmol) and
carbamidine hydrochloride 4 (1.2 mmol) were added at room temperature.
Mercury(II) chloride (1 mmol) was added slowly to the reaction mixture (slight
exothermic) and the mixture was allowed to stir for another 4 h at room
temperature. Initiation of the desulfurization was observed by the formation of
black HgS precipitate. Progress of the reaction was monitored by TLC using
ethyl acetate/hexane (3:7) as a mobile phase. After the completion of the
reaction, the reaction mixture was diluted with THF (5 mL) and filtered
through a Celite bed to remove the black precipitate of HgS. The filtrate was
concentrated in vacuum and purified by silica gel (60–120 mesh) column
chromatography using 12% ethyl acetate in hexane as a mobile phase to give
triazines 5. The same experimental protocol was followed for the preparation
of 2,5-diamino-1,3,5-triazines (Scheme 2, Table 1, entries 10–13) using
tetramethylguanidine instead of N,N-diethylamidines.
Acknowledgments
We thank Professor Harish Padh and Professor C. J. Shisoo,
Directors, B.V. Patel PERD centre, for their constant encouragement
and support.
Supplementary data
Supplementary data (general experimental procedure and spec-
tral data for representative compounds) associated with this article