Domino [3+2+1] heterocyclization of isothiocyanates with aryl amidines leading to polysubstituted 1,3,5-triazine derivatives

Article abstract of DOI:10.1016/j.tetlet.2013.01.086

Concise and efficient domino [3+2+1] heterocyclization of isothiocyanates with aryl amidines has been established for the synthesis of 1,3,5-triazine derivatives. The multicomponent domino reaction (MDR, AB₂ type) is easy to perform simply by m

Full text of DOI:10.1016/j.tetlet.2013.01.086

Tetrahedron Letters 54 (2013) 1743–1746
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Tetrahedron Letters
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Domino [3+2+1] heterocyclization of isothiocyanates with aryl amidines
leading to polysubstituted 1,3,5-triazine derivatives
⇑
⇑
Na Li, Man-Su Tu, Bo Jiang , Xiang Wang, Shu-Jiang Tu
School of Chemistry and Chemical Engineering, and Jiangsu Key Laboratory of Green Synthetic Chemistry for Functional Materials, Jiangsu Normal University, Xuzhou 211116,
PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Concise and efficient domino [3+2+1] heterocyclization of isothiocyanates with aryl amidines has been
established for the synthesis of 1,3,5-triazine derivatives. The multicomponent domino reaction (MDR,
AB2 type) is easy to perform simply by mixing inexpensive isothiocyanates and aryl amidines in the pres-
ence of NaOH under microwave heating. The present synthesis shows attractive properties such as con-
cise one-pot conditions, short reaction periods (15–24 min), and easy purifications. The resulting 1,3,5-
triazine derivatives are important structural motifs in organic and medicinal research.
Ó 2013 Elsevier Ltd. All rights reserved.
Received 7 October 2012
Revised 13 January 2013
Accepted 21 January 2013
Available online 29 January 2013
Keywords:
1,3,5-Triazine synthesis
[3+2+1] Heterocyclization
Multicomponent domino reactions
Nitrogen-containing heterocycles (azaheterocycles) are omni-
present in nature and are of great significance to life because their
structural subunits exist in many natural products such as vita-
mins, antibiotics, and alkaloids, as well as pharmaceuticals and
many more compounds.1 The 1,3,5-triazines and their derivatives
are the oldest class of extremely important heterocyclic com-
pounds and are used in a wide array of synthetic and industrial
applications. They have been found to exhibit anti-tumor,2 cortico-
trophin-releasing factor-1 receptor antagonist,3 leukotriene C4
(LTC4) antagonist,4 inosine monophosphate dehydrogenase
(IMPDH) inhibitory,5 and erm methyltransferase inhibitory activi-
ties.6 In the past several decades, many methodologies for the
preparation of 1,3,5-triazines with different substituents have been
developed, which involved nucleophilic substitution of cyanuric
chloride with different nucleophiles,5,7 two-component reaction
of biguanides with acid chlorides,8 or anhydrides,9 or carboxyl-
ates,6,10 cascade cyclization of acylamidines with amidines or
guanidines,11 two-step method of isothiocyanates,12 and recently
one-pot reaction of isothiocyanates, N,N-diethylamidines, and
carbamidines.13 However, most of these reactions suffered from
multisteps, the limited scope of substrates, tedious operation pro-
cedures, and longer reaction times. Therefore, the development of
new alternate and more efficient strategies for the synthesis of this
family of heterocyclic compounds by minimizing the formation of
waste and by-products, continues to be of great interest and
challenging.
On the other hand, multicomponent domino reactions (MDRs)
allow the creation of several bonds in a single operation and em-
body many features including atom- and step economy, conver-
gence, structural diversity, and reduction in the number of
workup procedures and purification processes, thereby minimizing
the generation of waste and rendering the transformations green.14
Based on the unique properties of intermediates, these processes
can be rationally designed, so that they serve as ideal approaches
for the efficient synthesis of structurally complex and functionally
diverse molecules that play the role of lead compounds in drug dis-
covery efforts.15 Therefore, MDRs have attracted enormous atten-
tion and became a powerful tool in organic chemistry.
Recently, we have been engaging in the development of unique
MDRs that can provide easy access to new core structures of chem-
ical and pharmaceutical interest.16,17 As a part of our study of this
topic, we now developed domino [3+2+1] heterocyclization of iso-
thiocyanates with aryl amidines, providing polyfunctionalized
1,3,5-triazine derivatives with good yields (Scheme 1).
Het.
R
NH
R
Het.
NH2
N
N
2
+
NaOH
DMF
MWI
Ar
Ar
N
Ar
N
C
N
H
N
S
C
S
Ar
S
1
1
3
⇑
Corresponding authors. Tel./fax: +86 516 83500065.
E-mail addresses: jiangchem@jsnu.edu.cn (B. Jiang), laotu@jsnu.edu.cn (S.-J. Tu).
Scheme 1. The multicomponent domino reaction of 1 with 2.
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.01.086

1744
N. Li et al. / Tetrahedron Letters 54 (2013) 1743–1746
Table 1
The great features of this chemistry are shown by the fact that
Optimization of reaction conditions
the domino construction of 1,3,5-triazine skeleton and its N-aryla-
tion was readily achieved via base-promoted multicomponent
reaction (AB2 type) in a one-pot operation. The present work rep-
resents the special example for the preparation of such important
types of 1,3,5-triazine derivatives.
In an initial study, benzamidine (2a, 1.0 equiv) was reacted with
4-chlorophenyl isothiocyanate (1a, 2.2 equiv) in DMF at 80 °C
using NaOH (0.2 equiv) as a base under microwave heating. The
reaction proceeded smoothly to provide polysubstituted 1,3,5-tria-
zines 3a in 58% yield. The structure of 3a was characterized on the
basis of its spectral and analytical data. Furthermore, the structural
elucidation was unequivocally determined by X-ray diffraction of
single crystals of 3j (Fig. 1) and 3l (See SI).
Encouraged by the above reported satisfactory results, we next
optimized this reaction conditions including different solvents and
bases (Table 1). The same reaction of 1a with 2a was investigated
using a variety of bases (0.2 equiv), such as K2CO3, NaOH, Et3N, and
NaOEt under microwave (MW) irradiation at 80 °C. The reaction
scarcely proceeded in the presence of K2CO3 (Table 1, entry 1).
When Et3N or NaOEt was used as a base catalyst, 3a was isolated
in low yield and this may be due to the formation of thiourea 4
as by-product. (Table 1, entries 2 and 3). Subsequently, the effect
of NaOH as a base promoter was investigated in this reaction.
0.2 equiv of NaOH gave 58% yield of the product 3a. A similar out-
come (56%) was observed when the amount of NaOH was in-
creased to 0.4 equiv (Table 1, entry 6). When 0.1 equiv of NaOH
was used, it resulted in slightly lower yield of the desired product
3a (Table 1, entry 5). Next, the reaction promoted by NaOH was
performed in different solvents such as EtOH (47%), DMF (58%),
and 1,4-dioxane (50%) in a sealed vessel under microwave irradia-
tion for 15 min. The best yield of product 3a (78%) was obtained in
DMF, as the reaction temperature was increased to 110 °C (Table 1,
entry 7).
Ph
Ar
S
Ar
N
N
N
C
S
H2N
N
C
S
Base
Solvent
MWI
Ar
Ar
+
Ar
+
Ph
+
N
H
N
H
N
H
N
S
HN
Ar
3a
1a
Ar = 4-chlorophenyl
2a
1a
4
Entry
Base (equiv)
Solvent
T (°C)
Time (min)
Yielda (%)
1
2
3
4
5
6
7
K2CO3 (0.2)
Et3N (0.2)
DMF
DMF
DMF
DMF
DMF
DMF
DMF
80
80
80
80
80
80
110
20
15
15
15
15
15
15
Trace
28
NaOEt (0.2)
NaOH(0.2)
NaOH (0.1)
NaOH (0.4)
NaOH(0.2)
35
58
42
56
78
a
Isolated yield.
2 did not hamper the reaction progress. Reactions of methyl-, bro-
mo-, chloro-, or fluoro-substituted phenyl isothiocyanates 1 with
aryl amidines 2, all proceeded well to afford the desired products
in good yields. Aryl amidines bearing electron-withdrawing groups
were examined and as anticipated, the reactions proceeded
smoothly to give the corresponding products in good yields. Pyri-
din-3-yl, pyridin-4-yl, and pyrimidin-2-yl amidines were also con-
verted into pyridin-3-yl, pyridin-4-yl, and pyrimidin-2-yl
substituted 1,3,5-triazine-2(1H)-thiones 3c–3e, 3h–3i, 3l–3n, 3q–
3s, and 3u–3v and the products were isolated in 60–78% yields.
The results exhibited the scope and generality of the new domino
reaction with respect to a range of amidine and isothiocyanate sub-
strates. Furthermore, halogen (Cl, and Br) containing substrates
were also well tolerated. These functional groups provide ample
opportunity for further functional group manipulations such as
using modern cross-coupling reactions.
Using the optimized reaction conditions, the scope of a variety
of structurally diverse isothiocyanates and aryl amidines were
investigated, and a series of new 1,3,5-triazine-2(1H)-thiones were
synthesized in good yields, with arylamino group in position 6 of
the 1,3,5-triazine-2(1H)-thione nucleus. As shown in Table 2, we
found that the substituents on the aromatic ring of aryl amidines
Similar to our previous domino processes,16,17 the present reac-
tion also showed the following attractive characteristics: (1) fast
reaction rates which enable the reaction to be completed within
15–24 min; (2) the convenient work-up which only needs simple
filtration since, the products directly precipitate out after the reac-
tion is finished and when its mixtures were neutralized with dilute
hydrochloric acid; (3) purification by chromatography can be
avoided, and the pure products can be easily acquired only by
washing the crude products with 95% EtOH; (4) simple and avail-
able substrates of amidines and isothiocyanates. Moreover, during
these domino processes, the construction of 1,3,5-triazine-2(1H)-
thione ring was accompanied by C@S and C@N bonds cleavage of
the isothiocyanates.
A plausible mechanism was proposed in Scheme 2. We hypoth-
esized that amidines 2 would attack isothiocyanates 1 first in the
presence of a base to generate an intermediate A, and then a sec-
ond addition between A and the second molecule of isothiocya-
nates 1 occurred, leading to bis-thiourea intermediate B, which
underwent intramolecular cyclization and subsequent dethiolation
to furnish the compound 3.
In summary, we have described a base-promoted domino
[3+2+1] heterocyclization as an alternative method for the synthe-
sis of a series of N-arylamino substituted 1,3,5-triazines with con-
comitant formation of three sigma-bonds in a one-pot manner.
This reaction provides a facile and efficient strategy for the con-
struction of structurally diverse 1,3,5-triazine skeleton. Features
of this strategy include short reaction times (15–24 min) and con-
venient one-pot operation. Further investigations are in progress in
Figure 1. X-ray structure of 3j.19

N. Li et al. / Tetrahedron Letters 54 (2013) 1743–1746
1745
Table 2
Syntheses of products 318
N
N
N
Ph
N
p-BrPh
N
N
N
N
N
N
N
N
p-ClPh
p-ClPh
p-ClPh
p-ClPh
N
H
S
N
H
N
S
N
H
N
S
N
H
S
p-ClPh
p-ClPh
p-ClPh
p-ClPh
3a, 15 min, 78%
3b, 18 min, 70%
3c, 22 min, 76%
p-BrPh
3d, 20 min, 72%
N
N
N
N
N
N
Ph
N
N
N
N
N
3,4-Cl2Ph
3,4-Cl2Ph
p-ClPh
3,4-Cl2Ph
N
H
N
S
N
H
N
S
N
H
N
S
N
H
N
S
3,4-Cl2Ph
3,4-Cl2Ph
p-ClPh
3,4-Cl2Ph
3f, 15 min, 78%
3e, 24 min, 63%
3g, 18 min, 72%
3h, 15 min, 75%
N
N
Ph
p-BrPh
N
N
N
N
N
N
N
N
Ph
Ph
p-FPh
Ph
N
H
N
S
N
H
N
S
N
H
N
S
N
H
N
S
Ph
Ph
p-FPh
Ph
3i, 22 min, 70%
3j, 15 min, 84%
3k, 18 min, 70%
3l, 16 min, 78%
N
N
N
N
N
Ph
p-BrPh
N
N
N
N
N
N
Ph
Ph
p-Tolyl
p-Tolyl
N
H
N
S
N
H
N
S
N
H
N
S
N
H
N
S
p
-Tolyl
p-Tolyl
Ph
Ph
3m, 15 min, 75%
3n, 20 min, 60%
3p, 18 min, 72%
3o, 15 min, 79%
N
N
Ph
p-BrPh
N
N
N
N
N
N
N
N
p-Tolyl
m-Tolyl
m-Tolyl
p-Tolyl
N
H
N
N
H
N
N
H
N
S
S
S
N
H
N
S
p-Tolyl
m-Tolyl
m-Tolyl
p-Tolyl
3s, 22 min, 76%
3t, 24 min, 75%
3q, 18 min, 78%
3r, 16 min, 75%
N
N
Ph
Ph
N
N
N
N
N
N
N
N
m-Tolyl
m-Tolyl
p-MeOPh
3-Cl-4-MePh
N
H
N
S
N
H
N
S
N
H
N
S
N
H
N
S
m-Tolyl
m-Tolyl
p-MeOPh
3-Cl-4-MePh
3u, 18 min, 76%
3v, 20 min, 74%
3w, 20 min, 77%
3x, 24 min, 84%
our laboratory to synthesize more complex products containing
1,3,5-triazine core and test their biological activity.
21102124), the Priority Academic Program Development (PAPD)
of Jiangsu Higher Education Institutions, the NSF of Jiangsu Educa-
tion Committee (11KJB150016), and Jiangsu Science and Technol-
ogy Support Program (No. BE2011045), and Qing Lan Projec. We
thank Prof. Zhu-Jun Yao and Guigen Li for their generous
assistances.
Acknowledgments
We are grateful for financial support from the National Science
Foundation of China (Nos. 21232004, 21272095, 21072163, and

1746
N. Li et al. / Tetrahedron Letters 54 (2013) 1743–1746
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Scheme 2. The plausible mechanism for the formation of 1,3,5-triazines 3.
Supplementary data
Supplementary data (experimental details and spectroscopic
characterization of all compounds along with 1H, IR and mass
spectra) associated with this article can be found, in the online ver-
sion, at http://dx.doi.org/10.1016/j.tetlet.2013.01.086.
References and notes
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18. General procedure for the synthesis of compounds 3: In a 10 mL reaction vial,
benzamidine 2a (1.0 mmol), sodium hydroxide (0.2 mmol) and DMF (2.0 mL)
were mixed and then stirred for 10 min. Subsequently, the 4-chlorophenyl
isothiocyanate 1a (2.2 mmol) was added to the reaction mixture, and the
reaction vial was capped and pre-stirring for 20 s. The mixture was subjected
to microwave irradiation (time: 15 min, temperature: 110 °C; absorption level:
high; fixed hold time). Upon completion, monitored by TLC, the reaction
mixture was cooled to room temperature and was neutralized with 10%
hydrochloric acid. Then, the system was poured into the cool water and was
filtered to give crude product. The crude product was further purified by 95%
EtOH to give the corresponding pure products 3. 6-(4-chlorophenylamino)-1-(4-
chlorophenyl)-4-phenyl-1,3,5-triazine-2(1H)-thione (3a), Yellow solid, Mp 262–
263 °C, 1H NMR (400 MHz, DMSO-d6) d: 9.08 (s, 1H, NH), 8.20 (d, J = 6.8 Hz, 2H,
ArH), 7.67 (d, J = 7.6 Hz, 2H, ArH), 7.68–7.42 (m, 9H, ArH), 13C NMR (100 MHz,
DMSO-d6) d: 185.8, 163.1, 156.2, 137.3, 136.4, 134.0, 131.8, 131.1, 130.7, 130.3,
4. Hasegawa, Y.; Yanagisawa, T.; Okui, Y.; Sato, T.; Hosaka, K.; Chin, M.;
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130.1, 129.4, 127.3, 127.0, 125.9. IR (KBr, m
, cmÀ1): 3373, 1593, 1553, 1471,
1429, 1348, 1224, 1091, 1004, 988, 759, 705. HRMS (ESI): m/z calcd for
C
21H13Cl2N4S, 423.0232 [MÀH]À; found: 423.0241.
19. The single-crystal growth was carried out in DMF at room temperature. Crystal
data
for
3l
(CCDC-916140):
C
43H37N11OS2,
crystal
dimension
0.40 Â 0.30 Â 0.21 mm, Monoclinic, space group C2/c, a = 21.438(2) Å,
b = 11.0408(12) Å, c = 19.503(2) Å,
a
=
c
= 90°, b = 121.573(2)°, V = 3933.0(8)
Å3, Mr = 787.96, Z = 4, k = 0.71073 Å,
R1 = 0.0423, wR2 = 0.0925.
l(Mo K
a
) = 0.186 mmÀ1, F(000) = 1648,
9. Alkalay, D.; Volk, J.; Bartlett, M. F. J. Pharm. Sci. 1976, 65, 525.
10. Irikura, T.; Abe, Y.; Okamura, K.; Higo, K.; Maeda, A.; Morinaga, F.; Shirai, G.;
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