Synthesis of 2-Arylamino-1,3,5-triazines from 2-Aminotriazines with Aryl Halides via CuI-Catalyzed Ullmann Coupling Reaction

Article abstract of DOI:10.1055/s-0035-1561632

An efficient copper-catalyzed synthesis of 2-arylamino-1,3,5-triazines from 2-aminotriazines with aryl halides under mild conditions has been developed. The reaction occurred in moderate to good yields and tolerated aryl iodides containing functionalities

Full text of DOI:10.1055/s-0035-1561632

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© Georg Thieme Verlag Stuttgart · New York
2016, 27, A–D
letter
A
J. J. Li et al.
Letter
Synlett
Synthesis of 2-Arylamino-1,3,5-triazines from 2-Aminotriazines
with Aryl Halides via CuI-Catalyzed Ullmann Coupling Reaction
Jin Jing Lia
Kong Wua
Wei Zhoua
Hong Wanga
Dong-Mei Cui*a
Chen Zhang*b
R1
R1
X
CuI, DMEDA
N
N
N
N
R
+
R2
R
R2
K2CO3, MeCN, reflux
N
N
N
H2N
N
N
R3
H
R3
R = H, Me, Ph, OMe, OEt, F, Cl, CF3, NO2, CN, NHAc
X = I, Br
26 examples
up to 95% yield
a College of Pharmaceutical Science, Zhejiang University
of Technology, Hangzhou 310014, P. R. of China
cuidongmei@zjut.edu.cn
b School of Pharmaceutical Sciences, Zhejiang University,
Hangzhou 310058, P. R. of China
Received: 12.03.2016
Accepted after revision: 13.04.2016
Published online: 13.05.2016
tracting much attention in recent years, and it has become
one of the most versatile strategies for the synthesis of nat-
ural products, pharmaceuticals, organic functional materi-
als, and so on.4 Compared with other metals, the use of
Cu(I) presents the major advantages of being inexpensive
and easy to handle. Copper-catalyzed Ullmann-type C–N
coupling has a history of more than one hundred years, and
as a cost-effective and versatile C–N coupling, it is still ac-
tively used in the field of organic synthesis, including in-
dustrial processes.5,6 Herein, we report a copper-catalyzed
synthesis of 2-arylamino-1,3,5-triazines from 2-amino-
1,3,5-triazines with aryl halides.7
DOI: 10.1055/s-0035-1561632; Art ID: st-2016-w0172-l
Abstract An efficient copper-catalyzed synthesis of 2-arylamino-
1,3,5-triazines from 2-aminotriazines with aryl halides under mild con-
ditions has been developed. The reaction occurred in moderate to good
yields and tolerated aryl iodides containing functionalities such as ni-
triles, ethers, amides, and halogens. Aryl bromides were also well toler-
ated.
Key words aryl halides, 2-aminotriazines, 2-arylamino-1,3,5-triazines,
copper catalyst, coupling reaction
We initially examined the reaction between 4-iodoan-
isole (1a) and N2,N2-dimethyl-6-phenyl-1,3,5-triazine-2,4-
diamine (2a) in the presence of CuI (30 mol%), N,N′-dimeth-
ylethanediamine (DMEDA; 30 mol%) and K2CO3 (2 equiv) in
MeCN at reflux. The reaction proceeded to give exclusively
the 2-arylamino-1,3,5-triazine 3a in 60% yield (Table 1, en-
try 1). Improving the amounts of DMEDA to 90 mol% in-
creased the yield to 76% (Table 1, entry 7). Replacement of
K2CO3 by KOH or Cs2CO3 led to a lower yield and K3PO4 gave
satisfactory yield (Table 1, entries 9–11). Subsequently, we
screened different organic solvents and identified dioxane
also as the effective solvent for this C–N coupling reaction
(Table 1, entry 6). While DMF and THF resulted in no prod-
uct formation, DMSO and toluene as solvent only gave
yields of 37% and 58%, respectively (Table 1, entries 2–5).
We subsequently investigated the effect of various ligands
on the reaction’s yield. Both bipyridine and ethylenedi-
amine ligands gave inferior results (Table 1, entries 12 and
13). Moderate yields were obtained when CuI was replaced
by Cu2O, CuBr or Cu(OAc)2 resulting in slightly lower yields
(Table 1, entries 14–16). Reducing the amount of CuI result-
ed in a slightly lower yield (Table 1, entry 8).
A triazine fragment is a ubiquitous structure that occurs
in a wide variety of naturally occurring and synthetic com-
pounds exhibiting various important biological activities.
Among the triazines derivatives reported, 1,3,5-triazine de-
rivatives with arylamines substitution display several bio-
logical activities such as antibacterials, anti-HSV-1, anti-
cancer and anti-HIV activities.1 For this reason, the devel-
opment of synthetic protocols for functionalized 1,3,5-
triazines has always been an active area of research. Previ-
ous synthetic methods for such compounds mainly relied
on two approaches. One involves the formation of triazinic
ring by the reaction of substituted biguanides with carbox-
ylates, acid chlorides, anhydrides or by cyclization of acyl-
amidines with amidines or guanidines.2 The most common
synthetic methods for their preparation have been report-
ed, fundamentally based on nucleophilic displacement of
cyanuric chloride.3 Although widely used, this route has
some deficiencies: most notably, harsh conditions, and low
reaction yields resulting from the poor reactivity of its third
chlorine atom toward nucleophiles. Utilization of transi-
tion-metal-catalyzed cross-coupling reactions has been at-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–D

B
J. J. Li et al.
Letter
Synlett
Table 1 Optimization of the Reaction Conditions
Table 2 Scope of the Synthesis of 3a
Ph
N
Ph
Ph
Ph
CuI
DMEDA
I
MeO
[Cu]
N
N
N
N
N
N
Ar
X
N
N
+
+
Ar
K2CO3
MeCN
reflux
MeO
N
H
NMe2
N
N
NMe2
H2N
N
NMe2
H2N
N
NMe2
H
1
2a
3
1a
2a
3a
Yield (%)a
Entry
1
Ar
X
Time (h)
3
Yield (%)
Entry
[Cu]
Base
Temp (°C)
Solvent
1
2
1a
1b
1c
1d
1e
1f
4-MeOC6H4
2-MeOC6H4
4-EtOC6H4
4-MeC6H4
Ph
I
10
10
10
14
15
30
11
10
9
3a
3b
3c
3d
3e
3f
76
62
71
71
52
78
62
71
63
62
82
90
84
76
68
69
71
trace
trace
1
2
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K3PO4
KOH
reflux
140
MeCN
DMF
60
trace
37
58
N.R.
60
76
43
73
13
37
10
26
46
51
52
I
3
I
3
140
DMSO
toluene
THF
4
I
4
reflux
reflux
120
5
I
5
6
4-PhC6H4
4-FC6H4
I
6
dioxane
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
7b
8c
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
7
1g
1h
1i
I
3g
3h
3i
8
4-ClC6H4
3-ClC6H4
4-F3CC6H4
4-NCC6H4
4-O2NC6H4
4-AcNHC6H4
4-MeOC6H4
4-MeC6H4
Ph
I
9b
10b
11b
12d
13e
14b
15
16
9
I
10
11
12
13
14
15
16
17
18
19
1j
I
10
7
3j
1k
1l
I
3k
3l
Cs2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
I
21
18
20
10
10
10
24
24
1m
1n
1o
1p
1q
1r
I
3m
3a
3d
3e
3n
3e
3k
Br
Br
Br
Br
Cl
Cl
CuBr
Cu2O
Cu(OAc)2
a Reaction conditions: 1a (0.5 mmol), 2a (0.5 mmol), catalyst (0.15 mmol),
base (1.0 mmol), DMEDA (0.15 mmol), solvent (3 mL),10 h; isolated yields
are shown.
3,4,5-F3C6H2
Ph
b DMEDA (0.45 mmol).
1s
4-NCC6H4
c CuI (0.1 mmol).
a Reaction conditions: 1 (0.5 mmol), 2a (0.5 mmol), CuI (0.15 mmol), K2CO3
(1.0 mmol), DMEDA (0.45 mmol), MeCN (3 mL), reflux; isolated yields are
shown.
d Bipyridine (0.45 mmol) was used in place of DMEDA.
e Ethylenediamine (0.45 mmol) was used in place of DMEDA.
Having identified the optimal reaction conditions, the
scope of the reaction was explored with different substitut-
ed aryl halides 1 (Table 2). Electron-donating substituents
at the aryl iodides, such as o-methoxy, p-ethoxy, p-phenyl,
and p-methyl groups, also provided 2-arylamino-1,3,5-tri-
azines in good yields (Table 2, entries 1–4 and 6). In addi-
tion to electron-donating substitution, halogens such as Cl
and F were also tolerated, leading to the desired products
3g–i in 62−71% isolated yield (Table 2, entries 7–9). On the
other hand, the more electron-withdrawing CF3 group pro-
vided 3j in 62% yield (Table 2, entry 10). Moreover, labile
groups, such an AcNH, CN, and NO2 were suitable in this re-
action, with the corresponding 2-arylamino-1,3,5-triazines
3k–m being delivered in 82–90% yield (Table 2, entries 11–
13). In particular, a variety of aryl bromides, including
those with MeO, Me, and F substituents, showed a great
ability to react with 2-amino-1,3,5-triazines under these
conditions, providing the corresponding coupling products
in 68–76% yield (Table 2, entries14–17). Furthermore, aryl
chlorides failed to undergo copper-catalyzed C–N coupling
reaction (Table 2, entries 18 and 19).
Finally, we extended the newly developed coupling ami-
nation to 2-amino-1,3,5-triazines bearing various substitu-
ents. They worked well and afforded the corresponding
products in good yields (Scheme 1).
In conclusion, we have successfully developed a new
cross-coupling method for the synthesis of 2-arylamino-
1,3,5-triazines using CuI as catalyst.8 The method employs
readily available reagents and has broad scope and high
functional group tolerance. Further efforts to extend this
catalytic system to the preparation of other useful hetero-
cyclic compounds are currently underway in our laborato-
ries.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1561632.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
o
nrtogI
f
rmoaitn
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–D

C
J. J. Li et al.
Letter
Synlett
H
N
R1
N
N
R1
N
N
NH2
CuI, K2CO3
I
N
N
+
N
N
R
DMEDA, MeCN, reflux
R
R2
R3
R2
R3
3
1
2
H
Me
N
N
H
H
N
H
MeO
N
N
Ph
N
N
N
N
N
Cl
OMe
N
N
N
N
N
N
MeO
OMe
CN
NMe2
OMe
NMe2
3p: 61% (18 h)
NMe2
NMe2
3o: 67% (19 h)
3q: 66% (11 h)
3r: 61% (14 h)
H
H
H
H
N
N
N
Ph
N
N
Ph
N
N
N
H
Ph
N
N
S
N
N
N
N
N
N
N
N
N
N
OMe
NO2
NO2
N
N
OMe
OMe
N
O
N
O
NMe2
Ph
H
3s: 56% (15 h)
3t: 74% (10 h)
3u: 95% (15 h)
3v: 65% (16 h)
3w: 82% (14 h)
Scheme 1 Scope of the synthesis of 3
References and Notes
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Grunert, R. Eur. J. Med. Chem. 2006, 41, 219.
(2) (a) Chen, H.; Dao, P.; Laporte, A.; Garbay, C. Tetrahedron Lett.
2010, 51, 3174. (b) Shapiro, S. L.; Isaacs, E. S.; Parrino, V. A.;
Freedman, L. J. Org. Chem. 1961, 26, 68. (c) Alkalay, D.; Volk, J.;
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(c) Simanek, E. E.; Abdou, H.; Lalwani, S.; Lim, J.; Mintzer, M.;
Venditto, V. J.; Vittur, B. Proc. R. Soc. A 2010, 466, 1445. (d) Kim,
J. Y. H.; Lee, J. W.; Lee, W. S.; Ha, H.-H.; Vendrell, M.; Bork, J. T.;
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Tetrahedron 2006, 62, 9507.
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3040. (c) Evano, G.; Blanchard, N.; Toumi, M. Chem. Rev. 2008,
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(7) Dao, P.; Garbay, C.; Chen, H. X. Tetrahedron 2012, 68, 3856.
(8) Typical Experimental Procedure: To a mixture of 1,3,5-tri-
azine (0.5 mmol), aryl halide (0.5 mmol), DMEDA (0.45 mmol)
and K2CO3 (1 mmol) in MeCN (3 mmol) was added CuI (0.15
mmol). The resulting mixture was stirred at reflux. After com-
pletion of the reaction, the reaction mixture was cooled to r.t.,
concd NH3 (4 mL) and sat. NaCl (10 mL) were added, and the
organic phase was then extracted with EtOAc (3 × 15 mL). The
organic phase was dried over anhyd Na2SO4. The crude residue
was obtained after evaporation of the solvent in vacuum, and
the residue was purified by flash chromatography with petro-
leum and EtOAc as the eluent to give the pure product. N2-(4-
Methoxyphenyl)-N4,N4-dimethyl-6-phenyl-1,3,5-triazine-2,4-
diamine (3a): white solid; mp 166–167 °C. 1H NMR (500 MHz,
CDCl3): δ = 8.43 (dd, J = 8.2, 1.4 Hz, 2 H), 7.58 (d, J = 9.0 Hz, 2 H),
7.46–7.53 (m, 3 H), 7.17 (br, 1 H), 6.91 (d, J = 9.0 Hz, 2 H), 3.83 (s,
3 H), 3.34 (s, 3 H), 3.23 (s, 3 H). 13C NMR (125 MHz, CDCl3): δ =
170.6, 165.9, 164.5, 155.6, 137.4, 132.4, 131.3, 128.4, 128.2,
121.8, 114.1, 55.6, 36.4. IR (KBr): 3353, 3066, 2944, 1604, 1506,
1211, 1039, 829, 778, 704 cm–1. HRMS (ESI): m/z [M + H]+ calcd
for C18H20N5O: 322.1668; found: 322.1684. N2-(4-Methoxyphe-
nyl)-N4,N4-dimethyl-1,3,5-triazine-2,4-diamine (3s): white
solid; mp 161–163 °C. 1H NMR (500 MHz, CDCl3): δ = 8.40 (br, 1
H), 8.25 (s, 1 H), 7.50 (d, J = 8.2 Hz, 2 H), 6.88 (d, J = 8.2 Hz, 2 H),
3.80 (s, 3 H), 3.19 (s, 3 H), 3.16 (s, 3 H). 13C NMR (125 MHz,
CDCl3): δ = 165.3, 164.5, 163.3, 155.8, 131.8, 122.3, 114.0, 55.5,
36.3. IR (KBr): 3434, 3195, 2951, 1613, 1512, 1197, 1037, 831,
805 cm–1. HRMS (ESI): m/z [M + H]+ calcd for C12H16N5O:
246.1355; found: 246.1377. 4-Morpholino-N-(4-nitrophenyl)-
6-phenyl-1,3,5-triazin-2-amine (3u): yellow solid; mp 277–
278 °C. 1H NMR (500 MHz, DMSO-d6): δ = 10.41 (s, 1 H), 8.39
(dd, J = 8.5, 1.5 Hz, 2 H), 8.23 (d, J = 9.2 Hz, 2 H), 8.05 (d, J = 9.2
Hz, 2 H), 7.57–7.61 (m, 1 H), 7.52–7.58 (m, 2 H), 3.95 (br, 2 H),
(5) (a) Ullmann, F. Ber. Dtsch. Chem. Ges. 1903, 36, 2382. (b) Ma, D.;
Zhang, Y.; Yao, J.; Wu, S.; Tao, F. J. Am. Chem. Soc. 1998, 120,
12459. (c) Lang, F.; Zewge, D.; Houpis, I.; Volante, R. P. Tetrahe-
dron Lett. 2001, 42, 3251. (d) Goldberg, I. Ber. Dtsch. Chem. Ges.
1906, 39, 1691.
(6) For examples of N-arylation reaction, see: (a) Lawson, C. P. A. T.;
Slawin, A. M. Z.; Westwood, N. J. Chem. Commun. 2011, 47, 1057.
(b) Ma, D.; Cai, Q. Acc. Chem. Res. 2008, 41, 1450. (c) Monnier, F.;
Taillefer, M. Angew. Chem. Int. Ed. 2008, 47, 3096. (d) Jiang, L.;
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–D

D
J. J. Li et al.
Letter
Synlett
3.83 (br, 2 H), 3.68–3.76 (m, 4 H). 13C NMR (125 MHz, DMSO-
d6): δ = 170.3, 164.5, 164.3, 146.5, 141.1, 136.2, 132.0, 128.5,
128.2, 124.9, 119.1, 65.9, 43.6. IR (KBr): 3310, 2950, 2858, 1606,
1497, 1332, 1270, 1215, 1107, 846, 779, 701 cm–1. HRMS (ESI):
m/z [M + H]+ calcd for C19H19N6O3: 379.1519; found: 379.1524.
N2-(4-Methoxyphenyl)-N4,6-diphenyl-1,3,5-triazine-2,4-
diamine (3v): white solid; mp 143–145 °C. 1H NMR (500 MHz,
CDCl3): δ = 8.44 (d, J = 7.3 Hz, 2 H), 7.65 (d, J = 6.4 Hz, 2 H), 7.49–
7.58 (m, 5 H), 7.46 (br, 2 H), 7.35 (t, J = 7.3 Hz, 2 H), 7.11 (t, J =
7.4 Hz, 1 H), 6.92 (d, J = 8.4 Hz, 2 H), 3.84 (s, 3 H). 13C NMR (125
MHz, CDCl3): δ = 171.7, 164.9, 164.7, 156.2, 138.5, 136.5, 131.8,
131.3, 128.9, 128.4, 123.4, 123.0, 122.9, 120.5, 114.1, 55.6. IR
(KBr): 3338, 3061, 2832, 1597, 1516, 1244, 1208, 1036, 826,
777, 756, 700 cm–1. HRMS (ESI): m/z [M + H]+ calcd for
C
22H20N5O: 370.1668; found: 370.1671.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–D