Iridium-catalyzed cascade dehydrogenation, ring-closure reaction leading to 2,4,6-triaryl-1,3,5-triazines

Article abstract of DOI:10.1134/S1070363216020304

An efficient iridium-catalyzed dehydrogenation, ring-closure reaction, has been developed via a cascade sequence, in which [Cp?IrI₂]₂/Xantphos proved to be the most efficient catalyst for the synthesis of 2,4,6-triaryl-1,3,5-triazines from stable aryl-substituted alcohols and amidines. It was the first case of iridium catalyst successful application in such transformation.

Full text of DOI:10.1134/S1070363216020304

ISSN 1070-3632, Russian Journal of General Chemistry, 2016, Vol. 86, No. 2, pp. 380–386. © Pleiades Publishing, Ltd., 2016.
Iridium-Catalyzed Cascade Dehydrogenation,
Ring-Closure Reaction Leading to 2,4,6-Triaryl-1,3,5-triazines1
Gang Shia, Fei Hea, Youxin Chea, Caihua Nia, and Ying Lia,b
a The Key Laboratory of Food Colloids and Biotechnology, Ministry of Education,
School of Chemical and Material Engineering, Jiangnan University, Wuxi, Jiangsu Province, 214122 China
b National Engineering Laboratory for Cereal Fermentation Technology,
Jiangnan University, Wuxi, Jiangsu Province, 214122 China
e-mail: liying@jiangnan.edu.cn
Received August 18, 2015
Abstract—An efficient iridium-catalyzed dehydrogenation, ring-closure reaction, has been developed via a
cascade sequence, in which [Cp*IrI2]2/Xantphos proved to be the most efficient catalyst for the synthesis of
2,4,6-triaryl-1,3,5-triazines from stable aryl-substituted alcohols and amidines. It was the first case of iridium
catalyst successful application in such transformation.
Keywords: iridium catalysis, ring-closure reaction, dehydrogenation, 2,4,6-triaryl-1,3,5-triazines
DOI: 10.1134/S1070363216020304
INTRODUCTION
were encouraged to determine whether amidines could
undergo such transformation being common com-
mercially available compounds. Aryl-substituted 1,3,5-
triazines are important heterocycles that exhibit diverse
biological activity [4, 5]. In 2002 Díaz-Ortiz et al. [6]
reported the synthesis of 1,3,5-triazines under solvent-
free conditions catalyzed by silica-supported Lewis
acids. Achelle et al. [7] synthesized 1,3,5-triazines
with moderate yield via the Suzuki cross-coupling
reaction. Such transformation to 1,3,5-triazines could
also be performed from aldehydes [8]. The
straightforward method of synthesis of 2,4,6-triaryl-
1,3,5-triazines was carried out via copper-catalyzed
cyclization of N-benzyl-benzamidine [9]. Recently, Xie
et al. developed the ruthenium-catalyzed synthesis of
The cascade reactions [1] are considered to be a
powerful tool in organic chemistry as an efficient
approach to desired or natural compounds based on
relatively simple starting materials. A domino or
cascade sequence can also lead to an increase in
molecular complexity by combining a series of
reactions in one synthetic procedure. Possibility of
designing a “one-pot” sequence for constructing com-
plex molecules is highly favorable for chemists.
Among the reported methods, the Michael addition,
the Henry reaction and/or aldol reaction are often used
in a cascade manner for the purpose of obtaining the
desired compounds.
Recently, borrowing hydrogen strategy has
attracted considerable attention because it provides an
economically and environmentally sensible alternative
to the conventional alkylation of amines [2]. Under the
conditions of borrowing hydrogen methodology alcohols
are easily converted in situ into aldehydes or ketones,
that are more reactive than alcohols and easily react
with amines (Scheme 1) [3]. Although borrowing
hydrogen is considered to be a well-studied reaction,
dehydrogenation, as its first step, might lead the
reaction along a different reaction pathway if the
coupling partner is changed. Given this possibility, we
Scheme 1. Borrowing hydrogen reaction catalyzed by a
transition metal.
R'
R
N
R
R
OH
H
[M]
[M]H2
R'
H2NR'
R
N
O
1 The text was submitted by the authors in English.
H2O
380

IRIDIUM-CATALYZED CASCADE DEHYDROGENATION
Table 1. Screening of reaction conditionsa
381
Ph
N
NH
N
N
Cat. [Ir], Ligand
Cs2CO3, solvent
OH
NH
2 HCl
+
Ph
N
N
1a
Ligand
2a
Solvent Yieldb, % Entry no. Catalyst
3a
Entry no.
Catalyst
–
Ligand
Solvent
Yieldb, %
1
2
–
–
–
–
–
–
–
–
–
–
DMSO
DMSO
DMSO
DMSO
DMSO
Toluene
Xylene
DMF
<5
15
32
46
58
37
35
47
49
66
11
12
[Cp*IrI2]2
[Cp*IrI2]2
[Cp*IrI2]2
[Cp*IrI2]2
[Cp*IrI2]2
[Cp*IrI2]2
[Cp*IrI2]2
[Cp*IrI2]2
[Cp*IrI2]2
[Cp*IrI2]2
L1
L2
L3
L4
L4
L4
L4
L4
L4
L4
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
TBME
THF
71
77
73
81
41
69
62
21
8
IrCl3
3
[(COD)IrCl]2
[Cp*IrCl2]2
[Cp*IrI2]2
[Cp*IrI2]2
[Cp*IrI2]2
[Cp*IrI2]2
[Cp*IrI2]2
[Cp*IrI2]2
13
4
14
5
15c
16d
17e
18
6
7
8
9
DMAc
19
10
Dioxane
20
Et2O
<5
a
Reaction conditions: 1a (2.0 mmol), 2a (1 mmol), Cat. [Ir] (1 mol %), ligand (2 mol %), Cs2CO3 (1 mmol), solvent (2 mL), 110°C or
reflux, 20 h. b Isolated yield. c Reaction temperature 80°C. d Reaction temperature (140°C). e [Ir] (0.5 mol %).
2,4,6-triaryl-1,3,5-triazines [10a]. Here, we report the
synthesis of aryl substituted 1,3,5-triazines via iridium-
catalyzed dehydrogenation, ring-close cascade reaction
giving mo-derate to high yields of products (Scheme 2).
amidine hydrochloride (2a) for testing the reaction
activity upon catalysis by iridium (Table 1). The
reaction was initially conducted by using 1 equiv. of
Cs2CO3 in DMSO. Such procedure did not give even
trace amounts of the expected product (Table 1, entry 1).
The desired product was isolated with the yield 15% in
case 1 mol % of IrCl3 was introduced into the reaction
(Table 1, entry 2). Subsequently, the iridium catalysts
with DMSO as a solvent were tested. In that case
RESULTS AND DISCUSSION
The cascade dehydrogenation, ring-close reaction
of 3-pyridinemethanol (1a) was initiated by benz-
Scheme 2. Iridium-catalyzed cascade dehydrogenation ring-closure reaction.
NH
NH
R'
Dehydrogenation
R'
NH2
H2O
R
O
R
N
R
OH
[Ir]
[IrH2]
NH
Nucleophilic
addition
R'
NH2
H2
R'
N
Ring close
NH
R
NH2
R'
N
N
R'
N
H
N
R'
R
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382
GANG SHI et al.
Table 2. Substrate expansion experimenta,b
Ph
NH
[Cp*IrI2]2, xantphos
Cs2CO3, dioxane, 110oC
N
N
Ar
OH
Ph
NH2
HCl
+
Ar
N
Ph
1
2
3
Comp. no.
Formula
Ph
Yield, % Comp. no.
Formula
Ph
Yield, %
71
3a
81
3f
N
N
N
N
N
S
N
Ph
Ph
N
N
Ph
3b
75
3g
85
Ph
N
N
N
N
N
N
Ph
Ph
NO2
Ph
N
Ph
3c
71
64
3h
3i
88
81
N
N
N
N
Ph
N
Ph
N
MeO
Ph
3d
Ph
N
N
N
N
N
Ph
N
Ph
O2N
Cl
Ph
3e
69
N
N
O
N
Ph
a
Reaction conditions: 1 (2.0 mmol), 2 (1 mmol), [Cp*IrI2]2 (1 mol %), xantphos (2 mol %), Cs2CO3 (1 mmol), Dioxane (2 mL), 110°C,
20 h. b Isolated yields.
catalysis by [Cp*IrI2]2 gave slightly higher yield than
other cationic Ir(III) compounds (Table 1, entries 3–5).
Such solvents as toluene, xylene, DMF, and DMAc
demonstrated no positive effect in the process. Yield of
the process was increased up to 66% in the media of
dioxane (Table 1, entries 6–10).
Yield of the reaction was increased significantly by ap-
plication of phosphine ligands (Table 1, entries 11–14
and Scheme 3).
The scope of the reaction was studied with a series
of aromatic alcohols and benzamidine hydrochloride
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 86 No. 2 2016

IRIDIUM-CATALYZED CASCADE DEHYDROGENATION
Table 3. Substrate expansion experimenta,b
383
Ar'
NH
Ar' NH2
+
N
N
[Cp*IrI2]2, xantphos
Ar
OH
HCl
Cs2CO3, dioxane, 110oC
Ar
N
Ar'
3
1
2
Comp. no.
Formula
Cl
Yield, % Comp. no.
69
3n
Formula
Yield, %
61
3j
N
N
N
N
N
N
Cl
Cl
Cl
3k
75
3o
56
N
N
N
N
N
N
Cl
MeO
N
3l
66
3p
63
Cl
N
N
N
N
N
N
N
Cl
3m
71
3q
58
N
N
N
N
Cl
N
N
N
MeO
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 86 No. 2 2016

384
GANG SHI et al.
Table 3. (Contd.)
Comp. no.
3r
Formula
Cl
Yield, % Comp. no.
Formula
N
Yield, %
<5
66
3t
N
N
N
N
Cl
N
N
Cl
3s
<5
N
N
N
5
a
Reaction conditions: 1 (2.0 mmol), 2 (1 mmol), [Cp*IrI2]2 (1 mol %), xantphos (2 mol%), Cs2CO3 (1 mmol), dioxane (2 mL), 110°C,
20 h. b Isolated yields.
under optimized conditions. The substituents on pyridyl
methanol substrates had little impact on formation of
the desired products (Table 2, see 3a–3d). The effect
of substituents on the aromatic ring of alcohols was
studied. Benzamidine hydrochloride with benzyl
alcohols having electron-donating or electron-with-
drawing substituents produced moderate to high yields
(Table 2, see 3j–3l). Furyl- and thiazolyl- heterocyclic
alcohols reacted under the optimized conditions with
satisfactory yields (Table 2, see 3e–3f).
affected the reaction. Benzamidines possessing electron-
poor groups led to corresponding products in higher
yields than the electron-donating ones. The reaction of
n-octyl alcohol with benzamidine and alkyl amidines
did not run probably due to decomposition that took
place prior to dehydrogenation of alcohols [10a].
EXPERIMENTAL
Typical procedure for the synthesis of 3a.
[Cp*IrI2]2 (1 mol %, 0.01 mmol), xantphos (2 mol %,
0.02 mmol) and dioxane (2 mL) were stirred shortly in
a Schlenk tube at room temperature. Subsequently, 3-
pyridinemethanol (2.0 mmol), benzamidine hydro-
chloride (1.0 mmol), and cesium carbonate (1.0 mmol)
were added. The mixture was heated under 110°C for
20 h and then cooled down to room temperature. The
The reaction of substituted benzamidines with aryl
methanols (Table 3) catalyzed by [Cp*IrI2]2 gave the
corresponding 2,4,6-triaryl-1,3,5-triazines in high
yields. Generally, the reaction had high substituent
tolerance. Substituents with different electronic proper-
ties on the aryl ring of benzamidines significantly
Scheme 3. Ligands used in screening of reaction conditions.
PPh2
PPh2
PPh2
Fe
Ph2P
PPh3
O
PPh2
PPh2
L1
L2
L3
L4
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IRIDIUM-CATALYZED CASCADE DEHYDROGENATION
385
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yl)-1,3,5-triazine (3a) as a white solid.
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(4-methoxyphenyl)-4,6-diphenyl-1,3,5-triazine (3h)
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bis(4-chlorophenyl)-6-(pyridin-4-yl)-1,3,5-triazine
(3p) [10a], 2-(4-chloropyridin-2-yl)-4,6-di-p-tolyl-
1,3,5-triazine (3q) [10a], 2-(4-chloropyridin-2-yl)-4,6-
bis(4-chlorophenyl)-1,3,5-triazine (3r) [10a].
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CONCLUSIONS
2,4,6-Triaryl-1,3,5-triazines were synthesized
efficiently in iridium-catalyzed dehydrogenation, ring-
close reaction with the use of commercially available
[Cp*IrI2]2–xantphos as a catalyst system. The reaction
of aryl amidines in combination with different
substituted benzylic alcohols proceeded smoothly,
furnishing the desired products in moderate to high
yields.
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ACKNOWLEDGMENTS
We gratefully acknowledge financial support of this
work by the Research Fund for the Doctoral Program
of Higher Education (20130093120003), Fundamental
Research Funds for the Central Universities (JUSRP1023).
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