An I2-mediated aerobic oxidative annulation of amidines with tertiary amines: Via C-H amination/C-N cleavage for the synthesis of 2,4-disubstituted 1,3,5-triazines

Article abstract of DOI:10.1039/c8ob00635k

An iodine-mediated formal oxidative cycloaddition of amidines with tertiary amines was first demonstrated in air. Both symmetrical and unsymmetrical 2,4-disubstituted 1,3,5-triazines were obtained in up to 85% yields. It is noted that a tertiary amine was employed as a one carbon synthon of 1,3,5-triazines and two C-N bonds were formed in one pot. Control experiments revealed that the reaction underwent a radical pathway promoted by I⁺. The method is transition-metal-free, peroxide-free, and operationally simple to implement with a wide scope of substrates.

Full text of DOI:10.1039/c8ob00635k

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Takeharu Haino et al.
Solvent-induced emission of organogels based on tris(phenylisoxazolyl)
benzene
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I2-mediated aerobic oxidative annulation of amidines with tertiary
amines via C-H amination/C-N cleavage for the synthesis of 2,4-
disubstitued 1,3,5-triazines
Received 00th January 20xx,
Accepted 00th January 20xx
Yizhe Yana,b*, Zheng Lia, Chang Cuia, Hongyi Lia, Miaomiao Shia and Yanqi Liua,b*
DOI: 10.1039/x0xx00000x
www.rsc.org/
NH
NH•HCl
multi-step
Cu/O2
N
N
N
N
An iodine-mediated formal oxidative cycloaddition of amidines
with tertiary amines was first demonstrated under air. Both
symmetrical and unsymmetrical 2,4-disubstitued 1,3,5-triazines
were obtained in up to 85% yields. It is noted that tertiary amine
was employed as one carbon synthon of 1,3,5-triazines and two C-
N bonds were formed in one pot. Control experiments revealed
the reaction underwent a radical pathway promoted by I+. The
method is transition-metal-free, peroxide-free, and operationally
simple to implement with a wide scope of substrates.
formylation
reagents
+
+
a
Ph
Ph
N
N
Ph
Previous work
NH
R1 NH•HCl
NH
DMF
b
DMSO
R1
R2
R2 NH2•HCl
NH
R3
R1 NH2•HCl
NH
O
KI/TBHP
N
N
R3
R4
Our recent work
c
+
R1
N
R2
R2 NH2•HCl
R3 = H, Me,CH2OCH3
2,4-Disubstitued 1,3,5-triazines represent an important and
valuable class of nitrogen-containing heterocycles in organic
chemistry. Due to good biological activities, they have been
already widely applied in medicinal chemistry.1 Moreover, they
were used as a nitrogen ligand in fields of organometallic
materials and metal catalysis.2 Over the past decades, 2,4-
disubstitued 1,3,5-triazines were prepared via the direct
formylation and condensation of amidines with various
formylation reagents (Scheme 1a).3 However, only
symmetrical 2,4-disubstitued 1,3,5-triazines were obtained
with narrow substrate scope and low yields under harsh
conditions, which limited their further applications. Recently,
copper-catalyzed oxidative cyclization of amidines with various
carbon synthons has been developed for the synthesis of 2,4-
disubstituted 1,3,5-triazines (Scheme 1b).4 In these reactions,
the N-methyl of N,N-dimethylformamide (DMF) or S-methyl
group of dimethyl sulfoxide (DMSO) was employed as the
carbon source of 1,3,5-triazine ring. Although the reaction
yield was good and unsymmetrical products were first
obtained, copper catalyst was still required for this
transformation. More recently, our group has developed an
iodide-catalyzed formal oxidative [3+2+1] cycloaddition of
amidines with alkyl ethers, affording symmetrical and
R3
NH
H
R5
R1 NH•HCl
NH
I2/air
This work
d
N
N
N
R4
+
R3
R1
N
R2
R2 NH2•HCl
R3 = H, Me, Ph
Scheme 1 Strategies for the synthesis of 2,4-disubstituted 1,3,5-triazines
unsymmetrical 2,4-disubstitued 1,3,5-triazines in good yields
(Scheme 1c).5 In this reaction, alkyl ether was used as a novel
carbon source. Although transition metal was avoided, the use
of ether and tert-butyl hydroperoxide limited its industrial
expansion production due to potential explosion hazard.
Therefore, the development of a simple and environmentally
friendly protocol for 2,4-disubstitued 1,3,5-triazines remains
highly desirable.
On the other hand, tertiary amines have been developed as
a useful carbon source via C-H activation/C−N bond cleavage in
recent years. Many valuable compounds could be constructed
from various types of nucleophiles and tertiary amines.6
Recently, we7 and others5b,8 have realized the construction of
various nitrogen-containing heterocycles via the reaction of
nitrogen nucleophile with tertiary amines via C-H
amination/C−N bond cleavage. Inspired by these significant
findings and our research on metal-free synthesis of
heterocycles5,7,9, herein we report an iodine-mediated formal
oxidative [3+2+1] cycloaddition for the synthesis of 2,4-
disubstitued 1,3,5-triazines from amidines and tertiary amines
a.School of Food and Biological Engineering, Zhengzhou University of Light Industry,
Zhengzhou, 450000, P. R. China. E-mail: yanyizhe@mail.ustc.edu.cn
b.Collaborative Innovation Center of Food Production and Safety, Henan Province,
P. R. China.
† Electronic Supplementary Informaꢀon (ESI) available: Experimental procedures
and spectral datas and copies of NMR spectra for all products. See
DOI: 10.1039/x0xx00000x
under air (Scheme 1d).
A
series of symmetrical and
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unsymmetrical 2,4-disubstitued 1,3,5-triazines were obtained reaction solvents, such DMF, NMP and even H2O, didn’t
in up to 85% yields with good functional group compatibility. improve the reaction yield (Table 1, entries 15-17). The effect
The extra carbon atom of 1,3,5-triazine ring originated from of temperature on the reaction was also investigated. Notably,
tertiary amines via oxidative C(sp3)−H aminaꢀon and C(sp3)−N the desired product 3a was obtained in good 79% yield at
cleavage. The reaction is involved in a domino C-H amination 130 °C (Table 1, entry 18). When the reaction temperature was
of tertiary amine with amidine, C-N cleavage, nucleophilic further increased from 130 °C to 140 °C, 85% yield of 3a was
addition, condensation and aromatization process.
obtained. 3a was not detected in the absence of 2a, which
proved that only 2a provided one carbon synthon in this
reaction (Table 1, entry 20). Therefore, the optimal conditions
were established as described in entry 19.
Table 1 Optimization of reaction conditionsa
H
I2 (1 equiv)
Cs2CO3 (2 equiv)
NH
C
N
N
+
R1 NH2•HCl
1a-1o
H3C
N
N
Entry
Base
Solvent
Temp (°C) Yield (%)b
R1
N
R1
DMSO (1 mL)
air, 140 °C, 24 h
2a
3a-3o
1c,d
2c,e
3c
4
5
6
7
8
9
K2CO3
K2CO3
K2CO3
K2CO3
Na2CO3
Cs2CO3
tBuONa
tBuOK
KOH
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
130
140
140
30
24
40
47
32
59
22
trace
trace
trace
50
42
H
C
H
C
H
C
N
N
N
N
N
N
N
N
N
Cl
Cl
F
F
3c, 77%
3a, 85% (79%b)
3b, 40%
H
H
C
H
C
C
N
N
N
N
N
N
N
N
N
F3C
CF3 Br
Br Me
Me
Me
3d, 48%
3e, 53%
3f, 81%
10
11
12
13
14
15
16
17
18
19
20j
NaOH
K3PO4
KOAc
H
C
H
C
H
C
N
N
N
N
N
N
Me
Br
Br
N
N
N
n.d.
MeO
MeO
OMe
3i, 80%
3h, 55%
3g, 67%
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
25f, 30g,44h, 49i
H
C
H
C
H
C
Me
N
N
Me
EtO
N
N
OEt
N
N
39
35
trace
79
85
OMe
N
N
NMP
H2O
DMSO
DMSO
DMSO
N
3j, 58%
3k, 52%
3l, trace
H
C
H
C
H
C
N
N
N
N
N
N
n.d.
N
N
a Reaction conditions: 1a (0.4 mmol), 2a (1 equiv), I2 (1 equiv), base (2 equiv), solvent (1
N
N
N
mL), air, 24 h. b Isolated yield. c 12 h. d 20 mol % of I2 and 2 equiv of TBHP. e 20 mol % of
N
N
3o
, 20%
3m, 31%
3n, 45%
f
g
h
i
I2. 1 equiv of Cs2CO3. 1.5 equiv of Cs2CO3. 2.5 equiv of Cs2CO3. 3 equiv of Cs2CO3. j
no 2a used.
Scheme 2 Homocoupling oxidative annulation of amidinesa
a
Reaction conditions:
1 (0.4 mmol), 2a (1 equiv), I2 (1 equiv), Cs2CO3 (2 equiv),
Initially, we began our study with the reaction of 1 equiv of DMSO (1 mL), air, 140 °C, 24 h; Isolated yield. b 10 mmol scale.
benzamidine hydrochloride
(1a), 1 equiv of N,N,N',N'-
Under the optimal reaction conditions, the generality of this
synthetic protocol for various amidines was investigated
tetramethylethylenediamine (TMEDA, 2a), 20 mol % of iodine
as the catalyst, 2 equiv of tert-butyl hydroperoxide (TBHP, 70%
in aqueous) as the oxidant, and 2 equiv of K2CO3 as th base.
When the reaction mixture was heated in DMSO at 120 °C for
12 h, 2,4-diphenyl-1,3,5-triazine (3a) was obtained in 30% yield
(Table 1, entry 1). In the absence of TBHP, 3a was also
obtained in 24% yield, which indicated that peroxidant was not
essential to this reaction (Table 1, entry 2). The yield of this
reaction was obviously improved by increasing amount of
iodine to 1 equiv (Table 1, entry 3). Prolonging reaction time
also resulted in an increase of yield from 40% to 47% (Table 1,
entry 4). Among the examination of various bases, such as
Na2CO3, Cs2CO3, tBuONa, tBuOK, NaOH, KOH, K3PO4, and KOAc,
Cs2CO3, afforded 3a in a highest 59% yield (Table 1, entries 5-
12). No 3a was detected without any base (Table 1, entry 13).
Increasing or decreasing the amount of Cs2CO3 was inefficient
to the reaction yield (Table 1, entries 14). The variation of
1
(Scheme 2). Firstly, aryl amidines (1a-1k) bearing electron-
donating or electron-deficient groups on the phenyl ring could
be employed in this reaction, giving the desired and
symmetrical 2,4-diaryl-1,3,5-triazines (3a-3k) in moderate to
good yields. Notably, aryl amidines bearing electron-donating
groups (Me and OMe) gave higher yields than that bearing
electron-deficient ones (F, Br, and CF3). Moreover, ortho-
substitued aryl amidines (1k and 1l) gave a lower yield
compared to para-subsititued ones (1f and 1g) due to steric
hindrance. In addition, heterocyclic amidines were also
tolerated in this reaction. 1n gave the desired product 2,4-
di(pyridin-3-yl)-1,3,5-triazine in higher yield than 1m because
of electronic effect. It is noteworthy that C-X bond on the
phenyl ring and C−H bond of 1,3,5-triazine ring in products
provide the potential for further derivatizations.
3
2 | J. Name., 2012, 00, 1-3
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Table 2 Cross-coupling oxidative annulation of amidinesa
2 and 3). In addition, the reaction of 1j
,
1p and 1o with 1a also
gave the unsymmetrical products 3ja
,
3pa and 3oa in 14-27%
yields (Table 2, entries 4-6).
Then the substrate scope of amines
2
was also examined
under the optimal reaction conditions (Table 3). When various
amines bearing N-methyl group, such as N,N’-
dimethylethylenediamine (2b), N-methylpiperidine (2c), and N-
methylmorpholine (2d) were employed, the corresponding
product 3a were obtained in 40-43% yields (Table 3, entries 1-
3). In spite of low yield, the reaction of 1a with triethylamine
Product (Yield, %)b
Entry
R1 (1)
R2 (1’)
Unsymmetric
Symmetric
4-OMe-Ph
(1g)
4-OMe-Ph
(1g)
4-OMe-Ph
(1g)
3-OMe-Ph
(1j)
4-NO2-Ph
(1p)
cycloprop
yl (1o)
1
2
3
4
5
6
Ph (1a)
3ga (23)
3gc (16)
3gf (22)
3ja (16)
3pa (27)
3oa (14)
3a (33)
(
2e) could give the desired product 2-methyl-4,6-diphenyl-
4-Cl-Ph
(1c)
4-Me-Ph
(1f)
3c (35)
3f (25)
3a (28)
3a (27)
3a (15)
1,3,5-triazine (Table 3, entry 4). In addition, N,N-
dimethylbenzylamine, which have two types of C(sp3)-H bonds
adjacent to the nitrogen atom, afforded 3a and 2,4,6-
triphenyl-1,3,5-triazine
(3q
)
in 28% and 40% yields,
Ph (1a)
Ph (1a)
Ph (1a)
respectively. Notably, the reaction with secondary C-H bond
gave the corresponding product in higher yield than primary C-
H bond. This is probably because secondary C-H bond has
lower bond dissociation energy (BDE) than primary C-H bond
(Table 3, entry 5).
a
Reaction conditions: 1 (0.2 mmol), 1’ (0.8 mmol), 2a (1 equiv), I2 (1 equiv), Cs2CO3 (2
To gain an insight into the mechanism, several control
experiments were carried out (Scheme 3). First, only 18% yield
of 3a was obtained in the presence of one equiv of 2,2,6,6-
tetramethyl-1-piperidinyloxy (TEMPO) as the radical inhibitor.
This obvious inhibiting effect indicated that this reaction might
undergo a radical pathway (Scheme 3a). Fortunately, trace
amount of N,N,N'-trimethyl-N'-(((2,2,6,6-tetramethylpiperidin-
equiv), DMSO (1 mL), air, 140 °C, 24 h. b Isolated yield.
Subsequently, the cross-coupling reactions by employing
two different aryl amidines were performed (Table 2).
Expectedly, the desired unsymmetrical 2,4-disubstituted-1,3,5-
triazines were obtained with two homocoupling products
generated at the same time. Initially, the reaction of 4-
methoxybenzamidine (1g) and benzamidine (1a) in equimolar
ratio could afford two homocoupling products (3g and 3a) and
a cross-coupling product 3ga. To improve the yield of 3ga, the
molar ratio of 1g to 1a was changed into 1:4. To our delight,
3ga and 3a were obtained in 23% and 33% yield, respectively.
Meanwhile, the other homocoupling product 3g was not
detected (Table 2, entry 1). Similarly, when 1a was replaced
with 1c or 1d, the unsymmetrical products 3gc or 3gf could be
obtained in 16% and 22% yields, respectively (Table 2, entries
1-yl)oxy)methyl)ethane-1,2-diamine
and
2,2,6,6-
tetramethylpiperidin-1-yl hypoiodite as radical trapping
products were detected by LC-MS. This implied that a carbon
radical and an iodine radical were generated in situ,
respectively. In addition, iodine effect was also investigated by
using various iodine reagents, such as KI, NIS, and PhI(OAc)2.
Among three reactions, NIS gave 3a in a highest 71% yield. This
result indicated that I+ might be an active catalyst and I2/I+
redox process played an important role in the reaction.
On the basis of the results above and previous reports9,10, a
plausible mechanism was proposed (Scheme 4). Initially,
Table 3 Substrate scope of amines a
TMEDA gave a carbon radical
A via an oxidative C-H cleavage
a
Reaction conditions: 1a (0.4 mmol), 2 (1 equiv), I2 (1 equiv), Cs2CO3 (2 equiv),
DMSO (1 mL), air, 140 °C, 24 h. b Isolated yield.
Scheme 3 Control experiments for mechanistic studies
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Chem. Soc. Perkin Trans. 2, 1995,
B.-T. Ho, J. Heterocycl. Chem., 1965,
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2
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2
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promoted by I+, which was generated in situ from molecular
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iodine under air.11 Then the radical
A
was further changed into
via a single-electron-transfer (SET) process in
the presence of I+. Subsequently, the nucleophilic addition of
1a to provided an intermediate . A sequential C-N cleavage
of could generated an imine and a nucleophilic addition of
1a to provided an intermediate . Then could be
transformed to
aromatization of
an imine cation
B
B
C
5
6
C
D
D
E
E
F
by removing ammonia. Finally, an oxidative
F
could produce 3a under air.
Yao, C. Deng, R. Tang, X. Zhang and J. Li, Org. Lett., 2011, 13
,
In summary, we have developed an iodine-mediated
oxidative annulation of amidines and tertiary amines, affording
a variety of symmetrical and unsymmetrical 2,4-disubstitued
1,3,5-triazines. Tertiary amine was employed as one carbon
synthon via C−H/C−N cleavage. Compared to previous reports,
this novel protocol is distinguished by (1) transition-metal-free,
(2) operational simplicity, (3) peroxide-free, (4) good functional
groups tolerance. The synthesis of other nitrogen-containing
heterocycles using tertiary amines as the carbon source is
ongoing in our laboratory.
2184; (d) L. Zhang, C. Peng, D. Zhao, Y. Wang, H. Fu, Q. Shen
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We are grateful to the National Natural Science Foundation
of China (21502177), the Scientific and Technological
Breakthrough Plan of Henan Province (182102310903), the
Science and Technology Research Key Project of the
Department of Education of Henan Province (15A150005), the
Doctoral Research Foundation of Zhengzhou University of Light
Industry (2014BSJJ032), and the Grants Program of Youth
Backbone Teachers Training Object of Zhengzhou University of
Light Industry.
9
10 For oxidative C-H functionalization of tertiary amine, see: (a)
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11 For recent examples of iodine catalysis, see: (a) Y. Takeda, R.
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Organic & Biomolecular Chemistry
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DOI: 10.1039/C8OB00635K
Table of Conetents Entry
I2-mediated aerobic oxidative annulation of amidines
with tertiary amines via C-H amination/C-N cleavage
for the synthesis of 2,4-disubstitued 1,3,5-triazines
Yizhe Yana,b*, Zheng Lia, Chang Cuia, Hongyi Lia, Miaomiao Shia and Yanqi Liua,b*
aSchool of Food and Biological Engineering, Zhengzhou University of Light Industry, Zhengzhou,
450000, P. R. China. E-mail: yanyizhe@mail.ustc.edu.cn
bCollaborative Innovation Center of Food Production and Safety, Henan Province, P. R. China.
An iodine-mediated aerobic oxidative cycloaddition of amidines with
tertiary amines was first demonstrated, affording symmetrical and
unsymmetrical 2,4-disubstitued 1,3,5-triazines.