Alkyl Ether as a One-Carbon Synthon: Route to 2,4-Disubstituted 1,3,5-Triazines via C-H Amination/C-O Cleavage under Transition-Metal-Free Conditions

Article abstract of DOI:10.1021/acs.orglett.7b03171

A transition-metal-free oxidative formal [3 + 2 + 1] cycloaddition for the synthesis of symmetrical and unsymmetrical 2,4-disubstituted 1,3,5-triazines has been first demonstrated. The reaction is involved in a domino C-H amination of alkyl ethers with amidines, C-O cleavage, nucleophilic addition, condensation, and an oxidative aromatization process. Notably, two C-N bonds were constructed in one pot, and alkyl ethers were employed as a novel carbon source of 1,3,5-triazines. The preliminary mechanistic studies revealed the reaction underwent a radical pathway.

Full text of DOI:10.1021/acs.orglett.7b03171

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX-XXX
Alkyl Ether as a One-Carbon Synthon: Route to 2,4-Disubstituted
1,3,5-Triazines via C−H Amination/C−O Cleavage under Transition-
Metal-Free Conditions
Yizhe Yan,*,†,‡ Zheng Li,† Hongyi Li,† Chang Cui,† Miaomiao Shi,† and Yanqi Liu*,†
†School of Food and Biological Engineering, Zhengzhou University of Light Industry, Zhengzhou 450000, P. R. China
‡Collaborative Innovation Center of Food Production and Safety, Zhengzhou, Henan Province 450000, P. R. China
S
* Supporting Information
ABSTRACT: A transition-metal-free oxidative formal [3 + 2 + 1] cycloaddition for the synthesis of symmetrical and
unsymmetrical 2,4-disubstituted 1,3,5-triazines has been first demonstrated. The reaction is involved in a domino C−H
amination of alkyl ethers with amidines, C−O cleavage, nucleophilic addition, condensation, and an oxidative aromatization
process. Notably, two C−N bonds were constructed in one pot, and alkyl ethers were employed as a novel carbon source of
1,3,5-triazines. The preliminary mechanistic studies revealed the reaction underwent a radical pathway.
Scheme 1. Strategies for the Synthesis of 2,4-Disubstituted
1,3,5-Triazines
1,3,5-Triazines represent an important and valuable class of
nitrogen-containing heterocycles in natural products and
medicinal chemistry.1 In particular, a variety of 2,4-disubstituted
1,3,5-triazines exhibited good biological activities.2 Further-
more, it was also a useful ligand in the preparation of
organometallic materials3 and transition-metal catalysis.4 Over
the past decades, symmetrical 2,4-disubstituted-1,3,5-triazines
were mainly synthesized via the condensation and aromatiza-
tion of two molecular amidines with formylation reagents such
as (E)-N-((((dimethylamino)methylene)amino)methylene)-N-
methylmethanaminium chloride,5 1,1-diethoxy-N,N-dimethyl-
methanamine,6 5-(methoxymethylene)-2,2-dimethyl-1,3-diox-
ane-4,6-dione,7 and (Z)-(1,4,4-trichlorobuta-1,3-dien-1-yl)-
benzene8 via multistep reactions (Scheme 1a). However,
narrow substrate scope, low yield, and harsh reaction
conditions limited their applications. Recently, copper-catalyzed
oxidative cyclization of amidines with N,N-dimethylformamide
or dimethyl sulfoxide has been developed for the synthesis of
symmetrical and unsymmetrical 2,4-disubstituted 1,3,5-triazines
(Scheme 1b).9 The N-methyl group of DMF or S-methyl group
of DMSO was used as the carbon source in these reactions.
Although the reaction yield was good, transition metal was still
required, and N-methylformamide or methanthiol was
generated as environmentally unfriendly byproducts. Therefore,
the development of a simple and environmentally friendly
protocol for 2,4-disubstituted 1,3,5-triazines is highly desirable.
In recent years, transition-metal-catalyzed or metal-free direct
α-C(sp3)−H bond functionalization of ethers has emerged as
an important tool for direct construction of the C−X bond.10,11
However, to date, use of ethers as the carbon synthon of
heterocycles has rarely been reported via C−H functionaliza-
tion. In 2012, we developed an interesting metal-free α-
C(sp3)−H amination of ethers for the synthesis of quinazo-
lines.11 In the method, methyl tert-butyl ether was first
employed as the carbon source of heterocycles. Inspired by
this significant finding, herein we report a transition-metal-free
oxidative formal [3 + 2 + 1] cycloaddition for the synthesis of
2,4-disubstituted 1,3,5-triazines from amidines and ethers
(Scheme 1c). The extra carbon atom of 1,3,5-triazines
Received: October 11, 2017
© XXXX American Chemical Society
A
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Letter
originates from ethers via oxidative C(sp3)−H amination and
C−O cleavage. A series of symmetrical and unsymmetrical 2,4-
disubstituted 1,3,5-triazines were obtained in up to 85% yields
with good functional group compatibility. Notably, the reaction
is environmentally friendly because alcohol, ammonia, and
water are the waste materials.
pyridyl-substituted amidines (1n and 1o) also generated the
desired 2,4-dipyridyl-1,3,5-triazines in 30% and 28% yields,
respectively (Scheme 2, 2n and 2o). It is worth noting that the
C−X bond on the phenyl ring and the C−H bond at the C6
position of 1,3,5-triazines in all of the obtained products
provide the potential for further derivatization.
Subsequently, we expected to synthesize unsymmetrical 2,4-
disubstituted 1,3,5-triazines with this synthetic protocol.
Interestingly, the cross-coupling reactions occurred and
afforded the desired unsymmetrical products by employing
two different aryl amidines (Table 1). Initially, the reaction of
Initially, we began our study with the reaction of 1 equiv of
benzamidine hydrochloride (1a), 1 equiv of K2CO3 as the base,
2 equiv of tert-butyl hydroperoxide (TBHP, 70% in aqueous) as
the oxidant, and 20 mol % of KI as the catalyst. When the
reaction mixture was heated in 1 mL of methyl tert-butyl ether
(MTBE, 2a) at 120 °C for 12 h, 2,4-diphenyl-1,3,5-triazine (3a)
was obtained in 78% isolated yield (Table S1, entry 1). When
various iodine reagents, such as tetrabutylammonium iodide
(TBAI), I2, and N-iodosuccinimide (NIS), were used as the
catalyst, 3a was obtained in slightly lower yields compared to
KI (Table S1, entries 2−4). Among the examination of various
bases, such as Na2CO3, Cs2CO3, KOH, and tBuOK, tBuOK
afforded 3a in the highest yield, 83% (Table S1, entries 5−8).
Increasing the amount of tBuOK to 1.5 equiv or 2 equiv
obviously decreased the reaction yield (Table S1, entries 9 and
10). To make the reaction conditions mild, the reaction
temperature was decreased, which had a significant effect on the
reaction yields. Notably, the desired product 3a was obtained in
excellent 85% yield at 100 °C (Table S1, entries 11−14).
Therefore, the optimal conditions were established as described
in entry 11.
Table 1. Cross-coupling Reactions of Two Different
Amidines for the Synthesis of Unsymmetrical 2,4-
a
Disubstituted 1,3,5-Triazines
b
product (yield, %)
entry
R1 (1)
R2 (1′)
Ph (1a)
unsymmetric symmetric
1
2
3
4
5
6
4-OMePh (1g)
4-OMePh (1g)
4-OMePh (1g)
2-OEtPh (1l)
3ga (29)
3gc (15)
3gd (18)
3la (27)
3qa (17)
3pa (17)
3a (30)
3c (25)
3d (19)
3a (23)
3a (29)
3a (34)
4-ClPh (1c)
4-CF3Ph (1d)
Ph (1a)
4-NO2Ph (1q)
cyclopropyl (1p)
Ph (1a)
Under the optimal reaction conditions, we then explored the
generality of the synthetic protocol for various amidines 1
(Scheme 2). First, aryl amidines (1a−m) bearing electron-
Ph (1a)
a
Reaction conditions: 1 (0.2 mmol), 1′ (0.8 mmol), KI (20 mol %),
TBHP (2 equiv), tBuOK (1 equiv), MTBE (1 mL), 100 °C, 12 h.
b
Isolated yield.
Scheme 2. Homocoupling Reactions of Amidines for the
Synthesis of Symmetrical 2,4-Disubstituted 1,3,5-Triazines
a
4-methoxybenzamidine (1g) and benzamidine (1a) in equi-
molar ratio could afford three products 3g, 3ga, and 3a in 8%,
10%, and 28% yields, respectively. Due to the differences in
reactivity, the yield of 3a was higher than those of 3g and 3ga.
To improve the yield of unsymmetrical product 3ga, the
reaction of 1g and 1a in a ratio of 4:1 was performed, giving 3g,
3ga, and 3a in 13%, 12%, and 27% yields, respectively. To our
delight, the reaction of 1g and 1a in a ratio of 1:4 could
produce 3ga in 29% yield with a 30% yield of 3a, and anothor
homocoupling product 3g was not detected (Table 1, entry 1).
Similarly, unsymmetrical products 3gc and 3gd could be
obtained in 15 and 18% yields using 1c and 1d instead of 1a
(Table 1, entries 2 and 3). When 1g was replaced with 1l, 1q,
and 1p, the unsymmetrical products 3la, 3qa, and 3pa were
also obtained in 17−27% yields (Table 1, entries 4−6).
Then the substrate scope of ethers 2 was also investigated
under the optimal reaction conditions (Table 2). When diethyl
ether (2b) or ethyl tert-butyl ether (2c) was employed, the
corresponding product 3q was obtained in 63% or 67% yield,
respectively (Table 2, entries 1 and 2). In addition, 1,2-
dimethoxyethane, which has two types of C(sp3)−H bonds
adjacent to the oxygen atom, afforded 3a and 3r in 26% and
12% yields, respectively. Notably, the reaction with primary C−
H bond gave products in higher yields than secondary C−H
bond (Table 2, entry 3). Moreover, cyclic ethers were also
examined in the reaction. For example, 1,3-dioxolane (2d)
could give 3a in 34% yield via a direct oxidative C(sp3)−H
amination and condensation process (Table 2, entry 4).
Interestingly, 3a was isolated in 13% yield via an unexpected
C−C cleavage when 1,4-dioxane (2e) was used as the substrate
(Table 2, entries 5).
a
Reaction conditions: 1 (0.4 mmol), KI (20 mol %), TBHP (2 equiv),
b
tBuOK (1 equiv), MTBE (1 mL), 100 °C, 12 h; isolated yield. 10
mmol scale.
donating groups (Me and OMe) and electron-deficient groups
(F, Cl, Br, and CF3) could be employed in this reaction, giving
the desired symmetrical 2,4-diaryl-1,3,5-triazines (3a−m) in
moderate to good yields. It was noted that ortho-substituted
aryl amidines (1l and 1m) gave a yield similar to that of para-
subsitituted ones (1b and 1g) except for 1k. To our delight,
B
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a
hypervalent iodine catalysis. In fact, the initial colorless solution
was first changed to yellow and eventually colorless, indicating
an I−/I2 redox process. Finally, when MTBE was replaced with
methanol under standard conditions, only a trace amount of 3a
was detected (Scheme 3e). Therefore, a hydrolysis mechanism
of MTBE should be excluded.
Table 2. Substrate Scope of Ethers
On the basis of the results reported above and previous
reports,10,11 a plausible mechanism was proposed (Scheme 4).
Scheme 4. Plausible Mechanism
a
Reaction conditions: 1a (0.4 mmol), KI (20 mol %), TBHP (2
b
equiv), tBuOK (1 equiv), ether 2 (1 mL), 100 °C, 12 h. Isolated
yield.
To gain an insight into the mechanism, several control
experiments were carried out (Scheme 3). First, the desired
Initially, the decomposition of tert-butyl hydroperoxide
generates a tert-butoxy radical in the presence of iodide,
which was oxidized to molecular iodine. Then the tert-butoxy
radical abstracts a hydrogen atom of C(sp3)−H bond of MTBE
to give a tert-butoxymethyl radical A, which could generate an
oxonium ion B via a single-electron-transfer (SET) process in
the presence of iodine. Subsequently, the nucleophilic addition
of 1a to B provides an intermediate C. A sequential C−O
cleavage of C could generate an imine D, and then a
nucleophilic addition of 1a to D provides an intermediate E.
Then E could be transformed to F by removal of one molecule
of ammonia. Finally, 3a could be formed through an oxidative
aromatization. Overall, the I−/I2 catalytic cycle plays an
important role in C−N bond formations.
Scheme 3. Control Experiments for Mechanistic Studies
Recently, we12 and others13 have also developed new
strategies for the synthesis of heterocycles with N,N-
dimethylacetamide (DMA) as the carbon synthon. In these
reactions, an imine ion intermediate was usually generated in
situ. According to our proposed mechanism above, the
nucleophilic addition of 1 to the imine ion is expected to
occur. After optimization (see Table S2 for details), the
reaction of 1 with DMA afforded the desired products 3 in 45−
55% yields in the presence of 20 mol % of TBAI as the catalyst
(Scheme 5).
In summary, we have developed an oxidative annulation of
amidines and ethers, affording a variety of symmetrical and
unsymmetrical 2,4-disubstituted 1,3,5-triazines under transi-
tion-metal-free conditions. Compared to previous reports, this
novel protocol is distinguished by (1) being transition-metal-
free, (2) its operational simplicity, (3) the only wastes being
alcohol, ammonia, and water, (4) its good functional group
tolerance. The synthesis of valuable heterocycles using ethers as
the carbon source is ongoing in our laboratory.
product was not detected in the presence of 2 equiv of iodine
without TBHP, which indicated that TBHP should be
necessary as the radical initiator (Scheme 3a). Moreover, it
was observed that the reaction was obviously inhibited in the
presence of 2 equiv of 2,2,6,6-tetramethyl-1-piperidinyloxy
(TEMPO) as the radical inhibitor (Scheme 3b). Meanwhile, 1-
(tert-butoxymethoxy)-2,2,6,6-tetramethylpiperidine was de-
tected by LC−MS. This implied that tert-butoxymethyl radical
was generated from MTBE via C−H cleavage. In addition,
when 2 equiv of hypervalent iodine reagents, such as
PhI(OAc)2 or KIO, were employed instead of our catalytic
system, no desired product was obtained (Scheme 3d). This
result indicated that the reaction pathway was not involved in
C
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Scheme 5. Synthesis of Symmetrical 2,4-Diaryl-1,3,5-
triazines Using DMA as the Carbon Synthon
a
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a
Reaction conditions: 1 (0.4 mmol), TBAI (20 mol %), TBHP (2
equiv), K2CO3 (2 equiv), DMA (1 mL), 120 °C, 12 h; isolated yield.
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b03171.
(12) (a) Yan, Y.; Zhang, Y.; Feng, C.; Zha, Z.; Wang, Z. Angew.
Chem., Int. Ed. 2012, 51, 8077. (b) Yan, Y.; Li, H.; Li, Z.; Niu, B.; Shi,
M.; Liu, Y. J. Org. Chem. 2017, 82, 8628.
(13) Modi, A.; Ali, W.; Patel, B. K. Adv. Synth. Catal. 2016, 358, 2100.
Experimental procedure and spectroscopic data for all
compounds (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: yanyizhe@mail.ustc.edu.cn.
*E-mail: liuyanqi@zzuli.edu.cn.
ORCID
Yizhe Yan: 0000-0003-0190-3474
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to the National Natural Science Foundation of
China (21502177), the Science and Technology Research Key
Project of the Department of Education of Henan Province
(15A150005), the Doctoral Research Foundation of Zhengz-
hou University of Light Industry (2014BSJJ032), and the
Grants Program of Youth Backbone Teachers Training Object
of Zhengzhou University of Light Industry.
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