Heterogeneous selective synthesis of 1,2-dihydro-1,3,5-triazines from alcohols and amidines via Cu/OMS-2-catalyzed multistep oxidation

Article abstract of DOI:10.1016/j.catcom.2016.10.014

Copper supported on octahedral manganese oxide molecular sieve (OMS-2) which was obtained via reducing KMnO₄ by TBHP was prepared and found to be an efficient catalyst for the synthesis of 1,2-dihydro-1,3,5-triazines directly from alcohols and amidines in one-pot via multistep oxidation. The recyclable heterogeneous catalyst was characterized by BET, XRD, FTIR, TEM and SEM, and the catalytic system can tolerate a wide range of substrates under air with low catalyst loading of supported copper (0.25?mol%), employing OMS-2 as the electron-transfer mediator (ETM) and support.

Full text of DOI:10.1016/j.catcom.2016.10.014

Catalysis Communications 89 (2017) 34–39
Contents lists available at ScienceDirect
Catalysis Communications
journal homepage: www.elsevier.com/locate/catcom
Short communication
Heterogeneous selective synthesis of 1,2-dihydro-1,3,5-triazines from
alcohols and amidines via Cu/OMS-2-catalyzed multistep oxidation
Xu Meng a, Xiuru Bi a, Yanmin Wang a, Gexin Chen a, Baohua Chen b, Zhenqiang Jing c, Peiqing Zhao a,
⁎
a
State Key Laboratory for Oxo Synthesis and Selective Oxidation, Suzhou Research Institute of LICP, Lanzhou Institute of Chemical Physics (LICP), Chinese Academy of Sciences, Lanzhou 730000,
China
b
State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, China
Suzhou Institute of Nano-Tech and Nano-Bionic (SINANO), Chinese Academy of Sciences, Suzhou 215123, China
c
a r t i c l e i n f o
a b s t r a c t
Article history:
Copper supported on octahedral manganese oxide molecular sieve (OMS-2) which was obtained via reducing
KMnO4 by TBHP was prepared and found to be an efficient catalyst for the synthesis of 1,2-dihydro-1,3,5-triazines
directly from alcohols and amidines in one-pot via multistep oxidation. The recyclable heterogeneous catalyst
was characterized by BET, XRD, FTIR, TEM and SEM, and the catalytic system can tolerate a wide range of sub-
strates under air with low catalyst loading of supported copper (0.25 mol%), employing OMS-2 as the elec-
tron-transfer mediator (ETM) and support.
Received 2 September 2016
Received in revised form 15 October 2016
Accepted 17 October 2016
Available online 18 October 2016
Keyword:
© 2016 Elsevier B.V. All rights reserved.
Heterogeneous catalysis
Multistep oxidation
OMS-2
Supported catalyst
Triazine
1. Introduction
As a part of our continuing efforts on heterogeneous synthesis, we
have developed several systems for the heterocycles synthesis by
In recent years, multistep catalytic oxidation using green oxidants,
such as O2 and H2O2, has gained importance in organic synthesis and ca-
talysis compared with direct oxidation using stoichiometric amounts of
metallic oxidants because of environmental and economic factors [1]. In
particular, Backväll's group developed a series of Pd/BQ/Fe(Pc)/O2 sys-
tem which can improve electron-transfer via decreasing the redox bar-
riers between catalytic metals and oxidants by the use of electron-
transfer mediator (ETM) [2–7]. More recently, Sundén's group reported
a multistep electron transfer NHC catalytic system which was able to se-
lectively synthesize α,β-unsaturated esters via the introduction of qui-
none and Fe(Pc) as ETMs [8]. In 2015, Largeron's group used copper as
ETM to discover an o-iminoquinone-catalyzed multistep oxidation for
the synthesis of benzimidazoles initiated by transamination process
[9,10]. However, heterogeneous multistep catalytic oxidation is a
more acceptable pathway compared with the aforementioned homoge-
neous counterparts, due to the ease in separation, recovery and
recycling. Consequently, there is an incentive to develop a heteroge-
neous system able to catalyze the organic transformations by multistep
oxidation with green oxidants by the use of recyclable catalysts.
employing a series of manganese oxide-supported copper (Cu/OMS-2)
as catalysts and air as green oxidant [11–13]. In terms of catalytic mech-
anism, we envisaged the catalytic system combines two redox couples:
supported Cu acts as catalytic component and is reoxidized by mixed
valent OMS-2 [14–20], whereas support OMS-2 acts as ETM and is
reoxidized by O2 (Scheme 1). In this way, the electrons in an oxidation
transfer quickly from substrates to green oxidant via multistep oxida-
⁎
Corresponding author.
Scheme 1. Aerobic multistep oxidation using Cu as catalytic metal and OMS-2 as ETM and
E-mail address: zhaopq@licp.cas.cn (P. Zhao).
support.

X. Meng et al. / Catalysis Communications 89 (2017) 34–39
35
Scheme 2. Access to 1,2-dihydro-1,3,5-triazines catalyzed by Cu/OMS-2.
in supported catalyst Cu/OMS-2. In the presence of Cu/OMS-2,
polyfunctional 1,2-dihydro-1,3,5-triazines were synthesized in a highly
selective pathway directly from alcohols and N-arylamidines in one-pot
via multistep oxidation (Scheme 2).
2. Experimental
2.1. Catalyst preparation
1 mL of TBHP (70% water solution) was added to a buffer solution
consisting of 2.5 mL of acetic acid and 5 g of KOAc in 20 mL of deionized
water. A solution of 3.25 g of KMnO4 in 75 mL of deionized water was
then added dropwise to the above mixture while stirring. The resulting
solution was refluxed at 100 °C for 10 h, and the product OMS-2 was fil-
tered, washed, dried in air at 80 °C overnight to remove water and dried
at 120 °C for 2 h. Next, Support OMS-2 (2 g) was added to a 50 mL
round-bottom flask. A solution of Cu(NO3)2·3H2O (0.05 g) in deionized
water (20 mL) was added to OMS-2, and additional deionized water
(6 mL) was added to wash down the sides of the flask. Then the flask
was submerged into an ultrasound bath for 3 h at room temperature
and stirred for further 20 h at room temperature. After that, the water
was distilled under reduced pressure on a rotary evaporator at 80 °C
for more than 2 h. Finally, the black powder was dried into an oven at
110 °C for 4 h followed by calcination at 350 °C for 2 h.
Fig. 1. The XRD patterns of OMS-2, Cu/OMS-2 and OMS-2-Re.
tion generated by Cu/OMS-2, which can avoid unselective reactions.
With this in mind, we envisioned the possibility of employing recyclable
Cu/OMS-2-based materials to selectively synthesize important hetero-
cycles, like polyfunctional 1,2-dihydro-1,3,5-triazines, starting from
readily available substrates through multistep oxidation.
2.2. Typical procedure for the synthesis of dihydrotriazines
Polyfunctional dihydro-1,3,5-triazine is one of the most important
nitrogen-containing heterocycles because of their various biological ac-
tivities, such as antibacterial, antimalarial, antitumor and anti-inflam-
matory properties [21]. Furthermore, dihydrotriazine derivatives are
applied in commercialized herbicides, corrosion inhibitors and insecti-
cides [22]. However, the synthetic methods for polyfunctional 1,2-
dihydro-1,3,5-triazines are limited [23,24]. Herein, we would like to dis-
close that OMS-2 was prepared for the first time through the reduction
of KMnO4 by the low loading of TBHP and employed as support and ETM
Cu/OMS-2 (10 mg, 0.25 mol%), benzyl alcohol (2 mmol), N-
arylamidine (0.5 mmol), toluene (2 mL) were added to a flask with a
bar. The flask was stirred at 90 °C for 20 h under air. After cooling to
room temperature, the mixture was diluted with ethyl acetate and fil-
tered. The filtrate was removed under reduced pressure to get the
crude product, which was further purified by silica gel chromatography
(petroleum/ethyl acetate = 40/1–50/1 as eluent) to yield correspond-
ing product. The identity and purity of the products were confirmed
by 1H, 13C NMR spectroscopic and HRMS analysis.
Fig. 2. The TEM and SEM images of OMS-2.

36
X. Meng et al. / Catalysis Communications 89 (2017) 34–39
Fig. 3. The TEM and SEM images of Cu/OMS-2.
3. Results and discussion
or only using support OMS-2 as catalyst (Table 1, entries 1 and 2). Cat-
alytic amounts of commercial bulk CuO and nano-sized CuO could not
catalyze the reaction under the standard conditions as well (Table 1, en-
tries 3 and 4). Similarly, a physical mixture of CuO and OMS-2 did not
show any catalytic activity in the reaction (Table 1, entry 5). To our de-
light, the addition of Cu/OMS-2 (Cu: 0.25 mol%) led to the desired prod-
uct 1,2-dihydro-1,3,5-triazine (3a) in 91% isolated yield while another
cyclized product 4a was not observed (entry 6). Compared with Cu/li-
gand system of previous research [25], it is believed that OMS-2 en-
hanced the oxidative ability of supported Cu for converting benzyl
alcohol into benzaldehyde, next promoted nucleophilic attack ability
of amidine to carbonyl group, changed the reaction pathway by enhanc-
ing nucleophilicity of another molecule of amidine for the eventual ox-
idative cyclization as well (vide infra). Furthermore, above results
indicate highly dispersed copper species on OMS-2 might play an im-
portant role during the reaction. To confirm the reaction is an oxidative
process, the reaction was run under N2 and it did not proceed, which
means the oxygen in air played a role as terminal oxidant (entry 7).
After the reaction under N2, the XRD was used to analyze the catalyst,
which shows OMS-2 changed to a Mn3O4 phase (JCPDS card no. 24-
0734, Fig. S6, see ESI). Two other OMS-2-based catalysts, acid-modified
Cu/H-OMS-2 [12] (10 mg, Cu: 0.5 wt%) and hydroxide Cu(OH)x/OMS-2
[20] (10 mg, Cu: 1.3 wt%), were used to improve the reaction, but they
failed to show good selectivity (entries 8 and 9). Consequently, the op-
timal reaction conditions for the synthesis of 1,2-dehydro-1,3,5-triazine
can be indicated in entry 5 of Table 1 (for more optimizations and reuti-
lization of catalyst, see ESI).
Firstly, elemental analysis of the catalyst by atomic absorption spec-
trometry (AAS) indicated that the quantity of Cu in the sample was
0.5 wt.%. Next, X-ray diffraction (XRD) was used to analysis OMS-2,
Cu/OMS-2 and the OMS-2 material synthesized by conventional reflux
method (designated as OMS-2-Re) [15]. The patterns in Fig. 1 demon-
strated that the diffraction peaks of OMS-2 and Cu/OMS-2 were the
same as that of OMS-2-Re, which means OMS-2 was formed successful-
ly using TBHP as reductant and its supported catalyst was also typical
cryptomelane materials (JCPDS file #29-1020) [15]. No signals due to
copper metal (cluster) or copper oxide were observed, which suggests
that the copper oxide was low loading and highly dispersed on OMS-
2. Finally, OMS-2 and Cu/OMS-2 were characterized by transmission
electron microscope (TEM) and scanning electron microscope (SEM).
It was found that OMS-2 was very uniform in length and had a typical
uniformly nano-rod morphology (Fig. 2), which was in agreement
with the previous research [15]. Moreover, the width of the OMS-2
nanofibers was in 5–16 nm range based on the counting of 180 particles
(Fig. S3, see ESI). For Cu/OMS-2, the catalyst remained the fibers or nee-
dlelike morphology (Fig. 3) (For more characterization of OMS-2 and
Cu/OMS-2, see ESI).
According to previous reports, it is known OMS-2 has excellent
redox ability [11,16,17,19]. Therefore, we were supposed to direct use
alcohol as starting material which transforms in situ to aldehyde and
then reacts with two molecules of amidine to offer cyclized product
1,2-dihydro-1,3,5-triazine. A screening was conducted to optimize the
reaction conditions by reacting benzyl alcohol (1a) and N-arylamidine
(2a). Initially, background reactions were run in toluene under air at
90 °C, which demonstrates the reaction did not occur without catalyst
With the optimal conditions in hand, we continued to investigate
the scope of the reactions by employing a variety of alcohols with N-
phenylbenzimidamide (Scheme 3). Gratifyingly, benzyl alcohols with
Table 1
Optimization of the reaction conditionsa.
Entry
Catalyst
1a (mmol)
Solvent
Yield (%)b
3a
4a
1
2
3
4
–
2
2
2
2
2
2
2
2
2
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
0
0
0
0
0
0
0
0
0
0
0
19
24
OMS-2
CuO (10 mol%)
Nano-CuO (10 mol%)
CuO + OMS-2
Cu/OMS-2
Cu/OMS-2
Cu/H-OMS-2
Cu(OH)x/OMS-2
5c
6d
7e
8
0
95 (91)
0
76
52
9
a
Reaction conditions: 1a, 2a (0.5 mmol), catalyst (10 mg), solvent (2 mL), air, 90 °C, 20 h.
NMR yield using CH2Br2 an internal standard and isolated yield is given in parenthesis.
10 mol% of CuO and 10 mg OMS-2 were used.
10 mg of Cu/OMS-2 (Cu: 0.5 wt%) was used.
Under N2.
b
c
d
e

X. Meng et al. / Catalysis Communications 89 (2017) 34–39
37
Scheme 3. Synthesis of 1,2-dihydro-1,3,5-triazines using different alcohols. Reaction conditions: 1a (2 mmol), 2a (0.5 mmol), Cu/OMS-2 (10 mg), toluene (2 mL), air, 90 °C, 20 h, isolated
yields.
Scheme 4. Synthesis of 1,2-dihydro-1,3,5-triazines using benzyl alcohols and different N-arylamidines. Reaction conditions: 1a (2 mmol), 2a (0.5 mmol), Cu/OMS-2 (10 mg), toluene
(2 mL), air, 90 °C, 20 h, isolated yields.

38
X. Meng et al. / Catalysis Communications 89 (2017) 34–39
toluene
(a)
90 oC, air, 20 h
Ph
OH
Ph
O
2 mmol
Cu/OMS-2 (10 mg, 0.25 mol%), 89% GC Yield
OMS-2 (10 mg), 42% GC Yield
(b)
Ph
H
Ph
Ph
Cu/OMS-2 (0.25 mol%)
N
Ph
NH
0.5 mmol
N
N
Ph
+
2
Ph
O
toluene, air, 20 h
Ph
N
at 90 oC, 95% NMR Yield
at 70 oC, 22% NMR Yield
2 mmol
Scheme 5. Control experiments.
electron-withdrawing and electron-donating substituted groups
reacted with N-phenylbenzimidamide very well and selectively
furnished corresponding products 3a-3k in moderate to good yields.
However, we found that the steric effect influenced the reaction signif-
icantly, such as benzyl alcohol with substituent at the meta-position,
and the substrate showed the poor reactivity in the reaction under the
standard conditions (Scheme 3, 3d). However, disubstituted benzyl al-
cohols offered corresponding products in good yields probably because
substituents at para-positions balanced electron density of the benzene
ring and activated the benzyl alcohols (Scheme 3, 3h and 3i). Benzyl al-
cohol with sensitive substituent -NO2 was also compatible with the re-
action conditions, although the desired product 3l was isolated in a low
yield of 37%. Pleasingly, trans-cinnamyl alcohol was a good substrate in
the reaction and 56% yield of desired product 3m was isolated without
observation of cyclized product 1,2,4-trisubstituted-1H-imidazole-5-
carbaldehyde [26]. Furthermore, Cu/OMS-2/O2 system was able to oxi-
dize heteroaromatic alcohols, like pyridin-2-ylmethanol and thiophen-
2-ylmethanol, and convert them with N-phenylbenzimidamide into
the corresponding products selectively in moderate yields (Scheme 3,
3n and 3o). Interestingly, not only aromatic alcohols were suited for
the reactions, but aliphatic alcohols also worked smoothly and provided
the corresponding products in excellent yields (Scheme 3, 3p and q).
Following these encouraging results for a wide range of alcohols, we
could react with benzyl alcohols smoothly and offered desired products
with moderate to good yields. In particular, electron-rich N-
phenylbenzimidamides provided slightly higher yields of products
than electron-poor ones did. Unfortunately, the reaction did not work
with aliphatic amidines. We believe that the formation of imine from al-
dehydes and aliphatic amidines might be difficult under the standard
reaction conditions.
To gain insight into the reaction mechanism, control experiments
were conducted (Scheme 5). Firstly, it was found that Cu/OMS-2 was ef-
ficient for the oxidation of alcohol and OMS-2 oxidized alcohol to alde-
hyde in relatively low yield in the presence of air (Scheme 5, a). Next,
we direct employed aldehyde as the substrate reacting with N-
arylamidine under the standard reaction conditions, the high yield of
1,2-dihydro-1,3,5-triazine (3a) was obtained (Scheme 5, b). Further-
more, the reaction between aldehyde and N-arylamidine could perform
at even low temperature, like 70 °C, although the yield of desired prod-
uct was low (Scheme 5, b). The above experimental results suggested
that aldehyde was first formed via the oxidation of alcohol in situ and
further participated in the reaction with N-arylamidine. From the previ-
ous work of OMS-2-catalyzed imines synthesis [28], it is known that
OMS-2 materials were able to use as efficient catalysts for the synthesis
of imines via C\\N bond formation between alcohols and amines. Thus,
we proposed intermediate A (in Scheme 6) might be the next interme-
diate and tried to isolate it from condensation of aldehyde and N-
arylamidine for the further understanding of the reaction mechanism.
However, it was failed to isolate intermediate A even at low reaction
examined the scope of the reactions with
a variety of N-
phenylbenzimidamide (Scheme 4). Under the optimal reaction condi-
tions, many N-phenylbenzimidamides with different substituents
Scheme 6. Proposed mechanism.

X. Meng et al. / Catalysis Communications 89 (2017) 34–39
39
temperature perhaps because it is too unstable to isolate or it quickly
transforms in the reaction. Based on our experimental results and previ-
ous research of OMS-2-based materials catalyzed oxidations [12e, 12i], a
possible reaction pathway is proposed in Scheme 6. Initially, benzyl al-
cohol is oxidized in situ by Cu/OMS-2 via multistep oxidation using O2
as the terminal oxidant to benzaldehyde [27]. Then, the imine interme-
diate A is formed between benzaldehyde and N-arylamidine catalyzed
by Cu/OMS-2 with the elimination of H2O [28]. Notably, the intermedi-
ate A led to quinazoline under Cu/ligand/O2 system [25], while this
intra-molecular cyclized compound was not detected under Cu/OMS-
2/O2 system. It is believed that another molecule of N-arylamidine,
which possesses stronger nucleophilicity caused by the assistance of
OMS-2, attacks the imine intermediate A via inter-molecular nucleo-
philic addition of amino group to generate intermediate B after proton
transfer. Next, the intra-molecular nucleophilic addition of amino
group on B occurs quickly to form intermediate C. The symmetrical
dihydrotriazine D is formed after the elimination of aniline that is de-
tected by GCMS. Eventually, the desired product 1,2-dihydro-1,3,5-tri-
azine is obtained after tautomerization of D.
and the Project of National Science Foundation of Gansu Province (No.
1208RJZA266).
Appendix A. Supplementary data
Supplementary data to this article can be found online at doi:10.
1016/j.catcom.2016.10.014.
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We gratefully acknowledge the National Natural Science Foundation
of China (Grant Nos. 21403256, 21573261, 21372102) and the Suzhou
Industrial Technology and Innovation Project (Grant No. SYG201531)