Ruthenium-catalyzed synthesis of tri-substituted 1,3,5-triazines from alcohols and biguanides

Article abstract of DOI:10.1039/c6nj01620k

An efficient ruthenium-catalyzed synthesis of tri-substituted 1,3,5-triazines from alcohols and biguanides under mild conditions has been developed. The reaction occurred in moderate to good yields and tolerated benzyl alcohol containing functionalities s

Full text of DOI:10.1039/c6nj01620k

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Ruthenium-catalyzed synthesis of tri-substituted
1,3,5-triazines from alcohols and biguanides†
Cite this:DOI: 10.1039/c6nj01620k
Ming Zeng,a Tao Wang,a Dong-Mei Cui*a and Chen Zhang*b
Received (in Montpellier, France)
26th May 2016,
Accepted 6th September 2016
DOI: 10.1039/c6nj01620k
www.rsc.org/njc
An efficient ruthenium-catalyzed synthesis of tri-substituted 1,3,5- alkylating agents, alcohols are readily available and are considered
triazines from alcohols and biguanides under mild conditions has potential agents. Herein, we describe the successful synthesis of
been developed. The reaction occurred in moderate to good yields tri-substituted 1,3,5-triazines from biguanides with alcohols in the
and tolerated benzyl alcohol containing functionalities such as presence of ruthenium catalysts.
halogens. Monosubstituted to tetrasubstituted biguanidines also
afforded the desired products.
We initiated our studies by examining the reaction of benzyl
alcohol 1a with biguanide 2a to form triazine 3a in the presence
of ruthenium catalysts (Table 1). Using 2 mol% of Ru3(CO)12
A triazine fragment is a ubiquitous structure that occurs in a and 2 equiv. of t-BuOK in dioxane at 100 1C for 14 h, conversion
wide variety of naturally occurring and synthetic compounds to tri-substituted 1,3,5-triazine 3a could be observed in 74%
exhibiting various important biological activities. Among the yield (Table 1, entry 1). We observed that the formation of 3a
triazine derivatives reported, tri-substituted 1,3,5-triazine deri- was related to the temperature: lowering the reaction tem-
vatives display several biological activities such as antibacterial, perature to 80 1C or increasing the reaction temperature to
anti-HSV-1, anticancer and anti-HIV activities.1 For this reason, 130 1C resulted in a slightly lower yield (Table 1, entries 4 and 5).
the development of synthetic protocols for functionalized 1,3,5- t-BuOK proved to be the base of choice; MeONa, Cs2CO3, NaH,
triazines has always been an active area of research. The most and DBU did not give any product (Table 1, entries 6–9).
common synthetic methods have been reported, fundamentally Different solvents were screened, and dioxane was found to
based on the nucleophilic displacement of cyanuric chloride.2 be the best one (Table 1, entries 10–13). With the use of higher
The formation of a triazinic ring by the reaction of substituted or lower catalytic amounts of Ru3(CO)12 and t-BuOK, the yields
biguanides with carboxylates, acid chlorides, and anhydrides or of 3a did not increase (Table 1, entries 14–17). The by-product
by cyclization of acylamidines with amidines or guanidines has formation was observed using 2.5 equiv. of t-BuOK. In the case
also been reported.3 Additionally, the reaction of biguanides of other ruthenium catalysts, a similar yield was obtained when
with aldehydes gave only 3,6-dihydro-1,3,5-triazine derivatives.4 Ru3(CO)12 was replaced by Ru(COD)Cl2 (Table 1, entry 18).
On the other hand, the environmentally benign formation of Only moderate to good conversions were obtained when using
carbon–carbon and carbon–nitrogen bonds is a central, but still Ru(PPh3)2Cl2, Cp(PPh3)2RuCl and RuCl3 as catalysts (Table 1,
challenging, area of organic synthesis. In recent years, much entries 19–21). Finally, increasing the number of equivalents
attention has been paid to C- and N-alkylation reactions with of biguanide or alcohol resulted in lower conversions (Table 1,
alcohols as alkylating agents based on the ‘‘hydrogen auto- entries 22 and 23), no reaction was observed in the absence of
transfer (or hydrogen-borrowing) process’’ by a transition- the Ru catalyst or base (Table 1, entries 24 and 25).
metal-catalyst.5–9 In this process, an alcohol transfers hydrogen
With the optimized reaction conditions determined, the
to a transition metal catalyst and forms the corresponding substrate scope was further examined. As shown in Table 2,
aldehyde or ketone intermediate recognized as the key point we first examined the reactions of aromatic alcohols bearing
for the formation of the desired products. Compared to other various functional groups on the aromatic ring. Benzyl alcohols
with an electron-donating alkyl group on the benzene ring gave
good isolated yield of the corresponding 1,3,5-triazine (Table 2,
entry 2). With a more electron-donating alkoxy group, the expected
adducts were obtained (Table 2, entries 2–7). In addition, benzyl
alcohols bearing an electron-withdrawing group (F, Cl, Br) on the
a College of Pharmaceutical Science, Zhejiang University of Technology,
Hangzhou 310014, China. E-mail: cuidongmei@zjut.edu.cn
b School of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
† Electronic supplementary information (ESI) available. See DOI: 10.1039/c6nj01620k
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Table 1 Optimization of the reaction conditions
Table 3 Scope of the synthesis of 3aa
Time Temp.
Yielda
(%)
Entry Catalyst
Base
(h)
(1C)
Solvent
1
2
3
4
5
6
7
8
Ru3(CO)12
Ru3(CO)12
Ru3(CO)12
Ru3(CO)12
Ru3(CO)12
Ru3(CO)12
Ru3(CO)12
Ru3(CO)12
Ru3(CO)12
Ru3(CO)12
Ru3(CO)12
Ru3(CO)12
Ru3(CO)12
Ru3(CO)12
Ru3(CO)12
Ru3(CO)12
Ru3(CO)12
Ru(COD)Cl2
Ru(PPh3)2Cl2
t-BuOK 14
t-BuOK 10
t-BuOK 18
t-BuOK 14
t-BuOK 14
MeONa 14
Cs2CO3 14
100
100
100
130
80
100
100
100
100
Dioxane 74
Dioxane 47
Dioxane 56
Dioxane 58
Dioxane 62
Dioxane Trace
Dioxane Trace
NaH
DBU
14
14
Dioxane
Dioxane
—
—
47
a
All reactions were performed with 1.0 mmol of 1 and 1.0 mmol of 2
using Ru(COD)Cl2 (2 mol%), t-BuOK (200 mol%), and dioxane (5 mL) at
9
10
11
12
13
14b
15c
16d
17e
18
19
20
21
22f
23g
24
25
t-BuOK 14
t-BuOK 14
t-BuOK 14
t-BuOK 14
t-BuOK 14
t-BuOK 14
t-BuOK 14
t-BuOK 14
t-BuOK 14
t-BuOK 14
Reflux THF
Reflux Toluene 30
b
100 1C in a sealed reaction tube, isolated yields are shown. Ref. 13.
c
Ref. 14.
100
100
100
100
100
100
100
100
100
100
100
100
100
100
DMSO
DMF
25
5
Dioxane 10
Dioxane 48
Dioxane 58
Dioxane 60
Dioxane 74
Dioxane 55
Dioxane 49
Dioxane 62
Dioxane 21
Dioxane 60
in 65% and 63% yields, respectively (Table 2, entries 11 and 12).
Unfortunately, benzyl alcohols bearing nitro or hydroxy on the
benzene ring and alkyl alcohols such as methanol, n-butanol or
2-phenylethan-1-ol with 2a did not undergo the reaction under the
current reaction conditions. 1-Phenylethan-1-ol as secondary benzyl
alcohol failed to afford the product.
Cp(PPh3)2RuCl t-BuOK 14
RuCl3
Ru3(CO)12
Ru3(CO)12
Ru3(CO)12
—
t-BuOK 14
t-BuOK 14
t-BuOK 14
Furthermore, this reaction also occurred with benzyl alcohols
and a variety of biguanidines (Table 3). Cyclic amino substituted
biguanidines, such as morpholine, pyrrolidine, and piperidine
biguanidines, produced the corresponding products 3m–3o in
good yields. Monosubstituted, disubstituted, trisubstituted, or
tetrabiguanidine could be used as the starting materials, which
afforded tri-substituted 1,3,5-triazines 3p–3u. The yields of 3n
and 3q are also higher than those obtained using common
methods reported.13,14
A possible mechanism was proposed for the ruthenium-
catalyzed synthesis of 1,3,5-triazines from biguanides with
alcohols (Scheme 1). The ruthenium complex reacts with alcohol
1 to form ruthenium alkoxide, and then gives an intermediate
—
14
Dioxane
—
t-BuOK 14
Dioxane Trace
a
Reaction conditions: 1a (1.0 mmol), 2a (1.0 mmol), catalyst
(0.02 mmol), base (2 mmol), solvent (5 mL); isolated yields are shown.
b
e
c
d
t-BuOK (1.0 mmol). t-BuOK (2.5 mmol). Ru3(CO)12 (0.01 mmol).
f
g
Ru3(CO)12 (0.04 mmol). 1a (1.5 mmol). 2a (1.5 mmol).
benzene ring gave moderate yields to show lower reactivity (Table 2,
entries 8–10). Under the same reaction conditions heterocyclic
alcohols 1k and 1l were also converted into the expected products
Table 2 Scope of the synthesis of 3a
Entry
Ar
1
3
Yield (%)
1
2
C6H5
1a
1b
1c
1d
1e
1f
1g
1h
1i
3a
3b
3c
3d
3e
3f
3g
3h
3i
74
65
71
55
70
74
83
54
63
51
65
63
4-MeC6H4
4-MeOC6H4
3-MeOC6H4
2-MeOC6H4
2,3-(MeO)2C6H3
3,4-(MeO)2C6H3
4-FC6H4
4-ClC6H4
4-BrC6H4
2-Furanyl
2-Thiophenyl
3b
4b
5b
6b
7
8
9
10
11c
12b
1j
1k
1l
3j
3k
3l
a
All reactions were performed with 1.0 mmol of 1 and 1.0 mmol of 2a using
Ru(COD)Cl2 (2 mol%), t-BuOK (200 mol%), and dioxane (5 mL) at 100 1C for
14 h in a sealed reaction tube, isolated yields are shown. b 20 h. c 30 h.
Scheme 1 Plausible reaction mechanism.
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aldehyde 4 via b-hydride elimination.9–12 The aldehyde 4 is much
more reactive toward biguanide 2, and the dihydro-triazine 5 is
formed under the reaction conditions.4 Finally, the desired
product 3 is formed via dehydrogenative aromatization of 5
by the ruthenium catalyst or air oxidation.15 In all reaction,
aldehydes as intermediates could be detected.
In summary, we have developed a simple and efficient protocol
for the synthesis of tri-substituted 1,3,5-triazines via ruthenium
catalyzed reaction of alcohols with biguanides. The method
employs readily available reagents and has a broad scope and
high functional group tolerance. Detailed mechanistic studies and
scope expansion work are currently underway in our laboratory.
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Unless otherwise noted, materials were obtained from commer-
cial suppliers and used without further purification. t-BuOK (98%
purity) was purchased from Aladdin Industrial Corporation.
Thin layer chromatography (TLC) was performed using silica
gel 60 F254 and visualized using UV light. Column chromato-
graphy was performed with a silica gel (mesh 300–400).
1H NMR and 13C NMR spectra were recorded on a Bruker
Avance 500 MHz spectrometer in CDCl3 with Me4Si as an
internal standard. Data were reported as follows: chemical shift
in parts per million (d), multiplicity (s = singlet, d = doublet,
t = triplet, q = quartet, br = broad, and m = multiplet), coupling
constant in Hertz (Hz) and integration.
General procedure for the synthesis of 1,3,5-triazines
To a mixture of alcohols (1.0 mmol), biguanide hydrochloride
(1.0 mmol), and t-BuOK (2.0 mmol) in dioxane (5 mmol),
Ru(COD)Cl2 (2 mol%) was added. The resulting mixture was
then sealed and stirred for 12 h at 100 1C. After completion of
the reaction, the reaction mixture was cooled to room tem-
perature and extracted with ethyl acetate. The organic phase
was dried over anhydrous Na2SO4. The crude residue was
obtained after evaporation of the solvent in vacuum, and the
residue was purified by flash chromatography with CH2Cl2 and
CH3OH as eluents to give the pure product.
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