Base-mediated synthesis of unsymmetrical 1,3,5-triazin-2-amines via three-component reaction of imidates, guanidines, and amides or aldehydes

Article abstract of DOI:10.1021/acs.joc.7b01510

A simple and efficient method for the basemediated synthesis of unsymmetrical 1,3,5-triazin-2-amines has been developed. The protocol uses readily available imidates, guanidines, and amides or aldehydes as the starting materials, cesium carbonate as the base, no catalyst or additive is required, and the three-component reaction provides diverse 1,3,5-triazin-2-amines in moderate to good yields with tolerance of wide functional groups.

Full text of DOI:10.1021/acs.joc.7b01510

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Article
Base-mediated synthesis of unsymmetrical 1,3,5-triazin-2-amines via three-
component reaction of imidates, guanidines and amides or aldehydes
Liyang Pan, Zhen-Xing Li, Tao Ding, Xiaomin Fang, Wenkai Zhang, Hao Xu, and Yuanqing Xu
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b01510 • Publication Date (Web): 25 Aug 2017
Downloaded from http://pubs.acs.org on August 26, 2017
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Base-mediated synthesis of unsymmetrical 1,3,5-triazin-2-amines via three-
component reaction of imidates, guanidines and amides or aldehydes
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Liyang Pan,a,‡ Zhenxing Li,b,‡ Tao Ding,a Xiaomin Fang,a Wenkai Zhang,a Hao Xu,*,a,b Yuanqing Xu*,a
a College of Chemistry and Chemical Engineering, Henan University, Kaifeng 475004, P. R. China.
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b State Key Laboratory of Heavy Oil Processing, China University of PetroleumꢀBeijing, Beijing
102249, P. R. China.
Eꢀmail : xuhao@henu.edu.cn; 18937822307@163.com
ABSTRACT: A simple and efficient method for the baseꢀmediated synthesis of unsymmetrical 1,3,5ꢀ
triazinꢀ2ꢀamines has been developed. The protocol uses readily available imidates, guanidines and amꢀ
ides or aldehydes as the starting materials, cesium carbonate as the base, no any catalyst or additive is
required, and the threeꢀcomponent reaction provides diverse 1,3,5ꢀtriazinꢀ2ꢀamines in moderate to good
yields with tolerance of wide functional groups.
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INTRODUCTION
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1,3,5ꢀTriazines are important building blocks with wide application in pharmaceuticals, agrochemical
and functional materials.1 Direct synthesis of substituted 1,3,5ꢀtriazines from readily available substrates
mainly relied on the nucleophilic displacement of cynauric chloride,2 cyclotrimerization of nitriles,3 and
cyclization of aryl amidines with formylating reagents or others.4 However, these methods were restrictꢀ
ed to synthesis of symmetrical 1,3,5ꢀtriazines (Figure 1); because the unsymmetrical and symmetrical
1,3,5ꢀtriazines are always generated simultaneously during synthesis of unsymmetrical 1,3,5ꢀtriazines
by the previous methods, and they are difficult to be separated for their very close value of Rf. Thereꢀ
fore, the direct synthesis of unsymmetrical 1,3,5ꢀtriazines from readily available substrates is still a
great challenge.
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Figure 1. Symmetrical 1,3,5ꢀtriazines for traditional methods
Since 1,3,5ꢀtriazinꢀ2ꢀamines exhibit various biological and medicinal activities,5 various methods for
the synthesis of diverse 1,3,5ꢀtriazinꢀ2ꢀamines have been developed.6 However, the direct synthesis of
1,3,5ꢀtriazinꢀ2ꢀamines from readily available substrates is rare. In 2007, Maes’s group reported syntheꢀ
sis of 1,3,5ꢀtriazinꢀ2ꢀamines via oxidative amination of 1,3,5ꢀtriazine in excess of amineꢀethanol soluꢀ
tion using AgPy2MnO4 as the oxidant (Scheme 1A).6a In 2014, MartínezꢀAlvarez’ group developed a
simple and efficient method for triflic anhydrideꢀmediated oneꢀpot synthesis of 4,6ꢀdisubstituted 1,3,5ꢀ
triazinꢀ2ꢀamines via coupling of two different nitriles (Scheme 1B).6b Nevertheless, it is difficult to diꢀ
rectly prepare unsymmetrical 1,3,5ꢀtriazinꢀ2ꢀamines from readily available substrates. Meanwhile, the
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synthesis of unsymmetrical 1,3,5ꢀtriazinꢀ2ꢀamines with different bioactive groups is significant for the
research of new drugs and pesticides.
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Scheme 1. Direct synthesis of 1,3,5ꢀtriazinꢀ2ꢀamines from readily available substrates
Transitionꢀmetalꢀcatalyzed synthesis of Nꢀheterocycles is still dominant; and transitionꢀmetal cataꢀ
lysts are usually needed in the formation of 1,3,5ꢀtriazine framework, when readily available substrates
(such as DMF) are used.2,3b,4bꢀ4e Nonetheless, transitionꢀmetalꢀcatalyzed reactions have an insurmountaꢀ
ble disadvantage, due to the intrinsic toxicity of most transition metals and the arduous removal of tranꢀ
sition metal traces to the ppmꢀ or even ppbꢀlevel which is often required for pharmaceutical intermediꢀ
ates or final products. Furthermore, molecular oxygen (O2) has emerged as one of the most favorable
oxidants as impressively demonstrated by nature in chemical transformations. In continuation of our enꢀ
deavors to develop the simple synthetic methods of Nꢀheterocycles from readily available substrates,7
we herein report a baseꢀmediated synthesis of unsymmetrical 1,3,5ꢀtriazinꢀ2ꢀamines via threeꢀ
component reaction of imidates, guanidines and amides or aldehydes (Scheme 1Cꢀ1E).
RESULTS AND DISCUSSION
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Initially, ethyl 4ꢀmethylbenzimidate (1b) and guanidine hydrochloride (2a) were chosen as model
substrates to optimize the conditions including bases and temperatures. As shown in Table 1, nine bases
(4 equiv., relative to amount of 1b) were tested, Cs2CO3 showed the best activity (Table 1, entries 1ꢀ9).
The reaction did not work in the absence of base (entry 10). The amount of base also affected its practiꢀ
cal use; product 3a was obtained in 88% yield when amount of Cs2CO3 was increased to 5 equivalents
(entry 11); further increase of amount of Cs2CO3 did not lead to a higher yield (entry 12). Therefore, 5
equiv of Cs2CO3 was the best choice. Yield decreased when temperature was raised to 150 oC, owing to
hydrolysis of a small amount of imidate 1b (entry 14). It was noted that a high yield was also obtained
when the reaction was performed under nitrogen atmosphere (entry 15). However, the oxidant was alꢀ
ways needed in the formation of 1,3,5ꢀtriazine framework when DMF was used as the substrate in the
previous synthetic method.4d
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Table 1. Optimization of conditions on baseꢀmediated synthesis of 4ꢀ(pꢀtolyl)ꢀ1,3,5ꢀtriazinꢀ2ꢀamine (3b) via threeꢀ
component reaction of ethyl 4ꢀmethylbenzimidate (1b), guanidine hydrochloride (2a) and DMFa
Entry
Base
Temp
120
120
120
120
120
120
120
120
120
120
Yield (%)b
40
1
2
tꢀBuONa
CsOH
NaOH
Cs2CO3
K2CO3
Na2CO3
K3PO4
CsOAc
NaOAc
ꢀꢀ
19
3
25
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83
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30
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trace
trace
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trace
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11c
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
120
120
100
150
120
120
88
86
52
74
79
85
12d
13c
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14c
15c,e
16c,f
13
a
Reaction condition: 4ꢀmethylbenzimidate (1b) (0.3 mmol), guanidine hydrochloride (2a) (0.33 mmol), base (1.2
mmol), DMF (2 mL), reaction time (24 h) in a sealed Schlenk tube without exclusion of air. b Isolated yield. c Base (1.5
mmol). d Base (1.8 mmol). e under nitrogen atmosphere (1 atm). f under oxygen atmosphere (1 atm).
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Under the optimized conditions, various imidates and guanidines were used to investigate, and a seꢀ
ries of 6ꢀarylꢀ1,3,5ꢀtriazinꢀ2ꢀamines were synthesized in moderate to good yields (Table 2). The reaction
worked well for metaꢀ and para-substituted arylimidates (entries 2,3), and various electronꢀwithdrawing
groups (EWGs; Cl, Br, CF3; entries 4ꢀ6) and electronꢀdonating groups (EDGs, Me, OMe; entries 2, 3, 7)
in the substituents were completely tolerated. Delightfully, substituted guanidine was also tolerated to
afford 3h-3k in moderate to good yields (entries 8ꢀ11).
Table 2. Baseꢀmediated synthesis of 4ꢀarylꢀ1,3,5ꢀtriazinꢀ2ꢀamines 3 via threeꢀcomponent reaction of imidates 1, guaniꢀ
dines 2 and DMFa
Entry
1
Yield (%)b
90
1
2
3
2
3
88
75
2a
2a
5
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1b
1c
1d
1f
2b
2b
2b
10
11
a Reaction condition: 1 (0.3 mmol), 2 (0.33 mmol), Cs2CO3 (1.5 mmol), DMF (2 mL), reaction time (24 h) at 120 oC in
a sealed Schlenk tube without exclusion of air. b Isolated yield.
Considering that the reaction could be performed well in the absence of oxidant, we concluded that
the formyl group of DMF participated in the formation of 1,3,5ꢀtrianine framework via addition and
elimination of ꢀN(CH3)2 (For details, see Scheme 5). Encouraged by the above results and speculated
mechanism, N,Nꢀdimethylacetamide (DMA) was used as the substrate to replace DMF, and we also opꢀ
timized the reaction conditions (see Table S1 in the Supporting Information). Several 4ꢀmethylꢀ6ꢀarylꢀ
1,3,5ꢀtriazinꢀ2ꢀamines were prepared from imidates, guanidines and DMA (Scheme 2) under baseꢀ
mediated conditions. Futhermore, 4ꢀethylꢀ6ꢀarylꢀ1,3,5ꢀtriazinꢀ2ꢀamine derivative was also obtained in
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moderate yield when N,Nꢀdimethylpropionamide (DMP) was used as the substrate instead of DMA (4f
4
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in Scheme 2).
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Scheme 2. Baseꢀmediated synthesis of 4ꢀalkylꢀ6ꢀarylꢀ1,3,5ꢀtriazinꢀ2ꢀamines 4 via threeꢀcomponent reaction of imꢀ
idates 1, guanidines 2 and DMA or DMPa
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a Reaction condition: 1 (0.3 mmol), 2 (0.33 mmol), Cs2CO3 (1.5 mmol), anhydrous DMA (2 mL), reaction time (24 h)
at 150 oC under nitrogen atmosphere (1 atm). b Isolated yield. c Using anhydrous DMP to replace DMA.
Subsequently, imidates 1, guanidines 2 and aldehydes 5 were used as the substrates to prepare 4,6ꢀ
disubstituted 1,3,5ꢀtriazinꢀ2ꢀamine derivatives (Scheme 3). Firstly, ethyl benzimidate (1a), guanidine
hydrochloride (2a) and benzaldehyde (5a) were chosen as the model substrates to optimize reaction
conditions including bases, solvents, temperatures and atmospheres (Table S2 in the ESI). The molecuꢀ
lar oxygen (O2) in air was proved to be necessary to improve the yield of product 6a (Table S2, compare
entries 9ꢀ12). Under the optimized conditions, arylꢀdisubstituted 1,3,5ꢀtriazinꢀ2ꢀamines were prepared in
moderate to good yields (6aꢀi in Scheme 3); and aromatic aldehydes were well tolerated under the baseꢀ
mediated conditions. Furthermore, aliphatic aldehydes could also generate the relative products (6jꢀk in
Scheme 3).
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Scheme 3. Baseꢀmediated synthesis of disubstituted 1,3,5ꢀtriazinꢀ2ꢀamines 6 via threeꢀcomponent oxidative reaction of
ethyl imidates 1, guanidines 2 and aldehydes 5a
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a Reaction condition: 1 (0.3 mmol), 2 (0.9 mmol), 5 (0.6 mmol), Cs2CO3 (2.1 mmol), DMSO (3 mL), reaction time (24
h) at 150 oC in a sealed Schlenk tube without exclusion of air. b Isolated yield.
Some control experiments were performed to probe the mechanism. Reaction of 1b, 2a and DMFꢀd7
gave the deuterated product 3bb in 90 % yield (Scheme 4A), and only trace amount of nonꢀdeuterated
product was observed in the H1 NMR spectrum (Figure S1,S2 in the Supporting Information); this result
proved that DMF participated in the formation of 1,3,5ꢀtriazine framework, and served as the CꢀH
source. Reaction of 1b, 2a and DMA gave product 4b in 67 % yield (NMR determination, Figure S3 in
Supporting Information) under standard conditions (N2, 1 atm), and only 5 % yield (NMR determination,
Figure S3 in Supporting Information) of 3b was obtained (Scheme 4B); the result proved that the acyl
group of the DMA serve as the CꢀCH3 source in the formation of 4b. Under oxygen atmosphere, more
3b was obtained although 4b was still the main product (Scheme 4C; Figure S4,S5 in Supporting Inforꢀ
mation); the methyl of DMA served as the CꢀH source in the formation of little 3b under oxygen atmosꢀ
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phere, and a singleꢀelectron oxidation process could happen in the formation of 3b (examined by addiꢀ
tion of TEMPO; Figure S6 in Supporting Information).4d,8 Furthermore, addition of 1 equiv of TEMPO
(radical scavenger) had no effect for the formation of 3b or 4b under the standard conditions (Scheme
4D,4E); these results implied that the reaction underwent a nucleophilic additionꢀelimination process in
the formation of products 3 and 4.
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Scheme 4. (A) Baseꢀmediated threeꢀcomponent reaction of imidates 1b, guanidines 2a and deuterated DMF under
standard conditions; (B) Baseꢀmediated threeꢀcomponent reaction of imidates 1b, guanidines 2a and DMA under
standard conditions (N2, 1 atm); (C) Baseꢀmediated threeꢀcomponent reaction of imidates 1b, guanidines 2a and DMA
under oxygen atmosphere (1 atm); (D) Addition of 1 equiv of TEMPO (radical scavenger) for the synthesis of 3b under
standard conditions; (E) Addition of 1 equiv of TEMPO (radical scavenger) for the synthesis of 4b under standard
conditions.
Interestingly, under copperꢀcatalyzed conditions, the methyl of DMF could serve as the CꢀH source to
afford Nꢀheterocyclic compounds, such as symmetrical 1,3,5ꢀtriazines4d,4e or 1,2,4ꢀtriazoles.4e However,
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under metalꢀfree baseꢀmediated condition, the acyl group of DMF, DMA and DMP respectively served
as the CꢀH, CꢀCH3 and CꢀC2H5 source in our work.
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On the basis of the above control experiments and previous reports,4 a plausible reaction mechanism
is proposed in Scheme 5. At first, nucleophilic attack of guanidine 2 to imidate 1 leads to intermediate
M-1 in the presence of Cs2CO3; then the amino group of M-1 attacks the acyl group of the amide to
form the intermediate M-2; finally, intramolecular cyclization of M-2 gives the target product 3 or 4 via
an intramolecular additionꢀelimination process. When aldehyde 5 is used as the substrate and DMSO as
the solvent, the amino group of M-1 attacks the aldehyde 5 to form the intermediate M-3; then intramoꢀ
lecular oxidative dehydration/cyclization of M-3 provides the target product 6 under baseꢀmediated and
oxygenꢀoxidized conditions.
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Ar1
N
NHR2
NH HCl
—
R1
N
NHR2
N
N
Ar1
OC2H5
N
N
Alk
3 or 4
(Alk = H, CH3, C2H5)
1
R3
6
NH HCl
—
H
N
H2O
NHR2
base
H2N
base, air
H3C
CH3
base
Ar1
O
2
CH3
Alk
N
N
NH R2
R1
N
NH R2
NH
CH3
R3 CHO
5
Ar1
N
NH R2
N
Alk
NH
(Alk = H, CH3, C2H5)
N
NH2 NH
N
base, N2
R3
M-3
H3C
CH3
base
M-1
M-2
Scheme 5. Possible mechanism for the synthesis of products 3, 4 and 6
CONCLUSION
In conclusion, we have developed a simple and efficient method for the baseꢀmediated synthesis of
unsymmetrical 1,3,5ꢀtriazinꢀ2ꢀamines via threeꢀcomponent reaction of imidates, guanidines and amides
or aldehydes under transition metalꢀfree conditions. The unsymmetrical 1,3,5ꢀtriazine derivatives were
inaccessible to prepare directly from readily available substrates in the previous methods. The correꢀ
sponding mechanism is proposed for the synthesis of 4ꢀarylꢀ1,3,5ꢀtriazinꢀ2ꢀamines from imidates, guanꢀ
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idines and DMF; the formyl group of DMF serves as the CꢀH source in our work, which is different
from the previous reports that the methyl of DMF served as the CꢀH source for the formation of 1,3,5ꢀ
triazine framework. Based on the mechanism, we also use other amides and aldehydes to replace DMF,
and unsymmetrically disubstituted 1,3,5ꢀtriazinꢀ2ꢀamine derivatives are synthesized successfully. This
method can tolerate various functional groups, and presents a simple and efficient protocol for the direct
synthesis of unsymmetrical 1,3,5ꢀtriazinꢀ2ꢀamine derivatives from readily available substrates. Meanꢀ
while, this method will have a promising application in the direct synthesis of unsymmetrical 1,3,5ꢀ
triazinꢀ2ꢀamine drugs and pesticides.
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EXPERIMENTAL SECTION
General experimental procedures: Reagents were purchased and used without further purification.
Reactions were monitored by thin layer chromatography (TLC) and the products were obtained by colꢀ
13
umn chromatography on silica gel. Proton and carbon magnetic resonance spectra (1H NMR and C
NMR) were recorded using tetramethylsilane (TMS) in the solvent of CDCl3 as the internal standard (1H
13
NMR: TMS at 0.00 ppm,CHCl3 at 7.26 ppm; C NMR: CDCl3 at 77.16 ppm) or were recorded using
tetramethylsilane (TMS) in the solvent of DMSOꢀd6 as the internal standard (1H NMR: TMS at 0.00
ppm, DMSO at 2.50 ppm; 13C NMR: DMSO at 39.51 ppm).
General procedure for synthesis of compounds (3a-k): Substituted benzimidate hydrochloride 1
(0.3 mmol), guanidine hydrochloride 2 (0.33 mmol), Cs2CO3 (1.5 mmol, 489 mg) and DMF (2 mL)
were added to a 25 mL Schlenk tube charged with a magnetic stirrer. The reaction mixture was stirred at
120 oC for 24 h without exclusion of air. The resulting solution was concentrated on a rotary evaporator,
and the residue was purified by column chromatography on silica gel using petroleum ether/ethyl aceꢀ
tate as eluent to give the desired product 3a-k.
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4-Phenyl-1,3,5-triazin-2-amine (3a).9 Eluent: petroleum ether/ethyl acetate (4:1). Yield 46.5 mg
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(90 %). White solid, mp 203ꢀ204 C (lit.9 mp 203ꢀ204 °C). 1H NMR (DMSOꢀd6, 400 MHz, 25 °C) δ
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8.63 (s, 1H), 8.38ꢀ8.33 (m, 2H), 7.68ꢀ7.50 (m, 5H). 13C NMR (DMSOꢀd6, 100 MHz, 25 °C) δ 170.4,
167.1, 136.4, 132.5, 129.0, 128.4. GCꢀMS [M+H]+ m/z 172.36.
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4-(p-Tolyl)-1,3,5-triazin-2-amine (3b).10 Eluent: petroleum ether/ethyl acetate (4:1). Yield 49.2 mg
(88 %). White solid, mp 235.9ꢀ237.3 oC (lit.10 mp 235ꢀ236 °C). 1H NMR (DMSOꢀd6, 400 MHz, 25 °C) δ
8.56 (s, 1H), 8.22 (d, J = 8.2 Hz, 2H), 7.58 (s, 2H), 7.33 (d, J = 8.0 Hz, 2H), 2.38 (s, 3H). 13C NMR
(DMSOꢀd6, 100 MHz, 25 °C) δ 170.4, 167.0, 142.5, 133.7, 129.6, 128.4, 21.6. APCIꢀMS [M+H]+ m/z
186.96.
4-(m-Tolyl)-1,3,5-triazin-2-amine (3c). Eluent: petroleum ether/ethyl acetate (4:1). Yield 41.9 mg
(75 %). White solid, mp 184.7ꢀ186.0 oC. 1H NMR (DMSOꢀd6, 400 MHz, 25 °C) δ 8.62 (s, 1H), 8.21ꢀ
8.13 (m, 2H), 7.67 (s, 2H), 7.41 (m, 2H), 2.40 (s, 3H). 13C NMR (DMSOꢀd6, 100 MHz, 25 °C) δ 170.5,
167.0, 138.2, 136.3, 133.1, 128.9, 125.6, 21.5. ESIꢀMS [M+H]+ m/z 186.94. ESIꢀHRMS [M+H]+ m/z
calcd for C10H11N4 187.0984, found 187.0993.
4-(4-Chlorophenyl)-1,3,5-triazin-2-amine (3d). Eluent: petroleum ether/ethyl acetate (4:1). Yield
44.0 mg (71 %). White solid, mp 229.3ꢀ230.5 oC. 1H NMR (DMSOꢀd6, 400 MHz, 25 °C) δ 8.63 (s, 1H),
8.36ꢀ8.33 (m, 2H), 7.70 (s, 2H), 7.62ꢀ7.58 (m, 2H). 13C NMR (DMSOꢀd6, 100 MHz, 25 °C) δ 169.5,
167.1, 167.0, 137.3, 135.2, 130.1, 129.2. APCIꢀMS [M+H]+ m/z 206.95. ESIꢀHRMS [M+H]+ m/z calcd
for C9H8ClN4 207.0437, found 207.0447.
4-(4-Bromophenyl)-1,3,5-triazin-2-amine (3e).11 Eluent: petroleum ether/ethyl acetate (4:1). Yield
55.0 mg (73%). White solid, mp 241.4ꢀ242.6 oC (lit.11 mp 242ꢀ244 °C). 1H NMR (DMSOꢀd6, 400 MHz,
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°C) δ 169.6, 167.2, 167.0, 135.6, 132.1, 130.3, 126.4. APCIꢀMS [M+H]+ m/z 251.01.
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4-[4-(Trifluoromethyl)phenyl]-1,3,5-triazin-2-amine (3f). Eluent: petroleum ether/ethyl acetate
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(4:1). Yield 51.9 mg (72%). White solid, mp 201.7ꢀ202.9 oC. H NMR (DMSOꢀd6, 400 MHz, 25 °C) δ
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8.68 (s, 1H), 8.52 (d, J = 8.2 Hz, 2H), 7.92 (d, J = 8.2 Hz, 2H), 7.84 (s, 2H). 13C NMR (DMSOꢀd6, 100
MHz, DMSO) δ 169.2, 167.3, 167.0, 140.2, 132.1 (q, J = 31.8 Hz), 129.0, 126.1, 126.0, 125.9, 123.1.
APCIꢀMS [M+H]+ m/z 241.05. ESIꢀHRMS [M+H]+ m/z calcd for C10H8F3N4 241.0701, found
241.0709.
4-(4-Methoxyphenyl)-1,3,5-triazin-2-amine (3g).11 Eluent: petroleum ether/ethyl acetate (4:1).
Yield 51.6 mg (85%). White solid, mp 223.8ꢀ224.7 oC (lit.11 mp 225ꢀ228 °C). 1H NMR (DMSOꢀd6, 400
MHz, 25 °C) δ 8.56 (s, 1H), 8.34ꢀ8.28 (m, 2H), 7.56 (s, 2H), 7.10ꢀ7.05 (m, 2H), 3.85 (s, 3H). 13C NMR
(DMSOꢀd6, 100 MHz, 25 °C) δ 170.0, 166.9, 162.9, 130.3, 128.6, 114.4, 55.8. APCIꢀMS [M+H]+ m/z
202.97.
N-hexyl-4-(p-tolyl)-1,3,5-triazin-2-amine (3h). Eluent: petroleum ether/ethyl acetate (4:1). Yield
47.0 mg (58%). White solid, mp 88.5ꢀ89.4 oC. 1H NMR (CDCl3, 400 MHz, 25 °C) δ 8.64ꢀ8.42 (m, 1H),
8.30ꢀ8.13 (m, 2H), 7.29ꢀ7.09 (m, 2H), 6.30ꢀ5.68 (m, 1H), 3.50ꢀ3.33 (m, 2H), 2.38ꢀ2.30 (m, 3H), 1.60ꢀ
1.45 (m, 2H), 1.36ꢀ1.15 (m, 6H), 0.87ꢀ0.75 (m, 3H). 13C NMR (DMSOꢀd6, 100 MHz, 25 °C) δ 170.1,
169.8, 166.9, 166.4, 165.4, 165.3, 142.6, 142.5, 133.8, 133.6, 129.6, 128.5, 128.4, 40.7, 31.5, 31.4, 29.2,
29.0, 26.5, 22. 6, 22.5, 21.6, 14.4. 13C NMR (DMSOꢀd6, 150 MHz, 80 °C) δ 170.4, 166.9, 166.4, 165.7,
142.43, 134.1, 129.5, 128.5, 40.9, 31.5, 29.2, 26.5, 22.5, 21.5, 14.2. APCIꢀMS [M+H]+ m/z 271.25. ESIꢀ
HRMS [M+H]+ m/z calcd for C16H23N4 271.1923, found 271.1927.
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N-hexyl-4-(m-tolyl)-1,3,5-triazin-2-amine (3i). Eluent: petroleum ether/ethyl acetate (4:1). Yield
43.8 mg (54%). White solid, mp 69.0ꢀ71.1 oC. 1H NMR (DMSOꢀd6, 400 MHz, 25 °C) δ 8.69ꢀ8.49 (m,
1H), 8.25ꢀ8.05 (t, J = 11.2 Hz, 3H), 7.40 (s, 2H), 3.46ꢀ3.29 (m, 2H), 2.40 (s, 3H), 1.64ꢀ1.49 (m, 2H),
1.37ꢀ1.19 (m, 6H), 0.92ꢀ0.81 (m, 3H). 13C NMR (DMSOꢀd6, 100 MHz, 25 °C) δ 170.2, 169.9, 167.0,
166.4, 165.4, 165.3, 138.1, 136.5, 136.3, 133.2, 133.1, 128.9, 125.7, 125.6, 56.5, 49.1, 40.7, 31.5, 31.4,
29.2, 29.0, 26.5, 22.6, 22.5, 21.5, 19.0, 14.4. 13C NMR (DMSOꢀd6, 150 MHz, 80 °C) δ 166.9, 166.4,
165.7, 138.1, 133.0, 129.0, 128.8, 125.8, 40.9, 31.5, 29.2, 26.5, 22.5, 21.5, 14.2. APCIꢀMS [M+H]+ m/z
271.13. ESIꢀHRMS [M+H]+ m/z calcd for C16H23N4 271.1923, found 271.1940.
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4-(4-Chlorophenyl)-N-hexyl-1,3,5-triazin-2-amine (3j). Eluent: petroleum ether/ethyl acetate (4:1).
Yield 59.3 mg (68%). White solid, mp 105.5ꢀ106.3 oC. 1H NMR (DMSOꢀd6, 400 MHz, 25 °C) δ 8.66ꢀ
8.51 (m, 1H), 8.37ꢀ8.26 (m, 2H), 8.20 (t, J = 5.7 Hz, 1H), 7.56 (d, J = 7.6 Hz, 2H), 3.42ꢀ3.27 (m, 2H),
1.61ꢀ1.45 (m, 2H), 1.37ꢀ1.18 (m, 6H), 0.90ꢀ0.77 (m, 3H). 13C NMR (DMSOꢀd6, 100 MHz, 25 °C) δ
169.2, 168.9, 167.1, 166.5, 165.3, 165.2, 137.4, 137.3, 135.4, 135.2, 130.1, 129.1, 40.7, 31.5, 31.4, 29.1,
29.0, 26.5, 22.6, 14.4. 13C NMR (DMSOꢀd6, 150 MHz, 80 °C) δ 169.5, 169.2, 167.0, 166.5, 165.6,
137.4, 135.6, 135.5, 130.2, 129.1, 40.9, 31.4, 29.1, 26.5, 22.5, 14.2.APCIꢀMS [M+H]+ m/z 291.20. ESIꢀ
HRMS [M+H]+ m/z calcd for C15H20ClN4 291.1376, found 291.1382.
N-hexyl-4-[4-(trifluoromethyl)phenyl]-1,3,5-triazin-2-amine (3k). Eluent: petroleum ether/ethyl
acetate (4:1). Yield 60.3 mg (62%). White solid, mp 99.2ꢀ100.6 oC. 1H NMR (DMSOꢀd6, 400 MHz, 25
°C) δ 8.69ꢀ8.56 (m, 1H), 8.53ꢀ8.44 (m, 2H), 8.34ꢀ8.24 (m, 1H), 7.88ꢀ7.81 (m, 2H), 3.43ꢀ3.28 (m, 2H),
1.60ꢀ1.47 (m, 2H), 1.34ꢀ1.19 (m, 6H), 0.86ꢀ0.77 (m, 3H). 13C NMR (DMSOꢀd6, 100 MHz, 25 °C) δ
168.9, 168.6, 167.2, 166.6, 165.3, 140.4, 140.2, 132.2 (q, J = 31.9 Hz), 132.1 (q, J = 31.9 Hz), 129.0,
125.9, 123.1, 40.7, 40.5, 31.5, 31.4, 29.1, 29.0, 26.5, 22.5, 14.3. 13C NMR (DMSOꢀd6, 150 MHz, 80 °C)
δD6) δ 169.2, 169.0, 167.2, 166.6, 165.7, 140.7, 140.5, 132.7, 132.5, 132.4, 132.3, 132.2, 132.1, 132.0,
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129.2, 125.9, 123.7, 40.9, 31.4, 29.1, 26.5, 22.4, 14.2. APCIꢀMS [M+H]+ m/z 325.25. ESIꢀHRMS
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[M+H]+ m/z calcd for C16H20F3N4 325.1640, found 325.1653.
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4-(p-Tolyl)-1,3,5-triazin-6-d-2-amine (3bb). Eluent: petroleum ether/ethyl acetate (4:1). Yield 47.7
mg (85%). White solid, mp 235.9ꢀ237.3 oC. 1H NMR (DMSOꢀd6, 400 MHz, 25 °C) δ = 8.22 (d, J = 8.1,
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2H), 7.58 (s, 2H), 7.33 (d, J = 8.0, 2H), 2.38 (s, 3H). C NMR (DMSOꢀd6, 100 MHz, 25 °C) δ 170.4,
167.0, 166.7 (t), 142.5, 133.7, 129.6, 128.4, 40.6, 40.4, 40.2, 40.0, 39.8, 39.5, 39.3, 21.6. ESIꢀMS
[M+H]+ m/z 188.07. ESIꢀHRMS [M+H]+ m/z calcd for C10H10DN4 188.1041, found 188.1051.
General procedure for synthesis of compounds (4a-f). Substituted benzimidate hydrochloride 1
(0.3 mmol), guanidine hydrochloride 2 (0.33 mmol), Cs2CO3 (1.5 mmol, 488 mg), anhydrous DMA or
DMP (2 mL) were added to a 25 mL Schlenk tube charged with a magnetic stirrer. The reaction mixture
was stirred at 150 oC for 24 h under nitrogen atmosphere (1 atm). The resulting solution was concentratꢀ
ed on a rotary evaporator, and the residue was purified by column chromatography on silica gel using
petroleum ether/ethyl acetate as eluent to give the desired product 4a-f.
4-Methyl-6-phenyl-1,3,5-triazin-2-amine (4a).10 Eluent: petroleum ether/ethyl acetate (4:1). Yield
35.2 mg (63%). White solid, mp 158.5ꢀ160.2oC (lit.10 mp 159ꢀ160 °C). 1H NMR (DMSOꢀd6, 400 MHz,
25 °C) δ 8.36 (d, J = 7.2 Hz, 2H), 7.61ꢀ7.48 (m, 5H), 2.40 (s, 3H). 13C NMR (DMSOꢀd6, 100 MHz, 25
°C) δ 176.2, 170.5, 167.5, 136.6, 132.2, 128.9, 128.4, 25.7. ESIꢀMS [M+H]+ m/z 187.02.
4-Methyl-6-(p-tolyl)-1,3,5-triazin-2-amine (4b).10 Eluent: petroleum ether/ethyl acetate (4:1). Yield
36.0 mg (60%). White solid, mp 175.4ꢀ176.6 oC (lit.10 mp 185 °C). 1H NMR (DMSOꢀd6, 400 MHz, 25
°C) δ 8.23 (d, J = 8.1 Hz, 2H), 7.44 (s, 2H), 7.31 (d, J = 8.0 Hz, 2H), 2.37 (d, J = 7.4 Hz, 6H). 13C NMR
(DMSOꢀd6, 100 MHz, 25 °C) δ 176.1, 170.4, 167.4, 142.2, 133.9, 129.6, 128.4, 25.7, 21.6. ESIꢀMS
[M+H]+ m/z 201.06.
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4-Methyl-6-(m-tolyl)-1,3,5-triazin-2-amine (4c). Eluent: petroleum ether/ethyl acetate (4:1). Yield
34.2 mg (57%). White solid, mp 169.1ꢀ170.1 oC. 1H NMR (DMSOꢀd6, 400 MHz, 25 °C) δ 8.17 (s, 1H),
8.15ꢀ8.10 (m, 1H), 7.50 (s, 2H), 7.41ꢀ7.36 (m, 2H), 2.41ꢀ2.37 (m, 6H). 13C NMR (DMSOꢀd6, 100 MHz,
25 °C) δ 176.1, 170.5, 167.4, 138.07, 136.6, 132.9, 128.9, 128.8, 125.6, 25.7, 21.5. ESIꢀMS [M+H]+ m/z
201.06. ESIꢀHRMS [M+H]+ m/z calcd for C11H13N4 201.1140, found 201.1156.
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4-(4-Chlorophenyl)-6-methyl-1,3,5-triazin-2-amine (4d).11 Eluent: petroleum ether/ethyl acetate
(4:1). Yield 43.0 mg (65%). White solid, mp 248.8ꢀ249.1 oC (lit.11 mp 250ꢀ252 °C). 1H NMR (DMSOꢀ
d6, 400 MHz, 25 °C) δ 8.32 (d, J = 8.3 Hz, 2H), 7.64ꢀ7.50 (m, 4H), 2.38 (s, 3H). 13C NMR (DMSOꢀd6,
100 MHz, 25 °C) δ 176.3, 169.5, 167.4, 137.1, 135.4, 130.1, 129.1, 25.7. ESIꢀMS [M+H]+ m/z 220.99.
N-hexyl-4-methyl-6-phenyl-1,3,5-triazin-2-amine (4e). Eluent: petroleum ether/ethyl acetate (4:1).
Yield 41.4 mg (51%). White solid, mp 48.6ꢀ51.2 oC. 1H NMR (DMSOꢀd6, 400 MHz, 25 °C) δ 8.41ꢀ8.29
(m, 2H), 8.05ꢀ7.92 (m, 1H), 7.61ꢀ7.46 (m, 3H), 3.44ꢀ3.30 (m, 2H), 2.42ꢀ2.33 (m, 3H), 1.62ꢀ1.48 (m,
2H), 1.38ꢀ1.21 (m, 6H), 0.89ꢀ0.82 (m, 3H). 13C NMR (DMSOꢀd6, 100 MHz, 25 °C) δ 176.2, 175.5,
170.1, 169.8, 165.9, 136.7, 136.5, 132.3, 132.2, 128.9, 128.5, 128.4, 31.4, 31.4, 29.2, 26.5, 26.5, 26.2,
25.6, 22.5, 14.4. APCIꢀMS [M+H]+ m/z 271.19. ESIꢀHRMS [M+H]+ m/z calcd for C16H23N4 271.1923,
found 271.1925.
4-Ethyl-6-(p-tolyl)-1,3,5-triazin-2-amine (4f).12 Eluent: petroleum ether/ethyl acetate (4:1). Yield
35.4 mg (55%). White solid, mp 169.2ꢀ169.7 oC (lit.12 mp 164ꢀ165 °C). 1H NMR (DMSOꢀd6, 400 MHz,
25 °C) δ 8.30 (d, J = 8.1 Hz, 2H), 7.50 (s, 2H), 7.37 (d, J = 8.1 Hz, 2H), 2.69 (q, J = 7.6 Hz, 2H), 2.44
(s, 3H), 1.31 (t, J = 7.6 Hz, 3H). 13C NMR (DMSOꢀd6, 100 MHz, 25 °C) δ 179.8, 170.4, 167.5, 142.2,
134.0, 129.6, 128.4, 31.9, 21.6, 12.0. ESIꢀMS [M+H]+ m/z 215.08.
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General procedure for synthesis of compounds (6a-l). Substituted benzimidate hydrochloride 1
(0.3 mmol), guanidine hydrochloride 2 (0.9 mmol), aldehyde 5 (0.6 mmol), Cs2CO3 (2.1 mmol, 684
mg), anhydrous DMSO (3 mL) were added to a 25 mL Schlenk tube charged with a magnetic stirrer.
o
The reaction mixture was stirred at 150 C for 24 h without exclusion of air. The resulting solution was
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concentrated on a rotary evaporator, and the residue was purified by column chromatography on silica
gel using petroleum ether/ethyl acetate as eluent to give the desired product.
4,6-diphenyl-1,3,5-triazin-2-amine (6a)9. Eluent: petroleum ether/ethyl acetate (10:1). Yield 50.7
mg (68%). White solid, mp 172.2ꢀ172.9 oC (lit.9 mp 167ꢀ169 °C). 1H NMR (DMSOꢀd6, 400 MHz, 25
°C) δ 8.55ꢀ8.48 (m, 4H), 7.71 (s, 2H), 7.64ꢀ7.55 (m, 6H). 13C NMR (DMSOꢀd6, 100 MHz, 25 °C) δ
171.0, 168.0, 136.7, 132.5, 129.0, 128.6. ESIꢀMS [M+H]+ m/z 249.17.
4,6-di-p-tolyl-1,3,5-triazin-2-amine (6b).13 Eluent: petroleum ether/ethyl acetate(10:1). Yield 53.9
mg (65%). White solid, mp 225.2ꢀ226.3 oC (lit.13 mp 231 °C). 1H NMR (DMSOꢀd6, 400 MHz, 25 °C) δ
8.40 (d, J = 8.1 Hz, 4H), 7.62 (s, 2H), 7.37 (d, J = 8.0 Hz, 4H), 2.41 (s, 6H). 13C NMR (DMSOꢀd6, 100
MHz, 25 °C) δ 170.9, 167.9, 142.4, 134.1, 129.6, 128.6, 21.6. APCIꢀMS [M+H]+ m/z 277.07.
N-hexyl-4,6-diphenyl-1,3,5-triazin-2-amine (6c). Eluent:petroleum ether/ethyl acetate(10:1). Yield
48.9 mg (49%).Yellowish solidiquid mixture. 1H NMR (DMSOꢀd6, 400 MHz, 25 °C) δ 8.61ꢀ8.49 (m,
4H), 8.22ꢀ8.12 (m, 1H), 7.65ꢀ7.55 (m, 6H), 3.56ꢀ3.44 (m, 2H), 1.70ꢀ1.55 (m, 2H), 1.40ꢀ1.23 (m, 6H),
0.91ꢀ0.78 (m, 3H). 13C NMR(DMSOꢀd6, 100 MHz, 25 °C) δ 170.7, 170.4, 166.4, 136.9, 136.8, 132.5,
132.4, 129.0, 128.6, 128.5, 40.7, 31.5, 29.2, 26.6, 22.6, 14.4. ESIꢀMS [M+H]+ m/z 333.41. ESIꢀHRMS
[M+H]+ m/z calcd for C21H25N4 333.2079, found 333.2079.
4-(4-Chlorophenyl)-6-phenyl-1,3,5-triazin-2-amine (6d). Eluent: petroleum ether/ethyl acetate
(10:1). Yield 49.2 mg (58%). White solid, mp 190.3ꢀ190.8 oC. 1H NMR (DMSOꢀd6, 400 MHz, 25 °C) δ
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8.53ꢀ8.44 (m, 4H), 7.77 (s, 2H), 7.67ꢀ7.55 (m, 5H). 13C NMR (DMSOꢀd6, 100 MHz, 25 °C) δ 171.1,
170.0, 167.9, 137.3, 136.5, 135.6, 132.6, 130.3, 129.2, 129.1, 128.6. ESIꢀMS [M+H]+ m/z 283.19. ESIꢀ
HRMS [M+H]+ m/z calcd for C15H12ClN4 283.0750, found 283.0752.
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4-(4-Methoxyphenyl)-6-phenyl-1,3,5-triazin-2-amine (6e). Eluent: petroleum ether/ethyl aceꢀ
tate(10:1). Yield 45.1 mg (54%). White solid, mp 201.0ꢀ201.5 oC. 1H NMR (DMSOꢀd6, 400 MHz, 25
°C) δ 8.52ꢀ8.41 (m, 4H), 7.68ꢀ7.51 (m, 5H), 7.11 (d, J = 9.0 Hz, 2H), 3.87 (s, 3H). 13C NMR (DMSOꢀd6,
100 MHz, 25 °C) δ 170.8, 170.6, 167.8, 162.9, 136.8, 132.4, 130.4, 129.0, 128.5, 114.4, 55.9. APCIꢀMS
[M+H]+ m/z 279.07. ESIꢀHRMS [M+H]+ m/z calcd for C16H15N4O 279.1246, found 279.1270.
4-(4-Chlorophenyl)-6-(p-tolyl)-1,3,5-triazin-2-amine (6f). Eluent: petroleum ether/ethyl aceꢀ
tate(10:1). Yield 50.7 mg (57%). White solid, mp 216.2ꢀ217.4 oC. 1H NMR (DMSOꢀd6, 400 MHz, 25
°C) δ 8.55ꢀ8.49 (m, 2H), 8.42 (d, J = 8.2 Hz, 2H), 7.74 (s, 2H), 7.70ꢀ7.65 (m, 2H), 7.41 (d, J = 8.1 Hz,
2H), 2.45 (s, 3H). 13C NMR (DMSOꢀd6, 100 MHz, 25 °C) δ 171.0, 167.0, 167.9, 142.6, 137.2, 135.6,
133.8, 130.3, 129.7, 129.2, 128.6, 21.6. APCIꢀMS [M+H]+ m/z 297.05. ESIꢀHRMS [M+H]+ m/z calcd
for C16H14ClN4 297.0907, found 297.0911.
4-Phenyl-6-(4-(trifluoromethyl)phenyl)-1,3,5-triazin-2-amine (6g). Eluent: petroleum ether/ethyl
acetate (10:1). Yield 66.4 mg (70%). White solid, mp 158.6ꢀ159.3 oC. 1H NMR (CDCl3, 400 MHz, 25
°C) δ 8.57 (d, J = 8.1 Hz, 2H), 8.50ꢀ8.41 (m, 2H), 7.67 (d, J = 8.3 Hz, 2H), 7.53ꢀ7.38 (m, 3H), 5.59 (s,
2H). 13C NMR (CDCl3, 100 MHz, 25 °C) δ 171.1, 169.7, 166.6, 138.6, 134.9, 132.4 (q, J = 32.4 Hz),
131.3, 127.9, 127.6, 127.5, 124.3, 124.3, 121.6. ESIꢀMS [M+H]+ m/z 317.25. ESIꢀHRMS [M+H]+ m/z
calcd for C16H12F3N4 317.1014, found 317.1017.
4-(p-Tolyl)-6-(4-(trifluoromethyl)phenyl)-1,3,5-triazin-2-amine (6h). Eluent: petroleum ether/ethyl
acetate(10:1). Yield 63.4 mg (64%). White solid, mp 176.6ꢀ177.8 oC. 1H NMR (DMSOꢀd6, 400 MHz, 25
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°C) δ 8.66 (d, J = 8.1 Hz, 2H), 8.39 (d, J = 8.2 Hz, 2H), 7.95 (d, J = 8.3 Hz, 2H), 7.79 (s, 2H), 7.39 (d, J
= 8.1 Hz, 2H), 2.42 (s, 3H). 13C NMR (DMSOꢀd6, 100 MHz, 25 °C) δ 171.2, 169.7, 167.9, 142.8, 140.7,
133.7, 132.1 (q, J = 31.7 Hz), 129.7, 129.2, 128.6, 126.0, 125.9, 123.2, 21.6. APCIꢀMS [M+H]+ m/z
331.12. ESIꢀHRMS [M+H]+ m/z calcd for C17H14F3N4 331.1171, found 331.1169.
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4-(m-Tolyl)-6-(4-(trifluoromethyl)phenyl)-1,3,5-triazin-2-amine (6i). Eluent: petroleum ether/ethyl
acetate(10:1). Yield 51.5 mg (52%). White solid, mp 145.2ꢀ146.4 oC. 1H NMR (DMSOꢀd6, 400 MHz, 25
°C) δ 8.66 (d, J = 8.1 Hz, 2H), 8.30 (d, J = 8.9 Hz, 2H), 7.95 (d, J = 8.3 Hz, 2H), 7.82 (s, 2H), 7.50ꢀ7.42
(m, 2H), 2.44 (s, 3H). 13C NMR (DMSOꢀd6, 100 MHz, 25 °C) δ 171.3, 169.8, 167.9, 140.6, 138.3,
136.4, 133.3, 133.0, 132.7, 132.1 (q, J = 31.8 Hz), 129.3, 129.1, 129.0, 126.0, 125.9, 123.2, 21.5. APCIꢀ
MS [M+H]+ m/z 331.15. ESIꢀHRMS [M+H]+ m/z calcd for C17H14F3N4 331.1171, found 331.1174.
4-Pentyl-6-(p-tolyl)-1,3,5-triazin-2-amine (6j). Eluent: petroleum ether/ethyl acetate(10:1). Yield
25.4 mg (33%). White solid, mp 130.5ꢀ132.1 oC. 1H NMR (DMSOꢀd6, 400 MHz, 25 °C) δ 8.23 (d, J =
8.2 Hz, 2H), 7.42 (s, 2H), 7.31 (d, J = 8.0 Hz, 2H), 2.62ꢀ2.56 (m, 2H), 2.38 (s, 3H), 1.78ꢀ1.69 (m, 2H),
1.44ꢀ1.19 (m, 4H), 0.93ꢀ0.85 (m, 3H). 13C NMR (DMSOꢀd6, 100 MHz, 25 °C) δ 179.1, 170.4, 167.5,
142.2, 134.0, 129.6, 128.4, 38.7, 31.5, 27.2, 22.4, 21.6, 14.4. ESIꢀMS [M+H]+ m/z 257.22. ESIꢀHRMS
[M+H]+ m/z calcd for C15H21N4 257.1766, found 257.1776.
4-Pentyl-6-[4-(trifluoromethyl)phenyl]-1,3,5-triazin-2-amine (6k). Eluent: petroleum ether/ethyl
acetate (10:1). Yield 27.9 mg (30%). White solid, mp 118.9ꢀ120.4oC. 1H NMR (DMSOꢀd6, 400 MHz,
25 °C) δ 8.51 (d, J = 8.1 Hz, 2H), 7.90 (d, J = 8.3 Hz, 2H), 7.65 (s, 2H), 2.67ꢀ2.61 (m, 2H), 1.84ꢀ1.67
(m, 2H), 1.33 (m, J = 7.1, 3.6 Hz, 4H), 0.91ꢀ0.84 (m, 3H). 13C NMR (DMSOꢀd6, 100 MHz, 25 °C) δ
179.5, 169.3, 167.5, 140.6, 131.9 (q, J = 31.8 Hz), 129.1, 126.0, 125.9, 123.2, 38.6, 31.5, 27.2, 22.4,
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14.3. ESIꢀMS [M+H]+ m/z 311.31. ESIꢀHRMS [M+H]+ m/z calcd for C15H18F3N4 311.1484, found
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Supporting Information. Optimization tables of reaction conditions for the products 4 and 6, the 1H
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and C NMR spectra of these synthesized compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
* Eꢀmail : xuhao@henu.edu.cn; 18937822307@163.com.
ORCID
Hao Xu: 0000ꢀ0002ꢀ6069ꢀ3246
Author Contributions
‡ Liyang Pan and Zhenxing Li contributed equally to this work.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGEMENTS
This work was supported by National Natural Science Foundation of China (Grant No. 21502042,
51403051, 21477033, 21204018), Scientific Research Key Project Fund of Henan Provincial Education
Department (Grant No. 15A150041, 16A150003).
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