Base-catalyzed one-step synthesis of 5,7-disubstituted-1,2,4-triazolo[1,5-a]pyrimidines

Article abstract of DOI:10.1016/j.tetlet.2014.12.135

We report a practical high-yield synthesis of 5,7-disubstituted-1,2,4-triazolo[1,5-a]pyrimidines using a base-assisted cyclocondensation of chalcone and 1,2,4-triazol-3-amine in an open reaction vessel. The same conditions can also be used for the preparation of novel imidazo[1,2-a]pyrimidine derivatives.

Full text of DOI:10.1016/j.tetlet.2014.12.135

Accepted Manuscript
Base-catalyzed one-step synthesis of 5,7-disubstituted-1,2,4-triazolo[1,5-a]pyr-
imidines
Xinhua He, Shaymaa E. Kassab, Geoffrey Heinzl, Fengtian Xue
PII:
S0040-4039(14)02224-2
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.12.135
TETL 45660
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Accepted Date:
15 December 2014
26 December 2014
Please cite this article as: He, X., Kassab, S.E., Heinzl, G., Xue, F., Base-catalyzed one-step synthesis of 5,7-
disubstituted-1,2,4-triazolo[1,5-a]pyrimidines, Tetrahedron Letters (2015), doi: http://dx.doi.org/10.1016/j.tetlet.
2014.12.135
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Base-catalyzed one-step synthesis of 5,7-disubstituted-1,2,4-triazolo[1,5-a]pyrimidines
Xinhua Hea,b, Shaymaa E. Kassaba, Geoffrey Heinzla, and Fengtian Xuea,*
aDepartment of Pharmaceutical Sciences, University of Maryland School of Pharmacy, 20 Penn
Street, Baltimore, Maryland 2120
bCurrent Address: Beijing Institute of Pharmacology and Toxicology, 27 Taiping Road, Haidian
District, Beijing, 100850
*Correspondence to Professor Fengtian Xue at the Department of Pharmaceutical Sciences,
University of Maryland School of Pharmacy, 20 Penn Street, Baltimore, Maryland 21201
Phone: 410-706-8521
Email: fxue@rx.umaryland.edu
Keywords:
1,2,4-Triazolo[1,5-a]pyrimidines
Cyclocondensation
Chalcone
1,2,4-Triazol-3-amine
Imidazo[1,2-a]pyrimidines

Abstract
We report a practical high-yield synthesis of 5,7-disubstituted-1,2,4-triazolo[1,5-a]pyrimidines
using a base-assisted cyclocondensation of chalcone and 1,2,4-triazol-3-amine in an open
reaction vessel. The same conditions can also be used for the preparation of novel imidazo[1,2-
a]pyrimidine derivatives.
Graphic Abstract

5,7-Disubstituted-1,2,4-triazolo[1,5-a]pyrimidine is a privileged structure with a broad
range of biological applications. They have shown superior in vitro cytotoxicity than the anti-
cancer drug doxorubicin.1 The organotin(IV) and platinum(II) complexes of 5,7-disubstituted-
1,2,4-triazolo[1,5-a]pyrimidines demonstrate dose-dependent cytotoxic activity in multiple
cancer cell lines.2 Moreover, 5,7-disubstituted-1,2,4-triazolo[1,5-a]pyrimidines are inhibitors of
the casein kinase 1δ a potential treatment for neurological disorders.3 From a high throughput
screen, analogs of 1,2,4-triazolo[1,5-a]pyrimidine have been identified with neuroactive
activities as potential therapeutic agents for neurodegenerative diseases.4 In addition, 5,7-
disubstituted-1,2,4-triazolo[1,5-a]pyrimidines have shown promising inhibitory activities for
cellular secretion of the hepatitis B virus surface antigen as potential treatment for HBV
infection.5
Furthermore, 5,7-disubstituted-1,2,4-triazolo[1,5-a]pyrimidines have shown
antileishmanial activity against L. donovani promastigotes,6 and antibacterial activities against S.
marcescens.7 Therefore, the synthesis of 5,7-disubstituted-1,2,4-triazolo[1,5-a]pyrimidines has
received significant attention.
Two synthetic methods are known for the preparation of 1,2,4-triazolo[1,5-a]pyrimidines
(Scheme 1). The first method involves a two-step procedure beginning with chalcone and 1,2,4-
triazol-3-amine. Cyclocondensation of chalcone with 1,2,4-triazol-3-amine provides the dihydro-
triazolo-pyrimidine analogue,5 which can be oxidized using either N-bromosuccinimide (NBS)8
or Br2 to give 1,2,4-triazolo[1,5-a]pyrimidines.9 Considering NBS and Br2 are highly reactive
and cannot tolerate functionalities such as benzyl groups, allyl groups, olefins, hydroxyl groups,
nor α-hydrogens of a carbonyl,10 this method can only be used to prepare 1,2,4-triazolo[1,5-
a]pyrimidines with limited substitutions. The other method includes a thermal reaction between
chalcone and 1,2,4-triazol-3-amine either at high temperature (e.g., >220 °C in ethylene glycol7

and 190 °C in 1-methyl-2-pyrrolidinone11) or neat at 160 °C.12 It is also reported that 1,2,4-
triazolo[1,5-a]pyrimidines can be prepared in refluxing t-BuOH in the presence of the strong
base t-BuOK.13
In the course of our research program on novel therapeutics for diffuse large B-cell
lymphoma (DLBCL) and triple-negative breast cancer (TNBC), we performed a series of
reactions intended to synthesize a collection of compounds based on a 5,7-disubstituted-1,2,4-
triazolo[1,5-a]pyrimidine core. Motivated by the fact that dihydro-triazolo-pyrimidines can be
oxidized by atmospheric O2,7, 11 while cyclocondensation reactions can be accelerated in
presence of a base catalyst, we hypothesized that the formation of a 5,7-disubstituted-1,2,4-
triazolo[1,5-a]pyrimidine can be achieved by base-catalyzed cyclocondensation of chalcone and
1,2,4-triazol-3-amine in an open reaction vessel.
Scheme 1. Previous synthesis of 5,7-disubstituted-1,2,4-triazolo[1,5-a]pyrimidines.

To test this idea, we first tried the reactions of (E)-3-(4-chlorophenyl)-1-phenylprop-2-
en-1-one (2a) and 4H-1,2,4-triazol-3-amine (3a) in either ethanol (Table 1, entry 1) or DMF
(entry 2) at 120 °C in an open flask. No significant reaction was observed under either condition
after 24 h. However, we were pleased to find that addition of one equiv of KOH to the reaction
mixture in DMF led to the formation of 1,2,4-triazolo[1,5-a]pyrimidine in good yields after 24 h
(entry 3). With this encouraging result, we sought to screen bases used in the reaction (entries 4-
10), and found that while inorganic bases (entries 3-5) gave modest yields, tertiary amines, such
as TEA (entry 6) and DIPEA (entry 7), are more efficient with almost quantitative yields.
Similarly good yields were detected when DMAP was used as the base (entry 8). When weaker
bases such as NMM (entry 9) and pyridine (entry 10) were used, the reaction gave decreased
yields. We also studied the effect of the equiv of the base, and found that < 1 equiv of TEA gave
incomplete reactions (entries 11 and 12). When 2 equiv of TEA was used (entry 13), the
reaction yields started to drop due to the complicated reaction mixture.
Table 1. Optimization of Reaction Conditions for 1aa
Entry
Baseb, equiv
no base
Solvent
ethanol
DMF
yield 1a, %c
1
2
3
< 5
< 5
83
no base
KOH, 1.0
DMF

4
Cs2CO3, 1.0
K2CO3, 1.0
TEA, 1.0
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
66
77
95
95
86
36
61
74
72
84
5
6
7
DIPEA, 1.0
DMAP, 1.0
NMM, 1.0
Pyridine, 1.0
TEA, 0.25
TEA, 0.5
8
9
10
11
12
13
TEA, 2.0d
aThe reaction was carried out in an open vessel at 120 ℃ with 1.0 mmol of 2a, 2.0 mmol
of 3a and 1.0 mmol of base in 2.0 mL of solvent for 24 h. bKOH = potassium hydroxide, Cs2CO3
= cesium carbonate, K2CO3 = potassium carbonate, TEA = triethylamine, DMAP = 4-
(dimethylamino)pyridine, DIPEA = diisopropyl ethylamine, NMM = 4-methylmorpholine.
cDetermined by 1H NMR. dTLC indicated a complicated reaction in which significant amounts of
side products were observed.
Utilizing the optimized conditions, we next studied the scope of the reaction (Table 2).
Without further substitution, compound 1,3-diphenylpropan-1-one and 1,2,4-triazol-3-amine
reacted with a decreased rate. However, we isolated the product 5,7-diphenyl-1,2,4-triazolo[1,5-
a]pyrimidine 1b in very good yields after 48 h (entry 1). Using the same ketone starting material,
both electron-donating (entry 2) and electron-withdrawing (entry 3) substituents on the A-ring
reacted smoothly to give products 1c and 1d. Effects of the position of halogen substitutions on

the A-ring were also studied (entries 4-6), and the reactions gave consistently good yields for
compounds 1e-1g. Using 3-(4-isopropylphenyl)-1-(4-methoxyphenyl)propan-1-one as the
starting material, the reaction gave compound 1h in modest yields (entry 7). Other electron-
donating groups gave good yields (entries 8-11). It is noted that compound 1l cannot be
prepared using the procedure employing NBS/Br2.8-9 When 5-methyl-1,2,4-triazol-3-amine was
used as the starting material, the reactions gave compounds 1m-1p in good yields (entries 12-15).
Using 1-(4-hydroxyphenyl)-3-phenylpropan-1-one, the reaction also proceeded smoothly with
1,2,4-triazol-3-amine (entry 16) to give compound 1q in good yields, which cannot be
synthesized using previously reported methods. It is worthwhile to point out that all the products
were purified by a simple process of crystallization and filtration; no chromatography was
involved.
Table 2. Preparation of 5,7-disubstituted-1,2,4-triazolo[1,5-a]pyrimidinesa
entry
product
yield, %b
entry
product
yield, %b
1
90
9
87

2
94
10
85
3
88
11
87
4
5
92
86
12
13
86
83
6
89
14
75
7
73
15
89

8
80
16
78
aThe reaction was carried out at 120 ℃ with 1.0 mmol of 2a, 2.0 mmol of 3a and 1.0
b
mmol of base in 2.0 mL of DMF for 24 h. Isolated yields. The reaction was complete in 48 h.
c
We applied the optimized conditions to the preparation of imidazo[1,2-a]pyrimidines
(Scheme 2). As a bioisostere of 1,2,4-triazolo[1,5-a]pyrimidines, imidazo[1,2-a]pyrimidines are
also important in the pharmaceutical industry. They are employed, as the core structures, in
several clinically used anxiolytic drugs such as fasiplon, taniplon, and divaplon.14 We performed
reactions using compound 1a and imidazol-2-amine or 1H-benzo[d]imidazol-2-amine. Both
reactions proceeded smoothly to generate 5-(4-chlorophenyl)-7-phenylimidazo[1,2-a]pyrimidine
(1r) and 4-(4-chlorophenyl)-2-phenylbenzo[4,5]imidazo[1,2-a]pyrimidine (1s) in modest to good
yields (Scheme 2). Synthetic methods to benzimidazopyrimidines are known,15 however, to the
best of our knowledge, preparation of 5,7-diphenylimidazo[1,2-a]pyrimidines remains
challenging. One available method described by Kiselyov involves a three-step one-pot
synthesis beginning with α,β-unsaturated imines and amino heterocycles using strong base at -
78 ℃.16

Scheme 2. Preparation of 1r and 1s.a
Cl
Cl
N
N
N
H
N
H2N
O
N
1r
, 55%
2a
TEA, DMF
Cl
Cl
open vessel
120 oC, 24 h
N
N
N
N
H
N
H2N
O
1s
, 75%
2a
In summary, a facile one-step synthesis of 5,7-disubstituted-1,2,4-triazolo[1,5-
a]pyrimidines have been discovered, by which a variety of 5,7-disubstituted-1,2,4-triazolo[1,5-
a]pyrimidines, as well as the imidazole analogs, have been prepared in good yields.17
Acknowledgements
We gratefully acknowledge funding from the Department of Pharmaceutical Sciences,
University of Maryland School of Pharmacy.
Supplementary data
Supplementary data associated with this article can be found in the online version.

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Typical procedure for the synthesis of compound 1a: To a solution of (E)-3-(4-
chlorophenyl)-1-phenylprop-2-en-1-one (242 mg, 1.0 mmol) and 1,2,4-triazol-3-amine (168 mg,
2.0 mmol) in DMF (2.0 mL) was added TEA (140 µL, 1.0 mmol). The reaction mixture was
allowed to stir at 120 ℃ until (E)-3-(4-chlorophenyl)-1-phenylprop-2-en-1-one was completely

consumed (TLC, ethyl acetate/hexanes = 1:4 (v/v)). The solvent was removed, and to the
resulting residue was added water (10 mL). The mixture was ultrasonically agitated for 30 min
and then filtered. The filtrate was washed using water (20 mL × 5) and dried to yield 7-(4-
1
chlorophenyl)-5-phenyl-[1,2,4]triazolo[1,5-a]pyrimidine 1a (291 mg, 0.95 mmol, 95%): H
NMR (400 MHz, DMSO-d6) δ 7.61 (m, 3H), 7.74-7.76 (d, J = 8.4 Hz, 2H), 8.20 (s, 1H), 8.34-
13
8.36 (d, J = 8.4 Hz, 2H), 8.39-8.41 (m, 2H), 8.72 (s, 1H); C NMR (100 MHz, DMSO-d6) δ
107.3, 128.3, 129.1, 129.5, 130.3, 131.8, 132.2, 136.5, 136.9, 146.8, 156.3, 156.5, 161.1; LC-MS
(M+H+) calcd for C17H12ClN4 307, found 307.

Graphic Abstract