Microwave-assisted synthesis of 2-aminopyrimidines from silica gel-adsorbed propargyl alcohols and guanidine

Article abstract of DOI:10.3987/COM-12-12522

A novel methodology toward the synthesis of 2-aminopyrimidines has been developed. The silica gel adsorbed propargyl alcohols and guanidine easilygive the corresponding 2-aminopyrimidines under microwave irradiation.

Full text of DOI:10.3987/COM-12-12522

HETEROCYCLES, Vol. 85, No. 8, 2012, pp. -. © 2012 The Japan Institute of Heterocyclic Chemistry
Received, 5th June, 2012, Accepted, 26th June, 2012, Published online, 28th June, 2012
DOI: 10.3987/COM-12-12522
MICROWAVE-ASSISTED SYNTHESIS OF 2-AMINOPYRIMIDINES
FROM SILICA GEL-ADSORBED PROPARGYL ALCOHOLS AND
GUANIDINE
Qing-Zhen Chen,2 Zong-Cang Ding,1 Yan-Li Ma,1 Zhen-Dong Wang,1 and
Zhuang-Ping Zhan*1,2
1
Department of Chemistry, College of Chemistry and Chemical Engineering,
2
Xiamen University, Xiamen, 361005, Fujian, P. R. China.
School of
Pharmaceutical Sciences, Xiamen University, Xiamen, 361005, Fujian, P. R.
China. e-mail: zpzhan@xmu.edu.cn
Abstract – A novel methodology toward the synthesis of 2-aminopyrimidines has
been developed. The silica gel adsorbed propargyl alcohols and guanidine easily
give the corresponding 2-aminopyrimidines under microwave irradiation.
2-Aminopyrimidines and their derivatives have been given particular interest due to their diverse
biological properties (Figure 1).1 For instance, naturally occurring Meridianin A-E show cytotoxicity
towards murine tumor cell lines,1a and Variolin B isolated from the Antarctic sponge Kirkpratickia
varialosa display excellent antitumor and antiviral activity.1b In pharmaceutical market, Pyrimethamine,1c
Rosuvastatin1d and Imatinib1e have got huge success in virtue of their distinguished activity against
malaria, dyslipidemia and chronic myeloid leukemia (CML), respectively.
H2N
N
N
OH
N
NH2
H2N
N
N
N
Cl
NH2
N
N
R
N
H
N
H2N
Meridianin A-E
Pyrimethamine
Variolin B
F
N
N
H
N
N
OH
OH
N
COOH
N
HN
N
N
N
O
SO2CH3
Rosuvastatin
Imatinib
Figure 1
In the past few decades, the construction of 2-aminopyrimidine moiety has been generally relying on: 1)

Aminationof2-Clor 2-Br-pyrimidines;2 or 2) Condensation of guanidines with 1,3-dicarbonyl compounds
or their synthetic equivalents, such as α,β-unsaturated ketones.3 Thus, the development of straightforward
and efficient methodologies for the synthesis of 2-aminopyrimidines is still highly desirable.
Lately, our research interest has been focusing on the heterocycle synthesis based on propargyl alcohols.
We have demonstrated that various heterocycles can be easily accessed by the
propargylation-cycloisomerization tandem reaction.4 Herein, as part of ongoing efforts in our laboratory,
we report our recent progress on the synthesis of 2-aminopyrimidines from propargyl alcohols and
guanidine for the first time.
Table 1. Optimization of Reaction Conditionsa
Br
OH
NH
NH2
+
H2N
TMS
N
Br
N
NH2
3a
2
1a
entry
Reaction medium
catalyst
time
24 h
Yield(%)b
1
PhCl, reflux
PhCl, reflux
PhCl, MW c
PhCl, reflux
PhCl, reflux
PhCl, reflux
PhCl, reflux
PhCl, reflux
PhCl, reflux
PhCl, reflux
PhCl, reflux
PhCl, reflux
Silica gel, MW d
-
15
17
18
20
37
22
23
29
42
24
27
39
53
2
Cu(OTf)2
Cu(OTf)2
Bi(OTf)3
In(OTf)3
Zn(OTf)2
FeCl3
8 h
3
5 min
8 h
4
5
8 h
6
8 h
7
10 h
10 h
10 h
8 h
8
BiCl3
9
InCl3
10
11
12
13
p-TSA
TfOH
8 h
Silica gel
-
8 h
5 min
15 min 26
K10
montmorillonite,
MW d
14
15
-
Silica gel, MW d
Silica gel, MW d
Cu(OTf)2
5 min
5 min
34
47
16
FeCl3
a Reactions run with 0.5 mmol 1, 1 mmol 2, and 0.05 mmol catalyst.
b Isolated yields refer to 1a.
c Performed in a sealed tube, irradiation at 700 W.
d 1 g of adsorbed reagent was used, irradiation at 700 W.
We initially investigated the reaction of propargyl alcohol 1a and guanidine 2. The reaction was run in the

absence of any catalyst, using chlorobenzene as the solvent. Although all the starting material was
consumed in the reaction, we were only able to obtain the desired product in 15% yield. The
trimethylsilyl group had fallen off during work-up (Table 1, entry 1). The rest of products were obtained
as complex mixtures, and their structures were not determined. We suspect them some decomposed
products.
On the basis of our recent work concerning the Cu(OTf)2-catalyzed synthesis of pyrimidines from
propargyl alcohols and amidine,4e substrates 1a and 2 were treated with 20 mol% of Cu(OTf)2 in
refluxing chlorobenzene. Unfortunately, the yield was still rather low (Table 1, entry 2). In recent years,
organic synthesis has greatly benefited from the development of microwave technology.5 We found that
the reaction time was sharply shortened under microwave irradiation, but the yield was not increased
(Table 1, entry 3).
We next screened various other Lewis acid catalysts to optimize the formation of 3a. However, none of
them were able to remarkably improve the reaction efficiency (Table 1, entries 4-9). Other non-metal
catalysts, such as 4-methylbenzenesulfonic acid, trifluoromethanesulfonic acid and silica gel, also failed
to facilitate this transformation (Table 1, entries 10-12).
Combinations of the adsorbed reagents and microwave irradiation were used to carry out a wide range of
reactions.6 Thus, we attempted the MW-assisted synthesis of 2-aminopyrimidine 3a under solvent-free
condition. Silica gel was first chosen as the adsorbed reagents, due to its characteristic properties, such as
thermal stability and acidity character. We were delighted to find that the reaction accomplished in a
shortened time with an increased yield (Table 1, entry 13).7 K10 montmorillonite showed lower activity as
the adsorbed reagent (Table 1, entry 14). Our further study revealed that the employment of silica-adsorbed
metal catalysts failed to improve the yield of 3a (Table 1, entries 15-16).
With optimized conditions in hand (Table 1, entry 13), the substrate scope of the reaction was examined.
A diverse collection of propargyl alcohols underwent this reaction, offering a facile access to
2-aminopyrimidines (Table 2). The alkyne terminus of 1 could accommodate different substituted group
(R2 = n-butyl, cyclopropyl, TMS and phenyl). Substrate 1d’ containing a terminal alkyne moiety also
took part in the reaction (R2 = H; Table 2, entry 4). Although the same product was obtained in the
examples involving 1d and 1d’, the employment of a TMS group led to a considerably improved yield
(Table 2, entry 3 vs 4). Various aromatic and heteroaromatic substrates were successfully employed in the
reaction to give the corresponding 2- aminopyrimidines. A number of functional groups, such as bromo,
methoxy, and methoxycarbonyl, were tolerated under the reaction conditions, allowing the further
elaboration of the products (Table 2, entries 6-9). However, the methoxycarbonyl group had an obvious
adverse impact on this reaction. In addition, aliphatic propargyl alcohols (R1 = aliphatic) failed to afford
the desired 2-aminopyrimidines under this condition.

Table 2. Synthesis of 2-Aminopyrimidines 3a
R1
OH
NH
NH2
R1
N
H2N
R2
R2
N
NH2
1
2
3
Entry
1
Product 3
Yield b
Substrate 1
Time
Ph
OH
N
15 min
47%
Ph
n-Bu
N
NH2
n-Bu
3b
1b
Ph
OH
N
Ph
Ph
2
5 min
37%
N
NH2
1c
3c
Ph
N
OH
N
3
4
5
5 min
6 min
5 min
72%
41%
61%
TMS
NH2
1d
3d
Ph
OH
N
Ph
N
NH2
1d'
OH
3d
Ph
N
Ph
Ph
N
NH2
Ph
1e
3e
OMe
OH
6
7 min
5 min
59%
60%
Ph
Ph
N
N
MeO
Ph
NH2
1f
3f
OH
OMe
OMe
MeO
7
8
OMe
N
N
1g
Ph
NH2
3g
Br
OH
5 min
7 min
56%
23%
Ph
Br
1h
N
N
Ph
NH2
3h
OH
CO2Me
Ph
MeO2C
9
1i
N
Ph
N
NH2
3i
OH
10
5 min
7 min
47%
42%
Ph
N
1j
Ph
N
NH2
3j
OH
S
11
N
S
Ph
Ph
N
NH2
1k
3k
a Propargyl alcohol 1 (0.5 mmol) and guanidine 2 (1 mmol)
were adsorbed on 1 g of silica gel and irradiated at 700 W.
b Isolated yields refer to 1.

In conclusion, we have developed a facile method for the synthesis of 2-aminopyrimidines. The silica gel
adsorbed propargyl alcohols and guanidine give the corresponding 2-aminopyrimidines under microwave
irradiation. The amino group allows further elaboration of the products. Further studies of the application
of this methodology to the total synthesis of bioactive natural products are ongoing in our laboratories.
ACKNOWLEDGEMENTS
We thank the NSFC (No. 21072159), the 973 Projects (No. 2011CB935901), the NFFTBS (No. J1030415)
and the Science & Technology Bureau of Xiamen (No. 3502Z20103006) for financial support of this
project.
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7. Experimental procedure: To a dry 10-mL flask, propargyl alcohol 1a (0.5 mmol), guanidine (2,
1mmol), CH2Cl2 (2 mL) and silica gel (1 g) were successively added, and were mixed uniformly.
Then the solvent was removed under reduced pressure, the residue was then transferred into the
domestic microwave oven and irradiated at 700 W. The progress of the reactions was monitored by
TLC using CH2Cl2 as eluent. Upon completion, the mixture was extracted into CH2Cl2 (5 mL), then
the solvent was removed under reduced pressure. Further purification by column chromatography
(petroleum ether and EtOAc as eluent) gave the desired product 3a.