Au(I)-catalyzed domino intramolecular cyclization for the synthesis of 2,4-disubstituted pyrimidines

Article abstract of DOI:10.1016/j.catcom.2015.10.017

An efficient Au-catalyzed domino intramolecular cyclization reaction has been developed for the construction of pyrimidine derivatives from ynals and amidines at room temperature for 3 h. This transformation provides a new method for the formation of C-C

Full text of DOI:10.1016/j.catcom.2015.10.017

Catalysis Communications 73 (2016) 109–112
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Catalysis Communications
journal homepage: www.elsevier.com/locate/catcom
Short Communication
Au(I)-catalyzed domino intramolecular cyclization for the synthesis of
,4-disubstituted pyrimidines
2
Haiying Zhan, Longbin Chen, Jingwen Tan, Hua Cao ⁎
School of Chemistry and Chemical Engineering, Guangdong Pharmaceutical University, Zhongshan 528458, P.R. of China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 6 August 2015
Received in revised form 10 October 2015
Accepted 12 October 2015
Available online 23 October 2015
An efficient Au-catalyzed domino intramolecular cyclization reaction has been developed for the construction of
pyrimidine derivatives from ynals and amidines at room temperature for 3 h. This transformation provides a new
method for the formation of C–C and C–N bonds via intramolecular cyclization.
©
2015 Published by Elsevier B.V.
Keywords:
Pyrimidines
Gold
Domino reaction
Synthesis
Intramolecular cyclization
1
. Introduction
[22] developed three-component coupling reaction for the synthe-
sis of pyrimidine derivatives involving a variety of functionalized
enamines, triethyl orthoformate, and ammonium acetate, and Hu
[23] developed facile reaction for the construction of benzofuro
[3,2-d]pyrimidines from 3-chlorochromenones and amidines. However,
an efficient, environmentally benign and atom-economic reaction syn-
thesis of pyrimidines still remains a challenge.
Gold-catalyzed reactions [24–35] are probably the most versatile
and extensively used processes for the synthesis of heterocyclic
compounds in one single operation. Due to their synthetic efficiency
they have attracted attention in organic chemistry. Therefore, the
development of new and efficient domino reaction for the synthesis
of various heterocyclic compounds through gold-catalyzed reactions
continues to attract broad interest. Herein, an efficient Au-catalyzed
domino reaction has been described for the synthesis of pyrimidine
derivatives.
Pyrimidines and its derivatives as important fine chemicals [1–3]
have been frequently found in many natural products and drugs and
have exhibited a wide range of biological activities, such as antican-
cer, [4] anti-inflammatory properties, [5] antibacterial [6] and ca-
sensing receptor antagonists [7]. It is not surprising, therefore, that
great efforts have been directed toward developing synthetic routes
[
8–18] for the construction of this privileged structure. The availabil-
ity of convenient synthetic transformations to prepare heterocyclic
units for the synthesis of those compounds is of great demand. The
classical method for the construction of pyrimidine derivatives
mainly involves condensation of amidines with 1,3-dicarbonyl com-
pounds [19] (Scheme 1).
Recently, one of the ways to achieve this aim is the develop-
ment of domino process that allow the sequential transformation
of two or more reactions in the same reaction vessel, thereby min-
imizing the number of laboratory operations, the generation of
waste chemicals, time, and cost. Several synthetic routes have
been described for the synthesis of these heterocycles. In 2014
Fandrick [20] described a general and rapid process to prepare py-
rimidines utilizing amidines and activated olefins (Scheme 2); in
2. Results and discussion
Initially, 3-phenylpropiolaldehyde (1a) and cyclopropane-
carboximidamide (2a) were chosen as the substrates to investigate
the synthesis of 2-cyclopropyl-4-phenylpyrimidine (3a). The re-
sults of the optimization study for the domino intramolecular cycli-
zation reaction synthesis of 3a are summarized in Table 1. We were
pleased to observe that the desired product 3a was obtained in 63%
2
013 Frutos and Wei [21] described one-step process for the syn-
thesis of 2,5-disubstituted pyrimidines from Nitriles; Konakahara
yield in the presence of AuCl and K
entry 1). Subsequently, the desired product 3a was obtained in 51%
and 78% yields in the presence of AuCl and PPh AuCl, respectively
2 3
CO in DMF at 50 °C for 3 h
(
⁎
Corresponding author.
E-mail address: caohua@gdput.edu.cn (H. Cao).
3
3
http://dx.doi.org/10.1016/j.catcom.2015.10.017
566-7367/© 2015 Published by Elsevier B.V.
1

110
H. Zhan et al. / Catalysis Communications 73 (2016) 109–112
Scheme 1. Formation of pyrimidines
(
entries 2–3). Other bases were next tested. But, the product 3a
prepare pyrimidines which are broadly applicable for the synthesis of
biologically active molecules.
was formed with low yield or not detected in the presence of
Cs CO , NaOH, t-BuOK, DBU, NEt (entries 4–8). Among them,
CO was a more efficient base than the other tested. The result
2
3
3
K
2
3
Acknowledgments
encouraged us to improve the yield of this domino reaction by
employing different solvents. Other solvents (entries 9–15), such
as DMSO, EtOH, THF, CH Cl , CH CN, dioxane, and toluene were
2 2 3
also afforded in moderate to good yields. Among the solvents, we
were pleased to find that the product 3a was readily formed in
This research was financially supported by National Natural
Science Foundation of China (21302023) and the Project of Depart-
ment of Education of Guangdong Province (2013KJCX0111 and
2
014KTSCX120).
8
2 2
8% yield in CH Cl . Finally, the optimization of reaction tempera-
ture showed that room temperature is optimal. The control experiment
without gold was carried out and only a trace of desired product was
formed.
Under the optimized conditions, the substrate scopes were ex-
plored, and the results are described in Table 2. 1a was fixed as the
substrate to test various substituted amidines (entries 1–10). All of
the reactions proceeded smoothly under the optimized conditions
and provided the 2,4-disubstituted pyrimidine derivatives in good
yields. It was also worth noting that alkyl and aryl substituted
amidines were proved to be suitable for this Au-catalyzed domino
Appendix A. Supplementary data
Supplementary data to this article can be found online at http://dx.
doi.org/10.1016/j.catcom.2015.10.017.
Table 1
a
Optimization of reaction conditions.
process. Notably, the results had showed that F, Cl, Br, CH
3
and
OCH substituted on the pyridine ring were also well-tolerated
3
under the optimized conditions and led to a beneficial effect on the
reaction outcome. In addition, nicotinimidamide was also afforded
in 77% yield. Subsequently, oct-2-ynal (1b) was employed as the
substrate (entries 11–16). The corresponding products were also
obtained in 80–84% yields.
Entry
Catalyst
AuCl
Base
Solvent
T(°C)
Yield(%)b
1
2
3
4
5
6
7
8
9
K
2
K
2
K
2
CO
CO
CO
3
3
3
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMSO
EtOH
THF
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
80
rt
63
51
78
74
5b
–
30
27
66
42
70
88
81
77
75
56
91
5b
–
To gain further insight into the mechanism of this Au-catalyzed
transformation, a control reaction was carried out (Scheme 3). The
AuCl
3
Ph
Ph
3
PAuCl
PAuCl
intermediate product 4 was treated with Ph
c was formed in 93% yield. On the basis of these experimental re-
sults, a tentative mechanistic was proposed in Scheme 4. K CO
3
PAuCl and the product
3
Cs
2 3
CO
3
3
Ph PAuCl
NaOH
t-BuOK
DBU
-
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
3
PAuCl
3
PAuCl
3
PAuCl
3
PAuCl
3
PAuCl
3
PAuCl
3
PAuCl
3
PAuCl
3
PAuCl
3
PAuCl
2
3
promoted dehydration of 1a with 2a formed intermediate A which
then was activated by a gold catalyst to give the intermediate B.
The intermediate B underwent the nucleophilic attack of nitrogen to-
ward alkyne to generate intermediate C prior to the formation of
product 3.
NEt
3
K
2
K
2
K
2
K
2
K
2
K
2
K
2
CO
CO
CO
CO
CO
CO
CO
3
3
3
3
3
3
3
10
11
12
13
14
15
CH
CH
2
Cl
CN
2
3
In summary, we have developed a general and efficient Au-catalyzed
domino intramolecular cyclization process synthesis of 2,4-disubstitut-
dioxane
toluene
CH Cl
ed pyrimidines in CH
Cl
2 2
at rt. This method provides a simple route to
16
Ph PAuCl
K2CO3
3
2
2
2
2
2
2
2
2
1
1
1
7
8
9
Ph
–
3
PAuCl
K
K
–
2
CO
CO
3
CH
CH
CH
Cl
Cl
Cl
c
2
3
rt
rt
d
Ph
3
PAuCl
a
Reaction conditions: catalyst (3 mol%), 1a (0.5 mmol), 2a (0.6 mmol), base (1.0 mmol),
solvent (3.0 mL).
b
Yields determined by GC analysis using n-octadecane as internal standard.
c
3
In the absence of Ph PAuCl.
d
Scheme 2. Synthesis of pyrimidines
In the absence ofKCO
3
.

H. Zhan et al. / Catalysis Communications 73 (2016) 109–112
Table 2 (continued)
111
Table 2
Synthesis of pyrimidines.
a
Entry
9
R1
R2
Product
Entry
1
R1
R2
Product
Ph
3
3-CH O–Ph
Ph
cyclopropyl
1a
10
Ph
pyridin-3-yl
2
3
Ph
Ph
CH
Ph
3
1
1
CH
3
(CH
(CH
2
)
4
cyclopropyl
1b
4
Ph
4-F–Ph
12
CH
3
)
2 4
Ph
1
1
3
4
CH
CH
3
(CH
(CH
2
)
4
4-F–Ph
5
Ph
4-Cl–Ph
3
)
2 4
4-Cl-Ph
6
Ph
4-Br–Ph
1
1
5
6
CH
CH
3
(CH
(CH
2
)
4
4-Br–Ph
7
8
Ph
Ph
3-F–Ph
3
)
2 4
3-F–Ph
3
4-CH -Ph
a
Isolated yields.

112
H. Zhan et al. / Catalysis Communications 73 (2016) 109–112
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