Heterogeneous gold(I)-catalyzed cyclization between ynals and amidines: An efficient and practical synthesis of 2,4-disubstituted pyrimidines

Article abstract of DOI:10.1080/00397911.2019.1631347

A novel and highly efficient heterogeneous gold(I)-catalyzed cyclization between ynals and amidines has been developed that proceeds smoothly under mild conditions and provides a general and practical method for the synthesis of a wide variety of 2,4-disu

Full text of DOI:10.1080/00397911.2019.1631347

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: https://www.tandfonline.com/loi/lsyc20
Heterogeneous gold(I)-catalyzed cyclization
between ynals and amidines: An efficient and
practical synthesis of 2,4-disubstituted pyrimidines
Minhua Jiang, Quan Nie & Mingzhong Cai
To cite this article: Minhua Jiang, Quan Nie & Mingzhong Cai (2019): Heterogeneous gold(I)-
catalyzed cyclization between ynals and amidines: An efficient and practical synthesis of 2,4-
disubstituted pyrimidines, Synthetic Communications, DOI: 10.1080/00397911.2019.1631347
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https://doi.org/10.1080/00397911.2019.1631347
Heterogeneous gold(I)-catalyzed cyclization between ynals
and amidines: An efficient and practical synthesis of
2
,4-disubstituted pyrimidines
a,b
a
a
Minhua Jiang , Quan Nie , and Mingzhong Cai
a
Key Laboratory of Functional Small Organic Molecule, Ministry of Education and College of Chemistry
b
and Chemical Engineering, Jiangxi Normal University, Nanchang, China; School of New Energy Science
and Engineering, Xinyu University, Xinyu, China
ABSTRACT
ARTICLE HISTORY
A novel and highly efficient heterogeneous gold(I)-catalyzed cycliza-
tion between ynals and amidines has been developed that proceeds
smoothly under mild conditions and provides a general and practical
method for the synthesis of a wide variety of 2,4-disubstituted pyri-
midines with high atom-economy, good to high yield, and recyclabil-
ity of the gold(I) catalyst. The present method is an attractive
alternative to construct substituted pyrimidines.
Received 16 March 2019
KEYWORDS
Cyclization; gold;
heterogeneous catalysis;
pyrimidine; ynal
GRAPHICAL ABSTRACT
Introduction
Pyrimidine and its derivatives are ubiquitous in biologically active molecules, naturally
[
1]
products, and functional materials. They exhibit a wide range of biological activities,
including antibacterial, anticancer, antimycobacterial, anti-inflammatory, and antimalar-
[
2]
ial. Besides, pyrimidines can be employed as potential candidates for light emitting
CONTACT Mingzhong Cai
caimzhong@163.com
Key Laboratory of Functional Small Organic Molecule, Ministry of
Education and College of Chemistry and Chemical Engineering, Jiangxi Normal University, Nanchang 330022, China.
Supplemental data for this article can be accessed on the publisher’s website.
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/lsyc.
ß 2019 Taylor & Francis Group, LLC

2
M. JIANG ET AL.
3]
[
devices. In view of their remarkable importance, the synthesis of pyrimidine deriva-
tives has attracted considerable interest from chemists and pharmacologists.
Traditionally, pyrimidines could be prepared by the condensation reactions of amidines
[
4]
[5]
or amidinium salts with 1,3-dicarbonyl compounds, a,b-unsaturated ketones, and
[
6]
ynones. Recently, transition-metal-catalyzed multicomponent reactions have provided
a powerful and useful alternative strategy for the construction of pyrimidines with vari-
[
7]
[8]
[9]
[10]
[11]
[12]
ous catalysts such as Ti, Ir, Mn, Pd,
Zn,
and Cu.
In addition, various
other synthetic approaches that do not employ transition metals have also been reported
[
13]
for the construction of pyrimidine derivatives.
However, the majority of these meth-
ods suffered from some drawbacks such as harsh reaction conditions (microwave irradi-
ation, strong basic conditions), the use of expensive and moisture-sensitive reagents,
starting materials that require multistep preparation, expensive catalysts, non-
recyclability of metal catalysts, and less atom efficiency. Therefore, development of an
efficient, environmentally benign and atom-economic reaction for the acquisition of
pyrimidines from readily available starting materials under mild conditions still repre-
sents a continuing challenge.
During the past two decades, homogeneous gold complexes-catalyzed organic reac-
[
14]
tions have become a highly useful and powerful tool in organic synthesis.
Recently,
[
15]
[16]
gold-catalyzed syntheses of N-heterocyclic compounds such as pyrroles,
indoles,
[
17]
[18]
oxazoles,
and pyrimidines
have received much attention because of their high effi-
ciency and mild reaction conditions, which strongly enriched the field of heterocyclic
chemistry. However, application of these homogeneous gold complexes in large-scale
synthesis or in industry remains a challenge because expensive gold catalysts are diffi-
cult to recover from the reaction mixture and are difficult to recycle. Recycling of
homogeneous metal catalysts, especially expensive and/or toxic heavy metal complexes,
is a task of great economic and environmental importance in the chemical and pharma-
ceutical industries. Immobilization of the existing homogeneous gold catalysts through
covalent bond formation with functional groups on various supports appears to be an
[
19]
attractive solution to this problem.
Recently, we reported the synthesis of an MCM-
4
1-immobilized phosphine gold(I) complex [MCM-41-PPh -AuCl] and its catalytic
3
performance in the direct Csp2–C bond functionalization of arylalkynes through a
sp
20]
[
nitrogenation process to amides.
In order to extend the application range of this het-
erogeneous gold(I) complex, herein we report an efficient heterogeneous gold(I)-cata-
lyzed domino cyclization of ynals and amidines by using MCM-41-PPh -AuCl as a
3
recyclable catalyst under mild conditions, providing 2,4-disubstituted pyrimidines in
good to high yields (Scheme 1).
Scheme 1. Heterogeneous gold(I)-catalyzed synthesis of 2,4-disubstituted pyrimidines.

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3
Scheme 2. Synthesis of the MCM-41-PPh -AuCl catalyst.
3
Results and discussion
The MCM-41-PPh -AuCl catalyst was easily synthesized by a simple procedure from
3
[
20]
readily available reagents as illustrated in Scheme 2.
First, mesoporous MCM-41 was
reacted with 1-(4-(diphenylphosphino)phenyl)-3-(3-(triethoxysilyl)propyl)urea in toluene
under reflux for 24 h, followed by the silylation with Me SiCl in toluene at room tem-
3
perature for 24 h to give a triphenylphosphine-functionalized MCM-41 material [MCM-
4
1-PPh ]. Then, the latter underwent a coordination reaction with Me SAuCl in
3
2
dichloromethane (DCM) under mild conditions to provide an MCM-41- immobilized
phosphine gold(I) complex [MCM-41-PPh -AuCl] as a gray powder. The gold content
3
ꢀ
1
of the heterogeneous catalyst was found to be 0.37 mmol g by ICP-AES analysis.
The MCM-41-immobilized phosphine gold(I) complex [MCM-41-PPh -AuCl] was
3
then employed as catalyst for the domino cyclization of ynals and amidines. Initial
experiments with 3-phenylpropiolaldehyde 1a and cyclopropanecarboximidamide 2a
were performed to optimize the reaction conditions, and the results are summarized in
ꢁ
Table 1. At first, various bases were tested at 50 C with DMF as solvent (entries 1–6).
The use of Cs CO and K CO as bases afforded the desired product 3a in 69% and
2
3
2
3
73% yields, respectively while NaOH and t-BuOK were ineffective, and organic bases
such as DBU and Et N gave low yields. The reaction did not occur at all without a base
3
(
entry 7). We next examined the effect of solvents on the model reaction with K CO3
2
as base (entries 8-14). When MeCN, DCM, dioxane and toluene were used as solvents,
the desired 3a were obtained in 71-83% yields and DCM was found to be the most effi-
cient (entry 11), whilst other solvents such as DMSO, THF and EtOH were substantially
less effective. The optimization of reaction temperature indicated that room temperature
is optimal (entries 11, 15, and 16). In the absence of MCM-41-PPh -AuCl, the reaction
3
proceeded very slowly and only a trace amount of 3a was detected (entry 17). When a
homogeneous Ph PAuCl was used as catalyst, the desired 3a was also isolated in 86%
3
yield, which indicates that the catalytic activity of MCM-41-PPh -AuCl was comparable
3
to that of Ph PAuCl (entry 18). Finally, the amount of the catalyst was screened.
3

4
M. JIANG ET AL.
Table 1. Cyclization of 3-phenylpropiolaldehyde and cyclopropanecarboximidamide in different
a
conditions.
ꢁ
b
Entry
Base
Cs CO
CO
NaOH
t-BuOK
DBU
Solvent
Temp. ( C)
Yield (%)
1
2
3
4
5
6
7
8
9
2
3
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMSO
MeCN
THF
DCM
Dioxane
Toluene
EtOH
DCM
DCM
DCM
DCM
DCM
DCM
50
50
50
50
50
50
50
50
50
50
50
50
50
50
R.t.
80
R.t.
R.t.
R.t.
R.t.
69
73
Trace
0
25
21
0
61
76
65
83
72
71
36
85
51
Trace
86
59
86
K
2
3
Et
3
N
–
K
K
K
K
K
K
K
K
K
K
K
K
K
2
CO
3
CO
3
CO
3
CO
3
CO
3
CO
3
CO
3
CO
3
CO
3
CO
3
CO
3
CO
3
CO
3
2
2
2
2
2
2
2
2
2
2
2
2
1
1
1
1
1
1
1
1
1
1
2
a
0
1
2
3
4
5
6
7
8
9
0
c
d
e
f
3
Reaction conditions: 1a (0.5 mmol), 2a (0.6 mmol), MCM-41-PPh -AuCl (3 mol%), base (1.0 mmol), solvent (3 mL) under
Ar for 3 h.
Isolated yield.
Without MCM-41-PPh -AuCl.
3
b
c
d
e
Ph
3
PAuCl (3 mol%) was used instead of 3 mol% of MCM-41-PPh
-AuCl was used for 12 h.
3
mol% of MCM-41-PPh -AuCl was used for 2 h.
3
-AuCl.
1
mol% of MCM-41-PPh
3
f
5
Reducing the amount of the catalyst to 1 mol% resulted in a decreased yield and required
a longer reaction time (entry 19), whilst increasing the amount of the catalyst to 5 mol%
did not enhance the yield significantly (entry 20). Therefore, the optimized reaction con-
ditions for this transformation are the use of 3 mol% of MCM-41-PPh -AuCl with K CO
3
2
3
as base in DCM as solvent at room temperature for 3 h (Table 1, entry 15).
With the optimal reaction conditions in hand, we started to investigate the scope of
this heterogeneous gold(I)-catalyzed domino cyclization reaction by using a variety of
amidines and various ynals as substrates, and the results are summarized in Table 2.
First, 3-phenylpropiolaldehyde 1a was fixed as the substrate to examine various substi-
tuted amidines. Acetimidamide 2b and pivalimidamide 2c displayed a similar reactivity
with 2a and the reactions with 1a proceeded effectively to afford the desired products
3
2
b and 3c in 86% and 83% yields, respectively. In addition to alkyl-substituted amidines
a–2c, aryl-substituted amidines were also suitable substrates for this heterogeneous
gold(I)-catalyzed domino process. For example, the reaction of benzimidamide 2d with
a gave the expected product 3d in 88% yield. Substituted benzimidamides bearing
either an electron-donating or electron-withdrawing group 2e–2i could also undergo
1

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a,b
Table 2. Heterogeneous gold(I)-catalyzed synthesis of pyrimidines.
a
Reaction conditions:
3 2 3
1 (0.5 mmol), 2 (0.6 mmol), MCM-41-PPh -AuCl (3 mol%), K CO
(
1.0 mmol), DCM (3 mL) at room temperature under Ar for 3 h.
b
Isolated yield.

6
M. JIANG ET AL.
Scheme 3. Heterogeneous gold(I)-catalyzed gram-scale synthesis of 2-methyl-4-phenylpyrimidine (3b).
the domino cyclization with 1a smoothly to provide the corresponding 2,4-disubstituted
pyrimidines 3e-3i in 77–87% yields. Notably, a heteroaryl-substituted amidine such as
isonicotinimidamide 2j was also compatible with the standard conditions and furnished
the expected product 3j in 78% yield. Subsequently, 3-arylpropiolaldehydes 1b–1d and
oct-2-ynal 1e as the substrates were examined and the results are also listed in Table 2.
As shown in Table 2, 3-phenylpropiolaldehydes 1b–1d bearing a strongly electron-with-
drawing or electron-donating group could undergo domino cyclization reaction with
acetimidamide 2b effectively to give the corresponding products 3k–3m in high yields.
The reactions of oct-2-ynal 1e with various alkyl, aryl or heteroaryl-substituted amidines
also proceeded smoothly to afford the corresponding 2,4-disubstituted pyrimidines
3
n–3v in 78–86% yields. A range of functional groups including methyl, methoxy, tert-
butyl, cyclopropyl, fluoro, chloro, bromo, ester, nitro, and pyridyl was well tolerated.
Interestingly, when 3-(trimethylsilyl)propiolaldehyde 1f was employed as the substrate,
the cyclization reaction with various aryl-substituted amidines also worked well, but the
desilylation products 3w–3z were obtained in 58–64% yields due to basic conditions.
The present method provides a simple, general, and practical route to construct pyrimi-
dine derivatives under mild conditions.
One of the concerns of polymer-bound catalysis reactions is large scale reproduction.
In order to demonstrate synthetic utility of the developed methodology, we next
attempted gram-scale synthesis of 2-methyl-4-phenylpyrimidine (3b) through this het-
erogeneous gold(I)-catalyzed domino process (Scheme 3). To our delight, the treatment
of 3-phenylpropiolaldehyde 1a (1.302 g, 10 mmol) with acetimidamide hydrochloride 2b
(1.134 g, 12 mmol) in the presence of MCM-41-PPh-AuCl (820 mg, 0.3 mmol) and
K CO (2.764 g, 20 mmol) in DCM (40 mL) at room temperature under Ar for 5 h
2
3
afforded the desired 3b (1.379 g) in 81% yield.
To confirm that the observed catalysis arises from the gold sites on the channel inner
walls of MCM-41 and not from the leached gold species in the solution, we carried out
the cyclization reaction of 3-phenylpropiolaldehyde 1a and cyclopropanecarboximida-
mide 2a and removed the catalyst from the reaction mixture by filtration at approxi-
mately 40% conversion of 1a. After removal of the MCM-41-PPh -AuCl catalyst, the
3
catalyst-free filtrate was again stirred with addition of K CO (1.0 equiv.) at room tem-
2
3
perature for 2 h. In this case, no significant increase in conversion of 1a was observed,
which demonstrates that leached Au species from the MCM-41-PPh -AuCl catalyst are
3
not responsible for the observed conversion. It was also verified by ICP-AES analysis
that no gold species could be detected in the filtrate (below 0.2 ppm). These results indi-
cate that the actual catalytic activity should be attributed to MCM-41-PPh -AuCl and
3
not to the leached Au species in the solution.

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Scheme 4. Proposed catalytic cycle.
A plausible mechanism for the heterogeneous gold(I)-catalyzed cyclization reaction
between ynals and amidines is shown in Scheme 4. First, K CO -promoted dehydration of
2
3
ynals 1 with amidine hydrochlorides 2 occurs to produce imine intermediate A. The coord-
ination of the MCM-41-PPh -AuCl catalyst to alkyne moiety in the imine intermediate A
3
generates an MCM-41-immobilized alkyne-gold(I) complex intermediate B. Then, the latter
undergoes an intramolecular nucleophilic attack of nitrogen toward alkyne moiety to give
an MCM-41-immobilized vinylgold cation intermediate C. Finally, protonolysis of the
Au–C bond in intermediate C via a 1,3-proton shift affords the target product 3 and regen-
erates the MCM-41-PPh -AuCl catalyst to complete the catalytic cycle.
3
For the practical application of a heterogeneous precious metal catalyst, it is import-
ant to examine its ease of separation, stability and reusability. The MCM-41-PPh -AuCl
3
catalyst can be easily separated and recovered by a simple filtration of the product mix-
ture. We next investigated the recycling of the catalyst in the cyclization reaction of 3-
phenylpropiolaldehyde 1a with benzimidamide 2d under the standard conditions. After
completion of the first reaction cycle, the catalyst was separated by a simple filtration
and washed with distilled water and ethanol. After being air-dried, it can be reused dir-
ectly without further purification. The recovered gold catalyst was reused for seven
times, and the yield of 3d in eight consecutive runs was found to be 88, 86, 87, 86, 85,
8
4, 84, and 83%. In addition, the gold content of the recovered catalyst after eight con-
ꢀ
1
secutive runs was determined to be 0.36 mmol g by ICP-AES analysis, which revealed
a negligible gold leaching.
Conclusions
In summary, we have developed a general, efficient and practical heterogeneous gold(I)-
catalyzed intermolecular cyclization of ynals and amidines at room temperature leading
to 2,4-disubstituted pyrimidines, which are broadly applicable for the synthesis of

8
M. JIANG ET AL.
bioactive molecules. The present method has some attractive advantages such as readily
available starting materials, straightforward and simple procedure, mild reaction condi-
tions, good yields, and easy recyclability of the catalyst, thereby providing an attractive
alternative to construct pyrimidine derivatives.
Experimental
All reagents were obtained from commercial sources and used as received without fur-
ther purification. All solvents were dried and distilled prior to use. All reactions were
conducted under an atmosphere of argon. The products were purified by flash column
chromatography on silica gel. A mixture of light petroleum ether and ethyl acetate was
1
generally employed as eluent. H NMR and 13C NMR spectra were recorded on a
Bruker Avance 400 NMR spectrometer (400 MHz or 100 MHz, respectively) in CDCl3
as solvent with TMS as internal reference. Melting points were determined on a Beijing
Tech Instrument Co., LTD X-6 melting point apparatus and are uncorrected. HRMS
spectra were recorded on a Q-Tof spectrometer with micromass MS software using elec-
trospray ionization (ESI). Gold content was determined with inductively coupled plasma
atom emission Atomscan16 (ICP-AES, TJA Corporation).
[
20]
Preparation of MCM-41-PPh -AuCl
3
A mixture of the mesoporous MCM-41 (2.1 g) and 1-(4-(diphenylphosphino)phenyl)-3-
(
1
3-(triethoxysilyl)propyl)urea (0.788 g, 1.5 mmol) in dry toluene (120 mL) was stirred at
ꢁ
10 C for 24 h under Ar. The resulting solid product was filtered, washed with CHCl
3
ꢁ
(20 mL), and dried in vacuum at 140 C for 3 h. The dried solid powder was then stirred
with Me SiCl (3.0 g) in dry toluene (90 mL) at room temperature for 24 h. The resulting
3
ꢁ
product was filtered, washed with acetone (3 ꢂ 20 mL), and dried in vacuum at 100 C
for 6 h to afford 2.621 g of triphenylphosphine-functionalized material MCM-41-PPh .
3
ꢀ
1
The phosphine content was determined to be 0.47 mmol g by elemental analysis.
In a 100 mL reaction tube, MCM-41-PPh3 (1.20 g) was mixed with Me SAuCl
2
(
125 mg, 0.42 mmol) in dry CH Cl (40 mL). The reaction mixture was stirred at room
2 2
temperature for 8 h under Ar. The resulting solid product was filtered, washed with
ꢁ
CH Cl (2 ꢂ 10 mL), and dried at 80 C in vacuum for 4 h to give 1.175 g of a gray
2
2
gold(I) complex [MCM-41-PPh -AuCl]. The gold content was determined to be
3
ꢀ
1
0
.37 mmol g by ICP-AES.
General procedure for heterogeneous Au(I)-catalyzed synthesis of pyrimidines
A mixture of ynal 1 (0.5 mmol), amidine hydrochloride 2 (0.6 mmol), K CO3
2
(
1.0 mmol), and MCM-41-PPh -AuCl (41 mg, 0.015 mmol) in DCM (3 mL) was stirred
3
at room temperature for 3 h (TLC monitored). The resulting mixture was then diluted
with ethyl acetate (15 mL) and filtered. The gold catalyst was washed with distilled water
(
5 mL), and dry ethanol (2 ꢂ 5 mL) and reused in the next run. The filtrate was concen-
trated under reduced pressure and the residue was purified by chromatography on silica
gel (eluent: petroleum ether/ethyl acetate) to afford the desired product 3.

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Full experimental detail, characterization data of all compounds. This material can be
found via the “Supplementary Content” section of this article’s webpage.
Funding
We thank the National Natural Science Foundation of China [No. 21462021], the Natural
Science Foundation of Jiangxi Province of China [No. 20161BAB203086] and Key Laboratory of
Functional Small Organic Molecule, Ministry of Education [No. KLFS-KF-201704] for finan-
cial support.
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