An efficient synthesis of 4,6-substituted pyrrolo[3,2-d]pyrimidines by silver-catalyzed cyclization of acetylene amine

Article abstract of DOI:10.1016/j.tetlet.2016.04.077

A silver catalyzed cyclization of acetylene amine was developed to synthesize 4,6-substituted pyrrolo[3,2-d]pyrimidine, a bioactive isosteric scaffold of purine. Starting from simple commercially available acetylenes and pyrimidines, the method was found

Full text of DOI:10.1016/j.tetlet.2016.04.077

Tetrahedron Letters 57 (2016) 2418–2421
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Tetrahedron Letters
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An efficient synthesis of 4,6-substituted pyrrolo[3,2-d]pyrimidines
by silver-catalyzed cyclization of acetylene amine
a
a,
a,c,
Rui Xie a,y, Ying Hu b,y, Huixin Wan d, Yanwei Hu a, , Shaohua Chen , Shilei Zhang , Yinan Zhang
⇑
⇑
⇑
a Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases & Department of Medicinal Chemistry, College of Pharmaceutical Sciences,
Soochow University, 199 Ren’ai Road, Suzhou 215123, China
b Department of Pharmacy, Suzhou Vocational Health College, 28 Kehua Road, Suzhou 215009, China
c College of Pharmacy, University of Kentucky, 789 South Limestone Street, Lexington, KY 40536, USA
d Central Research Institute of Shanghai Pharmaceuticals Holding Co., Ltd, Tower 4, No. 898 Ha Lei Road, Pudong New District, Shanghai 201203, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A silver catalyzed cyclization of acetylene amine was developed to synthesize 4,6-substituted pyrrolo
[3,2-d]pyrimidine, a bioactive isosteric scaffold of purine. Starting from simple commercially available
acetylenes and pyrimidines, the method was found to be compatible with wide chemical functionalities,
leading to a series of pyrrolo[3,2-d]pyrimidines in 84–91% yields.
Received 24 February 2016
Revised 19 April 2016
Accepted 20 April 2016
Available online 20 April 2016
Ó 2016 Elsevier Ltd. All rights reserved.
Keywords:
Heterocycles
Transition-metal catalysts
Cyclization
Bioactive molecules
Pyrrolo[3,2-d]pyrimidine (1) is a privileged heterocyclic frame-
work and can be considered as a 9-carbon surrogate of purine.
Consequently, these isosteric molecules containing pyrrolo[3,2-d]
pyrimidine are widely recognized as purine nucleoside phosphory-
lase (PNP) inhibitors,1 HER2/EGFR dual inhibitors,2 antivirus
reagents,3 human 50-methylthioadenosine phosphorylase (MTAP)
inhibitors,4 and DPP-IV inhibitors for the treatment of diabetes.5
This scaffold also exhibits extensive biological activities,6 such as
dihydrofolate reductase inhibitors, neuropeptide Y5 receptor
antagonists, and antitubulin agents.
Since the pyrrolo[3,2-d]pyrimidine structure does not occur in
nature, a number of synthetic methods have been reported
(Fig. 1). For example, (1) the most common methods utilized con-
densation of the 2,3-di-substituted pyrrole to form the pyrimidine
ring;7 (2) Madelung indole synthetic strategy was also conducted
on the ortho-methyl-N-acyl pyrimidine to prepare the pyrrole moi-
ety;8 (3) alternatively starting from 6-methyl-5-nitropyrimidin,
pyrrolo[3,2-d]pyrimidine was achieved by a Leimgruber–Batcho
indole synthesis including sequential DMF formylation and
reductive cyclization;9 (4) and Sonogashira coupling was recently
introduced to ortho-halogen aminopyrimidine, which was followed
by a cyclization of the acetylene amine intermediate.2b,10
In our effort to prepare a new type of HER2/EGFR dual inhibi-
tors, the pyrrolo[3,2-d]pyrimidine (1) with 4,6-substitution was
highly needed (Fig. 2). Although the post 6-position functionaliza-
tion on pyrrolo[3,2-d]pyrimidine scaffold is a direct choice, it
always involved an aromatic hydrogen subtraction coupled with
expensive and sensitive organolithium reagents.11,12 Among the
existing strategies mentioned above, Sonogashira coupling is the
most convenient strategy to introduce the 6-substitution by vary-
ing the R1 group on acetylene, however, such a coupling method
was never reported on 4-phenylamino pyrimidine substrates. The
only 4,6-substituted pyrrolo[3,2-d]pyrimidine example has to
deploy a phenylether group as a placeholder and then a nucle-
ophilic substituted by the specific 4-phenylamino groups.2b
Herein, we wish to develop an efficient coupling method that can
assemble 4,6-substituted pyrrolo[3,2-d]pyrimidines directly from
4-phenylamino pyrimidine and various acetylenes.
The initial preparation of substrates 5 was started from a com-
mercially available pyrimidine 2 (Scheme 1). Nucleophilic aromatic
substitution with aniline produced 4-phenylamino pyrimidine
intermediate 3, which showed lower Sonogashira reactivity to
acetylene. Further halogen exchange to iodides 4 enhanced the
yields of the desired acetylene amines 5. Having various acetylene
amines in hand, we first chose substrate 5a to investigate the
cyclization condition (Table 1). To our surprise, the most used
⇑
Corresponding authors. Tel.: +86 15262441086, +86 18913127448; fax: +86
512 65880959.
E-mail addresses: huyanwei@suda.edu.cn (Y. Hu), zhangshilei@suda.edu.cn
(S. Zhang), ynzhang@sibs.ac.cn (Y. Zhang).
y
These authors contributed equally to this work.
http://dx.doi.org/10.1016/j.tetlet.2016.04.077
0040-4039/Ó 2016 Elsevier Ltd. All rights reserved.

R. Xie et al. / Tetrahedron Letters 57 (2016) 2418–2421
2419
6
Table 1
N 7
1N
2
The cyclization optimization of 5a to 6aa
8
N 9
H
4
N
3
R2
N
o
H
N
h
Purine
c
t
EtO2C
H2N
a
NO2
Me
B
-
HN
r
R1
y
e
N
b
t
g
u
s
HN
r
e
t
g
NH2
a
r
H
N
m
i
R3
N
e
L
1
R2
4
N
3
H
N
N
N
N
R1
5a
6
6a
R3
N
2
7
g
R1
n
u
l
e
y
d
g
a
e
Pyrrolo[3,2-d]pyrimidine
t
M
Entry
Catalyst
PdCl2
Pb(OAc)2
Pd(PPh3)2Cl2
Pb(OAc)2 + PPh3
RhCl3
RuCl3
AuCl
CuI
Solvent
T (°C)
Time (h)
Yield (%)
a
R2
N
r
t
R2
N
s
4
2
H
N
R1
1
2
3
4
5
6
7
8
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
Toluene
CH3CN
THF
80
80
80
80
80
80
80
80
80
80
80
70
90
100
90
90
90
30
30
30
30
30
30
30
30
30
30
30
40
24
20
24
24
24
3
2
5
7
0
0
0
67
80
82
77
81
88
85
87
81
85
NH2
N
O
R3
X
R3
N
Me
Figure 1. Representative synthetic methods to pyrrolo[3,2-d]pyrimidine.
9
Ag2O
10
11
12
13
14
15
16
17
AgNO3
AgOAc
AgNO3
AgNO3
AgNO3
AgNO3
AgNO3
AgNO3
NH2
O
N
O
N
R1
H
N
NH2
I
N
N
N
R1
Ref. 2b
R2
NH
4
N
N
R1
this work
NH
N
6
a
To a solution of compound 5a (0.3 mmol) in DMF (5 mL) was added catalyst
(0.06 mmol, 20 mol %). The resulting mixture was stirred at a specific temperature
until the reaction was completed and monitored by TLC.
N
NH2
I
R1
+
1
target molecule ( )
Figure 2. Synthetic strategy to 4,6-substituted pyrrolo[3,2-d]pyrimidine.
optimized reaction condition (entries 1–10, Table 2). The position
of substituents on the 4-phenylamino moiety was well tolerated;
while the electron properties were also compatible in the cycliza-
tion reaction and gave comparable yields ranging from 84% to 91%.
We also investigated the use of different acetylenes as coupling
partners to 4-phenylamino pyrimidines. The results showed that
both aliphatic and aromatic acetylenes are favorable in this reac-
tion. All the reactions examined gave exclusive high yields of the
desired 4,6-substituted pyrrolo[3,2-d]pyrimidines (entries 11–20,
Table 2).
To demonstrate the robustness of the silver-catalyzed cycliza-
tion of acetylene amine, we selected some representative and
interesting substrates, such as 6a and 6k, for scale-up experiments
(20 mmol). The total yields (56% for 6a and 59% for 6k from the
starting material 2, see Supplementary data) were similar to those
of the small-scale results listed in Scheme 1 and Table 2.
4,6-Substituted pyrrolo[3,2-d]pyrimidines 6 can undergo fur-
ther transformations to add substituent diversity (Scheme 2). For
example, a Mannich reaction occurred at 7-position of 6k when
it was treated with HCHO and HNMe2, and a useful dimethylamino
methyl group was introduced. In addition, an esterification
of 6k followed by methylation at 4-position gave ester 9 as a
product.
NH2
R2
Cl
N
R2
HN
NH2
Cl
NH2
Cl
NaI/HI, H2O
N
N
HCl, EtOH
N
3
2
R2
R2
HN
R1
HN
NH2
NH2
I
PdCl2(PPh3)2/CuI
N
N
THF/Et3N
N
5
N
R1
4
Scheme 1. Preparation of substrates 5.
palladium catalysts in this cyclization gave a little amount of the
4,6-substituted pyrrolo[3,2-d]pyrimidine (entries 1–4, Table 1).
Next examination of other transition metal catalysts found Cu(I)
and Ag(I) led to the product in good yields (entries 5–9, Table 1),
and AgNO3 gave the best yield up to 82% (entries 10 and 11,
Table 1). Further tuning of the reaction temperature showed rais-
ing the temperature to 90 °C marginally improved the yield to
88% (entries 12–14, Table 1). Although most solvents screened here
generated similar results, we considered DMF as the optimal con-
dition due to its good solubility of pyrimidine substrates (entries
15–17, Table 1).
In summary, an efficient synthesis of 4,6-substituted pyrrolo
[3,2-d]pyrimidines was developed. Silver nitrite was found to be
the robust catalyst to enable the cyclization of acetylene amine
intermediates possessing diverse functionalities, leading to an
efficient preparation of a series of potential bioactive molecules.
This method would enrich our combinatorial library construction
of HER2/EGFR dual inhibitors, which is undergoing in our
laboratory.
To explore the scope of electronic and steric substituents on the
4-phenylamino moiety, various substituents were exposed to the

2420
R. Xie et al. / Tetrahedron Letters 57 (2016) 2418–2421
Table 2
Scope of silver catalyzed cyclization of acetylene aminesa
R2
R2
HN
HN
NH2
H
N
N
N
R1
N
N
R1
5
6
Entry
1
6
Yield (%)
88
Entry
11
6
Yield (%)
88
HN
HN
Br
Br
H
N
H
N
OH
N
N
N
N
6a
6k
HN
Cl
Cl
HN
H
N
H
N
2
3
89
87
12
13
84
88
NHBoc
N
N
N
N
6b
6l
HN
Br
HN
H
N
H
N
N
N
3
N
N
6c
6d
6m
HN
Br
Br
HN
Br
H
N
H
N
4
5
6
7
8
9
87
91
85
84
88
86
14
15
16
17
18
19
86
89
91
90
90
90
N
N
N
N
6n
HN
Br
HN
H
N
H
N
N
N
10
N
N
6e
6f
6o
HN
Me
Me
HN
Br
Br
H
N
H
N
N
N
N
N
6p
HN
HN
H
N
H
N
N
N
N
N
6q
6g
6h
HN
OMe
OMe
HN
Br
Br
H
N
H
N
N
N
Cl
N
N
6r
HN
HN
H
N
H
N
N
N
Br
N
N
6s
6i

R. Xie et al. / Tetrahedron Letters 57 (2016) 2418–2421
2421
Table 2 (continued)
Entry
6
Yield (%)
Entry
20
6
Yield (%)
Me
HN
Br
OCH3
H
N
HN
Me
N
10
89
91
H
N
N
N
6t
N
6j
a
To a solution of compound 5 (0.3 mmol) in DMF (5 mL) was added AgNO3 (10 mg, 0.06 mmol). The resulting mixture was stirred at 90 °C until the reaction was completed
and monitored by TLC.
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HCHO, HNMe2
dioxane/H2O
CH3I, K2CO3
DMF
89%
78%
O
Br
NH
Br
NH
H
OH
N
N
O
N
N
N
N
7
9
N
Scheme 2. Derivatizations of compound 6k.
Acknowledgments
The work was supported by National Natural Science Founda-
tion of China (Grant No. 21202112), Ph.D. Programs Foundation
of Ministry of Education of China (20123201120019) and PAPD
(A Project Funded by the Priority Academic Program Development
of Jiangsu Higher Education Institutions).
Supplementary data
Supplementary data (experimental procedures, characteriza-
tion, 1H and 13C NMR spectra of compounds 1–6) associated with
this article can be found, in the online version, at http://dx.doi.
org/10.1016/j.tetlet.2016.04.077.
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