One-pot synthesis of 2,4-diamino-substituted thieno[3,2-d]pyrimidines

Article abstract of DOI:10.1002/cjoc.201090245

An efficient one-pot synthetic approach to 2,4-diamino-substituted thieno[3,2-d]pyrimidines from 2,4-dichlorothieno[3,2-d]pyrimidine was described.

Full text of DOI:10.1002/cjoc.201090245

FULL PAPER
One-pot Synthesis of 2,4-Diamino-substituted
Li, Xiaoyinga(李肖T颖h) ieno[3,2-d]pyrimidines
Zhang, Yangmingb(张仰明)
Tang, Jiea(汤杰)
Yang, Fan*,a(杨帆)
Nan, Fajun*,b(南发俊)
a Department of Chemistry and Institute of Medicinal Chemistry, East China Normal University,
3663 North Zhong Shan Road, Shanghai 200062, China
b The National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences,
189 Guoshoujing Road, Shanghai 201203, China
An efficient one-pot synthetic approach to 2,4-diamino-substituted thieno[3,2-d]pyrimidines from
2,4-dichlorothieno[3,2-d]pyrimidine was described.
Keywords privileged structure, 2,4-dichlorothieno[3,2-d]pyrimidine, one-pot
Introduction
our previous work, we have reported that the two chlo-
rine atoms in 2- and 4-position showed different reac-
tivity and chloride at 4-position can be removed under
mild hydrogenation condition in the presence of
NaHCO3.5 Considering this reactivity difference of the
two chlorine atoms, we propose that various organic
amines will attack these two chlorine atoms sequentially,
therefore, introduction of two different amino groups in
a one-pot way would be feasible. To our delight, this
approach turned out to be a good alternative method to
As an ideal source for lead discovery, privileged
structures refer to a single molecular framework that is
able to provide ligands for diverse receptors. Since it
was first addressed by Evans et al. in 1988,1 many
skeletons have been identified as privileged structures
and this concept has attracted much attention of me-
dicinal chemists. Nowadays, the construction of com-
pounds libraries based on privileged structures followed
by diverse screening has evolved into a practical strat-
egy to obtain lead compounds with more efficiency.
Thienopyrimidine skeletons are typical privileged
structures with occurrence in a variety of biological ac-
tive compounds. For example, some 2-alkoxy or 2-
alkyl-subsituted thienopyrimidinones show significant
antifungal and antibacterial activities.2a-2d Modification
on 5- and 6-position of thienopyrimidine has led to a
series of N,N-diaryl ureas which potently inhibit both
vascular-growth factor (VEGF) and platelet-derived
growth factor (PDGF) receptor tyrosine kinases.3 As a
continuous work to our previous synthetic methodology
study on selective dechlorination of 2,4-dichloropyrimi-
dines, we intend to develop an efficient synthetic ap-
proach to introduce diverse functional groups through
selective nucleophilic substitution of the chlorine at 2-
and 4-position, so as to explore their chemical space.
Our preliminary study results are described here.
2,4-diamino-substituted
thieno[3,2-d]pyrimidines,
which is much more efficient than traditional stepwise
manner, which requires chromatographic purification
upon each reaction step (Scheme 1).
Scheme
1
One-pot synthesis of 2,4-diamino-substitued
thieno[3,2-d]pyrimidines
In a typical procedure, 2,4-dichlorothieno[3,2-d]-
pyrimidine was dissolved in a suitable aprotic solvent
[dimethylsulphoxide (DMSO), N-methyl-2-pyrrolidine
(NMP) or N,N-dimethylformamide (DMF)]. To this
solution, arylamines (1.5 equiv.) and NaHCO3 (2 equiv.)
were added and the mixture was heated to 100 ℃. It
usually took 3— 4 h to complete the replacement of
4-chlorine atom. Then, without intermediate separation,
a variety of aliphatic amines (5— 10 equiv.) was added
directly and the mixture was heated again to 100 ℃ for
In our research, 2,4-dichlorothieno[3,2-d]pyrimidine
was chosen since it was readily prepared by literature
method as starting material for 2,4-disubstitued thieno-
[3,2-d]pyrimidine. Traditionally 2,4-disubstitued thieno-
[3,2-d]pyrimidines were prepared in a stepwise way.4 In
*
E-mail: yfan@chem.ecnu.edu.cn, fjnan@mail.shcnc.ac.cn; Tel./Fax: 0086-021-62232100, 0086-021-50800954
Received February 22, 2010; revised March 17, 2010; accepted April 20, 2010.
Project supported by the National Natural Science Foundation of China (No. 30725049) and the National Science & Technology Major Project Key
New Drug Creation and Manufacturing Program (No. 2009ZX 09302-001).
Chin. J. Chem. 2010, 28, 1437— 1440
© 2010 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
1437

Li et al.
FULL PAPER
5— 10 h. After routine workup and silica-gel chroma-
tographic purification, 2,4-diamine-substituted thieno-
[3,2-d]pyrimidines were obtained in moderate to good
yields (38%— 94%). The results are summarized in Ta-
ble 1.
Table 1 One-pot synthesis of 2,4-diamine-substituted thieno[3,2-d]pyrimidines
Time/h
Step 2
Entry
1
R1
R2
Solvent
Product
Yield/% (isolated)
88
Step 1
3
DMSO
5
A2-1
2
3
DMF
3
3
10
5
A2-2
A2-3
49
83
DMSO
4
5
6
DMSO
NMP
3
3
3
5
A2-4
A2-5
A2-6
71
75
79
10
5
DMSO
7
DMF
3
3
3
3
10
5
A2-7
A2-8
A2-9
A2-10
38
58
78
38
8
DMSO
DMSO
NMP
9
5
10
10
1438
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© 2010 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2010, 28, 1437— 1440

One-pot Synthesis of 2,4-Diamino-substituted Thieno[3,2-d]pyrimidines
Continued
Yield/% (isolated)
Time/h
Entry
11
R1
R2
Solvent
DMSO
Product
Step 2
Step 1
3
5
A2-11
58
65
72
12
13
DMF
3
3
10
5
A2-12
A2-13
DMSO
14
DMSO
3
5
A2-14
90
15
16
17
18
NMP
3
3
3
3
10
5
A2-15
A2-16
A2-17
A2-18
41
43
94
90
DMSO
DMF
10
5
DMSO
19
20
DMSO
NMP
3
3
5
A2-19
A2-20
93
58
10
Because 4-chlorine atom is much more reactive than
2-chlorine atom, 2,4-dichlorothieno[3,2-d]pyrimidine
reacted with various anilines to give mono-substituted
compounds within 3 h, regardless of the electron-
donating or -withdrawing substitutes at the aromatic
rings. However, particularly in the cases of anilines
bearing electron-withdrawing groups, excess anilines
(1.5 equiv.) were necessary to prevent side-products
formation. Boiling point of the second amine is an im-
portant parameter in step 2 reactions. Amines with low
boiling point usually lead to low yields (Entries 2, 7 and
12) even large excess of amines (10 equiv.) are em-
ployed, while amines with high boiling points usually
lead to satisfying yields. In the case of piperidine, low
yield was usually resulted from the difficult products
separation by flash silica-gel chromatography. For
3-aminopropan-1-ol, solvent seemed to be critical. NMP
is the solvent of choice, the reaction did not proceed at
all in DMSO or DMF, which was in accordance with
literature reports.6 Many functional groups (halogen,
hydroxy and alkyne) at aromatic rings are tolerable, and
this permits further derivation possible from these
Chin. J. Chem. 2010, 28, 1437— 1440
© 2010 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
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Li et al.
FULL PAPER
2,4-diamino-substituted thieno[3,2-d]-pyrimidines via
cross-coupling reaction, click reaction, ester- or amide-
formation reaction.
237580e.]
(b) Walter, H. WO 9914202, 1999 [Chem. Abstr. 1999, 130,
252368k.]
In conclusion, a practical and efficient one-pot ap-
proach to 2,4-diamino-substituted thieno[3,2-d]-pyrimi-
dines was developed. The obtained diamino-substituted
products with more functional groups make it easy for
further structure modifications through simple known
reactions.
(c) Aboulwafa, O. M.; Ismail, K. A.; Koreshin, E. A.
Farmaco 1992, 47, 63.
(d) Chambhare, R. V.; Khadse, B. G.; Bobde, A. S.;
Bahekar, R. H. Eur. J. Med. Chem. 2003, 38, 89.
Dai, Y. J. J. Med. Chem. 2005, 48, 6066.
Peng, J. S.; Lin, W. Q.; Jiang, D. H.; Yuan, S. X.; Chen, Y.
W. J. Comb. Chem. 2007, 9, 431.
3
4
5
6
Zhang, Y. M.; Gu, M.; Ma, H.; Tang, J.; Lü, W.; Nan, F. G.
Chin. J. Chem. 2008, 26, 962.
Gillespie, R. J.; Cliffe, I. A. Bioorg. Med. Chem. Lett. 2008,
18, 2920.
References
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Horton, D. A.; Bourne, G. T.; Smythe, M. L. Chem. Rev.
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(E1002223 Lu, Y.)
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© 2010 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2010, 28, 1437— 1440