One-pot synthesis of thieno [2,3-d] pyrimidin-4-ol derivatives mediated by polyphosphonic anhydride

Article abstract of DOI:10.1016/j.tetlet.2012.06.017

An efficient synthesis of thiopyrimidines with different substituents in position 2 is described. A rapid, mild and high yielding microwave-assisted one-pot cyclization of 5-substituted 2-amino thiophene-3-carboxamide derived from Gewald reaction¹ with T3P and different acids gives the corresponding thiopyrimidines. The significant feature of this method includes less reaction time, high purity and reduced toxicity of the reaction.

Full text of DOI:10.1016/j.tetlet.2012.06.017

Tetrahedron Letters 53 (2012) 4639–4643
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One-pot synthesis of thieno [2,3-d] pyrimidin-4-ol derivatives mediated by
polyphosphonic anhydride
Subba Poojari a, P. Parameswar Naik b, , G. Krishnamurthy b
⇑
a Syngene International Ltd, Biocon Park, Plot Nos. 2 & 3, Bommasandra IV Phase, Jigani Link Road, Bangalore 560 099, India
b Department of P.G. Studies and Research in Chemistry, Sahadri Science College (Autonomous), Shimoga 577 203, India
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient synthesis of thiopyrimidines with different substituents in position 2 is described. A rapid,
mild and high yielding microwave-assisted one-pot cyclization of 5-substituted 2-amino thiophene-3-
carboxamide derived from Gewald reaction1 with T3P and different acids gives the corresponding thio-
pyrimidines. The significant feature of this method includes less reaction time, high purity and reduced
toxicity of the reaction.
Received 24 March 2012
Revised 4 June 2012
Accepted 6 June 2012
Available online 21 June 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Thiopyrimidines
Propylphosphonic anhydride
Microwave initiator
Heteroaromatic
HO
Over the past few years, the poly phosphonic acid cyclic anhy-
dride has attracted significant interest as an efficient and mild cou-
pling reagent and dehydrating agent. This is due to its efficient
functional group tolerance, low toxicity1 and low epimerization
tendency and easy work-up procedures. Accordingly, a variety of
new applications have been developed for this reagent, including
the direct conversion of ketoximes to amides, and aldoximes to ni-
triles,2 the synthesis of alkenes from alcohols,3 peptide synthesis,4
the formation of isonitriles from formamide,5 oxidation of alco-
hols,6 ester synthesis,7 C–C coupling reactions,8 the conversion of
carboxylic acids into azides,9 the Lossen10 and preparation of
substituted heterocycles (Scheme 1).
The thiopyrimidine core moiety is a versatile heterocyclic sys-
tem, occurring in a variety of compounds with a broad spectrum
of biological activities,11 consequently, thiopyrimidines and its
derivatives continue to capture the attention of organic and medic-
inal chemists and a variety of well established methods are now
available for their production. Moreover, they are important inter-
mediate organic synthesis providing access to other highly desir-
able structures (Scheme 2).
O
S
N
N
NH2
NH2
R2
T3P, TEA
CH2Cl2, 120 °C,
MW, 20 min
S
R1
R1
R1 = CH3, NO2, R2=Acids.
Scheme 1.
However, despite their common use, most reported methods to
prepare these heterocyclics suffer from long reaction times and of-
ten require the use of strong acid media. Consequently, new mild
and expedient protocols for this valuable and widely utilized reac-
tion are of significant importance.
Polyphosphonic anhydride13 is a mild water scavenger, but its
synthetic utility has not been investigated in the synthesis of fused
pyrimidine derivatives. Herein we report an efficient and opera-
tionally simple one-pot synthesis of fused pyrimidines.
The classical reactions between 5-substituted 2-amino thio-
phene-3-carboxamide (1a, 1 equiv) or 2-amino-5-(4-nitrophenyl)
thiophene-3-carboxamide (1b, 1 equiv) and carboxylic acid (4a,
1.1 equiv) in the presence of T3P (50% solution in EtOAc, 2.5 equiv)
were used.14 The reaction mixture was heated at 120 °C under
microwave irradiation for 20 min with 2.5 equiv of T3P (Table 1,
entry 2). Further optimization showed that use of T3P (2.5 equiv)
was appropriate for the full conversion of 1a and 1b and requires
only 20 min of microwave irradiation at 120 °C. Increasing the
equivalent of T3P and also reducing the reaction time lowered
the cyclized products (Table 1, entry, 5).
The synthesis of substituted thiopyrimidines from 5-substi-
tuted 2-amino thiophene-3-carboxamide12 and carboxylic acids
is the most widely used synthetic procedure. This reaction involves
the base catalysed amidations followed by the elimination of
water.
⇑
Corresponding author. Tel.: +91 9448158393; +91 8182240435.
E-mail address: parashchem@gmail.com (P. Parameswar Naik).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.06.017

4640
S. Poojari et al. / Tetrahedron Letters 53 (2012) 4639–4643
O
Pr
OH
P
O
O
P
OH
P
O
P
R2
Pr
O
DCM
TEA
O
P
O
P
Pr
R2
OH
O
O
O
Pr
O
O
O
O
Pr
O
O
NH2
H
O
OH
Pr
NH2
NH
O
P
Pr
OH
Pr
O
O
P
R2
O
P
Pr
OH
P
O
Pr
O
P
NH2
P
O
O
S
O
O
O
O
S
6
R2
R1
R1
O
H
O
O
R2
NH
NH
O-
P
OH
O
P
Pr
NH
NH
Pr
MW
Pr
O
P
OH
O
O
O
S
S
R2
R1
O+
R1
OH
P
O
P
OH
- H2O
H
Pr
Pr
P
O
O
O
O
O
Pr
NH
N
R2
S
R1
HO
S
N
N
R2
R1
Scheme 2.
4-actamido cinnamic acid (4f) and 3-[3-(trifluoromethyl) phenyl]
propionic acid (4m) they gave the corresponding cyclic compounds
in good yields (entries 6 and 14) after heating at 120 °C for extra
10 min compared to 4a. 2,3-Dihydro 1,4-benzodixine -2-carboxylic
acid (4g) and cyclopentanoic acid (4p) both performed well, afford-
ing 88% and 94% yields of the desired products (2g) and (2p)
respectively. The reaction with substituted substrates such as 6-
chloro-2-fluoro-3-methylbenzoic acid (4i) and 4-(trifluoro-
methyl)-1,3-thiazole-2-carboxylic acid (4s) was carried out in
two steps. Firstly, the intermediate amide derivative was formed
by heating at 60 °C for 10 min followed by cyclization at 120 °C
for 20 min. This procedure furnished the desired products in an
excellent yield (91% and 86% entries 9 and 19).
Table 1
Screening optimal conditions
Entry
T3P (equiv)
Time (min)
Temp (oC)
Yield (%)
1
2
3
4
5
1.5
2.5
1.0
3.0
5.0
0.5
0.0
30
20
20
20
10
30
20
120
120
130
120
120
120
120
55
98
50
67
30
20
NRb
6
7a
a
Reaction was performed in the absence of T3P.
No reaction.
b
A set of substituted carboxylic acids were investigated. In gen-
eral, carboxamide bearing electron- donating (entries 1–16) or
electron withdrawing groups (entries 17–23) were well tolerated
affording good to excellent yields of the corresponding products.
We have developed a convenient one pot method for the
synthesis of thieno [2,3-d] pyrimidin-4-ol derivatives. We have
also provided rapid, mild and high yielding protocol for the intra-
molecular cyclization with T3P under microwave irradiation.
This method seems to be convenient for large scale preparation
due to the ease of isolation of products in good purity by simple
work-up. Moreover, these new protocols allow for an iterative
analogue library synthesis approach for lead optimization to be
employed for the rapid synthesis of library compounds.
The intramolecular cyclization was mediated by T3P and not via
a thermal process; a control experiment without the addition of
T3P was performed. As expected, there were no cyclized products
when the carboxamide was heated at 120 °C in chloroform in the
absence of T3P. (LC/MS analysis). (Table 1, entry 7).
The transformation of carboxylic acids 4a–4w into the corre-
sponding substituted fused thiopyrimidines (see Table 2) however,
occurred rapidly under microwave irradiation. Although the reac-
tion proceeded well with 4-benzyloxy benzoic acid (4a) a longer
reaction time was needed (20 min) to achieve full conversion.
The use of aliphatic acid and heterocyclic acids also required slight
adjustment of the conditions. In case of linear acids such as

S. Poojari et al. / Tetrahedron Letters 53 (2012) 4639–4643
4641
Table 2
Synthesis of thiopyrimidines derivatives from 1a and 1b with various acids
Entry
Amide
Acid (R2)
Product
Yielda (%)
O
HO
N
OH
O
N
O
1
1a
S
94
97
2a
HO
4a
O
OH
N
Br
N
2
3
1a
1a
S
4b
Br
2b
HO
HO
O
N
O
S
N
95
S
O
O
S
O
2c
HO
4c
O
O
N
N
S
4
5
1a
1a
98
92
OH
OH
O
2d
4d
O
HO
N
N
N
S
N
N
N
2e
5e
O
HO
N
O
N
N
6
7
1a
1a
1a
1a
1a
98
88
87
91
H
S
H
N
OH
4f
2f
O
O
HO
O
N
O
OH
N
S
O
O
4g
2g
O
HO
N
O
N
S
S
OH
8
N
S
N
4h
2h
OH
F
HO
F
N
N
9
S
Cl
Cl
2i
4i
HO
O
HO
O
N
N
O
10
87
H
S
N
NH
2
4j
2j
(continued on next page)

4642
S. Poojari et al. / Tetrahedron Letters 53 (2012) 4639–4643
Table 2 (continued)
Entry
Amide
Acid (R2)
Product
Yielda (%)
HO
OH
H
O
N
N
Cl
O
S
N
O
Cl
NH
N
O
11
1a
92
O
4k
OH
2k
F
HO
F
O
12
13
1a
1a
92
99
N
S
N
N
4l
2l
HO
OH
O
N
O
O
N
S
4m
2m
O
HO
F
F
OH
N
F
F
F
F
14
15
16
17
1a
1a
1a
1b
98
84
94
96
N
S
4n
4o
2n
HO
OH
O
H
N
N
O
N
H
N
S
O
2o
OH
HO
N
O
4p
N
S
2p
O
HO
N
F
OH
F
N
S
F
F
O
O2N
O
F
F
4q
3a
HO
O
N
N
N
O
F
OH
OH
O
18
19
1b
1b
86
93
N
S
O2N
4r
3b
O
HO
F
F
N
N
F
N
S
N
F
F
S
O2N
O2N
S
4s
3c
O
HO
OH
N
N
S
20
21
1b
1b
84
89
N
N
H
H
3d
4t
O
HO
O
O
O
N
OH
N
O
N
N
4u
S
O2
N
3e

S. Poojari et al. / Tetrahedron Letters 53 (2012) 4639–4643
4643
Table 2 (continued)
Entry
Amide
Acid (R2)
Product
Yielda (%)
O
HO
OH
N
O
O
22
23
1b
84
97
O
N
S
O2N
4v
O
3f
HO
O
N
OH
1b
4w
N
S
O2
N
3g
1a = 2-amino-5-(4-methylphenyl)thiophene-3-carboxamide.
O
NH2
NH2
S
1b = 2-amino-5-(4-nitrophenyl)thiophene-3-carboxamide.
O
NH2
NH2
S
O2N
a
Isolated yield.
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Acknowledgement
The authors are thankful to Dr. Santosh Kulkarni, Syngene Inter-
national Ltd for his assistance and valuable advice.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.06.
017.
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