One-pot synthesis of 5H-1,3,4-thiadiazolo[3,2-a] pyrimidin-5-one derivatives

Article abstract of DOI:10.1039/c4ra02714k

A novel and efficient one-pot method has been developed for the synthesis of 2-substituted-5H-1,3,4-thiadiazolo[3,2-a]pyrimidin-5- one derivative by the combination of [3 + 3] cycloaddition, reduction, deamination reactions. The fused heterocyclic compoun

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Oneꢀpot synthesis of 5Hꢀ1,3,4ꢀthiadiazolo[3,2ꢀ
a]pyrimidinꢀ5ꢀone derivatives
Cite this: DOI: 10.1039/x0xx00000x
HongꢀRu Dong,a ZhongꢀLian Gao,a RongꢀShan Li,a YiꢀMing Hu, b HengꢀShan Dong*
a and ZhiꢀXiang Xie a
Received 00th January 2014,
Accepted 00th January 2014
DOI: 10.1039/x0xx00000x
www.rsc.org/
fusedꢀring
systems
2ꢀsubstitutedꢀ5Hꢀ1,3,4ꢀthiadiazolo[3,2ꢀ
A novel and efficient oneꢀpot method has been developed for
a]pyrimidinꢀ5ꢀone derivatives 3aꢀo were synthesized by the oneꢀpot
reaction of the corresponding 2ꢀaminoꢀ5ꢀsubstituedꢀ1,3,4ꢀ
thiadiazoles 2aꢀo and ethyl cyanoacetate under present of catalytic
the synthesis of 2ꢀsubstitutedꢀ5
]pyrimidinꢀ5ꢀone derivative by the combination of [3+3]
cycloaddition, reduction, deamine reactions. The fused
heterocyclic compounds 2ꢀsubstitutedꢀ5 ꢀ1,3,4ꢀthiadiazolo
[3,2ꢀ ]pyrimidinꢀ5ꢀones was synthesized by the catalytic
diversityꢀoriented. As an extension of the synthetic
methodology, some ꢀPyrido[1,2ꢀ ]pyrimidinꢀ4ꢀone 4aꢀc
Hꢀ1,3,4ꢀthiadiazolo[3,2ꢀ
a
agent (Scheme 1).
H
S
a
O
H2N
N
H
NH2
R
OH
N
POCl3
4
H
a
O
N
was synthesized. The πꢀπ accumulation structure of
supramolecular selfꢀassembly was discussed in the crystal.
N
S
N
CNCH2CO2CH2CH3
P2O5, HCO2H
N
R
NH2
R
S
Thiadiazolopyrimidines, analogous structure compounds display
an important role in pharmacological chemistry. The nucleus and a
number of its substituted products exhibit interesting biological and
pharmacological properties.1ꢀ10 Because of their importance; the
synthesis of these compounds has attracted considerable attention. In
recent years, many papers concerning the synthesis of 2,7ꢀ
3a-o
2a-o
The typical three-step
synthesis
to a one-pot process
Acid cat.
Acid cat.
deamine
[
3+3}
cyclo
-add
ition
O
N
O
N
N
N
S
HCO2H
N
disubstitutedꢀ1,3,4ꢀthiadiazolo[3,2ꢀa]pyrimidinꢀ5ꢀone
derivatives
N
R
R
have been reported.11ꢀ15 However, little attention has been paid to the
synthesis of 2ꢀsubstitutedꢀ1,3,4ꢀthiadiazolo[3,2ꢀa]pyrimidinꢀ5ꢀones,
which are unsubstituted on the 7ꢀposition. And up to now, there are
few reports on the synthesis of them in literature. The structure of
1,3,4ꢀthiadiazolo[3,2ꢀa]pyrimidinꢀ5ꢀone was alike with mother
structure of importance quinolone antimicrobial agents. The study on
methodology of synthesis or the structure of them and their
derivatives analogous compounds in biological and pharmacological
fields was importance.
reduction
S
NH
NH2
Scheme 1 The synthesis of 2ꢀsubstitutedꢀ5Hꢀ1,3,4ꢀthiadiazolo[3,2ꢀ
a]pyrimidinꢀ5ꢀone derivatives for combination
of [3+3]
cycloaddition, eduction, eamine
When a solution of 2ꢀaminoꢀ5ꢀsubstitutedꢀ1,3,4ꢀthiadiazole, ethyl
cyanoacetate and CH3ONa in dry methanol was refluxed, the 2ꢀ
cyanoꢀNꢀ(5ꢀsubstitutedꢀ1,3,4ꢀthiadiazolꢀ2ꢀyl)acetamide
2
was
given.17 Previously, the solution of 2ꢀaminoꢀ5ꢀsubstitutedꢀ1,3,4ꢀ
thiadiazole, ethyl cyanoacetate and CH3ONa in dry methanol was
refluxed, the reaction gave other structure compound, 5,6ꢀdihydroꢀ5ꢀ
iminoꢀ2ꢀsubstitutedꢀ1,3,4ꢀthiadiazolo[3,2ꢀa]pyrimidinꢀ7ꢀone18 3. The
same type reaction gave difference form results. The ring conversion
reaction of 5,6ꢀdihydroꢀ5ꢀiminoꢀ2ꢀsubstitutedꢀ1,3,4ꢀthiadiazolo[3,2ꢀ
The twoꢀsteps synthesis method of 2ꢀaminoꢀ7ꢀsubstitutedꢀ1,3,4ꢀ
thiadiazolo[3,2ꢀa]pyrimidinꢀ5ꢀone derivatives have been reported,
which was prepared from 2ꢀaminoꢀthiadiazole derivatives and βꢀketo
esters, but yield was low.13ꢀ14 Cascade, tandem, oneꢀpot,
multicomponent domino reactions, atom economy, catalystꢀfree, ring
opening, supramolecular selfꢀassembly and diversityꢀoriented
synthesis (DOS) are increasingly applied to the construction of
natural and designed molecules.16 A novel and efficient oneꢀpot
method has been developed for the synthesis of 2ꢀsubstitutedꢀ5Hꢀ
1,3,4ꢀthiadiazolo[3,2ꢀa]pyrimidinꢀ5ꢀone derivative. Some novel
o
a]pyrimidinꢀ7ꢀone in formic acid at 100 C for 10 h was carried to
6,7ꢀdihydroꢀ7ꢀiminoꢀ2ꢀsubstitutedꢀ1,3,4ꢀthiadiazolo[3,2ꢀ
a]pyrimidinꢀ5ꢀone 4.19 The reaction of 2ꢀaminoꢀ5ꢀsubstitutedꢀ1,3,4ꢀ
thiadiazole, ethyl cyanoacetate and methanesulfonic acidꢀphosphorus
pentoxide
gave
6,7ꢀdihydroꢀ7ꢀiminoꢀ2ꢀsubstitutedꢀ1,3,4ꢀ
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DOI: 10.1039/C4RA02714K
thiadiazolo[3,2ꢀa]pyrimidinꢀ5ꢀone 4.16 In same starting materials,
reagents, solvents and catalytic agent, the reaction gives different
products to the intermediate 2ꢀcyanoꢀNꢀ(5ꢀsubstitutedꢀ1,3,4ꢀ
thiadiazolꢀ2ꢀyl)acetamide 2 or 5,6ꢀdihydroꢀ5ꢀiminoꢀ2ꢀsubstitutedꢀ
1,3,4ꢀthiadiazolo[3,2ꢀa]pyrimidinꢀ7ꢀone 3. With same starting
materials, reagents and solvents, the reaction also gives equally type
products under different catalytic agent. 6,7ꢀDihydroꢀ7ꢀiminoꢀ2ꢀ
7
4ꢀbromophenyl
furanꢀ2ꢀyl
45
3g
3h
3i
8
52.5
69.5
82
9
2ꢀchlorophenyl
3ꢀmethylphenyl
2ꢀbromophenyl
2ꢀfluorophenyl
benzyl
10
3j
substitutedꢀ1,3,4ꢀthiadiazolo[3,2ꢀa]pyrimidinꢀ5ꢀone
4
could be
11
56
3k
3l
synthesized by 2ꢀ3 steps or one step from 2ꢀaminoꢀ5ꢀsubstitutedꢀ
1,3,4ꢀthiadiazole. The diversity synthesis is shown in Scheme 2.
12
62
N
N
N
13
67
3m
3n
3o
R
S
N
O
1) EtO2CCH2CN,
MeONa/MeOH,
H
14
2ꢀmethoxyphenyl
2ꢀmethylphenyl
85
2
2) AcOH-H2O,pH=5
15
76
NH
N
1) EtO2CCH2CN,
MeONa/MeOH,
[a] Isolated yield
N
N
N
N
The tandem reaction of diversityꢀoriented synthesis was carried
out by method of typical threeꢀstep synthesis to a oneꢀpot process
under the presence phosphorus pentoxideꢀformic acid. How, the
target product was given by formic acid which was thinked for the
reductant of EschweilerꢀClarke and LeuckartꢀWallach reaction
conditions.20ꢀ21 The synthesis of a new series of 2ꢀsubstitutedꢀ5Hꢀ
1,3,4ꢀthiadiazolo[3,2ꢀa]pyrimidinꢀ5ꢀone derivatives 3aꢀo was
combination of [3+3] cycloaddition, reduction, deamine reactions
and 30~93% yield, which is the tandem reaction. The reaction was
combination of many type and step reactions in oneꢀpot reaction, 7ꢀ
imino was given by Tsuji modes,16 was eliminated by tandem
reaction of reduction and deamine when methanesulfonic acidꢀ
phosphorus pentoxide was changed to formic acidꢀphosphorus
pentoxide as the catalytic agent. Compounds 2aꢀo were synthesized
by the method reported in the literature.18,22ꢀ32 The mechanism of
synthesis is shown in Scheme 3.
NH2
R
R
S
S
2) AcOH-H2O
O
1
3
1) EtO2CCH2CN,
P2O5/CH3SO3H,
HCOOH,
reflux, 10 h.
2) NH4OH-H2O
O
N
S
N
R
N
NH
4
Scheme 2 The synthesis of 6,7ꢀdihydroꢀ7ꢀiminoꢀ2ꢀsubstitutedꢀ1,3,4ꢀ
thiadiazolo[3,2ꢀa]pyrimidinꢀ5ꢀone
In order to obtain new 6,7ꢀdihydroꢀ7ꢀiminoꢀ2ꢀsubstitutedꢀ1,3,4ꢀ
thiadiazolo[3,2ꢀa]pyrimidinꢀ5ꢀone derivatives, the reaction of 2ꢀ
aminoꢀ5ꢀsubstitutedꢀ1,3,4ꢀthiadiazoles 2aꢀo and ethyl cyanoacetate
under the presence of phosphorus pentoxide and formic acid was
utilized. The phosphorus pentoxide or formic acid was utilized
respectively to the reaction catalytic of 2ꢀaminoꢀ5ꢀsubstitutedꢀ1,3,4ꢀ
thiadiazoles 2aꢀo and ethyl cyanoacetate, but phosphorus pentoxide
and formic acid has not been utilized together to the reaction. Here,
we obtained the synthesis of a new series of 2ꢀsubstitutedꢀ5Hꢀ1,3,4ꢀ
thiadiazolo[3,2ꢀa]pyrimidinꢀ5ꢀone derivatives 3aꢀo. The synthesis
pathway is shown in Table 1.
O
N
N
CNCH2CO2C2H5
P2O5, HCOOH
N
S
N
R
R
NH2
S
N
2a-o
3a-o
CNCH2CO2C2H5
H+ or P2O5, HCOOH
O
-NH3,-H+
O
N
S
H
N
N
N
R
R
Table 1 Diversityꢀsynthesis oriented of compounds 2aꢀo to 3aꢀo
H
N
N+
H
S
N
NH
O
O
S
H
O
N
N
CNCH2CO2C2H5
P2O5, HCOOH
H+
NH2NHCNH2
N
S
HCO
2H
N
R
O
R
NH2
O
OH
R
POCl3
S
N
N
N
N
N
-CO2
R
H
O
H
1a-o
R
3a-o
2a-o
H
N
S
N
S
N
N
Entry
Substrate
R
Yield(%)[a]
H
H
90
1
2ꢀethoxyphenyl
4ꢀmethylphenyl
3ꢀmethoxyphenyl
4ꢀmethoxyphenyl
phenyl
3a
Scheme 3 The reaction mechanism of transformation of 2aꢀo to 3aꢀo
2
75
3b
3c
3d
3e
3f
Seeing that above, the synthesis of target product was explored by
2ꢀaminoꢀ5ꢀ(4ꢀmethylphenyl)ꢀ1,3,4ꢀthiadiazole, ethyl cyanoacetate,
phosphorus pentoxide and concentrated H2SO4. The reaction was
carried out at 100ꢀ105 oC for 12 h, monitored by TLC, which didn’t
give relevant target product. Then, the synthesis of the targe product
was probed by the addition of 2ꢀaminoꢀ5ꢀ(2ꢀethoxyphenyl)ꢀ1,3,4ꢀ
thiadiazole, ethyl cyanoacetate, phosphorus pentoxide and glacial
acetic acid, and so it didn’t give the target product. When we only
choose phosphorus pentoxideꢀformic acid as condensation reagent at
3
4
5
6
78.5
93
30
4ꢀchlorophenyl
48
2 | J. Name., 2012, 00, 1-3
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the same conditions, the target product (3d) was obtained in yield of Figure 3 A Mercury (1.4, CCDC, 2005) view of the molecular
93%. Phosphorus pentoxideꢀformic acid was an efficient structure of 3i36
condensation regent for the synthesis of 2ꢀsubstitutedꢀ5Hꢀ1,3,4ꢀ
thiadiazolo[3,2ꢀa]pyrimidinꢀ5ꢀone derivatives 3aꢀo. The synthesis
reaction didn’t give target product by 2ꢀaminoꢀ5ꢀsubstitutedꢀ1,3,4ꢀ
thiadiazole, ethyl cyanoacetate, phosphorus pentoxide and glacial
acetic acid (or concentrated H2SO4 or methanesulfonic acid), but
target product was given by formic acid which is the reducing
reagent as LeuckartꢀWallach, EschweilerꢀClarke reaction conditions.
The tandem reaction of 2ꢀaminoꢀ5ꢀsubstitutedꢀ1,3,4ꢀthiadiazole,
ethyl cyanoacetate and methanesulfonic acidꢀphosphorus pentoxide
gave
6,7ꢀdihydroꢀ7ꢀiminoꢀ2ꢀsubstitutedꢀ1,3,4ꢀthiadiazolo[3,2ꢀ
a]pyrimidinꢀ5ꢀone.16 Then the imino group of 7ꢀposition was
reductive converted to amino by formic acid.20,33 After elimination
of ammonia, the target product was given under acid alike Fischer
indole synthesis.34 Described herein is our approach, which reduces
the typical threeꢀstep synthesis to a oneꢀpot process. The mechanism
of reaction is shown in Scheme 3. The molecular structure of the
product 3d and 3i was established by the Xꢀray diffraction (Fig 1，
Fig 2). The supramolecular structure of compound 40a is
shown in Figure 3.
Figure 1 A Mercury (1.4, CCDC, 2005) view of the molecular
structure of 3d35
Figure 4. The π-π accumulation structure of 3i supramolecular self-assembly.
As an extension of the synthetic methodology, some 4Hꢀ
Pyrido[1,2ꢀa]pyrimidinꢀ4ꢀone 4aꢀe was synthesized. The synthesis
pathway is shown in Table 2.
Table 2 Diversityꢀsynthesis oriented of compounds 4aꢀc.
O
CNCH2CO2C2H5
N
R
P2O5, HCOOH
N
NH2
N
R
4a-c
Entry
1
Substrate
R
Yield(%)[a]
20
H
4a
2
3
4
7ꢀ methyl
7ꢀchloro
2ꢀchloro
37.5
33
4b
4c
4e
Figure 2. The π-π accumulation structure of 3d supramolecular self-assembly.
42.5
[a] Isolated yield
Conclusions
In conclusion, a novel and efficient oneꢀpot method has been
developed for the synthesis of 2ꢀsubstitutedꢀ5 ꢀ1,3,4ꢀ
thiadiazolo[3,2ꢀ ]pyrimidinꢀ5ꢀone derivative by the tandem
H
a
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DOI: 10.1039/C4RA02714K
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reaction of [3+3] cycloaddition, reduction, deamine reactions
under the present of formic acidꢀphosphorus pentoxide as the
catalytic agent. The fused heterocyclic compounds 2ꢀ
substitutedꢀ5Hꢀ1,3,4ꢀthiadiazolo[3,2ꢀa]pyrimidinꢀ5ꢀones was
synthesized by the catalytic diversityꢀoriented.
Notes and references
a College of Chemistry and Chemical Engineering, State Key Laboratory
of Applied Organic Chemistry, Institute of Organic Chemistry, Lanzhou
University, Lanzhou, Gansu 730000, P, R China
b
The School of Nuclear Science and Technology, Lanzhou University,
Lanzhou, Gansu 730000, P, R China
†
Footnotes should appear here. These might include comments
relevant to but not central to the matter under discussion, limited
experimental and spectral data, and crystallographic data.
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/c000000x/
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36. 3i, C11H6ClN3OS, crystal size 0.38×0.35×0.31 mm3, space group
P2(1)/n (monoclinic),
=98.505(6)º,
=1056(7) Å3,
(MoKa)=0.542mmꢀ1. Data were measured on a Bruker SMART APEX
diffractometer (MoKa radiation, =0.71073 Å) at 296 K, and the
structure was solved by direct methods. Of 5348 reflections
collected, 2061 were unique reflections Rint =0.0237);
data/restraints/parameters 2061/0/154; final indices [ >2σ( )]: R1
=0.0330, w 2 =0.0846; R indices (all data): R1 =0.0397, wR2
=0.0902. CCDC 779674 contains the supplementary
a
=10.838(4),
b
=4.9244(19),
c
=20.011(7) Å,
β
V
Z
=4, ρcalcd=1.658
g
cmꢀ3,
ꢀ
λ
(
R
I
I
R
crystallographic data for 3d. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre at
www.ccdc.cam.ac.uk/data_request/cif.
19. K. Takenaka, T. Tsuji, J. Heterocyclic Chem. 1996, 33, 1367ꢀ1370.
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4 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 2012

Page 5 of 5
RSC Advances
View Article Online
DOI: 10.1039/C4RA02714K
One-pot synthesis of 5H-1,3,4-thiadiazolo [3,2-a]pyrimidin-5-one derivatives
H.-R. Dong, Z.-L. Gao, R.-S. Li, Y.-M. Hu, H.-S. Dong,* Z.-X. Xie *
Abstract
A novel and efficient one-pot method has been developed for the synthesis of
2-substituted-5H-1,3,4-thiadiazolo[3,2-a]pyrimidin-5-one derivative by the tandem
reaction of [3+3] cycloaddition, reduction, deamine.
O
O
O
N
O
N
S
N
N
S
R
N
S
N
N
H
O
H
R
R
N
NH
O
N
N N
S
H
N
H
N
N
N
S
H
N
R
NH2
H
R
a
+H
N
H
H
O
N
S
N
N
S
N
R
NH2
R
CNCH2CO2CH2CH3
P2O5, HCO2H
N
O
N
N
R
N
NH2
R
4a-c