Synthesis of a novel series of thieno[3,2-d]pyrimidin-4-(3H)-ones

Article abstract of DOI:10.1055/s-0029-1218697

2-Aminothieno[3,2-d]pyrimidin-4-ones were synthesized in one step by condensation of 3-amino(benzo)thiophene car-boxylate with chloroformamidine hydrochloride. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0029-1218697

1428
SHORT PAPER
Synthesis of a Novel Series of Thieno[3,2-d]pyrimidin-4-(3H)-ones
Ismail Abdillahi, Gilbert Kirsch*
Laboratoire d’Ingénierie Moléculaire et Biochimie Pharmacologique, Institut Jean Barriol, FR CNRS 2843, 1 Boulevard Arago,
57070 METZ, France
Fax +33(3)87325801; E-mail: kirsch@.univ-metz.fr
Received 20 January 2010; revised 26 January 2010
Dedicated to Professor Willi Kantlehner for his contribution to iminium salts chemistry
R1
S
R1
R2
O
R1
R2
Cl
Abstract: 2-Aminothieno[3,2-d]pyrimidin-4-ones were synthe-
sized in one step by condensation of 3-amino(benzo)thiophene car-
boxylate with chloroformamidine hydrochloride.
CO2R3
i–iii
iv
R2
CN
NH2
1a–g
Key words: heterocycles, condensation, 3-aminothiophene-2-car-
boxylate, thieno[3,2-d]pyrimidinone, chloroformamidine hydro-
chloride
Scheme 3 Reagents and conditions: (i) POCl3, DMF, 60 °C, 5 h; (ii)
hydroxylamine chloride, EtOH; (iii) Ac2O; (iv)(a) Na2S·9H2O, DMF,
XCH2CO2Et/Me (X = Br, Cl), EtONa/MeONa or (b) HSCH2CO2Et/
Me, K2CO3, DMF.
In continuation of our synthetic studies with 3-amino-2-
substitued thiophenes,1 we describe here a new approach
to thieno[3,2-d]pyrimidin-4(3H)-ones. The synthesis was
devised to enable the condensed heterocycle structure to
be used as a scaffold for preparing new biologically active
compounds.
Ethyl 3-aminothiophene-2-carboxylate (1h) was prepared
from a-chloroacrylonitrile in excellent yield (90%;
Scheme 4).13 In most cases, thiophenes 1 were obtained in
good yields (Table 1).
2-Aminothieno[3,2-d]pyrimidinones have previously
been described in the literature and have been used as a
scaffold for preparing a range of biologically active com-
pounds;2,3,4 the isomeric [3,2-d]pyrimidin-4(3H)-one de-
rivatives, however, were not previously known. We
describe here their preparation from ethyl or methyl 3-
aminothiophene-2-carboxylate and chloroformamide hy-
drochloride as shown in Scheme 1.
S
NC
Cl
i
CO2R
NH2
1h
Scheme 4 Reagents and conditions: (i) HSCH2CO2Et, EtOH, EtONa.
Table 1 Formation of Thiophenes 1
NH2
R2
Entry R1
R2
R3
Product
Overall
yield (%)
N
R2
R1
NH2
i
NH
R1
S
2a–i
CO2R3
1
2
3
4
5
6
7
8
Ph
H
H
H
H
H
Et
1a
1b
1c
1d
1e
1f
74
82
83
72
60
40
74
90
S
O
4-MeC6H4
4-ClC6H4
4-MeOC6H4
t-Bu
Et
Scheme 1 Reagents and conditions: (i) chloroformamidine hydro-
chloride, dimethylsulfone, 140–150 °C, 4 h.
Et
Me
Et
Chloroformamide hydrochloride was prepared in one step
from cyanamide and anhydrous hydrogen chloride in ex-
cellent yield (Scheme 2).5 The amino thiophenes esters
(1a–g) were synthesized from b-chloropropenonitrile ob-
tained from b-chloropropenal as described previously
(Scheme 3).6–14
c-Hex
Me
Et
1,2-dihydronaphthalene
H
1g
1h
H
Et
NH
Cl
i
95%
HCl
H2N
H2N CN
To extend the scope of our synthesis, we also prepared
methyl 3-amino-5-nitrobenzo[b]thiophene-2-carboxylate
by direct condensation of 2-chloro-3-cyano-5-nitroben-
zene with methyl thioglycolate under basic conditions.
The synthesis is similar to that described by Beck15 and in-
volves a nitro group displacement (Scheme 5).
Scheme 2 Reagents and conditions: (i) anhyd HCl, Et2O, r.t.
SYNTHESIS 2010, No. 9, pp 1428–1430
Advanced online publication: 09.03.2010
x
x
.
x
x
.2
0
1
0
DOI: 10.1055/s-0029-1218697; Art ID: Z01210SS
© Georg Thieme Verlag Stuttgart · New York

SHORT PAPER
Novel Thieno[3,2-d]pyrimidin-4-(3H)-ones
1429
S
The various 3-aminothiophene (benzothiophene) carbox-
ylates were condensed with chloroformamide hydrochlo-
ride by heating the mixture in dimethylsulfone at 140–
150 °C for four hours to afford the corresponding pyrimi-
dinone (Scheme 1 and Table 2).
O2N
Cl
CO2Me
94%
i
O2N
CN
NH2
1i
Scheme 5 Reagents and conditions: (i) HSCH2CO2Me, DMF, K2CO3.
Having prepared the pyrimidinone scaffold, functional
transformation will be performed by introducing side
chains on the amino group. Transformation of the pyrim-
idinone into the chloropyrimidines will allow the intro-
duction of nucleophiles via SNAr reaction, or aryl and
aminoaryl side chains by palladium-catalyzed coupling
reactions.
Table 2 Thieno[3,2-d]pyrimidinone Derivatives 2
Thiophene 1
Pyrimidinone 2
Yield
(%)
N
NH2
NH2
Ph
S
NH
67
57
40
45
67
Melting points were determined on a Stuart SMP3 apparatus and are
Ph
CO2Et
NH2
O
1
uncorrected. H and 13C NMR spectra were recorded on a AC
S
2a
Bruker 250 MHz spectrometer in either CDCl3 or DMSO-d6. Mass
spectra were recorded on a MicroTof-Q 98.
N
NH2
MeC6H4
S
NH
Synthesis of 2-Aminoaryl[3,2-d]pyrimidin-4(3H)-ones 2a–i;
General Procedure
MeC6H4
ClC6H4
MeOC6H4
t-Bu
CO2Et
O
S
A mixture of the appropriate thiophene and chloroformamidine hy-
drochloride (1:4) in dimethylsulfone (4 equiv) was heated at 140–
150 °C for 4 h. The mixture was cooled to r.t., H2O (15 mL) was
added and ammonium hydroxide was used to neutralize the solu-
tion. The precipitate was filtered and washed with H2O (3 × 100
mL). After drying over P2O5 in vacuum, the product was either re-
crystallized from MeOH or purified by column chromatography.
2b
N
NH2
NH2
ClC6H4
S
NH
CO2Et
O
S
2c
N
O
NH2
NH2
2-Amino-6-phenylthieno[3,2-d]pyrimidin-4(3H)-one (2a)
Column chromatography purification (CHCl3–MeOH, 5%).
MeOC6H4
S
NH
CO2Et
Yield: 67%; brown solid; mp 318 °C.
1H NMR (250 MHz, DMSO-d6): d = 6.47 (s, 2 H, NH2), 7.36–7.48
(m, 4 H, 4 × CH), 7.74–7.77 (m, 2 H, 2 × CH), 11.07 (s, 1 H, NH).
13C NMR (62.9 MHz, DMSO-d6): d = 111.3, 119.8, 125.8 (2 × C),
129.2 (3 × C), 132.9, 149.9, 154.5, 157.9, 160.7.
S
2d
N
NH2
NH2
t-Bu
NH
S
CO2Et
O
MS: m/z = 244.05 [M + H]+.
S
2e
NH2
NH
2-Amino-6-(4-methylphenyl)thieno[3,2-d]pyrimidin-4(3H)-one
(2b)
Yield: 57%; beige solid; mp 357 °C (MeOH).
N
NH2
52
CO2Et
NH2
1H NMR (250 MHz, DMSO-d6): d = 2.33 (s, 3 H, CH3), 6.42 (s,
S
O
S
2
2 H, NH2), 7.26 (d, J = 7.5 Hz, 2 H, 2 × CH), 7.34 (s, 1 H, CH),
2f
7.64 (d, 2J = 7.5 Hz, 2 H, 2 × CH), 11 (s, 1 H, NH).
13C NMR (62.9 MHz, DMSO-d6): d = 20.8, 110.9, 119.2, 125.7,
129.7, 130.2, 139.0, 150.1, 154.5, 158.0, 160.0.
NH2
NH
N
86
30
90
CO2Et
MS: m/z = 280.05 [M + Na]+.
S
S
O
2-Amino-6-(4-chlorophenyl)thieno[3,2-d]pyrimidin-4(3H)-one
(2c)
Yield: 40%; brown solid; mp 321–323 °C (MeOH).
1H NMR (250 MHz, DMSO-d6): d = 6.58 (s, 2 H, NH2), 7.44 (s,
1 H, CH), 7.50 (d, 2J = 7.5 Hz, 2 H, 2 × CH), 7.78 (d, 2J = 7.5 Hz,
2 H, 2 × CH).
13C NMR (62.9 MHz, DMSO-d6): d = 111.7, 120.1, 127.6, 129.2,
131.7, 133.8, 148.6, 154.4, 157.7, 159.5, 178.8.
2g
N
NH2
NH2
NH
S
CO2Et
O
S
2h
O2N
NH2
NH
N
NH2
MS: m/z = 299.99 [M + Na]+.
O2N
CO2Me
S
2-Amino-6-(4-methoxyphenyl)thieno[3,2-d]pyrimidin-4(3H)-
one (2d)
Yield: 45%; brown solid; mp 325 °C (MeOH).
S
O
2i
Synthesis 2010, No. 9, 1428–1430 © Thieme Stuttgart · New York

1430
I. Abdillahi, G. Kirsch
SHORT PAPER
1H NMR (250 MHz, DMSO-d6): d = 3.80 (s, 3 H, CH3), 6.60 (s, 2 H,
NH2), 7.00 (d, 2J = 7.5 Hz, 2 H, 2 × CH), 7.29 (s, 1 H, CH), 7.68–
7.71 (d, 2J = 7.5 Hz, 2 H, 2 × CH).
13C NMR (62.9 MHz, DMSO-d6): d = 55.3, 110.5, 114.6, 117.8,
125.4, 127.4, 150.5, 154.0, 157.5, 160.2.
2-Amino-8-nitro[1]benzothieno[3,2-d]pyrimidin-4(3H)-one (2i)
Yield: 90%; yellow solid; mp 350 °C (MeOH).
1H NMR (250 MHz, DMSO-d6): d = 7.01 (s, 2 H, NH2), 8.30 (m,
2 H, 2 × CH), 8.76 (m, 1 H, CH), 11.15 (s, 1 H, NH).
13C NMR (62.9 MHz, DMSO-d6): d = 113.0, 118.3, 122.3, 125.2,
133.6, 145.0, 146.5, 155.5, 158.1, 162.7.
MS: m/z = 274.064 [M + Na]+.
2-Amino-6-tert-butylthieno[3,2-d]pyrimidin-4(3H)-one (2e)
Yield: 67%; yellow solid; mp 344 °C (MeOH).
Acknowledgment
1H NMR (250 MHz, DMSO-d6): d = 1.33 (s, 9 H, 3 × CH3), 6.31 (s,
We thank EGIDE for financial support to I.A. We also thank
Alzchem Trostberg GmbH (Germany) for a gift of cyanamide. We
thank Dr P. Magri for determining the melting points.
2 H, NH2), 6.75 (s, 1 H, CH), 10.91 (s, 1 H, NH).
13C NMR (62.9 MHz, DMSO-d6): d = 31.5, 34.8, 109.9, 118.6,
154.3, 158.0, 159.9, 164.9.
MS: m/z = 246.067 [M + Na]+.
References
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48, 5261.
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2-Amino-6,7,8,9-tetrahydro[1]benzothieno[3,2-d]pyrimidin-
4(3H)-one (2f)
Yield: 52%; yellow solid; mp 323 °C (MeOH).
1H NMR (250 MHz, DMSO-d6): d = 1.75–1.80 (m, 6 H, 2 × CH2),
2.70–2.72 (m, 2 H, CH2), 6.42 (s, 2 H, NH2), 10.91 (s, 1 H, NH).
13C NMR (62.9 MHz, DMSO-d6): d = 21.5, 22.8, 23.0, 25.5, 108.8,
130.2, 144.2, 154.3, 157.8, 158.9.
(4) Shishoo, C. J.; Devani, M. B.; Pathak, U. S.; Ananthan, S.;
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MS: m/z = 222.07 [M + H]+.
2-Amino-5,6-dihydronaphtho[2¢,1¢,4,5]thieno[3,2-d]pyrimidin-
4(3H)-one (2g)
Yield: 86%; brown solid; mp 360 °C (MeOH).
1H NMR (250 MHz, DMSO-d6): d = 2.7–2.8 (m, 2 H, CH2), 2.9–3.0
(m, 2 H, CH2), 6.59 (s, 2 H, NH2), 7.2–7.3 (m, 3 H, 3 × CH), 7.38–
7.44 (m, 1 H, CH).
13C NMR (62.9 MHz, DMSO-d6): d = 20.8, 27.6, 110.4, 123.27,
126.3, 127.7, 128.8, 130.0, 131.0, 134.3, 136.0, 142.0, 154.4, 157.9.
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MS: m/z = 292.05 [M + Na]+.
2-Aminothieno[3,2-d]pyrimidin-4(3H)-one (2h)
Yield: 30%; beige solid; mp >350 °C (MeOH).
1H NMR (250 MHz, DMSO-d6): d = 6.46 (s, 2 H, NH2), 6.96 (d,
2J = 5.25 Hz, 1 H, CH), 7.93 (d, 2J = 5.25 Hz, 1 H, CH).
13C NMR (62.9 MHz, DMSO-d6): d = 112.2, 123.4, 134.4, 154.2,
158.2, 159.4.
MS: m/z = 190 [M + Na]+.
Synthesis 2010, No. 9, 1428–1430 © Thieme Stuttgart · New York