Synthesis of 3-substituted 2-thioxo-2,3-dihydro-1H-benzofuro[3,2-d] pyrimidin-4(1H)-ones

Article abstract of DOI:10.1080/00397910701462831

With the purpose of searching for new biologically active compounds, a method of synthesis of new heterocyclic systems [3-alkyl(aryl)-2-thioxo-2,3- dihydro-1H-benzofuro[3,2-d]pyrimidin-4(1H)-ones] has been developed. The method is based on the interaction

Full text of DOI:10.1080/00397910701462831

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Synthesis of 3‐Substituted
2‐Thioxo‐2,3‐dihydro‐1H‐benzofuro[3,2‐ d ]
pyrimidin‐4(1H)‐ones
Olena V. Il'chenko a , Oleg V. Zaremba b , Sergiy M. Kovalenko a , Aliaksandr
A. Sherakov c & Valentin P. Chernykh a
a National University of Pharmacy , Kharkiv, Ukraine
b Institute of Combinatorial Organic Chemistry , Kharkiv, Ukraine
c Center for Examination and Tests in Health Service, Republican Unitary
Enterprise , Minsk, Byelarus
Published online: 09 Aug 2007.
To cite this article: Olena V. Il'chenko , Oleg V. Zaremba , Sergiy M. Kovalenko , Aliaksandr A. Sherakov
& Valentin P. Chernykh (2007) Synthesis of 3‐Substituted 2‐Thioxo‐2,3‐dihydro‐1H‐benzofuro[3,2‐ d ]
pyrimidin‐4(1H)‐ones, Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 37:15, 2559-2568, DOI: 10.1080/00397910701462831
To link to this article: http://dx.doi.org/10.1080/00397910701462831
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Synthetic Communicationsw, 37: 2559–2568, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701462831
Synthesis of 3-Substituted 2-Thioxo-
2,3-dihydro-1H-benzofuro[3,2-d]
pyrimidin-4(1H)-ones
Olena V. Il’chenko
National University of Pharmacy, Kharkiv, Ukraine
Oleg V. Zaremba
Institute of Combinatorial Organic Chemistry, Kharkiv, Ukraine
Sergiy M. Kovalenko
National University of Pharmacy, Kharkiv, Ukraine
Aliaksandr A. Sherakov
Center for Examination and Tests in Health Service, Republican Unitary
Enterprise, Minsk, Byelarus
Valentin P. Chernykh
National University of Pharmacy, Kharkiv, Ukraine
Abstract: With the purpose of searching for new biologically active compounds, a
method of synthesis of new heterocyclic systems [3-alkyl(aryl)-2-thioxo-2,3-
dihydro-1H-benzofuro[3,2-d]pyrimidin-4(1H)-ones] has been developed. The
method is based on the interaction of ethyl 3-isothiocyanato-1-benzofurane-2-carbox-
ylate in 2-propanol with amines in the presence of an equimolecular quantity of
triethylamine.
Keywords: ethyl 3-isothio-cyanato-1-benzofurane-2-carboxylate, 2-thioxo-2,3-
dihydro-1H-benzofuro[3,2-d]pyrimidin-4(1H)-one
Received in Poland August 10, 2006
Address correspondence to Sergiy M. Kovalenko, National University of Pharmacy,
53, Pushkinska Str., Kharkiv 61002, Ukraine. E-mail: kosn@ic.kharkov.ua
2559

2560
O. V. Il’chenko et al.
The present article presents a suitable synthetic route to the novel heterocyclic
system of 2-thioxoquinazoline-4-one. Because the systems containing the
2-thioxoquinazoline-4-one moiety do possess many types of physiological
activity, they have been extensively studied for several years.[1–6]
2-Thioxoquinazoline-4-one derivatives are known to exhibit anxiolytic,[7,8]
antihypertensive, fungicidal, antidepressant, and antihyperlipaemic, properties.[9]
The synthesis of some novel 4-oxo-2-thioxo-1,2,3,4-tetrahydroquinazo-
lines[10] and thienopyrimidin-4-ones[11] has been recently developed in our
laboratory and reported in some papers. The results obtained prompted us to
investigate further with the idea of designing molecules containing both
benzofuran and pyrimidine moieties.
Among the benzofuran derivatives there are a lot of substances possessing
the following activities: anti-inflammatory, antiarythmic, haemostatic, anti-
bacterial, fungicidal, antiviral, antitumor, and antioxidant ones.[12] It should
be expected that the newly synthesized related compounds may possibly
possess interesting pharmacological properties.
The literature survey shows only one article on the synthesis of 2-thioxo-
2,3-dihydro-1H-benzofuro[3,2-d]pyrimidin-4(1H)-ones, which were obtained
by the continuous boiling of the mixture of aryl isothiocyanate and 3-amino-1-
benzofuran-2-carboxamide in the acetic acid (Scheme 1). However, it should
be noted that the aromatic isothiocyanates were used in this reaction and the
yield of the products does not exceed the range of 42–58%.[13]
The traditional synthesis of annelated 4-oxo-2-thioxopyrimidine systems
is carried out by the condensation of o-aminoesters with substituted isothio-
cyanates.[14] In our investigations, the more effective synthetic route
for 4-oxo-2-thioxo-1,2,3,4-tetrahydroquinazolines[10] and thienopyrimidin-4-
ones[11] has been developed. It is based on the condensation of the 2-methyl-
carboxyaryl(thienyl)isothiocyanates with different aliphatic and aromatic
amines, aminoacids, hydrazines, hydrazides, sulfohydrazides, and thiosemi-
carbasides. This method has certain advantages compared with the traditional
ones. The first advantage is the possibility of useing the expanded set of
Scheme 1.

2-Thioxo-2,3-dihydro-1H-benzofuro[3,2-d]pyrimidin-4(1H)-ones
2561
“aminic” components. This approach has been found to be effective for the
generation of combinatorial matrixes and synthesis of combinatorial
libraries. The next advantages are both the improved yield and the purity of
the combinatorial library products with relation to the same characteristics
of ordinary synthesized products.
In the present article, we have researched both the traditional and
novel synthetic pathways to the 2-thioxo-2,3-dihydro-1H-benzofuro[3,2-
d]pyrimidin-4(1H)-ones, which had not been applied to the synthesis of
these products before.
According to the first way, the synthesis of 3-substituted-2-thioxo-2,3-
dihydro-1H-benzofuro[3,2-d]pyrimidin-4(1H)-ones was been carried out by
the interaction of 3-amino-1-benzofuran-2-ethylcarboxylate (1) with isothio-
cyanates (2) in dimethylformamide (Scheme 2). The first stage of the
reaction is the formation of corresponding N,N0-disubstituted thioureas (3),
which have not been isolated from the reaction mixture. The thioureas (3)
were then readily cyclized while heating in the alkaline solution to form the
3-substituted
ones (4c–e, g).
2-thioxo-2,3-dihydro-1H-benzofuro[3,2-d]pyrimidin-4(1H)-
It should be mentioned that the reaction proceeds more readily in the case
of aryl- and benzylisothiocyanates than in the case when alkyl ones are
utilized. One can see that longer reaction time (3–6 h) was required for alky-
lisothiocyanates, and the yields of the products were lower (55–68%).
The second method is based on the reaction of 2-ethoxycarbonyl-3-iso-
thiocyanato-1-benzofuran (6) with ammonia or primary aliphatic and
aromatic amines 7b–k in the presence of triethylamine, which leads to
the formation of 3-N-substituted-2-thioxo-2,3-dihydro-1H-benzofuro[3,2-
d]pyrimidin-4(1H)-ones 4a–m (Scheme 3). The intermediate compound 6
has been prepared through the interaction of ethyl 3-amino-1-benzofuran-2-
carboxylate (1) with thiophosgene 5. The synthesis of 6 has been carried out
in binary chloroform–water mixture at room temperature. The hydrogen
chloride has been neutralized by aqueous potassium carbonate. The isothiocya-
nate 6 was used without special purification for further transformations.
1H NMR spectra of the compounds (4a–m) possess the specific ABCD
signals of the system of the benzofuran moiety protons as the combination
of the pair of doublets of H-6 protons (7.60–7.82 ppm) and H-9 protons
Scheme 2.

2562
O. V. Il’chenko et al.
Scheme 3. (7a): R ¼ H, (7b): R ¼ CH3, (7c): R ¼ Ph, (7d): R ¼ 4-F-Ph, (7e): R ¼
4-(OCH3-Ph), (7f): R ¼ C4H9 (7g): R ¼ CH2-Ph, (7h): R ¼ (CH2)2-OCH3, (7i):
R ¼ CH2-(4-F-Ph), (7j): R ¼ CH2-(4-OCH3-Ph), (7k): R ¼ CH2-(4-CH3-Ph), (71):
R ¼ CH2COOH, (7m): R ¼ (CH2)2COOH.
(7.95–8.24 ppm) and the pair of triplets of H-7 protons (7.50–7.79 ppm) and
H-8 protons (7.30–7.67 ppm). The NH group proton’s signal appears as the
broaded singlet at 13.8–14.0 ppm. The signals of the protons of the substitu-
ents in the 3-position are also present as the corresponding multiplets at 6.50–
7.46 ppm when the moiety is aromatic and at 0.98–5.6 ppm when it is
aliphatic.
The IR spectra of the compounds synthesized show several specific
absorption bands. There are the strong band of S55P group of pyrimidinic
ring at 1663–1715 sm21 and vibration bands of C55S group at 1214–1288
cm21. The absorption bands of the C55C group of aromatic rings appear at
intervals from 1477 to 1622 cm21
.
The electronic absorption spectra (EAS) of propanol solutions of 3-
substituted-2-thioxo-2,3-dihydro-1H-benzofuro[3,2-d]pyrimidin-4(1H)-ones
at interval 38000–25000 cm21 show two electronic p ! pꢀ transitions with
the maximum at 30540–34760 cm21 and at 29800–30080 cm21. In the short-
wavelength part of the spectra at interval 48000–38000 cm21, some intensity
overlapped bands that are characteristic absorption for p-conjugated systems
are observed.
Thus, as a result of a comparative study of two approaches to the synthesis
of 3-substituted-2-thioxo-2,3-dihydro-1H-benzofuro[3,2-d]pyrimidin-4(1H)-
ones, the interaction of 3-isothiocyanato-1-benzofuran-2-ethylcarboxylate
(6) with different amines (7) in the presence of tryethylamine leads to the
formation of 3-N-substituted-2-thioxo-2,3-dihydro-1H-benzofuro[3,2-d]
pyrimidin-4(1H)-ones (4a–m). The application of the given method
allowed us to expand considerably a line of derivatives of the given class of
compounds and gave us an opportunity of introduction of various aminic com-
ponents in the reaction.
EXPERIMENTAL
Melting points were measured with a Buchi B-520 melting-point apparatus
and are not corrected. Elemental analysis was carried out within þ0.4% of
the theoretical value. IR spectra were recorded on Bruker Tensor-27

2-Thioxo-2,3-dihydro-1H-benzofuro[3,2-d]pyrimidin-4(1H)-ones
2563
spectrometer in KBr. UV spectra were recorded on Specord M40 spectrometer
in 2-propanol. 1H NMR spectra were recorded on Varian WXR-400
(200-MHz) spectrometer in DMSO-d6 using TMS as an internal standard.
The course of reaction was supervised by the thin-layer chromatography
(TLC) method on aluminum sheets precoated with Silufol UV254 silica gel
(5 cm ꢁ 15 cm) (Kavalier, Czech Republic), eluent ethyl acetate–toluene
system of the solvents 1:2. LC/MS spectra were obtained on a Shimadzu
LS–10 VP, Gilson–215 apparatus, the automatic supply of the samples on
mass spectrometer API 165EX, detector UV (215 and 254 nm), and ELS on
Luna–C 18 column, Phenomenex, 5 cm ꢁ 2 mm. According to LC/MS
data, all compounds have purity more than 95%.
Ethyl 3-amino-1-benzofuran-2-carboxylate (1) was prepared using the
described approach.[15]
Ethyl 3-Isothiocyanato-1-benzofuran-2-carboxylate (6)
To a stirred mixture of 100 mL of chloroform and 50 mL of water, 100 mmol
(20.5 g) of 3-amino-1-benzofuran-2-ethylcarboxylate (1) were added. Then a
solution of 110 mmol (12.7 g) of thiophosgene in 50 mL of chloroform was
added dropwise. The reaction mixture was stirred at room temperature for
2–3 h, and a solution of 250 mmol (34.5 g) of K2CO3 in 50 mL of water
was added. The organic phase was washed with water (3 ꢁ 100 mL) and
dried over MgSO4, and the solvent was evaporated in vacuo. The crude
product was crystallized from 2-propanole. Yield 89%.
General Procedure for the Preparation of 3-Alkyl(aryl)-2-tioxo-
2,3-dihydro-1H-benzofuro[3,2-d]pyrimidin-4(1H)-ones (4a–k)
Method A (4c–e, g)
A solution of 5 mmol (1 g) of ethyl 3-amino-1-benzofurane-2-carboxylate (1)
and 5.5 mmol of appropriated isothiocyanate (2c–e, g) in 10 mL of dimethyl-
formamide was heated at reflux for 3–6 h. Then a solution of KOH [4 mmol
(0.2 g) in 100 mL of water] was added, and the mixture was refluxed for 1 h.
After cooling, the reaction mixture was diluted with 20 mL of water, and the
precipitate was filtered and recrystallized from a mixture of 2-propanol and
dimethylformamide. Yield 78–91%.
Method B (4c–e, g, i, j, k)
To a solution of 20 mmol (4.95 g) of 3-isothiocyanato-1-benzofuran-2-ethyl-
carboxylate (6) in 5–7 mL of 2-propanol, 22 mmol of primary amine (7) and
22 mmol (2.2 g) of triethylamine were added. The reaction mixture was

2564
O. V. Il’chenko et al.
heated with stirring at 60–708S for 3 h. Then 5 mL of acetic acid were added,
and the resulting precipitate was filtered, washed with water, and crystallized
from a suitable solvent. Yield 70–91%.
Method C (4a, b, f, h)
To a solution of 20 mmol (4.95 g) of 3-isothiocyanato-1-benzofuran-2-ethyl-
carboxylate (6) in 5–7 mL of 2-propanol, 22 mmol of primary amine (7) and
22 mmol (2.2 g) of triethylamine were added dropwise. The resulting mixture
was heated at refluxe for 1 h and cooled, and acetic acid was added to
pH ¼ 4–5. The resulting precipitate was filtered, washed with water, and
crystallized from a suitable solvent. Yield 75–95%.
Method D (4l, m)
To a solution of 40 mmol (10.0 g) of 3-isothiocyanato-1-benzofuran-2-ethyl-
carboxylate (6) in 5–7 mL of 2-propanol, a solution of triethylamine salt of
amino acid (60 mmol of acid and 11.4 mL triethylamine) in 10 mL of
2-propanole was added. The reaction mixture was heated at reflux for ꢀ1 h.
After cooling, the mixture was acidified by hydrochloric acid to pH 2.5–
3.0, and the resulting precipitate was filtered and crystallized from dimethyl-
formamide. Yield 82–85%.
Data
2-Thioxo-2,3-dihydro-1H-benzofuro[3,2-d]pyrimidin-4(1H)-one (4a): Yield
95%. Light brown solid, mp 278–2808C; IR (cm21): 3392, 2999, 2889, 1687,
21
1616, 1557, 1512, 1218; UV (n, cm 21, 1 1023, L mol
cm21): 44060
.
.
(16.3), 41640 (15.1), 34760 (16.1); 1H NMR (200 MHz, DMSO-d6), d, ppm:
d 7.70 (d, J ¼ 9.1 Hz, 1H), 7.62 (t, J ¼ 4.5 Hz, 1H), 7.45 (t, J ¼ 4.5 Hz,
1H), 8.12 (d, J ¼ 9.1 Hz, 1H), 12.75 (s, 1H, NH), 13.6 (s, 1H, NH). LC/MS
(m/z, rel.%): 219 (100) [M þ ], 203 (60), 185 (8), 150 (18), 130 (55), 115
(48). Anal. calcd. for C10H6N2O2S (218.2): H, 2.77; C, 55.04; N, 12.84; S,
14.69. Found: H, 2.78; C, 55.04; N, 12.82; S, 14.67.
3-Methyl-2-thioxo-2,3-dihydro-1H-benzofuro[3,2-d]pyrimidin-4(1H)-
one (4b): Yield 89%. White solid, mp .3008C; IR (cm21): 3206, 3088,
3028, 2991, 2920, 1686, 1664, 1622, 1550, 1288; UV (n, cm 21, 1 1023
,
21
cm21): 44600 (9.1), 34720 (11.9), 30540 (2.4); 1H NMR
.
L mol
.
(200 MHz, DMSO-d6), d, ppm: d 7.74 (d, J ¼ 7.7 Hz, 1H), 7.63
(t, J ¼ 6.4 Hz, 1H), 7.40 (t, J ¼ 6.4, 1H), 8.13 (d, J ¼ 7.7 Hz, 1H), 13.8
(br s, 1H, NH), 3.55 (s, 3H, NCH3). Anal. calcd. for C11H8N2O2S (232.3):
H, 3.47; C, 56.89; N, 12.06; S, 13.81. Found: H, 3.49; C, 56.90; N, 12.02;
S, 13.83.

2-Thioxo-2,3-dihydro-1H-benzofuro[3,2-d]pyrimidin-4(1H)-ones
2565
3-Phenyl-2-thioxo-2,3-dihydro-1H-benzofuro[3,2-d]pyrimidin-4(1H)-
one (4c): Yield 91%. White solid, mp 273–2758C; IR (cm21): 3412, 3143,
3062, 2958, 2894, 1679, 1622, 1544, 1214; UV (n, cm–1, 1 1023
,
21
cm21): 43880 (28.3), 34380 (27.9); 1H NMR (400 MHz,
.
L mol
.
DMSO-d6), d, ppm: d 7.82 (d, J ¼ 7.9 Hz, 1H), 7.70 (t, J ¼ 5.3 Hz, 1H),
7.42 (t, J ¼ 5.3 Hz, 1H), 8.24 (d, J ¼ 7.9 Hz, 1H), 13.90 (br s, 1 H, NH),
7.20–7.46 (m, 5H). Anal. calcd. for C16H10N2O2S (294.3): H, 3.42; C,
65.29; N, 9.52; S, 10.89. Found: H, 3.41; C, 65.29; N, 9.50; S, 10.87.
3-(4-Fluorophenyl)-2-thioxo-2,3-dihydro-1H-benzofuro[3,2-d]pyrimidin-
4(1H)-one (4d): Yield 78%. White solid, mp 2838C; IR (cm21): 3400, 3104,
3032, 2997, 2890, 1715, 1622, 1544, 1216; UV (n, cm–1, 1 1023
,
21
cm21): 43980 (11.8), 34440 (12.3); 1H NMR (400 MHz,
.
L mol
.
DMSO-d6), d, ppm: d 7.82 (d, J ¼ 7.7 Hz, 1H), 7.69 (t, J ¼ 6.2 Hz, 1H),
7.50 (t, J ¼ 6.2 Hz, 1H), 8.23 (d, J ¼ 6.2 Hz, 1H), 14.00 (br s, 1H, NH),
7.24–7.36 (m, 5H). LC/MS (m/z, rel.%): 625 (29) [2M þ ], 313 (94)
[M þ ], 279 (59), 202 (100), 149 (15), 130 (47). Anal. calcd. for
C16H9FN2O2S (312.3): H, 2.90; C, 61.53; N, 8.97; S, 10.27. Found: H,
2.92; C, 61.54; N, 8.99; S, 10.25.
3-(4-Methoxyphenyl)-2-thioxo-2,3-dihydro-1H-benzofuro[3,2-d]pyrimidin-
4(1H)-one (4e): Yield 82%. White solid, mp 280–2818C; IR (cm21): 3405,
3096, 2892, 2837, 1711, 1622, 1548, 1510, 1215; UV (n, cm–1, 1 1023
,
21
cm21): 43420 (17.8), 34440 (13.9); 1H NMR (400 MHz,
.
L mol
.
DMSO-d6), d, ppm: d 7.80 (d, J ¼ 8.8 Hz, 1H), 7.68 (t, J ¼ 5.9 Hz, 1H),
7.49 (t, J ¼ 5.9 Hz, 1H), 8.23 (d, J ¼ 5.9 Hz, 1H), 13.80 (br s, 1H, NH),
7.01 (d, J ¼ 11.8 Hz, 2H), 7.16 (d, J ¼ 11.8 Hz, 2H), 3.55 (s, 3H, NCH3).
Anal. calcd. for C17H12N2O3S (324.4): H, 3.73; C, 62.95; N, 8.64; S, 9.89.
Found: H, 3.72; C, 62.95; N, 8.62; S, 9.88.
3-Butyl-2-thioxo-2,3-dihydro-1H-benzofuro[3,2-d]pyrimidin-4(1H)-one
(4f): Yield 86%. White solid, mp 269–2718C; IR (cm21): 3225, 3079, 2958,
21
2932, 2868, 1676, 1621, 1549, 1286; UV (n, cm21, 1 1023, L mol
cm21):
.
.
1
44380 (15.3), 40740 (11.5), 34820 (18.7); H NMR (400 MHz, DMSO-d6),
d, ppm: d 7.79 (d, J ¼ 7.5 Hz, 1H), 7.62 (t, J ¼ 7.5 Hz, 1H), 7.46
(t, J ¼ 6.25 Hz, 1H), 8.16 (d, J ¼ 7.5 Hz, 1H), 13.8 (br s, 1H, NH), 4.30
(t, 2H, N-CH2), 1.30 (m, 2H, CH2), 1.70 (m, 2H, CH2), 0.98 (t, 3H, SH3).
LC/MS (m/z, rel.%): 549 (21) [2M þ ], 275 (83) [M þ ], 219 (58), 202
(100), 149 (21), 121 (52). Anal. calcd. for C14H14N2O2S (274.3): H, 5.14;
C, 61.29; N, 10.21; S, 11.69. Found: H, 5.14; C, 61.31; N, 10.22; S, 11.71.
3-Benzyl-2-thioxo-2,3-dihydro-1H-benzofuro[3,2-d]pyrimidin-4(1H)-one
(4g): Yield 78%. White solid, mp 287–2888C; IR (cm21): 3228, 3076, 3031,
21
2901, 1678, 1550, 1287; UV (n, cm –1, 1 1023, L mol
cm21): 44140
.
.
(11.1), 34420 (12.1); 1H NMR (400 MHz, DMSO-d6), d, ppm: d 7.79

2566
O. V. Il’chenko et al.
(d, J ¼ 8.6 Hz, 1H), 7.69 (t, J ¼ 5.7 Hz, 1H), 7.67 (t, J ¼ 5.7 Hz, 1H), 8.20
(d, J ¼ 5.7 Hz, 1H), 14.00 (br s, 1H, NH), 7.14–7.36 (m, 5H), 5.60 (s, 2H,
NCH2). LC/MS (m/z, rel.%): 617 (14) [2M þ ], 331 (18), 309 (100)
[M þ ], 149 (18), 122 (55). Anal. calcd. for C17H12N2O2S (308.4): H, 3.92;
C, 66.22; N, 9.08; S, 10.40. Found: H, 3.93; C, 66.22; N, 9.12; S, 10.39.
3-(2-Methoxyethyl)-2-thioxo-2,3-dihydro-1H-benzofuro[3,2-d]pyrimidin-
4(1H)-one (4h): Yield 75%. White solid, mp 273–2758C; IR (cm21): 3215,
3087, 2891, 2831, 1680, 1549, 1477, 1286, 1215; UV (n, cm21, 1 1023
,
21
cm21): 44040 (14.5), 34480 (18.7); 1H NMR (400 MHz,
.
L mol
.
DMSO-d6), d, ppm: d 7.72 (d, J ¼ 7.6 Hz, 1H), 7.69 (t, J ¼ 5.1 Hz, 1H),
7.62 (t, J ¼ 5.1 Hz, 1H), 8.12 (d, J ¼ 7.6 Hz, 1H), 13.80 (br s, 1H, NH),
4.55 (dd, 2H, N-CH2), 3.65 (dd, 2H, CH2), 3.30 (s, 3H, OSH3). LC/MS
(m/z, rel.%): 277 (31) [M þ ], 245 (94), 202 (100), 150 (9), 130 (63), 121
(13). Anal. calcd. for C13H12N2O3S (276.3): H, 4.38; C, 56.51; N, 10.14; S,
11.60. Found: H, 4.39; C, 56.52; N, 10.12; S, 11.62.
3-(4-Fluorobenzyl)-2-thioxo-2,3-dihydro-1H-benzofuro[3,2-d]pyrimidin-
4(1H)-one (4i): Yield 70%. White solid, mp 2858C; IR (cm21): 3220, 3079,
3006, 2907, 1663, 1622, 1547, 1284, 1217; UV (n, cm–1, 1 1023
,
21
cm21): 43980 (24.6), 34360 (26.7); 1H NMR (400 MHz,
.
L mol
.
DMSO-d6), d, ppm: d 7.78 (d, J ¼ 6.1 Hz,1H), 7.66 (t, J ¼ 6.1 Hz, 1H),
7.46 (t, J ¼ 6.1 Hz, 1H), 8.19 (d, J ¼ 9.1 Hz, 1H), 14.01 (br s, 1H, NH),
7.00–7.43 (m, 4H), 5.60 (s, 2H, CH2). LC/MS (m/z, rel.%): 327 (49)
[M þ ], 149 (24), 122 (49), 109 (100). Anal. calcd. for C17H11FN2O2S
(326.3): H, 3.40; C, 62.57; N, 8.58; S, 9.82. Found: H, 3.39; C, 62.57; N,
8.60; S, 9.83.
3-(4-Methoxybenzyl)-2-thioxo-2,3-dihydro-1H-benzofuro[3,2-d]pyrimidin-
4(1H)-one (4j): Yield 78%. White solid, mp 2768C; IR (cm21): 3212, 3086,
3012, 2960, 2907, 1676, 1550, 1511, 1287, 1214; UV (n, cm21, 1 1023
,
21
cm21): 44340 (10.1), 40260 (5.2), 34460 (9.6); 1H NMR
.
L mol
.
(400 MHz, DMSO-d6), d, ppm: 7.77 (d, J ¼ 6.7 Hz,1H), 7.65 (t, J ¼ 6.7 Hz,
1H), 7.45 (t, J ¼ 6.7 Hz, 1H), 8.17 (d, J ¼ 6.7 Hz, 1H), 13.90 (br s, 1H,
NH), 6.50–7.35 (2d, 4H), 5.60 (s, 2H, CH2), 3.70 (s, 3H, OCH3). LC/MS
(m/z, rel.%): 340 (20) [M þ ], 149 (15), 121 (100), 115 (8). Anal. calcd. for
C18H14N2O3S (338.4): H, 4.17; C, 63.89; N, 8.28; S, 9.48. Found: H, 4.17;
C, 63.90; N, 8.26; S, 9.49.
3-(4-Methylbenzyl)-2-thioxo-2,3-dihydro-1H-benzofuro[3,2-d]pyrimidin-
4(1H)-one (4k): Yield 83%. White solid, mp 2828C; IR (cm21): 3232, 3076,
2900, 2837, 1676, 1664, 1550, 1518, 1284; UV (n, cm–1, 1 1023
,
21
cm21): 44440 (13.7), 34420 (12.7); 1H NMR (400 MHz,
.
L mol
.
DMSO-d6), d, ppm: d 7.79 (d, J ¼ 6.6 Hz, 1H), 7.66 (t, J ¼ 9.8 Hz, 1H),
7.47 (t, J ¼ 9.8 Hz, 1H), 8.18 (d, J ¼ 6.6 Hz, 1H), 14.01 (br s, 1H, NH),

2-Thioxo-2,3-dihydro-1H-benzofuro[3,2-d]pyrimidin-4(1H)-ones
2567
7.08 (d, J ¼ 6.6 Hz, 2H), 7.23 (d, J ¼ 6.6 Hz, 2H), 5.60 (s, 2H, CH2), 2.10
(s, 3H, OCH3). LC/MS (m/z, rel.%): 645 (23) [2M þ ], 323 (100) [M þ ],
219 (41), 149 (23), 105 (100). Anal. calcd. for C18H14N2O2S (322.4): H,
4.38; C, 67.06; N, 8.69; S, 9.95. Found: H, 4.39; C, 67.06; N, 8.70; S, 9.93.
2-[4-Oxo-2-thioxo-1,4-dihydro-1H-benzofuro[3,2-d]pyrimidin-3(2H)-yl]
acetic Acid (4l): Yield 82%. Light brown solid, mp .3008C; IR (cm21):
3223, 3084, 2942, 2784, 1687, 1626, 1550, 1479, 1269; UV (n, cm 21, 1
21
1023, L mol
cm21): 44580 (39.5), 33780 (45.4), 34660 (52.7); 1H
.
.
NMR (400 MHz, DMSO-d6), d, ppm: d 7.78 (d, J ¼ 8.93 Hz, 1H), 7.67
(t, J ¼ 7.14 Hz, 1H), 7.48 (t, J ¼ 7.14 Hz, 1H), 8.17 (d, J ¼ 8.93 Hz, 1H),
14.02 (s, 1H, NH), 4.58 (m, 2H, NCH2), 13.01 (br s, 1H, OH). LC/MS
(m/z, rel.%): 553 (16) [2M þ ], 294 (6), 277 (53) [M þ ], 259 (31), 202
(100), 149 (19), 130 (81), 121 (31). Anal. calcd. for C12H8N2O4S: H, 2.92;
C, 52.17; N, 10.14; S, 11.61. Found: H, 2.91; C, 52.17; N, 10.16; S, 11.62.
3-[4-Oxo-2-thioxo-1,4-dihydro-1H-benzofuro[3,2-d]pyrimidin-3(2H)-yl]
propanoic acid (4m): Yield 85%. White solid, mp 2758C; IR (cm21): 3202,
2904, 1682, 1625, 1550, 1477, 1279, 1214; UV (n, cm–1, 1 1023
,
21
cm21): 43880 (32.5), 34560 (39.3), 33740 (35.2); 1H NMR
.
L mol
.
(400 MHz, DMSO-d6), d, ppm: d 7.78 (d, J ¼ 8.93 Hz, 1H), 7.66
(t, J ¼ 7.14 Hz, 1H), 7.46 (t, J ¼ 7.14 Hz, 1H), 8.16 (d, J ¼ 8.93 Hz, 1H),
13.90 (br s, 1H, NH), 4.60 (m, 2H, NCH2), 2.70 (m, 2H, NCH2CH2), 12.45
(s, 1H, OH). LC/MS (m/z, rel.%): 291 (40) [M þ ], 273 (43), 219 (77),
202 (100), 149 (13), 130 (33). Anal. calcd. for C13H10N2O4S (290.30):
H, 3.47; C, 53.79; N, 9.65; S, 11.05. Found: H, 3.49; C, 53.76; N, 9.66;
S, 11.03.
REFERENCES
1. Tan, P.-Z.; Baldwin, R. M.; Fu, T.; Charney, D. S.; Innis, R. B. Rapid synthesis of
F-18 and H-2 dual-labeled altanserin, a metabolically resistant PET ligand for
5-HT2A receptors. J. Labelled Compounds Radiopharm. 1999, 42 (5), 457–467.
2. Seiji, S.; Seiichi, U.; Shunichi, H.; Michinori, T.; Takashi, O. Jpn. Patent
62198670, 1986; Chem. Abstr. 1988, 108, 94581.
3. Michinori, T.; Takashi, O.; Seiji, S.; Seiichi, U.; Shunichi, H. Jpn. Patent
62258369, 1986; Chem. Abstr. 1988, 109, 149556.
4. Sohda, T.; Makino, H.; Baba, A. Eur. Patent EP 0567107, 2001; Chem. Abstr.
1994, 120, 217712.
5. Eto, H.; Koda, T.; Ogawa, Y.; Katori, T. Jpn. Patent 60075488, 1983; Chem. Abstr.
1985, 103, 142003.
6. Carson, M.; LeMahieu, R. A.; Tilley, J. W. Eur. Patent EP 142057, 1984; Chem.
Abstr. 1985, 103, 160530.
7. Chen, C.; Webb, T. R.; McCarthy, J. R.; Moran, T. J. U.S. Patent 6,255,310, 2001;
Chem. Abstr. 1997, 127, 234327e.

2568
O. V. Il’chenko et al.
8. Emling, F.; Starck, D.; Bach, A.; Teschendorf, H.-J.; Steiner, G.; Wicke, K.;
Dullweber, U.; Garcia-Ladona, X. German Patent 19,734,444, 1999; Chem.
Abstr. 1999, 130, 168389k.
9. Chakravarty, P. K.; Greenlee, W. J.; Kim, D.; Mantlo, N. B.; Patchett, A. A. U.S.
Patent 5,223,501, 1993; Chem. Abstr. 1993, 118, 213104d.
10. Ivachtchenko, A. V.; Kovalenko, S. M.; Drushlyak, O. G. Synthesis of substituted
4-oxo-2-thioxo-1,2,3,4-tetrahydroquinazolines and 4-oxo-3,4-dihydroquinazoline-
2-thioles. J. Comb. Chem. 2003, 5, 775–788.
11. Ivachtchenko, A. V.; Kovalenko, S. M.; Tkachenko, O. V.; Parkhomenko, O. O.
Synthesis of substituted thienopyrimidine-4-ones. J. Comb. Chem. 2004, 6,
573–583.
12. Oganesjan, E. T.; Kadieva, M. G.; Smirnova, L. P. The state and perspectives for
biologically active compounds search among benzofuran derivatives. J. Pharm.
Chem. 2001, 3, 47–55.
13. Reddy, B. S.; Reddy, A. P.; Veeranagaiah, V. One-pot synthesis of 3-aryl-2,3-
dihydro-2-thioxobenzofuro[3,2-d]pyrimidin-4(1H)-ones. Indian J. Chem., Sect.
B 1988, 27B (12), 1131–1133.
14. Vandenberk, J.; Kennis, L.; der Heertum, A. V. U.S. Patent 4,522,945, 1985;
Chem. Abstr. 1982, 97, 216203.
15. Trofimov, F. A.; Leljak, G. F.; Shevchenko, L. I.; Grinev, A. N. Condensation of
the salicylic acid nitrile with some a-halogencarbonyl compounds. J. Heterocycl.
Comp. 1974, 9, 1171–1173.