Copper-catalyzed coupling reaction of 2-thioxo-4-quinazolinone and thieno[3,2-d]pyrimidin-4-one methane sulphonamide with aryl iodides: Preparation of potential COX-2 selective inhibitors

Article abstract of DOI:10.1080/00397910701820236

Thio-aryl methane sulfonamide derivatives of 4-quinazolinone and thieno[2,3-d]pyrimidin-4-one were synthesized using powdery copper/copper(I) iodide as catalyst; their structural elucidation is also reported. These derivatives were planned as sulfur bioisosteres of selective COX-2 inhibitor drugs. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910701820236

This article was downloaded by: [Selcuk Universitesi]
On: 19 December 2014, At: 20:28
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered office:
Mortimer House, 37-41 Mortimer Street, London W1T 3JH, UK
Synthetic Communications: An International
Journal for Rapid Communication of
Synthetic Organic Chemistry
Publication details, including instructions for authors and subscription
information:
http://www.tandfonline.com/loi/lsyc20
Copper‐Catalyzed Coupling Reaction
of 2‐Thioxo‐4‐quinazolinone and
Thieno[3,2‐d]pyrimidin‐4‐one Methane
Sulphonamide with Aryl Iodides: Preparation
of Potential COX‐2 Selective Inhibitors
Antonio Perdicaro a , Giuseppe Granata a , Agostino Marrazzo a & Andrea
Santagati a
a Department of Pharmaceutical Science , University of Catania , Catania,
Italy
Published online: 15 Feb 2008.
To cite this article: Antonio Perdicaro , Giuseppe Granata , Agostino Marrazzo & Andrea Santagati (2008)
Copper‐Catalyzed Coupling Reaction of 2‐Thioxo‐4‐quinazolinone and Thieno[3,2‐d]pyrimidin‐4‐one
Methane Sulphonamide with Aryl Iodides: Preparation of Potential COX‐2 Selective Inhibitors, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry, 38:5,
723-737, DOI: 10.1080/00397910701820236
To link to this article: http://dx.doi.org/10.1080/00397910701820236
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”)
contained in the publications on our platform. However, Taylor & Francis, our agents, and our
licensors make no representations or warranties whatsoever as to the accuracy, completeness, or
suitability for any purpose of the Content. Any opinions and views expressed in this publication
are the opinions and views of the authors, and are not the views of or endorsed by Taylor &
Francis. The accuracy of the Content should not be relied upon and should be independently
verified with primary sources of information. Taylor and Francis shall not be liable for any
losses, actions, claims, proceedings, demands, costs, expenses, damages, and other liabilities
whatsoever or howsoever caused arising directly or indirectly in connection with, in relation to or
arising out of the use of the Content.
This article may be used for research, teaching, and private study purposes. Any substantial
or systematic reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or
distribution in any form to anyone is expressly forbidden. Terms & Conditions of access and use
can be found at http://www.tandfonline.com/page/terms-and-conditions

Synthetic Communicationsw, 38: 723–737, 2008
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701820236
Copper-Catalyzed Coupling Reaction of
2-Thioxo-4-quinazolinone and Thieno[3,2-d]
pyrimidin-4-one Methane Sulphonamide
with Aryl Iodides: Preparation of Potential
COX-2 Selective Inhibitors
Antonio Perdicaro, Giuseppe Granata, Agostino Marrazzo,
and Andrea Santagati
Department of Pharmaceutical Science, University of Catania, Catania,
Italy
Abstract: Thio-aryl methane sulfonamide derivatives of 4-quinazolinone and
thieno[2,3-d]pyrimidin-4-one were synthesized using powdery copper/copper(I)
iodide as catalyst; their structural elucidation is also reported. These derivatives
were planned as sulfur bioisosteres of selective COX-2 inhibitor drugs.
Keywords: copper catalyst, COX-2 selective inhibitors, sulphonamides, thio-aryl
derivatives
INTRODUCTION
In the search for new anti-inflammatory drugs acting as specific COX-2 inhibi-
tors (coxibs) through modifications of well-known selective agents, two new
series of potential selective COX-2 inhibitors have been designed by bioisos-
terically replacing the C55C bond[1,2] in the coxibs stilbene scaffold with a
sulfur atom or molecular hybridization using the 4-quinazolinone or thieno-
pyrimidin-4-one heterocyclic systems[3–5] (Fig. 1).
Received in Poland August 15, 2007
Address correspondence to Andrea Santagati, Department of Pharmaceutical
Science, University of Catania, Viale A. Doria, 6 95125 Catania, Italy. E-mail:
asantaga@unict.it
723

724
A. Perdicaro et al.
Figure 1. Rational drug design—coxibs stilbene scaffold.
Among the derivatives synthesized were difluorobenzene and thio-
cycloesyl derivatives with structural features of leads L-745,337 and NS398
respectively (Fig. 1).
The thio-aryl derivatives could be realized with satisfactory yields
through the use of powdery copper/copper(I) iodide as catalyst in the
reaction of aryl iodides with the thiolic form of the heterocyclic systems.
This catalyzed reaction was conducted at reflux in common solvents,
water and ethanol, and following previous reactions from our laboratories[6]
on other heterocyclic systems, it is the simplest method to form aryl
sulphur bonds in heterocycles containing the 2-thioxo-4-pyrimidinone
system.

Potential COX-2 Selective Inhibitors
RESULTS
725
Starting compounds were 3-isothiocyanate-thiophene 2a and 2-isothiocyanate
methyl anthranilate 2b, prepared in acetone at room temperature without the
production of pollutants from the reaction of the corresponding amino esters
and thiophosgene (Scheme 1).
The reaction at room temperature of isothiocyanate 2a and 2b with
hydrazine or mesylhydrazine and the subsequent treatment of the resulting
thiosemicarbazide 3a or methylsulfonyl hydrazino 4a or 4b, according to
the methods reported by Wamhoff,[7] with refluxing hydroxide ethanolic or
aqueous solution afforded the amino-thioxo sodium salt 5 and aqueous or
ethanolic solution of sodium or potassium salt of sulphonamide derivative
7a and 7b; acidification with hydrochloric acid gave the amino-thioxo deriva-
tive 6 and the thioxo-methanesulfonamides 7a and 7b, respectively
(Scheme 1).
The pyrimidine structure, instead of a seven-membered ring, of the
amino-thioxo derivatives 5 and 6 was confirmed by independent preparations
of 2-ethoxyphenyl derivative of 5H-[1,3,4]thiadiazolo[3,2-a]thieno[3,2-d]
Scheme 1.

726
A. Perdicaro et al.
Scheme 2.
pyrimidin-5-one 6a, a new heterocyclic system. The thioaryl derivatives 8a,
8b, 9a, 9b, 10a, and 10b were obtained in satisfactory yield by coupling the
thioxo derivatives 7a or 7b and suitable aryl iodides in refluxing slightly
basic water/ethanol solution in the presence of powdery copper/copper(I)
iodide (Scheme 1).
To complete the pharmacological profile of the series, thio-cycloexyl
derivatives 11a and 11b were prepared in dimethylformamide at 808C, in
the presence of potassium carbonate, from the reaction of sulfolnylamide
derivatives 7a and 7b, respectively, with cycloexyl iodide (Scheme 2).
The proposed structures were confirmed by elemental analysis, IR, and 1H
1
and 13C NMR spectra. H NMR spectra at 6.45 ppm for compound 5 and
6.36 ppm for compound 6 gave the signal attributable to amino group NH2
and showed the signal attributable to NH of methylsulfonamide group in
the region of 11.0–11.6 ppm; the NMR spectra of thio-aryl derivatives
1
showed the chemical shifts of multiplet aromatic signals. In the H NMR
spectrum, cycloesyl derivatives 11a and 11b showed the multiplet of ten
methylenes in the region of 1.3–2.0 ppm and the multiplet of proton
bonded to carbon adjacent to sulfur at position at 3.5–3.8 ppm.
Scheme 3.

Potential COX-2 Selective Inhibitors
727
The reaction of methyl derivative 12a or 12b with methanesulfonyl
chloride gave the disulfonate 13a and 13b (Scheme 3) that with subsequent
alkaline hydrolysis gave the monomesyl derivatives 14a and 14b, identical
to those obtained from methylation of methanesulfonamide derivatives 7a
and 7b, respectively. The two independent preparations of 14a and 14b
confirmed the proposed sulphonamide structure 7a and 7b and also that
sulfur was more reactive than nitrogen adjacent to the sulphonic group.
EXPERIMENTAL
Chemistry
1H and 13C NMR spectra were recorded at 200 MHz on a Varian Gemini 200
spectrometer; chemical shifts (d) are reported in parts per million (ppm) from
tetramethylsilane as internal standard. Coupling constants (J ) are in hertz
(Hz). IR spectra were recorded on a Perkin-Elmer 1600 series FT-IR in
potassium bromide disks. Microanalyses for C, H, N, and S were obtained
from an EA 1108 elemental analyzer Fisons Carlo-Erba instrument.
Analyses indicated by the symbols of the elements or functions were within
+0.4% of the theoretical values. Melting points are uncorrected and were
determined in open capillary tubes on an SMP1 apparatus (Stuart Scientific,
Staffordshire). The melting points of all crude compounds were within 38C
of the pure product: therefore, as synthetic intermediates, they could be
used without further purification. The purity of compounds was checked by
thin-layer chromatography (TLC) on Merck silica-gel 60 F-254 plates. All
commercial chemicals were purchased from Aldrich, Fluka, Merk,
Lancaster, and Carlo Erba and were used without further purification.
Methyl 3-Isothiocyanatothiophene-2-carboxylate (2a)
A
solution of methyl 3-amino-2-thiophenecarboxylate (1.7 g, 99%,
10.8 mmol) in acetone (20 ml) was added slowly dropwise at room tempera-
ture to a stirred solution of thiophosgene (0.8 ml, 97%, d ¼ 1.508,
10.15 mmol) in acetone (10 ml). After 20 min of stirring at room temperature,
water was added (200 ml); the solid separated was collected, washed first with
5% sodium hydroxide and then with water, dried, and crystallized from
petroleum ether to give isothiocyanate 2a as yellow microcrystals. Yield
80%; mp 54–568C. The isothiocyanate preparation with a different method
was reported by Gutschow and Powers[8] and referenced herein. IR (KBr):
1
2145 and 2095 (NCS), 1710 (C55O) cm21; H NMR (DMSO-d6): d 3.82
(s, 3H, OCH3), 7.96 (d, J ¼ 5.2 Hz, 1H, H-thiophene), 7.24 (d, J ¼ 5.2 Hz,
1H, H-thiophene).

728
A. Perdicaro et al.
Methyl 3-[(Hydrazinocarbonothioyl)amino]thiophene-2-
carboxylate (3a)
Isothiocyanate 2a (1.20 g, 6.0 mmol) in chloroform (15 ml) was added
dropwise to a stirred solution of hydrazine hydrate (0.35 ml, 7.0 mmol) in
dichloromethane (15 ml) at room temperature. After the addition was
complete, the mixture was stirred at room temperature for 2 h. The resulting
solid was collected, washed with dichloromethane, dried, and crystallized
from ethanol to give 3a as a white powder. Yield 90%; mp 225–2288C dec.
IR (KBr): 3340, 3260 and 3165 (NH2 or NH), 1680 (C55O) cm21; 1H NMR
(DMSO-d6): d 3.81 (s, 3H, CH3), 4.94 (s, 2H, NH2), 7.81 (d, J ¼ 5.4 Hz,
1H, H-thiophene), 8.93 d, J ¼ 5.4 Hz, 1H, H-thiophene), 9.61 (s, 1H, NH),
11.80 (s br, 1H, NH).
Methyl 3(f[2(Methylsulfonyl)hydrazino]carbonothioylgamino)-
thiophene-2-carboxylate (4a)
Isothiocyanate 2a (1.8 g, 9.0 mmol) in dichloromethane (20 ml) was added
dropwise to a stirred solution of methanesulfonyl hydrazide (0.90 g, 98%,
8.0 mmol) in dichloromethane (25 ml) at room temperature. After the
addition was complete, the mixture was stirred at room temperature for 2 h.
The resulting solid was collected, washed with dichloromethane, dried, and
recrystallized from ethanol to give 4a as colorless microcrystals. Yield
55%; mp 202–2048C dec. IR (KBr): 3300 and 3230 (NH2 or NH), 1675
(C55O), 1315 and 1150 (SO2-N) cm21 1H NMR (DMSO-d6): d 3.10
;
(s, 1H, CH3), 3.85 (s, 1H, CH3), 7.90 (d, J ¼ 5.6 Hz, 1H, H-thiophene),
8.84 (d, J ¼ 5.6 Hz, 1H, H-thiophene), 9.96, 10.62, and 11.41 (s, 1H, NH).
3-Amino-2-thioxo-2,3-dihydrothieno[3,2-d]pyrimidin-4(1H)-one (6)
from Its Sodium Salt (5)
A mixture of hydrazino-thioxo 3a (1.0 g, 4.3 mmol) in a solution of sodium
hydroxide (0.180 g, 4.5 mmol) in ethanol (60 ml) was refluxed under
stirring for 1 h; the resulting solid was collected while hot, washed with
warm dioxane, and dried to give 5 as white powder. Yield 80%; mp
285–2888C dec. IR (KBr): 3409 and 3260 (NH2), 1641 (C55O) cm21
;
1H NMR (DMSO-d6): d 6.45 (s, 2H, NH2), 6.90 (d, J ¼ 5.4 Hz, 1H,
H-thiophene), 7.73 (d, J ¼ 5.4 Hz, 1H, H-thiophene).
Concentrated hydrochloric acid was added dropwise to a mixture of
sodium salt 5 (0.4 g, 1.8 mmol) in water (40 ml) under stirring until pH
3–4; the mixture was stirred for 1 h. The resulting solid was collected,
washed with water, and recrystallized from dimethylformamide/water to
give 6 as a white powder. Yield 90%; mp 234–2378C dec. IR (KBr): 3285

Potential COX-2 Selective Inhibitors
729
1
and 3165 (NH2 or NH), 1650 (C55O); H NMR (DMSO-d6): d 6.36 (s, 2H,
NH2), 7.03 (d, J ¼ 5.3 Hz, 1H, H-thiophene), 8.15 (d, J ¼ 5.3 Hz, 1H,
H-thiophene), 13.62 (s br, 1H, NH).
2-(2-Ethoxyphenyl)-5H-[1,3,4]thiadiazolo[3,2-a]thieno[3,2-d]
pyrimidin-5-one (6a)
From Amino Ester 1
A
mixture of 2-chloro-5-(2-ethoxyphenyl)-1,3,4-thiadiazole[9] (0.19 g,
0.8 mmol) and amino ester 1 (0.125 g, 99%, 0.8 mmol) was heated in an oil
bath at 2208C until the evolution of hydrochloric acid was complete. After
cooling, the reaction mixture was treated with warm ethanol and filtered.
The resulting solid was treated with NaHCO3 5%, collected, washed with
water, dried, and crystallized from dimethylformamide/water to give 7 as a
white powder. Yield 40%; mp 264–2668C. IR (KBr): 1695 (C55O) cm21
;
1H NMR (DMSO-d6): d 1.52 (t, J ¼ 6.8 Hz, 3H, CH3), 3.34 (s, 3H, CH3),
4.33 (q, J ¼ 6.8 Hz; 2H, CH2), 7.29–8.30 (m, 6H, Ar-H, and 2 ꢀ H-
thiophene).
From Amino-thioxo Derivative 6
A mixture of amino-thioxo derivative 6 (0.27 g, 1.38 mmol), phosphorus
pentoxide (0.3 g), methasulfonic acid (0.6 ml), and 2-ethoxybenzoic acid
(2.0 g, 98%, 11.8 mmol) was heated at 1308C for 2 h. After cooling to room
temperature, the reaction mixture was treated with ice water, and 5%
sodium hydroxide was added until pH 9–10. The resulting solid was
collected, washed with water, dried, and crystallized from dimethylforma-
mide/water to give 7 as a white powder. Yield 50%. The spectral and analyti-
cal data of the two samples were identical, and the mixture melting point was
not depressed.
N-(4-Oxo-2-thioxo-1,4-dihydrothieno[3,2-d]pyrimidin-3(2H)-yl)
methanesulfonamide (7a)
A solution of mesyltiosemicarbazide 4a (0.7 g, 2.3 mmol) and sodium
hydroxide (0.180 g, 4.6 mmol) in water (40 ml) was refluxed under stirring
for 2 h. After cooling to room temperature, the solution was filtered and
acidified with concentrated hydrochloric acid until pH 3–4. The resulting
solid was collected, washed with water, dried, and crystallized from dimethyl-
formamide/water to give 7a as white microcrystals. Yield 75%; mp 276–
2788C dec. IR (KBr): 3250 and 3170 (NH), 1665 (C55O), 1335 and 1155

730
A. Perdicaro et al.
(SO2-N) cm21
;
1H NMR (DMSO-d6): d 3.26 (s, 3H, CH3), 7.04
(d, J ¼ 5.2 Hz; 1H, H-thiophene), 8.24 (d, J ¼ 5.2 Hz, 1H, H-thiophene),
10.46 (s, 1H, NH), 13.66 (s, 1H, NH). 13C NMR (DMSO-d6): d 44.49,
114.15, 117.49, 138.97, 145.13, 155.38, 176.32.
2-(f3-[(Methylsulfonyl)amino]-4-oxo-3,4-dihydrothieno[3,2-d]
pyrimidin-2-ylgthio)benzoic Acid (8a)
Methane sulfonamide 7a (0.185 g, 0.67 mmol) was dissolved in water
(30 ml) and KOH (75 mg, 1.34 mmol). 2-Jodobenzoic acid (0.17 g, 98%,
0.67 mmol), dissolved in a small amount of 5% sodium hydroxide, and
powdery copper (30 mg)/copper(I) iodide (20 mg) were added to the
stirred solution. The mixture was heated at reflux under stirring for 7 h
and then filtered while hot; the resulting solution was cooled to room temp-
erature and acidified with concentrated hydrochloride acid until pH 4–5.
The white solid separated was collected, washed with water, dried and
crystallized from water/dioxane to give 8a as a white powder. Yield
40%; mp 219–2228C. IR (KBr): 3310 (NH), 1690 (C55O), 1340 and
1150 (SO2-N) cm21 1H NMR (DMSO-d6): d 3.36 (s, 3H, CH3), 7.07
;
(d, J ¼ 4.6 Hz, 1H, H-thiophene), 7.35–7.88 (m, 4H, Ar-H), 8.16
(d, J ¼ 4.6 Hz, 1H, H-thiophene), 11.49 (s br, 1H, NH), 13.22 (s br,
1H, COOH). 13C NMR (DMSO-d6): d 43.93, 118.55, 124.78, 128.19,
129.93, 130.46, 131.82, 136.08, 136.94, 137.38, 155.35, 155.95, 162.34,
176.53.
N-[2-[(2,4-Dinitrophenyl)thio]-4-oxothieno[3,2-d]pyrimidin-3(4H)-yl]
methanesulfonamide (9a)
Methane sulfonamide 7a (0.25 g, 0.9 mmol) was dissolved in ethanol/water
(20 ml/20 ml) and KOH (0.1 g, 1.8 mmol). 2,4-Dinitroiodobenzene (0.27 g,
98%, 0.9 mmol) and powdery copper (30 mg)/copper(I) iodide (20 mg)
were added to the stirred solution. The mixture was heated at reflux under
stirring for 7 h and filtered while hot; after cooling to room temperature, the
solution was poured in water (150 ml). The solution was filtered and
acidified with concentrated hydrochloric acid until pH 3–4: a yellow solid
mass separated that was collected, washed with water, dried, and crystallized
from ethanol /water to give 9a as a yellow powder. Yield 40%; mp .1128C
1
dec. IR (KBr): 3225 (NH), 1695 (C55O), 1345 and 1155 (SO2-N) cm21; H
NMR (DMSO-d6): d 3.36 (s, 3H, CH3), 7.11 (d, J ¼ 5.2 Hz, 1H,
H-thiophene), 8.18–8.88 (m, 3H, Ar-H), 8.23 (d, J ¼ 5.2 Hz, 1H,
H-thiophene), 11.66 (s br, 1H, NH). 13C NMR (DMSO-d6): d 43.77,
120.48, 124.61, 126.63, 127.20, 131.55, 132.18, 133.00, 144.92, 146.61,
154.22, 164.71, 170.01.

Potential COX-2 Selective Inhibitors
731
N-[2-[(2,4-Difluorophenyl)thio]-4-oxothieno[3,2-d]pyrimidin-(4H)-yl]
methanesulfonamide (10a)
Methane sulfonamide 7a (0.25 g, 0.9 mmol) was dissolved in ethanol/water
(20 ml/20 ml) and KOH (0.1 g, 1.8 mmol). 2,4-Difluoroiodobenzene
(0.22 g, 98%, 0.12 ml, 0.9 mmol, d ¼ 2.006) and powdery copper (30 mg)/
copper(I) iodide (20 mg) were added to the stirred solution. The mixture
was heated at 808C under stirring for 7 h; after cooling to room temperature,
the mixture was filtered. The solution was poured in water (150 ml); the
resulting solution was filtered and acidified with concentrated hydrochloric
acid until pH 3–4. The mixture was held at room temperature for 4 h, and
the separated white solid was collected, washed with water, dried, and crystal-
lized from ethanol/water to give 10a as a white powder. Yield 50%; mp 210–
1228C. IR (KBr): 3215 (NH), 1700 (C55O), 1350 and 1160 (SO2-N) cm21
;
1H NMR (DMSO-d6): d 3.37 (s, 3H, CH3), 7.11 (d, J ¼ 5.2 Hz, 1H,
H-thiophene), 7.18–7.79 (m, 3H, Ar-H), 8.20 (d, J ¼ 5.2 Hz, 1H,
H-thiophene), 11.52 (s, 1H, NH). 13C NMR (DMSO-d6): d 44.09, 105.21
(t, J ¼ 26.15), 114.40 (d, J ¼ 14.6), 112.65 (d, 18.25), 118.76, 124.81,
137.68, 138.95 (d, J ¼ 9.75), 155.33, 155.90, 160.71, 161.84, 166.83.
N-[2-(Cyclohexylthio)-4-oxothieno[3,2-d]pyrimidin-3(4H)yl]-
methanesulfonamide (11a)
A mixture of methane sulfonamide 7a (0.180 g, 0.65 mmol), cyclohexyl
iodide (0.2 ml, 98%, d 1.625), and potassium carbonate (0.18 g) in dimethyl-
formamide (2 ml) was heated at 808C under stirring for 12 h; after cooling to
room temperature, the mixture was acidified with hydrochloric acid and then
poured in water (100 ml). The resulting solid was collected, washed with
water, dried, and crystallized from petroleum ether to give 11a as a white
power. Yield 45%; mp 92–958C dec. IR (KBr): 3195 (NH), 1695 (C55O),
1
1350 and 1155 (SO2-N) cm21; H NMR (DMSO-d6): d 1.34–2.02 (m, 10H,
cycloexyl), 3.28 (s, 3H, CH3), 3.66 (s, 1H, S-CH3), 7.33 (d, J ¼ 5.2 Hz, 1H,
H-thiophene), 8.24 (d, J ¼ 5.2 Hz, 1H, H-thiophene), 11.15 (s br, 1H, NH).
3-Amino-2-(methylthio)thieno[3,2-d]pyrimidin-4(3H)-one (12a)
A mixture of sodium salt 5 (0.2 g, 0.85 mmol) and methyl iodide (0.16 ml,
99%, d ¼ 2.27) in water (30 ml) was stirred at room temperature for 1.5 h.
The resulting solid was collected, washed with water, dried, and crystallized
from ethanol to give 12a as pale microneedles. Yield 60%; mp 223–2258C.
1
IR (KBr): 3310 and 3250 (NH2), 1680 (C55O) cm21; H NMR (DMSO-d6):
d 2.40 (s, 3H, CH3), 5.81 (s, 2H, NH2), 7.30 (d, J ¼ 5.2 Hz, 1H,
H-thiophene), 8.13 (d, J ¼ 5.2 Hz, 1H, H-thiophene).

732
A. Perdicaro et al.
N-(Methylsulfonyl)-N-[2-(methylthio)-4-oxothieno[3,2-
d]pyrimidin-3(4H)-yl]methanesulfonamide) (13a)
A solution of methanesulfonyl chloride (0.22 ml, 2.85 mmol, 99.5%,
d ¼ 1.480) in dichloromethane (10 ml) was added slowly dropwise at room
temperature to a stirred solution of methyl derivative 12a (0.170 g,
0.8 mmol) and triethylamine (1 ml) in dichloromethane (20 ml). The
mixture was stirred at room temperature for 3 h; the organic phase was
washed with water, dried on sodium sulphate, and concentrated under
vacuum to give a solid that was collected and washed with diethyl ether to
give derivative 13a as a yellow solid (resulted pure on TLC). Yield 66%;
1
mp 195–1978C. IR (KBr): 1705 (C55O), 1380 and 1165 (SO2-N) cm21; H
NMR (DMSO-d6): d 2.59 (s, 3H, CH3), 3.77 (s, 6H, 2 ꢀ CH3-SO2), 7.42 (d,
J ¼ 5.3 Hz, 1H, H-thiophene), 8.37 (d, J ¼ 5.3 Hz, 1H, H-thiophene).
N-[2-(Methylthio)-4-oxothieno[3,2-d]pyrimidin-3(4H)-yl]
methanesulfonamide (14a)
From Hydrolysis of Dimesyl Derivative 13a
A mixture of dimesyl derivative 13a (81 mg, 0.22 mmol) in a solution of
potassium hydroxide (1 M) in water (10 ml) and tetrahydrofuran (90 ml)
was stirred for 1 h at room temperature; the resulting solution was acidified
with concentrated hydrochloric acid until pH 4–5 and then extracted with
ethyl acetate. The organic phase was concentrated under vacuum to give a
residue that was collected and dissolved in sodium hydroxide 10%. The
resulting solution was filtered and acidified with concentrated hydrochloric
acid until pH 4–5. The solid separated was collected, washed with water,
and dried to give the monomesyl derivative 14a as a white powder (resulted
pure at TLC). Yield 35%; mp 197–2008C. IR (KBr): 3110 (NH), 1650
(C55O), 1355 and 1165 (SO2-N) cm21 1H NMR (DMSO-d6): d 2.46
;
(s, 3H, CH3), 3.31 (s, 3H, CH3), 7.36 (d, J ¼ 5.3 Hz, 1H, H-thiophene),
8.26 (d, J ¼ 5.3 Hz, 1H, H-thiophene), 11.23 (s, 1H, NH).
From Monomesyl Derivative 7a
Methyl iodide (0.15 g, 99%, d ¼ 2.27) was added to a solution of tioxo-
monomesyl derivative 7a (0.17 g, 0.6 mmol) in water (20 ml) and KOH
(46 mg, 0.82 mmol), and the mixture was stirred at room temperature for
1.5 h. The mixture was filtered, and the filtrate was acidified with concentrated
hydrochloride acid until pH 4–5. The solid separated was collected, washed
with water, and dried to give 14a as a white powder (resulted pure at TLC).

Potential COX-2 Selective Inhibitors
733
Yield 55%; the spectral and analytical data of the two samples were identical,
and the mixture melting point was not depressed.
Methyl 2-(f[2-(Methylsulfonyl)hydrazino]carbonothioylgamino)
benzoate (4b)
Methyl 2-isothiocyanatobenzoato (2b)[10] (2.0 g, 10.4 mmol) in dichloro-
methane (20 ml) was added dropwise at room temperature to a stirred
solution of methanesulfonyl hydrazide (1.0 g, 98%, 8.9 mmol) in dichloro-
methane (25 ml). After the addition was complete, the mixture was stirred at
room temperature for 4 h. The resulting solid was collected, washed with
dichloromethane, dried, and recrystallized from ethanol to give 4b as an
amorphous white solid. Yield 50%; mp 188–1908C. IR (KBr): 3240 and
3155 (NH), 1695 (C55O), 1355 and 1155 (SO2-N) cm21 1 H NMR (DMSO-
;
d6): d 3.09 (s, 3H, CH3), 3.86 (s, 3H, OCH3), 7.21–7.95 (m, 3H, Ar-H), 8.80
(d, 1H, Ar-H), 9.86 (s, 1H, NH), 10.39 (s, 1H, NH), 11.36 (s, 1H, NH).
N-(4-Oxo-2-thioxo-1,4-dihydroquinazolin-3(2H)-yl)methane
Sulfonamide (7b) from Its Dipotassium Salt of N-(4-Oxo-2-thioxo-
1,4-dihydroquinazolin-3(2H)-yl)methanesulfonamide (4b)
A solution of mesyltiosemicarbazide 4b (1.0 g, 3.3 mmol) and potassium
hydroxide (0.45 g, 8.0 mmol) in ethanol (20 ml) was refluxed under stirring for
3 h; after cooling to room temperature, the resulting precipitate was collected,
washed with warm ethanol, and dried to give the potassium salt of 7b as a
white amorphous solid. Yield 90%; mp 280–2838C. The compound was hygro-
scopic and was immediately kept in a dessicator. IR (KBr): 1680 (C55O) cm21
1H NMR (DMSO-d6): d 2.92 (s, 3H, CH3), 6.85–7.75 (m, 4H, ArH).
;
Concentrated hydrochloric acid was added to a stirred solution of
potassium salt of 7b (0.3 g, 0.86 mmol) in water (30 ml) until pH 3–4. The
resulted precipitate was collected, washed with water, dried, and crystallized
from dioxane/water to give 7b as white powder. Yield 79%, mp 263–2648C
1
dec. IR (KBr): 3225 (NH), 1665 (C55O), 1335 and 1150 (SO2-N) cm21; H
NMR (DMSO-d6): d 3.27 (s, 3H, CH3), 7.33–8.01 (m, 4H, ArH), 10.42
(s, 1H, NH), 13.20 (s, 1H, NH). 13C NMR (DMSO-d6): d 45.11, 115.28,
115.98, 124.89, 127.78, 136.31, 138.90, 158.66, 175.98.
2-(f3-[(Methylsulfonyl)amino]-4-oxo-3,4-dihydroquinazolin-2-
ylgthio)benzoic Acid (8b)
Methane sulphonamide 7b (0.16 g, 0.57 mmol) was dissolved in water
(30 ml), and KOH (64 mg, 1.14 mmol), 2-jodobenzoic acid (0.14 g, 98%,

734
A. Perdicaro et al.
0.57 mmol) (dissolved in a small amount of 5% of sodium hydroxide), and
powdery copper (30 mg)/copper(I) iodide (20 mg) were added. The mixture
was heated at reflux under stirring, and after 7 h, it was filtered while hot.
The resulting solution was cooled to room temperature and acidified with con-
centrated hydrochloride acid until pH 4–5. The white solid separated was
collected, washed with water, dried, and crystallized from dioxane/water to
give 8b as a white powder. Yield 79%; mp 212–2158C. IR (KBr): 3310
(NH), 1705 (C55O) cm21 1H NMR (DMSO-d6): d 3.28 (s, 3H, CH3),
;
7.21–8.05 (m, 8H, Ar-H), 11.37 (s, 1H, NH), 13.01 (s, 1H, COOH). 13C
NMR (DMSO-d6): d 47.78, 119.36, 126.36, 126.46, 126.73, 129.81, 130.39,
131.66, 135.51, 136.85, 138.40, 146.13, 159.60, 160.04, 168.71.
N-2-[(2,4-Dinitrophenyl)thio]-4-oxoquinazolin-3(4H)-yl]
Methanesulfonamide (9b)
Methanesulphonamide 7b (0.27 g, 0.98 mmol) was dissolved in ethanol/
water (20 ml/20 ml) and KOH (0.110 g, 1.96 mmol). 2,4-Dinitroiodobenzene
(0.27 g, 98%, 0.9 mmol) and powdery copper (30 mg)/copper(I) iodide
(20 mg) were added to the stirred solution; the mixture was heated at reflux
under stirring for 7 h and filtered while hot. After cooling to room temperature,
the solution was poured in water (150 ml); the resulting solution was filtered
and acidified with concentrated hydrochloric acid until pH 3–4. The yellow
solid separated was collected, washed with water, dried, and crystallized
from ethanol/water to give 9b as a yellow powdery. Yield 40%, mp 149–
1518C dec. IR (KBr): 3220 (br, NH), 1705 (C55O), 1345 and 1155 (SO2-N)
1
cm21; H NMR (DMSO-d6): d 3.16 (s, 3H, CH3), 7.13–7.61 (m, 3H, Ar-
H), 8.05–8.80 (m, 4H, Ar-H), 11.60 (s, 1H, NH). 13C NMR (DMSO-d6): d
45.10, 119.95, 120.67, 125.10, 125.59, 126.13, 126.57, 133.28, 135.08,
138.41, 145.88, 147.36, 151.86, 160.44, 161.01.
N-[2-[(2,4-Difluorophenyl)thio]-4-oxoquinazolin-3(4H)-yl]
Methanesulfonamide (10b)
Methane sulphonamide 7b (0.16 g, 0.57 mmol) was dissolved in ethanol/
water (20 ml/20 ml) and KOH (64 mg, 1.15 mmol). 2,4-Difluoroiodobenzene
(0.15 g, 98%, 0.075 ml, 0.6 mmol, d ¼ 2.006) and copper powder (30 mg)/
copper(I) iodide (20 mg) were added to the stirred solution. The mixture
was heated at 808C under stirring for 7 h; after cooling to room temperature,
the mixture was filtered, and the solution was poured in water (150 ml). The
resulting solution was filtered and acidified with concentrated hydrochloric
acid until pH 3–4. The white solid separated was collected, washed with
water, dried, and crystallized from ethanol/water to give 10b as a white
powder. Yield 40%; mp 229–2308C. IR (KBr): 3275 (NH), 1695 (C55O),

Potential COX-2 Selective Inhibitors
735
1
1335 and 1150 (SO2-N) cm21; H NMR (DMSO-d6): d 3.37 (s, 3H, CH3),
7.2–8.10 (m, 7H, Ar-H), 11.46 (s, 1H, NH). 13C NMR (DMSO-d6):
d 43.87, 105.06 (t, J ¼ 26.75), 112.50 (d, J ¼ 22.45), 119.29, 126.44,
126.74, 126.84, 135.66, 139 (d, J ¼ 10.30), 146.10, 158.09, 159.56, 160.50,
165.50.
N-[2-(Cyclohexylthio)-4-oxoquinazolin-3(4H)yl]
methanesulfonamide (11b)
A mixture of 7b (0.18 g, 0.67 mmol), cyclohexyl iodide (0.2 ml, 98%,
d ¼ 1.625), and potassium carbonate (0.18 g) in dimethylformamide (2 ml)
was heated at 808C under stirring for 12 h. After cooling to room temperature,
the mixture was acidified with hydrochloric acid and then poured in water
(100 ml). The resulting solid was collected, washed with water, dried, and
crystallized from petroleum ether to give 11b as a white power. Yield 30%;
mp 176–1788C. IR (KBr): 3215 (NH), 1710 (C55O), 1325 and 1150
(SO2N) cm21 1H NMR (DMSO-d6): d 1.45–2.05 (m, 10H, cycloexyl),
;
3.29 (s, 3H, CH3), 3.72 (s, 1H, S-CH), 7.38–8.10 (m, 4H, Ar-H), 11.14
(s br, 1H, NH).
3-Amino-2-(methylthio)quinazolin-4(3H)-one (12b)
A mixture of potassium salt of 3-amino-2,3-dihydro-2-thioxo-4(1H)-quinazo-
linone[11] (1.0 g g, 4.3 mmol) and methyl iodide (0.85 ml, 99%, d ¼ 2.27) in
water (50 ml) was stirred at room temperature for 1.5 h. The resulting solid
was collected, washed with water, dried, and crystallized from ethanol/
water to give 12b as amorphous white solid. Yield 50%; mp 153–1548C.
1
IR (KBr): 3315 and 3210 (NH2), 1680 (C55O) cm21; H MNR (DMSO-d6):
d 2.43 (s, 3H, CH3), 5.77 (s, 2H, NH2), 7.37–8.08 (m, 4H, Ar-H).
N-(Methylsulfonyl)-N-[2-(methylthio)-4-oxoquinazolin3(4H)yl]
methanesulfonamide (13b)
A solution of methanesulfonyl chloride (0.22 ml, 2.85 mmol, 99.5%,
d ¼ 1.480) in dichloromethane (10 ml) was added slowly dropwise at room
temperature to a stirred solution of methyl derivative 12b (0.165 g,
0.8 mmol) and triethylamine (1 ml) in dichloromethane (20 ml). The
mixture was stirred at room temperature for 3 h; the organic phase was
washed with water, dried on sodium sulphate, and concentrated under
vacuum to give a solid, which was collected and washed with diethyl ether
to give derivative 13b as a pale yellow solid (resulted pure on TLC). Yield
73%; mp 167–1698C dec. IR (KBr): 1710 (C55O), 1380 and 1160 (SO2-N)

736
A. Perdicaro et al.
cm21; 1H NMR (DMSO-d6): d 2.59 (s, 3H, CH3), 3.77 (s, 6H, 2 ꢀ CH3-SO2),
7.47–8.05 (m, 4H, Ar-H).
N-[2-(Methylthio)-4-oxoquinazolin-3(4H)-yl]
methanesulfonamide (14b)
From Hydrolysis of Dimesyl Derivative 13b
A mixture of dimesyl derivative 13b (0.08 g, 0.22 mmol) in a solution of
potassium hydroxide (1 M) in water (10 ml) and tetrahydrofuran (90 ml)
was stirred for 1 h at room temperature; the resulting solution was acidified
with concentrated hydrochloric acid until pH 4–5 and then extracted with
ethyl acetate. The organic phase was concentrated under vacuum to give a
residue that was collected and dissolved in sodium hydroxide 10%. The
resulting solution was filtered and acidified with concentrated hydrochloric
acid until pH 4–5. The solid separated was collected, washed with water,
and dried to give the monomesyl derivative 14b as a white powder (resulted
pure at TLC). Yield 86%; mp 193–958C. IR (KBr): 3245 (NH), 1695
(C55O), 1345 and 1155 (SO2-N) cm21 1H NMR (DMSO-d6): d 2.46
;
(s, 3H, CH3), 3.31 (s, 3H, CH3), 7.45–8.11 (m, 4H, Ar-H), 11.16 (s, 1H, NH).
From Monomesyl Derivative 7b
Methyl iodide (0.4 ml, 99%, d ¼ 2.27) was added to a solution of 7b (0.16 g,
0.6 mmol) and potassium hydroxide (46 mg, 0.82 mmol) in water (20 ml). The
mixture was stirred at room temperature for 12 h. The mixture was filtered,
and the filtrate was acidified with concentrated hydrochloride acid until pH
4–5. The solid separated was collected, washed with water, and dried to
give 14b as a white powder (resulted pure at TLC). Yield 24%. The
spectral and analytical data of the two samples were identical, and the
mixture melting point was not depressed.
REFERENCES
1. DeWitt, D. L. Cox-2-selective inhibitors: the new super aspirins. Mol. Pharmacol.
1999, 55, 625–631.
2. Dannhart, G.; Werner, K. Cyclooxygenase inhibitors—Current status and future
prospects. Eur. J. Med. Chem. 2001, 36, 109–126.
3. Russo, F.; Santagati, M.; Santagati, A.; Amico-Roxas, M.; Bitetti, R.; Russo, A.
Ricerche chimiche e farmacologiche su derivati del 5H-1,3,4-tia(oxa)dia-
zolo[2,3-b]chinazolin-5-one. Il Farmaco Ed. Sc. 1981, 36, 292–301.
4. Russo, F.; Santagati, A.; Santagati, M.; Caruso, A.; Trombadore, S.; Amico-
Roxas, M. Synthesis and pharmacological properties of benzothienothiadiazolo-
pyrimidine derivatives. Il Farmaco Ed. Sc. 1987, 42, 437–447.

Potential COX-2 Selective Inhibitors
737
5. Santagati, A.; Granata, G.; Marrazzo, A.; Santagati, M. Synthesis and effects on
the COX-1 and COX-2 activity in human blood ex vivo of derivatives containing
the benzothieno[3,2-a]pyrimidin-4-one heterocyclic system. Arch. Pharm. Pharm.
Med. Chem. 2003, 336, 429–435.
6. Granata, G.; Barbagallo, S.; Perdicaro, A.; Marrazzo, A.; Santagati, A.;
Lombardo, L.; Cardile, V. Synthetic approaches to bridghead nitrogen methanesul-
phonamide derivatives of 3-amino-2-thioxo-2,3-dihydrothieno[2,3-d]pyrimidin-
4(1H)-ones, potential COX-2 selective inhibitors. J. Heterocycles Chem. 2006,
43, 1099–1104.
7. Wamhoff, W. Advances in Heterocycles Chemistry: Heterocycles, b-Enamino
Esters, Versatile Synthons in Heterocyclic Synthesis; Academic Press: Orlando,
FL, 1985.
8. Gutschow, M.; Powers, J. A new dimerization reaction producing 2-amino-9-oxo-
pyrrolo[2,1-b]quinazoline-1-carbonitriles and analogous pyrrolo[1,2-a]thieno[3,2-
d]pyrimidinecarbonitriles. J. Hetrocycl. Chem. 2001, 38, 419–424.
9. Russo, F.; Santagati, M.; Santagati, A. Sintesi e Reazioni di Alcuni 5H-1,3,4-tia-
diazolo[2,3-b]chinazolin-5-one-2,7-sostituiti. Il Farmaco Ed. Sc. 1979, 34,
688–697.
10. Grafe, I.; Kottke, K.; Kuhmstedt, H.; Knoke, D. Synthese von 3-Hetaryl-4-oxo-2-
thioxo-und 3-Hetaryl-2,4-dioxo-1,2,3,4-tetrahydrochinazolinen. Pharmazie 1990,
45, 530–531.
`
11. Santagati, A.; Modica, M.; Monsu Scolaro, L.; Santagati, M. New synthetic
approaches to fused heterocycloquinazolines. J. Chem. Res., Miniprint 1999,
460–470.