Some aspects on acyclo-4-[quinazolin-3-yl]benzenesulfonamide non-nucleosides synthesis

Article abstract of DOI:10.1080/10426500490459678

The reaction of 4-[1,2,3,4-tetrahydroquinazolin-2,4-dion-3-yl] benzenesulfonamide 4 and 4-[2-thioxo-1,2,3,4 tetrahydroquniazolin-4-on-3-yl] benznesulfonamide 5 with chloromethylethyl ether, chloromethylbenzyl ether, and (2-acetoxyethoxy)methyl bromide aff

Full text of DOI:10.1080/10426500490459678

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Phosphorus, Sulfur, and Silicon and the Related
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SOME ASPECTS ON ACYCLO- 4-[QUINAZOLIN-3-
YL]BENZENESULFONAMIDE NON-NUCLEOSIDES
SYNTHESIS
Abd El-Hamid a & A. A. Ismail a
a Menoufia University , Egypt
Published online: 16 Aug 2010.
To cite this article: Abd El-Hamid & A. A. Ismail (2004) SOME ASPECTS ON ACYCLO- 4-[QUINAZOLIN-3-
YL]BENZENESULFONAMIDE NON-NUCLEOSIDES SYNTHESIS, Phosphorus, Sulfur, and Silicon and the Related Elements, 179:6,
1055-1063, DOI: 10.1080/10426500490459678
To link to this article: http://dx.doi.org/10.1080/10426500490459678
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Phosphorus, Sulfur, and Silicon, 179:1055–1063, 2004
ꢀC
Copyright Taylor & Francis Inc.
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500490459678
SOME ASPECTS ON ACYCLO-
4-[QUINAZOLIN-3-YL]BENZENESULFONAMIDE
NON-NUCLEOSIDES SYNTHESIS
Abd El-Hamid and A. A. Ismail
Menoufia University, Egypt
(Received May 18, 2003; accepted October 5, 2003)
The reaction of 4-[1,2,3,4-tetrahydroquinazolin-2,4-dion-3-yl]benze-
nesulfonamide 4 and 4-[2-thioxo-1,2,3,4 tetrahydroquniazolin-4-on-3-
yl]benznesulfonamide 5 with chloromethylethyl ether, chloromethylben-
zyl ether, and (2-acetoxyethoxy)methyl bromide afforded compounds
7a–c, 8a,b, and 13 which are analogues to MKC-442, TNK 561, and
HEPT.
Keywords: Benzenesulfonamide; MKC-442; quinazolines; non-
nucleosides; TNK 561
A wide spectrum of biological activities associated with quinazolines
and their condensed derivatives, some derivatives show antiviral, CNS-
depressant, anticonvulsant, antimalaric, and anticancer activity.1–5
HIV is known as the causative agent for AIDS,6 enormous efforts have
been made to understand the life cycle of this retrovirus, in order to de-
fine biochemical targets for its selective inhibition by chemotherapeutic
agent. Reverse transcriptase (RT), the polymerase specifically coded by
HIV, was in this respect one of the first targets to be identified for the
development of anti-AIDS drugs. These drugs acting as inhibitors of the
reverse transcriptase enzyme, through interaction with reverse tran-
scriptase (RT) at an “allosteric” binding pocket7 which is proximal to
the catalytic site for DNA synthesis.8 Structure activity studies in the 1-
[(2-hydroxyethoxymethyl)-6-phenylthio]thymine or HEPT9,10 have re-
sulted in the identification of several new promising clinical candidates,
The authors would like to thank DANIDA establishment Denmark, which supports
the project “Development of New Drugs Against Hepatitis” at the Chemistry Department,
Faculty of Science, Menoufia University for the laboratory facilities and spectroscopic
measurements.
Address correspondence to A. A. Ismail, Department of Chemistry, Faculty of Science,
Menoufia University, Egypt. E-mail: Abdelhamede2002@yahoo.com
1055

1056
A. El-Hamid and A. A. Ismail
including MKC-442 and TNK 561.11,∗ As a part of our program of re-
search on the synthesis of new glycosides with considerable biological
activity.12−14
RESULTS AND DISCUSSION
The aim of the work mentioned in this article, synthesis of ana-
logues MKC-442, TNK 561, and HEPT Which bearing benzensul-
fonamide 7b,c, 8b,c, and 13. It is expected that the benzenesul-
fonamide will exhibit high biologically activity.15 The treatment of
dimethyl N-(4-oxo-2-thioxo-1,2,3,4-tetrahydro-3-quinazolinylsulfonyl)]
dithiocarbonoimidate 316 with 10% ClCH2COOH yielded 4-[1,2,3,4-
tetrahydroquina-zolin-2,4-dion-3-yl]benzenesulfonamide 4. While the
treatment of compound 3 with 4N HCl afforded 4-[2-thioxo-1,2,3,4-
tetrahydroquinazolin-4-on-3-yl]benzenesulfonamide 5. 4-(Quinazolin-
3-yl)benzenesulfonamide derivatives 4 or 5 were further reacted with
chloromethylethyl ether, chloromethylbenzyl ether or chloromethyl
methylsulphide in dry DMF and sodium hydride to produce compounds
7a,c and 8a,b which are analogues to MKC-442 and TNK 561. It
is expected that the benzenesulfonamide strong electron withdraw-
ing group will directed the electrophilic reaction in 4-[2-thioxo-1,2,3,4-
tetrahydroquinozolin-4-on-3-yl]benzenesulfonamide 5 towards the ni-
trogen and not the sulfur atoms to form N1- Nucleosides 8a,b. On
the other hand when the benzenesulfonamide was replaced by an aryl
group, the electrophilic reaction was directed towards the sulfur atom
to produce S2-nucleosides.17
∗MKC-442 demonstrating higher synthestic anti-HIV activity with AZT than neuirap-
ine will soon enter clinical studies.

Benzenesulfonamides
1057
SCHEME 1

1058
A. El-Hamid and A. A. Ismail
4-[Quinazolin-3-yl]benzenesulfonamide derivatives 4 or 5 were
reacted with isopropyl bromide, secondary butyl bromide, allyl
bromide, or benzyl bromide to form non-nucleoside compounds
11a–f. 4-[1,2,3,4-Tetrahydroquinazolin-2,4-dion-3-yl]benzenesufona-
mide 4 was reacted with (2-acetoxyethoxy)methyl bromide 10 to furnish
12. Deacetylation of 12 was done by methanolic ammonia to give 4-[2-
(2-hydroxyethoxy)methyl-1,2,3,4-tetrahydroquinazolin-2,4-dion-3-yl]
benzenesulfonamide 13 which is analogue to HEPT.
SCHEME 2
EXPERIMENTAL
NMR spectra were recorded on a Bruker 250 FT NMR spectrome-
ter, TMS as internal standard. MS were recorded on a varian MAT.
311A spectrometer. The silica gel (0.040–0.63 nm) was used for CC

Benzenesulfonamides
1059
purchased from Merck. Results of elemental analysis were in acceptable
range.
4-[1,2,3,4-Tetrahydroquinazolin-2,4-dion-3-yl]-
benenesulfonamide (4)
Compound 3 (450 mg, 1 mmol) in 10 ml of 10% ClCH2COOH was
stirred at room temperature for 24 h. The precipitate was formed, fil-
tered off, washed by 50 ml H2O. The crude product was purified by
crystallization from ethanol. Yield 82% as white solid; m.p. > 300◦C.
1H-NMR: 11.55 (s, 1H, NH); 8.01–7.75 (m, 10H, Ar H and NH2). 13C-
NMR: 166.53 (C-2); 154.37(C-4); 148.21, 144.27, 143.16, 139.79, 134.31,
131.99, 130.71, 127.05, 119.75, 118.69(C arom.). MS(EI). m/z 317(M+).
(Found C, 53.24; H, 3.33; N, 13.01 Calc. for C14H11N3O4S (MW = 317.07)
C, 53.00; H, 3.50; N, 13.50).
4-[2-Thioxo-1,2,3,4-tetrahydroquinazolin-4-on-3-yl]-
benzenesulfonamide (5)
Compounds 3 (450 mg, 1 mmol) in 20 ml of 4N HCl was refluxed for 2 h.
After cooling the white precipitate was formed, filtered off, washed by
50 ml H2O, and crystallization from ethanol. Yield 76% as white solid;
m.p. > 300◦C. 1H-NMR: 7.92–7.33 (m, 8 H, Ar H); 4.43(br, 2 H, NH2).
13C-NMR: 175.60(C S); 159.75(C-4); 143.66, 142.15, 139.58, 135.71,
129.85, 127.35, 126.48, 124.54, 116.11, 115.76(C arom.); MS(EI): m/z
333(M+). (Found: C, 50.31; H, 3.49; N, 12.70. Calc for C14H11N3O3S2
(MW = 333.63) C, 50.41; H, 3.33; N, 12.60).
General Procedure for Compounds 7, 8, 11, and 12
Quinazoline derivatives 4 or 5 (5 mmol) and NaH (6 mmol) in 10 ml
of dry DMF were stirred at room temperature for 1 h, then compounds
6, 9, or 10 (6 mmol) were added and the reaction mixture was stirred
8-24 h at room temperature (monitored by TLC analysis). The solvent
was evaporated under vacuum, the residue was dissolved in 20 ml ethyl
acetate and 30 ml H2O. The organic layer was extracted and dried over
anhydrous MgSO4. The product was purified by silica gel column chro-
matography (10% ethyl acetate/cyclohexane, v:v).
4-[1-Ethoxymethyl-1,2,3,4-tetrahydroquinazolin-
2,4-dion-3-yl]benzenesulfonamide (7a)
1
Yield 73% as a white solid; m.p. 189–190◦C. H-NMR: 8.06–7.55 (m,
8H, Ar H); 5.63 (s, 2H,H-1ꢁ); 3.67 (m, 2H, OCH2 CH3); 1.20 (t, 3H,

1060
A. El-Hamid and A. A. Ismail
OCH2 CH ). 13C-NMR: 161.25 (C-4); 150.67(C-2); 143.86, 139.08,
3
138.99, 135.48 129.69, 127.84, 126.31, 123.39, 115.46, 115.08 (C-
arom.); 73.00(C-1ꢁ) 63.59(O-CH2CH3);14.81(O CH2CH3). MS(EI): m/z
375(M+). (Found: C, 54.33; H, 4.50; N, 11.39 Calc. for C17H17N3O5S
(MW = 375.35) C, 54.39; H, 4.56; N, 11.21).
4-[1-Benzyloxymethyl-1,2,3,4-tetrahydroquinazolin-2,4-
dion-3-yl]benzenesulfonamide (7b)
1
Yield 63% as a white solid; m.p. 188–170◦C. H-NMR: 8.25–7.53 (m,
13H, Ar H); 4.46 (s, 2H, H-1ꢁ); 4.71 (s, 2H, O-CH Ph). MS(EI): m/z
2
437(M+). (Found: C, 60.13; H, 4.55; N, 9.37 Calc. for C22H19N3O5S
(MW = 437.41) C, 60.36; H, 4.37; N, 9.60).
4-[1-(Methylsulphide)methyl-1,2,3,4-tetrahydroquina-
zolin-2,4-dion-3-yl]benzenesulfonamide (7c)
Yield 78% as a white solid; m.p. 159-160◦C. 1H-NMR: 8.14–7.51(m, 8H,
Ar H); 4.04(s, 2H, H-1ꢁ); 2.60(s, 3H, S-CH ). 13C-NMR: 180–57(C-2);
3
155(C-4); 146.92 141.77, 139.80, 135.05, 130.57, 127.89, 126.49, 126.17,
126.08, 119.46 (C arom.); 67.87 (C-1ꢁ); 39.77( S CH3). (Found: C, 50.97;
H, 4.28; N, 11.01 Calc. for C16H15N3O4S2 (MW = 377.41) C, 51.06; H,
4.02; N, 11.16).
4-[1-Ethoxymethyl-2-thioxo-1,2,3,4-tetrahydroquina-
zolin-4-on-3-yl]benzenesulfonamide (8a)
Yield 69% a white solid; m.p. 189–170◦C.; 1H-NMR: 7.06–6.70 (m, 8H,
Ar H); 4.37 (s, 2H, 2H-1ꢁ); 3.61(m, 2H, OCH CH3); 1.56 (t, 3H,
2
OCH2CH ). 13C-NMR: 187.34 (C S); 162.22 (C-4); 180.78, 155.01,
3
148.89, 146.84, 141.63 140.02, 135.05, 130.54, 127.86, 128.23, 128.10
(C arom.); 72.45 (C-1ꢁ); 64.69 (OCH2CH3), 16.21 (O CH2–CH3). Found
C, 52.39 H, 4.01 N, 10.86 Calc. for C17H17N3O4S2(MW = 391.42) C,
52.17 H, 4.38 N, 10.73).
4-[1-Benzyloxymethyl-2-thioxo-1,2,3,4-tetrahydroquina-
zolin-4-on-3-yl]benzenesulfonamide (8b)
1
Yield 61%; m.p. 173–175◦C. H-NMR: 8.15–7.29 (m, 13H, Ar H); 5.53
(s, 2H, H-1ꢁ); 4.49(s, 2H, OCH Ph). 13C-NMR: 187.37(C S); 180.79 (C-
2
4); 154.81 148.88, 141.65, 139.99, 137.27, 135.07 128.18, 127.79, 127.83,
119.54 (C arom.); 72.127 (C-1ꢁ); 70.91 (O CH2Ph). (Found: C, 58.03; H,

Benzenesulfonamides
1061
4.52; N, 8.99 Calc. for C22H19N3O4S2 (MW = 453.50) C, 58.27 H, 4.22
N, 9.27).
4-[1-Isopropyl-1,2,3,4-tetrahydroquinzolin-2,4-dion-3-yl]-
benzenesulfonamide (11a)
1
Yield 82% as a white solid, m.p. 170–172◦C. H-NMR: 8.12–7.49 (m,
8H, ArH); 3.99 (m, 1H, CH(CH3)2) 1.35 (d, J = 6.78 Hz, 6H, CH (CH ) )
3 2
13C-NMR: 180.51 (C S); 155.87 (C-4); 147.21, 141.49, 139.87, 134.91,
130.49, 127.78, 128.39, 125.92, 125.87, 119.35 (Ar-C); 37.70 (CH(CH3)2),
22.20, 16.15 (CH(CH3)2); MS: m/z 359(M+) (Found: C, 56.62; H, 4.56; N,
11.55 Calc. for C17H17N3O4S (MW = 359.36) C, 56.31 H, 4.77 N, 11.63).
4-[1-(2-Butyl)-1,2,3,4-tetrahydroquinazolin-2,4-dion-3-
yl]benzenesulfonamide (11b)
Yield 85% as a white solid, m.p. 187–188◦C. 1H-NMR: 8.13–7.47(m, 8H,
Ar H) 3.93 (m, 1H, H-1ꢁ); 1.88 (m, 2H, CH -CH3); 1.26 (d, J = 6.95 Hz,
2
1H, CH ); 0.95 (m, 3H, CH2-CH ) 13C-NMR: 181.30 (C S), 158.65 (C-4);
2
3
147.83, 142.15, 140.62, 135.59, 131.09, 128.45, 127.08, 128.62, 126.54,
120.03, (C arom.); 44.58 (C-1ꢁ); 29.08 (CH2-CH3); 20.48 (CH3) 11.85
(CH2-CH3). (Found: C, 57.63 H, 5.42 N, 11.08 Calc. for C18H19N3O4S
(MW = 373.40) C, 57.90 H, 5.13 N, 11.25).
4-[1-Isopropyl-2-thioxo-1,2,3,4-tetrahydroquinazolin-4-
on-3-yl]benzenesulfonamide (11c)
Yield 78% as a white solid; m.p. 173–178◦C. 1H-NMR: 8.17–7.54 (m, 8H,
Ar H) 4.05 (m, 1H, H-1ꢁ); 1.38 (d, J = 6.79 Hz, 6H, CH(CH ) .13C-NMR:
3 2
187.28 (C S); 180.62 (C-4); 155.89, 147.23, 141.52, 139.89, 134.94,
130.51, 127.81, (m126.41, 125.96, 119.36 (C arom.); 37.73 (CH(CH3)2;
16.18 CH(CH3)2. (Found: C, 54.50 H, 4.22 N, 11.43 Calc for C17
H17N3O3S2 (MW = 375.47) C, 54.39 H, 4.56 N, 11.19).
4-[1-(2-Butyl)-2-thioxo-1,2,3,4-tetrahydroquinazolin-
4-on-3-yl]benzenesulfonamide (11d)
Yield 79% as a white solid; 163–165◦C. 1H-NMR: 8.15–7.51, 8H, ArH),
3.95 (m, 1H, H-1ꢁ); 1.72 (m, 2H, CH CH3); 1.35(d, J = 6.85 Hz, CH );
2
3
0.98(m, 3H, CH2-CH ). 13C-NMR: 187.23(C S); 180.62 (C-4);155.98
3
147.12, 141.48, 139.94, 134.89, 130.51, 130.51, 130.48, 127.78, 126.38,
119.35 (C arom.); 43.89 (C-1ꢁ); 28.39 (CH2CH3); 19.81 (CH3); 11.17

1062
A. El-Hamid and A. A. Ismail
(CH2CH ). (Found: C, 55.61 H, 5.20 N, 10.82 Calc. for C18H19N3O3S2
3
(MW = 389.45) C, 55.48; H, 4.92; N, 10.79).
4-[1-Allyl-2-thioxo-1,2,3,4-tetrahydroquinaolin-4-on-3-
yl]benzenesulfonamide (11e)
1
Yield 61% as a white solid, m.p. 168–170◦C. H-NMR: 8.13–7.50 (m,
8H, Ar H); 5.81 (m, H, CH CH2), 5.32 (dd, 2H, H-1ꢁ); 3.87 (d, J =
6.56 Hz, 2H, CH CH ). 13C-NMR: 187.97 (C S); 161.25 (C-4); 158.18,
2
147.71, 140.42, 135.63, 131.19, 128.49, 127.09, 128.68, 120.04, 119.52
(C arom.). (Found: C, 54.72 H, 3.97 N, 11.48. (Calc. for C17H15N3O3S2
(MW = 373.45) C, 54.68 H, 4.05 N, 11.25).
4-[1-Benzyl-2-thiox-1,2,3,4-tetrahydroquinazolin-
4-on-3-yl]benzenesulfonamide (11f)
1
Yield 83% as a white solid; m.p. 195–197◦C. H-NMR: 8.12–7.20 (m,
3 H, Ar H); 4.46 (s, 2H, CH Ph). 13C-NMR: 187.96 (C S); 161.22 (C-4);
2
156.40, 147.67, 142.28, 127.86, 127.77, 127.12, 126.87, 126.55, 120.07
(C arom.); 36.42 (CH2Ph). (Found: C, 59.33; H, 4.10; N, 10.14, calc. for
C21H17N3O3S2 (MW = 423.47) C, 59.56; H, 4.05, N, 9.92).
4-[2-(2-Acetoxyethoxy)methyl-1,2,3,4-tetrahydroquina-
zolin-2,4-dion-3-yl]benzenesulfonamide (12)
Yield 62% as a white solid; m.p. 160–162◦C. 1H-NMR: 8.42–7.63 (m, 8H,
Ar H); 5.49 (s, 2H, H-1ꢁ); 4.32 (m, 2H, O CH CH2) 4.13 (m, 2H, OCH2-
2
CH ), 2.18 (s, 3H, COCH ). 13C-NMR: 174.31 (COCH3), 170.40 (C-2),
2
3
163.01 (C-4), 161.06, 147.52, 146.30, 144.03, 134.62, 127.38, 127.20,
127.09, 126.70, 126.26 (C arom.). (Found: C, 52.47; H, 4.55; N, 9.80.
(Calc. for C19H19N3O7S (MW = 433.73) C, 52.61; H, 4.50,N 9.69).
4-[2-(2-Hydroxyethoxy)methyl-1,2,3,4-tetrahydroquina-
zolin-2,4-dion-3-yl]benzenesulfonamid (13)
Compound 12 (434.7 mg, 1 mmol) was dissolved in 10 ml methanol /NH3
and the reaction mixture was stirred at room temperature for 24 h un-
til TLC showed no starting material left. The solvent was evaporated
under vacuum and the residue was purified by silica gel column chro-
matography (50% ethyl acetate/cyclohexane, v:v) affords white solid
(370 mg, 86%); m.p. 150–152◦C. 1H-NMR: 8.12–7.43 (m, 8H, Ar H)
5.43 (s, 2H, H-1ꢁ), 3.71 (t, 2H, O CH CH2) 3.60 (t, 2H, OCH2CH ).
2
2
13C-NMR: 180.30 (C S); 147.49 (C-2); 145.10, 136.20, 134.82, 134.19,

Benzenesulfonamides
1063
132.82, 127.91, 127.01, 128.64, 126.30, 125.71 (C arom.); 75.11 (C-1ꢁ),
70.13 (O-CH2-CH2), 59.43 (O-CH2 − CH2). (Found: C, 52.00; H, 4.66; N,
10.91 Calc. for C17H17N3O6S (MW = 391.35) C, 52.17; H, 4.38; N, 10.86.
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