Synthesis of new quinazoline-2,4(1H,3H)-dione non-nucleoside analogues of the reverse transcriptase inhibitor TNK-651

Article abstract of DOI:10.3184/030823407X227101

The synthesis is described of a series of new non-nucleoside analogues of the reverse transcriptase inhibitor TNK-651 from quinazoline-2,4(1H,3H)-diones. Compounds 2a-c were silylated and treated with benzyl chloromethyl ether in the presence of CsI to give 1-benzyloxymethylquinazoline derivatives 3a-c. Treatment of the silylated quinazolinediones 2a-c with the appropriate acetals 5a-e in the presence of TMS triflate afforded the corresponding TNK-651 analogues 6-10.

Full text of DOI:10.3184/030823407X227101

358 RESEARCH PAPER
JUNE, 358–361
JOURNAL OF CHEMICAL RESEARCH 2007
Synthesis of new quinazoline-2,4(1H,3H)-dione non-nucleoside analogues
of the reverse transcriptase inhibitor TNK-651
Nasser R. El-Brollosy*
Department of Chemistry, Faculty of Science, Tanta University, Tanta 31527, Egypt
The synthesis is described of a series of new non-nucleoside analogues of the reverse transcriptase inhibitor TNK-
651 from quinazoline-2,4(1H,3H)-diones. Compounds 2a–c were silylated and treated with benzyl chloromethyl
ether in the presence of CsI to give 1-benzyloxymethylquinazoline derivatives 3a–c. Treatment of the silylated
quinazolinediones 2a–c with the appropriate acetals 5a–e in the presence of TMS triflate afforded the corresponding
TNK-651 analogues 6–10.
Keywords: reverse transcriptase inhibitors, anti-HIV drugs, quinazoline-2,4-diones, TNK-651 analogues
O
N
O
N
Effective treatment regimens for the human immunodeficency
virus (HIV-1) infection have included three main classes: those
that prevent the fusion of the viral envelope with the cellular
plasma membrane (fusion inhibitors), those that prevent
infection of target cells (reverse transcriptase inhibitors),
and those that prevent HIV-1-infected cells from yielding
infectious viruses (protease inhibitors).1
In recent years, much effort has been put into the design
and synthesis of HIV-1 non-nucleoside reverse transcriptase
inhibitors (NNRTIs). More than 30 structurally different
classes of compound have been identified as NNRTIs.2-4
The NNTRIs are highly specfic, as their binding site is a
hydrophobic pocket located approximately 10 Å from the
polymerase active site. They bind allosterically, forcng
the RT-subunit into an inactive conformation.5,6 One of
the first NNRTIs was 1-[(2-hydroxyethoxy)methyl]-6-
(phenylthio)thymine (HEPT).7,8 HEPT was considered a
lead compound for NNRTIs synthesis, even though it was
not very active itself. Among the many HEPT analogues
synthesised are 6-benzyl-1-(ethoxymethyl)-5-isopropyluracl
(Emivirine)9-11 and the corresponding 1-benzyloxymethyl
analogue (TNK-651)6 which showed high activity against
HIV-1.
Three NNRTIs have so far been formally licensed for
clinical use in the treatment of HIV infections, namely,
nevirapine (Viramune)12, delavirdine (Rescriptor)13 and
efavirenz (Sustiva, Stocrin)14. The quinazoline compound
DPC-083, a derivative of efavirenz, has marked activity
against HIV-1 strains with various mutations (L100I, K103N,
Y181C, Y188L, K103N + L100I and K103N + Y181C).15
Recently, I synthesised a series of quinazoline-2,4(1H,3H)-
dione non-nucleoside analogues of Emivirine,16 in an effort
to find new HIV inhibitors and as a part of my interest in
the chemistry of NNRTIs.17-23 The present study describes
the synthesis of novel quinazoline-2,4(1H,3H)-dione non-
nucleoside analogues of TNK-651.
i
Pr
HN
HN
O
S
O
HO
O
R
O
Emivirine, R = H
TNK-651, R = phenyl
HEPT
F C
3
F C
3
Cl
Cl
O
NH
N
H
O
N
H
O
Efavirenz
DPC-083
O
O
R
+
R
HO
H2N
HN
i. NaOH
ii. HCl
KOCN
O
N
H
1
2
BSA , CsI , CHCl
3
1-3
R
O
Cl
a
b
c
H
Cl
CH3
O
N
R
HN
O
O
Results and discussion
3
Quinazoline-2,4(1H,3H)-diones 2a–c were prepared by
treatment of the corresponding substituted anthranilic acd 1a–
c with potassium cyanate according to the method described
by Dunkel et al.24 Silylation of compounds 2a–c with N,O-
bis(trimethylsilyl)acetamide (BSA) in anhydrous chloroform
followed by alkylation with benzyl chloromethyl ether in the
presence of caesium iodide afforded the corresponding TNK-
651 analogues 3a–c in 74–78% yields (Scheme 1).
Scheme 1
(5c),18 bis-((E)-cnnamyloxy)methane (5d, R2 = H),18 bis-
((E)-2-methyl-3-phenylallyloxy)methane (5d, R2 = CH3)18
and bis(2-phenylethyloxy)methane (5e) were prepared
from the corresponding alcohols 1-indanol, 2-indanol, 3-
cyclohexene-1-methanol, (E)-cnnamyl alcohol, (E)-2-methyl-
3-phenyl-2-propen-1-ol and 2-phenylethanol, respectively, by
reaction with dibromomethane using potassium hydroxide in
anhydrous benzene in the presence of tetrabutylammonium
bromide according to the method of Nazaretyan et al.25
(Scheme 2)
Bis(indan-1-yloxy)methane (5a),22 bis(indan-2-yloxy)
methane (5b),22 bis-(3-cyclohexen-1-ylmethoxy)methane
* Correspondent. E-mail: brollosy@yahoo.com
Current address: Department of Pharmaceutical Chemistry, College
of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia.
PAPER: 07/4684

JOURNAL OF CHEMICAL RESEARCH 2007 359
Compounds 3b,c, 6a,b, 7a,b, 8a–c and 9a–d were tested
against wild-type HIV-1. No compounds exhibited significant
activity at 100 μM against HIV-1 in MT-4 cells.
CH2Br2
1
1
1
OH
R
O
O
R
n
R
n
n
KOH / Bu NBr
4
benzene
5
4
1
1
n
n
4,5
4,5
R
R
Experimental
NMR spectra were recorded on a Varian Gemini 2000 NMR
spectrometer at 300 MHz for 1H and 75 MHz for 13C with TMS as an
internal standard. Chemical shifts are reported in ppm (d), and signals
are expressed as s (singlet), d (doublet), t (triplet), q (quartet) or m
(multiplet). MALDI spectra were recorded on an IonSpec Fourier
Transform Ion Cyclotron Resonance Mass Spectrometer. Melting
points were determined on a Büchi melting point apparatus. Elemental
analyses were performed at the H.C. Ørsted Institute, University of
Copenhagen. The progress of reactions was monitored by TLC (DC-
alufolio 60 F254) from Merck. For column chromatography Merck
silica gel (0.040–0.063 mm) was used.
1
c
a
b
0
0
2
R
d
e
1
2
Scheme 2
Compounds 2a–c were silylated with BSA in anhydrous
acetonitrile and reacted with 5a and/or 5b using trimethylsilyl
trifluoromethanesulfonate(TMStriflate)asaLewisacdcatalyst26
togivethecorrespondingN(1)-indan-1-yloxymethylquinazolines
(6a,b) and indan-2-yloxymethylquinazolines (7a–c) in 73,
75 and 68–71% yields, respectively. 1-(Cyclohex-3-en-1-
ylmethyloxy)methyl-6-substituted-quinazoline-2,4(1H,3H)-
diones (8a–c) were obtained in 71–73% yields by silylation of
2a–c followed by treatment with the acetal 5c in the presence of
TMS triflate (Scheme 3).
1-Benzyloxymethylquinazoline-2,4(1H,3H)-diones (3a–c)
N,O-Bis(trimethylsilyl)acetamide (BSA) (0.87 ml, 0.035 mol)
was added to a suspension of quinazoline-2,4(1H,3H)-dione 2a–c
(1 mmol) in anhydrous CHCl3 (20 ml) and the mixture was stirred at
room temperature under nitrogen. After a clear solution was obtained
(20-30 min), benzyl chloromethyl ether (0.21 ml, 0.015 mol) and CsI
(0.26 g, 0.001 mol) were added. The reaction mixture was stirred at
room temperature under nitrogen for 3–4 h. Sat. aq. NaHCO3 (20 ml)
was added and the mixture was extracted with CH2Cl2 (3 × 50 ml).
The organic phase was collected, dried (MgSO4) and evaporated
under reduced pressure. The residue was chromatographed on silica
gel column using CHCl3 to give 3a–c.
Treatment of bis-((E)-cnnamyloxy)methane (5d, R2 = H) and/
or bis-((E)-2-methyl-3-phenylallyloxy)methane (5d, R2 = CH3)
with the silylated quinazolines 2a–c in anhydrous acetonitrile
in the presence of TMS triflate afforded 1-((E)-cnnamyloxy-
methyl)quinazoline-2,4(1H,3H)-dione(9a)and1-((E)-2-methyl-
3-phenylallyloxymethyl)quinazolines 9b–d in 79 and 78–81%
yields, respectively. Further, quinazoline-2,4(1H,3H)-dione
(2a) and its 6-methyl derivative 2c were silylated and reacted
with bis(2-phenylethyloxy)methane (5e) to furnish 1-(2-phenyl-
ethyloxymethyl)quinazoline-2,4(1H,3H)-dione (10a) and 6-
methyl-1-(2-phenylethyloxymethyl)quinazoline-2,4(1H,3H)-
dione (10b) in 71 and 73% yields, respectively (Scheme 3).
The fact that the N-alkylation furnished 1-alkylated products
was proved by the NOE enhancement of the aromatic proton
8-H when N-1 CH2 was irradiated.
1-(Benzyloxymethyl)quinazoline-2,4(1H,3H)-dione (3a): White
solid (215 mg, 76%); m.p. 169–171°C. 1H NMR (DMSO-d6, 300
MHz): δ 4.62 (s, 2H, CH2), 5.61 (s, 2H, CH2), 7.25–8.02 (m, 9H,
Harom), 11.63 (s, 1H, NH) ppm; 13C NMR (DMSO-d6, 75 MHz): δ 69.8
(CH2), 71.9 (CH2), 115.4, 115.8, 123.0, 127.2, 127.5, 128.1, 135.0,
137.6, 140.4 (Carom); 150.5 (C-2), 161.7 (C-4) ppm. MS (MALDI):
m/z 305 (M+ + Na, 37%). Anal. Calcd. for C16H14N2O3 (282.29): C
68.07, H 5.00, N 9.92. Found: C 68.00, H 4.93, N 9.80%.
1-(Benzyloxymethyl)-6-chloroquinazoline-2,4(1H,3H)-dione (3b):
1
White solid (247 mg, 78%), m.p. 200–202°C. H NMR (DMSO-d6,
300 MHz): δ 4.61 (s, 2H, CH2), 5.60 (s, 2H, CH2), 7.25–7.91 (m, 8H,
Harom), 11.78 (s, 1H, NH) ppm; 13C NMR (DMSO-d6, 75 MHz): δ
69.8 (CH2), 72.1 (CH2), 117.6, 117.8, 126.1, 127.3, 127.35, 127.5,
128.1, 134.6, 137.5, 139.3 (Carom), 150.3 (C-2), 160.7 (C-4) ppm. MS
(MALDI): m/z 339 (M+ + Na, 29%). Calcd for C16H13ClN2NaO3:
339.0506. Found: 339.0505.
1-(Benzyloxymethyl)-6-methylquinazoline-2,4(1H,3H)-dione (3c):
White solid (220 mg, 74%), m.p. 194–196°C. 1H NMR (DMSO-
d6, 300 MHz): δ 2.36 (s, 3H, CH3), 4.60 (s, 2H, CH2), 5.59 (s, 2H,
CH2), 7.26–7.79 (m, 8H, Harom), 11.56 (s, 1H, NH) ppm; 13C NMR
(DMSO-d6, 75 MHz): δ 19.9 (CH3), 69.7 (CH2), 71.9 (CH2), 115.55,
The mass spectra of all compounds containing chlorine
showed fragments corresponding to the typical pattern of
chlorine isotopes (35Cl and 37Cl).
O
O
O
R
R
R
HN
O
HN
i, ii (+5a)
i, ii (+5e)
HN
10
a
b
R
O
N
O
N
H
O
N
H
CH
2
O
3
6
10
i,
i, ii (+5d)
i, ii (+5b)
ii (+5c)
O
O
N
O
N
R
R
HN
R
HN
O
HN
O
O
N
O
2
O
R
R
9
O
2, 6-8
R
2
R
a
H
H
Cl
H
a
b
c
H
b
c
d
CH
CH
3
7
8
9
Cl
3
CH3
CH CH
3
3
Reagents: i, bis(trimethylsilyl)acetamide in MeCN,
ii, trimethylsilyl triflate and 5a-e
Scheme 3
PAPER: 07/4684

360 JOURNAL OF CHEMICAL RESEARCH 2007
115.3, 126.8, 127.5, 128.1, 132.4, 135.9, 137.6, 138.25 (Carom), 150.5
(C-2), 161.7 (C-4) ppm. MS (MALDI): m/z 319 (M+ + Na, 44%).
Calcd for C17H16N2NaO3: 319.1053. Found: 319.1049.
(DMSO-d6, 75 MHz): δ 19.9 (CH3), 39.0 (C-1', C-3'), 70.6 (C-2'),
77.6 (CH2), 115.4, 115.5, 124.4, 126.3, 126.8, 132.4, 136.0, 138.3,
140.5 (Carom), 150.5 (C-2), 161.7 (C-4) ppm. MS (MALDI): m/z (%)
345 (M+ + Na, 100). Anal. Calcd. for C19H18N2O3 (322.36): C 70.79,
H 5.63, N 8.69. Found: C 70.74, H 5.60, N 8.65%.
Bis-(2-phenylethyloxy)methane (5e).
2-Phenylethanol (12.2 g, 0.1 mol), dibromomethane (8.79 g,
0.0505 mol), and tetrabutylammonium bromide (1.74 g, 0.00535
mol) were added to potassium hydroxide (5.66 g, 0.101 mol) in
anhydrous benzene (30 ml), and the suspension was heated under
reflux for 5 hours. After cooling, H2O (50 ml) was added and the
resulting solution was extracted with ether (3 × 50 ml). The ether
phase was dried with anhydrous MgSO4 and evaporated. The residue
was chromatographed on silica gel column using CHCl3 to afford
5e as a colourless oil (8.1 g, 63%). 1H NMR (CDCl3, 500 MHz):
δ 2.91 (t, 4H, J = 7.0 Hz, 2 × CH2), 3.76 (t, 4H, J = 7.0 Hz,
2 × CH2), 4.73 (s, 2H, CH2), 7.26–7.37 (m, 10 H, Harom) ppm; 13C
NMR (CDCl3, 125 MHz): δ 36.3 (CH2), 68.5 (CH2), 95.2 (CH2),
126.2, 128.1, 128.9, 139.0 (Carom) ppm. MS (EI): m/z (%) 256 (M+,
3), 229 (5), 154 (3), 136 (11), 119 (16), 105 (100), 92 (49), 77 (13).
1-(3-Cyclohexen-1-ylmethoxymethyl)-quinazolines (8a–c): general
procedure
Quinazoline-2,4(1H,3H)-dione (2a–c, 1 mmol) was stirred in dry
acetonitrile (15 ml) under nitrogen and BSA (0.87 ml, 3.5 mmol)
was added. After a clear solution was obtained (10 min), the
mixture was cooled to –50°C and TMS triflate (0.18 ml, 1 mmol)
was added followed by the dropwise addition of bis-(3-cyclohexen-
1-ylmethoxy)methane (5c) (0.472 g, 2 mmol). The reaction mixture
was stirred at room temperature for 6 h, and the mixture was worked
up as for the preparation of compounds 6 and 7 to give the title
compounds.
1-(Cyclohex-3-en-1-ylmethoxymethyl)quinazoline-2,4(1H,3H)-
1
dione (8a): White solid (204 mg, 71%), m.p. 155–156°C. H NMR
(DMSO-d6, 300 MHz): δ 1.57–2.01 (m, 7H, 2 × CH2, CH), 3.41 (d,
J = 6.4 Hz, 2H, CH2), 5.53 (s, 2H, CH2), 5.53–5.63 (m, 2H, 2 × CH),
7.28–8.03 (m, 4H, Harom), 11.64 (s, 1H, NH) ppm; 13C NMR (DMSO-
d6, 75 MHz): δ = 23.8 (CH2), 24.8 (CH2), 27.7 (CH2), 33.1 (CH),
72.3 (CH2), 72.35 (CH2), 115.4, 115.7, 123.0, 126.7, 135.0, 140.4
(Carom), 125.7 (CH=), 127.2 (CH=), 150.5 (C-2), 161.7 (C-4) ppm.
MS (MALDI): m/z 309 (M+ + Na, 49%). Anal. Calcd. for C16H18N2O3
(286.33): C 67.12, H 6.34, N 9.78. Found: C 67.06, H 6.34, N 9.57%.
6-Chloro-1-(cyclohex-3-en-1-ylmethoxymethyl)quinazoline-
2,4(1H,3H)-dione (8b): White solid (235 mg, 73%), m.p. 162–164°C.
1H NMR (DMSO-d6, 300 MHz): δ 1.57–2.01 (m, 7H, 3 × CH2, CH),
3.40 (d, J = 6.4 Hz, 2H, CH2), 5.48 (s, 2H, CH2), 5.51–5.63 (m, 2H,
2 × CH), 7.48–7.92 (m, 3H, Harom), 11.79 (s, 1H, NH) ppm; 13C
NMR (DMSO-d6, 75 MHz): δ 23.6 (CH2), 24.8 (CH2), 27.7 (CH2),
33.1 (CH), 72.38 (CH2), 72.44 (CH2), 117.3, 117.7, 126.1, 126.6,
134.7, 139.3 (Carom), 125.7 (CH=), 127.3 (CH=), 150.25 (C-2),
160.7 (C-4) ppm. MS (MALDI): m/z 343 (M+ + Na, 37%). Calcd for
C16H17ClN2NaO3: 343.0820. Found: 343.0822.
1-(Cyclohex-3-en-1-ylmethoxymethyl)-6-methylquinazoline-
2,4(1H,3H)-dione (8c): White solid (212 mg, 71%), m.p. 173–175°C.
1H NMR (DMSO-d6, 300 MHz): δ 1.56–2.00 (m, 7H, 3 × CH2, CH),
2.36 (s, 3H, CH3), 3.39 (d, J = 6.4 Hz, 2H, CH2), 5.49 (s, 2H, CH2),
5.53–5.63 (m, 2H, 2 × CH), 7.35–7.80 (m, 3H, Harom), 11.56 (s, 1H,
NH) ppm; 13C NMR (DMSO-d6, 75 MHz): δ 19.9 (CH3), 23.8 (CH2),
24.8 (CH2), 27.7 (CH2), 33.1 (CH), 72.2 (CH2), 72.3 (CH2), 115.3,
115.5, 126.7, 132.4, 135.9, 138.3 (Carom), 125.7 (CH=), 126.8 (CH=),
150.5 (C-2), 161.7 (C-4) ppm. MS (MALDI) m/z 323 (M+ + Na,
54%). Calcd for C17H20N2NaO3: 323.1366. Found: 323.1367.
1-(Indanyloxymethyl)quinazolines (6a,b, 7a–c): general procedure
Quinazoline-2,4(1H,3H)-dione (2a–c, 1 mmol) was stirred in dry
acetonitrile (15 ml) under nitrogen and N,O-bis(trimethylsilyl)
acetamide (BSA) (0.87 ml, 3.5 mmol) was added.After a clear solution
was obtained (10 min), the mixture was cooled to –50°C and TMS
triflate (0.18 ml, 1 mmol) was added followed by the dropwise addition
of bis(indan-1-yloxy)methane (5a) or bis(indan-2-yloxy)methane
(5b) (0.56 g, 2 mmol). The reaction mixture was stirred at room
temperature for 5 h, and the reaction was quenched by addition of
sat. aq. NaHCO3 solution (5 ml). The mixture was evaporated under
reduced pressure and the residue was extracted with ether (3 × 50 ml).
The combined ether fractions were collected, dried (MgSO4) and
evaporated under reduced pressure. The products were purified by
silica gel column chromatography (20% ether in petroleum ether
(40–60°C)) to afford 6a,b and 7a–c.
1-(Indan-1-yloxymethyl)quinazoline-2,4(1H,3H)-dione (6a): White
solid (225 mg, 73%), m.p. 174–176°C. 1H NMR (DMSO-d6, 300
MHz): δ 1.90–1.95, 2.29–2.36 (2 × m, 2H, 2'-H), 2.76–2.80, 2.91–
2.97 (2 × m, 2H, 3'-H); 5.13 (dd, J = 4.4, 6.4 Hz, 1H, 1'-H), 5.63, 5.70
(2 × s, 2H, CH2), 7.09–8.04 (m, 8H, Harom), 11.70 (s, 1H, NH) ppm;
13C NMR (DMSO-d6, 75 MHz): δ 29.5 (CH2), 32.3 (CH2), 71.0 (CH),
80.6 (CH2), 115.5, 115.8, 123.1, 124.3, 126.2, 127.2, 127.8, 128.3,
135.1, 140.5, 142.2, 143.4 (Carom), 150.6 (C-2), 161.75 (C-4) ppm.
MS (MALDI): m/z (%) 331 (M+ + Na, 32). Calcd for C18H16N2NaO3:
331.1053. Found: 331.1049.
6-Chloro-1-(indan-1-yloxymethyl)quinazoline-2,4(1H,3H)-dione
(6b): White solid (256 mg, 75%), m.p. 171–172°C. 1H NMR (DMSO-
d6, 300 MHz): δ 1.89–1.93, 2.28–2.33 (2 × m, 2H, 2'-H), 2.74–2.79,
2.91–2.95 (2 × m, 3'-H), 5.12 (dd, J = 4.4, 6.4 Hz, 1H, 1'-H), 5.62, 5.68
(2 × s, 2H, CH2), 7.08–7.94 (m, 7H, Harom), 11.86 (s, 1H, NH) ppm;
13C NMR (DMSO-d6, 75 MHz): δ 29.5 (CH2), 32.2 (CH2), 71.1 (CH),
80.5 (CH2), 117.4, 117.9, 124.1, 124.6, 126.1, 126.2, 127.4, 128.3,
134.7, 139.4, 142.1, 143.4 (Carom), 150.3 (C-2), 160.7 (C-4) ppm. MS
(EI): m/z (%) 342 (M+, 11), 312 (6), 227 (25), 210 (34), 196 (31), 166
(67), 153 (38), 133 (97), 117 (100). Anal. Calcd. for C18H15ClN2O3
(342.78): C 63.07, H 4.41, N 8.17. Found: C 62.93, H 4.38, N 8.06.
1-(Indan-2-yloxymethyl)quinazoline-2,4(1H,3H)-dione (7a): White
solid (218 mg, 71%), m.p. 193–194°C. 1H NMR (DMSO-d6, 300
MHz): δ 2.85–2.92, 3.09-3.16 (2 × m, 4H, 1'-H, 3'-H), 4.54 (quint,
J = 3.7 Hz, 1H, 2'-H), 5.61 (s, 2H, CH2), 7.10–8.03 (m, 8H, Harom),
11.68 (s, 1H, NH) ppm; 13C NMR (DMSO-d6, 75 MHz): δ 38.95
(C-1', C-3'), 70.65 (C-2'), 77.7 (CH2), 115.4, 115.7, 123.1, 124.4,
126.3, 127.2, 135.1, 140.45, 140.5 (Carom), 150.55 (C-2), 161.7 (C-4)
ppm. MS (EI): m/z (%) 308 (M+, 9), 277 (4), 240 (7), 206 (3), 172 (6),
162 (4), 132 (19), 116 (100). Anal. Calcd. for C18H16N2O3 (308.33):
C 70.12, H 5.23, N 9.09. Found: C 70.10, H 5.19, N 8.99%.
1-(2-Alkenyloxymethyl)quinazolines (9a–d): general procedure
Quinazoline-2,4(1H,3H)-dione (2a–c, 1 mmol) was stirred in dry
acetonitrile (15 ml) under nitrogen and BSA (0.87 ml, 3.5 mmol) was
added. After a clear solution was obtained (10 min), the mixture was
cooledto–50°CandTMStriflate(0.18ml,1mmol)wasaddedfollowed
by the dropwise addition of bis((E)-cnnamyloxy)methane (5d,
R2 =H)(0.56g,2mmol)orbis((E)-2-methyl-3-phenylallyloxy)methane
(5d, R2 = CH3) (0.616 g, 2 mmol). The reaction mixture was stirred at
room temperature for 5 h, and the mixture was worked up as for the
preparation of compounds 6 and 7 to give compounds 9a and 9b–d,
respectively.
1-((E)-Cinnamyloxymethyl)quinazoline-2,4(1H,3H)-dione
(9a):
1
White solid (243 mg, 79%), m.p. 160–161°C. H NMR (DMSO-d6,
300 MHz): δ 4.25 (d, J = 5.8 Hz, 2H, CH2), 5.59 (s, 2H, CH2), 6.28
(td, J = 5.8, 16.1 Hz, 1H, CH), 6.59 (d, J = 16.1 Hz, 1H, CH), 7.23–
8.03 (m, 9H, Harom), 11.66 (s, 1H, NH) ppm; 13C NMR (DMSO-d6,
75 MHz): δ 68.55 (CH2), 71.7 (CH2), 123.1 (CH=), 115.4, 115.75,
125.6, 126.2, 127.2, 127.6, 128.5, 135.1, 136.2, 140.45 (Carom), 131.7
(CH=), 150.5 (C-2), 161.7 (C-4) ppm. MS (MALDI) m/z 331 (M+ +
Na, 41%). Anal. Calcd. for C18H16N2O3 (308.33): C 70.12, H 5.23,
N 9.09. Found: C 70.16, H 5.22, N 9.08%.
6-Chloro-1-(indan-2-yloxymethyl)quinazoline-2,4(1H,3H)-
1
dione (7b): White solid (231 mg, 68%), m.p. 214–216°C. H NMR
(DMSO-d6, 300 MHz): δ 2.84–2.91, 3.08–3.15 (2 × m, 4H, 1'-H, 3'-
H), 4.53 (quint, J = 3.7 Hz, 1H, 2'-H), 5.56 (s, 2H, CH2), 7.10–7.93
(m, 7H, Harom), 11.83 (s, 1H, NH) ppm; 13C NMR (DMSO-d6, 75
MHz): δ 38.9 (C-1', C-3'), 70.8 (C-2'), 77.7 CH2), 117.4 117.8 124.4,
126.1, 126.3, 127.4 134.7, 139.4 140.5 (Carom), 150.3 (C-2), 160.7
(C-4) ppm. MS (MALDI): m/z (%) 365 (M+ + Na, 89). Calcd for
C18H15ClN2NaO3: 365.0663. Found: 365.0660.
1-((E)-2-Methyl-3-phenylallyloxymethyl)quinazoline-2,4(1H,3H)-
1
dione (9b): White solid (257 mg, 80%), m.p. 165–166°C. H NMR
(DMSO-d6, 300 MHz): δ 1.75 (s, 3H, CH3), 4.16 (s, 2H, CH2), 5.61 (s,
2H, CH2), 6.49 (s, 1H, CH), 7.20–8.03 (m, 9H, Harom), 11.66 (s, 1H,
NH) ppm; 13C NMR (DMSO-d6, 75 MHz): δ 15.2 (CH3), 71.9 (CH2),
74.1 (CH2), 123.1 (CH=), 115.4, 115.7, 126.1, 126.4, 127.2, 128.1,
128.5, 134.4, 135.0, 140.5 (Carom), 136.8 (C(Me)=), 150.5 (C-2),
161.7 (C-4) ppm. MS (MALDI) m/z 345 (M+ + Na, 89%). Anal.
Calcd. for C19H18N2O3 (322.36): C 70.79, H 5.63, N 8.69. Found: C
70.79, H 5.60, N 8.62%.
1-(Indan-2-yloxymethyl)-6-methylquinazoline-2,4(1H,3H)-
1
dione (7c): White solid (221 mg, 69%), m.p. 187–189°C. H NMR
(DMSO-d6, 300 MHz): δ 2.35 (s, 3H, CH3), 2.84–2.90, 3.10-3.16
(2 × m, 4H, 1'-H, 3'-H), 4.52 (quint, J = 3.7 Hz, 1H, 2'-H), 5.55 (s, 2H,
CH2), 7.10–7.81 (m, 7H, Harom), 11.61 (s, 1H, NH) ppm; 13C NMR
PAPER: 07/4684

JOURNAL OF CHEMICAL RESEARCH 2007 361
6-Chloro-1-((E)-2-methyl-3-phenylallyloxymethyl)quinazoline-
2,4(1H,3H)-dione (9c): White solid (288 mg (81%), m.p. 157–158°C.
1H NMR (DMSO-d6, 300 MHz): δ 1.75 (s, 3H, CH3), 4.15 (s, 2H,
CH2), 5.59 (s, 2H, CH2), 6.48 (s, 1H, CH), 7.21–7.93 (m, 8H, Harom),
11.82 (s, 1H, NH) ppm; 13C NMR (DMSO-d6, 75 MHz): δ 15.3 (CH3),
72.0 (CH2), 74.1 (CH2), 126.3 (CH=), 117.3, 117.8, 126.4, 126.5,
127.4, 128.1, 128.5, 134.3, 134.7, 139.3 (Carom), 136.7 (C(Me)=),
150.2 (C-2), 160.7 (C-4) ppm. MS (MALDI): m/z 379 (M+ + Na,
34%). Calcd for C19H17ClN2NaO3: 379.0820. Found: 379.0824.
6-Methyl-1((E)-2-methyl-3-phenylallyloxymethyl)quinazoline-
2,4(1H,3H)-dione (9d): White solid (262 mg, 78%, m.p. 158–160°C.
1H NMR (DMSO-d6, 300 MHz): δ 1.74 (s, 3H, CH3), 2.36 (s, 3H,
CH3), 4.14 (s, 2H, CH2), 5.58 (s, 2H, CH2), 6.48 (s, 1H, CH), 7.20–
7.81 (m, 8H, Harom), 11.59 (s, 1H, NH) ppm; 13C NMR (DMSO-
d6, 75 MHz): δ 15.2 (CH3), 19.9 (CH3), 71.8 (CH2), 74.0 (CH2),
126.1 (CH=), 115.4, 115.55, 126.45, 126.9, 128.1, 128.5, 132.4,
134.4, 135.9, 138.3 (Carom), 136.8 (C(Me)=), 150.45 (C-2), 161.7
(C-4) ppm. MS (MALDI): m/z 359 (M+ + Na, 88%). Anal. Calcd.
for C20H20N2O3 (336.38): C 71.41, H 5.99, N 8.33. Found: C 71.40,
H 5.98, N 8.28%.
Received 4 June 2007; accepted 29 June 2007
Paper 07/4684 doi: 10.3184/030823407X227101
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1-(2-Phenylethyloxymethyl)quinazoline-2,4(1H,3H)-dione (10a):
1
White solid (211 mg, 71%), m.p. 136–137°C. H NMR (DMSO-d6,
500 MHz): δ 2.79 (t, J = 6.5 Hz, 2H, CH2), 3.75 (t, J = 6.5 Hz, 2H,
CH2), 5.51 (s, 2H, CH2), 7.13–7.99 (m, 9H, Harom), 11.61 (s, 1H, NH)
ppm; 13C NMR (DMSO-d6, 125 MHz): δ 35.7 (CH2), 69.35 (CH2),
72.6 (CH2), 115.9, 116.3, 123.5, 126.5, 127.7, 128.5, 129.3, 135.5,
139.0, 140.95 (Carom), 151.1 (C-2), 162.2 (C-4) ppm. MS (EI): m/z
(%) 296 (M+, 31), 219 (54), 205 (13), 191 (7), 175 (11), 161 (8), 119
(18), 105 (100). Anal. Calcd. for C17H16N2O3 (296.32): C 68.91, H
5.44, N 9.45. Found: C 68.89, H 5.41, N 9.32%.
6-Methyl-1-(2-phenylethyloxymethyl)quinazoline-2,4(1H,3H)-
1
dione (10b): white solid (227 mg, 73%), m.p. 145–146°C. H NMR
(DMSO-d6, 500 MHz): δ 2.35 (s, 3H, CH3), 2.78 (t, J = 6.5 Hz, 2H,
CH2), 3.73 (t, J = 6.5 Hz, 2H, CH2), 5.49 (s, 2H, CH2), 7.14–7.78 (m,
8H, Harom), 11.54 (s, 1H, NH) ppm; 13C NMR (DMSO-d6, 125 MHz):
δ 20.45 (CH3), 35.7 (CH2), 69.3 (CH2), 72.5 (CH2), 115.9, 116.1,
126.5, 127.3, 128.55, 129.2, 132.9, 136.3, 138.8, 139.0 (Carom), 151.1
(C-2), 162.2 (C-4) ppm. MS (EI): m/z (%) 310 (M+, 23), 295 (17),
233 (42), 219 (31), 205 (12), 191 (7), 135 (9), 91 (100). Anal. Calcd.
for C18H18N2O3 (310.35): C 69.66, H 5.85, N 9.03. Found: C 69.58,
H 5.84, N 8.99%.
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The author would like to thank Prof. Erik B. Pedersen,
Nucleic Acd Centre, Department of Chemistry, University of
Southern Denmark, Odense, Denmark, for his kind support
in obtaining microanalyses, NMR and mass spectra. Also,
he expresses his sincere apprecation to Prof. Claus Nielsen,
Retrovirus Laboratory, Department of Virology, State Serum
Institute, DK-2300 Copenhagen, Denmark, for the anti-HIV
screening.
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