Multistep parallel synthesis of quinazoline-2,4-diones by a fluorous biphasic concept without perfluorinated solvents

Article abstract of DOI:10.1002/hlca.200390010

Based on perfluoro-tagged benzyl alcohol adsorbed via fluorous-fluorous interactions on fluorous reversed-phase silica gel (FRPSG), we have performed a multistep synthesis leading finally to a small library of quinazoline-2,4-diones. The whole reaction sequence runs without isolation of intermediates and most importantly, without the need of perfluorinated solvents.

Full text of DOI:10.1002/hlca.200390010

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Multistep Parallel Synthesis of Quinazoline-2,4-diones by a Fluorous
Biphasic Concept without Perfluorinated Solvents
by Dominik Schwinn, Heiko Glatz, and Willi Bannwarth*
Universit‰t Freiburg, Institut f¸r Organische Chemie und Biochemie, Albertstrasse 21, D-79104 Freiburg
(phone: ‡‡ 49761203-6073; fax: ‡‡ 49761203-8705; e-mail: willi.bannwarth@organik.chemie.uni-freiburg.de)
Based on perfluoro-tagged benzyl alcohol adsorbed via fluorous fluorous interactions on fluorous
reversed-phase silica gel (FRPSG), we have performed a multistep synthesis leading finally to a small library of
quinazoline-2,4-diones. The whole reaction sequence runs without isolation of intermediates and most
importantly, without the need of perfluorinated solvents.
1. Introduction. Recently, fluorous chemistry techniques have emerged as an
attractive approach for efficient separation and isolation steps in conducting solution
chemistry [1]. Perfluoro-tagged compounds can be easily separated from organic
compounds via liquid-liquid extraction between a common organic solvent and a
perfluorinated solvent. Alternatively, solid-phase extraction on fluorous reversed-
phase silica gel (FRPSG) can be performed. The easy workup procedures allow for
efficient parallel synthesis and have, thus, found application in combinatorial chemistry
and catalytic processes [2].
We have recently reported on the synthesis of a perfluoro-tagged (benzyloxy)car-
bonyl protecting group and its application in a fluorous biphasic system to the synthesis
of two quinazoline-2,4-diones according to Scheme 1 [3].
Scheme 1. Synthesis of Quinazoline-2,4-diones 5a 5p in Liquid Phase
We had demonstrated that this multistep synthesis can be performed starting from 1
without isolation of intermediates, even if the individual steps do not proceed
quantitatively. The quinazoline-2,4-diones 5a and 5e as desired products were obtained

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189
by an intramolecular cyclization step induced by Et3N [4][5]. All intermediates but the
final quinazoline-2,4-diones were equipped with perfluoro tags and could, thus, be
removed from the desired products by extraction between perfluorinated and organic
medium without a chromatographic purification step.
Meanwhile, we have extended the approach to the synthesis of a small library of
quinazoline-2,4-diones (Table). The overall yields for the desired target compounds
were in the range from 35 90%.
Table. Yields of Quinazoline-2,4-diones 5a 5p Obtained by Employing Free Perfluoro Benzyl Alcohol 1 and
FRPSG-Immobilized Linker Material 6
No.
Yield [%]
FBEa)
66
FSPOSb)
47
5a
5b
5c
60
75
45
30
5d
70
73
5e
5f
90
70
29
35
5g
5h
43
85
77
90

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Table (cont.)
No.
Yield [%]
FBEa)
FSPOSb)
52
5i
67
5j
5k
46
54
43
83
5l
59
46
80
52
5m
5n
5o
35
51
29
42
5p
55
62
a) FBE ˆ Fluorous biphasic extraction. b) FSPOS ˆ Fluorous solid phase organic synthesis.

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191
The applied perfluorinated solvents are regarded as benign but they have the
disadvantage of being costly and environmentally persistent [6]. Thus, it would be of
great value to make use of the fluorous fluorous interactions without involvement of
perfluorinated solvents [7].
Here, we would like to report on such an approach in which we have performed the
synthesis of the quinazoline-2,4-dione library on perfluoro-tagged benzyl alcohol
adsorbed on fluorous reversed-phase silica gel (FRPSG) by fluorous fluorous
interactions [8][9].
2. Results and Discussion. The whole reaction sequence of the synthesis leading to
the desired quinazoline-2,4-diones 5a 5p is outlined in Scheme 2. Perfluoro-tagged
benzyl alcohol 1 was immobilized on FRPSG by evaporating a solution of 1 (0.4 mmol)
in Et2O in the presence of 5 g of FRPSG to yield 6.
Scheme 2. Synthesis of Quinazoline-2,4-diones 5a 5p Starting from FRPSG-Immobilized Benzyl Alcohol 6
For the coupling and (benzyloxy)carbonyl protection of anthranilic acids, immobilized
alcohol 6 was first reacted with diphosgene to yield 7 [10]. This material was divided
into four equal parts, and each part was reacted with a different anthranilic acid in the
presence of H¸nig×s base to yield intermediates 8a 8d. Each intermediate of this
material was again splitted into four equivalent portions each, and, again, each part was
reacted with four amines with O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium-tetra-
fluoroborate (TBTU) as coupling reagent to produce the amides 9a 9p ready for the
cyclization step induced by Et3N, leading to the envisaged target compounds 5a 5p [11].
The reaction steps were carried out in THF, which leads to a substantial release of
the perfluoro-tagged benzyl alcohol 1 into the solvent. Thus, the reaction takes place in
solution as well as on solid support. After each reaction step, the solvent was

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evaporated, and, then, the support was taken up in a mixture of MeCN/H2O and
filtered. The solvent switch caused a reattachment of the intermediates onto the
FRPSG support. Control experiments had shown that more than 99% of the
intermediates 1 4 remained on the FRPSG by applying this procedure.
In contrast, control experiments with unmodified silica gel and perfluoro-tagged
benzyl alcohol 1 in MeCN/H2O did not lead to a significant immobilization. More than
90% of 1 were found in solution.
After the final cyclization step the products 5a 5p were obtained after separation
from the FRPSG in pure form by crystallization out of the organic phase (see General
Procedure in Exper. Part). The whole reaction sequence was performed without
isolation of intermediates.
Yields of the 16 quinazoline-2,4-diones 5a 5p are summarized in the Table. In
essence, they correspond to those obtained in the parallel synthesis of 5a 5p in a
fluorous/organic biphasic system, followed by extraction with perfluorinated solvent.
The final cyclization step leads to regeneration of 6. This recycled material could be
re-used again for another round of synthesis according to Scheme 2. Compound 5p was
obtained in a yield of 35%.
The established system is a mimic of hydroxymethylated solid supports. Hence, it is
amenable to a whole range of different heterocyclic core structures obtainable by a
similar final intramolecular cyclization step [2]. Furthermore, the immobilized
perfluoro-tagged benzyl alcohol can be adapted to a broad scope of reaction conditions
without further evaluation, e.g., of the swelling properties of the solid-support material.
Conclusions. We were able to establish a straightforward multistep synthesis for
quinazoline-2,4-diones without isolation of intermediates. The solution-phase synthesis
started from the perfluoro-tagged benzyl alcohol 1, and the final products 5a 5p were
isolated by liquid-liquid extraction between perfluorinated and organic solvent.
The solid-phase synthesis of 5a 5p started from 6, in which the perfluoro-tagged
benzyl alcohol is attached to FRPSG by fluorousÀfluorous interactions. The products
were obtained in pure form after filtration from the FRPSG. This was possible, since all
unreacted intermediates but the final products carry a perfluorinated unit, which
renders them very lipophilic as compared to the quinazoline-2,4-diones. Most
importantly, the latter approach does not involve the application of perfluorinated
solvents. Furthermore, none of the individual steps has to go to completion. In addition,
we were also able to demonstrate that recycled 6 from the first run could be used for
another synthesis cycle (for 5p). The approach is generally applicable to the rapid
parallel multistep synthesis of different heterocyclic cores by cyclization protocols in
analogy to existing protocols on solid phase for hydroxymethylated resins.
The principle of detachment and reattachment by solvent switch is a new method
for solid-phase-supported synthesis. Since the attachment is based on fluorous fluo-
rous interactions, we would like to dub it as fluorous solid-phase organic synthesis
(FSPOS).
We would like to thank Dr. Keller, Mrs. Schonhard, and Mr. Reinbold for NMR spectra, Mr. Warth and Mr.
Wˆrth for mass spectra, and Mr. Hickl for elementary analysis. Furthermore, we would like to thank Degussa
AG for a free gift of perfluoro(triethoxy)silane and Byk Gulden Pharmaceuticals for financial support.

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193
Experimental Part
1. General. All reagents were obtained from Acros or Aldrich and were of highest purity available. THF was
dried over Na and was freshly distilled before use. M.p.: electrothermal digital melting device IA 9200;
uncorrected. NMR Spectra: at 250, 400 MHz (1H) and 100 MHz (13C); CDCl3 and (D6)DMSO solns.; chemical
shifts d in ppm rel. to Me4Si (ˆ0 ppm) for 1H and rel. to CHCl3 (77,00 ppm) for 13C as an internal reference; J in
Hz. MS: Finnigan MAT8200 (EI), MAT312 (CI), and TSQ-7000 (ESI) mass spectrometer.
2. Synthesis. A general procedure for rapid synthesis of quinazoline-2,4-diones with application of
immobilized linker 1 on FRPSG is given below. For exper. data concerning the synthesis in fluorous biphasic
system, see [3].
Preparation of FRPSG [12][13]. Silica gel (50 g; 35 70 mm; 550 m2/g) was activated by treatment with
150 ml of conc. HCl. The supension was stirred for 2 h at r.t. and for 3 h at 508 in a rotary evaporator. Then the
silica gel was filtered off, washed with 150 ml of MeOH/H2O 1:1, 150 ml of MeOH, 150 ml of CH2Cl2, and
150 ml of Et2O, and dried under high vacuum.
The activated silica gel was suspended in 150 ml of toluene (700 ppm H2O), and 1.4 g (7 mmol) of TsOH
and 35.8 g (0.07 mol) of (3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooctyl)(triethoxy)silane were added. The mixture
was stirred for 12 h at r.t., then for 24 h at 1008 in a rotary evaporator. The product was filtered off and washed
with 300 ml of MeOH, 300 ml of CH2Cl2, 500 ml of Et2O, and dried under high vacuum to give 74 g of FRPSG.
General Procedure for the Preparation of 4-[Tris(3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooctyl)silyl]benzyl
Alcohol Loaded Fluorous Reversed-Phase Silica Gel (FRPSG) (6). In a rotating flask, 0.43 mmol of 1 was
thoroughly mixed with 5 g of FRPSG and Et2O as a solvent. Et2O was evaporated, and the resulting powder was
treated with 3 Â 20 ml of anh. MeCN to remove traces of H2O.
Synthesis of 5a as an Example for the Preparation of Quinazoline-2,4-diones 5a 5p. A suspension of 0.1 g
(0.51 mmol) of trichloromethyl chloroformate and 10 mg of activated charcoal in 50 ml anh. THF were shaken
under Ar for 10 min. Within 10 min, 5.5 g of 6 were added to the suspension. After shaking at r.t. for 15 h, the
solvent and reagent were evaporated to give 7.
FRPSG-Bound chloroformate 7 (5.53 g), 0.28 g (2.0 mmol) of anthranilic acid, and 0.5 ml (3.0 mmol) of
H¸nig×s base were taken up in 50 ml anh. THF. The suspension was shaken at r.t. for 16 h. The solvent was
removed in vacuo, and the residue was rinsed with 5 Â 50 ml of MeCN/H2O 8 :1. The resulting powder was
treated with 3 Â 20 ml of anh. MeCN to remove traces of H2O.
Under Ar, 5.56 g of the FRPSG-bound carbamate 8a, 0.1 ml (1.0 mmol) furfurylamine, 0.3 ml (2.0 mmol) of
H¸nig×s base, and 0.32 g (1.0 mmol) of TBTU were suspended in 30 ml of anh. THF. The suspension was shaken
at r.t. for 16 h. The solvent was removed in vacuo, and the FRPSG was rinsed with 5 Â 50 ml of MeCN/H2O 8 :1
to give 9a.
The FRPSG-bound amide 9a (5.56 g) and 0.2 ml (2.0 mmol) of Et3N were taken up in 10 ml of DMF. The
suspension was heated in a sealed vial to 1208 for 16 h. After cooling, the vial was carefully opened, and the
mixture was washed with 100 ml of H2O. The resulting slurry was filtered, and the FRPSG was rinsed with 5 Â
40 ml of MeCN/H2O 8 :1 and concentrated in vacuo. During concentration, 48 mg (47%) of the desired
quinazoline-2,4-dione 5a precipitated from the aq./org. phase. The complete synthesis was performed in a
straightforward manner without isolation of intermediates.
Data of the 16 Quinazoline-2,4-diones. 3-[(Furan-2-yl)methyl]quinazoline-2,4-dione (5a). Yield 48 mg
(47%). M.p. 2458. 1H-NMR ((D6)DMSO, 400 MHz): 5.06 (s, CH2); 6.29 (d, J ˆ 2.6, 1 H (fur.)); 6.38 (t, J ˆ 2.5,
1 H (fur.)); 7.20 (m, 2 arom. H); 7.52 (s, 1 H (fur.)); 7.65 (t, J ˆ 7.8, 1 arom. H); 7.93 (d, J ˆ 8.0, 1 arom. H); 11.00
(s, NH). 13C-NMR ((D6)DMSO, 100 MHz): 36.1; 108.1; 109.8; 113.6; 114.9; 122.0; 127.3; 134.3; 139.0; 141.2;
‡
149.9; 150.0; 161.7. MS (70 eV): 242 (100, M ), 213 (16), 146 (22), 81 (45). Anal. calc. for C13H10N2O3 (242.23): C
64.46, H 4.16, N 11.56; found: C 64.33, H 4.10, N 11.52.
3-Benzylquinazoline-2,4-dione (5b). Yield 48 mg (45%). M.p.: 2298. 1H-NMR (CDCl3, 400 MHz): 5.26
(s, CH2); 7.02 (d, J ˆ 7.3, 1 arom. H); 7.19 7.31 (m, 4 arom. H); 7.50 (d, J ˆ 7.0, 2 arom. H); 7.58 (t, J ˆ 10.0,
1 arom. H); 8.12 (d, J ˆ 8.8, 1 arom. H); 9.65 (s, NH). 13C-NMR (CDCl3, 100 MHz): 44.3; 114.7; 114.9; 123.6;
‡
127.8; 128.5; 129.0; 135.2; 136.9; 138.5; 151.8; 162.4. MS (70 eV): 252 (100, M ), 235 (16), 147 (36), 91 (52).
Anal. calc. for C15H12N2O2 ¥ 0.2 H2O (255.69): C 70.46, H 4.81, N 10.95; found: C 70.16, H 4.90, N 10.78.
3-(3,4-Dimethoxyphenyl)quinazoline-2,4-dione (5c). Yield 38 mg (30%). M.p.: 2608 (subl.). 1H-NMR
((D6)DMSO, 500 MHz): 3.70 (s, Me); 3.81 (s, Me); 6.82 (dd, J ˆ 8.4, 2.1, 1 arom. H); 6.94 (d, J ˆ 2.4, 1 arom. H);
7.01 (d, J ˆ 8.5, 1 arom. H); 7.22 (d, J ˆ 7.75, 2 arom. H); 7.68 (t, J ˆ 8.6, 1 arom. H); 7.92 (d, J ˆ 7.5, 1 arom. H);
11.47 (s, NH). 13C-NMR ((D6)DMSO, 125.7 MHz): 55.6; 111.5; 112.9; 114.3; 115.1; 121.1; 122.4; 127.5; 128.4;
‡
135.1; 139.7; 148.5; 148.8 (12 arom. C); 150.3 (C(4)); 162.3 (C(2)). MS (70 eV): 298 (100, M ), 146 (88), 119

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(18), 97 (14), 81 (22), 71 (30), 69 (42), 57 (49). Anal. calc. for C16H14N2O4 (298.29): C 64.42, H 4.73, N 9.39;
found: C 64.34, H 4.97, N 9.23.
3-[2-(4-Chlorophenyl)ethyl]aminazoline-2,4-dione (5d). Yield 93 mg (73%). M.p.: 2328. 1H-NMR
((D6)DMSO, 500 MHz): 2.88 (t, J ˆ 7.9, CH2); 4.09 (t, J ˆ 8.0, CH2); 7.16 (d, J ˆ 8.2, 1 arom. H); 7.19 (t, J ˆ
7.5, 1 arom. H); 7.24 (d, J ˆ 8.5, 2 arom. H); 7.33 (d, J ˆ 8.5, 2 arom. H); 7.64 (t, J ˆ 7.7, 1 arom. H); 7.91 (d, J ˆ
7.9, 1 arom. H); 11.41 (s, NH). 13C-NMR ((D6)DMSO, 125.7 MHz): 32.6; 41.0; 113.7; 115.1; 122.5; 127.3; 128.3;
‡
130.5; 130.9; 135.0; 137.7; 139.3; 149.9; 161.7. MS (70 eV): 300 (19, M ), 162 (28), 146 (46), 138 (100), 119 (23),
90 (16); Anal. calc. for C16H13ClN2O2 (300.74): C 63.90, H 4.36, N 9.31; found: C 63.53, H 4.48, N 9.33.
7-Chloro-3-[(furan-2-yl)methyl]quinazoline-2,4-dione (5e). Yield 34 mg (29%). M.p.: 2568. 1H-NMR
((D6)DMSO, 500 MHz): 5.05 (s, CH2); 6.29 (d, J ˆ 2.6, 1 H (fur.)); 6.37 (t, J ˆ 2.5, 1 H (fur.)); 7.19 (s, 1 H
(fur.)); 7.25 (d, J ˆ 7.9, 1 arom. H); 7.53 (s, 1 arom. H); 7.92 (d, J ˆ 8.0, 1 arom. H); 11.71 (s, NH). 13C-NMR
((D6)DMSO, 125.7 MHz): 42.7; 108.0; 110.5; 112.6; 114.6; 122.8; 129.5; 139.5; 140.5; 142.1; 149.6; 150.1; 160.8.
‡
MS (70 eV): 276 (100, M ), 247 (17), 180 (36), 129 (76), 81 (91). Anal. calc. for C13H9ClN2O3 (276,67): C 56.43,
H 3.28, N 10.13; found: C 55.98, H 3.02, N 9.82.
3-Benzyl-7-chloroquinazoline-2,4-dione (5f). Yield 43 mg (35%). M.p.: 2718. 1H-NMR ((D6)DMSO,
250 MHz): 4.98 (s, CH2); 7.09 7.22 (m, 7 arom. H); 8.03 (d, J ˆ 8.3, 1 arom. H); 11.55 (s, NH). 13C-NMR
((D6)DMSO, 100 MHz): 43.2; 112.7; 114.6; 122.8; 127.1; 127.5; 128.3; 129.5; 137.1; 139.5; 140.5; 150.1; 161.3. MS
‡
(70 eV): 286 (100, M ), 269 (18), 181 (35), 154 (24), 132 (33), 91 (93), 65 (22). Anal. calc. for C15H11ClN2O2
(286.71): C 62.84, H 3.87, N 9.77; found: C 62.68, H 3.87, N 9.66.
7-Chloro-3-(3,4-dimethoxyphenyl)quinazoline-2,4-dione (5g). Yield 109 mg (77%). M.p.: 2958 (dec.).
1H-NMR ((D6)DMSO, 250 MHz): 3.77 (s, Me); 3.87 (s, Me); 6.88 (dd, J ˆ 8.4, 2.1, 1 arom. H); 7.01 (d, J ˆ 2.4,
1 arom. H); 7.07 (d, J ˆ 8.5, 1 arom. H); 7.28 (m, 2 arom. H); 7.33 (d, J ˆ 2.5, 1 arom. H); 7.98 (d, J ˆ 8.3, 1 arom.
H); 11.67 (s, NH). 13C-NMR ((D6)DMSO, 100 MHz): 55.6; 111.5; 112.8; 113.3; 114.4; 121.0; 122.5; 128.1; 129.6;
‡
139.3; 140.8; 148.5; 148.8; 150.1; 161.5. MS (70 eV): 332 (52, M ), 317 (12), 286 (12), 180 (45) , 91 (100). Anal.
calc. for C16H13ClN2O4 (332,74): C 57.75, H 3.94, N 8.42; found: C 57.88, H 4.13, N 8.28.
7-Chloro-3-[2-(4-chlorophenyl)ethyl]quinazoline-2,4-dione (5h). Yield 128 mg (90%). M.p. 2408 (subl.).
1H-NMR ((D6)DMSO, 400 MHz): 2.98 (t, J ˆ 7.9, CH2); 4.20 (t, J ˆ 8.0, CH2); 7.29 (d, J ˆ 2.0, 1 arom. H); 7.32
7.41 (m, 3 arom. H); 7.48 (d, J ˆ 8.2, 2 arom. H); 11.68 (s, NH). 13C-NMR ((D6)DMSO, 100 MHz): 32.5; 41.1;
‡
112.7; 114.4; 122.7; 128.3; 129.4; 130.5; 130.9; 137.6; 139.3; 149.8; 161.1. MS (70 eV): 334 (7, M ), 180 (22), 138
(100), 103 (14). Anal. calc. for C16H12Cl2N2O2 (335.18): C 57.33, H 3.61, N 8.36; found: C 57.11, H 3.44, N 7.97.
3-[(Furan-2-yl)methyl]-1-methylquinazoline-2,4-dione (5i). Yield 57 mg (52%). M.p. 1868. 1H-NMR
((D6)DMSO, 250 MHz): 3.46 (s, Me); 5.10 (s, CH2); 6.25 (d, J ˆ 3.4, 1 H (fur.)); 6.32 (d, J ˆ 3.4, 1 H (fur.)); 7.25
(t, J ˆ 7.9, 1 arom. H); 7.40 (d, J ˆ 8.6, 1 arom. H); 7.47 (s, 1 H (fur.)); 7.73 (t, J ˆ 8.1, 1 arom. H); 7.99 (d, J ˆ 7.6,
1 arom. H). 13C-NMR ((D6)DMSO, 100 MHz): 30.7; 37.5; 95.8; 108.2; 110.5; 114.7; 122.9; 127.8; 135.6; 140.4;
‡
142.1; 150.0; 150.2; 160.7. MS (70 eV): 256 (45, M ), 227 (7), 177 (9), 104 (10), 81 (100). Anal. calc. for
C14H12N2O3 (256.26): C 65.62, H 4.72, N 10.93; found: C 65.13, H 4.69, N 10.72.
3-Benzyl-1-methylquinazoline-2,4-dione (5j). Yield 49 mg (43%). M.p. 1318. 1H-NMR ((D6)DMSO,
250 MHz): 3.39 (s, Me); 5.00 (s, CH2); 7.05 7.21 (m, 6 arom. H); 7.33 (d, J ˆ 8.3, 1 arom. H); 7.65 (t, J ˆ 7.9,
1 arom. H); 7.92 (d, J ˆ 7.9, 1 arom. H). 13C-NMR ((D6)DMSO, 100 MHz): 30.7; 44.2; 114.6; 114.7; 122.8; 127.1;
‡
127.6; 127.9; 128.3; 135.3; 137.2; 140.5; 150.1; 161.2. MS (70 eV): 266 (100, M ), 161 (22), 132 (29), 105 (22), 91
(67), 77 (22). Anal. calc. for C16H14N2O2 ¥ 0.2H2O (269,89): C 71.20, H 5.30, N 10.37; found: C 70.72, H 5.32, N
10.14.
3-(3,4-Dimethoxyphenyl)-1-methylquinazoline-2,4-dione (5k). Yield 110 mg (83%). M.p. 2408. 1H-NMR
((D6)DMSO, 250 MHz): 3.43 (s, MeN); 3.60 (s, MeO); 3.71 (s, MeO); 6.71 (dd, J ˆ 8.3, 2.2, 1 arom. H); 6.84
(d, J ˆ 2.4, 1 arom. H); 6.92 (d, J ˆ 8.9, 1 arom. H); 7.22 (t, J ˆ 8.0, 1 arom. H); 7.40 (d, J ˆ 8.5, 1 arom. H); 7.72
(t, J ˆ 7.9, 1 arom. H); 7.94 (d, J ˆ 7.9, 1 arom. H). 13C-NMR ((D6)DMSO, 100 MHz): 30.7; 55.6; 55.7; 111.5;
‡
112.6; 114.6; 115.4; 120.9; 122.7; 128.0; 129.0; 135.5; 140.7; 148.5; 148.8; 150.6; 161.5. MS (70 eV): 312 (100, M ),
297 (32), 266 (30), 159 (23), 132 (18), 104 (37), 91 (26), 77 (25). Anal. calc. for C17H16N2O4 (312.32): C 65.38, H
5.16, N 8.97; found: C 64.92, H 5.27, N 8.50.
3-[2-(4-Chlorophenyl)ethyl]-1-methylquinazoline-2,4-dione (5l). Yield 107 mg (80%). M.p. 1648. 1H-NMR
((D6)DMSO, 250 MHz): 2.87 (t, J ˆ 7.9, CH2); 3.44 (s, Me); 4.14 (t, J ˆ 7.9, CH2); 7.22 7.38 (m, 5 arom. H); 7.45
(d, J ˆ 8.3, 1 arom. H); 7.78 (t, J ˆ 8.0, 1 arom. H); 8.03 (d, J ˆ 7.9, arom. H). 13C-NMR ((D6)DMSO, 100 MHz):
30.6; 32.5; 42.1; 114.6; 114.7; 122.7; 127.7; 128.4; 130.5; 131.0; 135.3; 137.7; 140.3; 150.1; 160.9. MS (70 eV): 314
‡
(12, M ), 189 (10), 176 (100), 138 (18), 105 (23), 77 (17). Anal. calc. for C17H15ClN2O2 ¥ 0.2 H2O (317.68): C
64.27, H 4.82, N 8.82; found: C 63.97, H 5.18, N 8.81.

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1,3-Bis[(furan-2-yl)methyl]quinazoline-2,4-dione (5m). Yield 71 mg (52%). M.p. 1508. 1H-NMR
((D6)DMSO, 400 MHz): 5.15 (s, CH2); 5.36 (s, CH2); 6.32 (d, J ˆ 3.4, 1 H (fur.)); 6.35 6.41 (m, 2 H (fur.));
6.45 (d, J ˆ 3.4, 1 H (fur.)); 7.31 (t, J ˆ 7.7, 1 arom. H); 7.52 (s, 1 H (fur.)); 7.57 (s, 1 H (fur.)); 7.59 (d, J ˆ 8.6,
1 arom. H); 7.76 (t, J ˆ 7.9, 1 arom. H); 8.07 (d, J ˆ 8.1, 1 arom. H). 13C-NMR ((D6)DMSO, 100 MHz): 37.7;
39.0; 108.2; 108.8; 110.6; 110.7; 114.8; 115.0; 123.1; 128.1; 135.4; 139.4; 142.2; 142.8; 149.4; 149.9; 150.0; 160.6.
‡
MS (70 eV): 322 (37, M ), 241 (58), 198 (48), 146 (74), 81 (100). Anal. calc. for C18H14N2O4 (322.31): calc: C
67.07, H 4.38, N 8.69; found: C 66.86, H 4.07, N 8.68.
3-Benzyl-1-[(furan-2-yl)methyl]quinazoline-2,4-dione (5n). Yield 41 mg (29%). M.p. 1488. 1H-NMR
((D6)DMSO, 400 MHz): 5.17 (s, CH2); 5.38 (s, CH2); 6.39 (d, J ˆ 3.3, 1 H (fur.)); 6.43 (d, J ˆ 3.3, 1 H (fur.));
7.21 7.36 (m, 6 arom. H); 7.57 (s, 1 H (fur.)); 7.60 (d, J ˆ 8.4, 1 arom. H); 7.76 (t, J ˆ 8.1, 1 arom. H); 8.07 (d, J ˆ
7.7, 1 arom. H). 13C-NMR ((D6)DMSO, 100 MHz): 38.9; 44.3; 108.6; 110.5; 114.8; 114.9; 123.1; 127.5; 128.0;
‡
128.3; 135.3; 137.0; 139.4; 142.7; 149.4; 150.3; 160.9. MS (70 eV): 332 (47, M ), 251 (12), 198 (16), 170 (7), 146
(30), 91 (14), 81 (100). Anal. calc. for C20H16N2O3 (332.35): calc: C 72.28, H 4.85, N 8.43; found: C 72.23, H 4.93,
N 8.34.
3-(3,4-Dimethoxyphenyl)-1-[(furan-2-yl)methyl]quinazoline-2,4-dione (5o). Yield 68 mg (42%). M.p.
1938. 1H-NMR ((D6)DMSO, 250 MHz): 3.82 (s, Me); 3.77 (s, Me); 5.40 (s, CH2); 6.44 (d, J ˆ 3.3, 1 H (fur.));
6.51 (d, J ˆ 3.3, 1 H (fur.)); 6.88 (d, J ˆ 8.5, 1 arom. H); 6.99 7.09 (m, 2 arom. H); 7.34 (t, J ˆ 7.3, 1 arom. H);
7.61 7.69 (m, 1 arom. H, 1 H (fur.)); 7.81 (t, J ˆ 7.9, 1 arom. H); 8.09 (d, J ˆ 7.9, 1 arom. H). 13C-NMR
((D6)DMSO, 100 MHz): 38.9; 55.6; 108.7; 110.6; 111.5; 112.8; 114.8; 115.6; 120.9; 122.8; 128.1; 128.8; 135.2;
‡
139.7; 142.7; 148.5; 148.8; 149.5; 150.4; 161.3. MS (70 eV): 378 (38, M ), 153 (15), 138 (31), 81 (100). Anal. calc.
for C21H18N2O5 (378.38): calc: C 66.66, H 4.79, N 7.40; found: C 66.60, H 5.03, N 7.48.
3-[2-(4-Chlorophenyl)ethyl]-1-[(furan-2-yl)methyl]quinazoline-2,4-dione (5p). Yield 100 mg (62%). M.p.
1688. 1H-NMR ((D6)DMSO, 500 MHz): 2.90 (t, J ˆ 7.8, CH2); 4.18 (t, J ˆ 7.9, CH2); 5.33 (s, CH2); 6.37 (d, J ˆ 3.4,
1 H (fur.)); 6.39 (d, J ˆ 3.4, 1 H (fur.)); 7.21 7.33 (m, 5 arom. H); 7.55 7.59 (m, 1 arom. H, 1 H (fur.)); 7.74
(t, J ˆ 7.7, 1 arom. H); 8.04 (d, J ˆ 7.7, 1 arom. H). 13C-NMR ((D6)DMSO, 100 MHz): 32.4; 38.9; 42.1; 108.6;
110.5; 114.7; 114.8; 122.9; 127.9; 128.3; 130.5; 135.1; 137.5; 139.3; 142.7; 149.4; 150.0; 160.9. MS (70 eV): 380 (8,
‡
M ), 242 (53), 146 (11), 138 (8), 81 (100). Anal. calc. for C21H17ClN2O3 (380.82): calc: C 66.23, H 4.50, N 7.36;
found: C 66.38, H 4.54, N 6.94.
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Received August 16, 2002