Synthesis and reactions of some 2-Vinyl-3H-quinazolin-4-ones

Article abstract of DOI:10.1016/S0040-4020(00)00595-0

A simple, high-yielding synthesis of 2-vinyl-3H-quinazolin-4-one, 2-(1-chlorovinyl)-3H-quinazolin-4-one and 2-(1-bromovinyl)-3H-quinazolin-4-one. The 2-vinylquinazolinones 11a and 14 participate readily in nucleophilic addition reactions. Treatment with both carbon and nitrogen nucleophiles results in a clean conversion into a variety of 2-substituted 3H-quinazolin-4-one derivatives. The 2-(1-halovinyl)-3H-quinazolin-4-ones 11b and 11c reacted with carbon nucleophiles to give several derivatives of 2-substituted 3H-quinazolin-4-one, such as dihydrofurancarboxylic ethyl ester 23. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4020(00)00595-0

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 7245–7253
Synthesis and Reactions of some 2-Vinyl-3H-quinazolin-4-ones
*
Anette Witt and Jan Bergman
¨
¨
Unit for Organic Chemistry, Department of Biosciences, Karolinska Institute and Sodertorn University College, Novum Research Park,
SE-141 57 Huddinge, Sweden
Received 14 December 1999; revised 7 June 2000; accepted 22 June 2000
Abstract—A simple, high-yielding synthesis of 2-vinyl-3H-quinazolin-4-one, 2-(1-chlorovinyl)-3H-quinazolin-4-one and 2-(1-bromo-
vinyl)-3H-quinazolin-4-one. The 2-vinylquinazolinones 11a and 14 participate readily in nucleophilic addition reactions. Treatment with
both carbon and nitrogen nucleophiles results in a clean conversion into a variety of 2-substituted 3H-quinazolin-4-one derivatives. The 2-(1-
halovinyl)-3H-quinazolin-4-ones 11b and 11c reacted with carbon nucleophiles to give several derivatives of 2-substituted 3H-quinazolin-4-
one, such as dihydrofurancarboxylic ethyl ester 23. ᭧ 2000 Elsevier Science Ltd. All rights reserved.
Introduction
mediate.10–12 Several other methods are available such as
cathodic reduction of 2-nitrobenzonitrile.13 Although the
construction of the quinazolinone skeleton has been
extensively described in the literature,7,14 it is surprising to
note that very few 2-vinyl derivatives of 3H-quinazolin-4-
ones are known. In this paper we will discuss a simple, high-
yielding synthesis of vinylquinazolinones 11a–c and 14.
Furthermore the reactivity of compounds 11a–c and 14
towards several nucleophiles to give 2-substituted 3H-
quinazolin-4-one derivatives is reported.
3H-Quinazolin-4-one 1 is a frequently encountered unit in
natural products1 such as l-vasicinone (2),2 chrysogine (3)3
and drugs4 such as methaqualone (4),5 febrifugine (5) and
isofebrifugine (6). The latter two compounds are potent but
toxic antimalaria drugs, the stereochemistry of which has
recently been revised.6 Molecules based on quinazoline and
quinazolinone exhibit a multitude of interesting pharmaco-
logical activities,7 including anticonvulsant, antibacterial
and antidiabetic activity.8,9
Several 2-styrylquinazolin-4(3H)-ones 7 (R1ˆC6H5) have
been prepared since 191015 and some derivatives have
been demonstrated to possess significant growth inhibitory
activity against L1210 murine leukaemia cells.9 In this
context the recently developed anticancer drug CP-31398,
N I-{2-[(E)-2-(4-methoxy-phenyl)-vinyl]-quinazolin-4-yl}-
N,N-dimethyl-propane-1,3-diamine, is also of interest.16
Nevertheless very few derivatives of 7 (R1ˆH) have been
reported in the literature. Fuks17 has given an example,
where 7 (R1ˆH, R2ˆi-Pr) was prepared in a low yield by
reacting the nitrilium salt 8 with methyl anthranilate and
Skibo et al. has reported the preparation of 5,8-dihydroxy-
2-vinyl-3H-quinazolin-4-one.18 The parent compound 11a
however, has only been mentioned briefly in a patent.19
The most common synthetic method to 2-substituted 3H-
quinazolin-4-one is based on the acylation–cyclisation of
anthranilic acid (or a derivative, e.g. 2-aminobenzonitrile)
and proceeds usually via an o-amidobenzamide inter-
Keywords: cyclisation; Michael reactions; quinazolinones.
* Corresponding author. Tel.: ϩ46-8-608-9204; fax: ϩ46-8-711-68-69;
e-mail: jabe@cnt.ki.se
0040–4020/00/$ - see front matter ᭧ 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00595-0

7246
A. Witt, J. Bergman / Tetrahedron 56 (2000) 7245–7253
Scheme 1.
Scheme 2. (i) Methylamine in water 60%, rt, 67%. (ii) 3-Chloropropionyl chloride, 1,4-dioxane, 0ЊC, 75%. (iii) 0.5 M Na2CO3(aq) in 10% MeOH, heat, 23%.
Results and Discussion
(Table 1). Some analogous additions in the 2- and 4-vinyl-
pyridine21 and 2-, 6- and 8-vinylpurine22 series have been
investigated previously. Likewise the sulfur nucleophile,
2-mercaptoethanol, had been added to 5,8-dihydroxy-2-
vinyl-3H-quinazolin-4-one.18
2-(3-Chloropropionylamino)-benzamide (10a) was readily
obtained from anthranilamide (9) and 3-chloropropionyl
chloride. Cyclisation and dehydrohalogenation of 10a was
effected conveniently with sodium hydroxide in aqueous
ethanol to the desired product 11a in an overall yield of
77% (Scheme 1). The halosubstituted vinylquinazolinones
11b and 11c were synthesised analogously in overall yields
of 66%.
The stabilised anion of diethyl acetamidomalonate reacted
readily with 11a or 14 in the presence of a slight excess of
base to form the Michael adduct 16a and 17a respectively
(Scheme 4, Table 1, entries 1 and 2). Compound 16a
crystallised readily from ethanol, while compound 17a
was isolated by column chromatography on silica gel as a
colourless oil. Indole, as nucleophile, reacted at the
3-position with 11a or 14 in refluxing acetic acid. The
desired compounds 16b and 17b were obtained in good
yields (Table 1, entries 3 and 4).
The N-substituted analogue of 11a, 14, was similarly
prepared (Scheme 2). Thus methylamine in water was
added to isatoic anhydride and the corresponding anthranil-
amide 1220 was treated with 3-chloropropionyl chloride
to yield 2-(3-chloropropionylamino)-N-methyl-benzamide
(13). Compound 13 underwent cyclisation in refluxing
0.5 M Na2CO3(aq) containing 10% MeOH to 14, which
was isolated after separation on silica gel in an overall
yield of 12%.
The first attempt to react 11a or 14 with nitrogen
nucleophiles failed using non-catalytic conditions. When a
catalytic amount of acetic acid was added in methanol21 the
aminoquinazolinones 16c,d and 17c,d were isolated
(Table 1, entries 5, 6, 7 and 8). Compounds 16c,d have
been prepared earlier by cyclisation of the corresponding
2-(3-aminopropionylamino)-benzamide with base in
alcoholic solution.23 The 2-vinylquinazolinones 11a and
14 were also allowed to react with sodium azide and the
expected products, 16e and 17e, were isolated by column
chromatography on silica gel (Table 1, entries 9 and 10).
Compounds 16f24 and 17f could be similarly prepared
(Table 1, entries 11 and 12).
The low yield is due to the fact that the cyclisation of
compound 13 was not straightforward and the methoxy
adduct 15a was also isolated along with the vinylquinazo-
linone 14 (Scheme 3). When 13 was treated with sodium
hydroxide in aqueous ethanol the ethoxy adduct 15b was the
sole product.
The vinylquinazolinones 11a and 14 were considered to be
good acceptors in Michael type additions and in fact a
variety of substituted alkylquinazolinones could be prepared
The halosubstituted vinylquinazolinones 11b,c were
expected to be good acceptors in Michael type additions
and should therefore after dehydrohalogenation give rise
to various derivatives of 7. However when 11b,c were
treated with carbon nucleophiles only cyanide as nucleo-
phile gave the expected product 20 (Scheme 6). Hydrolysis
of 20 gave a complex product pattern. However the
expected acid 19 could be prepared by an alternative method
(Scheme 5).
Scheme 3.

A. Witt, J. Bergman / Tetrahedron 56 (2000) 7245–7253
7247
Table 1. Addition of nucleophiles
Entry
2-Vinyl-quinazolinone
Nucleophile
Reagent
Solvent
EtOH
THF
HOAc
HOAc
MeOH
MeOH
MeOH
Time (h)
Yield (%)
1
2
3
4
5
6
7
8
11a
14
11a
14
11a
14
11a
14
Diethyl acet-amidomalonate
Diethyl acet-amidomalonate
Indole
Na
NaH
3
24
4
80, 16a
41, 17a
95, 16b
75, 17b
49, 16c
85, 17c
84, 16d
100, 17d
48, 16e
50, 17e
76, 16f
23, 17f
–
–
Indole
4
Diethylamine
Diethylamine
Piperidine
HOAca
20
20
20
20
20
20
24
1.5
HOAca
HOAca
Piperidine
HOAca
MeOH
9
11a
14
Azide
Azide
–
–
–
–
THF/H2O
THF/H2O
EtOH/H2O
0.5 M Na2CO3
10
11
12
11a
Cyanide
Cyanide
14b
c
a Catalytic amount.
b One-pot synthesis starting with compound 13.
c 0.5 M Na2CO3(aq) in 10% MeOH was used as solvent.
Scheme 4.
Scheme 5.
The acid 18, readily prepared from anthranilamide (9) and
maleic anhydride, was cyclised by sodium acetate in acetic
anhydride to the desired acid 19 in an overall yield of 37%
(Scheme 5). It might be added that Kulkarni25 has described
a synthesis, wherein 19 was prepared by condensation of
2-methyl-3H-quinazolin-4-one and chloral, followed by
hydrolysis.
The stabilised anion of diethylmalonate reacted readily with
11b,c in the presence of a slight excess of base to form the
Scheme 6. (i) NaCN, EtOH, water, heat, 66%. (ii) Diethylmalonate, NaH, dry THF, heat, 60%. (iii) Diethyl acetamido-malonate or ethyl acetoacetate, Na,
EtOH, heat. 22 (53%) or 23 (5%).

7248
A. Witt, J. Bergman / Tetrahedron 56 (2000) 7245–7253
cyclopropane derivative 21 (Scheme 6). A reasonable
mechanism involves an initial Michael type addition
followed by cyclisation. Various cyclopropane adducts
from diethylmalonate have been prepared similarly.26 The
vinylquinazolinones 11b,c were allowed to react with
diethyl acetamidomalonate or ethyl acetoacetate, and the
cyclisation products 22 and 23 were isolated. Two dia-
stereomers of 22 were isolated by column chromatography
on silica gel. Due to difficulties in the isolation of compound
23 by column chromatography on silica gel the yield was
only 5%. Additional material was isolated in 40% yield and
according to NMR and GC–MS there were at least two
products, which probably are diastereomers of a cyclo-
propane adduct. Interestingly cyclopropane products and
2,3-dihydrofuran derivatives have been isolated after treat-
ment of methyl (E)- and (Z)-2-bromo-4,4-dimethoxy-2-
butenoates with base.26b,27
(18.3 g, 81 mmol) in 5% NaOH (200 mL) and EtOH
(100 mL) was heated to reflux for 5 min, whereupon the
solution was allowed to cool for 15 min and then acidified
with HOAc (20 mL). The resulting precipitate was collected
and washed with water to give compound 11a (14.0 g,
100%) as a white solid; mp 170–190ЊC (dec.); IR (KBr)
3185, 3060, 2928, 1682, 1578, 1468, 1342, 983, 944,
77 cmϪ1; dH 5.81 (1H, dd, Jˆ7.3, 4.6 Hz), 6.54–6.59 (2H,
m), 7.47 (1H, ddd, Jˆ8.1, 6.9, 1.2 Hz), 7.64 (1H, d,
Jˆ8.1 Hz), 7.78 (1H, ddd, Jˆ7.8, 6.9, 1.5 Hz), 8.09 (1H,
dd, Jˆ7.8, 1.2 Hz), 12.27 (1H, s); dC 121.2 (s), 125.1 (t),
125.8 (d), 126.4 (d), 127.2 (d), 130.7 (d), 134.4 (d), 148.6
(s), 150.9 (s), 161.7 (s); MS (EI) m/z (rel. intensity) 173
(Mϩϩ1, 12%), 172 (Mϩ, 100), 146 (25), 119 (98), 90
(22), 54 (20), 44 (75); Anal. Calcd for C10H8N2O: C,
69.76; H, 4.68; N, 16.27. Found: C, 69.64; H, 4.64; N, 16.16.
2-(2,3-Dichloropropionylamino)-benzamide (10b). Simi-
larly prepared as compound 10a using anthranilamide 9 and
2,3-dichloropropionyl chloride. Yield; 77%. Beige solid;
mp 150–155ЊC (dec.); IR (KBr) 3369, 3174, 1678, 1642,
1584, 1519, 1396, 1296, 1122, 980, 871, 756, 644 cmϪ1; dH
(500 MHz) 4.08 (1H, dd, Jˆ11.9, 5.0 Hz), 4.19 (1H, dd,
Jˆ11.9, 5.1 Hz), 5.16 (1H, dd, Jˆ5.1, 5.0 Hz), 7.21 (1H,
dd, Jˆ7.8, 7.3 Hz), 7.54 (1H, ddd, Jˆ8.3, 7.3, 1.0 Hz), 7.80
(1H, s), 7.84 (1H, dd, Jˆ7.8, 1.0 Hz), 8.30 (1H, s), 8.44 (1H,
d, Jˆ8.3 Hz), 12.45 (1H, s); dC 46.3 (t), 59.2 (d), 120.3 (d),
120.6 (s), 123.5 (d), 128.6 (d), 132.3 (d), 138.4 (s), 164.6 (s),
170.4 (s). The product thus obtained was used without
further purification.
Experimental
NMR spectra were recorded in DMSO-d6 solutions, unless
otherwise stated, on a Bruker Avance DPX 300 spectro-
1
meter, operating at 300 MHz for H and 75 MHz for 13C,
respectively; d values are given in ppm or, where indicated,
on a JOEL (500 MHz) instrument. IR spectra were recorded
on a Perkin–Elmer 1600 FT-IR instrument. Mass spectra
were recorded on a Micromass Platform II spectrometer,
using the direct-inlet system, or a Hewlett–Packard GC/
MS system (HP 6890 series GC system/HP 5973 mass
selective detector) equipped with a capillary column
(HP-5MS column with 5% phenyl methyl siloxane) both
operating in the electron impact (EI) mode at 70 eV.
Fragments larger than 20% of the base peak are given.
Element analyses were performed by H. Kolbe Mikro-
analytisches Laboratorium, Mu¨lheim an der Ruhr,
Germany. HRMS analyses were performed by Sveriges
Lantbruksuniversitet (SLU), Uppsala, Sweden. Melting
points were determined on a Bu¨chi Melting Point B-545
and are uncorrected. All solvents were purified by distilla-
tion or were HPLC grade. Column chromatography was
done on silica gel 60 (230–400 mesh ASTM, Merck),
TLC analyses were run on Merck Silica Gel 60 F254 plates.
2-(1-Chlorovinyl)-3H-quinazolin-4-one (11b). Similarly
prepared as compound 11a using the benzamide 10b.
Yield; 86%. Beige solid; mp 148–158ЊC (dec.); IR (KBr)
3438, 3179, 3049, 1670, 1581, 1448, 1341, 1154, 976, 960,
772 cmϪ1; dH 6.06 (1H, d, Jˆ2.3 Hz), 6.67 (1H, d,
Jˆ2.3 Hz), 7.45 (1H, ddd, Jˆ7.9, 6.9, 1.1 Hz), 7.64 (1H,
d, Jˆ7.8 Hz), 7.74 (1H, ddd, Jˆ8.1, 6.9, 1.4 Hz), 8.09 (1H,
dd, Jˆ8.1, 1.1 Hz); dC 121.1 (t), 121.5 (s), 125.9 (d), 126.3
(d), 127.3 (d), 133.6 (d), 135.0 (s), 148.8 (s), 151.9 (s), 164.8
(s); GC/MS (EI) m/z (rel. intensity) 208 (Mϩϩ2, 16%), 206
(Mϩ, 49), 171 (100). HRMS (EI) m/z Calcd for C10H7N2OCl
206.0247: found 206.0231.
2-(2,3-Dibromopropionylamino)-benzamide (10c). Simi-
larly prepared as compound 10a using anthranilamide 9 and
2,3-dibromopropionyl chloride. Yield; 88%. Light brown
solid; mp 162–164ЊC (dec.); IR (KBr) 3382, 3188, 1668,
1582, 1521, 1398, 1300, 751, 641 cmϪ1; dH 3.98 (2H, d,
Jˆ7.2 Hz), 5.01 (1H, t, Jˆ7.2 Hz), 7.20 (1H, dd, Jˆ7.6,
7.4 Hz), 7.54 (1H, dd, Jˆ8.2, 7.4 Hz), 7.79–7.88 (2H, m),
8.35 (1H, s), 8.38 (1H, d, Jˆ8.2 Hz), 12.24 (1H, s); dC 31.9
(t), 46.2 (d), 120.5 (s), 120.6 (d), 123.6 (d), 128.7 (d), 132.3
(d), 138.5 (s), 164.9 (s), 170.4 (s). The product thus obtained
was used without further purification.
2-(3-Chloropropionylamino)-benzamide (10a). 3-Chloro-
propionyl chloride (13.3 g, 0.1 mol) was added to a solution
of anthranilamide 9 (29.0 g, 0.2 mol) in 1,4-dioxane
(80 mL) during 20 min at 0ЊC under a nitrogen atmosphere.
The mixture was stirred at room temperature for 1 h and
then diluted with water until precipitate appeared, which
was collected and washed with water to give compound
10a (18.3 g, 77%) as a white solid; mp 117–119ЊC; IR
(KBr) 3387, 3171, 1696, 1623, 1584, 1522, 1447, 1390,
1290, 1122, 870, 758, 640 cmϪ1; dH 2.83 (2H, t,
Jˆ6.1 Hz), 3.87 (2H, t, Jˆ6.1 Hz), 7.12 (1H, dd, Jˆ7.6,
7.4 Hz), 7.49 (1H, dd, Jˆ7.9, 7.4 Hz), 7.73 (1H, s), 7.80
(1H, d, Jˆ7.6 Hz), 8.27 (1H, s), 8.45 (1H, d, Jˆ7.9 Hz),
11.78 (1H, s); dC 40.4 (t), 40.5 (t), 119.8 (s), 120.3 (d),
122.6 (d), 128.6 (d), 132.2 (d), 139.3 (s), 167.8 (s), 170.7
(s). The product thus obtained was used without further
purification.
2-(1-Bromovinyl)-3H-quinazolin-4-one (11c). Similarly
prepared as compound 11a using the benzamide 10c.
Yield; 75%. Light yellow solid; mp 180–190ЊC (dec.); IR
(KBr) 3180, 3046, 2919, 1666, 1604, 1469, 1342, 1153, 975,
914, 775 cmϪ1; dH 6.45 (1H, d, Jˆ3.5 Hz), 7.00 (1H, d,
Jˆ3.5 Hz), 7.55 (1H, dd, Jˆ8.0, 7.1 Hz), 7.71 (1H, d,
Jˆ8.0 Hz), 7.84 (1H, ddd, Jˆ8.1, 7.1, 1.2 Hz), 8.13 (1H,
2-Vinyl-3H-quinazolin-4-one (11a). A mixture of 10a

A. Witt, J. Bergman / Tetrahedron 56 (2000) 7245–7253
7249
d, Jˆ8.1 Hz), 12.50 (1H, s); dC 121.2 (s), 123.0 (s), 125.9
(d), 127.3 (t), 127.6 (d), 127.8 (d), 134.8 (d), 147.8 (s), 149.2
(s), 161.7 (s); GC/MS (EI) m/z (rel. intensity) 252 (Mϩϩ2,
35%), 250 (36), 171 (100); Anal. Calcd for C10H7N2OBr:
C, 47.84; H, 2.81; N, 11.16. Found: C, 47.91; H, 2.88; N,
11.10.
C, 70.95; H, 5.41; N, 15.04. Found: C, 70.84; H, 5.45; N,
15.08.
15a (rfˆ0.30), 250 mg (8.4%) as a white solid; mp 87–
88ЊC; IR (KBr) 3069, 2903, 1686, 1593, 1474, 1336,
1111, 1058, 967, 767, 693, 640 cmϪ1; dH 3.09 (2H, t,
Jˆ7.0 Hz), 3.30 (3H, s), 3.52 (3H, s), 3.81 (2H, t,
Jˆ7.0 Hz), 7.45 (1H, dd, Jˆ7.9, 7.3 Hz), 7.55 (1H, d,
Jˆ7.9 Hz), 7.75 (1H, ddd, Jˆ8.0, 7.3, 1.2 Hz), 8.07 (1H,
d, Jˆ8.0 Hz); dC 30.0 (q), 34.2 (t), 58.2 (q), 69.0 (t), 119.8
(s), 126.1 (d), 126.2 (d), 126.6 (d), 134.1 (d), 146.7 (s),
155.7 (s), 161.3 (s); Anal. Calcd for C12H16N2O2: C,
66.04; H, 6.47; N, 12.84. Found: C, 65.86; H, 6.38; N, 12.69.
2-Amino-N-methylbenzamide (12). Methylamine in water
(40 mL, 60%) was added to isatoic anhydride (16.2 g,
0.1 mol), portionwise under stirring and controlling the
CO2 release. The reaction mixture was maintained at room
temperature for 1 h. The solution was neutralised with 2 M
HCl (ϳ20 mL) and the resulting precipitate was collected
and washed with water to give compound 12 (10.0 g, 67%)
as a grey solid; mp 79–81ЊC (Lit.,20b mp 79–80ЊC); IR
(KBr) 3424, 3306, 3068, 1619, 1587, 1538, 1309, 1159,
748 cmϪ1; dH 2.71 (3H, d, Jˆ4.5 Hz), 6.39 (2H, s), 6.48
(1H, ddd, Jˆ8.0, 7.0, 1.0 Hz), 6.67 (1H, dd, Jˆ8.3,
0.9 Hz), 7.10 (1H, ddd, Jˆ8.3, 7.0, 1.3 Hz), 7.45 (1H, dd,
Jˆ8.0, 1.3 Hz), 8.17 (1H, d, Jˆ3.6 Hz); dC 26.0 (q), 114.6
(d), 114.8 (s), 116.3 (d), 127.9 (d), 131.5 (d), 149.5 (s),
169.4 (s); MS (EI) m/z (rel. intensity) 151 (Mϩϩ1, 3%),
150 (Mϩ, 42), 120 (47), 119 (25), 92 (32), 65 (22), 44
(58), 40 (100).
3-Methyl-2-(2-ethoxyethyl)-3H-quinazolin-4-one (15b).
A mixture of 13 (5.35 g, 22 mmol) in 5% NaOH (60 mL)
and EtOH (30 mL) was heated to reflux for 5 min. The
solution was allowed to cool and then acidified with
HOAc (10 mL). The solvent was concentrated under
reduced pressure to a volume of 20 mL and poured on
water (15 mL). The resulting precipitate was collected and
purified by chromatography on a silica gel column (1:1,
ethyl acetate in hexane as the eluent) to give compound
15b (2.06 g, 40%) as a beige solid; mp 80–81ЊC; IR
(KBr) 2976, 2864, 1690, 1598, 1474, 1338, 1111, 778,
696 cmϪ1; dH 1.10 (3H, t, Jˆ7.0 Hz), 3.09 (2H, t,
Jˆ7.0 Hz), 3.49 (2H, q, Jˆ7.0 Hz), 3.53 (3H, s), 3.84
(2H, t, Jˆ7.0 Hz), 7.45 (1H, dd, Jˆ8.0, 7.1 Hz), 7.55 (1H,
d, Jˆ8.0 Hz), 7.75 (1H, dd, Jˆ8.1, 7.1 Hz), 8.08 (1H, d,
Jˆ8.1 Hz); dC 15.1 (q), 30.0 (q), 34.5 (t), 65.5 (t), 66.9
(t), 119.7 (s), 126.1 (d), 126.2 (d), 126.6 (d), 134.1 (d),
146.7 (s), 155.7 (s), 161.2 (s). HRMS (EI) m/z Calcd for
C13H16N2O2 232.1212: found 232.1203.
2-(3-Chloropropionylamino)-N-methylbenzamide (13).
Similarly prepared as compound 10a using the benzamide
12 and 3-chloropropionyl chloride. Yield; 75%. White
solid; mp 140–141ЊC; IR (KBr) 3311, 3096, 2975, 1684,
1625, 1599, 1516, 1444, 1289, 758, 694 cmϪ1; dH 2.79 (3H,
d, Jˆ4.5 Hz), 2.84 (2H, t, Jˆ6.2 Hz), 3.87 (2H, t,
Jˆ6.2 Hz), 7.14 (1H, dd, Jˆ7.7, 7.4 Hz), 7.48 (1H, ddd,
Jˆ8.3, 7.4, 1.0 Hz), 7.71 (1H, d, Jˆ7.8 Hz), 8.39 (1H, d,
Jˆ8.3 Hz), 8.69 (1H, s), 11.48 (1H, s); dC 26.2 (q), 40.2 (t),
40.5 (t), 120.5 (d), 120.9 (s), 122.8 (d), 127.9 (d), 131.8 (d),
138.6 (s), 167.8 (s), 168.6 (s); MS (EI) m/z (rel. intensity)
242 (Mϩϩ2, 8%), 240 (Mϩ, 23), 150 (100), 146 (77), 120
(95), 119 (56), 92 (37), 90 (24), 65 (35), 63 (38), 55 (34), 44
(50). The product thus obtained was used without further
purification.
2-Acetylamino-2-[2-(4-oxo-3,4-dihydroquinazolin-2-yl)-
ethyl]-malonic acid diethyl ester (16a). Sodium (1.19 g,
52 mmol) was dissolved in EtOH (120 mL) at room
temperature under a nitrogen atmosphere. Diethyl acetami-
domalonate (11.38 g, 52 mmol) and the vinylquinazolinone
11a (8.81 g, 51 mmol) were added and the reaction mixture
was heated to reflux for 3 h. Water (40 mL) and HOAc
(4 mL) were added and the clear solution was allowed to
crystallise over night. White crystals were collected and
washed with EtOH to give compound 16a (16.0 g, 80%);
mp 173–174ЊC; IR (KBr) 3265, 3032, 2892, 1748, 1674,
1640, 1613, 1529, 1467, 1260, 1188, 777 cmϪ1; dH 1.14
(6H, t, Jˆ7.1 Hz), 1.91 (3H, s), 2.47–2.63 (4H, m), 4.05–
4.15 (4H, m), 7.43 (1H, ddd, Jˆ8.0, 6.8, 1.2 Hz), 7.58 (1H,
d, Jˆ8.0 Hz), 7.75 (1H, ddd, Jˆ8.0, 6.8, 1.2 Hz), 8.06 (1H,
dd, Jˆ8.0, 1.2 Hz), 8.33 (1H, s), 12.25 (1H, s); dC 13.8 (q),
22.2 (q), 28.9 (t), 29.7 (t), 61.7 (t), 65.5 (s), 120.8 (s), 125.7
(d), 125.9 (d), 126.6 (d), 134.2 (d), 148.7(s), 156.4 (s), 161.8
(s), 167.4 (s), 169.3 (s); Anal. Calcd for C19H23N3O6: C,
58.60; H, 5.95; N, 10.79. Found: C, 58.70; H, 6.06; N, 10.72.
3-Methyl-2-vinyl-3H-quinazolin-4-one (14) and 3-methyl-
2-(2-methoxyethyl)-3H-quinazolin-4-one (15a). A mixture
of 13 (3.28 g, 14 mmol) in 0.5 M Na2CO3 aqueous solution
with 10% MeOH (70 mL) was heated to reflux for 1.5 h.
The reaction mixture was neutralised with 2 M HCl and
extracted with ethyl acetate (50 mL×3). The combined
extracts were dried (MgSO4) and concentrated under
reduced pressure to afford a solid residue, which was puri-
fied by chromatography on a silica gel column (1:1, ethyl
acetate in hexane as the eluent).
14 (rfˆ0.48), 580 mg (23%) as a white solid; mp 123–
125ЊC; IR (KBr) 3074, 3035, 1670, 1560, 1470, 1416,
1336, 1300, 1132, 932, 773, 694 cmϪ1; dH 3.56 (3H, s),
5.79 (1H, dd, Jˆ10.7, 1.9 Hz), 6.44 (1H, dd, Jˆ16.6,
1.9 Hz), 7.01 (1H, dd, Jˆ16.6, 10.7 Hz), 7.46 (1H, dd,
Jˆ8.0, 7.0 Hz), 7.62 (1H, d, Jˆ8.0 Hz), 7.76 (1H, dd,
Jˆ7.9, 7.0 Hz), 8.08 (1H, dd, Jˆ7.9, 1.3 Hz); dC 30.4 (q),
120.0 (s), 126.2 (t), 126.2 (d), 126.5 (d), 127.1 (d), 129.8 (d),
134.2 (d), 146.9 (s), 152.3 (s), 161.1 (s); MS (EI) m/z (rel.
intensity) 187 (Mϩϩ1, 8%), 186 (Mϩ, 68), 185 (100), 68
(33), 44 (29), 42 (23), 40 (36); Anal. Calcd for C11H10N2O:
2-Acetylamino-2-[2-(3-methyl-4-oxo-3,4-dihydroquina-
zolin-2-yl)-ethyl]-malonic acid diethyl ester (17a).
Diethyl acetamidomalonate (380 mg, 1.7 mmol) dissolved
in dry THF (5 mL) was added to a suspension of NaH
(42 mg, 1.8 mmol) in dry THF (5 mL) at room temperature
under a nitrogen atmosphere. After 15 min the vinylquina-
zolinone 14 (293 mg, 1.6 mmol) in dry THF (5 mL) was
added and the mixture allowed to stand at room temperature

7250
A. Witt, J. Bergman / Tetrahedron 56 (2000) 7245–7253
over night. The mixture was quenched with HOAc (0.2 mL)
and concentrated under reduced pressure to afford a yellow
oil, which was purified by chromatography on silica gel
column (4:1, ethyl acetate in hexane as the eluent) to give
compound 17a (260 mg, 41%) as a colourless oil; IR (neat)
3368, 2979, 1738, 1668, 1599, 1474, 1201, 1013, 775,
698 cmϪ1; dH (CDCl3) 1.24 (6H, t, Jˆ7.1 Hz), 2.04 (3H,
s), 2.78–2.90 (4H, m), 3.60 (3H, s), 4.16–4.28 (4H, m),
6.93 (1H, s), 7.44 (1H, dd, Jˆ7.8, 6.9 Hz), 7.59 (1H, d,
Jˆ7.8 Hz), 7.69 (1H, ddd, Jˆ8.2, 6.9, 1.5 Hz), 8.22 (1H,
dd, Jˆ8.2, 1.2 Hz); dC (CDCl3) 13.9 (q), 23.0 (q), 30.0 (t),
30.2 (t), 30.3 (q), 62.7 (t), 65.6 (s), 120.1 (s), 126.4 (d),
126.6 (d), 126.8 (d), 134.0 (d), 146.9 (s), 155.6 (s), 162.3
(s), 167.7 (s), 169.4 (s); Anal. Calcd for C20H25N3O6: C,
59.54; H, 6.25; N, 10.42. Found: C, 59.46; H, 6.34; N, 10.32.
Jˆ8.0 Hz), 7.75 (1H, ddd, Jˆ7.9, 7.0, 1.2 Hz), 8.06 (1H,
dd, Jˆ7.9, 1.3 Hz); dC 11.9 (q), 32.0 (t), 46.1 (t), 49.8 (t),
120.8 (s), 125.7 (d), 125.9 (d), 126.7 (d), 134.9 (d), 149.0
(s), 156.9 (s), 161.8 (s).
2-(2-Diethylaminoethyl)-3-methyl-3H-quinazolin-4-one
(17c). Diethylamine (distilled from CaH2, 149 mg, 2 mmol)
and HOAc (0.1 mmol) were added to a mixture of the vinyl-
quinazolinone 14 (190 mg, 1 mmol) in MeOH (10 mL). The
solution was heated to reflux over night. After evaporation,
the residue was dissolved in ice-water (ϳ20 mL). The
aqueous solution was made basic with 2 M NaOH and
extracted with ethyl acetate (25 mL×2). The combined
extracts were dried (MgSO4) and concentrated under
reduced pressure to give compound 17c (225 mg, 85%) as
a yellow oil; IR (neat) 2970, 1674, 1599, 1474, 1421, 1338,
1011, 774, 697 cmϪ1; dH (CDCl3) 1.05 (6H, t, Jˆ7.1 Hz),
2.60 (4H, q, Jˆ7.1 Hz), 2.96 (4H, s), 3.62 (3H, s), 7.39 (1H,
dd, Jˆ7.9, 6.9 Hz), 7.59 (1H, d, Jˆ7.9 Hz), 7.67 (1H, ddd,
Jˆ8.0, 6.9, 1.3 Hz), 8.21 (1H, dd, Jˆ8.0, 0.8 Hz); dC
(CDCl3) 12.3 (q), 31.0 (q), 34.0 (t), 47.6 (t), 50.6 (t),
120.6 (s), 126.7 (d), 127.1 (d), 127.2 (d), 134.4 (d), 147.6
(s), 156.5 (s), 162.9 (s); Anal. Calcd for C15H21N3O:
C, 69.47; H, 8.16; N, 16.20. Found: C, 69.56; H, 8.04; N,
16.11.
2-[2-(1H-Indol-3-yl)-ethyl]-3H-quinazolin-4-one (16b).
A mixture of the vinylquinazolinone 11a (1.02 g,
5.9 mmol) and indole (0.79 g, 6.7 mmol) in HOAc (6 mL)
was heated to reflux for 4 h. A white precipitate was
collected and washed with EtOH to give compound 16b
(1.62 g, 95%); mp 302–303ЊC; IR (KBr) 3176, 3043,
2918, 1682, 1613, 1469, 1335, 1231, 1072, 770,
732 cmϪ1; dH 2.95–3.01 (2H, m), 3.15–3.22 (2H, m),
6.96 (1H, dd, Jˆ7.9, 7.0 Hz), 7.06 (1H, dd, Jˆ8.0,
7.0 Hz), 7.15 (1H, d, Jˆ2.0 Hz), 7.33 (1H, d, Jˆ8.0 Hz),
7.44 (1H, ddd, Jˆ7.9, 7.0, 1.0 Hz), 7.60–7.65 (2H, m), 7.76
(1H, ddd, Jˆ8.1, 7.0, 1.5 Hz), 8.09 (1H, dd, Jˆ8.1, 1.1 Hz),
10.79 (1H, s), 12.28 (1H, s); dC 22.7 (t), 35.7 (t), 111.4 (d),
113.3 (s), 118.2 (d), 118.5 (d), 120.8 (s), 121.0 (d), 122.4
(d), 125.7 (d), 125.9 (d), 126.8 (d), 127.0 (s), 134.3 (d),
136.2 (s), 148.9 (s), 157.3 (s), 161.9 (s); MS (EI) m/z (rel.
intensity) 290 (Mϩϩ1, 3%), 289 (Mϩ, 15), 130 (100), 44
(47), 40 (33); Anal. Calcd for C18H15N3O: C, 74.72; H, 5.22;
N, 14.52. Found: C, 74.64; H, 5.31; N, 14.44.
2-(2-Piperidin-1-yl-ethyl)-3H-quinazolin-4-one
(16d).
Similarly prepared as compound 16c using the vinylquina-
zolinone 11a and piperidine. Yield; 84%. Compound 16d
was recrystallised from ethyl acetate to yield an analytically
pure substance. White solid; mp 148–149ЊC (Lit.,23 mp
148ЊC); IR (KBr) 3168, 3100, 2933, 2745, 1680, 1620,
1609, 1468, 1248, 894, 769 cmϪ1; dH 1.31–1.40 (2H, m),
1.40–1.53 (4H, m), 2.35–2.45 (4H, m), 2.66–2.81 (4H, m),
7.43 (1H, dd, Jˆ8.0, 7.2 Hz), 7.57 (1H, d, Jˆ8.0 Hz), 7.75
(1H, ddd, Jˆ8.0, 7.2, 1.0 Hz), 8.06 (1H, dd, Jˆ8.0, 0.6 Hz),
12.24 (1H, s); dC 24.0 (t), 25.6 (t), 31.8 (t), 53.6 (t), 55.8 (t),
120.8 (s), 125.6 (d), 125.9 (d), 126.7 (d), 134.2 (d), 148.9
(s), 156.7 (s), 161.7 (s).
2-[2-(1H-Indol-3-yl)-ethyl]-3-methyl-3H-quinazolin-4-one
(17b). Similarly prepared as compound 16b using the vinyl-
quinazolinone 14. Yield; 75%. White solid; mp 185–186ЊC;
IR (KBr) 3262, 1665, 1588, 1470, 1340, 1232, 1008,
742 cmϪ1; dH 3.20 (4H, s), 3.52 (3H, s), 6.97 (1H, dd,
Jˆ7.9, 7.1 Hz), 7.07 (1H, dd, J ˆ7.9, 7.1 Hz), 7.24 (1H,
d, Jˆ2.2 Hz), 7.35 (1H, d, Jˆ7.9 Hz), 7.47 (1H, ddd,
Jˆ7.9, 7.0, 1.0 Hz), 7.58 (1H, d, Jˆ7.9 Hz), 7.66 (1H, d,
Jˆ7.9 Hz), 7.78 (1H, ddd, Jˆ8.1, 7.0, 1.4 Hz), 8.11 (1H, dd,
Jˆ8.1, 1.0 Hz), 10.82 (1H, s); dC 21.8 (t), 29.9 (q), 35.3 (t),
111.4 (d), 113.5 (s), 118.3 (d), 118.3 (d), 119.8 (s), 120.9
(d), 122.6 (d), 126.2 (d), 126.2 (d), 126.8 (d), 127.1 (s),
134.1 (d), 136.3 (s), 147.0 (s), 157.5 (s), 161.4 (s); Anal.
Calcd for C19H17N3O: C, 75.23; H, 5.65; N, 13.85. Found:
C, 75.19; H, 5.77; N, 13.81.
3-Methyl-2-(2-piperidin-1-yl-ethyl)-3H-quinazolin-4-one
(17d). Similarly prepared as compound 17c using the vinyl-
quinazolinone 14 and piperidine (distilled from CaH2).
Yield; 100%. Light yellow oil; IR (neat) 2934, 2854,
1674, 1599, 1474, 1422, 1338, 1118, 1012, 773, 698
cmϪ1; dH (CDCl3) 1.40–1.53 (2H, m), 1.58–1.68 (4H, m),
2.47–2.63 (4H, m), 2.85–2.98 (2H, m), 2.98–3.10 (2H, m),
3.63 (3H, s), 7.41 (1H, dd, Jˆ8.1, 6.9 Hz), 7.60 (1H, d,
Jˆ8.1 Hz), 7.69 (1H, dd, Jˆ8.1, 6.9 Hz), 8.23 (1H, dd,
Jˆ8.1, 1.4 Hz); dC (CDCl3) 24.3 (t), 25.9 (t), 30.7 (q),
33.0 (t), 54.7 (t), 56.1 (t), 120.4 (s), 126.6 (d), 126.9 (d),
127.0 (d), 134.2 (d), 147.3 (s), 155.9 (s), 162.6 (s); Anal.
Calcd for C16H21N3O: C, 70.82; H, 7.80; N, 15.48. Found:
C, 70.67; H, 7.89; N, 15.32.
2-(2-Diethylaminoethyl)-3H-quinazolin-4-one (16c). Di-
ethylamine (149 mg, 2 mmol) and HOAc (0.1 mmol) were
added to a mixture of the vinylquinazolinone 11a (175 mg,
1 mmol) in MeOH (10 mL). The solution was heated to
reflux over night. After evaporation, the residue was recrys-
tallised from hexane to give compound 16c (123 mg, 49%)
as white crystals; mp 115–117ЊC (Lit.,23 mp 122ЊC); IR
(KBr) 3172, 3034, 2974, 2799, 1682, 1618, 1466, 1320,
1206, 1067, 904, 776 cmϪ1; dH 0.93 (6H, t, Jˆ7.1 Hz),
2.48 (4H, q, Jˆ7.1 Hz), 2.70 (2H, t, Jˆ6.9 Hz), 2.83 (2H,
t, Jˆ6.9 Hz), 7.43 (1H, dd, Jˆ8.0, 7.0 Hz), 7.57 (1H, d,
2-(2-Azidoethyl)-3H-quinazolin-4-one (16e). Sodium
azide (0.34 g, 5.2 mmol) dissolved in water (5 mL) was
added to a stirred solution of the vinylquinazolinone 11a
(0.58 g, 3.4 mmol) in THF (25 mL). After 1 h at room
temperature the solution was heated to 60ЊC over night.
The solution was acidified with 10% HCl and then diluted
with water (50 mL). The aqueous phase was extracted with
ethyl acetate (2×50 mL). The combined extracts were dried

A. Witt, J. Bergman / Tetrahedron 56 (2000) 7245–7253
7251
(Na2SO4) and concentrated under reduced pressure to afford
a solid residue, which was purified by chromatography on
silica gel column (1:1, ethyl acetate in hexane as the eluent,
rfˆ0.38) to give compound 16e (0.35 g, 48%) as a white
solid; mp 152–153ЊC; IR (KBr) 3170, 3033, 2972, 2914,
2087, 1677, 1614, 1469, 1253, 883, 780, 690 cmϪ1; dH 2.90
(2H, t, Jˆ6.6 Hz), 3.77 (2H, t, Jˆ6.6 Hz), 7.47 (1H, dd,
Jˆ7.9, 7.1 Hz), 7.60 (1H, d, Jˆ7.9 Hz), 7.78 (1H, ddd,
Jˆ8.1, 7.1, 1.4 Hz), 8.08 (1H, dd, Jˆ8.1, 1.3 Hz), 12.27
(1H, s); dC 33.9 (t), 47.5 (t), 120.9 (s), 125.7 (d), 126.3
(d), 126.8 (d), 134.4 (d), 148.5 (s), 154.6 (s), 161.6 (s);
MS (EI) m/z (rel. intensity) 216 (Mϩϩ1, 1%), 215 (Mϩ,
8) 187 (73), 186 (38), 160 (82), 132 (33), 120 (28), 119
(100), 92 (31), 90 (28), 77 (24), 64 (22), 63 (23), 44 (59),
43 (72), 41 (30), 40 (65); Anal. Calcd for C10H9N5O: C,
55.81; H, 4.21; N 32.54. Found: C, 56.02; H, 4.28; N, 32.64.
resulting precipitate was collected after 48 h and washed
with water. The solid residue was purified by chromato-
graphy on a silica gel column (1:1, ethyl acetate in hexane
as eluent, rfˆ0.20) to give compound 17f (0.15 g, 23%) as a
white solid; mp 197–199ЊC; IR (KBr) 2946, 2249, 1671,
1609, 1472, 1422, 1327, 1137, 779, 698 cmϪ1; dH 2.95 (2H,
t, Jˆ6.7 Hz), 3.25 (2H, t, Jˆ6.7 Hz), 3.52 (3H, s), 7.49 (1H,
ddd, Jˆ8.0, 6.9, 1.0 Hz), 7.61 (1H, d, Jˆ8.0 Hz), 7.79 (1H,
ddd, Jˆ8.1, 6.9, 1.5 Hz), 8.11 (1H, d, Jˆ8.1, 1.1 Hz); dC
13.3 (t), 29.3 (t), 29.4 (q), 119.8 (s), 120.5 (s), 126.2 (d),
126.6 (d), 126.8 (d), 134.3 (d), 146.4 (s), 154.8 (s), 161.1 (s);
Anal. Calcd for C12H11N3O: C, 67.59; H, 5.20; N, 19.71.
Found: C, 67.78; H, 5.21; N, 19.75.
N-(3-carboxy-acryloyl)-anthranilamide (18). Maleic
anhydride (7.94 g, 81 mmol) was added to a mixture of
anthranilamide 9 (10.01 g, 74 mmol) in dichloromethane
(130 mL) at 40ЊC and within 1–2 min a new yellow pre-
cipitate was formed. Stirring was continued for 0.5 h and the
resulting precipitate was collected to give 18 (16.19 g, 94%)
as a yellowish solid; mp 180–182ЊC; IR (KBr) 3443, 3355,
3229, 1717, 1671, 1584, 1540, 1402, 1252, 972, 840,
748 cmϪ1; dH 6.26 (1H, d, J ˆ12.0 Hz), 6.55 (1H, d,
Jˆ12.0 Hz),7.16 (1H, ddd, Jˆ7.9, 7.2, 0.8 Hz), 7.51 (1H,
ddd, Jˆ8.3, 7.2, 1.2 Hz), 7.74 (1H, s), 7.82 (1H, dd, Jˆ7.9,
1.2 Hz), 8.28 (1H, s), 8.45 (1H, d, Jˆ8.3 Hz), 11.93 (1H, s),
12.97 (1H, s); dC 120.1 (s), 120.5 (d), 123.0 (d), 128.6 (d),
129.1 (d), 132.2 (d), 133.5 (d), 139.0 (s), 163.4 (s), 166.5 (s),
170.5 (s). The product thus obtained was used without
further purification.
3-Methyl-2-(2-azidoethyl)-3H-quinazolin-4-one
(17e).
Similarly prepared as compound 16e using the vinylquina-
zolinone 14 and sodium azide to give compound 17e, which
was purified by chromatography on silica gel column (1:1,
ethyl acetate in hexane as the eluent, rfˆ0.52). Yield; 50%.
White solid; mp 65–67ЊC; IR (KBr) 2936, 2101, 1666,
1603, 1477, 1295, 1132, 956, 779, 697 cmϪ1; dH 3.16
(2H, t, Jˆ6.3 Hz), 3.52 (3H, s), 3.82 (2H, t, Jˆ6.3 Hz),
7.48 (1H, ddd, Jˆ8.0, 7.0, 1.0 Hz), 7.59 (1H, d,
Jˆ8.0 Hz), 7.79 (1H, ddd, Jˆ8.0, 7.0, 1.5 Hz), 8.11 (1H,
dd, Jˆ8.0, 1.1 Hz); dC 29.6 (q), 33.7 (t), 47.0 (t), 119.8 (s),
126.2 (d), 126.4 (d), 126.7 (d), 134.2 (d), 146.5 (s), 155.2
(s), 161.2 (s); MS (EI) m/z (rel. intensity) 230 (Mϩϩ1,
Ͻ0.1%), 229 (Mϩ, 2) 185 (39), 174 (35), 146 (23), 77
(22), 69 (29), 57 (27), 55 (32), 45 (22), 44 (82), 43 (81),
42 (25), 41 (43), 40 (100). In contrast to the azide 16e the
azide 17e was to unstable to allow elemental analysis.
3-(4-Oxo-3,4-dihydroquinazolin-2-yl)-acrylic acid (19).
A mixture of 18 (2.34 g, 10 mmol) and NaOAc (0.51 g,
6.2 mmol) in acetic anhydride (15 mL) was stirred at
room temperature over night and then poured into water
(75 mL). Stirring was continued for 3–4 h and the resulting
precipitate was collected to give compound 19 (0.84 g,
39%) as a yellow solid; mp 256–258ЊC (dec.) (Lit.,25 mp
262–263ЊC); IR (KBr) 3436, 3202, 1692, 1651, 1589, 1470,
1339, 1183, 981, 764, 623 cmϪ1; dH 7.05 (1H, d,
Jˆ15.8 Hz), 7.26 (1H, d, Jˆ15.8 Hz), 7.53 (1H, dd,
Jˆ8.0, 7.1 Hz), 7.69 (1H, d, Jˆ8.0 Hz), 7.82 (1H, dd,
Jˆ7.9, 7.1 Hz), 8.11 (1H, d, Jˆ7.9 Hz), 12.52 (1H, s); dC
121.7 (s), 125.9 (d), 127.3 (d), 127.7 (d), 129.0 (d), 134.6
(d), 135.9 (d), 148.3 (s), 149.5 (s), 161.5 (s), 166.4 (s).
3-(4-Oxo-3,4-dihydroquinazolin-2-yl)-propionitrile (16f).
The vinylquinazolinone 11a (0.52 g, 3.0 mmol) was added
to a solution of sodium cyanide (0.30 g, 6.1 mmol) in EtOH
(20 mL) and water (5 mL). The reaction mixture was heated
to reflux over night and then quenched with 2 M HCl. After
evaporation, the solid residue was taken up in saturated
NaHCO3/ethyl acetate (1:1). The aqueous phase was
extracted with ethyl acetate (25 mL×4), the combined
organic phases were dried (MgSO4) and concentrated
under reduced pressure to give compound 16f (0.46 g,
76%). Compound 16f was recrystallised from ethanol to
yield an analytically pure substance. White solid; mp
225ЊC (dec.) (Lit.,21 mp 243.5ЊC); IR (KBr) 3171, 3042,
2982, 2246, 1686, 1626, 1605, 1470, 1418, 1339, 1252,
905, 773, 688, 638 cmϪ1; dH 2.94–2.99 (4H, m), 7.48
(1H, dd, Jˆ8.2, 7.0 Hz), 7.62 (1H, d, Jˆ8.2 Hz), 7.79
(1H, ddd, Jˆ8.1, 7.0, 1.5 Hz), 8.09 (1H, dd, Jˆ8.1,
1.2 Hz), 12.31 (1H, s); dC 13.4 (t), 29.5 (t), 120.1 (s),
121.0 (s), 125.8 (d), 126.5 (d), 126.9 (d), 134.5 (d), 148.4
(s), 154.3 (s), 161.5 (s).
3-(4-Oxo-3,4-dihydroquinazolin-2-yl)-acrylonitrile (20).
The halosubstituted vinylquinazolinone 11c (0.50 g,
2.0 mmol) was added to a solution of sodium cyanide
(0.20 g, 4.1 mmol) in EtOH (20 mL) and water (5 mL).
The reaction mixture was heated to reflux over night and
then quenched with 2 M HCl. The resulting precipitate was
collected to give the conjugated nitrile 20 (0.26 g, 66%) as a
brown solid; mp 240ЊC (dec.); IR (KBr) 3424, 3178, 3062,
2925, 2224, 1666, 1469, 1277, 1144, 964, 770 cmϪ1; dH
6.95 (1H, d, Jˆ16.5 Hz), 7.31 (1H, d, Jˆ16.5 Hz), 7.58
(1H, dd, Jˆ7.9, 7.0 Hz), 7.71 (1H, d, Jˆ7.9 Hz), 7.86
(1H, ddd, Jˆ8.0, 7.0, 1.5 Hz), 8.14 (1H, dd, Jˆ8.0,
1.3 Hz), 12.57 (1H, s); dC 106.7 (d), 117.2 (s), 121.8 (s),
126.0 (d), 127.7 (d), 127.8 (d), 134.8 (d), 142.7 (d), 147.9
(s), 148.3 (s), 161.2 (s); Anal. Calcd for C11H7N3O:
C, 67.00; H, 3.58; N, 21.31. Found: C, 66.65; H, 4.25; N,
20.88.
3-(3-Methyl-4-oxo-3,4-dihydroquinazolin-2-yl)-propio-
nitrile (17f). A mixture of 13 (0.72 g, 3.0 mmol) in 0.5 M
Na2CO3 aqueous solution (25 mL) was heated to reflux.
When the mixture became clear sodium cyanide (0.24 g,
4.9 mmol) and methanol (3 mL) were added, whereupon
the solution was refluxed for 1.5 h and allowed to cool to
room temperature before quenching with 2 M HCl. The

7252
A. Witt, J. Bergman / Tetrahedron 56 (2000) 7245–7253
2-(4-Oxo-3,4-dihydroquinazolin-2-yl)-cyclopropane-1,1-
dicarboxylic acid diethyl ester (21). Diethylmalonate
(390 mg, 2.4 mmol) was added to a suspension of NaH
(60 mg, 2.5 mmol) in dry THF (13 mL) at room temperature
under a nitrogen atmosphere. After 15 min was the halo-
substituted vinylquinazolinone 11b (420 mg, 2.0 mmol) in
dry THF (7 mL) added and the mixture was heated to reflux
for 3 h. The mixture was quenched with diluted HOAc and
concentrated under reduced pressure to afford compound 21
(400 mg, 60%) as a light brown solid; IR (KBr) 3424, 2979,
1737, 1674, 1610, 1471, 1208, 769, 630 cmϪ1; dH 0.80 (3H,
t, Jˆ7.1 Hz), 1.20 (3H, t, Jˆ7.1 Hz), 1.76 (1H, dd, Jˆ8.7,
4.6 Hz), 2.25 (1H, dd, Jˆ7.0, 4.6 Hz), 2.99 (1H, dd, Jˆ8.7,
7.0 Hz), 3.87 (2H, q, Jˆ7.1 Hz), 4.17 (2H, q, Jˆ7.1 Hz),
7.36–7.52 (2H, m), 7.74 (1H, ddd, Jˆ8.1, 6.9, 1.4 Hz), 8.06
(1H, dd, Jˆ8.1, 1.4 Hz), 12.60 (1H,s); dC 13.5 (q), 13.9 (q),
18.1 (t), 27.9 (d), 37.9 (s), 60.8 (t), 61.8 (t), 120.9 (s), 125.8
(d), 126.2 (d), 126.5 (d), 134.4 (d), 148.0 (s), 152.7 (s),
161.6 (s), 165.2 (s), 168.3 (s); GC/MS (EI) m/z (rel. inten-
sity) 331 (Mϩϩ1, 1%), 330 (Mϩ, 8), 285 (23), 284 (100),
239 (27), 210 (20), 184 (84); Anal. Calcd for C17H18N2O5:
C, 61.81; H, 5.49; N, 8.48. Found: C, 61.64; H, 5.36; N,
8.29.
62.8 (s), 74.8 (d), 121.5 (s), 125.9 (d), 127.1 (d), 127.3 (d),
134.6 (d), 147.8 (s), 152.9 (s), 161.4 (s), 167.0 (s), 170.1 (s),
170.3 (s); Anal. Calcd for C17H17N3O6: C, 56.82; H, 4.77; N,
11.69. Found: C, 56.75; H, 4.86; N, 11.55.
2-Methyl-5-(4-oxo-3,4-dihydroquinazolin-2-yl)-4,5-dihy-
dro-furan-3-carboxylic acid ethyl ester (23). Similarly
prepared as compound 22 using the halosubstituted vinyl-
quinazolinone 11b (420 mg, 2.0 mmol) and ethyl aceto-
acetate (130 mg, 2.3 mmol). The precipitate was purified
by chromatography on a silica gel column (1:1, ethyl acetate
in hexane as the eluent, rfˆ0.39) to yield compound 23
(30 mg, 5%) as a white solid; mp 152–154ЊC; IR (KBr)
3449, 3181, 2925, 1680, 1648, 1607, 1468, 1226, 1080,
772 cmϪ1; dH 1.21 (3H, t, Jˆ7.1 Hz), 2.20 (3H, s), 3.10–
3.37 (2H, m), 4.11 (2H, q, Jˆ7.1 Hz), 5.53 (1H, dd, Jˆ8.1,
10.9 Hz), 7.53 (1H, ddd, Jˆ7.9, 7.0, 1.0 Hz), 7.68 (1H, d,
Jˆ7.9 Hz), 7.82 (1H, ddd, Jˆ8.1, 7.0, 1.5 Hz), 8.12 (1H, dd,
Jˆ8.1, 1.2 Hz), 12.46 (1H, s); dC 13.7 (q), 14.3 (q), 33.3 (t),
59.2 (t), 79.4 (d), 101.6 (s), 121. 5 (s), 125.8 (d), 127.0 (d),
127.3 (d), 134.5 (d), 148.0 (s), 154.2 (s), 161.6 (s), 164.7 (s),
166.6 (s); GC/MS (EI) m/z (rel. intensity) 301 (Mϩϩ1, 4%),
300 (Mϩ, 22), 255 (44), 239 (100), 211 (68), 185 (24); Anal.
Calcd for C16H16N2O4: C, 63.99; H, 5.37; N, 9.33. Found: C,
64.11; H, 5.41; N, 9.26.
3-Acetylamino-2-oxo-5-(4-oxo-3,4-dihydroquinazolin-2-
yl)-tetrahydro-furan-3-carboxylic acid ethyl ester (22).
Sodium (60 mg, 2.6 mmol) was dissolved in EtOH
(20 mL) at room temperature under a nitrogen atmosphere.
Diethyl acetamidomalonate (590 mg, 2.7 mmol) and the
References
halosubstituted
vinylquinazolinone
11c
(580 mg,
2.3 mmol) were added and the reaction mixture was heated
to reflux for 3 h. Water (3 mL) and HOAc (0.3 mL) were
added and the reaction mixture was concentrated under
reduced pressure to afford a beige oil, which was purified
by chromatography on a silica gel column (9:1, ethyl acetate
in hexane as the eluent).
1. Johne, S. Prog. Chem. Org. Nat. Prod. 1984, 46, 159–229.
2. Eguchi, S.; Suzuki, T.; Okawa, T.; Matsushita, Y.; Yashima, E.;
Okamoto, Y. J. Org. Chem. 1996, 61, 7316–7319.
3. (a) Bergman, J.; Brynolf, A. Tetrahedron 1990, 46, 1295–1310.
(b) Bergman, J. J. Chem. Res. (S) 1997, 224.
4. Johne, S. In Supplements to the 2nd Edition of Rodd’s Chem-
istry of Carbon Compounds, Ansell, M. F. Ed.; Elsevier:
Amsterdam, 1995; Vol. IV I/J, pp 223–240.
first diastereoismer (rfˆ0.46, 100% ethyl acetate), 320 mg
(39%) as a white solid; mp 197–199ЊC; IR (KBr) 3394,
3086, 2974, 1795, 1736, 1679, 1610, 1371, 1296, 1216,
1168, 1071, 778 cmϪ1; dH 1.27 (3H, t, Jˆ7.1 Hz), 1.98
(3H, s), 2.98 (1H, dd, Jˆ13.6, 9.4 Hz), 3.24 (1H, dd,
Jˆ13.6, 7.3 Hz), 4.27 (2H, q, Jˆ7.1 Hz), 5.52 (1H, dd,
Jˆ9.4, 7.3 Hz), 7.57 (1H, dd, Jˆ7.8, 7.0 Hz), 7.70 (1H, d,
Jˆ7.8 Hz), 7.85 (1H, ddd, Jˆ8.1, 7.0, 1.5 Hz), 8.14 (1H, dd,
Jˆ8.1, 1.2 Hz), 8.92 (1H, s), 12.25 (1H, s); dC 13.7 (q), 21.9
(q), 36.2 (t), 62.8 (t), 63.8 (s), 76.0 (d), 121.7 (s), 125.9 (d),
127.5 (d), 127.5 (d), 134.7 (d), 147.7 (s), 152.2 (s), 161.2 (s),
166.6 (s), 169.8 (s), 170.3 (s); MS (EI) m/z (rel. intensity)
360 (Mϩϩ1, 63%), 359 (Mϩ, 84), 300 (41), 286 (50), 256
(52), 200 (28), 184 (39), 183 (46), 173 (100), 147 (49), 43
(71); Anal. Calcd for C17H17N3O6: C, 56.82; H, 4.77; N,
11.69. Found: C, 56.74; H, 4.83; N, 11.65.
5. Kacker, I. K.; Zaheer, S. H. J. Indian Chem. Soc. 1951, 28, 344–
346.
6. (a) Kobayashi, S.; Ueno, M.; Suzuki, R.; Ishitani, H.; Kim,
H-S.; Wataya, Y. J. Org. Chem. 1999, 64, 6833–6841. (b) Takaya,
Y.; Tasaka, H.; Chiba, T.; Uwai, K.; Tanitsu, M.-A.; Kim, H.-S.;
Wataya, Y.; Miura, M.; Takeshita, M.; Oshima, Y. J. Med. Chem.
1999, 42, 3163–3166. (c) Uesato, S.; Kuroda, Y.; Kato, M.;
Fujiwara, Y.; Hase, Y.; Fujita, T. Chem. Pharm. Bull. 1998, 46,
1–5. (d) Kobayashi, S.; Ueno, M.; Suzuki, R.; Ishitani, H.
Tetrahedron Lett. 1999, 40, 2175–2178.
7. Armarego, W. L. F. Adv. Heterocycl. Chem. 1979, 24, 1–62.
8. Mayer, J. P.; Lewis, G. S.; Curtis, M. J.; Zhang, J. Tetrahedron
Lett. 1997, 38, 8445–8448.
9. Jiang, J. B.; Hessan, D. P.; Dusak, B. A.; Dexter, D. L.; Kang,
G. J.; Hamel, E. J. Med. Chem. 1990, 33, 1721–1728.
10. (a) von Niementowski, St. J. Prakt. Chem. 1895, 51, 564–572.
(b) Bogert, M. T.; Gotthelf, A. H. J. Am. Chem. Soc. 1900, 22,
522–535. (c) Meyer, J. F.; Wagner, E. C. J. Org. Chem. 1943, 8,
239–252.
second diastereoisomer (rfˆ0.31, 100% ethyl acetate),
120 mg (14%) as a white solid; mp 216–219ЊC; IR (KBr)
3366, 2980, 1780, 1749, 1681, 1620, 1469, 1206, 1058,
772 cmϪ1; dH 0.98 (3H, t, Jˆ7.1 Hz), 1.98 (3H, s), 2.83
(1H, dd, Jˆ13.8, 9.0 Hz), 3.39 (1H, dd, Jˆ13.8, 5.1 Hz),
4.00–4.12 (2H, m), 5.67 (1H, dd, Jˆ9.0, 5.1 Hz), 7.55 (1H,
ddd, Jˆ7.9, 6.9, 1.1 Hz), 7.67 (1H, d, Jˆ7.9 Hz), 7.83 (1H,
ddd, Jˆ8.1, 6.9, 1.5 Hz), 8.13 (1H, dd, Jˆ8.1, 1.2 Hz), 8.89
(1H, s), 12.51 (1H, s); dC 13.4 (q), 21.9 (q), 35.7 (t), 62.4 (t),
11. Bandgar, B. P. Synth. Commun. 1997, 27, 2065–2068.
12. Filachione, E. M.; Lengel, J. H.; Fisher, C. H. J. Am. Chem.
Soc. 1944, 66, 494–496.
13. Estrada, E.; Rieker, A. Z. Naturforsch 1994, 49b, 1566–1568.
14. Larksarp, C.; Alper, H. J. Org. Chem. 2000, 65, 2773–2777
(references cited therein).

A. Witt, J. Bergman / Tetrahedron 56 (2000) 7245–7253
7253
¨
˚
15. Bogert, M. T.; Beal, G. D.; Amend, C. G. J. Am. Chem. Soc.
1910, 32, 1654–1664.
16. Foster, B. A.; Coffey, H. A.; Morin, M. J.; Rastinejad, F.
Science 1999, 286, 2507–2510.
17. Fuks, R. Eur. Polym. J. 1973, 9, 835–845.
18. (a) Dempcy, R. O.; Skibo, E. B. Bioorg. Med. Chem. Lett.
1992, 2, 1427–1434. (b) Dempcy, R. O.; Skibo, E. B. Bioorg.
Med. Chem. 1993, 1, 39–43.
22. (a) Overas, A. T.; Bakkestuen, A. K.; Gundersen, L.-L. Acta
Chem. Scand. 1997, 51, 1116–1124. (b) Liu, F.; Dalhus, B.;
Gundersen, L.-L.; Rise, F. Acta Chem. Scand. 1999, 53, 269–279.
23. Ahmed, A.; Narang, K. S.; Nath Ray, J. J. Indian Chem. Soc.
1938, 15, 152–159.
24. Yanai, M.; Kinoshita, T.; Takeda, S. Chem. Pharm. Bull. 1968,
16, 972–976.
25. Kulkarni, P. V. J. Indian Chem. Soc. 1942, 19, 180–182.
26. (a) Hjelt, E. Chem. Ber. 1884, 17, 2833–2835. (b) Takei, H.;
Fukuda, Y.; Sugaya, K.; Taguchi, T.; Kawara, T. Chem. Lett. 1980,
1307–1310.
19. German Pat. 1,170,144 (to BASF), 1964.
20. (a) Staiger, P. R.; Wagner, E. C. J. Org. Chem. 1953, 18,
¨
1427–1439. (b) Weddige, A.; Korner, M. J. Prakt. Chem. 1887,
36, 141–165.
27. Farina, F.; Maestro, M. C.; Martin, M. V.; Soria, M. L.
Tetrahedron 1987, 43, 4007–4014.
21. (a) Reich, H. E.; Levine, R. J. Am. Chem. Soc. 1955, 77, 4913–
4915. (b) Magnus, G.; Levine, R. J. Am. Chem. Soc. 1956, 78,
4127–4130.