Application of organolithium in organic synthesis: A simple and convenient procedure for the synthesis of more complex 6-substituted 3H-quinazolin-4-ones

Article abstract of DOI:10.1007/s00706-003-0110-5

6-Methyl-3H-quinazolin-4-one reacted with alkyllithium reagents at -78°C in THF to give 2-alkyl-1,2-dihydro-6-methyl-3H-quinazolin-4-ones in high yields. However, no reaction took place when LDA was used as the lithium reagent. 6-Bromo-3H-quinazolin-4-one reacted with excessive butyllithium to give 2-butyl-1,2-dihydro-3H-quinazolin-4-ones in very good yields. However, the lithiation of 6-bromo-3H-quinazolin-4-one was achieved by the use of a combination of methyllithium (1.1 equivalents) and tert-butyllithium (2.2 equivalents) at -78°C in THF. The dilithio reagent thus obtained reacted with a variety of electrophiles (H₂O, iodoethane, benzaldehyde, anisaldehyde, cyclohexanone, 2-hexanone, benzophenone, phenyl isothiocyanate, TITD) to give the corresponding 6-substituted 3H-quinazolin-4-ones in excellent yields. Reaction of the dilithio reagent with 1,3-dibromopropane gave 6,6′-(propanediyl)bis(3H-quinazolin-4-one). Springer-Verlag 2003.

Full text of DOI:10.1007/s00706-003-0110-5

Monatshefte f€ur Chemie 135, 323–331 (2004)
DOI 10.1007/s00706-003-0110-5
Application of Organolithium
in Organic Synthesis: A Simple
and Convenient Procedure
for the Synthesis of More Complex
6-Substituted 3H-Quinazolin-4-ones
ꢀ
Gamal A. El-Hiti
Department of Chemistry, Faculty of Science, Tanta University, Tanta 31527, Egypt
Received August 20, 2003; accepted (revised) August 28, 2003
Published online December 30, 2003 # Springer-Verlag 2003
Summary. 6-Methyl-3H-quinazolin-4-one reacted with alkyllithium reagents at ꢁ78ꢂC in THF to give
2-alkyl-1,2-dihydro-6-methyl-3H-quinazolin-4-ones in high yields. However, no reaction took place
when LDA was used as the lithium reagent. 6-Bromo-3H-quinazolin-4-one reacted with excessive
butyllithium to give 2-butyl-1,2-dihydro-3H-quinazolin-4-ones in very good yields. However, the
lithiation of 6-bromo-3H-quinazolin-4-one was achieved by the use of a combination of methyllithium
(1.1 equivalents) and tert-butyllithium (2.2 equivalents) at ꢁ78ꢂC in THF. The dilithio reagent thus
obtained reacted with a variety of electrophiles (H2O, iodoethane, benzaldehyde, anisaldehyde, cyclo-
hexanone, 2-hexanone, benzophenone, phenyl isothiocyanate, TITD) to give the corresponding
6-substituted 3H-quinazolin-4-ones in excellent yields. Reaction of the dilithio reagent with 1,3-dibro-
mopropane gave 6,60-(propanediyl)bis(3H-quinazolin-4-one).
Keywords. 3H-Quinazolin-4-one; Nucleophilic addition; Bromine-lithium exchange; Dilithio
reagent; Electrophiles.
Introduction
Recently, it was observed that lithiation of various heterocyclic compounds using
lithium reagents at low temperature followed by reactions with electrophiles
resulted in the production of substituted heterocycles in good yields [1]. Literature
reveals that current attention is focused on the preparation of substituted quinazo-
line derivatives via directed lithiation in order to improve their biological activities
ꢀ
Present address: Centre for Clean Chemistry, Department of Chemistry, University of Wales Swansea,
E-mail: g.a.el-hiti@swansea.ac.uk
Swansea SA2 8PP, UK

324
G. A. El-Hiti
[2–5]. More recent work involved successful lithiation of 3-tert-butoxycarbonyl-
3H-quinazolin-4-one using lithium diisopropylamide (LDA) [6]. The reactions of
the dilithio reagent thus formed with electrophiles followed by removal of the tert-
butoxycarbonyl group afforded the corresponding 2-substituted derivatives [6].
As a part of our own interest in heterocyclic chemistry [7], particularly in the
use of directed lithiation in organic synthesis [8], we have shown that lithiation of
various 3H-quinazolin-4-ones produced a wide range of more complex 2-substi-
tuted 3H-quinazolin-4-one derivatives in very good yields [9, 10]. Synthesis of the
3H-quinazolin-4-one ring system, which provides the backbone for compounds
having numerous pharmacological activities [11], is an interesting challenge. We
now report on the successful synthesis of 6-substituted 3H-quinazolin-4-ones via
bromine–lithium exchange of 6-bromo-3H-quinazolin-4-one.
Results and Discussion
6-Methyl-3H-quinazolin-4-one (1) was prepared according to Ref. [12]. It was
hoped that lithiation of 1 would take place as for 2-methyl-3H-quinazolin-4-one
[11], so that substitution of the hydrogen of the methyl group at position 6 by
lithium could be achieved, followed by reactions with electrophiles to give the
corresponding 6-substituted derivatives. However, it was found that lithiation of
1 did not take place with alkyllithiums. Instead, nucleophilic attack by alkyl-
lithiums occurred at the imine bond to give 1,2-addition products. The reactions
of 1 with one equivalent of alkyllithiums (tert-butyllithium, n-butyllithium,
methyllithium) at ꢁ78ꢂC in THF took place within 15 minutes to give 2-alkyl-
1,2-dihydro-6-methyl-3H-quinazolin-4-ones (2–4) (Scheme 1) in high yields
(85–90%).
1
The compounds 2–4 are fluorescent. Their structures were confirmed by H
1
NMR, 13C NMR, mass spectra, and high resolution mass spectral data. Their H
NMR spectra showed a characteristic H-2 signal in the ꢀ ¼ 4.31–4.77 ppm region,
and their 13C NMR spectra showed that C-2 appears in the ꢀ ¼ 61–72 ppm region
(see Experimental for details).
It was found that lithiation of 1 with a less nucleophilic lithium reagent, such as
lithium diisopropylamide (LDA) did not take place and only starting material was
recovered, indicating that no reaction took place under the conditions tried. No
further attempts were made to try to find conditions under which lithiation of 1
could be effected.
Scheme 1

Application of Organolithium in Organic Synthesis
325
Scheme 2
Unfortunately, lithiation of 1 was not successful; therefore attention was turned
next to replacing the methyl group at position 6 with bromine that could be
replaced with lithium via bromine-lithium exchange. Initially, lithiations of 6-
bromo-3H-quinazolin-4-one (5) [13] using tert- and n-butyllithium in THF at
ꢁ78ꢂC were attempted. Unfortunately, reactions with a number of electrophiles
(H2O, iodoethane and benzaldehyde) produced low yields of the desired products
along with 2-butyl-1,2-dihydro-3H-quinazolin-4-ones 6 and 7. However, if 4 equi-
valents of tert- and n-butyllithium were used, 6 and 7 were obtained in 88 and 79%
isolated yields (Scheme 2).
1
Compounds 6 and 7 are also fluorescent. The H NMR spectra of 6 and 7
showed a characteristic H-2 signal at ꢀ ¼ 4.35 and ꢀ ¼ 5.50 ppm. Their 13C NMR
spectra showed that C-2 appears at ꢀ ¼ 72.55 and ꢀ ¼ 67.38 ppm (see Experimental
for details).
However, compound 5 was successfully lithiated using a combination of
methyllithium and tert-butyllithium in THF at ꢁ78ꢂC. Lithiation of 5 took place
on nitrogen to form the monolithio reagent 8 using methyllithium (1.1 equivalents),
followed by bromine-lithium exchange using tert-butyllithium (2.2 equivalents) to
give the dilithio reagent 9 (Scheme 3). To test the extent to which the dilithio
reagent 9 had formed, it was protonated using aqueous saturated ammonium chlo-
ride solution to give 3H-quinazolin-4-one (10) in 91% isolated yield. In order to
Scheme 3

326
G. A. El-Hiti
Scheme 4
test the versatility of the intermediate dilithio reagent 9, it was reacted with other
electrophiles (iodoethane, benzaldehyde, anisaldehyde, cyclohexanone, 2-hexa-
none, benzophenone, phenyl isothiocyanate, tetra-iso-propylthiuram disulfide
(TITD)) to give the corresponding 6-substituted 3H-quinazolin-4-ones (11–18)
(Scheme 3) in good yields (81–91%).
No N-substitution was observed, even with excessive iodoethane (2 equiva-
1
lents) as electrophile. The structures of 10–18 were confirmed by H NMR, 13C
NMR, mass spectra, and high resolution mass spectral data (see Experimental for
1
details). The H NMR spectrum of 18 showed that the methyl and CH protons of
the iso-propyl groups appeared as broad signals at room temperature and as doublet
and heptet signals at 80ꢂC indicating that there is restricted rotation about the C–S
and C–N bonds at room temperature. Similar observations have been made pre-
viously for 3-amino- and 3-acylamino-3H-quinazolin-4-one derivatives [14].
Finally, reaction of the dilithio reagent of 5 with 1,3-dibromopropane (0.55
equivalent) in THF at ꢁ78ꢂC gave 19 (Scheme 4) in 71% isolated yield. The
NMR and mass spectra confirmed the structure of 19.
In conclusion, the reaction accommodates a range of more complex substitu-
tents into the benzene ring of the 3H-quinazolin-4-one system. Therefore, it repre-
sents a convenient, clean, and simple procedure for the high yield synthesis of
6-substituted 3H-quinazolin-4-ones, which might be difficult to prepare by other
means.
Experimental
1
Melting points were determined on an electrothermal melting MEL-TEMP II apparatus. H and 13C
NMR spectra were recorded in DMSO-d6 using a Bruker AC400 spectrometer operating at 400 MHz
for 1H and 100 MHz for 13C. Chemical shifts are reported in parts per million relative to tetramethyl-
silane. Low-resolution mass spectra were recorded on a Quattro II triple quadrupole mass spectrometer
(electron impact: 70eV; chemical ionization: ammonia). Accurate mass data were obtained on a MAT
900 instrument. UV and visible spectra were recorded in CHCl3 using a Unicam UV300 UV-visible
spectrometer. Fluorescence spectra were recorded in CHCl3 using a Perkin Elmer LS50B luminescence
spectrometer. Butyllithium and methyllithium were obtained from Aldrich and were estimated prior to
use by the method of Watson and Eastham [15]. THF was distilled from sodium benzophenone ketyl.
Compounds 1 and 5 were prepared according to Refs. [12, 13]. Their analytical data agreed with the
published work.
Synthesis of 2-Alkyl-6-methyl-1,2-dihydro-3H-quinazolin-4-ones 2–4
To a cold (ꢁ78ꢂC), stirred solution of 0.32 g of 1 (2.0mmol) in 50cm3 of dry THF under N2 was added
a solution of 2.2 mmol of alkyllithium. The yellow solution obtained was stirred at ꢁ78ꢂC for 15min
and then allowed to warm to room temperature. The mixture was quenched with 20cm3 of aq. sat.

Application of Organolithium in Organic Synthesis
327
NH4Cl. The organic layer was washed with 2 ꢃ 20cm3 of H2O, dried (MgSO4), and the solvent was
evaporated under reduced pressure. The products were recrystallised form methanol to give 2–4.
2-tert-Butyl-6-methyl-1,2-dihydro-3H-quinazolin-4-one (2, C13H18N2O)
Yield 90%; mp 197–189ꢂC; 1H NMR: ꢀ ¼ 0.88 (s, C(CH3)3), 2.15 (s, CH3), 4.31 (t, J ¼ 2.2 Hz, H-2),
6.33 (s, exch., NH), 6.71 (d, J ¼ 8.2 Hz, H-8), 7.02 (dd, J ¼ 8.2, 1.6 Hz, H-7), 7.36 (d, J ¼ 1.6 Hz, H-5),
7.75 (s, exch., NH) ppm; 13C NMR: ꢀ ¼ 20.40 (q, C(CH3)3), 24.90 (q, CH3), 37.57 (s, C(CH3)3), 72.65
(d, C-2), 114.18 (d), 114.47 (s, C-4a), 124.93 (s, C-6), 127.27 (d), 134.29 (d), 146.60 (s, C-8a), 164.13
(s, C-4) ppm; EI-MS: m=z (%) ¼ 218 (Mþ, 59), 201 (100), 187 (41), 174 (63), 161 (85), 57 (44); CI-
MS: m=z (%) ¼ 219 (MHþ, 100), 161 (12), 57 (5); HRCI-MS: C13H19N2O (MHþ), calcd 219.1497,
found 219.1496; UV-Vis (CHCl3): ꢁmax ¼ 345nm; Fluorescence (CHCl3): ꢁmax ¼ 421 nm.
2-Butyl-6-methyl-1,2-dihydro-3H-quinazolin-4-one (3, C13H18N2O)
1
Yield 85%; mp 129–130ꢂC; H NMR: ꢀ ¼ 0.88 (t, J ¼ 7.2 Hz, CH3), 1.30 (sextet, J ¼ 7.2 Hz, CH2),
1.39 (m, CH2), 1.61 (m, CH2), 2.18 (s, CH3), 4.63 (t, J ¼ 5.3 Hz, H-2), 6.37 (s, exch., NH), 6.67 (d,
J ¼ 8.2 Hz, H-8), 7.05 (dd, J ¼ 8.2, 1.6Hz, H-7), 7.40 (d, J ¼ 1.6 Hz, H-5), 7.85 (s, exch., NH) ppm;
13C NMR: ꢀ ¼ 14.30 (q, CH3), 20.44 (q, CH3), 22.45 (t, CH2), 25.84 (t, CH2), 34.98 (t, CH2), 64.90 (d,
C-2), 114.87 (d), 115.44 (s, C-4a), 125.86 (s, C-6), 127.57 (d), 134.19 (d), 146.73 (s, C-8a), 164.42 (s,
C-4) ppm; EI-MS: m=z (%) ¼ 218 (Mþ, 47), 201 (100), 187 (45), 161 (80), 105 (22), 57 (51); CI-MS:
m=z (%) ¼ 219 (MHþ, 100), 161 (32); HRCI-MS: C13H19N2O (MHþ), calcd 219.1497, found
219.1497; UV-Vis (CHCl3): ꢁmax ¼ 317 nm; Fluorescence (CHCl3): ꢁmax ¼ 413 nm.
2,6-Dimethyl-1,2-dihydro-3H-quinazolin-4-one (4, C10H12N2O)
Yield 87%; mp 211–213ꢂC; 1H NMR: ꢀ ¼ 1.30 (d, J ¼ 6.0 Hz, CH3), 2.18 (s, CH3), 4.77 (q, J ¼ 6.0 Hz,
H-2), 6.43 (s, exch., NH), 6.61 (d, J ¼ 8.0 Hz, H-8), 7.07 (dd, J ¼ 8.0, 2.0 Hz, H-7), 7.41 (d, J ¼ 2.0 Hz,
H-5), 7.87 (s, exch., NH) ppm; 13C NMR: ꢀ ¼ 20.45 (q, CH3), 21.51 (q, CH3), 61.32 (d, C-2), 114.78
(d), 115.59 (s, C-4a), 126.17 (s, C-6), 127.67 (d), 134.21 (d), 147.00 (s, C-8a), 164.60 (s, C-4) ppm; EI-
MS: m=z (%) ¼ 176 (Mþ, 17), 161 (100), 134 (18), 106 (16), 104 (22), 77 (31); CI-MS: m=z (%) ¼ 194
(MþþNH4, 6), 177 (MHþ, 100), 161 (6); HRCI-MS: C10H13N2O (MHþ), calcd 177.1028, found
177.1027; UV-Vis (CHCl3): ꢁmax ¼ 337 nm; Fluorescence (CHCl3): ꢁmax ¼ 417 nm.
Synthesis of 2-Butyl-1,2-dihydro-3H-quinazolin-4-ones 6 and 7
To a cold (ꢁ78ꢂC), stirred solution of 0.45 g of 5 (2.0mmol) in 50cm3 of dry THF under N2 was added
a solution of 8.0 mmol of butyllithium. The yellow solution obtained was stirred at ꢁ78ꢂC for 30 min.
It was then allowed to warm to room temperature and quenched with 20cm3 of aq. sat. NH4Cl. The
organic layer was separated, washed with 2ꢃ 20 cm3 of H2O, dried (MgSO4), and the solvent was
evaporated under reduced pressure. The products were recrystallised form methanol to give 6 and 7.
2-tert-Butyl-1,2-dihydro-3H-quinazolin-4-one (6, C12H16N2O)
Yield 86%; mp 190–191ꢂC; 1H NMR: ꢀ ¼ 0.86 (s, C(CH3)3), 4.35 (t, J ¼ 2.2 Hz, H-2), 6.47 (s, exch.,
NH), 6.58 (dt, J ¼ 8.0, 1.9 Hz, 1H), 6.78 (d, J ¼ 8.0 Hz, 1H), 7.18 (dt, J ¼ 8.0, 1.9Hz, 1H), 7.55 (dd,
J ¼ 8.0, 1.9Hz, 1H), 7.82 (s, exch., NH) ppm; 13C NMR: ꢀ ¼ 24.84 (q, C(CH3)3), 37.38 (s, C(CH3)3),
72.55 (d, C-2), 113.98 (d), 114.45 (s, C-4a), 116.37 (d), 127.40 (d), 133.43 (d), 148.70 (s, C-8a), 163.99
(s, C-4) ppm; EI-MS: m=z (%) ¼ 204 (Mþ, 2), 187 (3), 147 (100), 130 (10), 92 (15), 65 (16), 57 (26);
CI-MS: m=z (%) ¼ 222 (MþþNH4, 5), 205 (MHþ, 100), 187 (2), 147 (20); HRCI-MS: C12H17N2O

328
G. A. El-Hiti
(MHþ), calcd 205.1341, found 205.1339; UV-Vis (CHCl3): ꢁmax ¼ 334 nm; Fluorescence (CHCl3):
ꢁmax ¼ 406 nm.
2-Butyl-1,2-dihydro-3H-quinazolin-4-one (7, C12H16N2O)
1
Yield 79%; mp 125–126ꢂC; H NMR: ꢀ ¼ 1.67 (t, J ¼ 7.2 Hz, CH3), 2.09 (sextet, J ¼ 7.2 Hz, CH2),
2.19 (m, CH2), 2.46 (m, CH2), 5.46 (s, exch., NH), 5.49 (t, J ¼ 4.3 Hz, H-2), 7.40 (t, J ¼ 8.1 Hz, 1H),
7.35 (d, J ¼ 8.1 Hz, 1H), 8.03 (dt, J ¼ 8.1, 1.5 Hz, 1H), 8.41 (dd, J ¼ 8.1, 1.5 Hz, 1H), 8.71 (s, exch.,
NH) ppm; 13C NMR: ꢀ ¼ 16.62 (q, CH3), 25.07 (t, CH2), 28.34 (t, CH2), 37.70 (t, CH2), 67.43 (d, C-2),
117.31 (d), 117.85 (s, C-4a), 119.98 (d), 130.31 (d), 136.12 (d), 151.51 (s, C-8a), 167.34 (s, C-4) ppm;
EI-MS: m=z (%) ¼ 204 (Mþ, 2), 160 (10), 147 (100), 130 (16), 119 (20), 92 (36), 65 (22), 41 (95); CI-
MS: m=z (%) ¼ 222 (MþþNH4, 6), 205 (MHþ, 100), 147 (11); HRCI-MS: C12H17N2O (MHþ), calcd
205.1341, found 205.1340; UV-Vis (CHCl3): ꢁmax ¼ 309nm; Fluorescence (CHCl3): ꢁmax ¼ 407 nm.
General Procedure for the Synthesis of 6-Substituted 3H-Quinazolin-4-ones 10–19
A solution of methyllithium in ether (2.2 cm3, 1.0 M, 2.2 mmol) was added to a cold (ꢁ78ꢂC), stirred
solution of 0.45 g of 5 (2.0mmol) in 50cm3 of dry THF under N2. After 5 min a solution of tert-
butyllithium in pentane (2.6cm3, 1.7M, 4.4mmol) was added and the resultant yellow solution
obtained was stirred at ꢁ78ꢂC for 1 h to complete the formation of the dilithio reagent 9. An electro-
phile (2.2mmol), in 8 cm3 of dry THF if solid, otherwise neat, was added. The reaction mixture was
stirred for 2 h at ꢁ78ꢂC, then removed from the cooling bath and allowed to warm to room tempera-
ture. The mixture was diluted with 20cm3 of ethyl acetate and quenched with 20cm3 of aq. sat. NH4Cl.
The organic layer was separated, washed with 2 ꢃ 20cm3 of H2O, dried (MgSO4), and the solvent was
evaporated under reduced pressure. The products were recrystallised form methanol or ethyl acetate to
give 10–19. Compound 19 was obtained using 1,3-dibromopropane (1.1 mmol) as the electrophile.
3H-Quinazolin-4-one (10)
Yield 91%; mp 217ꢂC (Ref. [16] 215.5–216.5ꢂC).
6-Ethyl-3H-quinazolin-4-one (11, C10H10N2O)
Yield 84%; mp 183–185ꢂC; 1H NMR: ꢀ ¼ 1.20 (t, J ¼ 7.6 Hz, CH3), 2.71 (q, J ¼ 7.6 Hz, CH2), 7.57 (d,
J ¼ 8.1 Hz, H-8), 7.65 (dd, J ¼ 8.1, 2.0 Hz, H-7), 7.91 (d, J ¼ 2.0Hz, H-5), 8.03 (s, H-2), 12.18 (s,
exch., NH) ppm; 13C NMR: ꢀ ¼ 15.72 (q, CH3), 28.16 (t, CH2), 122.67 (s, C-4a), 124.21 (d), 127.48
(d), 134.04 (d), 143.04 (d), 144.93 (s, C-6), 147.19 (s, C-8a), 161.17 (s, C-4) ppm; EI-MS: m=z
(%) ¼ 174 (Mþ, 69), 159 (100), 146 (12), 132 (10), 118 (8), 104 (13), 91 (13), 77 (18); CI-MS:
m=z (%) ¼ 192 (MþþNH4, 7), 175 (MHþ, 100), 147 (18), 52 (15); HRCI-MS: C10H11N2O (MHþ),
calcd 175.0871, found 175.0870.
6-(Hydroxyphenylmethyl)-3H-quinazolin-4-one (12, C15H12N2O2)
1
Yield 81%; mp 178–179ꢂC; H NMR: ꢀ ¼ 5.87 (s, CH), 6.12 (s, exch., OH), 7.22 (t, J ¼ 7.3 Hz,
1Harom), 7.33 (t, J ¼ 7.3 Hz, 2Harom), 7.41 (d, J ¼ 7.3 Hz, 2Harom), 7.62 (d, J ¼ 8.3 Hz, H-8), 7.81
(dd, J ¼ 8.3, 1.5 Hz, H-7), 8.06 (s, H-2), 8.13 (d, J ¼ 1.5 Hz, H-5), 12.22 (s, exch., NH) ppm; 13C
NMR: ꢀ ¼ 74.00 (d, CH), 122.56 (s, C-4a), 123.18 (d), 126.19 (d), 127.31 (d), 128.59 (d), 132.98 (d),
134.68 (d), 144.74 (s, Carom), 145.42 (s, C-6), 145.52 (d, C-2), 148.04 (s, C-8a), 161.16 (s, C-4) ppm;
EI-MS: m=z (%) ¼ 252 (Mþ, 24), 173 (66), 147 (100), 105 (62), 90 (30), 77 (82), 51 (48); CI-MS: m=z

Application of Organolithium in Organic Synthesis
329
(%) ¼ 270 (MþþNH4, 2), 253 (MHþ, 61), 237 (12), 147 (100), 98 (25); HRCI-MS: C15H13N2O2
(MHþ), calcd 253.0977, found 253.0976.
6-[Hydroxy(4-methoxyphenyl)methyl]-3H-quinazolin-4-one (13, C16H14N2O3)
1
Yield 83%; mp 221–222ꢂC; H NMR: ꢀ ¼ 3.72 (s, CH3), 5.81 (s, CH), 6.01 (s, exch., OH), 6.89 (d,
J ¼ 7.7 Hz, 2Harom), 7.31 (d, J ¼ 7.7 Hz, 2Harom), 7.60 (d, J ¼ 8.5 Hz, H-8), 7.77 (dd, J ¼ 8.5, 1.9 Hz, H-
7), 8.06 (s, H-2), 8.11 (d, J ¼ 1.9 Hz, H-5), 12.20 (s, exch., NH) ppm; 13C NMR: ꢀ ¼ 55.37 (q, CH3),
73.58 (d, CH), 113.95 (d), 122.51 (s, C-4a), 123.04 (d), 127.38 (d), 127.96 (d), 132.96 (d), 137.64 (s,
Carom), 145.07 (s, C-6), 145.36 (d, C-2), 147.95 (s, C-8a), 158.60 (s, Carom), 161.19 (s, C-4) ppm; EI-
MS: m=z (%) ¼ 282 (Mþ, 41), 265 (10), 173 (52), 147 (91), 135 (61), 109 (100), 90 (43), 77 (88), 63
(38); CI-MS: m=z (%) ¼ 300 (MþþNH4, 5), 383 (MHþ, 91), 265 (100), 147 (18), 52 (14); HRCI-MS:
C16H15N2O3 (MHþ), calcd 283.1082, found 283.1078.
6-(1-Hydroxycyclohexyl)-3H-quinazolin-4-one (14, C14H16N2O2)
Yield 85%; mp 217–219ꢂC; 1H NMR: ꢀ ¼ 1.28–1.98 (m, 5CH2), 4.95 (s, exch., OH), 7.61 (d,
J ¼ 8.3 Hz, H-8), 7.91 (dd, J ¼ 8.3, 2.0 Hz, H-7), 8.06 (s, H-2), 8.24 (d, J ¼ 2.0Hz, H-5), 12.19 (s,
exch., NH) ppm; 13C NMR: ꢀ ¼ 22.05 (t, CH2), 25.41 (t, CH2), 38.59 (t, CH2), 71.89 (s, C–OH),
121.70 (d), 122.22 (s, C-4a), 127.03 (d), 131.96 (d), 145.18 (d, C-2), 147.54 (s, C-6), 150.20 (s, C-8a),
161.35 (s, C-4) ppm; EI-MS: m=z (%) ¼ 244 (Mþ, 19), 226 (17), 201 (100), 188 (41), 159 (19), 145
(31), 115 (22), 90 (33), 77 (40), 63 (42), 55 (69); CI-MS: m=z (%) ¼ 262 (MþþNH4, 2), 245 (MHþ,
51), 227 (22), 147 (100), 116 (53), 98 (70), 84 (39); HRCI-MS: C14H17N2O2 (MHþ), calcd 245.1290,
found 245.1286.
6-(1-Hydroxy-1-methylpentyl)-3H-quinazolin-4-one (15, C14H18N2O2)
1
Yield 88%; mp 128–129ꢂC; H NMR: ꢀ ¼ 0.76 (t, J ¼ 7.2 Hz, CH3), 0.88–1.25 (m, 2CH2), 1.46 (s,
CH3), 1.66–1.76 (m, CH2), 5.09 (s, exch., OH), 7.60 (d, J ¼ 8.5Hz, H-8), 7.84 (dd, J ¼ 8.5, 1.8 Hz, H-
7), 8.06 (s, H-2), 8.18 (d, J ¼ 1.8 Hz, H-5), 12.16 (s, exch., NH) ppm; 13C NMR: ꢀ ¼ 14.33 (q, CH3),
22.89 (t, CH2), 26.15 (t, CH2), 30.51 (q, CH3), 43.99 (t, CH2), 73.16 (s, C–OH), 122.00 (d), 122.17 (s,
C-4a), 126.97 (d), 132.03 (d), 145.13 (d, C-2), 147.41 (s, C-6), 148.47 (s, C-8a), 161.34 (s, C-4) ppm;
EI-MS: m=z (%) ¼ 246 (Mþ, 2), 189 (100), 173 (12), 147 (30), 57 (18); CI-MS: m=z (%) ¼ 264
(MþþNH4, 4), 247 (MHþ, 78), 231 (24), 189 (18), 164 (17), 147 (100), 111 (26), 98 (30); HRCI-
MS: C14H19N2O2 (MHþ), calcd 247.1446, found 247.1448.
6-(Hydroxydiphenylmethyl)-3H-quinazolin-4-one (16, C21H16N2O2)
1
Yield 88%; mp 182–183ꢂC; H NMR: ꢀ ¼ 6.55 (s, exch., OH), 7.07–7.19 (m, 10Harom), 7.47 (d,
J ¼ 8.1 Hz, H-8), 7.53 (dd, J ¼ 8.1, 1.9 Hz, H-7), 7.76 (s, H-2), 7.92 (d, J ¼ 1.9Hz, H-5), 11.94 (s,
exch., NH) ppm; 13C NMR: ꢀ ¼ 80.79 (s, C–OH), 121.91 (s, C-4a), 124.75 (d), 126.99 (d), 127.11 (d),
127.60 (d), 128.10 (d), 134.58 (d), 145.78 (d, C-2), 146.78 (s, C-6), 147.57 (s, Carom), 147.99 (s, C-8a),
161.19 (s, C-4) ppm; EI-MS: m=z (%) ¼ 328 (Mþ, 12), 312 (14), 251 (68), 223 (52), 173 (53), 145
(22), 105 (91), 90 (23), 77 (100), 51 (26); CI-MS: m=z (%) ¼ 346 (MþþNH4, 5), 329 (MHþ, 72), 311
(75), 200 (27), 147 (100); HRCI-MS: C21H17N2O2 (MHþ), calcd 329.1290, found 329.1291.
6-(Phenylaminothiocarbonyl)-3H-quinazolin-4-one (17, C15H11N3SO)
Yield 82%; mp 262–264ꢂC; 1H NMR: ꢀ ¼ 7.30 (t, J ¼ 7.4 Hz, 1Harom), 7.46 (t, J ¼ 7.4 Hz, 2Harom), 7.74
(d, J ¼ 8.1 Hz, H-8), 7.83 (d, J ¼ 7.4 Hz, 2Harom), 8.21 (s, H-2), 8.31 (dd, J ¼ 8.1, 2.2 Hz, H-7), 8.57 (d,

330
G. A. El-Hiti
J ¼ 2.2 Hz, H-5), 12.09 (s, exch., NH), 12.41 (s, exch., NH) ppm; 13C NMR: ꢀ ¼ 122.17 (s, C-4a),
124.65 (d), 124.98 (d), 126.78 (d), 127.33 (d), 128.92 (d), 134.11 (d), 140.29 (s, Carom), 140.33 (s, C-6),
147.15 (d, C-2), 150.69 (s, C-8a), 161.06 (s, C-4), 196.09 (s, CS) ppm; EI-MS: m=z (%) ¼ 281 (Mþ,
22), 248 (16), 189 (100), 172 (14), 162 (13), 134 (12), 110 (22), 90 (18), 77 (47), 65 (27), 51 (23); CI-
MS: m=z (%) ¼ 282 (MHþ, 100), 252 (15), 189 (8), 161 (16), 147 (7), 94 (40), 52 (33); HRCI-MS:
C15H12N3SO (MHþ), calcd 282.0701, found 282.0704.
6-(Diisopropyldithiocarbamoyl)-3H-quinazolin-4-one (18, C15H19N3S2O)
Yield 81%; mp 245–246ꢂC; 1H NMR (80ꢂC): ꢀ ¼ 1.49 (d, J ¼ 6.8 Hz, 4CH3), 4.83 (heptet, J ¼ 6.8 Hz,
2CH), 7.66 (d, J ¼ 8.4Hz, H-8), 7.74 (dd, J ¼ 8.4, 2.1 Hz, H-7), 8.08 (s, H-2), 8.12 (d, J ¼ 2.1 Hz,
H-5), 11.89 (s, exch., NH) ppm; 13C NMR (80ꢂC): ꢀ ¼ 19.13 (q, CH3), 53.18 (d, CH), 122.39 (s, C-4a),
126.73 (d), 129.38 (s, C-6), 133.51 (d), 141.24 (d), 145.57 (d, C-2), 148.75 (s, C-8a), 159.40 (s, C-4),
192.67 (s, CS) ppm; EI-MS: m=z (%) ¼ 321 (Mþ, 100), 278 (33), 221 (5), 177 (12), 144 (27), 102 (55),
60 (34), 43 (85); CI-MS: m=z (%) ¼ 322 (MHþ, 7), 179 (12), 146 (100), 116 (9), 102 (13); HRCI-MS:
C15H20N3S2O (MHþ), calcd 322.1048, found 322.1045.
6,60-(1,3-Propanediyl)bis(3H-quinazolin-4-one) (19, C19H16N4O2)
Yield 71%; mp >300ꢂC; 1H NMR: ꢀ ¼ 1.95 (t, J ¼ 7.0 Hz, CH2), 2.74 (t, J ¼ 7.0Hz, 2CH2), 7.56 (d,
J ¼ 8.2 Hz, 2H-8), 7.65 (dd, J ¼ 8.2, 2.0Hz, 2H-7), 7.92 (d, J ¼ 2.0 Hz, 2H-5), 8.11 (s, 2H-2), 12.10 (s,
exch., 2NH) ppm; 13C NMR: ꢀ ¼ 33.73 (t, CH2), 34.68 (t, CH2), 122.66 (s, C-4a), 126.24 (d), 127.22
(d), 135.38 (d), 141.26 (s, C-6), 145.36 (d, C-2), 146.56 (s, C-8a), 161.01 (s, C-4) ppm; EI-MS: m=z
(%) ¼ 332 (Mþ, 12), 290 (10), 173 (40), 160 (48), 159 (91), 146 (35), 132 (31), 117 (25), 104 (26), 90
(48), 77 (63), 64 (100), 51 (65); CI-MS: m=z (%) ¼ 350 (MþþNH4, 8), 333 (MHþ, 93), 293 (25), 161
(37), 147 (100), 137 (26), 112 (22), 98 (38); HRCI-MS: C19H17N4O2 (MHþ), calcd 333.1351, found
333.1351.
Acknowledgements
I thank Prof. K. Smith, Centre for Clean Chemistry, University of Wales Swansea, UK for recording the
NMR and mass spectra. I also thank the Royal Society of Chemistry for an international author grant.
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