One-pot, simple, and convenient synthesis of 2-Thioxo-2,3- dihydroquinazolin-4(1H)-ones

Article abstract of DOI:10.1007/s00706-007-0747-6

A simple and convenient method for the synthesis of diverse 2-thioxo-2,3-dihydroquinazolin-4(1H)-ones was developed as one-pot reaction of anthranilic acid esters, primary amines, and bis(benzotriazolyl)methanethione in presence of the amidine base DBU.

Full text of DOI:10.1007/s00706-007-0747-6

Monatshefte fu¨r Chemie 139, 43–48 (2008)
DOI 10.1007/s00706-007-0747-6
Printed in The Netherlands
One-pot, Simple, and Convenient Synthesis of 2-Thioxo-2,3-
dihydroquinazolin-4(1H)-ones
Vinod K. Tiwari1;ꢀ, Desh D. Singh2, Hakkim A. Hussain1, Bhuwan B. Mishra1, and Archana Singh1
1
Department of Chemistry, Faculty of Science, Banaras Hindu University, Varanasi, India
2
Institute of Biomedical Science, Bundelkhand University, Jhansi, India
Received June 11, 2007; accepted June 19, 2007; published online November 15, 2007
# Springer-Verlag 2007
Summary. A simple and convenient method for the syn-
thesis of diverse 2-thioxo-2,3-dihydroquinazolin-4(1H)-ones
was developed as one-pot reaction of anthranilic acid esters,
The preparative methods leading to these mole-
primary amines, and bis(benzotriazolyl)methanethione in
drug discovery research is beyond doubt of para-
mount importance for the synthesis chemist.
cules include the reaction of (i) substituted anthranilic
presence of the amidine base DBU.
acids or its functional derivatives with isothiocyanates
[6a, b], thioureas [6c], excess of refluxing formamide
Keywords. Amines; Benzotriazole; Cyclization; DBU;
Thioxoquinazolinones.
[6d], imidates [6e], methyl N-aryldithiocarbamates
[6f, g], ammonium aryldithiocarbamates [6h, i],
amine and CS2 in basic medium [6j], RNHCOOEt
and imidazole [6k], amine and sodium cyanate,
CSCl2 either in presence of NEt3 [6l] or hydrazine
[6m], polymer supported FeCl3, orthoesters, and
Introduction
The synthesis of thioxoquinazolinone heterocycles
has become the cornerstone for synthetic chemists
and gained extensive importance in medicinal chem-
amines under solvent free conditions [6m], (ii) iso-
istry because of their diverse pharmacological activ-
thiocyanates either with dimethylsulfoxonium-2-
ities including antimycobacterial [1a–d], antifungal
(methylamino)benzoylmethylide [7a] or in refluxing
[1e], antimalarial [1f], antihypertensive [2a–c], an-
tihistaminic [2d–i], local anesthetic [3a], anti-
N-methylanthranilonitrile followed by hydrolysis
[7b], (iii) urethanes either with aniline or with acet-
Parkinson [3b], cardiotonic [3c], anticancer [3d],
antiviral [3e–g], and thymidylate synthase inhibitory
with amines [7f] or with urethanes [7g], (vi) 1,10-
activities [3h, i]. Several simple and condensed qui-
anilides [7c], (iv) anthranilamides with carbonyl
compounds [7d, e], (v) N-acylanthranilic acids either
nazolines are also known to exhibit potent CNS ac-
tivities as analgesic [4a–c], anti-inflammatory [4d–f],
carbonyldiimidazole and amines [7h, i], (vii) ani-
lines, CS2, NaOH in DMSO followed by treatment
and anti-convulsant activities [4g, h]. Besides these,
the quinazolinone skeleton is frequently encountered
as building block for hundreds of naturally occurring
with Me2SO4 and then alkyl anthranilate in ethanol
[2i], (viii) dithiocarbamate, e.g. 4-oxo-3H-quinazo-
lin-3-yl) dithiocarbamic methyl ester (obtained from
alkaloids [5], and hence the exploration of this skel-
anthranilic acid and anhydride) with amines [7j], (ix)
eton as privileged new chemical entities (NCEs) in
oxidation of 2-aminobenzonitrile followed by treat-
ment with acid halides in basic condition [8a], (x)
ꢀ
oxidation of 3-arylimino-2-indolinones with peracid
[8b], (xi) acidic treatment of 2-(3-phenylthioureido)-
Corresponding author. E-mails: tiwari_chem@yahoo.co.in,
vtiwari@ucdavis.edu

44
V. K. Tiwari et al.
benzoic acid [8c], (xii) isotoic anhydride either with
isothiocyanate [8d, e], or with amine and isothiocya-
nates under MW irradiation [8f], (xiii) aza-Wittig
reactions of R-azido imides [8g, h], and (xiv) cy-
clization of substituted 2-(methylcarboxy)benzenei-
sothiocyanates either with amines [8i], or amino acids,
hydrazines, hydrazides, sulfohydrazides, or thiosemi-
carbazides [8j]. Through polymer supported synthesis
several combinatorial assemblies of quinazolinones
and their thioxo derivatives have also been well docu-
mented in literature [7h, 9a–i].
Although some of these synthesis methods are
very useful, most of them are associated with one
or the other limitations, such as involving two or more
steps, use of toxic chemicals, e.g. thiophosgene, em-
ployment of harsh reaction conditions, long reaction
times, low reaction yields, and moreover the low
availability of starting materials. Due to these facts
and reasons, the synthesis of thioxoquinazolines with
diverse substitution patterns by a simple, safe, and
high yielding methodology has become a field of
increasing interest in synthetic and medicinal chem-
istry during the past few years, and in this fascinat-
ing field we wish to report a new, convenient, and
good to high yielding one-pot method through ben-
zotriazole mediated strategy.
tion of reaction, and additionally, BtH is cheap and
can be recovered and recycled for further use [10].
Therefore we tried to search for an alternate route for
the synthesis of heterocycles having thioxoquina-
zolinone skeleton based on our similar recently re-
ported method [11]. During the course of our studies
for the development of biologically active glycocon-
jugates, DBU has been found to be an efficient and
mild catalyst [12]. According to our above men-
tioned experience, we selected organic soluble ami-
dine base DBU comprising an excellent balance
between reactivity and selectivity. Based on these
observations and in continuation of our investigation
to search for benzotriazole mediated synthesis meth-
odology, we wish to report a new, simple, and practical
one-pot method for the synthesis of thioxoquina-
zolines with different substitution patterns by the reac-
tion of various primary amines with anthranilic acids
or its ester derivatives using the bis(benzotriazolyl)-
methanethione (3) in presence of DBU. The reac-
tion is clean, smooth, and less time consuming,
where the desired thioxoquinazolines started to
form after 1 h. We tried the reaction with several sol-
vents and found the reaction is good with anhydrous
CH2Cl2 and DMF. To the best of our knowledge
this is the first report of benzotriazole mediated
and DBU catalyzed one-pot synthesis of 2-thioxo-
4(3H)-quinazolinones. The methodology is conve-
nient, safe, and high yielding with unsubstituted
anthranilic acid esters (Scheme 1).
Results and Discussion
Looking for a very easy and convenient synthesis
of thioxoquinazolinones, we turned our attention to
bis(benzotriazolyl)methanethione, and decided to
check whether it is possible to find a simple and di-
rect one-pot procedure that may be compatible with
some other substituents. Very recently we have re-
ported a simple and practical one-pot method for the
synthesis of diverse dithiocarbamates using benzo-
triazole methodology [11]. Benzotriazole not only
can easily enter into molecules by a variety of reac-
tions, but can easily be cleaved too after the comple-
Anthranilic acids or its methyl esters 1a–1d were
reacted with different amines 2 (viz. benzyl amine,
3-chlorobenzyl amine, aniline, 3-fluoroaniline, 4-
chloroaniline, p-toludine, p-anisidine, cyclohexyl
amine, n-octyl amine, n-dodecyl amine, etc.) using
bis(benzotriazolyl)methanethione (3) and DBU in
refluxing CH2Cl2 for 3 h yielding the desired 2-
thioxo-4(1H)-quinazolinones (Scheme 1) in good
yields (52–89%) as shown in Table 1. Thus, e.g. re-
fluxing solution of benzyl amine, bis(benzotria-
Scheme 1

Synthesis of 2-Thioxo-2,3-dihydroquinazolin-4(1H)-ones
45
Table 1. One-pot synthesis of 2-thioxo-2,3-dihydroquinazolin-4(1H)-ones 4a–4n with DBU as base
Entry
Comp
R1
R2
R3
Time=h
Yield=%
1
2
3
4
4
5
6
7
9
10
11
12
13
14
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
H
H
H
H
H
H
H
H
H
H
H
H
CH3
CH3
CH3
CH3
CH3
C6H5CH2
C6H5
3-Cl–C6H4CH2
3-F–C6H4
3-F–C6H4
CH3(CH2)6CH2
CH3(CH2)10CH2
4-COOEt–C6H4
Cyclohexyl
C6H5
4-Me–C6H4
4-OMe–C6H4
4-Cl–C6H4
3
3
3
3
4
3
3
4.5
3
4
89
85
82
78
52
80
80
54
72
55
55
54
50
52
H
7-chloro
H
H
6,8-dichloro
H
H
H
H
H
H
4
4
4
4
3-Cl,4-Me–C6H3
zolyl)methanethione (3) in presence of DBU with
methyl anthranilate in anhydrous dichloromethane
yielded the desired N3-benzyl-2-thioxo-2,3-dihydro-
1H-quinazolin-4-one (4a) via the Bt-equivalent iso-
thiocyanate intermediate in good yield (89%). The
product was isolated by column chromatography
using SiO2 (20% EtOAc in n-hexane) and by its
spectroscopic data and microanalysis, the structure
has been confirmed as cyclic (4a), not an open chain
thiourea. The reactions with other amines, e.g. cy-
clohexyl amine, n-octyl amine, n-dodecyl amine,
aniline, and substituted anilines were also found to
proceed smoothly. However, with methyl substitution
on N-1, the reactions proceeded with sluggish rate
and afforded the product in comparatively low yield.
In our one-pot addition-cyclation, yields are high
particularly with N1-unsubstituted anthranilic esters;
however with N1-substituted one, e.g. N-CH3, the re-
action yield is comparatively low, i.e. in general with
N1-unsubstituted derivatives, the cyclization is facile.
The reason can easily be understood as depicted in
Scheme 1. The mechanism proposed for the reac-
tion involves the addition of amine to 3 via route
A resulting in the formation of thiocarbamoylbenzo-
triazoles I that on addition of 1 yielded uncyclized
thiourea II. Route B involves primarily the addition
of 1 to 3, thiocarbamoylbenzotriazoles III thus ob-
tained on elimination of Bt-H (in case of N1 un-
substitution) resulted in isothiocyanates IV, which
finally on addition of amine afforded the same uncyc-
Scheme 2

46
V. K. Tiwari et al.
N3-Phenyl-2-thioxo-2,3-dihydroquinazolin-4(1H)-one
lized intermediate II. The cyclization of II proceeds
in a similar reported way [12b], which involves ab-
straction of a proton from the terminal amido func-
tionality by DBU giving a thioureidyl anion that
results in thioquinazolinones 4a–4n through cycla-
tive amidation.
(4b, C14H10N2OS)
Yield 85%; mp >260ꢂC; IR (KBr): ꢀꢀ¼ 3248.0 (NH), 1663.3
(C¼O), 1529.5, 1196.8cmꢄ1; MS: m=z ¼ 255 [Mþ H]þ;
1H NMR (300MHz, CDCl3): ꢁ ¼ 11.72 (s, 1H, NH), 8.05
(d, J ¼ 7.8 Hz, 1H, Ar–H), 7.79 (t, J ¼ 7.8 Hz, 1H, Ar–H),
7.49–7.31 (m, 7H, Ar–H) ppm.
In conclusion, we developed a new and useful one-
pot synthesis protocol for diverse 2-thioxo-4(3H)-qui-
nazolinones (through a benzotriazole methodology)
by DBU catalyzed addition of anthranilic acid=ester
and amines to bis(benzotriazolyl)methanethione. The
method is convenient, simple in handling, and good
to high yielding. Results are encouraging and are
needed to be investigated in an extensive manner
to develop the total synthesis of natural products
containing the thioxoquinazolinone skeleton.
N3-(3-Fluorophenyl)-2-thioxo-2,3-dihydroquinazolin-4(1H)-
one (4d, C14H9N2FOS)
Yield 78%; mp 263ꢂC; IR (KBr): ꢀꢀ¼ 3242.2, 1660.7, 1531.2,
1200.2cmꢄ1; MS: m=z ¼ 273 [M þ H]þ; 1H NMR (300 MHz,
CDCl3): ꢁ ¼ 11.76 (s, 1H, NH), 8.05 (d, J ¼ 7.8 Hz, 1H, Ar–
H), 7.80 (t, J ¼ 7.8 Hz, 1H, Ar–H), 7.57–7.50 (m, 2H, Ar–H),
7.41 (t, J ¼ 7.5 Hz, 1H, Ar–H), 7.25–7.20 (m, 3H, Ar–H)
ppm; 13C NMR (CDCl3, 75MHz): ꢁ ¼ 136.45, 131.21,
128.72, 126.34, 125.19, 117.71, 116.23, 116.07, 115.77 ppm.
N3-(3-Fluorophenyl)-2-thioxo-2,3-dihydro-7-chloro-
quinazolin-4(1H)-one (4e, C14H8N2FClOS)
Experimental
Yield 52%; IR (KBr): ꢀꢀ¼ 34.54.8, 1658.1, 1615.5, 1258.4,
1
1207.7cmꢄ1; H NMR (300 MHz, CDCl3): ꢁ ¼ 11.75 (s, 1H,
Glassware was dried over an open flame before use in con-
nection with an inert atmosphere (N2) and solvents were evap-
orated under reduced pressure. Thin layer chromatography
(TLC) was performed using silica gel 60 F-254 plates with
I2 vapors as detecting agents followed by spraying with
Draggendorff reagent. Silica gel (230–400 mesh) was used
for column chromatography. TMS (0.0ppm) was used as an
NH), 8.00 (d, J ¼ 7.8 Hz, 1H, Ar–H), 7.50–7.18 (m, 6H, Ar–
H) ppm.
N3-n-Octyl-2-thioxo-2,3-dihydroquinazolin-4(1H)-one
(4f, C16H22N2OS)
Yield 80%; mp 138ꢂC; IR (KBr): ꢀꢀ¼ 3448.9, 2925.8, 2855.3,
1650.9, 1538.6, 1379.1, 1348.4, 1161.1cmꢄ1; MS: m=z ¼
291[M þ H]þ; 1H NMR (300MHz, CDCl3): ꢁ ¼ 10.10 (s,
1H, NH), 8.13 (d, J ¼ 7.8 Hz, 1H, Ar–H), 7.65 (t, J ¼
7.5 Hz, 1H, Ar–H), 7.32 (t, J ¼ 7.5 Hz, 1H, Ar–H), 4.50 (t,
J ¼ 7.2 Hz, 2H, NCH2), 1.77 (m, 2H, CH2), 1.25 (m, 10H,
5CH2), 0.88 (t, J ¼ 6.6Hz, 3H, CH3) ppm.
1
internal standard in H NMR. Infrared spectra were recorded
as KBr pellets by a Perkin Elemer RX-1 spectrometer. Melting
points were determined on a Buchi 535 melting point appara-
tus. Elemental analyses were performed on a Perkin-Elmer
2400 C, H, N analyzer and results were found to be within
ꢁ0.4% of the calculated values.
N3-Benzyl-2-thioxo-2,3-dihydroquinazolin-4(1H)-one
N3-n-Dodecyl-2-thioxo-2,3-dihydroquinazolin-4(1H)-one
(4g, C20H30N2OS)
(4a, C15H12N2OS)
To 0.45 g bis(benzotriazolyl)methanethione (3, 1.61 mmol) dis-
solved in 20cm3 anhydrous CH2Cl2, 175 mm3 benzyl amine
(1.61 mmol) were added slowly at 0ꢂC under N2 atmosphere.
The mixture was stirred for 5 min and then 210 mm3 methyl
anthranilate (1a, 1.62 mmol) and DBU (240 mm3, 1.60 mmol)
were added. After 5 min of stirring the reaction was brought
to room temperature and stirred for further 10 min and
finally refluxed for 3 h. Progress of the reaction was moni-
tored by TLC. The reaction mixture was washed with
5% Na2CO3 solution followed by 10 cm3 distilled H2O
to keep the reaction mixture free from liberated benzotria-
zole, extracted with 2ꢃ75 cm3 CH2Cl2, dried (anhydrous
Na2SO4), and was concentrated under reduced pressure.
The crude mass thus obtained was purified over SiO2 col-
umn using 20% EtOAc in n-hexane as eluent to afford 0.38g
(89%) 4a as colorless solid. Mp 248ꢂC; IR (KBr): ꢀꢀ¼ 3220.3
(NH), 1662.2 (C¼O), 1205.2 (C¼S) cmꢄ1; MS: m=z ¼ 269
Yield 80%; IR (KBr): ꢀꢀ¼ 3440.1, 2915.2, 2880.7, 1644.2,
1553.2, 1189.1 cmꢄ1
;
1H NMR (300MHz, CDCl3): ꢁ ¼
10.11 (s, 1H, NH), 8.13 (d, J ¼ 7.8 Hz, 1H, Ar–H), 7.66 (t,
J ¼ 7.5 Hz, 1H, Ar–H), 7.33 (t, J ¼ 7.5 Hz, 1H, Ar–H), 4.51 (t,
J ¼ 7.2 Hz, 2H, NCH2), 1.76 (m, 2H, CH2), 1.30–1.20 (m,
18H, 9CH2), 0.88 (t, J ¼ 6.9 Hz, 3H, CH3) ppm.
N1-Methyl-N3-phenyl-2-thioxo-2,3-dihydroquinazolin-
4(1H)-one (4j, C15H12N2OS)
Yield 55%; mp >260ꢂC; MS: m=z ¼ 269 [Mþ H]þ; IR
1
(KBr): ꢀꢀ¼ 1692.5, 1608.2, 1480.2, 1384.4, 1209.2 cmꢄ1; H
NMR (300MHz, CDCl3): ꢁ ¼ 8.09–7.01 (m, 9H, Ar–H), 3.96
(s, 3H, NCH3) ppm.
N1-Methyl-N3-(4-methylphenyl)-2-thioxo-2,3-dihydro-
quinazolin-4(1H)-one (4k, C16H14N2OS)
1
Yield 55%; mp 250ꢂC; IR (KBr): ꢀꢀ¼ 1695.2, 1608.1,
[Mþ H]þ; H NMR (300 MHz, CD3COCD3): ꢁ ¼ 11.74 (s,
1
1515.4, 1385.2, 1220.6 cmꢄ1; H NMR (300 MHz, CDCl3):
1H, NH), 8.06 (d, J ¼ 7.5 Hz, 1H, Ar–H), 7.69 (d, J ¼
7.5 Hz, 1H, Ar–H), 7.50–7.25 (m, 7H, Ar–H), 5.78 (s, 2H,
CH2Ph) ppm.
ꢁ ¼ 7.00–7.90 (m, 8H, Ar–H), 3.97 (s, 3H, NCH3), 2.43 (s,
3H, ArCH3) ppm.

Synthesis of 2-Thioxo-2,3-dihydroquinazolin-4(1H)-ones
47
N1-Methyl-N3-(4-methoxyphenyl)-2-thioxo-2,3-dihydro-
quinazolin-4(1H)-one (4l, C16H14N2O2S)
JM, Bishop JAM, O’Connor BM, Calvertt AH (1991) J
Med Chem 34: 1594
Yield 54%; mp 234ꢂC; IR (KBr): ꢀꢀ¼ 1691.4, 1512.9, 1384.6,
1215.8 cmꢄ1; 1H NMR (300MHz, CDCl3): ꢁ ¼ 7.00–8.11 (m,
8H, Ar–H), 3.97 (s, 3H, N–CH3), 3.71 (s, 3H, OCH3) ppm.
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Acknowledgements
We are grateful to Dr. R. P. Tripathi, Senior Scientist, Central
Drug Research Institute, Lucknow, India for discussion and
the Department of Science and Technology, New Delhi for
financial support.
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