An efficient synthesis of thio- and thiazoloquinazolinones by the electrochemical oxidation of catechols in the presence of 2-mercapto-4(3H)- quinazolinone

Article abstract of DOI:10.1055/s-0028-1083258

Thio- and thiazoloquinazolinones were synthesized efficiently by the anodic oxidation of catechols in the presence of 2-mercapto-4(3H)-quinazolinone in aqueous solution. 4-Methylcatechol and 3-methoxycatechol convert into thioquinazolinones via an EC (E:

Full text of DOI:10.1055/s-0028-1083258

PAPER
3963
An Efficient Synthesis of Thio- and Thiazoloquinazolinones by the
Electrochemical Oxidation of Catechols in the Presence of 2-Mercapto-
4(3H)-quinazolinone
S
ynthesis of Thio-
l
and Th
i
iazoloquinaz
R
olinones eza Fakhari,*a Kobra Hasheminasab,a Hamid Ahmar,a Abdolali Alizadehb
a
Department of Chemistry, Faculty of Sciences, Shahid Beheshti University G. C., P.O. Box 19396-4716, Tehran, Iran
Fax +98(21)22431683; E-mail: a-zavareh@sbu.ac.ir
Department of Chemistry, Tarbiat Modares University, Tehran 18716, Iran
b
Received 29 July 2008; revised 16 September 2008
Table 1 Electrochemical Synthesis of 4 and 6
Abstract: Thio- and thiazoloquinazolinones were synthesized effi-
ciently by the anodic oxidation of catechols in the presence of 2-
mercapto-4(3H)-quinazolinone in aqueous solution. 4-Methylcate-
chol and 3-methoxycatechol convert into thioquinazolinones via an
EC (E: electron transfer, C: chemical reaction) pathway. Catechol,
3-methylcatechol, and 3,4-dihydroxybenzoic acid convert into thia-
zoloquinazolinones via an ECEC pathway.
OH
O
OH
R1
NH
+
N
SH
R2
1a–e
3
Key words: electrochemical synthesis, phenols, thiols, heterocy-
cles, decarboxylation
OH
O
N
OH
R2
O
N
OH
R1
OH
NH
N
Quinazolinone A and its derivatives (Figure 1) are known
to have a broad range of pharmaceutical properties, such
as anticancer, anti-inflammatory, anticonvulsant, and an-
tidiuretic activities.1–7 The presence of the thiazole ring in
many natural and synthetic quinazolinones has generated
interesting biological properties.8,9 Moreover, thiazo-
lo[2,3-b]quinazolinones B (Figure 1) are potentially inter-
esting from a biological and synthetic point of view. A
number of classic methods for the preparation of thiazolo-
quinazolinones have been developed. These include the
reaction of heteroaromatic 2-aminoesters with 2-(meth-
ylthio)-2-thiazoline,10 solid-phase methods,11 condensa-
tion of o-aminobenzoic acid hydrochloride with the
appropriate a- or w-thiocyanato ketone,12 condensation of
substituted anthranilic acids or esters with methyl 2-chlo-
rothiazole-5-carboxylate,13 reaction of anthranilic acid
with 2-chlorobenzothiazole, and the reaction of ethyl-
anthranilate with 2-chlorobenzothiazole.14,15
S
R1
S
6
4
Product
R1
R2
Yielda
(%)
Appliedpotential
(V)
4a
4b
6c
H
Me
H
92
87
79
68
90
0.20
0.15
0.25
0.35
0.20
OMe
H
H
6cb
H
CO2H
H
6e
Me
a Isolated yield.
b Decarboxylated product.
The electrochemical oxidation of catechols 1a–e in the
presence of 2-mercapto-4(3H)-quinazolinone (3) results
in a smooth 1:1 addition reaction in water at ambient tem-
perature to produce thioquinazolinones 4 and thiazolo-
quinazolinones 6 (Table 1). Cyclic voltammetry of a 1
mM solution of catechol 1c in water–acetonitrile (90:10)
containing 0.15 M phosphate buffer (pH 7.4) results in
one anodic (A1) and corresponding cathodic peak (C1)
(Figure 2, curve a), which is related to the transformation
of catechol 1c into the corresponding o-benzoquinone 2c
and vice versa through a quasi-reversible two-electron
process (Scheme 1).
In this paper, we report a simple electrochemical method
for the synthesis of several novel thio- and thiazolo-
quinazolinone derivatives from catechols 1a–e and 2-
mercapto-4(3H)-quinazolinone (3) (Table 1).
O
O
NH
N
S
N
N
A
B
A peak current ratio (IPC1/IPA1) of nearly one, particularly
during the repetitive recycling of potential, can be consid-
ered as a criterion for the stability of o-benzoquinone pro-
duced at the surface of the electrode under the
Figure 1 Quinazolinone A and thiazolo[2,3-b]quinazolinones B
SYNTHESIS 2008, No. 24, pp 3963–3966
x
x.
x
x
.
2
0
0
8
Advanced online publication: 01.12.2008
DOI: 10.1055/s-0028-1083258; Art ID: Z17508SS
© Georg Thieme Verlag Stuttgart · New York

3964
A. R. Fakhari et al.
PAPER
chol 1c in the presence of 1 mM 2-mercapto-4(3H)-
quinazolinone (3). Decrease of cathodic peak height is re-
lated to the coupling reaction between the o-quinone de-
rived from catechol 2c and 2-mercapto-4(3H)-
quinazolinone (3). The cyclic voltammogram of 1 mM 2-
mercapto-4(3H)-quinazolinone (3) is also shown in
Figure 2 (curve c), for comparison.
Because the oxidation potential peaks of 1c and 3
(Figure 2) are close together, and we wanted to minimize
the oxidation of 3 to achieve higher selectivity, we applied
0.25 V potential versus Ag/AgCl/KCl(3 M) in the prepar-
ative synthesis processes (Table 1). Multicyclic voltam-
metry of 1c in the presence of 3 shows a new peak A0
appearing in the second cycle, parallel to the shift of the
A1 peak in a positive potential direction (Figure 3). This
new peak is related to the electrochemical oxidation of in-
termediate 4c (Scheme 1). The positive shift of the A1
peak in the presence of 3 is due to the formation of a thin
film of product on the surface of the electrode, which de-
creases the performance of the electrochemical process.
Figure 2 Cyclic voltammograms (scan rate = 100 mV·s–1, r.t.): (a)
1 mM of 1c, (b) 1 mM of 1c in the presence of 1 mM of 3; (c) 1 mM
of 3 at a glassy carbon electrode (1.8 mm diameter) in 0.15 M phos-
phate buffer (pH 7.4).
R1
R1
R2
R2
OH
OH
O
O
– 2 e–, – 2 H+
1a–e
2a–e
R1
O
N
R1
O
R2
S
R2
O
OH
OH
NH
NH
SH
O
N
3
2a–d
4a–d
O
R1
O
N
O
N
R1
R2
R2
S
O
O
OH
– 2 e–, – 2 H+
NH
NH
NH
N
S
OH
5c,d
4c,d
R1
Figure 3 Multicyclic voltammograms. Conditions: 1 mM catechol
1c, 2-mercapto-4(3H)-quinazolinone (3), glassy carbon electrode (1.8
mm diameter), H2O–MeCN (90:10), 0.15 M phosphate buffer/sup-
porting electrolyte (KH2PO4/K2HPO4, pH 7.4), scan rate 100 mV·s–1,
r.t.
O
R2
R1
O
O
OH
OH
N
S
N
S
5c,d
6c
As shown in Table 1, we have obtained various deriva-
tives of thio- and thiazoloquinazolinones from the reac-
tion of catechols 1a–e and 2-mercapto-4(3H)-
quinazolinone (3). The possible mechanism for the forma-
tion of products 4 and 6 is shown in Scheme 1. The initial
event is the nucleophilic attack of 2-mercapto-4(3H)-
quinazolinone (3) on o-quinone 2 (Scheme 1). For 4-
methyl- and 3-methoxycatechol (1a and 1b), the reaction
was stopped at this step to give products 4a and 4b
(Schemes 1 and 2, Table 1). But in the case of catechols
1c–e, the reaction was continued to give cyclic com-
pounds 6c and 6e (Schemes 1 and 2). For 3,4-dihydroxy-
benzoic acid (1d) electro-decarboxylation occurred to
give product 6c (Scheme 1 and Table 1, entry 4). It should
be mentioned that for each of 3-methoxy- and 3-methyl-
a R1 = H, R2 = Me
b R1 = OMe, R2 = H
c R1 = R2 = H
d R1 = H, R2 = COOH
e R1 = Me, R2 = H
Scheme 1 Proposed mechanism for the electrooxidation of ca-
techols in the presence of 2-mercapto-4(3H)-quinazolinone
experimental conditions. In other words, chemical reac-
tions such as hydroxylation16 and dimerization17 are too
slow to be observed on the time scale of the cyclic voltam-
metry. The electrochemical oxidation of catechols 1a–e
was also studied in the presence of 2-mercapto-4(3H)-
quinazolinone (3) as a nucleophile. Figure 2 (curve b)
shows the cyclic voltammogram obtained for 1mM cate-
Synthesis 2008, No. 24, 3963–3966 © Thieme Stuttgart · New York

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Synthesis of Thio- and Thiazoloquinazolinones
3965
O
O
OH
OH
OH
N
OH
N
OH
HO
OH
NH
HO
S
N
O
S
OMe
O
6e
OMe
4b
NH
SH
1e
1b
O
N
OH
OH
OH
OH
NH
N
3
X
N
N
S
S
OMe
Scheme 2 Possible products for the electrooxidation of 3-methoxy- and 3-methylcatechol (1b and 1e) in the presence of 2-mercapto-4(3H)-
quinazolinone
13C NMR (75 MHz, DMSO-d6): d = 20.20 (CH3), 114.22 (CH of
catechol (1b and 1e) two possible products can be predict-
Ar), 118.29 (CH of Ar), 120.44 (Cipso–CO), 124.18 (CH of Ar),
126.06 (CH of Ar), 126.42 (CH of Ar and Cipso–S), 134.63 (CH of
Ar), 134.92 (Cipso–CH3), 144.00 (Cipso–OH), 148.17 (Cipso–OH),
148.92 (Cipso–N), 156.24 (C=O), 161.98 (C=N).
ed (Scheme 2), but we obtained selectively 4b from 3-
methoxycatechol (1b) and 6e from 3-methylcatechol (1e).
MS (EI, 70 eV): m/z (%) = 300 (50) [M+], 267 (100), 249 (20), 178
(60), 124 (20), 90 (60), 63 (20), 39 (40).
Chemicals were purchased from Merck, Aldrich, and Fluka, and
were used without further purification. All experiments were car-
ried out at r.t. Cyclic voltammetry (CV) was performed on a
mAutolab potentiostat/galvanostat type III and preparative analysis
was carried out on an EG&G PAR A Model 174 A potentiostat/gal-
vanostat. The working electrode (WE) used in the voltammetry ex-
periment was a glassy carbon disc (1.8 mm diameter) and platinum
wire was used as the counter electrode (CE). The WE used in con-
trolled-potential coulometry and macroscale electrolysis was an as-
sembly of three carbon rods (8 mm diameter, 4 cm long) and a large
platinum gauze (3 cm × 3 cm) constituted the CE. The WE poten-
tials were measured versus Ag/AgCl/KCl (3 M) as a reference elec-
trode. All electrodes were obtained from Azar Electrode, Urmia, I.
R., Iran. NMR spectra were recorded on a Bruker DRx-300 Avance
instrument. IR spectra were recorded on a Bruker IFS-66 FT-IR
spectrophotometer. Mass spectra were obtained on a QP-1100EX
Shimadzu GC-MS (EI, 70 eV). Melting points of the products were
obtained on an electrothermal melting point model 9200.
2-[(3,4-Dihydroxy-5-methoxyphenyl)thio]quinazolin-4(3H)-one
(4b)
White solid; mp 223–224 °C (dec).
IR (KBr): 3329 (OH), 1652 (C=O), 1576 and 1554 (Ar) cm–1.
1H NMR (300 MHz, DMSO-d6): d = 3.76 (s, 3 H, OCH3), 6.70 (s, 1
H, CH of Ar), 6.74 (s, 1 H, CH of Ar), 7.34 (d, 3JHH = 7.64 Hz, 1 H,
3
CH of Ar), 7.39 (t, JHH = 7.64 Hz, 1 H, CH of Ar), 7.68 (t,
3JHH = 7.64 Hz, 1 H, CH of Ar), 8.01 (d, 3JHH = 7.64 Hz, 1 H, CH of
Ar), 9.16 (br, 2 H, 2 OH), 12.42 (br, 1 H, NH).
13C NMR (75 MHz, DMSO-d6): d = 56.53 (OCH3), 111.64 (CH of
Ar), 114.65 (CH of Ar), 117.16 (Cipso–CO), 120.53 (CH of Ar),
126.14 (CH of Ar), 126.44 (CH of Ar and Cipso–S), 134.92 (CH of
Ar), 136.84 (Cipso–OCH3), 146.50 (Cipso–OH), 148.92 (Cipso–N),
148.96 (Cipso–OH), 156.9 (C=O), 162.1 (C=N).
MS (EI, 70 eV): m/z (%) = 316 (10) [M+], 284 (6), 178 (100), 140
(75), 119 (70), 92 (52), 51 (30).
Electro-organic Synthesis of 4 and 6; General Procedure
A mixture (100 mL) of H2O–MeCN (90:10) containing 0.15 M
phosphate buffer/supporting electrolyte (KH2PO4/K2HPO4, pH 7.4)
was pre-electrolyzed at the applied potential (Table 1) in an undi-
vided cell. Subsequently, catechol 1 (2 mmol) and 3 (2 mmol) were
added to the cell. Finally, the electrolysis was performed at the same
potential (Table 1). The electrolysis was terminated when the decay
of the current became more than 95%. The process was interrupted
several times during the electrolysis and the carbon anode was
washed in acetone to reactivate it. At the end of the electrolysis, the
cell was placed in a refrigerator and left overnight. The precipitated
solid was collected by filtration and was then washed several times
with distilled H2O. Then the products were characterized by IR, 1H
NMR, and 13C NMR spectroscopy and MS.
8,9-Dihydroxy-12H-benzothiazolo[2,3-b]quinazolin-12-one (6c)
Pale green solid; mp 217–218 °C (dec).
IR (KBr): 3412 (OH), 1705 (C=O), 1627 and 1569 (Ar) cm–1.
1H NMR (300 MHz, DMSO-d6): d = 7.29 (s, 1 H, CH of Ar), 7.49
(t, 3JHH = 6.18 Hz, 1 H, CH of Ar), 7.62 (d, 3JHH = 6.18 Hz, 1 H, CH
of Ar), 7.83 (d, 3JHH = 6.18 Hz, 1 H, CH of Ar), 8.28 (t, 3JHH = 6.18
Hz, 1 H, CH of Ar), 8.46 (s, 1 H, CH of Ar), 9.63 (br, 2 H, 2 OH).
13C NMR (75 MHz, DMSO-d6): d = 106.86 (CH of Ar), 109.05 (CH
of Ar), 112.87 (Cipso–S), 118.47 (Cipso–CO), 125.77 (CH of Ar),
126.01 (CH of Ar), 126.90 (CH of Ar), 128.44 (Cipso–N), 135.02
(CH of Ar), 145.12 (Cipso–N), 145.70 (Cipso–OH), 147.22 (Cipso
OH), 158.26 (C=O), 160.06 (C=N).
–
2-[(4,5-Dihydroxy-2-methylphenyl)thio]quinazolin-4(3H)-one
(4a)
MS (EI, 70 eV): m/z (%) = 284 (5) [M+], 178 (100), 119 (35), 92
(31), 64 (17), 43 (12).
Pale brown solid; mp 227–228 °C (dec).
IR (KBr): 3415 (OH), 2899 (CH3), 1657 (C=O), 1578 and 1514 (Ar)
cm–1.
8,9-Dihydroxy-7-methyl-12H-benzothiazolo[2,3-b]quinazolin-
12-one (6e)
Pale brown solid; mp 242–243 °C (dec).
1H NMR (300 MHz, DMSO-d6): d = 2.18 (s, 3 H, CH3), 6.77 (s, 1
H, CH of Ar), 6.94 (s, 1 H, CH of Ar), 7.28 (d, 3JHH = 7.71 Hz, 1 H,
3
CH of Ar), 7.37 (t, JHH = 7.71 Hz, 1 H, CH of Ar), 7.66 (t,
IR (KBr): 3517 (OH), 2965 (CH3), 1715 (C=O), 1580 and 1553 (Ar)
cm–1.
3JHH = 7.71 Hz, 1 H, CH of Ar), 8.00 (d, 3JHH = 7.71 Hz, 1 H, CH of
Ar), 9.39 (br, 2 H, 2 OH), 12.46 (br, 1 H, NH).
1H NMR (300 MHz, DMSO-d6): d = 2.26 (s, 3 H, CH3), 3.6 (br, 2
H, 2 OH), 7.14 (s, 1 H, CH of Ar), 7.47 (t, 3JHH = 7.97 Hz, 1 H, CH
Synthesis 2008, No. 24, 3963–3966 © Thieme Stuttgart · New York

3966
A. R. Fakhari et al.
PAPER
of Ar), 7.57 (d, 3JHH = 7.97 Hz, 1 H, CH of Ar), 7.81 (t, 3JHH = 7.97
Hz, 1 H, CH of Ar), 8.18 (d, 3JHH = 7.97 Hz, 1 H, CH of Ar).
(4) Lingaiah, B. V.; Ezikiel, G.; Yakaiah, T.; Reddy, G. V.; Rao,
P. S. Synlett 2006, 2507.
(5) Connolly, D. J.; Guiry, P. J. Synlett 2001, 1707.
(6) Mhaske, S. B.; Argade, N. P. Tetrahedron 2006, 62, 9787.
(7) Abdel-Jalil, R. J.; Voelter, W.; Saeed, M. Tetrahedron Lett.
2004, 45, 3475.
(8) Rewcastle, G. W.; Palmer, B. D.; Bridges, A. J.; Showalter,
H. D. H.; Sun, L.; Nelson, J.; McMichael, A.; Kraker, A. J.;
Fry, D. W.; Denny, W. A. J. Med. Chem. 1996, 39, 918.
(9) Besson, T.; Guillard, J.; Rees, C. W. Tetrahedron Lett. 2000,
41, 1027.
13C NMR (75 MHz, DMSO-d6): d = 16.87 (CH3), 106.02 (CH of
Ar), 113.90 (Cipso–CO), 118.21 (Cipso–CH3), 119.28 (Cipso–S),
125.35 (CH of Ar), 125.62 (CH of Ar), 127.13 (CH of Ar), 127.19
(Cipso–N), 134.85 (CH of Ar), 144.21 (Cipso–N), 145.69 (Cipso–OH),
147.10 (Cipso–OH), 159.24 (CO), 160.2 (C=N).
MS (EI, 70 eV): m/z (%) = 298 (100) [M+], 283 (25), 269 (25), 178
(5), 149 (15).
(10) Sauter, F.; Frohlich, J.; Chowdhury, A. Z. M. S.; Hametner,
C. Monatsh. Chem. 1997, 128, 503.
Acknowledgment
(11) Bouillon, I.; Krchnak, V. J. Comb. Chem. 2007, 9, 912.
(12) Dhami, K. S.; Arora, S. S.; Narang, K. S. J. Med. Chem.
1963, 6, 450.
Financial support from the Research Affairs of Shahid Beheshti
University is gratefully acknowledged.
(13) LeMahieu, R. A.; Carson, M.; Welton, A. F.; Baruth, H. W.;
Yaremko, B. J. Med. Chem. 1983, 26, 107.
(14) McCarty, J. E. J. Org. Chem. 1962, 27, 2673.
(15) (a) Bose, P. K.; Pathak, K. B. J. Indian Chem. Soc. 1934, 11,
463. (b) Kate, L. J. Am. Chem. Soc. 1958, 76, 712.
(16) Papouchado, L.; Petrie, G.; Adams, R. N. J. Electroanal.
Chem. 1972, 38, 389.
References
(1) Cohen, E.; Klarberg, B.; Vaughan, J. R. J. Am. Chem. Soc.
1960, 82, 2731.
(2) Wolf, J. F.; Rathman, T. L.; Sleevi, M. C.; Campbell, J. A.;
Greenwood, T. D. J. Med. Chem. 1990, 33, 161.
(3) Padia, J. K.; Field, M.; Hinton, J.; Meecham, K.; Pablo, J.;
Pinnock, R.; Roth, B. D.; Singh, L.; Suman-Chauhan, N.;
Trivedi, B. K.; Webdale, L. J. Med. Chem. 1998, 41, 1042.
(17) Nematollahi, D.; Rafiee, M.; Samadi-Meybodi, A.
Electrochim. Acta 2004, 49, 2495.
Synthesis 2008, No. 24, 3963–3966 © Thieme Stuttgart · New York