Regioselective syntheses of 1-aryl-substituted-5H-[1,3]thiazolo[3,2-a] quinazoline-5-ones during sonogashira coupling

Article abstract of DOI:10.1080/10426507.2010.503211

Reaction of 2-mercaptopropargylquinazoline-4-one with various aryliodides catalyzed by Pd-Cu leads to the regioselective formation of 1-arylsubstituted- 5H-[1,3]thiazolo-[3,2-a]quinazoline-5-ones. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/10426507.2010.503211

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Phosphorus, Sulfur, and Silicon and the
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Regioselective Syntheses of 1-Aryl-
substituted-5H-[1,3]thiazolo[3,2-
a]quinazoline-5-ones During Sonogashira
Coupling
Mohammad Bakherad a , Ali Keivanloo a , Zahra Kalantar a & Vahid
Keley a
a School of Chemistry , Shahrood University of Technology ,
Shahrood, Iran
Published online: 07 Mar 2011.
To cite this article: Mohammad Bakherad , Ali Keivanloo , Zahra Kalantar & Vahid Keley (2011)
Regioselective Syntheses of 1-Aryl-substituted-5H-[1,3]thiazolo[3,2-a]quinazoline-5-ones During
Sonogashira Coupling, Phosphorus, Sulfur, and Silicon and the Related Elements, 186:3, 464-470, DOI:
10.1080/10426507.2010.503211
To link to this article: http://dx.doi.org/10.1080/10426507.2010.503211
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Phosphorus, Sulfur, and Silicon, 186:464–470, 2011
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426507.2010.503211
REGIOSELECTIVE SYNTHESES OF
1-ARYL-SUBSTITUTED-5H-[1,3]THIAZOLO[3,2-
a]QUINAZOLINE-5-ONES DURING SONOGASHIRA
COUPLING
Mohammad Bakherad, Ali Keivanloo, Zahra Kalantar,
and Vahid Keley
School of Chemistry, Shahrood University of Technology, Shahrood, Iran
GRAPHICAL ABSTRACT
O
O
N
Pd (PPh3)2Cl2, CuI
Et3N, CH3CN, r.t.
N
+ ArI
N
S
N
S
H
ArH2C
Abstract Reaction of 2-mercaptopropargylquinazoline-4-one with various aryliodides cat-
alyzed by Pd–Cu leads to the regioselective formation of 1-arylsubstituted-5H-[1,3]thiazolo-
[3,2-a]quinazoline-5-ones.
Keywords Aryl iodide; Pd-catalyzed; quinazoline; Sonogashira coupling; thiazoloquinazoline
INTRODUCTION
Quinazolinones are classes of fused heterocycles that are of considerable interest
because of their diverse range of biological properties, such as anticancer, diuretic, anti-
inflammatory, anticonvulsant, and antihypertensive activities.1–3 There has been consider-
able interest in transition metal–mediated cycloaddition reactions of aldehydes in organic
synthesis,4 especially those involving palladium.5,6 Attempts to annulate intramolecularly
onto alkynes using palladium have generally resulted in multiple alkyne insertion and
subsequent cyclization back to the pre-existing aromatic ring.7 Although a few multistep
procedures8 are available for the synthesis of carbocyclic9 and heterocyclic compounds10
using palladium, this annulation strategy has not been utilized for the syntheses of thia-
zoloquinazolinones.
Received 3 May 2010; accepted 16 June 2010.
The authors would like to thank the Research Council of Shahrood University of Technology for the support
of this work.
Address correspondence to Mohammad Bakherad, Faculty of Chemistry, Shahrood University of Technol-
ogy, Shahrood 3619995161, Iran. E-mail: m.bakherad@yahoo.com
464

REGIOSELECTIVE SYNTHESES DURING SONOGASHIRA COUPLING
465
In continuation of our recent studies11–13 on the palladium-catalyzed reactions of
acetylenic substrates leading to heterocyclic compounds of biological significance, we
became interested in the regioselective syntheses of substituted thiazoloquinazolinones
using palladium–copper catalysis.
RESULTS AND DISCUSSION
When 2-propargylmercaptoquinazoline-4-one 2 was treated with aryl halides 3a–i
in triethylamine in the presence of bis(triphenylphosphin)palladium chloride and copper
iodide, 1-aryl-substituted-5H-[1,3]thiazolo[3,2-a]quinazoline-5-ones 4 were obtained in
moderate to good yields.
In the first step, 2-thioxo-2,3-dihydroquinazoline-4(1H)-one 1 was reacted with
propargyl bromide to give the corresponding 2-propargylmercaptoquinazoline-4-one 2.14
O
O
NH
EtOH
NH
BrH2C C CH
+
N
H
1
S
N
S
2
Heteroannulation of 2 through palladium–copper catalysis in the presence of aryl
iodides 3a–i led to the formation of either 1-aryl-substituted-5H-[1,3]thiazolo[3,2-a]
quinazoline-5-ones 4 or 3-aryl-substituted-5H-[1,3]thiazolo[2,3-b]quinazoline-5-ones 5.
When 2 was treated with 2-nitro-1-iodobenzene 3a and triethylamine in the presence
of bis(triphenylphosphine)palladium chloride and copper iodide under an argon atmosphere
in acetonitrile, a single compound was obtained, as detected by TLC. The 1H NMR spectrum
of the product showed one aromatic proton at δ 6.64, characteristic of a fused thiazole ring,
as well as benzylic protons at δ 4.95.
Bis(triphenylphosphine)palladium chloride and cuprous iodide were found to be the
catalyst and co-catalyst, respectively. Reactions were carried out with either just copper(I)
iodide or just Pd(II) chloride, as the catalyst led to very poor yields of products. The results
are tabulated in Table 1.
Mechanistically, either thiazolo[3,2-a]quinazoline-5-ones 4 or thiazolo[2,3-b]
quinazoline-5-ones 5 are the possible products, as illustrated in Scheme 1: (a) formation
of ArPdI (II) through oxidative addition of Pd(0) (I) to ArI15; (b) transmetallation of
ArPdI with the Cu salt of (III), generating the alkynyl palladium species (IV); (c)
reductive elimination of Pd(0) to yield the alkynes (V); and (d) isomerization to the allenic
intermediates16 (VI), which then cyclize to product 4 or 5.
However, other mechanisms for this reaction are also plausible, for example, a 5-exo-
dig cyclization may be triggered simply by the formation of an Ar–Pd(II) species followed
by reduction, elimination, and isomerization. This type of cyclization has been observed
for acetylenic lactams.17
The structures of 4 and 5 were established by comparing their spectra with those
for the well-established compounds 6 (IR, υ
1695 cm−1) and 7 (IR, υ
1640
(C O)
(C O)
cm )
−1 14,18,19 (Scheme 2). The IR spectra for 4 or 5 were quite similar to that for 7. Therefore,
we can conclude that one-pot condensation, cyclization, and isomerization of acetylenic
compounds regioselectively afford 4.

466
M. BAKHERAD ET AL.
Pd(PPh3)2Cl2
a
ArI
3a-i
Pd(0)
ArPdI
(I)
(II)
Cu
O
PdAr
O
N
O
NH
b
NH
NH
S
N
S
N
S
Cu
(III)
(IV)
Pd(0)
Ar
O
O
CHAr
c
NH
NH
C
C
N
S
N
S
(VI)
(V)
d
O
N
O
N
CH2Ar
S
N
S
N
5
ArH2C
4
Scheme 1 Proposed mechanism for the formation of either thiazolo[3,2-a]quinazoline-5-ones 4 or thiazolo[2,3-
b]quinazoline-5-ones 5 at room temperature. Reagents and conditions: (a) Reduction of Pd(II) to Pd(0) with alkyne
and Et3N; (b) CuI, Et3N; (c) isomerization to an allene with CuI, Et3N; (d) nucleophilic attack on the allene (VI)
to generate the product 4 or 5.
O
N
O
CH3
N
N
S
S
N
H3C
6
7
Scheme 2

REGIOSELECTIVE SYNTHESES DURING SONOGASHIRA COUPLING
467
Table 1 Melting points and yields of 1-aryl-substituted-5H-[1,3]thiazolo[3,2-a]quinazoline-5-onesa
Entry
Ar
Mp (◦C)
239–241
Yield (%)
70
4a
4b
4c
252–254
257–259
72
82
4d
4e
4f
230–232
264–266
244–246
75
88
85
4g
236–238
72

468
M. BAKHERAD ET AL.
Table 2 Melting points and yields of 1-aryl-substituted-5H-[1,3]thiazolo[3,2-a]quinazoline-5-onesa (Continued)
Entry
Ar
Mp (◦C)
255–257
Yield (%)
65
4h
4i
287–289
80
aReaction reagents and conditions: 2 (1.3 mmol), 3a–i (1 mmol), Et3N (3 mmol), Pd(PPh)3Cl2 (0.03 mmol),
CuI (0.06 mmol), and CH3CN (6 mL) at room temperature for 12 h.
As shown in the Scheme 2, the allenic intermediates (VI) could undergo cyclization
either around N1 or N3 of quinazoline. Due to the better nucleophilic power of the N1 site
relative to the N3 site, cyclization occurs at the former one.
In conclusion, we have established the first successful one-pot condensation, re-
gioselective cyclization, and isomerization for the syntheses of 1-arylsubstituted-5H-
[1,3]thiazolo[3,2-a]quinazoline-5-ones. The method is easy to carry out under relatively
mild conditions. Since there is no need for the use of any toxic reagents, it can be consid-
ered relatively eco-friendly. The process is thus amenable to the regioselective synthesis of
thiazolo[3,2-a]quinazoline-5-ones.
EXPERIMENTAL
Melting points were recorded on an Electrothermal type 9100 melting point apparatus.
Elemental analyses were performed by Ferdowsi University, Mashhad, Iran.
Syntheses of 1-Aryl-substituted-5H-[1,3]thiazolo[3,2-
a]quinazoline-5-ones 4a–i
A mixture of aryl iodide (1 mmol), (PPh3)2PdCl2 (0.03 mmol), Cul (0.06 mmol), and
triethylamine (3.0 mmol) was stirred in acetonitrile (6 mL) under an argon atmosphere.
2-Propargylmercaptoquinazoline-4-one 2 (1.3 mmol) was then added, and the mixture was
stirred at room temperature for 12 h. The solid substance formed was filtered, washed with
water, and recrystallized from ethanol (Table 1).

REGIOSELECTIVE SYNTHESES DURING SONOGASHIRA COUPLING
469
1-(2-Nitrobenzyl)-5H-[1,3]thiazolo[3,2-a]quinazoline-5-one 4a
IR (KBr, νmax cm−1): 1625, 1520, 1350, 1642. 1H NMR (500 MHz, CDCl3 δ ppm):
4.95 (s, 2H, CH2), 6.64 (s, 1H, CH of thiazole), 7.52–7.79 (m, 4H, ArH), 8.01–8.20 (m,
2H, ArH), 8.23–8.42 (m, 2H, ArH), Anal. Calcd. for C17H11N3O3S: C, 60.52; H, 3.29; N,
12.46; S, 9.50. Found: C, 60. 38; H, 3.14; N, 12.32; S, 9.62%.
1-(3-Nitrobenzyl)-5H-[1,3]thiazolo[3,2-a]quinazoline-5-one 4b
1
IR (KBr, νmax cm−1): 1623, 1510, 1350. H NMR (500 MHz, CDCl3 δ ppm): 4.80
(s, 2H, CH2), 6.70 (s, 1H, CH of thiazole), 7.33 (s, 1H, ArH), 7.54–7.65 (m, 3H, ArH),
8.04–8.23 (m, 4H, ArH), Anal. Calcd. for C17H11N3O3S: C, 60.52; H, 3.29; N, 12.46; S,
9.50. Found: C, 60. 41; H, 3.17; N, 12.57; S, 9.32%.
1-(4-Nitrobenzyl)-5H-[1,3]thiazolo[3,2-a]quinazoline-5-one 4c
IR (KBr, νmax cm−1): 1625, 1510, 1340. 1H NMR (500 MHz, CDCl3 δ ppm): 4.84 (s,
2H, CH2), 6.66 (s, 1H, CH of thiazole), 7.53–7.65 (m, 4H, ArH), 8.04–8.15 (m, 2H, ArH),
8.25 (d, J = 7.9 Hz, 2H, ArH), Anal. Calcd. for C17H11N3O3S: C, 60.52; H, 3.29; N, 12.46;
S, 9.50. Found: C, 60. 28; H, 3.13; N, 12.61; S, 9.24%.
1-(4-Cyanobenzyl)-5H-[1,3]thiazolo[3,2-a]quinazoline-5-one 4d
IR (KBr, νmax cm−1): 2240, 1620. 1H NMR (500 MHz, CDCl3 δ ppm): 4.54 (s, 2H,
CH2), 6.75 (s, 1H, CH of thiazole), 7.50–7.72 (m, 4H, ArH), 7.80–8.97 (m, 2H, ArH), 8.15
(d, J = 8.2 Hz, 2H, ArH), Anal. Calcd. for C18H11N3OS: C, 68.12; H, 3.49; N, 13.24; S,
10.10. Found: C, 68.30; H, 3.32; N, 13.43; S, 9.92%.
1-(2-Methyl-4-nitrobenzyl)-5H-[1,3]thiazolo[3,2-a]quinazoline-5-one 4e
1
IR (KBr, νmax cm−1): 1625, 1525, 1345. H NMR (500 MHz, CDCl3 δ ppm): 2.30
(s, 3H, CH3), 4.75 (s, 2H, CH2), 6.46 (s, 1H, CH of thiazole), 7.60–7.80 (m, 3H, ArH),
8.11–8.27 (m, 3H, ArH), 8.47 (d, J = 8.2 Hz, 1H, ArH), Anal. Calcd. for C18H13N3O3S:
C, 61.53; H, 3.73; N, 11.96; S, 9.13. Found: C, 61.70; H, 3.82; N, 11.81; S, 9.27%.
1-(2-Chloro-4-nitrobenzyl)-5H-[1,3]thiazolo[3,2-a]quinazoline-5-one 4f
IR (KBr, νmax cm−1): 1630, 1518, 1350. 1H NMR (500 MHz, CDCl3 δ ppm): 4.84 (s,
2H, CH2), 6.78 (s, 1H, CH of thiazole), 7.60–7.68 (m, 2H, ArH), 7.85–8.05 (m, 2H, ArH),
8.23 (s, 1H, ArH), 8.32–8.52 (m, 2H, ArH), Anal. Calcd. for C17H10ClN3O3S: C, 54.92;
H, 2.71; N, 9.54; S, 8.62. Found: C, 55.14; H, 2.83; N, 9.69; S, 8.45%.
1-(4-Chloro-2-nitrobenzyl)-5H-[1,3]thiazolo[3,2-a]quinazoline-5-one 4g
IR (KBr, νmax cm−1): 1627, 1525, 1350. 1H NMR (500 MHz, CDCl3 δ ppm): 4.89 (s,
2H, CH2), 6.62 (s, 1H, CH of thiazole), 7.24 (d, J = 7.6 Hz, 1H, ArH), 7.63–7.84 (m, 2H,
ArH), 7.95–8.14 (m, 2H, ArH), 8.21–8.28 (m, 1H, ArH), 8.47 (d, J = 8.7 Hz, 1H, ArH),

470
M. BAKHERAD ET AL.
Anal. Calcd. for C17H10ClN3O3S: C, 54.92; H, 2.71; N, 9.54; S, 8.62. Found: C, 54.77; H,
2.61; N, 9.66; S, 8.40%.
1-(3-Chloro-4-nitrobenzyl)-5H-[1,3]thiazolo[3,2-a]quinazoline-5-one 4h
IR (KBr, νmax cm−1): 1625, 1520, 1345. 1H NMR (500 MHz, CDCl3 δ ppm): 4.74 (s,
2H, CH2), 6.78 (s, 1H, CH of thiazole), 7.53–7.72 (m, 4H, ArH), 8.05–8.20 (m, 3H, ArH),
Anal. Calcd. for C17H10ClN3O3S: C, 54.92; H, 2.71; N, 9.54; S, 8.62. Found: C, 55.20; H,
2.88; N, 9.43; S, 8.76%.
1-(3-Chloro-4-cyanobenzyl)-5H-[1,3]thiazolo[3,2-a]quinazoline-5-one 4i
IR (KBr, νmax cm−1): 1628, 1510, 1340, 1642. 1H NMR (500 MHz, CDCl3 δ ppm):
4.86 (s, 2H, CH2), 6.71 (s, 1H, CH of thiazole), 7.49–7.78 (m, 5H, ArH), 7.98–8.20 (m,
2H, ArH), Anal. Calcd. for C18H10ClN3OS: C, 61.45; H, 2.87; N, 11.94; S, 9.11. Found:
C, 61.68; H, 3.02; N, 12.14; S, 9.30%.
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