Efficient synthesis of 2-methylenethiazolo[2,3-b]quinazolinone derivatives

Article abstract of DOI:10.1055/s-0034-1379499

Substituted o-amino-N-(prop-2-yn-1-yl) aromatic amides easily reacted with carbon disulfide (CS₂) in the presence of potassium hydroxide (KOH) in EtOH under reflux conditions. Cyclization reaction followed by a favored 5-exo-dig ring closure af

Full text of DOI:10.1055/s-0034-1379499

SYNLETT
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
© Georg Thieme Verlag Stuttgart · New York
2015, 26, 173–176
letter
173
M. Mahdavi et al.
Letter
Synlett
Efficient Synthesis of 2-Methylenethiazolo[2,3-b]quinazolinone
Derivatives
Mohammad Mahdavia
Maryam Bialamb
Mina Saeedic
Farnaz Jafarpourb
Alireza Foroumadia
Abbas Shafiee*a
O
O
N
R
R
OH
NH2
N
S
X
X
a Department of Medicinal Chemistry, Faculty of Pharmacy and
Pharmaceutical Sciences Research Center, Tehran University of
Medical Sciences, Tehran 14176, Iran
shafieea@tums.ac.ir
b School of Chemistry, College of Science, University of Tehran,
PO Box 14155-6455, Tehran, Iran
c Persian Medicine and Pharmacy Research Center, Tehran Uni-
versity of Medical Sciences, Tehran, Iran
Received: 13.09.2014
Accepted after revision: 29.10.2014
Published online: 09.12.2014
Later, as shown in Scheme 1, Shiau et al.12 investigated
the same strategy with more details only for the synthesis
of 2-methylene-2,3-dihydro-5H-thiazolo[2,3-b]quinazolin-
5-one (6). The synthetic route was started from the reaction
of anthranilic acid (1) and allyl isothiocyanate (2). The ob-
tained product, 3-allyl-2-thioxo-2,3-dihydroquinazolin-
4(1H)-one (3), reacted with Br2 and CCl4 to give 3-(2,3-di-
bromopropyl)-2-thioxo-2,3-dihydroquinazolin-4(1H)-one
(4) which was transformed to 2-(bromomethyl)-2,3-dihy-
dro-5H-thiazolo[2,3-b]quinazolin-5-one (5) in the presence
of sodium carbonate in DMF–H2O. Finally, the reaction of 5
with benzylpiperazine afforded 2-methylene-2,3-dihydro-
5H-thiazolo[2,3-b]quinazolin-5-one (6, Scheme 1).
Herein, in continuation of our efforts to synthesize nov-
el heterocycles,13 we focused on the preparation of various
2-methylene-thiazolo[2,3-b]quinazolinones 11 starting
from different 2-amino benzoic acids 7 (Scheme 2). For this
purpose, various substituted o-amino-N-(prop-2-yn-1-yl)
aromatic amides 9 were easily prepared by the reaction of
2-aminobenzoic acids 7 and propargylamine (8) in the
presence of hydroxybenzotriazole (HOBt) and N,N′-diiso-
propylcarbodiimide (DIC) in anhydrous CH2Cl2 according to
the procedure reported by Jablonski et al.14 Then, the cy-
clization reaction of compounds 9 was comprehensively in-
vestigated.
DOI: 10.1055/s-0034-1379499; Art ID: st-2014-b0765-l
Abstract Substituted o-amino-N-(prop-2-yn-1-yl) aromatic amides
easily reacted with carbon disulfide (CS2) in the presence of potassium
hydroxide (KOH) in EtOH under reflux conditions. Cyclization reaction
followed by a favored 5-exo-dig ring closure afforded 2-methylene-
thiazolo[2,3-b]quinazolinone derivatives in good yields.
Key words 2-methylene-thiazolo[2,3-b]quinazolinones,
amine, carbon disulfide, fused quinazolinone, 5-exo-dig
propargyl-
Quinazolinone derivatives are a vital structural motif in
a variety of biologically active compounds.1 Their valuable
properties, such as antitumor,2 anticonvulsant,3 anti-in-
flammatory,4 and epidermal growth factor receptor (EGFR)
tyrosine kinase inhibitory activities,5 have attracted a great
deal of attention. Also, they have been well known as pepti-
domimetic scaffold.6 Among the various quinazolinones,
fused derivatives possess an extensive array of biological
activities. At this juncture, thiazolo[2,3-b]quinazolinones
are found in a variety of bioactive compounds in medicinal
chemistry. Anticancer and antimicrobial,7 antihyperten-
sive,8 as well as herbicidal activities9 have been reported in
the literature. Accordingly, there has been significant inter-
est in developing synthetic methods for their efficient and
user-friendly construction.
In spite of the important biological properties of thiazo-
lo[2,3-b]quinazolinone, the literature lacks various reports
on the practical library-based synthetic procedures. Previ-
ously, some derivatives were prepared using condensation
reaction between allyl isothiocyanate and different anthra-
nilic acids followed by the bromination of the resulted
3-allyl-2-thioxo-2,3-dihydroquinazolin-4(1H)-one deriva-
tives.10,11
Alkynes are versatile building blocks in organic transfor-
mations, and the intramolecular addition of a heteronuc-
leophile such as oxygen, nitrogen, and sulfur to triple bond
leads to the formation of heterocyclic rings.15
Usually these reactions need to be activated in the pres-
ence of an electrophilic reagent.16 According to Baldwin’s
rules,17 the oxygen and nitrogen cyclization are usually con-
trollable. It is clear that the particular properties of sulfur,
such as larger atomic size and greater polarizability, leads to
stronger nucleophilicity and low regioselectivity.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 173–176

174
M. Mahdavi et al.
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Synlett
O
O
OH
N
MeCN, r.t.
24 h
S
C
+
N
NH2
N
H
S
2
1
3
O
N
N
5
O
O
Br
N
Br
HN
Na2CO3
Br2
N
N
CCl4
Br
S
S
DMF–H2O
N
N
H
S
6
4
Scheme 1 Synthesis of 2-methylene-2,3-dihydro-5H-thiazolo[2,3-b]quinazolin-5-one (6)12
O
O
O
N
R
R
R
OH
N
NH2
H
HOBt, DIC
CS2 10, KOH
N
+
X
NH2
X
NH2
dry CH2Cl2
r.t., 48 h
EtOH, reflux
3–8 h
S
X
7
8
9
11
X = C, N
Scheme 2 Synthesis of 2-methylene-thiazolo[2,3-b]quinazolinone derivatives 11
Table 1 Investigation of Various Conditions for the Reaction of 9a to
Obtain the Corresponding Product 11a
Recently, we successfully reported the synthesis of ben-
zoxazepino[4,5-a]quinazolinones through base-promoted
7-exo-dig hydroamination of 3-substituted 2-[2-(prop-2-
yn-1-yloxy)phenyl]-2,3-dihydroquinazolin-4(1H)-ones in
the absence of transition-metal catalysts.13b In this study,
we focused on the intramolecular cyclization of substituted
o-amino-N-(prop-2-yn-1-yl) aromatic amides 9 in the reac-
tion with CS2 (10) to obtain the title compounds 11
O
O
CS2
N
N
H
5-exo-dig
ring closure
S
N
NH2
9a
11a
Entry
Solvent
Base (equiv)
Temp (°C)
Yield (%)a
(Scheme 2).
Hence, we selected 2-amino-N-(prop-2-yn-1-yl)benz-
1
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
DMF
–
r.t.
0
amide (9a) as a model substrate to react with CS2 (10) and
examined various conditions including different tempera-
ture, bases/reagents, and solvents (Table 1). Table 1 shows
that utilizing KOH in EtOH under reflux conditions afforded
product 11a in good yield (Table 1, entries 3 and 4).
Also, it was revealed that the corresponding product
was formed when the reaction mixture was heated at the
boiling point of the solvent. According to our results, an
equivalent amount of base was sufficient, and higher
amounts did not improve the yield of reaction.
With these results in hand, various 2-methylene-thiazo-
lo[2,3-b]quinazolinones 11a–h were prepared using differ-
ent substituted o-amino-N-(prop-2-yn-1-yl) aromatic am-
ides 9. All substrates possessing electron-rich as well as
electron-poor substituents underwent potassium hydrox-
ide promoted cyclization reaction with CS2 followed by 5-
exo-dig ring closure to give the corresponding products 11
in relatively short reaction time (3–8 h), and commonly
good yields were achieved (Scheme 2, Table 2).
2
KOH (1)
KOH (1)
KOH (2)
NaOH (1)
Et3N (1)
K2CO3 (1)
piperidine (1)
L-proline (1)
KOH (1)
KOH (1)
KOH (1)
r.t.
trace
85
85
70
5
3
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
4
5
6
7
30
10
15
65
50
60
8
9
10
11
12
PhMe
1,4-di-
oxane
a Isolated yields.
All products were characterized using IR and NMR spec-
troscopy, and all data confirmed the structures of the syn-
thesized compounds.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 173–176

175
M. Mahdavi et al.
Letter
Synlett
Table 2 Synthesis of 2-Methylene-thiazolo[2,3-b]quinazolinones 1119
(4) Balakumar, C.; Lamba, P.; Kishore, D. P.; Narayana, B. L.; Rao, K.
V.; Rajwinder, K.; Rao, A. R.; Shireesha, B.; Narsaiah, B. Eur. J.
Med. Chem. 2010, 45, 4904.
(5) Hu, S.; Xie, G.; Zhang, D. X.; Davis, C.; Long, W.; Hu, Y.; Wang, F.;
Kang, X.; Tan, F.; Ding, L.; Wang, Y. Bioorg. Med. Chem. Lett. 2012,
22, 6301.
(6) Fowler, K. W.; Huang, D.; Kesicki, E. A.; Ooi, H. C.; Oliver, A.;
Ruan, F.; Treiberg, J.; Puri, K. D. US Patent RE44599, 2013.
(7) Gali, R.; Banothu, J.; Porika, M.; Velpula, R.; Hnamte, S.;
Bavantula, R.; Abbagani, S.; Busi, S. Bioorg. Med. Chem. Lett.
2014, 24, 4239.
O
O
R
R
CS2, KOH
N
N
H
EtOH, reflux
3–8 h
S
X
NH2
X
N
9
11
Entry
R
X
Prod-
uct 11
Mp (°C)
Time Yield
(h)
(%)a
(8) Saeva, G. A.; Georgiev, V. S. US Patent 4738964, 1988.
(9) (a) Seybold, G.; Wuerzer, B. US Patent 4473391, 1984.
(b) Seybold, G.; Wuerzer, B. US Patent 4486221, 1984.
(10) Sachdev, H. S.; Dhami, K. S.; Atwal, M. S. Tetrahedron 1961, 14,
304.
1
2
H
C
11a
11b
220–222
(lit.11 202)
3
85
5-Me
C
160–162
(lit.11 150)
4
80
3
4
4,5-(MeO)2
4-Cl
C
C
11c
11d
221–223
5
4
75
70
(11) Dhami, K. S.; Sachdev, H. S.; Narang, K. S. J. Sci. Ind. Res. 1956, 15,
690.
170–171
(lit.18 167)
(12) Shiau, C.-Y.; Chern, J.-W.; Liu, K.-C.; Chan, C.-H.; Yen, M.-H.;
Cheng, M.-C.; Wang, Y. J. Heterocycl. Chem. 1990, 27, 1467.
(13) (a) Mahdavi, M.; Asadi, M.; Saeedi, M.; Rezaei, Z.; Moghbel, H.;
Foroumadi, A.; Shafiee, A. Synlett 2012, 23, 2521. (b) Mahdavi,
M.; Foroughi, N.; Saeedi, M.; Karimi, M.; Foroumadi, A.;
Alinezhad, H.; Shafiee, A.; Akbarzadeh, T. Synlett 2014, 25, 385.
(c) Esmaeili-Marandi, F.; Saeedi, M.; Mahdavi, M.; Yavari, I.;
Foroumadi, A.; Shafiee, A. Synlett 2014, 25, 2605.
(14) Jablonski, J. J.; Basu, D.; Engel, D. A.; Geysen, H. M. Bioorg. Med.
Chem. 2012, 20, 487.
5
6
5-Cl
C
C
11e
11f
190–192
(lit.10 193)
4
7
70
65
C4H4 (3-amino-2-
naphthoic acid)
190–192
7
8
4-O2N
H
C
11g
11h
180–181
180–182
8
8
50
45
N
a Isolated yields.
(15) Ren, X.-F.; Turos, E.; Lake, C. H.; Churchill, M. R. J. Org. Chem.
1995, 60, 6468.
(16) Ren, X.-F.; Turos, E. Tetrahedron Lett. 1993, 34, 1575.
(17) (a) Baldwin, J. E. J. Chem. Soc., Chem. Commun. 1976, 734.
(b) Baldwin, J. E.; Thomas, R. C.; Kruse, L. I.; Silberman, L. J. Org.
Chem. 1977, 42, 3846.
In conclusion, a practical and easy approach was estab-
lished for the preparation of 2-methylene-thiazolo[2,3-b]-
quinazolinones through the potassium hydroxide promoted
cyclization reaction of substituted o-amino-N-(prop-2-yn-
1-yl) aromatic amides and CS2 followed by 5-exo-dig ring
closure in EtOH under reflux conditions. Various benefits
such as easy workup and lack of time-consuming purifica-
tion steps make this work useful for organic as well as me-
dicinal chemists to develop novel thiazoloquinazolinone-
based drugs.
(18) Pura, M. S.; Sachdev, H. S.; Ralhan, N. K. Indian J. Chem. 1964, 2,
258.
(19) Synthesis
of
2-Methylene-thiazolo[2,3-b]quinazolinone
Derivatives 11 – General Procedure
A mixture of substituted o-amino-N-(prop-2-yn-1-yl) aromatic
amides 9 (1 mmol), CS2 (10, 2 mmol), and KOH (1 mmol) in
EtOH (8 mL) was heated at reflux for 3–8 h. After completion of
reaction (checked by TLC), the reaction mixture was cooled to
r.t. and poured into cold H2O. The precipitate was filtered off to
obtain pure products 11 with no need for further purification.
2-Methylene-2,3-dihydro-5H-thiazolo[2,3-b]quinazolin-5-
one (11a)
Acknowledgment
This research was supported by grants from the Research Council of
Tehran University of Medical Sciences and the Iran National Science
Foundation (INSF).
Yield 0.18 g (85%); white solid; mp 220–222 °C (lit.11 202 °C). IR
(KBr): 2937, 1665, 1582, 1553 cm–1. 1H NMR (400 MHz, CDCl3):
δ = 5.12 (t, J = 2.4 Hz, 2 H, CH2), 5.37 (q, J = 2.4 Hz, 1 H, =CH2),
5.50 (q, J = 2.4 Hz, 1 H, =CH2), 7.42 (td, J = 7.6, 0.8 Hz, 1 H, H7),
7.56 (dd, J = 7.6, 0.8 Hz, 1 H, H9), 7.72 (td, J = 7.6, 1.5 Hz, 1 H, H8),
8.22 (dd, J = 7.6, 1.5 Hz, 1 H, H6). 13C NMR (100 MHz, CDCl3):
δ = 54.2, 108.3, 119.3, 126.2, 126.3, 126.6, 133.1, 134.8, 148.8,
158.1, 159.9. Anal. Calcd for C11H8N2OS: C, 61.09; H, 3.73; N,
12.95. Found: C, 60.87; H, 3.58; N, 13.14.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0034-1379499.
S
u
p
p
ortioInfgrmoaitn
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u
p
p
ortiInfogrmoaitn
References and Notes
7-Methyl-2-methylene-2,3-dihydro-5H-thiazolo[2,3-
b]quinazolin-5-one (11b)
(1) Khan, I.; Ibrar, A.; Abbas, N.; Saeed, A. Eur. J. Med. Chem. 2014,
76, 193.
(2) Chen, X.; Du, Y.; Sun, H.; Wang, F.; Kong, L.; Sun, M. Bioorg. Med.
Chem. Lett. 2014, 24, 884.
Yield 0.18 g (80%); deep yellow solid; mp 160–162 °C (lit.11
150 °C). IR (KBr): 1669, 1621, 1581 m–1 1H NMR (400 MHz,
.
CDCl3): δ = 2.47 (s, 3 H, CH3), 5.11 (t, J = 2.4 Hz, 2 H, CH2), 5.35
(q, J = 2.4 Hz, 1 H, =CH2), 5.48 (q, J = 2.4 Hz, 1 H, =CH2), 7.45 (d,
J = 8.4 Hz, 1 H, H9), 7.53 (dd, J = 8.4, 1.6 Hz, 1 H, H8), 8.00 (s, 1 H,
H6). 13C NMR (100 MHz, CDCl3): δ = 21.2, 54.2, 108.1, 119.0,
(3) Ugale, V. G.; Bari, S. B. Eur. J. Med. Chem. 2014, 80, 447.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 173–176

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126.0, 126.1, 133.3, 136.1, 136.4, 146.8, 157.0, 159.9. Anal.
Calcd for C12H10N2OS: C, 62.59; H, 4.38; N, 12.16. Found: C,
62.41; H, 4.52; N, 11.97.
H, 2.81; N, 11.17. Found: C, 52.57; H, 2.93; N, 11.28.
2-Methylene-2,3-dihydro-5H-benzo[g]thiazolo[2,3-
b]quinazolin-5-one (11f)
7,8-Dimethoxy-2-methylene-2H-thiazolo[2,3-b]quinazolin-
5(3H)-one (11c)
Yield 0.17 g (65%); yellow solid; mp 190–192 °C. IR (KBr): 1628,
1573, 1401 cm–1. 1H NMR (400 MHz, CDCl3): δ = 5.13–5.15 (m, 2
H, CH2), 5.37–5.38 (m, 1 H, =CH2), 5.50–5.51 (m, 1 H, =CH2), 7.52
(t, J = 6.5 Hz, 1 H, H9), 7.62 (t, J = 6.5 Hz, 1 H, H8), 7.98 (d, J = 6.5
Hz, 1 H, H10), 8.00 (s, 1 H, H11), 8.07 (d, J = 6.5 Hz, 1 H, H7), 8.13
(s, 1 H, H6). 13C NMR (100 MHz, CDCl3): δ = 53.9, 108.1, 116.8,
123.1, 123.6, 125.8, 126.2, 128.3, 128.6, 128.7, 128.8, 129.4,
137.0, 163.2, 163.6. Anal. Calcd for C15H10N2OS: C, 67.65; H,
3.78; N, 10.52. Found: C, 67.83; H, 3.57; N, 10.37.
Yield 0.21 g (75%); deep yellow solid; mp 221–223 °C. IR (KBr):
1672, 1605, 1580 cm–1. 1H NMR (400 MHz, CDCl3): δ = 3.98 (s, 3
H, OCH3), 4.00 (s, 3 H, OCH3), 5.12 (t, J = 2.4 Hz, 2 H, CH2), 5.35
(q, J = 2.4 Hz, 1 H, =CH2), 5.48 (q, J = 2.4 Hz, 1 H, =CH2), 6.98 (s, 1
H, H9), 7.52 (s, 1 H, H6). 13C NMR (100 MHz, CDCl3): δ = 54.3,
56.2, 56.3, 105.5, 106.9, 108.1, 117.2, 133.4, 145.2, 148.5, 155.1,
156.4, 159.4. Anal. Calcd for C13H12N2O3S: C, 56.51; H, 4.38; N,
10.14. Found: C, 56.34; H, 4.50; N, 9.96.
2-Methylene-8-nitro-2H-thiazolo[2,3-b]quinazolin-5(3H)-
one (11g)
8-Chloro-2-methylene-2,3-dihydro-5H-thiazolo[2,3-
b]quinazolin-5-one (11d)
Yield 0.13 g (50%); yellow solid; mp 180–182 °C. IR (KBr): 1669,
Yield 0.17 g (70%); off-white solid; mp 170–171 °C (lit.18
1535, 1613, 1488, 1350 cm–1 1H NMR (400 MHz, DMSO-d6):
.
167 °C). IR (KBr): 2918, 1685, 1602, 1568 cm–1
.
1H NMR (400
δ = 5.12 (t, J = 1.9 Hz, 2 H, CH2), 5.35 (q, J = 1.9 Hz, 1 H, =CH2),
5.48 (q, J = 1.9 Hz, 1 H, =CH2), 6.49 (dd, J = 1.7 Hz, 1 H, H9), 6.66
(dd, J = 6.9, 1.7 Hz, 1 H, H7), 7.72 (d, J = 6.9 Hz, 1 H, H6). 13C NMR
(100 MHz, DMSO-d6): δ = 53.8, 105.9, 108.2, 114.1, 127.3, 133.3,
150.3, 154.5, 156.7, 157.7, 158.4. Anal. Calcd for C11H7N3O3S: C,
50.57; H, 2.70; N, 16.08. Found: C, 50.39; H, 2.57; N, 15.87.
2-Methylene-2,3-dihydro-5H-pyrido[2,3-d]thiazolo[3,2-
a]pyrimidin-5-one (11h)
MHz, CDCl3): δ = 5.27 (t, J = 1.9 Hz, 2 H, CH2), 5.37 (q, J = 1.9 Hz,
1 H, =CH2), 5.61 (q, J = 1.9 Hz, 1 H, =CH2), 7.37 (dd, J = 8.8, 2.0 Hz,
1 H, H7), 7.62 (d, J = 2.0 Hz, 1 H, H9), 8.27 (d, J = 8.8 Hz, 1 H, H6).
13C NMR (100 MHz, CDCl3): δ = 53.6, 115.2, 117.2, 123.3, 125.5,
125.8, 128.4, 149.0, 157.6, 159.5, 163.8. Anal. Calcd for C11H7-
ClN2OS: C, 52.70; H, 2.81; N, 11.17. Found: C, 52.91; H, 2.68; N,
10.92.
7-Chloro-2-methylene-2,3-dihydro-5H-thiazolo[2,3-
b]quinazolin-5-one (11e)
Yield 0.10 g (45%); deep yellow solid; mp 180–182 °C. IR (KBr):
1
2915, 1681, 1609 cm–1. H NMR (400 MHz, DMSO-d6): δ = 5.22
Yield 0.17 g (70%); white solid; mp 192–192 °C (lit.10 193 °C). IR
(KBr): 2915, 1681, 1609, 1574 cm–1. 1H NMR (400 MHz, CDCl3):
δ = 5.11 (s, 2 H, CH2), 5.37 (d, J = 2.0 Hz, 1 H, =CH2), 5.50 (d,
J = 2.0 Hz, 1 H, =CH2), 7.60 (d, J = 7.1 Hz, 1 H, H9), 7.62 (dd,
J = 7.1, 2.0 Hz, 1 H, H8), 8.27 (d, J = 2.0 Hz, 1 H, H6). 13C NMR (100
MHz, CDCl3): δ = 54.2, 108.6, 117.1, 123.6, 126.1, 127.8, 130.8,
135.1, 146.7, 157.2, 158.5. Anal. Calcd for C11H7ClN2OS: C, 52.70;
(t, J = 1.5 Hz, 2 H, CH2), 5.63 (q, J = 1.5 Hz, 1 H, =CH2), 5.65 (q,
J = 1.5 Hz, 1 H, =CH2), 6.60 (dd, J = 6.2, 3.8 Hz, 1 H, H7), 8.04 (dd,
J = 6.2, 1.5 Hz, 1 H, H6), 8.17 (dd, J = 3.8, 1.5 Hz, 1 H, H8). 13C NMR
(100 MHz, DMSO-d6): δ = 51.9, 105.5, 111.8, 120.3, 120.9, 123.3,
140.0, 153.4, 159.7, 168.6. Anal. Calcd for C10H7N3OS: C, 55.29;
H, 3.25; N, 19.34. Found: C, 55.42; H, 3.36; N, 19.52.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 173–176

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