An efficient synthesis of 4-alkyl-2(1H)-quinazolinones and 4-alkyl-2-chloroquinazolines from 1-(2-alkynylphenyl)ureas

Article abstract of DOI:10.1016/j.tetlet.2009.09.130

An efficient synthesis of 4-alkyl-2(1H)-quinazolinones has been achieved by cyclization of 1-(2-alkynylphenyl)ureas (2 R₂ = alkyl) in dichloroethane catalyzed by TfOH. In the case of aryl substitution (2 R₂ = aryl), a mixture of quin

Full text of DOI:10.1016/j.tetlet.2009.09.130

Tetrahedron Letters 50 (2009) 6841–6843
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
An efficient synthesis of 4-alkyl-2(1H)-quinazolinones and
4-alkyl-2-chloroquinazolines from 1-(2-alkynylphenyl)ureas
*
*
Honggen Wang, Lanying Liu, Yong Wang, Changlan Peng, Jiancun Zhang , Qiang Zhu
State Key Laboratory of Respiratory Diseases, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510663, People’s Republic of China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 10 July 2009
Revised 15 September 2009
Accepted 22 September 2009
Available online 25 September 2009
An efficient synthesis of 4-alkyl-2(1H)-quinazolinones has been achieved by cyclization of 1-(2-alkynyl-
phenyl)ureas (2 R2 = alkyl) in dichloroethane catalyzed by TfOH. In the case of aryl substitution (2
R2 = aryl), a mixture of quinazolinone tautomers is obtained in dichloroethane with TFA as co-solvent.
Chlorination of the resulting mixture affords 4-alkyl-2-chloro-quinazolines as sole products.
Ó 2009 Elsevier Ltd. All rights reserved.
Quinazoline and quinazolinone derivatives have attracted
considerable interest for medicinal chemists due to their broad
spectrum of biological activities such as anticancer, diuretic, anti-
inflammatory, anticonvulsant, and antihypertensive activities.1
Although there are numerous methods for the syntheses of quinaz-
oline and quinazolinone derivatives, no general and practical meth-
ods for the syntheses of diversified 4-alkylquinazolines and 4-alkyl-
2(1H)-quinazolinones are available.2 Herein we report a novel strat-
egy for the conversion of readily available 2-alkynylanilines 1 to
diversified 4-alkyl-2-chloroquinazolines and 4-alkylquinazolinones
which could be served as precursors for the synthesis of 4-alkyl-2-
substituted quinazolines (Scheme 1).
R2
N
R2
N
R2
N
R1
R1
R1
N
H
O
N
R3
N
Cl
R2
R2
NH2
R1
R1
N
O
NH2
1
H
2-Alkynylanilines 1 with various alkyl and aryl substituents at
the other end of triple bond were first transformed to their corre-
sponding urea derivatives according to the literature method with
minor modification in good to almost quantitative yields (Table
1).3 Anilines with aryl substituents worked better than those with
alkyl substituents (Table 1, entries 8–14). The ratio of HOAc to H2O
was determined by the solubility of 1 in the co-solvent. The reac-
tion was very clean and the crude products were pure enough
for further reaction without purification after normal work-up in
most cases.
The reaction conditions were optimized with 1-(2-(1-hexy-
nyl)phenyl)urea 2a as substrate and the results are summarized
in Table 2. The solvent was screened first in the presence of
2.0 equiv of TfOH as a catalyst (Table 2, entries 1–6).4 Dichloroeth-
ane (DCE) was superior to other solvents and afforded the desired
product in good yield (85%, Table 2, entry 1). The yield was lower in
dichloromethane under reflux overnight probably due to its lower
boiling point (Table 2, entry 2). A range of acids were tested with
DCE as a solvent (Table 2, entries 9–13). Among these acids, con-
centrated sulfuric acid can produce the product in reasonable yield
Scheme 1. Retrosynthetic analysis of 4-alkylquinazolines.
(62%, Table 2, entry 12).5 The reaction was also conducted with TFA
and HOAc as solvents. HOAc cannot catalyze the reaction at all.
Although as high as 81% of product can be isolated in TFA as a sol-
vent, the yield was much lower using 2.0 equiv of TFA in DCE (Ta-
ble 2, entries 8 and 9). The results suggested that stronger acid
TfOH was more efficient in this reaction. The amount of TfOH
was also optimized from catalytic (0.1 equiv) to excess (3.0 equiv).
The yield can be maximized to 91% with 1.5 equiv of TfOH (Table 2,
entry 17).
With the optimized conditions established, 1-(2-alkynylphe-
nyl)ureas 2 with alkyl substituents were tested first. Good to excel-
lent yield of 2-(1H)-quinazolinones 3 with a variety of alkyl groups
on the C-4 was obtained (Table 3, entries 1–4). Substitutions on the
aromatic ring affected the yields very sensitively (Table 3, entries 5
and 6). Electron-donating group (methyl) favored the reaction
while electron-withdrawing group (chloro) disfavored the reaction
dramatically (28%).6
When cyclization of 2h with a phenyl substituent was applied
under the same condition, an unexpected indole derivative 4h
was obtained in 71% yield (Scheme 2). When the acidity of the cat-
* Corresponding authors.
E-mail address: zhu_qiang@gibh.ac.cn (Q. Zhu).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.09.130

6842
H. Wang et al. / Tetrahedron Letters 50 (2009) 6841–6843
Table 1
Table 3
Synthesis of 1-(2-alkynylphenyl)ureas 2 from 2-alkynylanilines 1a
TfOH-catalyzed cyclization of 1-(2-alkynylphenyl)ureas 2 in DCEa
R2
R2
N
R2
NH2
R2
R1
R1
HOAc/H2O
R1
R1
TfOH, DCE, reflux
+
KOCN
NH2
O
NH2
N
H
2
O
N
H
2
N
H
O
1
3
Entry
R1
R2
HOAc/H2O
Product
Yield (%)
Entry
2
Product 3
Yieldb (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
H
H
H
H
n-Bu
t-Bu
Bn
Cyclohexyl
TMS
TMS
TMS
Ph
4-BrC6H4
4-ClC6H4
3-ClC6H4
2-ClC6H4
Ph
2:1
3:1
2.5:1
3:1
2:1
4:1
4:1
3:1
5:1
5:1
4:1
4:1
5:1
5:1
5:1
4:1
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
2o
2p
88b
70b
97c
81b
95c
98c
98c
95c
98c
99c
96c
95c
98c
96c
98c
99c
1
2
3
4
5
6
2b
2c
2d
2e
2f
3b, R1 = H, R2 = t-Bu
3c, R1 = H, R2 = Bn
91
79
98
75
89
28
3d, R1 = H, R2 = cyclohexyl
3e, R1 = H, R2 = H
H
3f, R1 = Me, R2 = H
3g, R1 = Cl, R2 = H
Me
Cl
H
H
H
H
H
Me
Cl
H
2g
a
Heating a solution of 1-(2-alkynylphenyl)ureas 2 (0.5 mmol) in DCE (3 mL) to
reflux in the presence of TfOH (0.75 mmol) overnight.
b
Isolated yield.
Ph
4-MeC6H4
4-MeOC6H4
H
TfOH:DCE = 1: 2,
a
reflux
NH2
O
To a suspension of 2-alkynylanilines 1 (0.5 mmol) in water (2.0 mL) was added
HOAc under sonication until the starting material was all dissolved. A solution of
KOCN (3.0 equiv) in minimum amount of H2O was added to the above-mentioned
solution and was stirred for about 20 min at ambient temperature.
N
71%
N
H
2h
H
4h
b
Purified by column chromatography.
Extracted with EtOAc and washed with H2O, saturated NaHCO3, and brine, and
c
used without further purification.
DCE/TFA reflux
Table 2
Cyclization of 1-(2-(1-hexynyl)phenyl)urea 2a under various conditionsa
POCl3, reflux,
55%
N
+
N
NH
NH2
O
N
N
Cl
N
H
3h
O
N
H
5
O
N
H
N
O
6h
H
2a
3a
Scheme 2. Cyclization of 1-(2-(2-phenylethynyl)phenyl)urea 2h under different
conditions.
Entry
Solvent
Acid (equiv)
Yieldb (%)
1
2
3
4
5
6
7
8
9
DCE
TfOH (2.0)
TfOH (2.0)
TfOH (2.0)
TfOH (2.0)
TfOH (2.0)
TfOH (2.0)
AcOH (solvent)
TFA (solvent)
TFA (2.0)
85
69
32
Trace
34
Trace
Trace
81
DCM
EtOH
Ether
n-Hexane
Acetonitrile
AcOH
TFA
was formed as a sole product in 55% overall yield from 2h. The aro-
maticity of the quinazoline locked the double bond inside the ring.
The two-step strategy was then applied to other aryl substi-
tuted 1-(2-alkynylphenyl)ureas 2i–2n (Table 4). Functionalities
Table 4
DCE
28
TFA-catalyzed cyclization of 1-(2-alkynylphenyl)ureas 2 and subsequent chlorination
with POCl3
10
11
12
13
14
15
16
17
18
19
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
p-TsOH (2.0)
BF3ÁOEt2 (2.0)
9
a
Trace
62
31
9
14
63
91
86
68
Concd H2SO4 (2.0)
TMSOTf (2.0)
TfOH (0.1)
Ar
Ar
R1
R1
DCE/TFA
reflux
POCl3
reflux
NH2
O
N
TfOH (0.5)
TfOH (1.0)
TfOH (1.5)
TfOH (2.5)
N
H
N
Cl
DCE
DCE
2
6
TfOH (3.0)
Entry
2
Product 6
Yieldb (%)
a
Heating a solution of 1-(2-(1-hexynyl)phenyl)urea 2a (0.5 mmol) in individual
solvent (3 mL) to reflux in the presence of acid catalyst overnight.
1
2
3
4
5
6
2i
2j
2k
2l
2m
2n
6i, R1 = H, Ar = 4-BrC6H4
6j, R1 = H, Ar = 4-ClC6H4
6k, R1 = H, Ar = 3-ClC6H4
6l, R1 = H, Ar = 2-ClC6H4
6m, R1 = Me, Ar = Ph
70
67
71
80
49
Trace
b
Isolated yield.
6n, R1 = Cl, Ar = Ph
alyst was reduced from TfOH to TFA, the expected quinazolinone
3h was indeed produced but together with its tautomer 5. We
failed to separate them in pure form. They equilibrated to the mix-
tures again soon after column chromatography. The tautomers
were treated with POCl3 and 2-chloro-4-benzylquinazoline 6h
a
Heating a solution of 1-(2-alkynylphenyl)ureas 2 (0.5 mmol) in TFA (1 mL) and
DCE (2 mL) to reflux. After normal work-up, the crude product was treated with
POCl3 under reflux.
b
Isolated yield.

H. Wang et al. / Tetrahedron Letters 50 (2009) 6841–6843
6843
R
N
R
R
R
NH2
O
H+
-H+
NH
NH2
O
path a
N
H
O
N
N
H
O
N
H
H
2
5
A
3
path b H+
Ar
-H+
H+, H2O
Ar
NH2
Ar
+
CO2 + NH4
+
NH
NH2
N
N
H
O
O
4
B
C
Scheme 3. Mechanism of cyclization of 1-(2-alkynylphenyl)ureas 2 under different acids.
such as chloride and bromide on the aromatic ring away from
Supplementary data
the urea moiety tolerated (Table 4, entries 1–4), while chloro
substitution on the left aromatic ring (R1) ruined the reaction
(Table 4, entry 6). Electron-donating groups such as methyl
and methoxy in substrates 2o and 2p favored the formation of
indoles exclusively even under the ‘milder’ conditions (result
not shown).7
The possible reaction mechanism is depicted in Scheme 3.
When R is an alkyl group, formation of A is preferred since the vi-
nyl cation intermediate can be stabilized by the neighboring aro-
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.09.130.
References and notes
1. (a) Connolly, D. J.; Cusack, D.; O’Sullivan, T. P.; Guiry, P. J. Tetrahedron 2005, 61,
10153–10202; (b) Witt, A.; Bergman, J. Curr. Org. Chem. 2003, 7, 659–677; (c)
Eguchi, S. Top. Heterocycl. Chem. 2006, 6, 113–156.
2. (a) Mangalagiu, I.; Benneche, T.; Undheim, K. Tetrahedron Lett. 1996, 37, 1309–
1312; (b) Bergman, J.; Brynolf, A.; Elman, B.; Vuorinen, E. Tetrahedron 1986, 42,
3697–3706; (c) Wiklund, P.; Bergman, J. Org. Biomol. Chem. 2003, 1, 367–372; (d)
Movassaghi, M.; Hill, M. D. J. Am. Chem. Soc. 2006, 128, 14254–14255; (e)
Portela-Cubillo, F.; Scott, J. S.; Walton, J. C. J. Org. Chem. 2009, 74, 4934–4942.
3. Kurzer, F. Org. Synth. 1963, Coll. 4, 49.
4. Klumpp, D. A.; Rendy, R.; Zhang, Y.; McElrea, A.; Gomez, A.; Dang, H. J. Org. Chem.
2004, 69, 8108–8110.
5. Wang, Y.; Peng, C.; Liu, L.; Zhao, J.; Su, L.; Zhu, Q. Tetrahedron Lett. 2009, 50,
2261–2265.
6. General procedure for compounds 3: A solution of 1-(2-alkynylphenyl)ureas 2
(0.5 mmol) in DCE (3 mL) was heated to reflux in the presence of TfOH
(0.75 mmol) overnight. Ethyl acetate was added and the mixture was washed
successively with saturated NaHCO3, H2O, and brine. The organic layer was
separated and dried over Na2SO4. The concentrated residue was purified by
column over silica gel. Compound 3a: 1H NMR (400 MHz, CDCl3): d 12.99 (br,
1H), 7.89 (d, J = 8.0 Hz, 1H), 7.67 (t, J = 7.6 Hz, 1H), 7.55 (d, J = 8.0 Hz, 1H), 7.28 (t,
J = 7.6 Hz, 1H), 3.11 (t, J = 7.6 Hz, 2H), 1.92–1.84 (m, 2H), 1.47–1.36 (m, 4H), 0.92
(t, J = 7.2, 3H); 13C NMR (100 MHz, CDCl3): d 180.5, 158.6, 142.0, 135.0, 125.9,
123.2, 116.9, 115.8, 35.5, 31.8, 27.6, 22.5, 14.0; MS (EI, m/z) 216 [M]+; HRMS (EI)
calcd for C13H16N2O: 216.1257 [M]+, found: 216.1256.
7. General procedure for compounds 6: A solution of 1-(2-alkynylphenyl)ureas 2
(0.5 mmol) in TFA (1 mL) and DCE (2 mL) was heated to reflux overnight. After
removal of most solvents, ethyl acetate was added and the mixture was washed
with saturated NaHCO3, H2O, and brine. The solution was dried over Na2SO4 and
concentrated under vacuum. To the completely dried residue was added POCl3
(3 mL) and stirred under reflux overnight. The excess POCl3 was evaporated
under vacuum and the residue was diluted with EtOAc. The mixture was washed
with saturated NaHCO3, H2O, and brine, successively. The organic layer was
separated and dried over Na2SO4. The concentrated residue was purified by
column chromatography over silica gel. Compound 6h: 1H NMR (400 MHz,
CDCl3): d 8.13 (d, J = 8.4 Hz, 1H), 7.96 (d, J = 8.4 Hz, 1H), 7.86 (t, J = 7.2 Hz, 1H),
7.59 (t, J = 6.8 Hz, 1H), 7.32–7.26 (m, 4H), 7.21 (t, J = 6.0 Hz, 1H), 4.60 (s, 2H); 13C
NMR (100 MHz, CDCl3): d 173.1, 157.0, 152.3, 136.9, 134.8, 128.9, 128.7, 128.4,
128.0, 127.0, 125.6, 122.4, 41.3; MS (EI, m/z) 254 [M]+; HRMS (EI) calcd for
C15H11N2Cl: 254.0605 [M]+, found: 254.0604.
matic group. Subsequent cyclization leads to
5
which
tautomerizes to its more stabilized form 3. When R is an aryl
group, competitive formation of B is preferred followed by five-
membered indole formation. The carboxamide moiety on nitrogen
of indole is easily cleaved under strong acid in the presence of
moisture. Path b is especially favored when the Ar is substituted
with an electron-donating group, such as methyl and methoxy in
2o and 2p. When changing TfOH to milder acid TFA, path a is pos-
sible even for some aryl-substituted 1-(2-alkynylphenyl)ureas 2.
However in this case, tautomerization of 5 to 3 is not exclusively
since the double bond can also be stabilized by the aromatic group.
In summary, we have demonstrated an efficient method for the
synthesis of 4-alkyl-2(1H)-quinazolinones and 4-alkyl-2-chloro-
quinazolines from 1-(2-alkynylphenyl)ureas 2. Substitution on
the other end of the triple bond is decisive for the acid applied.
1-(2-Alkynylphenyl)ureas 2 can be prepared in high yields from
readily available 2-alkynylanilines. The construction of a focused
library of 4-alkyl-2-substitutedquinazolines from products of cur-
rent method is underway in our laboratories.
Acknowledgments
This work was financially supported by Start-up Foundation for
New Investigators from Guangzhou Institute of Biomedicine and
Health (GIBH) and National Science Foundation of China
(20942001).