An efficient one-step synthesis of 2-arylquinolin-4(1H)-ones with the aid of a low-valent titanium reagent

Article abstract of DOI:10.1016/j.tetlet.2011.08.089

A short and facile synthesis of a series of 2-arylquinolin-4(1H)-ones was accomplished in good yields via the novel reductive cyclization of 2-nitrochalcones promoted by TiCl₄/Zn. This method has the advantages of accessible starting materials,

Full text of DOI:10.1016/j.tetlet.2011.08.089

Tetrahedron Letters 52 (2011) 5633–5635
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Tetrahedron Letters
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An efficient one-step synthesis of 2-arylquinolin-4(1H)-ones with the aid
of a low-valent titanium reagent
⇑
Fang Sun, Xuan Zhao, Daqing Shi
Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou 215123, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A short and facile synthesis of a series of 2-arylquinolin-4(1H)-ones was accomplished in good yields via
the novel reductive cyclization of 2-nitrochalcones promoted by TiCl4/Zn. This method has the advanta-
ges of accessible starting materials, one-step procedure, convenient manipulation, and moderate to high
yields.
Received 7 May 2011
Revised 29 July 2011
Accepted 16 August 2011
Available online 25 August 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Low-valent titanium
Cyclization
Quinolin-4(1H)-one
Low-valent titanium reagents have an exceedingly high ability
to promote reductive coupling reaction of carbonyl compounds
and are attracting increasing interest in organic synthesis.1 Many
other functional groups can also be coupled.2 Recently, we have
focused on the synthesis of heterocyclic compounds using low-
valent titanium reagent. We have previously reported the synthe-
sis of quinazolin-4(3H)-ones,3 pyrroles,4 quinazoline-2,4-diones,5
indazol-3(2H)-ones,6 and naphtho[1,2-e][1,3]oxazine7 induced by
low-valent titanium reagent.
tions for the preparation of 2-(4-methylphenyl)quinolin-4(1H)-one
2a.
First, different types of low-valent titanium systems were inves-
tigated as reductive reagent for this reaction (Table 1, entries 1–5).
TiCl4/Zn (1:2) gave the best result of synthesis of 2a (80%) (entry 1).
Further optimization of the reaction conditions revealed that the
use of 3 equiv of TiCl4/Zn (1:3) at 40 °C (Table 1, entry 10) gave re-
sults superior to those under the other reaction conditions (Table 1,
entries 6–9 and 11–12).
The 2-arylquinolin-4(1H)-one core structure represents a highly
privileged and biologically relevant molecular scaffold which oc-
curs in many natural products.8–11 Over the last years, the interest
in 2-arylquinolin-4(1H)-ones and their analogs has been the sub-
ject of extensive study as potential anti-tumor, anti-mitotic, and
cytotoxic agents12 as well as anti-platelet agents.11 To construct
this intriguing 2-aryl-4-quinolone scaffold, several synthesis meth-
ods have been developed from different starting materials.13
Among them, reductive cyclization of 2-nitrochalcones attracts
more attention because diverse starting materials are readily avail-
able via Aldol condensation of 2-nitroacetophenone with benzal-
dehyde derivatives. However, the main disadvantage of this
method is the use of Ru and Pt catalyst in high temperature
(170 °C) and high pressure (30–40 bar of CO) (Scheme 1, a).14 Here
we wish to describe a new method induced by the TiCl4/Zn system
for the one-step synthesis of 2-arylquinolin-4(1H)-ones using 2-
nitrochalcones as the starting material (Scheme 1, b).
In order to apply this reaction to library synthesis, various kinds
of 2-nitrochalcones were subjected to give the corresponding
a. Previous Methods
Ru3(CO)12 / Tol-BIAN
CO, EtOH/H2O, 170 °C, 30 atm
O
O
NO2 Ar
N
H
Ar
Pd(OAc)2 / TMPhen
CO, Toluene, 170 °C, 30 bar
b. This Work
O
O
TiCl4/Zn, THF, 40 °C, 2 h
In
a
preliminary study, 1-(2-nitrophenyl)-3-(4-methyl-
N
H
Ar
phenyl)prop-2-en-1-one 1a was used to define the reaction condi-
Ar
NO2
2
1
⇑
Corresponding author. Tel.: +86 0512 65880049.
E-mail addresses: dqshi@263.net, dqshi@suda.edu.cn (D. Shi).
Scheme 1. The synthesis of 2-arylquinolin-4(1H)-ones from 2-nitrochalcones.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.08.089

5634
F. Sun et al. / Tetrahedron Letters 52 (2011) 5633–5635
Table 1
Table 2
Optimization for the synthesis of 2a
Synthesis of compound 215
O
O
O
O
TiCl4 - Zn
TiCl4-M
THF
THF, 40 °C, 2 h
N
N
H
2
Ar
NO2
NO2 Ar
H
CH3
1
CH3
2a
1a
Entry
Ar
Compd
Isolated
yield (%)
Mp (°C)
Lit. mp (°C)
Entry
TiCl4/M system
Ratioa
Temperature (°C)
Isolated yield (%)
1
2
3
4
5
6
7
8
TiCl4/Zn (1:2)
TiCl4/Mg (1:2)
TiCl4/Fe (1:2)
TiCl4/Al (1:2)
TiCl4/Sm (1:2)
TiCl4/Zn (1:2)
TiCl4/Zn (1:2)
TiCl4/Zn (1:2)
TiCl4/Zn (1:3)
TiCl4/Zn (1:3)
TiCl4/Zn (1:3)
TiCl4/Zn (1:3)
1:3
1:3
1:3
1:3
1:3
1:1
1:2
1:4
1:3
1:3
1:3
1:3
rt
rt
rt
rt
rt
rt
rt
rt
80
75
72
65
68
55
70
65
84
90
82
78
1
2
3
4
5
6
7
8
9
10
4-CH3C6H4
4-CH3OC6H4
4-FC6H4
2a
2b
2c
2d
2e
2f
2g
2h
2i
88
87
70
80
89
79
85
86
85
80
287–289
290–292
>300
290–292
295–297
322–325
318–320
288–290
>260
4-BrC6H4
>300
3,4-OCH2OC6H3
Thiophene-2-yl
4-N(CH3)2C6H4
4-ClC6H4
3,4-(CH3O)2C6H3
3-ClC6H4
285–286
270–271
>300
247–249
248–250
278–280
>300
252–254
241–243
>260
9
rt
10
11
12
40
60
Reflux
2j
a
Ratio of 1a and TiCl4.
fore, this method is not suitable for the preparation of 2-alkylquin-
olin-4(1H)-ones.
Because the nitro compounds are easy to be reduced to amines
by the low-valent titanium reagent,16 we think this reaction may
proceed through the intermediate amine 4. As shown in Scheme
3, the nitro compound was reduced by the low-valent titanium re-
agent to generate amine 4, which was then followed by subsequent
Lewis acid promoted Michael addition and dehydrogenation to
achieve the product.
To prove this point, we chose 1a as the starting material. Com-
pound 1a was firstly reduced to 20-aminochalcone 4 by FeS-
O4ꢀ7H2O, which was isolated and identified by spectral data.
Then intermediate 4 was reacted with the low-valent titanium
reagent in THF. To our surprise, 2,20-di(4-methylphenyl)-2,3,-dihy-
dro-1H,10H-4,40-biquinolinylidene 5 was obtained as our final
product (Scheme 3), while the one we desired, 2a, was not
2-arylquinolin-4(1H)-ones. The results are summarized in Table 2.
All of the 2-nitrochalcones gave the expected products either bear-
ing electron-withdrawing groups (such as halide) or electron-
donating groups (such as alkyl group, alkoxyl group) in moderate
to good yields under the same reaction conditions. Therefore, we
can conclude that the electronic nature of the substituents has
no significant effect on this reaction.
In order to demonstrate the efficiency and the applicability of
the present method, we performed the reductive cyclization of
4,4-dimethyl-1-(2-nitrophenyl)pent-2-en-1-one (1k) under the
optimized conditions. However, the desired product 2-(tert-butyl)
quinolin-4(1H)-one (2k) can not obtained, 1-(2-aminophenyl)-
4,4-dimethylpent-2-en-1-one (3) was obtained (Scheme 2). There-
O
O
X
N
H
C(CH3)3
C(CH3)3
2k
3
TiCl4 - Zn
O
THF, 40 °C, 2 h
NO2
C(CH3)3
1k
NH2
Scheme 2. The reaction of 4,4-dimethyl-1-(2-nitrophenyl)pent-2-en-1-one induced by TiCl4/Zn.
O
N
H
2a
O
O
CH3
X
.
FeSO4 7H2O
TiCl4-Zn
THF
H
NH2
N
NO2
NH4OH
CH3
CH3
CH3
4
1a
CH3
N
H
5
Scheme 3. The reaction of 20-aminochalcone induced by TiCl4/Zn.

F. Sun et al. / Tetrahedron Letters 52 (2011) 5633–5635
5635
Ti
(I)
O
O
O
O
Ti(0)
Ti(0)
- TiO(II)
Ar
Ar
NO2
Ar
NO
N
O
Ar
Ti(I)
N
O
O
1
6
Ti (I)
O
OTi (I)
OH
N
-H
- TiO(II)
tautomerization
hydrolysis
N
H
Ar
N
Ar
Ar
7
2
Scheme 4. The proposed reaction mechanism.
8. Sondheimer, F.; Meisels, A. J. Org. Chem. 1958, 23, 762.
9. Doodwin, S.; Smith, A. F.; Velasquez, A. A.; Horning, E. C. J. Am. Chem. Soc. 1959,
81, 6209.
detected. This indicated that in this reaction the nitro compound
was not simply reduced to amines.
According to literature,17 we suppose the following mechanism
to explain this reaction. TiCl4 is reduced by Zn dust to give low-va-
lent titanium species. In the initial step, 1 was reduced by low-valent
titanium to nitroso-compound 6. Then reductive nitroso-compound
10. Michael, J. P. Nat. Prod. Rep. 1997, 14, 605.
11. (a) Xia, Y.; Yang, Z. Y.; Xia, P.; Bastow, K. F.; Tachibana, Y.; Kuo, S. C.; Hamel, E.;
Hackl, T.; Lee, K. H. J. Med. Chem. 1998, 41, 1155; (b) Huang, L. J.; Hsieh, M. C.;
Teng, C. M.; Lee, K. H.; Kuo, S. C. Bioorg. Med. Chem. 1998, 6, 1657; (c) Ko, T. C.;
Hour, M. J.; Lien, J. C.; Teng, C. M.; Lee, K. H.; Kuo, S. C.; Huang, L. J. Bioorg. Med.
Chem. 2001, 11, 279; (d) Xia, Y.; Yang, Z. Y.; Xia, P.; Hackl, T.; Hamel, E.; Mauger,
A.; Wu, J. H.; Lee, K. H. J. Med. Chem. 2001, 44, 3932; (e) Xia, Y.; Yang, Z. Y.; Xia,
P.; Hackl, T.; Hamel, E.; Mauger, A.; Wu, J. H.; Lee, K. H. Bioorg. Med. Chem. Lett.
2003, 13, 2891; (f) Hadjeri, M.; Peiller, E. L.; Beney, C.; Deka, N.; Lawson, M. A.;
Dumontet, C.; Boumendjel, A. J. Med. Chem. 2004, 47, 4964; (g) Lai, Y. Y.; Huang,
L. J.; Lee, K. H.; Xiao, Z.; Bastow, K. F.; Yamori, T.; Kuo, S. C. Bioorg. Med. Chem.
2005, 13, 265.
12. (a) Xia, Y.; Yang, Z. Y.; Xia, P.; Bastow, K. F.; Tachibana, Y.; Kao, S. C.; Hamel, E.;
Hackl, T.; Lee, K. H. J. Med. Chem. 1998, 41, 1155; (b) Xia, Y.; Yang, Z. Y.; Xia, P.;
Hackl, T.; Hamel, E.; Mauger, A.; Wu, J. H.; Lee, K. H. J. Med. Chem. 2001, 44,
3932; (c) Xia, Y.; Yang, Z. Y.; Xia, P.; Hackl, T.; Hamel, E.; Mauger, A.; Wu, J. H.;
Lee, K. H. Bioorg. Med. Chem. Lett. 2003, 13, 2891; (d) Hadjeri, M.; Peiller, E. L.;
Beney, C.; Deka, N.; Lawson, M. A.; Dumontet, C.; Boumendjel, A. J. Med. Chem.
2004, 47, 4964; (e) Lai, L. Y.; Huang, I. J.; Lee, K. H.; Xiao, Z.; Bastow, K. F.;
Yamori, T.; Kao, S. C. Bioorg. Med. Chem. 2005, 13, 265.
13. (a) Chen, B. C.; Huang, X.; Wang, J. Synthesis 1987, 482; (b) Kasahara, A.; Izumi,
T.; Watabe, H.; Takahashi, S. Chem. Indust. 1981, 121; (c) Kuo, S. C.; Lee, H. Z.;
Juang, J. P.; Lin, Y. T.; Wu, T. S.; Chang, J. J.; Lednicer, D.; Paull, K. D.; Lin, C. M.;
Hamel, E.; Lee, K. H. J. Med. Chem. 1993, 36, 1146; (d) Mphahlele, M. J. J.
Heterocycl. Chem. 2010, 47, 1.
14. (a) Tollari, S.; Cenini, S.; Ragaini, F.; Cassar, L. J. Chem. Soc., Chem. Commun.
1994, 1741; (b) Annunziata, R.; Cenini, S.; Palmisano, G.; Tollari, S. Synth.
Commun. 1996, 26, 495; (c) Ragaini, F.; Sportiello, P.; Cenini, S. J. Organomet.
Chem. 1999, 577, 283.
6 reacted with a,b-unsaturated ketone and gave the intermediate 7.
Then the product 2 was obtained by hydrolysis and tautomerization
(Scheme 4).
In conclusion, a series of 2-arylquinolin-4(1H)-ones were syn-
thesized via the reductive cyclization of 2-nitrochalcones induced
by low-valent titanium reagent (TiCl4/Zn). Compared to the re-
ported methods, this method has the advantages of easily available
starting materials, mild reaction condition, avoiding the use of
toxic transition metal, short reaction time, high yields, and conve-
nient manipulation.
Acknowledgments
We acknowledge the financial support from the Foundation of
the Natural Science Foundation of China (No. 21072144), the Major
Basic Research Project of the Natural Science Foundation of the
Jiangsu Higher Education Institutions (No. 10KJA150049) and Key
Laboratory of Organic Synthesis of Jiangsu Province (No. KJS0812).
15. Typical experimental procedure: TiCl4 (0.7 mL, 6 mmol) was added dropwise
using a syringe to a stirred suspension of zinc powder (1.17 g, 18 mmol) in
freshly distilled anhydrous THF (10 mL) at room temperature (rt) under a dry
Supplementary data
N
2 atmosphere. After completion of the addition, the mixture was refluxed for
Supplementary data associated with this Letter can be found, in
the online version, at doi:10.1016/j.tetlet.2011.08.089.
2 h. The suspension of the low-valent titanium reagent formed was cooled to
rt, and a solution of 2-nitrochalcones 1 (2 mmol) in THF (5 mL) was added
dropwise. The reaction mixture was stirred under the temperature of 40 °C for
2 h. After this period, the thin layer chromatography (TLC) analysis of the
mixture showed the completion of this reaction. The mixture was then
quenched with 5% HCl (30 mL) and extracted with CHCl3 (3 ꢁ 50 mL). The
extracts were washed with water (3 ꢁ 50 mL) and dried over anhydrous
Na2SO4. After evaporation of the solvent under reduced pressure, the crude
products were purified by recrystallization from 95% ethanol. 2-(4-
Methylphenyl)quinolin-4(1H)-one (2a): Light yellow solid; mp 287–289 °C
(Lit.18 290–292 °C); IR (KBr, cmꢂ1): 3350, 3021, 2919, 1714, 1645, 1614,
1580, 1514, 1361, 819, 750; 1H NMR (400 MHz, DMSO-d6): d 2.38 (s, 3H, CH3),
6.30 (s, 1H, CH), 7.30 (t, J = 10.0 Hz, 1H, ArH), 7.37 (d, J = 10.0 Hz, 2H, ArH), 7.63
(t, J = 9.6 Hz, 1H, ArH), 7.73 (t, J = 12.0 Hz, 3H, ArH), 8.07 (d, J = 10.4 Hz, 1H,
ArH), 11.64 (s, 1H, NH); HRMS calculated for C16H13NO [M]+: 235.0997, found:
235.0997.
References and notes
1. (a) McMurry, J. E. Acc. Chem. Res. 1974, 7, 281; (b) McMurry, J. E. Acc. Chem. Res.
1983, 16, 405; (c) McMurry, J. E. Chem. Rev. 1989, 89, 1513.
2. (a) Lenoir, D. Synthesis 1989, 883; (b) Fürstner, A.; Bogdanovi, B. Angew. Chem.,
Int. Ed. 1996, 35, 2443; (c) Shi, D. Q.; Chen, J. X.; Chai, W. Y.; Chen, W. X.; Kao, T.
Y. Tetrahedron Lett. 1993, 34, 2863.
3. Shi, D. Q.; Rong, R. C.; Wang, J. X.; Zhuang, Q. Y.; Wang, X. S.; Hu, H. W.
Tetrahedron Lett. 2003, 44, 3199.
4. (a) Shi, D. Q.; Dou, G. L.; Shi, C. L.; Li, Z. Y.; Ji, S. J. Synthesis 2007, 3117; (b) Dou,
G. L.; Shi, D. Q. J. Comb. Chem. 2008, 10, 810.
5. Shi, D. Q.; Dou, G. L.; Li, Z. Y.; Ni, S. N.; Li, X. Y.; Wang, X. S.; Wu, H.; Ji, S. J.
Tetrahedron 2007, 63, 9764.
16. Ceorge, J.; Chandraseharan, S. Synth. Commun. 1983, 13, 495.
6. Dou, G. L.; Shi, D. Q. J. Comb. Chem. 2009, 11, 1073.
17. Li, J.; Shi, D. Q.; Chen, W. X. Heterocycles 1997, 45, 2381.
7. Shi, D. Q.; Rong, S. F.; Dou, G. L.; Wang, M. M. J. Comb. Chem. 2010, 12, 25.
18. Om, V. S.; Randhir, S. K. Synth. Commun. 2010, 40, 277.