Aqueous synthesis of N-phenyl/alkyl-2-quinolinone-3-carboxylic acids from coumarin-3-carboxylic acids

Article abstract of DOI:10.1080/00397910903399690

An efficient, ecofriendly aqueous synthesis of aromatic/aliphatic amines with coumarin-3-carboxylic acid in a one pot reaction in a sealed tube or InCl₃/ H₂^O in open vessel to afford N-phenyl/alkyl-2-quinolinones is achieved. This method provides high yield of products in shorter time, making it a useful process for the synthesis of structurally diversified 2-quinolinones from corresponding coumarins. Copyright

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Aqueous Synthesis of N-Phenyl/alkyl-2-
quinolinone-3-carboxylic Acids from
Coumarin-3-carboxylic Acids
H. N. Harishkumar a , Vijay Kumar Hulikal b & K. M. Mahadevan a
a Department of Postgraduate Studies and Research in Chemistry,
School of Chemical Sciences, Kuvempu University, Shankaraghatta,
Karnataka, India
b Bio-organics and Applied Materials Pvt. Ltd., Bangalore, India
Available online: 15 Oct 2010
To cite this article: H. N. Harishkumar, Vijay Kumar Hulikal & K. M. Mahadevan (2010): Aqueous
Synthesis of N-Phenyl/alkyl-2-quinolinone-3-carboxylic Acids from Coumarin-3-carboxylic Acids,
Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic
Chemistry, 40:22, 3281-3289
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Synthetic Communications1, 40: 3281–3289, 2010
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910903399690
AQUEOUS SYNTHESIS OF N-PHENYL/ALKYL-2-
QUINOLINONE-3-CARBOXYLIC ACIDS FROM
COUMARIN-3-CARBOXYLIC ACIDS
H. N. Harishkumar,1 Vijay Kumar Hulikal,2
and K. M. Mahadevan1
1Department of Postgraduate Studies and Research in Chemistry, School of
Chemical Sciences, Kuvempu University, Shankaraghatta, Karnataka, India
2Bio-organics and Applied Materials Pvt. Ltd., Bangalore, India
An efficient, ecofriendly aqueous synthesis of aromatic/aliphatic amines with coumarin-3-
carboxylic acid in a one pot reaction in a sealed tube or InCl3/ H2O in open vessel to afford
N-phenyl/alkyl-2-quinolinones is achieved. This method provides high yield of products in
shorter time, making it a useful process for the synthesis of structurally diversified 2-quino-
linones from corresponding coumarins.
Keywords: Coumarin-3-carboxylic acid; N-phenyl=alkyl-2-quinolinones; one pot
INTRODUCTION
Quinoline derivatives are widely known in medicinal chemistry because they
are present in a wide range of natural products[1] and drugs.[2] Substituted
N-phenyl=alkyl-2-quinolinones represent the structural basis of many biologically
active compounds, such as protein kinase inhibitors, immune modulators, anti-ulcer
agents, hypoglycemics, farnesyl transferase inhibitors, and antiviral agents.[3a–f] Only
a few practical procedures are known for the synthesis of N-substituted-2-quinoli-
nones that involve the coupling of nor-quinolinones with aryl halides,[4] boronic
acids,[5] or organolead reagents.[6] In addition to these, some examples were also
given in which coumarins were directly aminolyzed upon treatment with aminoben-
zimidazoles.[7] On the other hand, ammonia and primary amines are known to react
with 2-pyrones to afford the corresponding 2-pyridones.[8]
In spite of these syntheses, there is still a wide scope for simple, convenient, and
ecofriendly synthesis. Moreover, the conversions of coumarins into various N-substi-
tuted quinolones with the reaction of aliphatic=aromatic amines have not been
explored extensively. Hence, in the present study, we report the preliminary results
of a simple synthesis of N-substituted quinolone using water.
Received August 2, 2009.
Address correspondence to K. M. Mahadevan, Department of Postgraduate Studies and Research
in Chemistry, School of Chemical Sciences, Kuvempu University, Shankaraghatta, Karnataka 577 451,
India. E-mail: mady_kmm@yahoo.co.uk
3281

3282
H. N. HARISHKUMAR, V. K. HULIKAL, AND K. M. MAHADEVAN
Table 1. Screening of the effect of solvent for the synthesis of N-phenyl=alkyl-2-quinolinone-3-carboxylic
acids at reflux temperature
Entry
Solvent
Conditions
Time (h)
Yield (%)a
1
2
3
4
5
6
7
8
EtOH
EtOH
DMSO
Sealed tube
Open vessel
Sealed tube
Open vessel
Sealed tube
Open vessel
Sealed tube
Open vessel
1
16
1
20–30
10
–
DMSO
Water
1
–
1
95
60
6
Water
H2O=10% (NaOH)
H2O=10% (NaOH)
18
1
16
3
aIsolated yields.
RESULTS AND DISCUSSION
The reaction was performed with molar equivalents of coumarin-3-carboxylic
acid 1 (100 mg, 5 mmol) and aniline 2 (53 mg, 5 mmol) in absolute alcohol at reflux
temperature. When the reaction was monitored by thin-layer chromatography
(TLC), it shows less conversion of products and incomplete reaction even at longer
reaction time. However, the effort to obtain N-phenyl-2-quinolinones 3a was unsuc-
cessful in various solvents (Table 1) under the same reaction condition. Hence, while
searching an alternative method, we carried out this reaction in water (Scheme 1)
(entries 6 and 7, Table 1).
Thus, the reaction of molar equivalents of coumarin-3-carboxylic acid 1
(100 mg, 5 mmol) and aniline 2a (53 mg, 5 mmol) was refluxed in water (5 ml). Inter-
estingly, the reaction occurred smoothly in water at reflux temperature in 10 h.
Further, it was noticed that the reaction time and yield of the products were signifi-
cantly increased when the reaction was performed in a sealed tube refluxing in a sand
bath (Table 1).
Similarly, we also observed that the rate of aminolysis of coumarin-3-
carboxylic acids with aryl amines was slow in our series and usually required longer
reaction time when compared to aliphatic amines. However, yields of the products
were not much affected. For these reasons, we intended to seek an alternative route
that would tolerate a variety of amines, providing good yields and reduction in the
reaction time. Further, we thought to use a Lewis acid catalyst to increase the
Scheme 1. Synthesis of N-phenyl=alkyl-2-quinolinones.

N-PHENYL/ALKYL-2-QUINOLINONE-3 CARBOXYLIC ACIDS
3283
Table 2. Synthesis of various N-phenyl=alkyl-2-quinolinones in InCl3=H2O
Comp.
Amine (R1)
Product
Time (h)
Yield (%)a
Mp (ꢀC)
3a
0.5
94
160–162
129–131
179–180
3b
1.5
2.0
95
93
3c
3d
4.0
94
178–180
3e
3.0
2.5
1.0
95
90
90
201–202
3f
145–146
3g
169–170
(Continued )

3284
H. N. HARISHKUMAR, V. K. HULIKAL, AND K. M. MAHADEVAN
Table 2. Continued
Comp.
Amine (R1)
Product
Time (h)
Yield (%)a
Mp (ꢀC)
184–185
3h
0.5
95
3i
3j
1.0
1.0
93
95
178–180
147–148
3k
1.0
90
194–195
3l
1.0
1.0
90
96
200–202
3m
190–191
185–188
3n
3o
1.5
1.5
95
94
200–202
(Continued )

N-PHENYL/ALKYL-2-QUINOLINONE-3 CARBOXYLIC ACIDS
Table 2. Continued
3285
Comp.
3p
Amine (R1)
Product
Time (h)
Yield (%)a
Mp (ꢀC)
165–167
2.0
97
aIsolated yield.
efficiency of this reaction. Through a literature survey, we came to know that indium
trichloride was an effective catalyst in the Diels–Alder reactions in water media[9]
and was also known to facilitate imino Diels–Alder reaction in the synthesis of tetra-
hydrofuro=pyrano quinolines[10] in water. In continuation of our work,[11] and in
view of developing an environmentally benign synthesis, here we trace out the possi-
bility of using indium trichloride in water in our synthesis.
When we did this reaction in the presence of indium trichloride (20 mol%) in
water, the reaction went smoothly to give good yield and a reduction in the reaction
time (Table 2). The formation of the products N-phenyl=alkyl-2-quinolinone-3-car-
boxylic acids 3a–m is postulated through nucleophilic addition of the amine group
to the pyran ring system and subsequent cyclization of intermediate A, affording
2-quinolinone-3-carboxylic acids 3a–m, as illustrated in Scheme 2. The results of pre-
liminary investigations during these reactions are presented in this article. To the
best of our knowledge, this is the first report in which the coumarin nucleus can
be directly converted into quinoline-2-ones with a wide variety of aromatic and ali-
phatic amines. Further exploration of this reaction with various substituted coumar-
ins is under way in this laboratory.
Scheme 2. Mechanism of synthesis of N-phenyl=alkyl-2-quinolinones.

3286
H. N. HARISHKUMAR, V. K. HULIKAL, AND K. M. MAHADEVAN
In conclusion, various N-phenyl=alkyl-2-quinolinone-3-carboxylic acids could
be synthesized without catalyst in a sealed tube by refluxing on a sand bath using
water as media. Thus, efficient, ecofriendly, water-mediated cyclization of
aromatic=aliphatic amines and coumarin-3-carboxylic acid in a one pot reaction
to afford N-phenyl=alkyl-2-quinolinones is achieved. This method provides excellent
yield of products in less time, making it a useful process for the synthesis of structur-
ally diversified 2-quinolinones from corresponding coumarins.
EXPERIMENTAL
Products were identified by their physical and spectroscopic data, all the melt-
ing points were recorded in open capillaries. The purity of the compounds were
1
checked by thin-layer chromatography (TLC) on silica gel. H NMR spectra were
recorded on a Bruker 400-Hz spectrometer using CD3OD as a solvent. Mass spectra
were recorded on a Jeol SX102 ¼ DA-6000 (10 kV) fast atomic bombardment mass
spectrometer. Solvents, chemicals, and reagents were purchased from Merck Chemi-
cal Company in high-grade quality.
General Procedure for the Synthesis of N-Phenyl-2-quinolinones (3a)
Method A. Coumarin-3-carbaxylic acid (100 mg, 5 mmol) was taken in a
sealed tube containing 5 ml of water and aniline (53 mg, 5 mmol). The mixture was
heated on a sand bath for 1 h. After the completion of the reaction as indicated
by liquid chromatography–mass spectrometry (LC-MS), the compound was
extracted with ethyl acetate (50 mL ꢁ 2), dried with anhydrous sodium sulfate, con-
centrated in vacuum, and purified by column chromatography. Further, the com-
pound was analyzed by ultra performance liquid chromatography (UPLC)-mass,
1H NMR, and 13C NMR. Melting points were recorded in an open capillary. Other
quinolinones were prepared similarly.
Method B. A mixture of coumarin-3-carbaxylic acid (100 mg, 5 mmol), ani-
line (53 mg, 5 mmol), and indium trichloride (20 mol%) were taken in 20 ml of water.
Then the mixture was heated on a water bath for the appropriate time. After the
completion of the reaction as indicated by LC-MS analysis, the compound was
extracted with ethyl acetate (50 mL ꢁ 2), dried with sodium sulfate, concentrated
in vacuo, and purified by column chromatography. Further, the compound was
1
analyzed by UPLC-mass, H NMR, and 13C NMR. Melting points were recorded
in an open capillary. Other quinolinones were prepared similarly.
Selected Data
1
Compound 3a. IR (KBr, cmꢂ1): 3600, 1733.9, 1606.8. H NMR (300 MHz,
CD3OD) d: 8.72 (s, 1H), 7.80 (m, 2H), 7.42 (m, 2H), 7.14 (m, 2H), 6.80 (m, 3H);
13C NMR (100 MHz, CD3OD) d: 166.1, 160.8, 156.2, 150.2, 146.6, 135.6, 131.2,
131.5, 130.1, 126.3, 126.3, 120.5, 119.7, 119.3, 117.5, 117.49. MS: m=z ¼ 266.3 (M þ 1).
Compound 3b. IR (KBr, cmꢂ1): 3626, 1700, 1598. 1H NMR (300 MHz,
CD3OD) d: 8.10 (s, 1H), 7.84 (d, J ¼ 1.48 Hz, 1H), 7.76 (t, J ¼ 1.2 Hz, 1H), 7.44

N-PHENYL/ALKYL-2-QUINOLINONE-3 CARBOXYLIC ACIDS
3287
(m, 2H), 6.87 (m, 3H), 6.64 (m, J ¼ 1.84 Hz, 1H); 13C NMR (75 MHz, CDCl3) d:
166.5, 161, 156.8, 150.6, 155, 147, 140, 131.5, 130.1, 126.6, 126.6, 120.58, 120.5,
120.5, 116.4, 116.4. MS: m=z ¼ 284.2 (M þ 1), 285.3 (M þ 2).
Compound 3c. IR (KBr, cmꢂ1): 3625.2, 1739.6, 1609.1H NMR (300 MHz,
CD3OD) d: 8.79 (s, 1H), 7.83 (m, 2H), 7.44 (m, 2H), 7.12 (t, J ¼ 2.52 Hz, 1H),
6.96 (m, 1H), 6.82 (t, J ¼ 10.4 Hz, 1H), 6.66 (m, 1H); 13C NMR (75 MHz, CDCl3)
d: 166.5, 161, 156.8, 127.8, 155, 147, 140, 148, 135.14, 126.9, 126.8, 121.0, 121.0,
120.8, 100.3, 116.4. MS: m=z ¼ 392.1 (M þ 1).
Compound 3d. IR (KBr, cmꢂ1): 3243.6, 1715.6, 1599.4. 1H NMR (300 MHz,
CD3OD) d: 8.29 (s, 1H), 7.08 (m, 2H), 7.39 (m, 2H), 7.23 (s, 1H), 7.08 (m, 1H), 6.83
(m, 1H), 4.11 (s, 2H); 13C NMR (100 MHz, CDCl3) d: 166.7, 163.8, 155.8, 126.8,
146.5, 146.5, 140, 147, 135.14, 126.9, 126.8, 121.0, 121.0, 120.8, 135, 128.4, 55.8.
MS: m=z ¼ 348.2 (M þ 2).
Compound 3e. IR (KBr, cmꢂ1): 3620, 1738, 1615. 1H NMR (300 MHz,
CD3OD) d: 8.18 (s, 1H), 7.69 (m, 1H), 7.62 (m, 1H), 7.44 (s, 4H), 7.36 (t, J ¼
6.8 Hz, 2H), 4.10 (s, 2H); 13C NMR (100 MHz, CDCl3): 166.5, 163.2, 155.3, 126.1,
146.2, 146, 139, 146, 133.1, 121.9, 124.8, 120.8, 120.0, 119.8, 134, 126.4, 56.3. MS:
m=z ¼ 314.3 (M þ 1), 314.3 (M þ 2).
Compound 3f. IR (KBr, cmꢂ1): 3638, 1749, 1632. 1H NMR (400 MHz,
CD3OD) d: 8.24 (s, 1H), 7.69 (d, J ¼ 7.64 Hz, 1H), 7.63 (t, J ¼ 11.2 Hz, 3H), 7.34
(t, J ¼ 7.72 Hz, 4H), 4.17 (s, 2H); 13C NMR (100 MHz, CDCl3) d: 166.5, 163.2,
161.8 155.3, 126.1, 146.2, 146, 139, 146, 133.1, 128.9, 124.0, 120.0, 126.8, 134,
113.6, 113.6, 56.3. MS: m=z, 363.2 (M þ 1).
Compound 3g. IR (KBr, cmꢂ1): 3708, 3616, 1629. 1H NMR (300 MHz,
CD3OD) d: 8.22 (s, 1H), 7.69 (d, J ¼ 10.28 Hz, 1H), 7.63 (t, J ¼ 9.4 Hz, 1H), 7.36
(m, 2H), 3.12 (s, 1H), 2.10 (s, 2H), 1.84 (s, 2H), 1.70 (d, J ¼ 12.56 Hz, 1H), 1.34
(m, 5H); 13C NMR (100 MHz, CDCl3) d: 166.5, 163.2, 155.3, 126.1, 146.2, 146,
139, 146, 133.1, 128.9, 50.2, 31.2, 31.2, 23.1, 23.1, 27.8. MS : m=z ¼ 271.3 (M þ 1).
Compound 3h. IR (KBr, cmꢂ1): 3592, 1698, 1612. 1H NMR (400 MHz,
CD3OD) d: 8.18 (s, 1H), 7.69 (m, 1H), 7.68 (m, 1H), 7.36 (m, 2H), 2.74 (d,
J ¼ 7.12 Hz, 2H), 1.94 (m, 1H), 1.09 (d, J ¼ 10.72 Hz, 6H); 13C NMR (75 MHz,
CDCl3) d: 166.3, 163.5, 155.3, 126.1, 146.2, 146, 139, 146, 133.14, 128.9, 60.1, 28,
20.3, 20.3. MS: m=z, 246.2 (M þ 1), 247.2 (M þ 2).
Compound 3i. IR (KBr, cmꢂ1): 3584, 1690, 1608. 1H NMR (300 MHz,
CD3OD) d: 8.27 (s, 1H), 7.71 (m, 1H), 7.64 (m, 1H), 7.37 (m, 2H), 3.45 (m, 1H),
1.30 (d, J ¼ 8.72 Hz, 6H); 13C NMR (75 MHz, CDCl3) d: 166.3, 162.5, 154.3,
126.1, 146.2, 146, 139, 146, 133.14, 128.9, 47, 22.3, 22.3. MS: m=z, 232.2 (M þ 1).
Compound 3j. IR (KBr, cmꢂ1): 3621, 1770, 1622.8 1H NMR (400 MHz,
CD3OD) d: ¼8.42 (s, 1H), 7.74 (m, 1H), 7.39 (t, J ¼ 7.2 Hz, 3H), 2.84 (d, J ¼ 7.6 Hz,
2H), 1.12 (m, 1H), 0.69 (m, 2H), 0.38 (m, 2H); 13C NMR (75 MHz, CDCl3) d: 166.3,
162.8, 154.3, 126.1, 146.2, 146, 139, 146, 133.1, 128.9, 59.9, 8, 2.1, 2.1. MS: m=z,
243.3 (M þ 1).

3288
H. N. HARISHKUMAR, V. K. HULIKAL, AND K. M. MAHADEVAN
Compound 3k. IR (KBr, cmꢂ1): 3606, 1701, 1620. 1H NMR (400 MHz,
CD3OD) d: 8.14 (s, 1H), 7.69 (dd, J ¼ 1.6 Hz, 1H), 7.63 (m, 1H), 7.36 (d, J ¼ 8.2 Hz,
2H), 1.82 (m, 6H), 1.42 (d, J ¼ 3.8 Hz, 3H), 1.06 (d, J ¼ 3.1 Hz, 1H), 1.05 (m, 2H);
13C NMR (75 MHz, CDCl3) d: 166.2, 161.8, 154.3, 126.1, 146.2, 146, 139, 146,
133.14, 128.9, 50.5, 30, 30, 29.3, 29.2, 29.2, 20.4. MS: m=z, 286.3 (M þ 1), 287.3
(M þ 2).
Compound 3l. IR (KBr, cmꢂ1): 3583, 1682, 1604. 1H NMR (400 MHz,
CD3OD) d ¼ 8.16 (s, 1H), 7.69 (m, 1H), 7.62 (m, 1H), 7.36 (m, 2H), 2.08 (m, 2H),
1.5 (m, 10H) 1.48 (m, 3H); 13C NMR (75 MHz, CDCl3) d: 166.3, 162.8, 154.3,
126.1, 146.2, 146, 139, 146, 133.14, 128.9, 50.8, 35.3, 31.4, 31, 33.1, 24, 28.8, 28.4,
29.6, 29.6, 28.3, 28.3, 15.1. MS: m=z, 287.4 (M þ 1).
1
Compound 3m. IR (KBr, cmꢂ1): 1708, 1604, 3221. H NMR (400 MHz,
CD3OD) d: 8.24 (s, 1H), 7.74 (d, J ¼ 7.44 Hz, 1H), 7.63 (m, 4H), 7.35 (m, 4H),
4.16 (s, 2H); 13C NMR (75 MHz, CDCl3) d: 166.3, 162.6, 154.2, 126.3, 146.2,
146.1, 143.4, 139, 146, 133.1, 128.9, 56.3, 128.9, 128.2, 127.3, 128.9, 56.1. MS:
m=z, 280.3 (M þ 1).
Compound 3n. IR (KBr, cmꢂ1): 1708, 1604, 3221. 1H NMR (400 MHz,
DMSO-d6) d: 8.698–8.8649 (m, 1H), 7.676 (d, J ¼ 9.2 Hz, 1H), 6.799 (d, d, J ¼ 2.3,
9.2, 1H), 6.612 (d, J ¼ 2, 1H), 3.50–3.44 (m, 4H), 3.138 (t, J ¼ 9.6, 2H),
1.826–1.175 (m, 1H), 1.130 (t, J ¼ 6.8, 6H), 0.888 (d, J ¼ 6.8, 6H). 13C NMR
(100 MHz, CDCl3) d: 168.3, 161.6, 151.2, 140.3, 135.2, 126.5, 126.1, 111.2, 100.3,
53.6, 48.5, 26.1, 23.7, 19.6, 13.3,MS: m=z, 317.3 (M þ 1).
Compound 3o. IR (KBr, cmꢂ1): 1708, 1604, 3221. 1H NMR (400 MHz,
DMSO-d6) d: 8.181 (s, 1H), 7.412 (d, J ¼ 9.6 Hz, 1H), 6.715 (d, d, J ¼ 2.58, 8.91,
1H), 6.485 (d, J ¼ 2.4, 1H), 3.51–3.41 (m, 4H), 2.941 (d, J ¼ 9.9, 1H), 1.956 (d,
J ¼ 9.9, 2H), 1.817–1.646 (m, 4H), 1.347 (d, J ¼ 12.6, 4H), 1.244–1.161 (m, 6H).
13C NMR (100 MHz, CDCl3) d: 169.3, 162.3, 150.2, 143.9, 136.2, 126.2, 116.3,
109.3, 49.3, 48.1, 30.5, 27.0, 22.1, 13.2. MS: m=z, 343.3 (M þ 1).
Compound 3p. IR (KBr, cmꢂ1): 1708, 1604, 3221. 1H NMR (400 MHz,
DMSO-d6) d: 8.181 (s, 1H), 7.671 (d, J ¼ 9.3 Hz, 1H), 6.79 (d, J ¼ 9.9, 1H), 6.610
(s, 1H), 3.482 (t, J ¼ 10.7, 2H), 1.171–0.911 (m, 11H), 0.4469 (d, J ¼ 7.5, 2H),
0.203 (d, J ¼ 5.7 Hz, 2H). 13C NMR (100 MHz, CDCl3) d: 169.5, 162.0, 151.2,
143.3, 136.9, 126.9, 124.6, 108.4, 104.6, 59.1, 48.5, 13.2, MS: m=z, 315.2 (M þ 1).
ACKNOWLEDGMENT
The authors thank the Department of Postgraduate Studies and Research in
Chemistry, School of Chemical Sciences, Kuvempu University, for providing labora-
tory facilities.
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