Dipyridine cobalt chloride: A novel catalyst for the synthesis of coumarins via Pechmann condensation

Article abstract of DOI:10.3184/030823408X313997

Dipyridine cobalt chloride is a novel catalyst for the Pechmann condensation involving different phenols and ethylacetoacetate under solvent-free conditions using both conventional methods and microwave irradiation. It gives the corresponding coumarins in excellent yields with high purity. The catalyst is thermally stable, inexpensive and recyclable. A faster reaction and higher yields compared to the conventional method and no side products were identified using microwave irradiation. In this reaction, electron releasing groups on the phenol ring shown more reactivity and gave high yields than simple phenol. These products were identified by ¹H NMR, ¹³C NMR, MS, IR and elemental analysis.

Full text of DOI:10.3184/030823408X313997

232 RESEARCH PAPER
APRIL, 232–234
JOURNAL OF CHEMICAL RESEARCH 2008
Dipyridine cobalt chloride: a novel catalyst for the synthesis of coumarins
via Pechmann condensation
Janganati Venu Madhava, Bowroju Suresh Kuarma, Pola Someshwara, Bavanthula Rajithaa*
Yerram Reddy Thirupathi Reddyb and Peter A. Crooksb
aDepartment of Chemistry, National Institute of Technology, Warangal, AP, India
bDepartment of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536, USA
Dipyridine cobalt chloride is a novel catalyst for the Pechmann condensation involving different phenols and
ethylacetoacetate under solvent-free conditions using both conventional methods and microwave irradiation.
It gives the corresponding coumarins in excellent yields with high purity. The catalyst is thermally stable, inexpensive
and recyclable. A faster reaction and higher yields compared to the conventional method and no side products were
identified using microwave irradiation. In this reaction, electron releasing groups on the phenol ring shown more
reactivity and gave high yields than simple phenol. These products were identified by 1H NMR, 13C NMR, MS, IR and
elemental analysis.
Keywords: coumarins, phenols, β-ketoester, CoPy2Cl2, Pechmann condensation, solvent free conditions
Coumarins display a wide variety of biological properties and
EtO
O
O
OH
O
O
CoPy2Cl2/ r.t
MW 300W
are used as additives in food, perfumes, cosmetics,1 optical
brighteners,2 dispersed fluorescent and laser dyes.3 Coumarin
itself and 7-hydroxycoumarin have been reported to inhibit
the proliferation of a number of human malignant cell lines in
vitro4,5 and have demonstrated activity against several types
of animal tumors.6-8 These compounds have also been shown
in clinical trials to possess activity against prostate cancer,
malignant melanoma and metastatic renal cell carcinoma.9,10
Coumarins are synthesised by different reactions such as
the Pechmann,11 Perkin,12 Knoevenagel,13 Reformatsky and
Wittig reactions.14,15 Amongst these reactions, the Pechmann
condensation is the most common for the synthesis of
coumarins, sinceitproceedsfromverysimplestartingmaterials
and furnish good yields. It involves the condensation of
phenols with β-keto esters in the presence of sulfuric acid as a
cyclising agent. The reaction can also be catalysed by different
acid catalysts, such as PPA,16 InCl3,17 ZrCl4,18 Yb(OTf)3,19-22
p-TsOH,23 BiCl324 and I2 or AgOTf25 and Sm(NO3)3 26 as well
as chloroaluminate ionic liquids.27,28 However, some of these
Lewis acids are moisture sensitive and require special care
in handling and storage. Some of these methods also need a
high reaction temperature, prolonged reaction time and drastic
reaction conditions. Furthermore, some of the catalysts are
expensive, and in some of the existing methods the catalysts
are destroyed in the work-up procedure and cannot be
recovered or re-used.
R
R
R1
R1
1
2
3
Scheme 1
at room temperature to yield desired coumarin in 1–3 h.
In comparison, the microwave technique is more advantageous
than conventional method. The method-A required a shorter
reaction time and yields are good with high purity. Method-
B required a longer reaction time to complete the reaction.
The results are given in Table 1.
In summary CoPy2Cl2 is an efficient reusable catalyst for
the Pechmann condensation of phenols and β-keto esters to
afford coumarins.
Experimental
Melting points were determined in open capillaries and are
uncorrected. The reactions were monitored by TLC and visualised
with UV light. IR spectra (KBr) were recorded on Shimadzu FTIR
model 8010 spectrometer and the 1H NMR spectra on Varian
Gemini 200 MHz spectrometer using TMS as an internal standard.
Mass spectra were recorded on a JEOL JMS D-300 Spectrometer.
All solvents and reagents were purchased from Aldrich and Fluka.
In connection with our earlier reports on coumarin
synthesis29,30 now we report the use of dipyridine cobalt
chloride31 for the Pechmann condensation. Recently we have
employed this catalyst for the synthesis of benzoxanthenes.32
The Lewis acid catalyst is a solid (violet coloured crystals),
soluble in water, stable in air, immiscible in common organic
solvents, reusable, and it has high thermal stability. In addition,
its toxicity is low. We examined the synthesis in microwave
and conventional methods (Scheme 1).
Procedure for the preparation of catalyst (CoPy2Cl2):
Cobalt chloride and pyridine were mixed in a 1:2 mol ratio in the
presence of methanol (solvent). The reaction mixture was refluxed
for 7–8 h. A solid was obtained, filtered and recrystallised from 1:2
ratio of water and methanol to afford pure violet colour crystals of
the complex.
General procedure for synthesis of coumarins
Method A (microwave irradiation): A mixture of the phenol 1
(1 mmol), β-ketoester 2 (1 mmol) and CoPy2Cl2 (0.01 mmol) was
added and the mixture was inserted in a microwave oven (BPL, 800T
model) on a silica gel solid support and irradiated at 300 W for the
appropriate time (Table 1). The progress of the reaction was checked
by TLC. The reaction mass was cooled to room temperature, water
(5 ml) was added and stirred for 2 min. The mixture was filtered
and recrystallised from ethanol to afford the expected products in
excellent yields 3.
Method B (conventional method): A mixture of the phenol 1
(1 mmol), β-ketoester 2 (1 mmol) and CoPy2Cl2 (0.01 mmol) was
stirred at room temperature for the appropriate time (Table 1).
Completion of the reaction was confirmed by TLC. After completion
of the reaction, water (5 ml) was added to the reaction mixture and
stirred for 2 min. The mixture was filtered and recrystallised from
ethanol to afford corresponding products in good yields 3.
Results and discussion
In the microwave conditions (method-A), the phenol and
β-ketoester were irradiated in the presence of CoPy2Cl2
(catalytic amount) without using any solvent at 300 W power
leveltoaffordthecorrespondingcoumarinin1–3min.Whenthe
reaction was carried out by the conventional method (method-
B), the phenol and β-ketoester in the presence of CoPy2Cl2
(catalytic amount), were stirred under solvent free conditions
* Correspondent. E-mail: rajitabhargavi@yahoo.com
PAPER: 08/5140

JOURNAL OF CHEMICAL RESEARCH 2008 233
Table 1 CoPy2Cl2 catalysed synthesis of coumarins
Entry
Phenol
Ester
Coumarin
Method-A
Method-B
M.p./°C
Time/min
Yield/%a
Time/min
Yield/%a
O
O
HO
HO
O
O
O
HO
OH
OH
1
2
97
1.5
94
18519
OEt
O
CH3
O
O
HO
2
3
4
2
2.5
1
95
96
96
2
3
93
92
94
18021
25720
28019
Cl
OEt
CH2Cl
O
O
HO
HO
O
O
HO
HO
OH
OH
Ph
OEt
Ph
O
O
O
O
O
O
O
O
1.5
OEt
O
OH CH3
O
OH
HO
O
HO
OH
O
O
5
1.5
95
2
93
18722
Cl
Cl
OEt
OH CH2Cl
OH
OH
OH
HO
HO
O
O
HO
HO
OH
OH
6
7
2
3
96
95
2
94
94
24219
13422
OEt
O
CH3
O
OH
OH
O
2.5
OEt
CH2Cl
HO
O
O
HO
OH
8
2
97
2.5
96
13729
OEt
CH3
O
OH
O
O O
9
3
3
96
67
3
3
94
58
15320
8129
OEt
OEt
OH
O
O
O
O
10
CH3
aYields refer to pure products and all products were characterised by comparison of their physical data and in 1H NMR, IR, and
mass spectral data with those authentic samples.
After filtration, the filtrate (water) containing the catalyst was
evaporated under reduced pressure to give a violet solid. The
recovered catalyst was washed with ether, dried at 85oC for 2 h under
high-pressure prior to use in a further reaction.
125.8, 123.1, 122.7, 115.9, 114.2, 109.8; EIMS, 70Ev, m/z: 238 (M+)
(4) (Entry 4): M.p. 280oC IR (KBr, cm-1): 3400, 3385, 1718,
1530: H NMR (DMSO-d6): δ 10.20 (s, 1H, OH), 9.89 (s, 1H, OH),
1
7.23 (s,1H, ArH), 6.98 (s, 1H, ArH),6.12 (s,1H, C-3H), 2.21 (s, 3H,
CH3).13C NMR (DMSO-d6): δ162.7, 160.1, 159.3, 152.6, 151.31,
112.9, 111.0, 105.5, 101.5, 22.5. EIMS, 70Ev: m/z: 192 (M+).
(5) (Entry 5): M.p. 187oC IR (KBr, cm-1): 3419, 3373, 1725,
1565: 1H NMR (DMSO-d6): δ 10.30 (s, 1H, OH), 10.05 (s, 1H, OH),
7.41 (s,1H, ArH), 6.95 (s, 1H, ArH), 6.32(s,1H, C-3H), 4.05 (s, 2H,
CH2).13C NMR (DMSO-d6): δ162.1, 160.7, 159.9, 153.7, 151.31,
118.9, 111.0, 108.5, 101.5, 43.5: EIMS, 70Ev: m/z: 226 (M+).
(6) (Entry 6): M.p. 242oC IR (KBr cm-): 3410, 3228, 1647, 1583:
1H NMR (DMSO-d6): δ 10.10 (s, 1H, OH), 9.51 (s, 1H, OH), 7.35 (d,
1H, ArH), 6.85 (d, 1H, ArH),6.15 (s,1H, C-3H), 2.20 (s, 3H, CH3).13C
NMR (DMSO-d6): δ161.7, 155.5, 153.3, 149.6, 145.21, 122.3, 114.2,
112.5, 110.3, 22.5. EIMS, 70Ev: m/z: 192 (M+).
Spectral data
(1) (Entry 1): M.p. 185oC. IR (KBr, cm-1): 3400, 1725, 1530; 1H NMR
(CDCl3): δ 10.12 (s, 1H, OH), 7.45 (d, 1H, ArH), 6.88 (d, 1H, ArH),
6.56 (s, 1H, ArH). 6.15 (s, 1H, C-3H), 2.15 (s, 3H, CH3): 13C NMR
(CDCl3): δ = 161.7, 159.6, 152.6, 151.80, 128.9, 113.9, 112.5, 111.5,
109.7, 22.0; EIMS, 70Ev, m/z: 176 (M+).
(2) (Entry 2): M.p. 180oC. IR (KBr, cm-1): 3389, 1705, 1522;
1H NMR (CDCl3): δ 10.09 (s, 1H, OH), 7.43 (d, 1H, ArH), 6.81 (d, 1H,
ArH), 6.50 (s, 1H, ArH). 6.14 (s,1H, C-3H), 3.72 (s, 2H, CH2): EIMS,
70Ev, m/z: 210 (M+).
(3) (Entry 3): M.p. 257oC. IR (KBr, cm-1): 3395, 1717, 1545;
1H NMR (DMSO-d6): δ 10.32 (s, 1H, OH), 7.14–7.41 (m, 5H, ArH),
6.95 (d, 2H, ArH), 6.82 (s, 1H, ArH). 6.31 (s,1H, C-3H): 13C NMR (75
MHz, DMSO-d6): δ = 162.7,157.3, 155.1, 151.7, 129.2, 128.7, 126.3,
(7) (Entry 7): M.p. 134oC IR (KBr, cm-1): 3421, 3275, 1565:
1H NMR (DMSO-d6): δ 10.31 (s, 1H, OH), 9.95 (s, 1H, OH), 7.31
(d,1H, ArH), 7.15 (d, 1H, ArH),6.21 (s,1H, C-3H), 3.92 (s, 2H,
PAPER: 08/5140

234 JOURNAL OF CHEMICAL RESEARCH 2008
CH2).13C NMR (DMSO-d6): δ161.7, 159.1, 149.3, 148.5, 147.31,
119.9, 115.7,114.1, 112.5, 42.8. EIMS, 70Ev: m/z: 226 (M+).
(8) (Entry 8): M.p. 137oC IR (KBr, cm-1) 3420, 1720,1530:
1H NMR (DMSO-d6): δ 10.42 (s, 1H, OH), 7.42 (d, 1H, ArH), 6.85
(d,1H, ArH),6.11 (s,1H, C-3H), 2.36 (s, 3H, CH3), 2.15 (s, 3H, CH3):
13C NMR (DMSO-d6): δ 161.3, 159.7, 154.6, 153.6, 123.9, 112.8,
112.5, 111.5, 110.7, 19.0, 8.9: EIMS, 70Ev: m/z: 190 (M+).
7
A. Maucher and E. Von Angerer, J. Cancer Res. Clin. Oncol., 1994, 120,
502.
B. Omarbasha, W.R. Fair and W.D. Heston, Cancer Res., 1989, 49, 3045.
M.E. Marshall, K. Butler and A. Fried, Mol. Biother., 1991, 3, 170.
8
9
10 J.L. Mohler, L.G. Gomella, E.D. Crawford, L.M. Glode, C.D. Zippe,
W.R. Fair and M.E. Marshall, Prostate., 1992, 20, 123.
11 S. Sethna and R. Phadke, Org React., 1953, 7, 1.
12 J.R. Johnson, Org React., 1942, 1, 210.
13 G. Jones, Org React., 1967, 15, 204.
14 R.L. Shriner, Org React., 1942, 1, 1.
15 I. Yavari, R. Hekmat-Shoar and A. Zonouzi, Tetrahedron Lett., 1998, 39,
2391.
16 A.J. Nadkarni and N.A. Kudav, Ind. J. Chem., 1981, 20B, 719-720.
17 D.S. Bose, A.P. Rudradas and M.H. Babu, Tetrahedron Lett., 2002, 43,
9195. and reference cited therein.
18 G. Smitha and C.S. Reddy, Synth. Commun., 2004, 34, 3997.
19 L.M. Wang, J.J. Xia, H. Tian, C.T. Qian and Y. Ma, Ind. J. Chem., 2003,
42B, 2097.
20 L.L. Woods and J. Sapp, J. Org. Chem., 1962, 27, 3703.
21 G. Zagotto, O. Gia, F. Baccichetti, E. Uriarte and M. Palum, Photochem.
Photobiol., 1993, 58, 486.
(9)(Entry9):M.p:153oC.IR(KBr, cm-1):1720,1530:1HNMR(DMSO-
d6): δ 7.25–7.50 (m, 6H, ArH), 6.11 (s, 1H, C-3H), 2.15(s, 3H, CH3). 13
C
NMR (DMSO-d6): δ 160.3, 156.7, 154.6, 143.6, 128.9, 127.8, 126.5, 126.3,
124.6, 122.7, 122.4, 121.5, 112.1, 22.9: EIMS, 70Ev: m/z: 210 (M+).
1
(10) (Entry 10): M.p: 81oC IR (KBr, cm-1):1720, 1530: H NMR
(DMSO-d6): δ 7.02–7.37 (m, 4H, ArH), 6.10 (s,1H, C-3H), 2.20 (s,
3H, CH3). 13C NMR (DMSO-d6): δ160.7, 152.6, 150.6, 128.9, 125.9,
125.6, 121.5, 111.5, 110.7, 22.0: EIMS, 70Ev: m/z: 160 (M+).
Financial assistance from CSIR (Grant No: 01(2061)/06/
EMR-11) New Delhi is greatly acknowledged.
Received 7 March 2008; accepted 2 April 2008
Paper 08/5140 doi: 10.3184/030823408X313997
22 M.S. Khaikin, N.L. Petrova and V.A. Kukhtin, Zh. Obshch. Khim., 1963,
33, 3941.
23 T. Sugino and K. Tanaka, Chem. Lett., 2001, 4, 110.
24 B.P. Sachin, P.B. Ramakrishna, P.R. Vivek and D.S. Shriniwas, Synth.
Commun., 2006, 36, 525.
25 W. Jie, D. Tianning, S. Wei and L. Yizhe, Synth. Commun., 2006, 39,
2949.
26 S.B. Sushilkumar and B.S. Devanand, Tetrahedron Lett., 2004, 45, 7999.
27 T. Sugino and K. Tanaka, Chem Lett., 2001, 30, 110.
28 P.R. Singh, D.U. Singh and S.D. Samant, Synlett., 2004, 1909.
29 B. Rajitha, V. Naveen Kumar, P. Someshwar, J. Venu Madhav, P. Narsimha
Reddy and Y. Thirupathi Reddy, Arkivoc, 2006, xii, 23.
30 Y. Thirupathi Reddy, Vijayakumar, N. Sonar, A. Crooks Peter, K. Dasari
Pavan, P. Narsimha Reddy and B. Rajitha, Synth Commun (in press).
2008.
References
1
2
3
R. O’Kennedy and R.D. Thornes, Coumarins: biology, applications and
mode of action, John Wiley and Sons, Chichester, 1997.
M. Zabradnik, The production and application of fluorescent brightening
agents, John Wiley and Sons, New York, 1992.
R.D.H. Murray, J. Mendez and S.A. Brown, The natural coumarins:
occurrence, chemistry and biochemistry, John Wiley and Sons, New York,
1982.
4
M.E. Marshall, J.L. Mohler, K. Edmonds, B. Williams, K. Butler,
M. Ryles, L. Weiss, D. Urban, A. Beuschen and M. Markiewicz, J. Cancer
Res. Clin. Oncol., 1994, 120, 39.
5
6
R.B. Myers, M. Parker and W.E. Grizzle, J. Cancer Res. Clin. Oncol.,
1994, 120, 11.
L.D. Raev, E. Voinova, I.C. Ivanov and D. Popov, Pharmazie., 1990, 45,
696.
31 J.D. Duntitz, Acta Cryst., 1957, 10, 307.
32 J. Venu Madhav, B. Suresh Kuarm and B. Rajitha, Arkivoc, 2008, ii, 204.
PAPER: 08/5140