Zirconyl chloride: A useful catalyst in the Pechmann coumarin synthesis

Article abstract of DOI:10.1055/s-2006-942362

Coumarin derivatives were prepared using zirconyl chloride octahydrate (1%) as a Pechmann catalyst, either neat or in some cases employing small volumes of ethanol as solvent. As result of this work, coumarins were obtained in moderate to good yields. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-942362

PRACTICAL SYNTHETIC PROCEDURES
1895
Zirconyl Chloride: A Useful Catalyst in the Pechmann Coumarin Synthesis
ynthesis C. Rodríguez-Domínguez,a,b Gilbert Kirsch*b
Zirconyl
C
u
hloride
C
ata
a
lysed Coum
n
arin
S
a
Departamento de Química, Centro de Química Farmacéutica, Calle 200 y 21,
Atabey, Playa, CP: 11600, Ciudad de la Habana, Cuba
b
Laboratoire d’Ingénierie Moléculaire et Biochimie Pharmacologique (LIMBP),
Université Paul Verlaine-Metz, 1, Boulevard Arago, 57078 Metz, France
Fax +33(38)7315801; E-mail: kirsch@univ-metz.fr
PSP
Received 21 November 2005; revised 31 January 2006
No66
Abstract: Coumarin derivatives were prepared using zirconyl chloride octahydrate (1%) as a Pechmann catalyst, either neat or in some
cases employing small volumes of ethanol as solvent. As result of this work, coumarins were obtained in moderate to good yields.
Key words: coumarins, zirconyl chloride, Pechmann reaction
CH2X
ZrOCl2⋅8H2O
Y
a, b, or c
R
R
80 °C, 24 h
or
60–65 °C, 24 h
OH
O
O
Scheme 1 Where X and Y are either H or Cl. a) Ethyl acetoacetate; b) Ethyl 2-chloroacetoacetate; c) Ethyl 4-chloroacetoacetate.
For a number of years, coumarins have received attention ing materials were quantitatively recovered, constituting a
from researchers due to their biological activity. The clas- limitation of the method. It should also be noted that cat-
sical Pechmann1 synthesis of such compounds involves echol and tert-butyl catechol do not react under these con-
the reaction of phenols with b-ketoesters, and requires sig- ditions.
nificant quantities of sulfuric acid as both catalyst and sol-
vent. Since this procedure inherently leads to large
24 h and, in some cases, a little ethanol was added as sol-
quantities of acidic waste, alternative, environmentally
friendly reagents and catalysts have been sought in order
ther at the 3- or 4-position, the reaction was performed at
to reduce the amount of acidic effluent that has to be treat-
ed, thus diminishing the total cost of the process.2
In a general way, the reaction was carried out at 80 °C for
vent. However, in the case of halogenated coumarins ei-
between 60 and 65 °C in order to avoid formation of res-
ins. Yields are not affected by longer reaction time, but an
We wish to report that catalytic amounts (1%) of zirconyl increase in the amount of catalyst results in lower yields.
chloride octahydrate in either neat reagent or in concen-
trated alcoholic solution enables coumarins to be prepared
The reagents were purchased from Acros Organics. Thin-layer
in good yields without the need for acidic solvent
chromatography (TLC) was carried out using silica gel plates Alu-
gram Sil G/UV 254 (CHCl3–EtOAc–AcOH, 8:6:1). The 1H and 13
C
(Scheme 1).
NMR spectra were recorded on an AC Bruker 250 MHz spectro-
meter using DMSO-d6 as both solvent and internal standard. The
chemical shifts are reported in ppm and coupling constants (J) in
Hz. Melting points were determined on a Stuart Scientific SMP 3
capillary melting point apparatus and are uncorrected. Mass spectra
were recorded on a HRMS Micromass Autospec 3F.
Bringing the catalyst concentration down to 1% is a great
improvement over the large quantities of sulfuric acid em-
ployed in the classical Pechmann method1 and even the
10% catalyst used in already improved procedures.2a,b,f
With this procedure, moderate to good yields and small
quantities of weakly acidic waste were obtained (Table 1).
However, the reaction requires the presence of a strong
activating group in the ring. With low activation (i.e. alkyl
groups) the reaction does not proceed. Thus, when we
carried out the same reaction on phenol, 2-bromophenol,
4-ethylphenol, 4-tert-butyl-2-methylphenol, 3-chlorophe-
nol, 4-chlororesorcin and 6-bromo-2-naphthol, the start-
Coumarin Synthesis; General Procedure
With unhalogenated acetoacetyl esters: Zirconyl chloride (1 mol%)
was added to an equimolar mixture of phenol and acetoacetyl ester
and stirred at 80 °C for 24 h. When all the starting material was con-
sumed (TLC), and while still hot, the mixture was poured into vig-
orously stirred cold water (20 mL/g of starting phenol). The
precipitate was filtered, washed with cold water and dried at 50 °C
overnight, yielding the coumarin. All reactions were performed on
a 5-g scale with respect to starting phenol.
With halogenated acetoacetyl esters: Zirconyl chloride (1 mol%)
was added to an equimolar mixture of phenol and acetoacetyl ester
and stirred at 60–65 °C for 2 h before EtOH (1 mL/g of phenol) was
SYNTHESIS 2006, No. 11, pp 1895–1897
x
x.
x
x
.
2
0
0
6
Advanced online publication: 05.05.2006
DOI: 10.1055/s-2006-942362; Art ID: Z22505SS
© Georg Thieme Verlag Stuttgart · New York

1896
J. C. Rodríguez-Domínguez, G. Kirsch
PRACTICAL SYNTHETIC PROCEDURES
Table 1 Synthesis of Coumarins Catalyzed by ZrOCl2·8H2O (1%)
Phenol (b-ketoester)a
Product
Yield (%)
91
Phenol (b-ketoester)a
Product
Yield (%)
64
CH3
CH3
HO
OH
HO
OH
OH
OH
OH
a
HO
O
O
HO
O
O
a
1
OH
3
98
86
CH3
CH3
Cl
O
Cl
O
HO
HO
OH
b
OH
OH
HO
O
HO
O
b
OH
2
4
92
48
CH2Cl
OH CH3
HO
OH
HO
5
O
O
HO
OH
HO
O
O
c
OH
a
8
13
58
77
94
H3CO
CH3
OH
OH CH3
H3CO
Cl
O
OH
a
O
O
HO
OH
HO
O
6
b
9
CH3
OH CH2Cl
OH
HO
OH
COOH
HO
O
O
HO
O
O
HO
OH
a
COOH
c
10
7
a The applied acetoacetate is indicated by a, b, or c (see also Scheme 1).
added. The reaction was stirred for an additional 22 h. When all the
starting material was consumed (TLC), the reaction was diluted
with EtOH (1 mL/g of phenol) and poured into vigorously stirred
cold water (20 mL/g of starting phenol). The precipitate was fil-
tered, washed with cold water and dried at 50 °C overnight, yielding
the coumarin. All reactions were performed on a 5-g scale with re-
spect to starting phenol.
13C NMR: d = 161.51, 156.78, 152.94, 149.23, 127.34, 115.52,
113.79, 111.85, 102.34, 16.21.
7,8-Dihydroxy-4-methylcoumarin (4-Methyldaphnetin) (3)
Yield: 4.87 g.
Mp 242–244 °C (Lit.2a 241–243 °C, Lit.5 234–235 °C).
1H NMR: d = 7.09 (d, J6–5 = 8.6 Hz, 1 H, H-6), 6.82 (d, J5–6 = 8.61
Hz, 1 H, H-5), 6.13 (s, 1 H, H-3), 2.35 (s, 3 H, CH3).
7-Hydroxy-4-methylcoumarin (4-Methylumbelliferone) (1)
Yield: 7.25 g.
13C NMR: d = 160.42, 154.14, 149.61, 143.53, 132.35, 115.69,
112.98, 112.32, 110.40, 18.45.
Mp 186–189 °C (Lit.3 185 °C).
1H NMR: d = 10.53 (s, 1 H, OH), 7.59 (d, J8–6 = 8.73 Hz, 1 H, H-8),
6.81 (dd, J6–5 = 2.03 Hz, J6–8 = 2.3 Hz, 1 H, H-6), 6.71 (d,
J5–6 = 2.22 Hz, 1 H, H-5), 6.13 (s, 1 H, H-3), 2.37 (s, 3 H, CH3).
3-Chloro-7,8-dihydroxy-4-methylcoumarin (3-Chloro-4-meth-
yldaphnetin) (4)
Yield: 7.70 g.
13C NMR: d = 161.33, 160.47, 155.01, 153.72, 126.8, 113.03,
112.20, 110.43, 102.37, 18.3.
Mp 267–268 °C (dec.) (Lit.6 265 °C).
1H NMR: d = 7.17 (d, J6–5 = 8.75 Hz, 1 H, H-6), 6.86 (d, J5–6 = 8.63
Hz, 1 H, H-5), 2.49 (s, 3 H, CH3).
3-Chloro-7-hydroxy-4-methylcoumarin (3-Chloro-4-methyl-
umbelliferone) (2)
Yield: 9.4 g.
13C NMR: d = 156.76, 149.83, 149.73, 141.62, 132.44, 116.31,
115.52, 113.09, 112.74, 16.43.
Mp 236–240 °C (Lit.4 242–243 °C).
4-Chloromethyl-7,8-dihydroxycoumarin (4-Chloromethyl-
daphnetin) (5)
Yield: 8.23 g.
1H NMR: d = 7.65 (d, J5–6 = 9.15 Hz, 1 H, H-5), 6.84 (dd,
J6–5 = 2.45 Hz, J6–8 = 2.43 Hz, 1 H, H-6), 6.72 (d, J8–6 = 1.83 Hz,
1 H, H-8), 2.51 (s, 3 H, CH3).
Mp 200–301 °C (Lit.7 198–199 °C).
Synthesis 2006, No. 11, 1895–1897 © Thieme Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
Zirconyl Chloride Catalysed Coumarin Synthesis
1897
1H NMR: d = 7.18 (d, J6–5 = 8.65 Hz, 1 H, H-6); 6.86 (d, J5–6 = 8.78
Hz, 1 H, H-5), 6.42 (s, 1 H, H-3), 4.94 (s, 2 H, CH2Cl).
4-Chloromethyl-5,7-dihydroxycoumarin (4-Chloromethyl-5-
hydroxyumbelliferone) (10)
Yield: 6.56 g.
13C NMR: d = 160.37, 151.64, 150.02, 143.93, 132.73, 115.72,
112.59, 111.21, 110.38, 41.75.
Mp 246–248 °C (Lit.2a 187–189 °C).
1H NMR: d = 10.94 (s, 1 H, OH), 10.42 (s, 1 H, OH), 6.28 (d,
J8–6 = 2.42 Hz, 1 H, H-8), 6.22–6.21 (m, 2 H, H-6 and H-3), 5.03 (s,
2 H, CH2), 2.48 (s, 3 H, CH3).
6-Methoxy-4-methylcoumarin (6)
Yield: 1.00 g.
Mp 163–165 °C (Lit.8 169 °C).
13C NMR: d = 161.72, 160.33, 157.34, 156.69, 152.22, 108.94,
100.02, 99.46, 95.02, 45.21.
1H NMR: d = 7.31 (d, J8–7 = 12.8 Hz, 1 H, H-8), 7.23 (d, J5–7 = 3.05
Hz, 1 H, H-5), 7.17 (d, J7–6 = 2.43 Hz, 1 H, H-7), 6.4 (s, 1 H, H-3),
3.84 (s, 3 H, CH3O), 2.44 (s, 3 H, CH3).
Acknowledgment
13C NMR: d = 160.04, 155.71, 153.12, 147.36, 120.23, 119.20,
117.62, 114.83, 108.24, 55.89, 18.32.
Authors want to thank to the Programme Alban, the European Uni-
on Programme of High Level Scholarships for Latin America (scho-
larship no. E04D040745CU) and Conseil Régional de Lorraine,
France, for supporting this work and Mrs Veronique Poddig for re-
cording the NMR spectra.
8-Carboxy-7-hydroxy-4-methylcoumarin (8-Carboxy-4-meth-
ylumbelliferone) (7)
Yield: 4.16 g.
Mp 266–268 °C.
1H NMR: d = 7.67 (d, J5–6 = 8.77 Hz, 1 H, H-5), 6.92 (d, J6–5 = 8.84
Hz, 1 H, H-6), 6.24 (s, 1 H, H-3), 2.38 (s, 3 H, CH3).
References
(1) Pechmann, V. H.; Duisberg, C. Ber. Dtsch. Chem. Ges.
1884, 17, 929.
13C NMR: d = 169.3, 166.7, 159.97, 159.31, 127.8, 113.15, 112.2,
110.9, 110.6, 18.5.
(2) (a) Sharma, V. M.; Reddy, J. J.; Lakshmi, P. S.; Krishna, P.
R. Tetrahedron Lett. 2005, 46, 6119. (b) Das, B.;
Venkateswarlu, K.; Mahender, G.; Holla, H. J. Chem. Res.
2004, 836. (c) Potdar, M. K.; Mohile, S. S.; Salunkhe, M. M.
Tetrahedron Lett. 2001, 42, 9285. (d) Reddy, B. M.; Reddy,
V. R.; Giridhar, D. Synth. Commun. 2001, 31, 3603. (e) De
S, K.; Gibbs, R. A. Synthesis 2005, 1231. (f) Bose, D. S.;
Rudradas, A. P.; Babu, M. H. Tetrahedron Lett. 2002, 43,
9195.
HRMS (EI+): m/z [M + H]+ calcd for C11H8O5: 220.178; found:
220.037.
5,7-Dihydroxy-4-methylcoumarin (5-Hydroxy-4-methylumbel-
liferone) (8)
Yield: 2.82 g.
Mp 289–290 °C (dec.) (Lit.9 292–293 °C).
1H NMR: d = 10.53 (s, 1 H, OH), 10.31 (s, 1 H, OH), 6.26 (d,
J8–6 = 1.82 Hz, 1 H, H-8), 6.16 (d, J6–8 = 2.45 Hz, 1 H, H-6), 5.85 (s,
1 H, H-3), 2.48 (s, 3 H, CH3).
(3) Russell, A.; Frye, J. R. Org. Synth., Coll. Vol. III; John Wiley
& Sons: New York, 1955, 281; Org. Synth. 1941, Vol. 21,
22.
13C NMR: d = 161.33, 160.38, 158.20, 156.76, 155.24, 109.08,
102.35, 99.34, 94.77, 23.70.
(4) Wheelock, C. E. J. Am. Chem. Soc. 1959, 81, 1348.
(5) John, E. V. O.; Israelstam, S. S. J. Org. Chem. 1961, 26, 240.
(6) Chakravarti, D. J. Indian Chem. Soc. 1931, 8, 407.
(7) Khaikin, M. S.; Petrova, N. L.; Kukhtin, V. A. J. Gen. Chem.
USSR (Engl. Transl.) 1963, 33, 3879; Zh. Obshch. Khim.
1963, 33, 3941.
3-Chloro-5,7-dihydroxy-4-methylcoumarin (3-Chloro-5-
hydroxy-4-methylumbelliferone) (9)
Yield: 5.38 g.
(8) Desai, R. D.; Mavani, G. K. Proc. Indian Acad. Sci., Sect. A
1942, 15, 11.
(9) Canter, J. J. Chem. Soc. 1931, 1255.
(10) Barris, E.; Israelstam, S. S. J. S. Afr. Chem. Inst. 1960, 13,
125.
Mp 317–319 °C (Lit.10 306–308 °C).
1H NMR: d = 10.79 (s, 1 H, OH), 10.46 (s, 1 H, OH), 6.32 (d, J8–
6 = 2.42 Hz, 1 H, H-8), 6.21 (d, J6–8 = 1.82 Hz, 1 H, H-6), 2.70 (s,
3 H, CH3).
13C NMR: d = 161.35, 157.88, 156.55, 154.32, 150.53, 113.86,
102.06, 99.94, 94.68, 20.18.
Synthesis 2006, No. 11, 1895–1897 © Thieme Stuttgart · New York