Meglumine sulfate catalyzed solvent-free one-pot synthesis of coumarins under microwave and thermal conditions

Article abstract of DOI:10.1080/00397911.2016.1201512

A convenient method has been developed for the Pechmann reaction of phenols and β-keto esters catalyzed by meglumine sulfate. Solvent-free conditions, inexpensive catalyst, short reaction times, high yield, and ease of purification of the products are the advantages of this protocol. This novel catalytic system is expected to contribute to the development of more benign Pechmann condensation reactions of phenols with β-keto esters.

Full text of DOI:10.1080/00397911.2016.1201512

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
Meglumine Sulfate Catalyzed Solvent Free One-
Pot Synthesis of Coumarins Under Microwave and
Thermal Conditions
Leila Moradi, Khadijeh Rabiei & Fateme Belali
To cite this article: Leila Moradi, Khadijeh Rabiei & Fateme Belali (2016): Meglumine Sulfate
Catalyzed Solvent Free One-Pot Synthesis of Coumarins Under Microwave and Thermal
Conditions, Synthetic Communications, DOI: 10.1080/00397911.2016.1201512
To link to this article: http://dx.doi.org/10.1080/00397911.2016.1201512
View supplementary material
Accepted author version posted online: 20
Jun 2016.
Published online: 20 Jun 2016.
Submit your article to this journal
View related articles
View Crossmark data
Full Terms & Conditions of access and use can be found at
http://www.tandfonline.com/action/journalInformation?journalCode=lsyc20
Download by: [University of Lethbridge]
Date: 20 June 2016, At: 23:33

Meglumine sulfate catalyzed solvent free one-pot synthesis of coumarins under
microwave and thermal conditions
Leila Moradi1,, Khadijeh Rabiei2, Fateme Belali1
1Department of Organic Chemistry, Faculty of Chemistry, University of Kashan, Kashan,
I. R. Iran 2Department of Chemistry, Faculty of Basic Science, Qom University of
Technology, Qom, Iran
Corresponding author Department of Organic Chemistry, Faculty of Chemistry,
University of Kashan, P.O. Box 8731753153, Kashan, I. R. Iran E-mail:
l_moradi@kashanu.ac.ir
Abstract
A convenient method has been developed for the Pechmann reaction of phenols and β-
keto esters catalyzed by meglumine sulfate. Use of solvent-free condition, inexpensive
catalyst, short reaction times, high yield and ease of purification of the products are the
advantages of this protocol. The pronounced advantage of this novel catalytic system is
expected to contribute to the development of more benign Pechmann condensation
reactions of phenols with β-keto esters.
Graphical Abstract
1

KEYWORDS: Meglumine sulfate, Coumarins, Solvent free, One-Pot reaction,
Microwave irradiation, acidic catalyst
1. INTRODUCTION
Coumarins as one of the most important of natural products are fragrant organic
compounds in the benzopyrone chemical class. They have been widely used in
pharmaceuticals [1], efficient laser dye and optical brightening agents [2], additives in
food and cosmetics [3,4]. These compounds have also shown numerous biological
activities, such as antitumor [5], antimicrobial [6], anti-HIV [7], anticancer [8] and
antioxidant [9].
Coumarins have been synthesized by several routes including Pechmann [10],
Knoevenagel [11], Wittig [12] and Reformatsky [13] reactions. the Pechmann reaction is
one of the simple direct methods for coumarins preparation, that proceeds from available
starting materials include phenols and β-keto esters or α,β-unsaturated carboxylic acids in
the presence of acid catalysts, such as sulfuric acid [10], phosphorus pentoxide [14],
trifluoroacetic acid [15], lewis acids such as ZrCl4 [16], ZnCl2, FeCl3, AlCl3 [17] TiCl4
[18], ionic liquids [19], ion exchange resins [20], cellulose sulfuric acid [21] and solid
acid catalysts [22]. Most of the reported methods suffer from one or more of the
disadvantages such as long reaction time, high temperature (150 °C) [23], vigorous
reaction conditions, the occurrence of side reactions and unavailability of the reagents, as
well as poor yields of the desired product. in fact, conventional methods, using strong
2

acid catalysts [15,24,25] performed in high temperature, prolonged reaction times, use of
excess catalyst (10-12 equivalent of sulfuric acid [24] and about 3-4 equivalent when
trifluoroacetic acid were used [15]) and environmental pollution from organic solvents.
The use of microwave irradiation has been developed for a number of organic synthesis
to reduce the reaction time, enhancement the reaction rate and to increase the yield of
products. This method has also been used for coumarin synthesis [26–30].
N-methyl D-glucamine or meglumine is an amino sugar with molecular formula of
C7H11NO5, which can be considered as an environmental friendly catalyst [31, 32]. Due
to advantages of solid state synthesis and in agreement to green chemistry protocol, we
set out to develop a solvent free preparation of coumarins using a non-polluting and
inexpensive catalyst. In this study, we report facile and convenient method for the
preparation of coumarins using meglumine sulfate as a new efficient catalyst in the
Pechmann reaction of a neat mixture of a phenol and β-keto ester derivatives.
2. RESULTS AND DISCUSSION
With attention to the importance of solid acidic catalyst, initially, we prepared sulfated
meglumine (MS) in a simple route (Scheme 1). In continuation of our research, we try to
develop a truly catalytic method for the formation of 4-substituted coumarins in the
presence of catalytic amount of MS as a high efficient acidic catalyst. For this mind, the
solvent free condensation reaction of substituted phenols (2.5 mmol) and dicarbonyl
3

compounds (2.5 mmol) in the presence of MS as a high efficient catalyst under thermal
condition has been investigated (Scheme 2).
To optimize the reaction conditions such as temperature, time of reaction and catalyst
amounts, we consider the reaction between resorcinol and ethylacetoacetate as a model
reaction. The results are summarized in Table 1.
As shown in this Table, in the presence of 0.01 g of catalyst, any product was obtained at
room temperature (Table 1. entry 1). On the other hand, the yield and time was found to
be more favorable when the reaction temperature increased to 100 °C (using 0.01 g of
catalyst). Also, with increasing the catalyst amount from 0.01 to 0.04 g, the reaction
moved faster with higher yield (Table 1, entry 9).
According to the above results, we conducted the same reactions using ethylacetoacetate
and a variety of substituted phenols in the presence of 0.04 g of MS under similar
conditions. As expected, satisfactory results were obtained (Table 2). As shown in Table
2, in all cases, the products have high yields but in some cases, the reaction times are
longer because of the hindrance in phenol or β-ketoester structures; on the other hand,
when the reaction was performed with inactive phenols, no product was achieved. In fact,
starting materials remained intact even after prolonged heating (entry 3k). All products
were characterized in detailed using physical and spectroscopic data (melting point,
FTIR, 1H and 13C NMR and elemental analysis) consistent in comparison with authentic
samples [33-39].
4

Because of the consideration microwave irradiation and conventional heating conditions,
in next step, the model reaction performed under both MW and conventional heating.
Table 3 is containing to results of the coumarin synthesis in thermal and MW conditions.
The comparison between the yield and times of reactions show that the yield of products
are high to excellent in both conditions but reactions in MW condition performed in short
times (6-8 min) and this can be considered as one of the important MW advantages in
compare with thermal method.
Compare the activity of various catalysts in Pechmann condensation of resorcinol and
ethyl acetoacetate in ratio of 1:1 (model reaction) was depicted in Table 4. Data show that
excellent yield of product was obtained when meglumine sulfate was used as a high
efficient catalyst both in thermal and microwave conditions.
2.1. The Proposed Reaction Mechanism
A possible mechanistic pathway has been proposed for the condensation reaction for the
synthesis of 7-hydroxy-4-methyl coumarin. It is based on proton transfer to keto group of
ethylacetoacetate from acid sites of catalyst followed by the nucleophilic attack of the
resorcinol to resulting an intermediate that rapidly undergoes cyclization (through acid
catalysed intra-molecular condensation) yielding 7-hydroxy-4-methyl coumarin (Scheme
3).
3. EXPERIMENTAL
5

3.1. Materials And Methods
Chemical reagents and solvents were purchased from the Merck and Aldrich Companies.
Furrier transform Infrared (FTIR) spectra were recorded using a Perkin-Elmer FT-IR 550
Spectrometer. Melting points were determined in open capillaries using an Electro
thermal MK3 apparatus. 1HNMR and 13CNMR spectra were recorded with a Bruker
Avance DRX-400 spectrometer at 400 and 100 MHz, respectively. The elemental
analyses were obtained from a Carlo ERBA Model EA 1108 analyzer carried out on
Perkin-Elmer 240c analyzer. Microwave assisted reactions were performed with a
Milestone ETHOS EZ apparatus, keeping irradiation power fixed and monitoring the
internal reaction temperature.
3.2. Preparation Of Meglumine Sulfate
A mixture of meglumine (1g) and dry chloroform (20 ml) was poured in a two-necked
100 ml round bottom flask equipped with ice bath in 0oC and mixed for awhile then
Chlorosulfonic acid (0.6 ml) was added dropwise to the mixture during 60 minutes and
stirred for 6h. After that, the product filtered and washed with ethanol (5 times) and
separated meglumine sulfate was dried in 90oC for 4h (scheme 2). The yield of the
obtained catalyst was about 90%. The concentration of H+ on the meglumine sulfate was
about 3.5 mmol/g from acid-base titration. Also elemental analysis (CHNS) demonstrated
that meglumine was sulfated successfully (C: 24%, H: 5.3%, N: 4.3%, S: 17%).
3.3. Synthesis Of 3a As General Procedure For Solvent Free, One-Pot Preparation
Of Coumarins Using MS Under Thermal And Microwave Conditions
6

Resorcinol (2.5 mmol), ethylacetoacetate (2.5 mmol) and catalytic amount of meglumine
sulfate (0.04 g) were mixed and heated at 100 oC in thermal conditions. In microwave
conditions, the reaction mixture subjected to microwave irradiation at power of 600W
and 60-70 oC for 6 minutes. The progress of the reaction was monitored by TLC. After
the completion of reaction, the reaction mixture was cooled to room temperature and 10
ml of EtOH was added. Then, obtained mixture poured into crushed ice and stirred for 10
min. The crude product was collected by filtration, washed with ice cold distilled water
and recrystallized from hot ethanol to afford pure corresponding pure product 3a (Scheme
1). Yellow powder: (Table 2), m.p 185-186 C; IR (KBr): 3498, 3113, 1605, 1669, 1450,
1390, 1213 cm-1; 1H NMR (Acetone-d6, 400 MHz): δ 9.62 (s, 1H, OH), 7.56 (d, J= 8.4
Hz, 1H, H-5), 6.83 (t, J= 6.4 Hz, 1H, H-6), 6.71 (s, 1H, H-8), 6.04 (s, 1H, H-3), 3.25 (s,
3H, CH3-C-4) ppm; 13C NMR (100 MHz, Acetone-d6): δ 161.18 (C-2), 160.39 (C-7),
155.39 (C-4), 153.15 (C-9), 126.36 (C-5), 112.70 (C-10), 112.61 (C-6), 110.75 (C-3),
102.39 (C-8), 17.67 (CH3) ppm.
4. CONCLUSION
A convenient method has been developed for the Pechmann reaction of phenols and β-
keto esters catalyzed by meglumine sulfate. Use of solvent-free condition, inexpensive
catalyst, short reaction times, high yield and ease of purification of the products are the
advantages of this protocol. The pronounced advantage of this novel catalytic system is
expected to contribute to the development of more benign Pechmann condensation
reactions of phenols with β-keto esters.
7

ACKNOWLEDGMENT
We are grateful to the University of Kashan Research Council for the partial support of
this work.
SUPPORTING INFORMATION
Full experimental detail, FTIR, 1H and 13C NMR and elemental analysis of synthesized
materials can be found via the “Supplementary Content’’ section of this article’s
webpage”.
REFERENCES
[1] O’Kennedy, R.; Thornes, R. D. Coumarins: Biology, Applications and mode of
action, John Wiley & Sons: Chicheste, 1997.
[2] Zabradnik, M.; The Production and Application of Fluorescent Brightening Agents,
John Wiley & Sons: New York, 1992.
[3] Takadate, A.; Tahara, T.; Fujino, H.; Goya, S. Chem. Pharm. Bull. 1982, 30, 4120-
4125.
[4] Jimeǐnez, M.; Mateo, J. J.; Mateo, R. J. Chromatogr. A. 2000, 870, 473-477.
[5] Weber, U. S.; Steffen, B.; Siegers, C. P. Res. Commun. Mol. Pathol. Pharmacol.
1998, 99, 193-206.
[6] Zaha, A. A.; Hazem, A. Microbiologica. 2002, 25, 213-222.
[7] Patil, A. D.; Freyer, A. J.; Drake, S.E.; Haltiwanger, R. C.; Bean, M. F.; Taylor, P. B.;
Caranfa, M. J.; Breen, A. L.; Bartus, H. R.; Johnson, R. K.; Hertzberg, R. P.; Westley, J.
W. J. Med. Chem. 1993, 36, 4131-4138.
8

[8] Maly, D. J.; Leonetti, F.; Backes, B.J.; Dauber, D. S.; Harris, J.L.; Craik, C. S.;
Ellman, J. A. J. Org. Chem. 2002, 67, 910-915.
[9] Yun, B. S.; Lee, I. K.; Ryoo, I. J.; Yoo, I. D. J. Nat. Prod. 2001, 64, 1238-1240.
[10] Pechmann, V. H.; Duisberg, C. Ber. 1884, 17, 929-979.
[11] Johnson, J. R. Org. React. 1942, 1, 210-256.
[12] Brafola, G.; Fringuelli, F.; Piermatti, O.; Pizzo, F. Heterocycles. 1996, 43, 1257-
1266.
[13] Jones, G. The Knoevenagel condensation reaction in organic reactions, John Wiley
& Sons: New York, 1967.
[14] Robertson, A.; Sandrock, W. F.; Henry, C. B. J. Chem. Soc. 1931, 2426-2432.
[15] Woods, L. L.; Sapp, J.; J. Org. Chem. 1962, 27, 3703-3705.
[16] Sharma, G. V. M.; Janardhan, R. J.; Sree, L. P.; Radha, K. P. Tetrahedron Lett.
2005, 46, 6119-6121.
[17] Robinson, R.; Weygand, F. J. Chem. Soc. 1941, 2, 386-414.
[18] Valizadeh, H.; Shockravi, A. Tetrahedron Lett. 2005, 46, 3501-3503.
[19] Potdar, M.K.; Mohile, S. S.; Salunkhe, M. M. Tetrahedron Lett. 2001, 42, 9285-
9287.
[20] John, E. V. O.; Israelstam, S. S.; J. Org. Chem. 1961, 26 240-242.
[21] Suresh Kuarm, B.; Venu Madhav, J.; Vijaya Laxmi, S.; Rajitha, B.; Thirupathi
Reddy, Y.; Narsimha Reddy, P.; Crooks, P. A. Synth. Commun. 2010, 40, 3358-3364.
[22] Sinhamahapatra, A.; Sutradhar, N.; Pahari, S.; Bajaj, H. C.; Panda, A. B. Appl.
Catal. A. General. 2011, 394, 93-100.
[23] Selvakumar, S.; Chidambaram, M.; Singh, A. P. Catal. Commun. 2007, 8, 777-783.
9

[24] Russel, A.; Frye, J. R. Org. Synth. 1941, 21, 22-27.
[25] Bulut, M.; Erk, C. Dyes Pigm. 1996, 30, 99-104.
[26] Manhas, M.; Ganguly, S. N.; Mukherjee, S.; Jain, A. K.; Bose, A. K. Tetrahedron
Lett. 2006, 47, 2423.
[27] Singh, V.; Kaur, S.; Sapehiyia, V.; Singh, J.; Kad, G. L. Catal. Commun. 2005, 6,
57.
[28] Fŕere, S.; Thiery, V.; Besson, T. Tetrahedron Lett. 2001, 42, 2791-2794.
[29] Reddy, Y. T.; Sonar, V. N.; Crooks, P.A.; Dasari, P. K.; Reddy, P. N.; Rajitha, B.
Synth. Commun. 2008, 38, 2082-2088.
[30] Hosamani, K M.; Reddy, D. S.; Devarajegowda, H. C. RSC. Adv. 2015, 5, 11261-
11271.
[31] Guo, R. Y.; An, Z. M.; Mo, L. P.; Wang, R. Z.; Liu, H. X.; Wang, S. X.; Zhang, Z.
H. ACS. Comb. Sci. 2013, 15, 557-563.
[32] Guo, R. Y.; An, Z. M.; Mo, L. P.; Yang, S. T.; Liu, H. X.; Wang, S. X.; Zhang, Z. H.
Tetrahedron. 2013, 69, 9931-9938.
[33] Reddy, B. M.; Thirupathi, B.; Patil, M. K. Open. Catal. J. 2009, 2, 33-39.
[34] Upadhyay, K. K.; Mishra, R. K.; Kumar, A. Catal. Lett. 2008, 121, 118-120.
[35] Vahdat, S. M.; J. Appl. Chem. 2012, 7, 57-59.
[36] Prajapati, D.; Gohain, M. Catal. Lett. 2007, 119, 59.
[37] Sun, P.; Hu, Z. Synth. Commun. 2005, 35, 1875-1880.
[38] Bahekar, S. S.; Shinde, D. B. Tetrahedron Lett. 2004, 45, 7999-8001.
[39] Singh, V.; Singh, J.; Kaur, K. P. J. Org. Chem. 1962, 27, 3703-3705.
[40] Borah, K. J.; Borah, R. Monatsh. Chem. 2011, 142, 1253-1257.
10

[41] Sudha, S.; Venkatachalam, K.; Priya, S. V.; Herbert Mabel, J.; Palanichamy, M.;
Murugesan V. J. Mol. Catal. A Chem. 2008, 291, 22-29.
[42] Singh, V.; Kaur, S.; Sapehiyia, V.; Singh, J.; Kad, G. L. Catal. Commun. 2005, 6,
57-59.
[43] Katkevičs, M.; Kontijevskis, A.; Mutule, I.; Sūna, E. Chem. Heterocycl. Compd.
2007, 43, 151-159.
11

Table 1. Effect of Temperature, time and amount of catalyst (MS) on the synthesis of
coumarinsa
Entry Catalyst (g) Temperature (oC) Time (min.) Yield b (%)
1
2
3
4
5
6
7
8
9
10
0.01
0.01
0.01
0.02
0.02
0.03
0.03
0.04
0.04
0.05
rt
240
120
120
100
100
80
-
70
15
35
50
60
65
75
87
92
92
100
70
100
70
100
70
60
40
100
100
40
50
a Resorcinol (2.5 mmol), ethylacetoacetate (2.5 mmol) under solvent free condition.
b Isolated yields.
12

Table 2. Synthesis of coumarin derivatives in the presence of MS
Entry Phenol
Derivative
R2
Product
Time
(min)
40
Yield
(%)a
92
M.P(oC)
HO
OH
OH
CH3
3a
3b
3c
CH3
185-186
(183-184)
[33]b
HO
HO
O
O
O
OH
CH3
CH3
CH3
40
50
91
90
243-245
(244-246)
[33]
HO
O
OH
OH
O
153-155
(154-156)
[34]
O
CH3
HO
HO
OH
OH
OH CH3
3d
3e
CH3
CH3
45
45
91
88
282-286
(283-285)
[33]
OH
HO
HO
O
O
O
CH3 CH3
250-253
(250-252)
[35]
O
CH3
13

HO
OH
Ph
3f
3g
3h
3i
Ph
45
50
50
50
55
90
89
88
90
90
257-259
(256-259)
[35]
HO
O
O
O
O
OH
Ph
Ph
194-197
(195-196)
[35]
HO
HO
OH
OH
HO
O
OH
OH Ph
Ph
245-247
(243-245)
[35]
OH
HO
O
H2N
OH
OH
OH
CH3
CH3
CH3
222–223
(221–224)
[36]
H2N
O
O
MeO
CH3
3j
160–161
(160–162)
[37]
MeO
O
O
O2N
3k
3l
CH3 N.R
120
65
-
-
OH
CH3
O
CH3
88
77-79
(78-80)
[38]
O
OH
OH
CH3
O
3m
CH3
40
91
180-182
(182-184)
[39]
HO
O
14

a Isolated yield
b References supply the relevant experimental data.
15

Table 3. Comparison of thermal and microwave conditions for coumarin synthesis.
Entry Thermal conditionsa Microwave conditionsb
Time (min.) Yield (%)c Time (min.) Yield (%)c
40
40
50
45
45
45
50
50
50
55
120
65
40
92
91
90
91
88
90
89
88
90
90
-
6
6
6
7
7
6
6
7
6
6
10
8
7
93
91
91
92
90
92
90
88
90
91
-
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
88
91
90
92
3m
a Temperature 100oC
b Power of 60 w and 60-70oC
c Isolated yield
16

Table 4. Comparison of meglumine sulphate with several catalysts in pechman
condensation of model reaction
Entry Catalyst
Temprature (oC) Time (min) Yield (%)
a
1
P4VP–H2SO4
70
7
85 [40]
60 [34]
91 [33]
80 [34]
78 [41]
81 [42]
62 [42]
89 [43]
72 [43]
93
2
SnCl2 2H2O
PEG-SO3H
80
75
10
5
3
80
4
H2SO4/silica gel
Al-MCM-41
120
150
-
5
3c
2
6
[bmim][HSO4]b
[bmim][HSO4]
CF3COOHb
7
80
12c
30
30
6
8
100
100
9
Amberlyst-15b
10
11
Meglumine sulphateb 60
Meglumine sulphate 100
40
92
a Poly(4-vinylpyridine)-supported sulfuric acid
b Microwave conditions
c Time in hours
17

Scheme 1. Coumarin synthesis in the presence of meglumine sulfate (MS) in thermal or
MW
18

Scheme 2. Synthesis of meglumine sulfate (MS)
19

Scheme 3. Plausible pathway for the formation of 7-hydroxy-4-methylcoumarin over
meglumine-OSO3H (MS)
20