A facile and efficient synthesis of tetrahydrobenzo[b]pyrans using lactose as a green catalyst

Article abstract of DOI:10.1007/s11164-014-1710-x

Lactose has been used as a mild, efficient, green, and inexpensive catalyst for the synthesis of tetrahydrobenzo[b]pyran derivatives via a one-pot, three-component condensation between aryl aldehydes, malononitrile, and dimedone in H₂O:EtOH at

Full text of DOI:10.1007/s11164-014-1710-x

Res Chem Intermed
DOI 10.1007/s11164-014-1710-x
A facile and efficient synthesis
of tetrahydrobenzo[b]pyrans using lactose as a green
catalyst
•
Fatemeh Noori Sadeh Malek Taher Maghsoodlou
•
•
Nourallah Hazeri Mehrnoosh Kangani
Received: 25 March 2014 / Accepted: 6 May 2014
Ó Springer Science+Business Media Dordrecht 2014
Abstract Lactose has been used as a mild, efficient, green, and inexpensive cat-
alyst for the synthesis of tetrahydrobenzo[b]pyran derivatives via a one-pot, three-
component condensation between aryl aldehydes, malononitrile, and dimedone in
H2O:EtOH at 60 °C. This method offers a considerable number of advantages
including short reaction time, high to quantitative yields, low cost, easy accesses,
and simple work-up.
Keywords Lactose Á Tetrahydrobenzo[b]pyran Á Malononitrile Á Dimedone
Introduction
Multi-component reactions (MCRs) have recently received a good deal of attention
because of several new bonds in a one-pot reaction, low number of reaction and
purification steps, selectivity, synthetic convergence, high atom economy, simplic-
ity, synthetic efficiency, short reaction time, facility of workup, and high yield of
products [1, 2]. Recently, MCRs have been the best way for the synthesis of
heterocycles, which have great value in design and discovery of biologically new
active compounds [1, 3–5]. Among them, Pyran annulated heterocylic derivatives
represent an important class of oxygen-containing heterocycles being the main
components of many naturally occurring products, and they are widely employed in
cosmetics and pigments [1]. 4H-Benzo[b]pyrans have occupied a vital place in drug
research because of their various biological and pharmacological activities such as
spasmolytic, diuretic, anticoagulant, anticancer, antianaphylactic antioxidant,
antileishmanial, antibacterial, antifungal, hypotensive, antiviral, antiallergenic,
F. N. Sadeh Á M. T. Maghsoodlou (&) Á N. Hazeri Á M. Kangani
Department of Chemistry, Faculty of Science, University of Sistan and Baluchestan,
P. O. Box 98135-674, Zahedan, Iran
e-mail: mt_maghsoodlou@chem.usb.ac.ir
123

F. N. Sadeh et al.
and antitumor activities [6–11]. Furthermore, they can be used as cognitive
enhancers for the treatment of neurodegenerative disease, including Alzheimer’s
disease, amyotrophic lateral sclerosis, Huntington’s disease, Parkinson’s disease,
AIDS-associated dementia, and Down’s syndrome, as well as for the treatment of
schizophrenia and myoclonus [12]. Finally, some of 4H-benzo[b]pyrans are useful
as photoactive materials [13]. Consequently, many methods for the synthesis of
these compounds have been reported including the use of microwaves [14],
ultrasonic irradiations [15], sodium bromide [15], hexadecyldimethylbenzyl
ammonium bromide [16], tetramethyl ammonium hydroxide [17], diammonium
hydrogen phosphate [18], fluoride ion [19], magnesium oxide [20], sodium selenite
[21], iodine [22], H6P2W12O62.H2O [23], tetrabutylammonium bromide [24],
cerium(III) chloride [25], lithium bromide [26], RE(PFO)3 [27], amberlite IRA-40
(OH) [28], acidic ion liquids [29], L-proline [30], ZnO-beta zeolite [31], trisodium
citrate [32], and basic ionic liquids [33]. Most of these synthetic methods suffer
from drawbacks such as employing toxic catalysts, strong basic conditions,
expensive and complex catalysts or reagents, many tedious steps, low yields of the
products, and long reaction times in most cases, which restricts their usages in
practical applications.
Recently, organic reactions in green solvents such as water, ethanol, and their
mixtures, devoid of harmful organic solvents in the presence of green catalysts, have
attracted a great deal of attention, as these solvents are inexpensive, safe, and
environmentally benign [34, 35]. In continuation of our research on using
inexpensive, easy-access, biodegradable, green catalysts, and solvents [36–39],
we focused our investigation to develop new synthetic methods for the preparation
of tetrahydrobenzo[b]pyrans using aryl aldehydes, malononitrile, and dimedone in
the presence of lactose as a catalyst (Fig. 1) in H2O/EtOH at 60 °C (Scheme 1).
This is a one-pot, three-component reaction in H2O/EtOH, which is not only
operationally simple, clean, and efficient, but also consistently gives the
corresponding products in good to excellent yields.
Experimental
Melting points and IR spectra of all compounds were measured on an Electro
1
thermal 9100 apparatus and FT-IR-JASCO-460 plus spectrometer. The H NMR
spectra were obtained on Bruker DRX-400 Avance instruments with DMSO and
acetone as a solvent. All reagents and solvents were obtained from Fluka and Merck
and used without further purification.
General procedure for the preparation of tetrahydrobenzo[b]pyrans
Lactose (40 mol%) was dissolved in H2O:EtOH (3:1) then aromatic aldehyde
(1 mmol), malononitrile (1 mmol), and dimedone (1 mmol) was added to mentioned
solution at 60 °C. The progress of the reaction was monitored by TLC. After
completion of the reaction, the mixture was cooled to room temperature and the
products were isolated by filtration and washed with water and recrystallized from
123

A facile and efficient synthesis of tetrahydrobenzo[b]pyrans
Fig. 1 Structure of lactose
OH
O
HO
HO
O
OH
OH
OH
O
OH
OH
R
CHO
O
O
+
O
(40 mol %)
Lactose
CN
CN
CN
+
R
H2O:EtOH (3:1)
60°C
O
NH2
3
1
2
4a-m
Scheme 1 Synthesis of tetrahydrobenzo[b]pyran derivatives in the presence of lactose in H2O:EtOH at
60 °C
ethanol (95 %) to afford pure products. Selected spectroscopic data of some products
are given in the following sections.
2-Amino-5,6,7,8-tetrahydro-7,7-dimethyl-5-oxo-4-phenyl-4H-chromene-3-
carbonitrile (Table 4, entry 1)
1
IR (KBr, cm-1): 3,390, 3,245, 2,960, 2,190, 1,676, 1,209; H NMR (400 MHz,
CDCl3) d (ppm): 1.07 (s, 3H), 1.14 (s, 3H), 2.25 (dd, J = 16.4 Hz, 2H,), 2.48, (s,
2H), 4.43 (s, 1H), 4.55 (s, 2H), 7.2, 7.3 (m, 5H).
2-Amino-5,6,7,8-tetrahydro-4-(4-hydroxyphenyl)-7,7-dimethyl-5-oxo-4H-
chromene-3-carbonitrile (Table 4, entry 5)
1
IR (KBr, cm-1): 3,285, 3,160, 2,960, 2,185, 1,675, 1,209; H NMR (400 MHz,
(DMSO-d6): d (ppm): 1.055(s, 3H), 1.12 (s, 3H), 2.25 (dd, J = 16.4 Hz, 2H), 2.463
(s, 2H), 4.36 (s, 1H), 4.53(s, 2H), 5.26 (s, 1H), 6.728–7.103 (dd, J = 8.4, 4H).
2-Amino-5,6,7,8-tetrahydro-4-(2,3-dimethoxyphenyl)-7,7-dimethyl-5-oxo-4H-
chromene-3-carbonitrile (Table 4, entry 7)
1
IR (KBr, cm-1): 3,305, 3,205, 2,945, 2,175, 1,676, 1,212; H NMR (400 MHz,
(DMSO-d6): d (ppm) = 1.08 (s, 3H), 1.12 (s, 3H), 2.22 (dd, J = 16 Hz, 2H), 2.44
123

F. N. Sadeh et al.
(dd, J = 17.6, 2H), 3.85 (s, 3H), 3.95 (s, 3H), 4.52(s, 2H), 4.74(s, 1H), 6.716–6.809
(dd, J = 8, 2H), 6.972 (t, J = 8, 1H).
2-Amino-5,6,7,8-tetrahydro-4-(4-methyl)-7,7-dimethyl-5-oxo-4H-chromene-3-
carbonitrile (Table 4, entry 11)
IR (KBr, cm-1): 3465, 3320, 2955, 2190, 1676, 1247; 1H NMR (400 MHz,
(DMSO-d6): d (ppm) = 1.08 (s, 3H), 1.12 (s, 3H), 2.23 (dd, J = 16.4 Hz, 2H), 2.30
(s, 3H), 2.40 (dd, J = 17.6, 2H), 4.52(s, 2H), 4.74(s, 1H), 6.716–6.809 (m, 2H),
6.972 (t, 1H).
Results and discussion
In order to optimize the reaction conditions, we studied the reaction of
benzaldehyde (1 mmol), malononitrile (1 mmol), and dimedone (1 mmol). As can
be seen in Tables 1 and 2, the best results were obtained at 60 °C in the presence of
0.012 g (40 mol%) lactose in H2O:EtOH (3:1). Also, we used sucrose and glucose
as a catalyst under the optimized reaction conditions and the results are summarized
in Table 3.
Table 1 Effect of amount of
catalyst for the synthesis of
tetrahydrobenzo[b]pyran
Entry
Catalyst loading (mol%)
Yield (%)
1
2
3
4
5
6
5
10
20
30
40
50
52
62
63
79
89
80
The optimize conditions are in
bold
Table 2 Influence of different
solvents and temperature on the
synthesis of
Entry
Solvent
Temperature (°C)
Yield (%)
1
2
3
4
5
6
7
8
H2O
70
70
70
70
r.t
79
73
82
68
–
tetrahydrobenzo[b]pyrans in the
presence of lactose (40 mol%)
H2O:EtOH(2:1)
H2O:EtOH(3:1)
H2O:EtOH(4:1)
H2O:EtOH(3:1)
H2O:EtOH(3:1)
H2O:EtOH(3:1)
H2O:EtOH(3:1)
40
50
60
46
71
89
The optimize conditions are in
bold
123

A facile and efficient synthesis of tetrahydrobenzo[b]pyrans
Table 3 Different catalytic systems and catalytic activity evaluation for the synthesis of tetra-
hydrobenzo[b]pyrans in the presence of lactose in H2O:EtOH (3:1) at 60 °C
Entry
Catalyst
Mol%
Time (min)
Yield (%)
1
2
3
Sucrose
Lactose
Glucose
40
40
40
30
30
35
58
63
54
R
CHO
O
O
O
(40 mol %)
Lactose
CN
CN
+
+
CN
R
H2O:EtOH (3:1)
60°C
O
NH2
3
1
2
4a-m
Scheme 2 Synthesis of tetrahydrobenzo[b]pyrans derivatives in the presence of lactose in H2O:EtOH
(3:1) at 60 °C
Table 4 Synthesis of tetrahydrobenzo[b]pyrans derivatives 4a–m via the condensation of aryl aldehydes
1, malononitrile 2, and dimedone 3 in the presence of lactose (40 mol%) in H2O:EtOH (3:1) at 60 °C
Entry Aromatic aldehyde
Product Time
(min)
Yield
(%)
MP (Obsd)
(°C)
MP (Lit)
(°C)
1
C6H5CHO
4a
4b
4c
4d
4e
4f
25
30
35
30
40
45
50
25
30
35
35
25
25
89
97
91
89
89
95
94
89
97
98
84
96
97
229–232
208–211
196–198
120–123
213–215
198–200
214–216
218–220
209–211
170–175
208–211
215–217
215–219
233–234 [19]
215–217 [31]
214–215 [40]
115–117 [27]
205–207 [31]
198–200 [19]
217–219 [41]
224–226 [40]
208–211 [20]
169–171 [31]
214–216 [17]
222–224 [19]
210–212 [42]
2
4-CL C6H4CHO
2-CL C6H4CHO
2,4-(CL)2 C6H3CHO
4-OH C6H4CHO
4-N(Me)2 C6H4CHO
2,3-(OMe)2 C6H3CHO
2-NO2 C6H5CHO
3-NO2 C6H5CHO
4-NO2 C6H5CHO
4-Me C6H5CHO
2-Furaldehyde
3
4
5
6
7
4g
4h
4i
8
9
10
11
12
13
4j
4k
4l
Thiophene-2-
carbaldehyde
4m
Using this optimized reaction, the scope and efficiency of the reaction were
explored for the synthesis of a wide variety of substituted tetrahydrobenzo[b]pyrans
using aryl aldehydes, malononitrile, and dimedone (Scheme 2). The results are
summarized in Table 4.
123

F. N. Sadeh et al.
HO
HO
HO
O
HO
HO
OH
O
O
O
HO
O
OH
HO
OH
CN
OH
HO
HO
HO
OH
OH
O
O
O
OH
HO
OH
OH
HO
OH
NC
CN
CN
OH
O
OH
OH
O
2
OH
+
Ar
HO
HO
OH
OH HO
HO
O
O
OH
OH
HO
O
Ar
C
H
3
O
OH
OH
HO
O
OH
O
OH
HO
HO
1
O
O
OH
HO
HO
O
OH
OH
O
O
O
5
O
HO
OH
OH
OH
OH
HO
OH
O
HO
HO
HO
HO
OH
OH
O
HO
OH
O
OH
OH
OH
OH
OH
O
H
Tautomerism
HO
HO
HO
HO
O
H
O
H
O
O
O
O
OH
OH
OH
OH
HO
OH
5
OH
4
O
HO
HO
O
HO
HO
OH
OH
OH
OH
HO
O
O
Ar
O
Ar
O
H
HO
O
CN
CN
NH
O
OH
OH
HO
C
N
O
7
HO
O
O
OH
O
OH
HO
HO
OH
OH
6
HO
HO
HO
O
HO
O
OH
OH
HO
OH
OH
OH
O
O
HO
O
OH
O
HO
OH
OH
OH
O
Ar
O
CN
NH2
8 (product)
Scheme 3 Suggested mechanism for lactose-catalyzed synthesis of tetrahydrobenzo[b]pyran derivatives
All reactions delivered good-to-excellent product yields and accommodated a
wide range of aromatic aldehydes containing electron-donating and electron-
withdrawing groups (Table 4, entries 1–11) without any significant substituent
effects. This three-component condensation reaction also proceeded with hetero-
aromatic aldehyde, such as 2-furaldehyde and thiophene-2-carbaldehyde and gave
the corresponding product in high yield (entries 12 and 13).
We proposed a mechanism for the synthesis of tetrahydrobenzo[b]pyran
derivatives in the presence of lactose as a catalyst. First, Knoevenagel condensation
between 1 and 2 produced 2-benzylidenemalononitrile 3, Michael addition of 3 with
5 (1,3-dicarbonyl compound), and followed cyclization, and tautomerization
afforded the corresponding product. We suggested that the lactose hydroxys group
has activated the carbonyl and nitrile groups (Scheme 3).
123

A facile and efficient synthesis of tetrahydrobenzo[b]pyrans
Conclusions
In summary, we report an eco-friendly and straightforward one-pot, three-
component condensation for the synthesis of 4H-tetrahydrobenzo[b]pyran deriva-
tives in the presence of lactose as a highly effective, green, and homogenous
catalyst. It is clear that lactose is an effective catalyst and it provides a facile and
useful method for the synthesis of 4H-tetrahydrobenzo[b]pyrans by condensation of
aromatic aldehydes, malononitrile, and dimedone. Lactose is inexpensive, clean,
safe, nontoxic, and it is easily obtained. Moreover, this method has several other
advantages including, high yields, operational simplicity, and clean and neutral
reaction conditions, which makes it a useful and attractive process for the synthesis
of a wide variety of biologically active compounds.
Acknowledgments We are thankful to the University of Sistan and Baluchestan Research Council for
the partial support of this research.
References
1. G.P. Ellis, in The Chemistry of Heterocyclic Compounds: Chromenes, Chromanones, and Chro-
mones, ed. by A. Weissberger, E.C. Taylor (Wiley, New York, 1977), p. 11
2. A. Shaabani, A. Maleki, A.H. Rezayan, A. Sarvary, Mol. Divers. 15, 41 (2011)
3. A. Shaabani, M. Mohammadpour Amini, S. Ghasemi, R. Ghadari, A.H. Rezayan, Y. Fazaeli, S. Feizi,
Chem. Pharm. Bull. 58, 270 (2010)
4. S. Banerjee, A. Horn, H. Khatri, G.A. Sereda, Tetrahedron Lett. 52, 1878 (2011)
5. S. Banerjee, G. Sereda, Tetrahedron Lett. 50, 6959 (2009)
6. L. Alvey, S. Prado, V. Huteau, B. Saint-JonisMichel, S. Koch, S.M. Cole, F.T. Tillequin, Y.L. Janin,
Bioorg. Med. Chem. 16, 8264 (2008)
7. T. Symeonidis, M. Chamilos, D.J. Hadjipavlou-Litina, M. Kallitsakis, K.E. Litinas, Bioorg. Med.
Lett. 19, 1139 (2009)
8. T. Narender, S. Shweta Gupta, Bioorg. Med. Chem. Lett. 14, 3913 (2004)
9. L. Lakshmi, K. Pandey, A. Kapil, N. Singh, M. Samant, A. Dube, Phytomedicine 14, 36 (2007)
10. D. Kumar, V.B. Reddy, S. Sharad, U. Dube, S. Kapur, Eur. J. Med. Chem. 44, 3805 (2009)
11. A.M. El-Agrody, M.H. El-Hakium, M.S. Abd El-Latif, A.H. Fekry, E.S.M. El-Sayed, K.A. El-
Gareab, Acta Pharm. 50, 111 (2000)
12. C.S. Konkoy, D.B. Fick, S.X. Cai, N.C. Lan, J. Keana, Chem. Abstr. 134, 29313a (2001)
13. D. Arnesto, W.M. Horspool, N. Martin, A. Ramos, C. Seaone, J. Org. Chem. 54, 3069 (1989)
14. I. Devi, P.J. Bhuyan, Tetrahedron Lett. 45, 8625 (2004)
15. S.J. Tu, H. Jiang, Q.Y. Zhung, C.B. Miu, D.Q. Shi, X.S. Wang, Y. Gao, Chin. J. Org. Chem. 23, 488
(2003)
16. T.S. Jin, A.Q. Wang, F. Shi, L.S. Han, L.B. Liu, T.S. Li, ARKIVOC xiv, 78 (2006)
17. S. Balalaie, M. Shiekh-Ahmadi, M. Barazjanian, Cat. Commun. 8, 1724 (2007)
18. S. Abdolmohammadi, S. Balalaie, Tetrhedron Lett. 48, 3299 (2007)
19. S. Gao, C.H. Tsai, C. Tseng, C.F. Yao, Tetrahedron 64, 9143 (2008)
20. M. Seifi, H. Sheibani, Catal. Lett. 126, 275 (2008)
21. R. Hekmatshor, S. Majedi, K. Bakhtiari, Cat. Commun. 9, 307 (2008)
22. Y.M. Ren, C. Cai, Cat. Commun. 9, 1017 (2008)
23. M.M. Heravi, B.A. Jani, F. Derikvand, F.F. Bamoharram, H.A. Oskooie, Cat. Commun. 10, 272
(2008)
24. J.M. Khurana, S. Kumar, Tetrahedron Lett. 50, 4125 (2009)
25. G. Shabitha, K. Harundhathi, K. Sudhakar, B.S. Sartry, J.S. Yadav, Synth. Commun. 39, 433 (2009)
26. W.O. Sun, P. Zhang, J. Fan, S.H. Chen, Z.H. Zhang, Synth. Commun. 40, 587 (2010)
27. L.M. Wang, J.H. Shao, H. Tian, Y.H. Wang, B. Liu, J. Fluor. Chem. 127, 97 (2006)
123

F. N. Sadeh et al.
28. M.M. Khodaei, K. Bahrami, A. Farrokhi, Synth. Commun. 40, 1492 (2010)
29. D. Fang, H.B. Zhang, Z.L. Liu, J. Heterocycl. Chem. 47, 63 (2010)
30. Y. Li, H. Chen, C. Shi, S. Ji, J. Comb. Chem. 12, 231 (2010)
31. S.S. Katkar, M.K. Lande, B.R. Arbad, S.T. Gaikwad, Chin. J. Chem. 29, 199 (2011)
32. J. Zheng, Y.Q. Li, Sch. Res. Libr. 3, 381 (2011)
33. P.P. Salvi, A.M. Mandhare, A.S. Sartape, D.K. Pawar, S.H. Han, S.S. Kolekar, C. R. Chim. 14, 878
(2011)
34. P.A. Grieco (ed.), Organic Synthesis in Water (Blackie Academic and Professional, London, 1998)
35. K. Ramesh, K. Karnakar, G. Satish, Y.V.D. Nageswar, Chin. Chem. Lett. 23, 1331 (2012)
36. N. Hazeri, M.T. Maghsoodlou, F. Mir, M. Kangani, H. Saravani, E. Mollashahi, Chin. J. Catal.
(2014). doi:10.1016/S1872-2067(14)60003-6
37. M. Kangani, N. Hazeri, M. Maghsoodlou, S. Salahi, Res. Chem. Intermed. (2013). doi:10.107/
s11164-013-1365-z
38. M.R. Mousavi, N. Hazeri, M.T. Maghsoodlou, S. Salahi, S.M. Habibi-Khorassani, Chin. Chem. Lett.
24, 411 (2013)
39. N. Hazeri, S.S. Sajadikhah, M.T. Maghsoodlou, M. Norouzi, M. Moin, S. Mohamadian-Souri, J.
Chem. Res. 3, 550 (2013)
40. T.S. Jin, A.Q. Wang, X. Wang, J.S. Zhang, T.S. Li, Synlett 5, 871 (2004)
41. S. Gurumurthi, V. Sundari, R. Valliappan, Eur. J. Chem. 6, 466 (2009)
42. N.M.A. El -Rahaman, A.A. El-Kateb, M.F. Mady, Synth. Commun. 37, 3961 (2007)
123