First example of multicomponent synthesis of 1-ethoxy-3-(4-aryl)-1-phenyl- 1H-benzo[f]chromene derivatives

Article abstract of DOI:10.1016/j.cclet.2011.11.025

A new series of 1-ethoxy-3-(4-aryl)-1-phenyl-1H-benzo[f]chromenes have been synthesized efficiently. The procedure involves the multicomponent reaction of 2-naphthol, acetophenone derivatives, and triethyl orthobenzoate catalyzing by efficient bis(2-anili

Full text of DOI:10.1016/j.cclet.2011.11.025

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Chinese Chemical Letters 23 (2012) 253–256
www.elsevier.com/locate/cclet
First example of multicomponent synthesis of
1-ethoxy-3-(4-aryl)-1-phenyl-1H-benzo[f]
chromene derivatives
b,
c
a
Saman Damavandi a, , Reza Sandaroos , Majid Vafaeei , Hamid Reza Molaei
*
*
a Department of Chemistry, Sarvestan Branch, Islamic Azad University, Sarvestan, Iran
b Department of Chemistry, Faculty of Science, Birjand University, Birjand, Iran
c Department of Chemistry, Mashhad Branch, Islamic Azad University, Mashhad, Iran
Received 9 October 2011
Available online 28 January 2012
Abstract
A new series of 1-ethoxy-3-(4-aryl)-1-phenyl-1H-benzo[f]chromenes have been synthesized efficiently. The procedure involves
the multicomponent reaction of 2-naphthol, acetophenone derivatives, and triethyl orthobenzoate catalyzing by efficient bis(2-
anilinotropone) Ti complex.
# 2011 Saman Damavandi. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords: Multicomponent reaction; Benzo[f]chromen; Catalyst
Natural products containing the chromene structure represent an important class of compounds [1,2]. Chromenes
and fused chromenes are biologically active compounds since they are used as cosmetics and pigments [3,4],
spasmolytic, diuretic, anticoagulant, antianaphylactic [5,6], antibacterial [7], anticancer agents [8], and as potent
apoptosis inducers [9]. Accordingly, many studies have been devoted to the synthesis of the chromene ring systems.
For instance, Claisen rearrangement of alkynyl aryl ethers from propargylic alcohols and naphthols under acid
catalysis to synthesis 2H-1-benzopyran derivatives has been reported [10]. In addition, one-pot synthesis of 1,3-
disubstituted-3H-benzo[f]chromenes has been reported by Yadav and coworkers [11]. Furthermore, several catalysts
have been utilized for the synthesis of substituted 4H-chromenes such as cetyltrimethylammonium chloride [12],
cetyltrimethylammonium bromide under ultrasound irradiation [13], KF/Al2O3 [14], TiCl4 [15], triethylamine [16]
and basic ionic liquids [17]. Moreover, recently we have reported synthesis of 1,3-diaryl-3H-benzo[f]chromenes using
ferric hydrogensulfate [18]. However, synthesis of 1-ethoxy-3-(4-aryl)-1-phenyl-1H-benzo[f]chromene has never
been reported up to now.
The usage of organometallic compounds will provide a broad exploration for new methods and techniques in
organic synthesis. Our interests lie in organometallics [19] prompt us to make a utilization of such catalysts. In the
course of our ongoing research for the efficient synthesis of a variety of heterocyclic compounds [20,21], we developed
* Corresponding authors.
E-mail addresses: Saman_Damavandi@yahoo.com (S. Damavandi), R_Sandaroos@yahoo.com (R. Sandaroos).
1001-8417/$ – see front matter # 2011 Saman Damavandi. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
doi:10.1016/j.cclet.2011.11.025

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S. Damavandi et al. / Chinese Chemical Letters 23 (2012) 253–256
O
Cl
Cl
Ti
EtO
EtO
2
N
OEt
X
OEt
H
H
H
H
O
Toluene, reflux
+ 2 EtOH + H2O
O
H
O
X
4a-4i
X= H (4a); p-Br (4b);p-Cl (4c); p-NO2 (4d); p-Me (4e); p-OMe (4f); p-OH (4g); p-F (4h); o-OMe (4i)
Scheme 1. Synthesis of benzo[f]chromene derivatives 4a–4i.
an efficient synthetic procedure for the synthesis of 1-ethoxy-3-(4-aryl)-1-phenyl-1H-benzo[f]chromenes from one-
pot condensation of 2-naphthol, acetophenone derivatives and triethyl orthobenzoate catalyzing by bis(2-
anilinotropone) Ti complex (Scheme 1).
1. Experimental
All chemicals were purchased from Merck, Fluka and Aldrich Chemical Companies. All yields refer to isolated
products. The products were characterized by their spectral data. IR spectra were recorded on a Shimadzu-IR 470
spectrophotometer. 1H NMR spectra were recorded on a Bruker 250-MHz spectrometer in chloroform as the solvent
and TMS as internal standard. Elemental analysis was performed on a Thermo Finnigan EA1112 elemental analyzer.
Bis(2-anilinotropone) Ti complex was prepared according to our previous report [19].
1.1. General procedure for the synthesis of benzo[f]chromene derivatives 4a-4i
A mixture of 2-naphthol (1 mmol), acetophenone derivatives (1 mmol), and triethyl orthobenzoate (1.1 mmol) and
bis(2-anilinotropone) Ti complex (0.15 mmol) in toluene (8 mL) was stirred at reflux temperature for the appropriate
time. The reaction was monitored by TLC and after completion of the reaction, the catalyst was simply recovered by
filtration and washed by n-hexane. The residue was concentrated in vacuum and the crude product was recrystallized
from EtOH:H2O (3:1) to obtain the pure product.
1-Ethoxy-1,3-diphenyl-1H-benzo[ f ]chromene (4a): After 7.5 h the yield was 87%; 1H NMR (250 MHz, DMSO-d6):
d 7.60–7.40 (m, 6 H, ArH), 7.35–7.05 (m, 10 H, ArH), 5.72 (s, 1 H, CH), 3.62 (q, 2 H, J = 15.2 Hz, CH2), 1.25 (t, 3 H,
J = 15.2 Hz, CH3). EIMS: m/z 378 (M+). Anal. Calcd. for C27H22O2: C, 85.69; H, 5.86%. Found: C, 85.38; H, 5.73%.
3-(4-Bromophenyl)-1-ethoxy-1-phenyl-1H-benzo[ f ]chromene (4b): After 8 h the yield was 86%; 1H NMR
(250 MHz, DMSO-d6): d 7.65–7.45 (m, 5 H, ArH), 7.35–7.08 (m, 10 H, ArH), 5.65 (s, 1 H, CH), 3.57 (q, 2 H,
J = 16.4 Hz, OCH2), 1.22 (t, 3 H, J = 16.4 Hz, CH3). EIMS: m/z 456 (M+). Anal. Calcd. for C27H21BrO2: C, 70.90; H,
4.63%. Found: C, 70.41; H, 4.52%.
1
3-(4-Chlorophenyl)-1-ethoxy-1-phenyl-1H-benzo[ f ]chromene (4c): After 8.5 h the yield was 90%; H NMR
(250 MHz, DMSO-d6): d 7.60–7.42 (m, 4 H, ArH), 7.35–7.10 (m, 11 H, ArH), 5.63 (s, 1 H, CH), 3.55 (q, 2 H,
J = 15.5 Hz, OCH2), 1.18 (t, 3 H, J = 15.8 Hz, CH3). EIMS: m/z 412 (M+). Anal. Calcd. for C27H21ClO2: C, 78.54; H,
5.13%. Found: C, 78.28; H, 5.03%.
1-Ethoxy-3-(4-nitrophenyl)-1-phenyl-1H-benzo[ f ]chromene (4d): After 8 h the yield was 80%; 1H NMR
(250 MHz, DMSO-d6): d 7.95 (m, 2 H, ArH), 7.62–7.40 (m, 5 H, ArH), 7.35–7.25 (m, 3 H, ArH), 7.25–7.05 (m, 5 H,
ArH), 5.90 (s, 1 H, CH), 3.63 (q, 2 H, J = 16.1 Hz, OCH2), 1.16 (t, 3 H, J = 16.3 Hz, CH3). EIMS: m/z 423 (M+). Anal.
Calcd. for C27H21NO4: C, 76.58; H, 5.00; N, 3.31%. Found: C, 76.11; H, 5.08; N, 3.36%.
1
1-Ethoxy-1-phenyl-3-p-tolyl-1H-benzo[ f ]chromene (4e): After 7 h the yield was 87%; H NMR (250 MHz,
DMSO-d6): d 7.60–7.40 (m, 3 H, ArH), 7.35–7.22 (m, 9 H, ArH), 7.20–7.05 (m, 3 H, ArH), 5.55 (s, 1 H, CH), 3.48 (q, 2
H, J = 14.3 Hz, OCH2), 2.24 (s, 3 H, CH3), 1.16 (t, 3 H, J = 14.5 Hz, CH3). EIMS: m/z 392 (M+). Anal. Calcd. for
C28H24O2: C, 85.68; H, 6.16%. Found: C, 85.38; H, 6.05%.
1-Ethoxy-3-(4-methoxyphenyl)-1-phenyl-1H-benzo[ f ]chromene (4f): After 9 h the yield was 90%; 1H NMR
(250 MHz, DMSO-d6): d 7.63–7.35 (m, 3 H, ArH), 7.30–7.15 (m, 8 H, ArH), 7.10–7.02 (m, 4 H, ArH), 5.77

S. Damavandi et al. / Chinese Chemical Letters 23 (2012) 253–256
255
..
HO
O
X
X
Ti
H2C
H3C
OEt
OEt
OEt
OEt
OEt
H
OEt
..
OH
O
Ti
O
X
1
X
X
OEt
OEt OH
O
OEt
Ti
-H2O
O
O
OH
4
3
2
Scheme 2.
(s, 1 H, CH), 3.72 (s, 3 H, OCH3), 3.44 (q, 2 H, J = 15.8 Hz, OCH2), 1.14 (t, 3 H, J = 15.6 Hz, CH3). EIMS: m/z 408
(M+). Anal. Calcd. for C28H24O3: C, 82.33; H, 5.92%. Found: C, 82.21; H, 5.83%.
4-(1-Ethoxy-1-phenyl-1H-benzo[ f ]chromen-3-yl)phenol (4g): After 7 h the yield was 88%; 1H NMR (250 MHz,
DMSO-d6): d 9.45 (s, 1 H, OH), 7.60–7.45 (m, 2 H, ArH), 7.35–7.20 (m, 10 H, ArH), 7.15–7.05 (m, 3 H, ArH), 5.65 (s,
1 H, CH), 3.52 (q, 2 H, J = 15 Hz, OCH2), 1.10 (t, 3 H, J = 15.3 Hz, CH3). EIMS: m/z 394 (M+). Anal. Calcd. for
C27H22O3: C, 82.21; H, 5.62%. Found: C, 81.98; H, 5.54%.
1-Ethoxy-3-(4-fluorophenyl)-1-phenyl-1H-benzo[ f ]chromene (4h): After 6 h the yield was 87%; 1H NMR
(250 MHz, DMSO-d6): d 7.60–7.50 (m, 4 H, ArH), 7.35–7.15 (m, 11 H, ArH), 5.57 (s, 1 H, CH), 3.40 (q, 2 H,
J = 13.7 Hz, OCH2), 1.07 (t, 3 H, J = 13.7 Hz, CH3). EIMS: m/z 396 (M+). Anal. Calcd. for C27H21FO2: C, 81.80; H,
5.34%. Found: C, 81.63; H, 5.27%.
1-Ethoxy-3-(2-methoxyphenyl)-1-phenyl-1H-benzo[ f ]chromene (4i): After 6 h the yield was 85%; 1H NMR
(250 MHz, DMSO-d6): d 7.55–7.45 (m, 4 H, ArH), 7.40–7.25 (m, 8 H, ArH), 7.25–7.05 (m, 3 H, Ar), 5.60 (s, 1 H, CH),
3.72 (s, 3 H, OMe), 3.41 (q, 2 H, J = 14.1 Hz, OCH2), 1.07 (t, 3 H, J = 14.1 Hz, CH3). EIMS: m/z 408 (M+). Anal.
Calcd. for C28H24O3: C, 82.33; H, 5.92%. Found: C, 82.22; H, 5.86%.
2. Results and discussion
Initial experiment was performed by the one-pot reaction of 2-naphthol, acetophenone and triethyl orthobenzoate
as the model reaction. When 2-naphthol (1 mmol) was treated with acetophenone (1 mmol) and triethyl orthobenzoate
(1 mmol) in the presence of a catalytic amount of bis(2-anilinotropone) Ti complex (0.015 mmol) at reflux condition
in toluene, the desired 1-ethoxy-1,3-diphenyl-1H-benzo[f]chromene (4a) was obtained in 87% yield. No
corresponding benzo[f]chromene was isolated in the absence of the catalyst highlighting the role of the catalyst
to promote the reaction. Encouraged by this success, we then extended the model reaction using different derivatives of
acetophenone. It was revealed that the electronic nature of substituted groups on acetophenone does not significantly
affect the reaction times as well as chemical yields.
The reasonable mechanism for the synthesis of 1-ethoxy-3-(4-aryl)-1-phenyl-1H-benzo[f]chromenes is illustrated
in Scheme 2. Naphthol C-alkylation via a Knoevenagel addition between 2-naphthol and triethyl orthobenzoate results
in a,b-unsaturated compound (1), possessing ethoxy substituent on its b position. Nucleophilic attack of enolized
acetophenone on b-position of the intermediate 1, gives the intermediate 2. Intramolecular cyclization of 2 gives 3
which undergoes dehydration to furnish product 4.
3. Conclusion
In summary, we have demonstrated an efficient, novel and clean synthesis of a new series of benzo[f]
chromene derivatives. 1-Ethoxy-3-(4-aryl)-1-phenyl-1H-benzo[f]chromenes were synthesized efficiently through

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S. Damavandi et al. / Chinese Chemical Letters 23 (2012) 253–256
multi-component cyclocondensations of 2-naphthol, acetophenone derivatives, and triethyl orthobenzoate
catalyzed by bis(2-anilinotropone) Ti complex.
References
¨
[1] A. Domling, Curr. Opin. Chem. Biol. 6 (2002) 306.
[2] B.M. Trost, Angew. Chem. Int. Ed. Engl. 34 (1995) 259.
[3] G.P. Ellis, A. Weissberger, E.C. Taylor (Eds.), The Chemistry of Heterocyclic Compounds. Chromenes, Chromanes, and Chromones, Wiley,
New York, 1997, p. 581.
[4] J. Poupaert, P. Carato, E. Colacino, Curr. Med. Chem. 12 (2005) 877.
[5] D. Triggle, J. Cell. Mol. Neurobiol. 23 (2003) 293.
[6] M. Kidwai, S. Saxena, M.K.R. Khan, et al. Bioorg. Med. Chem. Lett. 15 (2005) 4295.
[7] S.J. Mohr, M.A. Chirigos, F.S. Fuhrman, et al. Cancer Res. 35 (1975) 3750.
[8] M. Gao, K.D. Miller, G.D. Hutchins, et al. Appl. Radiat. Isot. 68 (2009) 110.
[9] X. Xu, J. Liu, L. Liang, et al. Adv. Synth. Catal. 351 (2009) 2599.
[10] J.S. Yadav, B.V.S. Reddy, S.K. Biswas, Tetrahedron Lett. 50 (2009) 5798.
[11] R. Ballini, F. Bigi, M.L. Conforti, Catal. Today 60 (2000) 305.
[12] T.S. Jin, J.C. Xiao, S.J. Wang, et al. Ultrason. Sonochem. 11 (2004) 393.
[13] X. Wang, D. Shi, S. Tu, Synth. Commun. 34 (2004) 509.
[14] K.B. Sunil, N. Srinivasulu, R. Udupi, et al. Russ. J. Org. Chem. 42 (2006) 1813.
[15] A.M. Shestopalov, Y.M. Emelianova, V.N. Nesterov, Russ. Chem. Bull. 51 (2002) 2238.
[16] K. Gong, H.L. Wang, L. Fang, Catal. Commun. 9 (2008) 650.
[17] Y.M. Ren, C. Cai, Catal. Commun. 9 (2008) 1017.
[18] H. Eshghi, G.H. Zohuri, S. Damavandi, et al. Chin. Chem. Lett. 21 (2010) 1423.
[19] R. Sandaroo, S. Damavandi, A. Nazif, et al. Chin. Chem. Lett. 22 (2011) 213.
[20] S. Damavandi, Heterocycl. Commun. 17 (2011) 79.
[21] S. Damavandi, R. Sandaroos, Heterocycl. Commun. 17 (2011) 121.