An expeditious regioselective synthesis of novel bioactive indole-substituted chromene derivatives via one-pot three-component reaction

Article abstract of DOI:10.1016/j.bmcl.2012.07.059

Novel fused 1H-benzo[f]chromen-indole derivatives were synthesized regioselectivly in good to high yields by triethyl amine catalyzed condensation of 3-cyanoacetylindoles, β-naphthol and aryl aldehydes in methanol under ultrasounic irradiations and conven

Full text of DOI:10.1016/j.bmcl.2012.07.059

Bioorganic & Medicinal Chemistry Letters 22 (2012) 5956–5960
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Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
An expeditious regioselective synthesis of novel bioactive
indole-substituted chromene derivatives via one-pot three-component reaction
Roghayeh Hossein nia a, Manouchehr Mamaghani a, , Khalil Tabatabaeian a, Farhad Shirini a, Mehdi Rassa b
⇑
a Department of Chemistry, Faculty of Sciences, University of Guilan, PO Box 41335-1914, Rasht, Iran
b Department of Biology, Faculty of Sciences, University of Guilan, PO Box 41335-1914, Rasht, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
Novel fused 1H-benzo[f]chromen-indole derivatives were synthesized regioselectivly in good to high
yields by triethyl amine catalyzed condensation of 3-cyanoacetylindoles, b-naphthol and aryl aldehydes
in methanol under ultrasounic irradiations and conventional conditions. The easy work-up of the prod-
ucts, rapidity, and mild reaction conditions are notable features of this protocol. The antibacterial activity
of the selected products was examined. Some products showed promising activities.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 20 April 2012
Revised 29 June 2012
Accepted 13 July 2012
Available online 24 July 2012
Keywords:
1H-benzo[f]chromen-indole
3-Cyanoacetylindoles
b-Naphthol
Ultrasound
Antibacterial activity
CN
Functionalized nitrogen and oxygen containing heterocycles
play a predominant role in medicinal chemistry and they have been
intensively used as scaffolds for drug development. Chromene
derivatives as an important class of compounds with diverse bio-
logical properties and therapeutic application have attracted many
attentions.1 They are prominent natural products, widely distrib-
uted among many plants.2 Natural derivatives of chromene also ex-
hibit a wide range of valuable physiological activities.3 Substituted
chromenes can bind to 5HT receptors, acting as antagonists4 and
were also reported as MAO and human b-secretase inhibitors.5,6
They have considerable biological importance, especially as poten-
tially useful pesticides,7,8 for its antihypoxic, hypotensive and
antiallergic properties,9 and inhibitors of cell proliferation with
potential anticancer effects.10 Chromene compounds display high
antifungal and antibacterial activities.11–14 Furthermore, chromene
derivatives have been found to possess anti-picornavirus proper-
ties, binding to virus capsids.15 They have strong antioxidant activ-
ities16 and also represent useful synthetic building blocks in organic
and medicinal chemistry.17–22 Thus, several synthetic pathways
have been used to prepare chromene derivatives.23
O
OH
R2
+
ArCHO
+
R1
N
H
1
2
3
Et3N
Ultrasound
or
MeOH
Reflux
R2
Ar
O
O
HN
R1
H2N
R1 = H, Me: R2 = H, Br
4
Ar = 4-FC6H4, 4-ClC6H4, 4-BrC6H4, 2,4-Cl2C6H3, 3-O2NC6H4, 3-MeOC6H4, 1,4-phenylene,
3-pyridyl, 2-naphthyl
Scheme 1. Synthesis of 1H-benzo[f]chromen-indole derivatives (4a–m).
On the other hand the indole nucleus is probably the most well-
known heterocycle, being a common and important feature of a
variety of natural products and medicinal agents.24 Compounds
carrying the indole moiety exhibit antibacterial and antifungal
activities.25
Therefore, it would be beneficial to design a system which com-
bines bio-labile nuclei such as indole and chromene in a molecular
framework and to evaluate their additive microbial effects.
As a consequence of our recent interests aimed at developing
new selective and environmentally benign methodologies for the
synthesis of heterocylic compounds,26 and guided by the observa-
tion that the presence of two or more different heterocyclic moie-
⇑
Corresponding author. Tel.: +98 131 7270344; fax: +98 131 3233262.
E-mail address: m-chem41@guilan.ac.ir (M. Mamaghani).
0960-894X/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2012.07.059

R. Hossein nia et al. / Bioorg. Med. Chem. Lett. 22 (2012) 5956–5960
5957
Table 1
Synthesis of products (4a–m) in conventional and Sonochemical methods
Entry
4
R1
R2
Ar
Conventional method
Sonochemical method
Time (min)
Yielda (%)
Time (min)
Yielda (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
4a
4b
4c
4d
4e
4f
4g
4h
4i
H
H
H
H
H
H
H
H
H
H
H
H
Me
H
H
H
H
H
H
H
Br
Br
Br
Br
Br
H
4-FC6H4
4-ClC6H4
4-BrC6H4
60 (4)b
60
90 (5)
50
45
80
89 (15)b
85
4
5
5
4
5
7
7
7
6
90
90
80
90
95
80
70
80
90
93
70
75
92
75 (8)b
90
2,4-Cl2C6H3
3-O2NC6H4
3-MeOC6H4
1,4-Phenylene
4-ClC6H4
2,4-Cl2C6H3
3-Pyridyl
2-Naphthyl
1,4-Phenylene
2,4-Cl2C6H3
91
78
72
80
90
60
70
85
4j
4k
4l
40 (5)b
90 (12)b
60
80 (10)b
68 (20)b
70
5
12
10
5
4m
80 (5)b
88 (10)b
a
Isolated yields.
Isolated yields at the same time as sonochemical method.
b
CN
CN
O
O
R2
R2
Ar
ArCHO
+
R1
R1
N
N
H
H
1
3
5
OH
2
R2
R2
Ar
O
Ar
O
CN
HO
HN
R1
O
HN
R1
H2N
4
6
Scheme 2. Mechanism of synthesis of products 4a–m.
O
NH2
NH
To optimize the reaction conditions, preparation of 4a was per-
formed as a model reaction. Therefore, the reaction of equimolar
amount of premade 3-cyanoacetylindoles (1),27 b-naphthol (2),
and 4-fluorobezaldehyde (3a) in the presence of various catalysts
(Et3N, DBU, pipyridine, Fe3+-montmorillonite, p-TSA, AcOH) and
different solvents (MeOH, acetonitrile, 1,4-dioxane, CH2Cl2, DMF
and EtOH) was studied at reflux condition. Excellent results, with
high yield (89%), and lower reaction time (60 min) were obtained
when triethyl amine (20 mol %) was used as catalyst in refluxing
methanol. Various chromene derivatives were prepared under
the optimized conditions. Under these conditions, the reaction pro-
ceeded smoothly providing a wide range of functionalized chrom-
enes (Table 1). Varification of the results in Table 1 revealed that
electron-releasing- groups provide products with lower yields,
and electron-withdrawing substituents improved the efficiency
of the reaction, providing the desired products with much higher
yields.
O
O
R2
R2
NH
O
NH2
R2 = H, Br
Figure 1. Structures of 4g and 4l.
ties in a single molecule often remarkably enhances the biocidal
profile, we investigated one-pot, three-component reaction of 3-
cyanoacetylindoles (1), b-naphthol (2), and various aryl aldehydes
(3) to afford a series of 1H-benzo[f]chromen-2-yl)(1H-indol-3-
yl)methanones (Scheme 1).
Based on the above results, mechanistically the formation of the
products (4a–m) can be visualized by initial Knoevenagel conden-
sation of 3-cyanoacetylindoles (1) and aryl aldehydes (3a–m), fol-
lowed by a Michael type nucleophilic addition of b- naphthol ring

5958
R. Hossein nia et al. / Bioorg. Med. Chem. Lett. 22 (2012) 5956–5960
Table 2
Antimicrobial activity of the compounds (4a–m)
Entry
Compound
Conc. of compound
lg/well
Antimicrobial activity (zone of inhibition in mm)
Salmonella enterica
Micrococcus luteus
Bacillus subtilis
Pseudomonas aeruginosa
1
2
3
4
5
6
7
8
9
10
11
12
13
4a
4b
4c
4e
4f
4g
4h
4i
12
12
12
12
12
12
12
12
12
12
12
15
30
6
33 (30)a
8
11
—
—
8
—
—
6
—
—
6
—
12
14
—
—
—
—
17 (19)a
—
—
—
—
—
—
6
—
10
29 (31)a
35 (37)a
7
17 (18)a
—
—
—
—
46 (45)a (45)b
30 (32)a (31)b
11
4j
4l
4m
30 (32)a (32)b
50 (50)a (50)b
10
—
17 (15)a
8
7
16 (15)a
10
Erythromycin
Tetracycline
16
18
a
Data of duplicated experiments.
Data of triplicated experiments.
b
to the enone intermediate (5), and subsequent cyclodehydration to
furnish regioselectively the desired compounds (Scheme 2).
The regioselectivity observed in this reaction may be rational-
ized by hard-soft-acid-base interaction in reaction intermediate 6
in which hydroxyl group prefer CN functionality rather than
carbonyl group.
reaction induced by ultrasound offered better yields and much
lower reaction times than the conventional heating.
This method involves mild reaction conditions and easy work-
up. These products were also evaluated for their antibacterial
activities. Most of the compounds exhibited excellent antibacterial
activity against Micrococcus luteus.
Interestingly this one-pot multicomponent approach also affor-
ded an efficient protocol for the synthesis of bis-(chromen-indoles)
4g and 4l (Fig. 1) in good yields (70–72%) (Table 1).
Acknowledgment
Recently, there has been an increasing interest in using ultra-
sonic irradiations as a clean, green and environmentally benign
source of energy for the preparation of organic compounds of
synthetic and biological value.28 Encouraged further by our recent
findings in facilitating the synthesis of important heterocyclic com-
pounds by exploiting ultrasound methodology,26a,b we investi-
gated the effect of ultrasonic irradiation on the synthesis of novel
The authors are grateful to the Research Council of University of
Guilan for the financial support of this research work.
References and notes
1. (a) Robert, S.; Bertolla, C.; Masereel, B.; Dogné, J.; Pochet, L. J. Med. Chem. 2008,
51, 3077; (b) Abrunhosa, L.; Costa, M.; Areias, F.; Venâncio, A.; Proença, F. J. Ind.
Microbiol. Biotechnol. 2007, 34, 787; (c) Chimenti, F.; Bizzarri, B.; Bolasco, A.;
Secci, D.; Chimenti, P.; Carradori, S.; Granese, A.; Rivanera, D.; Lilli, D.; Zicari, A.;
Scaltrito, M.; Sisto, F. Bioorg. Med. Chem. Lett. 2007, 17, 3065; (d) Kostova, I.
Mini-Rev. Med. Chem. 2006, 6, 365; (e) Nayyar, A.; Jain, R. Curr. Med. Chem. 2005,
12, 1873; (f) Fylaktakidou, K.; Hadjipavlou-Litina, K.; Litinas, K.; Nicolaides, D.
Curr. Pharm. Des. 2004, 10, 3813; (g) Asres, K.; Seyoum, A.; Veeresham, C.;
Bucar, F.; Gibbons, S.; Wilson, W.; Boykin, D. Phytother Res. 2005, 19, 557; (h)
Jain, N.; Kanojia, R.; Xu, J.; Jian-Zhong, G.; Pacia, E.; Lai, M.; Du, F.; Musto, A.;
Allan, G.; Hahn, D.; Lundeen, S.; Sui, Z. J. Med. Chem. 2006, 49, 3056; (i)
Frédérick, R.; Robert, S.; Charlier, C.; Ruyck, J.; Wouters, J.; Pirotte, B.; Masereel,
B.; Pochet, L. J. Med. Chem. 2005, 48, 7592.
2. Ellis, G. P. The Chemistry of Heterocyclic Compounds; Wiley, 1977. 31.
3. Horton, D. A.; Bourne, G. T.; Smythe, M. L. Chem. Rev. 2003, 103, 893.
4. Garino, C.; Tomita, T.; Pietrancosta, N.; Laras, Y.; Rosas, R.; Herbette, G.; Mai-
gret, B.; Quéléver, G.; Iwatsubo, T.; Kraus, J. J. Med. Chem. 2006, 49, 4275; (b)
Garino, C.; Tomita, T.; Pietrancosta, N.; Laras, Y.; Rosas, R.; Herbette, G.;
Maigret, B.; Quéléver, G.; Iwatsubo, T.; Kraus, J. Bioorg. Med. Chem. 2006, 16,
1995.
5. (a) Santana, L.; Uriarte, E.; González-Dıáz, H.; Zagotto, G.; Soto-Otero, R.;
Médez-Álvarez, E. J. Med. Chem. 2006, 49, 1149; Catto, M.; Nicolotti, O.;
Leonetti, F.; Carotti, A.; Favia, A.; Soto-Otero, R.; Méndez-Álvarez, E.; Carotti, A.
J. Med. Chem. 2006, 49, 4912; (c) Bruhlmann, C.; Ooms, F.; Carrupt, P.; Testa, B.;
Catto, M.; Leonetti, F.; Altomare, C.; Carotti, A. J. Med. Chem. 2001, 44, 3195; (d)
Chimenti, F.; Secci, D.; Bolasco, A.; Chimenti, P.; Bizzarri, B.; Granese, A.;
Carradori, S.; Yánez, M.; Orallo, F.; Ortuso, F.; Alcaro, S. J. Med. Chem. 2009, 52,
1935.
6. Maier, D.; Briner, C.; Ding, M.; Powell, M.; Jiang, Q.; Hill, G.; Heys, J.; Elmore, C.;
Pierson, M.; Mrzljak, L. J. Pharmacol. Exp. Ther. 2009, 330, 342–351.
7. Bowers, W. S. Biochem Pharmacology; Gilbert, L. I., Kerkut, G. A., Eds.;
Pergamon: Oxford, 1985; Vol. 8, p 551.
1H-benzo[f]chromen-2-yl)(1H-indol-3-yl)methanone
(4a–m).
Therefore an equimolar mixture of reactants 1, 2 and 3 in the pres-
ence of triethyl amine (20 mol %) in methanol (5 mL) were placed
in a Pyrex-glass open vessel and irradiated at 65 °C by ultrasonic
irradiations (40 kHz) to furnish the desired products (4a–m) in
very short reaction times (4–12 min) and good to excellent yields
(70–95%) (Table 1).
The structures of all the products were fully characterized by
spectroscopic (IR, 1H NMR, 13C NMR) and elemental analyses.29
The antibacterial activity of synthesized compounds 4a–m was
examined30 using Salmonella enterica (SE), Micrococcus luteus (ML),
Bacillus subtillis (BS) and Pseudomonas aeruginosa (PS). The results
are tabulated in Table 2. For comparison, two routinely used anti-
biotics, tetracycline and erythromycin, were also included. The re-
sults revealed that most of compounds 4a–m exhibit strong
activities towards Micrococcus luteus (a Gram-negative bacterium).
In addition, the results indicate that compounds 4a, 4e, 4h and 4l
have moderate growth inhibitory activities against B. subtilis (a
Gram-positive bacterium) as revealed by the diameters of their
inhibition zones. Among these substances, 4f and 4m show
moderate growth inhibitory effects on Pseudomonas aeruginosa (a
Gram-negative bacterium). Also 4a, 4b, 4j and 4m have moderate
activities against Salmonella enterica. All of the compounds listed
in Table 2 exhibit weak antimicrobial activities against B. subtilis.
In conclusion, we have developed a simple, efficient and versa-
tile one-pot three-component protocol for the synthesis of novel
derivatives of functionalized indole-substituted chromene deriva-
tives 4a–m in a regiochemical manner by the reaction of 3-cyano-
acetylindoles, b-naphthol, and arylaldehydes using triethyl amine
under ultrasonic irradiations and conventional conditions. The
8. Bowers, W. S.; Ohta, T.; Cleere, J. S.; Marsella, P. A. Science 1976, 193, 542.
9. (a) Aggarwal, Bharat B. Chem. Abstr. 123,188,575 PCT Int. Appl. WO 9518606
A1, 1995.; (b) Chem. Abstr. 123,276,072 U.S.S.R. SU 1746675 A1, 1994.
10. William, K.; Shailaja, K.; Songchun, J.; Hong, Z.; Jianghong, Z.; Shaojuan, J.;
Lifen, X.; Candace, C.; Re´al, D.; Nancy, B.; Louis, V.; Sylvie, C.; Jennifer, D.;
Giorgio, A.; Denis, L.; Serge, L.; Henriette, G.; Ben, T.; John, D.; Sui, X. C. Bioorg.
Med. Chem. Lett. 2005, 15, 4745.
11. Ahmed, M. M.; El-Saghier, M. B.; Naili, B. K.; Rammash, N. A.; Saleh Khaled, M.
K. Arkivoc 2007, xvi, 83.

R. Hossein nia et al. / Bioorg. Med. Chem. Lett. 22 (2012) 5956–5960
5959
12. Laurin, P.; Klich, M.; Dupis-Hamelin, C.; Mauvais, P.; Lassaigne, P.; Bonnefoy,
A.; Musicki, B. Bioorg. Med. Chem. Lett. 1999, 9, 2079.
13. Tarik, E. A.; Salah, A. A. A.; Hafez, M. E.; Faten, I. H.; Ali, Z. E. Turk. J. Chem. 2008,
32, 365.
14. Tilak, R.; Richa, K. B.; Rakesh, K. S.; Vivek, G.; Deepak, S.; Mohan, P. S. I. Eur. J.
Med. Chem. 2009, 44, 3209.
15. Cinzia, C.; Nicoletta, D. Bioorg. Med. Chem. 2010, 18, 6480.
16. Okram, M. S.; Nepram, S. D.; Dhanaraj, S. T.; Gurumayum, J. S. Eur. J. Med. Chem.
2010, 45, 2250.
1H, J = 8.0 Hz, Ar-H), 7.60 (d, 1H, J = 8.0 Hz), 7.72 (m, 1H, Ar-H), 7.81 (d, 1H,
J = 1.2 Hz, @CH-NH), 7.97 (d, 2H, J = 8.8 Hz, Ar-H), 8.79 (br., s, 2H, NH2), 11.68
(br., s, 1H, NH); 13C NMR (100 MHz, DMSO-d6): dC (ppm) 37.4, 89.3, 112.7,
117.2, 118.0119.6, 120.1, 120.7, 120.8, 122.4, 123.2, 125.4, 125.7, 127.7, 128.9,
129.0, 129.2, 129.5, 130.5, 131.3, 131.8, 136.4, 146.5, 147.6, 162.3, 187.9; Anal.
Cald for C28H19BrN2O2 (495.37): C, 67.89; H, 3.87; N, 5.66%. Found: C, 67.72; H,
3.80 N, 5.51%.
(3-Amino-1-(2,4-dichlorophenyl)-1H-benzo[f]chromen-2-yl)(1H-indol-3-
yl)methanone (4d). White solid; mp 229–230 °C; IR (KBr) (m
max/cmÀ1); 3443,
17. Nohara, A.; Kuriki, H.; Saijo, T.; Sugihara, H.; Kanno, M.; Sanno, Y. J. Med. Chem.
1977, 20, 141.
18. Nohara, A.; Umetani, T.; Ukawa, K.; Sanno, Y. Chem. Pharm. Bull. 1974, 22, 2959.
19. Ukawa, K.; Ishiguro, T.; Wada, Y.; Nohara, A. Heterocycles 1931, 1986, 24.
20. Hsung, R. P. J. Org. Chem. 1997, 62, 7904.
21. Hsung, R. P.; Zificsak, C. A.; Wei, L.-L.; Zehnder, L. R.; Park, F.; Kim, M.; Tran, T. T.
J. Org. Chem. 1999, 64, 8736.
22. Sosnovskikh, V. Ya.; Irgashev, R. A.; Levchenko, A. A. Tetrahedron 2008, 64,
6607.
3166, 1629, 1523, 1437, 1236, 1188, 1094, 1019, 805, 744; 1H NMR (400 MHz,
DMSO-d6): dH (ppm) 6.44 (s, 1H, CH), 6.88 (t, J = 7.6 Hz, 1H, Ar-H), 6.94 (d, 1H,
J = 8.8, Hz, Ar-H), 7.12–7.17 (m, 2H, Ar-H), 7.25 (d, 1H, J = 4.0 Hz, @CH-NH),
7.43–7.53 (m, 5H, Ar-H), 7.72–7.75 (m, 2H, Ar-H), 7.95–8.00 (m, 2H, Ar-H), 8.58
(br., s, 2H, NH2), 11.65 (br., s, 1H, NH); 13C NMR (100 MHz, DMSO-d6): dC
(ppm) 35.4, 89.1, 112.5, 117.4, 118.6, 119.8, 120.1, 120.7, 122.2, 123.0, 125.5,
125.9, 127.7, 128.5, 129.2, 129.3, 129.4, 129.8, 130.7, 131.2, 131.4, 131.8, 131.9,
136.5, 144.2, 147.7, 161.4, 188.4; Anal. Cald for C28H18Cl2N2O2 (485.36): C,
69.29; H, 3.74; N, 5.77%. Found: C, 69.20; H, 3.75; N, 5.89%.
23. (a) Puri, S.; Kaur, B.; Parmar, A.; Kumar, H. Ultrason. Sonochem. 2009, 16, 705;
(b) Ullah, E.; Appel, B.; Fischerb, Ch.; Langera, P. Tetrahedron 2006, 62, 9694; (c)
Adib, M.; Sheikhi, E.; Kavoosi, A.; Bijanzadeh, H. R. Tetrahedron 2010, 66, 9263;
(d) Li, J.; Tang, W.; Lu, L.; Su, W. Tetrahedron Lett. 2008, 49, 7117; (e) Devi, I.;
Bhuyan, P. J. Tetrahedron Lett. 2004, 45, 8625; (f) Abdolmohammadia, Sh.;
Balalaieb, S. Tetrahedron Lett. 2007, 48, 3299.
(3-Amino-1-(3-nitrophenyl)-1H-benzo[f]chromen-2-yl)(1H-indol-3-yl)methanone
(4e). Yellow solid; mp 213–215 °C; IR (KBr) (m
max/cmÀ1); 3434, 3138, 1632,
1524, 1438, 1344, 1195, 1086, 1024, 808, 757; 1H NMR (400 MHz, DMSO-d6):
dH (ppm) 6.13 (s, 1H, CH), 6.97 (t, 1H, J = 7.4 Hz, Ar-H), 7.15–7.27 (m, 2H, Ar-H),
7.34 (t, 1H, J = 7.8 Hz, Ar-H), 7.45–7.58 (m, 6H, Ar-H), 7.72 (d, 1H, J = 7.2 Hz, Ar-
H), 7.83–7.87 (m, 2H, Ar-H), 7.97–8.27 (m, 2H, Ar-H), 8.84 (br., s, 2H, NH2),
11.74 (br., s, 1H, NH); 13C NMR (100 MHz, DMSO-d6): dC (ppm) 37.7, 89.1,
112.7, 117.3, 118.0, 119.2, 120.4, 120.9, 121.3, 121.7, 122.5, 123.0, 125.6, 127.9,
128.8, 129.3, 130.0, 130.5, 131.3, 133.5, 136.5, 147.7, 148.1, 149.1, 162.2,
188.0; Anal. Cald for C28H19N3O4 (461.47): C, 72.88; H, 4.15; N, 9.11%. Found: C,
72.67; H, 4.10; N, 9.21%.
24. Houlihan, W. J.; Remers, W. A.; Brown, R. K. Indoles: Part I; Wiley: New York,
NY, 1992.
25. Sundberg, R. J. The Chemistry of Indoles; Academic: New York, NY, 1996.
26. Mamaghani, M.; Loghmanifar, A.; Taati, R. Ultrason. Sonochem. 2011, 18, 45; (b)
Nikpassand, M.; Mamaghani, M.; Shirini, F.; Tabatabaeian, K. Ultrason.
Sonochem. 2010, 17, 310; (c) Nikpassand, M.; Mamaghani, M.; Tabatabaeian,
K. Molecules 2009, 14, 1468; (d) Samimi, H. A.; Mamaghani, M.; Tabatabaeian,
K. J. Heterocycl. Chem. 2008, 45, 1765; (e) Samimi, H. A.; Mamaghani, M.;
Tabatabaeian, K. Heterocycles 2008, 75, 2825.
27. Slätt, J.; Romero, I.; Bergman, J. Synthesis 2004, 16, 2760.
28. (a) Mantu, D.; Moldoveanu, C.; Nicolescu, A.; Deleanu, C.; Mangalagiu, I. I.
Ultrason. Sonochem. 2009, 16, 452; (b) Li, J.-T.; Yin, Y.; Li, L.; Sun, M.-X. Ultrason.
Sonochem. 2010, 17, 11; (c) Pizzuti, L.; Martins, P. L. G.; Ribeiro, B. A.; Quina, F.
H.; Pinto, E. A.; Flores, F. C.; Venzke, D.; Pereira, C. M. P. Ultrason. Sonochem.
2010, 17, 34.
29. General: Melting points were measured on an electrothermal 9100 apparatus.
IR spectra were determined on a Shimadzo IR-470 spectrometer. 1H NMR and
13C NMR spectra were recorded on a 400 MHz Bruker DRX-400 in DMSO-d6 as
solvent and TMS as an internal standard. Chemical shifts on 1H and 13C NMR
were expressed in ppm downfield from tetramethylsilane. Sonication was
performed in Elmasonic S 40H ultrasonic cleaning unit. Elemental analyses
were done on a Carlo-Erba EA1110CNNO-S analyser and agreed with the
calculated values. All the chemicals were purchased from Merck and used
without further purification. All solvents used were dried and distilled
according to standard procedures.
(3-Amino-1-(3-methoxyphenyl)-1H-benzo[f]chromen-2-yl)(1H-indol-3-yl)
methanone (4f). White solid; mp 235–237 °C; IR (KBr) (m
max/cmÀ1); 3444,
3150, 1626, 1529, 1434, 1261, 1193, 1094, 1036, 873, 748; 1H NMR (400 MHz,
DMSO-d6): dH (ppm) 3.45 (s, 3H, OCH3), 6.16 (s, 1H, CH), 6.25 (s, 1H, Ar-H),
6.34 (d, 1H, J = 7.6 Hz, Ar-H), 6.57 (d, 1H, J = 8.0 Hz, Ar-H), 6.95–7.00 (m, 2H, Ar-
H), 7.19 (d, 1H, J = 7.6 Hz, Ar-H), 7.43–7.47 (m, 3H, Ar-H), 7.55 (d, 1H, J = 8.0 Hz,
Ar-H), 7.62 (d, 1H, J = 8.0 Hz, Ar-H), 7.75 (d, 1H, J = 8.0 Hz, Ar-H), 7.82 (d, 1H,
J = 2.0 Hz, @CH-NH), 7.97 (d, 2H, J = 8.8 Hz, Ar-H), 8.80 (br., s, 2H, NH2), 11.68
(br., s, 1H, NH); 13C NMR (100 MHz, DMSO-d6): dC (ppm) 37.7, 55.0, 89.7,
111.4, 112.6, 113.0, 117.2, 118.1, 119.0, 120.5, 120.7, 120.8, 122.4, 123.4, 125.3,
125.8, 127.5, 128.7, 129.1, 129.3, 130.0, 130.7, 131.3, 136.4, 147.7, 148.7, 159.5,
162.4, 188.0; Anal. Cald for C29H22N2O3 (446.5): C, 78.01; H, 4.97; N, 6.27%.
Found: C, 78.18; H, 4.85; N, 6.39%.
Bis-(3-amino-1-phenyl-1H-benzo[f]chromen-2-yl)(1H-indol-3-yl)methanone (4g).
White solid; mp 228–230 °C; IR (KBr) (m
max/cmÀ1); 3427, 1634, 1519,
1438,1232, 1186, 1092, 1022, 810, 747, 694; 1H NMR (400 MHz, DMSO-d6):
dH (ppm); 5.96 (s, 2H, CH), 6.48 (s, 4H, Ar-H), 6.86 (t, 2H, J = 7.4 Hz, Ar-H), 7.13
(t, 2H, J = 7.4 Hz, Ar-H), 7.35–7.45 (m, 6H, Ar- H), 7.47–7.50 (m, 4H, Ar-H), 7.63
(m, 4H, Ar-H), 7.91 (m, 4H, Ar-H), 8.64 (br., s, 4H, NH2), 11.54 (br., s, 2H, NH);
13C NMR (100 MHz, DMSO-d6): dC (ppm) 36.9, 89.7, 112.5, 117.2, 117.8, 120.7,
120.9, 122.3, 123.2, 125.3, 125.7, 126.8, 127.5, 128.8, 129.1, 130.5, 131.2, 136.3,
144.6, 147.8, 162.7, 187.6; Anal. Cald for C50H34N4O4 (754.83): C, 79.56; H,
4.54; N, 7.42%. Found: C, 79.43; H, 4.65; N, 7.28%.
General procedure for the synthesis of (4a–k): A mixture of equimolar amounts of
3-cyanoacetylindoles [27] (1 mmol), b-naphthol (1 mmol) and arylaldehydes
(1 mmol) in absolute methanol (5 mL) containing triethylamine (20 mol %) was
heated under reflux or by ultrasonic irradiations using Elmasonic
S
40H
(3-Amino-1-(4-chlorophenyl)-1H-benzo[f]chromen-2-yl)(5-bromo-1H-indol-3-yl)
ultrasonic cleaning unit. The progress of the reaction was monitored by TLC
(EtOAc/hexane 3:2). After completion of the reaction, the reaction mixture was
concentrated and cooled. The solid obtained was filtered off, washed with
ethanol and recrystallized from appropriate solvent to furnish the desired pure
product.
methanone (4h). White solid; mp 231–233 °C; IR (KBr) (m
max/cmÀ1); 3426,
3242, 1635, 1519, 1481, 1440, 1231, 1185, 1091, 1013, 803, 745; 1H NMR
(400 MHz, DMSO-d6): dH (ppm) 6.12 (s, 1H, CH), 6.84 (d, 2H, J = 8.4 Hz, Ar-H),
7.14 (d, 2H, J = 8.4 Hz, Ar-H), 7.30 (dd, 1H, J = 8.8, 1.6 Hz, Ar-H), 7.40–7.55 (m,
4H, Ar-H), 7.78 (s, 1H, Ar-H), 7.89 (d, 1H, J = 8.0 Hz, Ar-H), 7.94–7.99 (m, 3H, Ar-
H), 8.83 (br., s, 2H, NH2), 11.84 (br., s, 1H, NH); 13C NMR (100 MHz, DMSO-d6):
dC (ppm) 37.2, 89.2, 113.7, 114.6, 117.2, 120.2, 123.2, 125.0, 125.4, 126.4,
127.9, 128.0, 128.7, 128.9, 129.2, 129.5, 130.2, 130.5, 131.2, 131.3, 135.1, 145.8,
147.5, 162.6, 162.7, 187.1; Anal. Cald for C28H18BrClN2O2 (529.81): C, 63.48; H,
3.42; N, 5.29%. Found: C, 63.31; H, 3.28; N, 5.20%.
(3-Amino-1-(4-fluorophenyl)-1H-benzo[f]chromen-2-yl)(1H-indol-3-yl)methanone
(4a). White solid; mp 198–201 °C; IR (KBr) (m
max/cmÀ1); 3445, 3143, 1635,
1516, 1437, 1230, 1020, 803, 747; 1H NMR (400 MHz, DMSO-d6): dH (ppm)
6.16 (s, 1H, CH), 6.74–6.78 (m, 2H, Ar-H), 6.89 (t, 2H, J = 8.8 Hz, Ar-H), 6.97 (t,
1H, J = 7.4 Hz, Ar-H), 7.18 (t, 1H, J = 7.4 Hz, Ar-H), 7.46 (m, 3H, Ar-H), 7.53 (d,
1H, J = 8.0 Hz, Ar-H), 7.60 (d, 1H, J = 7.6 Hz, Ar-H), 7.74 (m, 1H, Ar-H), 7.79 (d,
1H, J = 2.0 Hz, @CH-NH), 7.97 (d, 2H, J = 8.8 Hz, Ar-H), 8.77 (br. s, 2H, NH2),
11.67 (br., s, 1H, NH); 13C NMR (100 MHz, DMSO-d6): dC (ppm) 37.0, 89.7,
112.6, 115.5, 115.7, 117.2, 118.0, 120.5, 120.7, 120.8, 122.4, 123.2, 125.8, 126.5
(d, 1JCF = 224.0 Hz), 128.6 (d, 3JC-F = 8.0 Hz), 128.8, 129.3 (d, 2JC–F = 22.0 Hz),
130.5, 131.3, 136.4, 143.3 (d, 4JC–F = 3.0 Hz), 147.6, 159.6, 162.1, 162.3, 188.0;
Anal. Cald for C28H19FN2O2 (434.46): C, 77.41; H, 4.41; N, 6.45%. Found: C,
77.30; H, 4.28; N, 6.34%.
(3-Amino-1-(2,4-dichlorophenyl)-1H-benzo[f]chromen-2-yl)(5-bromo-1H-indol-3-yl)
methanone (4i). white solid; mp 228–230 °C; IR (KBr) (m
max/cmÀ1); 3450,
3252, 1635, 1520, 1438, 1231, 1185, 1096, 1016, 849, 804, 744, 688; 1H NMR
(400 MHz, DMSO-d6): dH (ppm) 6.40 (s, 1H, CH), 6.98 (d, J = 8.4 Hz, 1H, Ar-H),
7.16 (dd, 1H, J = 8.6, 2.2 Hz, Ar-H), 7.26 (dd, 2H, J = 8.6, 1.8 Hz, Ar-H), 7.45–7.51
(m, 4H, Ar-H), 7.55 (s, 1H, Ar-H), 7.79 (d, 1H, J = 8.0 Hz, Ar-H), 7.88 (d, 1H,
J = 2.0 Hz, @CH-NH), 7.97–8.02 (m, 2H, Ar-H), 8.58 (br., s, 2H, NH2), 11.84 (br.,
s, 1H, NH); 13C NMR (100 MHz, DMSO-d6): dC (ppm) 35.3, 89.0, 113.6, 114.5,
117.4, 117.8, 120.2, 122.3, 122.7, 124.8, 125.6, 127.9, 128.0, 128.7, 129.2, 129.9,
130.6, 130.9, 131.2, 131.8, 131.9, 135.2, 144.0, 147.7, 161.6, 161.7, 187.5; Anal.
Cald for C28H17BrCl2N2O2 (564.26): C, 59.60; H, 3.04; N, 4.96%. Found: C, 59.68;
H, 3.24; N, 4.85%.
(3-Amino-1-(4-chlorophenyl)-1H-benzo[f]chromen-2-yl)(1H-indol-3-yl)methanone
(4b). White solid; mp 220–222 °C; IR (KBr) (m
max/cmÀ1); 3450, 3157, 1626,
1528, 14.81, 1437, 1193, 1092, 1014, 848, 744; 1H NMR (400 MHz, DMSO-d6):
dH (ppm) 6.16 (s, 1H, CH), 6.75 (s, 2H, Ar-H), 6.97 (s, 1H, Ar-H), 7.11–7.19 (m,
3H, Ar-H), 7.46–7.60 (m, 6H, Ar-H), 7.72–7.80 (m, 3H, Ar-H), 7.97 (br. s, 2H,
NH2), 8.79 (br., s, 1H, NH); 13C NMR (100 MHz, DMSO-d6): dC (ppm) 37.3, 89.4,
112.7, 117.2, 118.0, 120.2, 120.7, 120.8, 122.4, 123.2, 125.4, 125.7, 127.7, 128.8,
128.9, 129.2, 129.5, 130.5, 131.1, 131.3, 136.4, 146.0, 147.6, 162.3, 187.9; Anal.
Cald for C28H19ClN2O2 (450.92): C, 74.58; H, 4.25; N, 6.21%. Found: C, 74.64; H,
4.30; N, 6.26%.
3-Amino-1-(pyridin-3-yl)-1H-benzo[f]chromen-2-yl)(5-bromo-1H-indol-3-yl)
methanone (4j). White solid; mp 248–251 °C; IR (KBr) (m
max/cmÀ1); 3426, 3149,
1642, 1583, 1517, 1432, 1226, 1186, 1082, 1021, 846, 801, 745; 1H NMR
(400 MHz, DMSO-d6): dH (ppm) 6.18 (s, 1H, CH), 7.09–7.12 (m, 1H, Ar-H), 7.21 (d,
1H, J = 8.0 Hz, Ar-H), 7.31 (dd, 1H, J = 8.4, 1.2 Hz, Ar-H), 7.45–7.56 (m, 4H, Ar-H),
7.79 (d, 1H, J = 1.2 Hz, @CH-NH), 7.92 (d, 1H, J = 8.4 Hz, Ar-H), 7.97–8.04 (m, 4H,
Ar-H), 8.20–8.21 (m, 1H, Ar-H), 8.88 (br., s, 2H, NH2), 11.87 (s, 1H, NH); 13C NMR
(100 MHz, DMSO-d6): dC (ppm) 35.6, 88.8, 113.7, 114.6, 117.0, 117.2, 119.5,
123.0, 123.2, 124.3, 125.0, 125.5, 128.0, 128.1, 129.2, 129.8, 130.2, 131.3, 134.5,
135.1, 142.3, 147.6, 147.9, 148.0, 162.6, 162.7, 187.1; Anal. Cald for C27H18BrN3O2
(496.36): C, 65.34; H, 3.66; N, 8.46%. Found: C, 65.21; H, 3.48; N, 8.40%.
(3-Amino-1-(4-bromophenyl)-1H-benzo[f]chromen-2-yl)(1H-indol-3-yl)methanone
(4c). White solid; mp 220–222 °C; IR (KBr) (m
max/cmÀ1); 3448, 3221, 1639,
1518, 1236, 1095, 1011, 825, 748; 1H NMR (400 MHz, DMSO-d6): dH (ppm)
6.15 (s, 1H, CH), 6.68 (d, J = 8.4 Hz, 2H, Ar-H), 6.97 (t, 1H, J = 7.4 Hz, Ar-H), 7.19
(t, 1H, J = 7.6 Hz, Ar-H), 7.24 (d, 2H, J = 8.4 Hz, Ar-H), 7.45 (m, 3H, Ar-H), 7.54 (d,

5960
R. Hossein nia et al. / Bioorg. Med. Chem. Lett. 22 (2012) 5956–5960
2-((5-Bromo-1H-indol-3-yl)methyl)-1-(naphthalen-2-yl)-1H-benzo[f]chromen-3-
amine (4k). Pale brown solid; mp 256–258 °C; IR (KBr) (
max/cmÀ1); 3447, 1629,
H), 6.80 (d, 1H, J = 8.8 Hz, Ar-H), 7.05 (t, 1H, J = 7.6 Hz, Ar-H), 7.13–7.19 (m, 2H,
m
Ar-H), 7.28–7.33(m, 2H, Ar-H), 7.37–7.42(m, 2H, Ar-H), 7.48(d, 2H, J = 9.2 Hz, Ar-
H), 7.93 (d,1H, J = 8.0 Hz, Ar-H), 7.97 (d, 1H, J = 8.0 Hz, Ar-H), 8.71 (br., s, 2H, NH2),
11.50 (br., s, 1H, NH); 13C NMR (100 MHz, DMSO-d6): dC (ppm); 12.5, 35.3, 90.0,
111.6, 117.4, 118.0, 119.8, 120.4, 121.3, 122.9, 125.4, 126.1, 127.5, 128.3, 129.1,
129.2, 130.0, 130.7, 131.2, 131.5, 131.7, 132.0, 135.0, 139.6, 144.2, 147.6, 161.4,
161.5, 189.3; Anal. Cald for C29H20Cl2N2O2 (499.39): C, 69.75; H, 4.04; N, 5.61%.
Found: C, 69.61; H, 4.18; N, 5.54%.
1514, 1435, 1228, 1185, 1088, 1022, 880, 802, 742; 1H NMR (400 MHz, DMSO-
d6): dH (ppm) 6.29 (s, 1H, CH), 7.08 (d, 1H, J = 8.4 Hz, Ar-H), 7.17 (s, 1H, Ar-H),
7.29–7.37 (m, 3H, Ar-H), 7.43–7.53 (m, 5H, Ar-H), 7.64 (d, 1H, J = 8.8 Hz, Ar-H),
7.70 (m, 1H, Ar-H), 7.76 (d, 1H, J = 1.2 Hz, @CH-NH), 7.95–8.00 (m, 4H, Ar-H), 8.84
(br., s, 2H, NH2), 11.86 (br., s, 1H, NH); 13C NMR (100 MHz, DMSO-d6): dC (ppm)
38.0, 89.5, 113.6, 114.6, 117.2, 117.4, 120.4, 123.2, 123.3, 124.7, 125.0, 125.4,
125.7, 126.1, 126.6, 127.8, 127.9, 128.1, 128.8, 129.2, 129.5, 130.1, 130.7, 131.3,
132.0, 133.1, 135.1, 144.3, 147.6, 162.6, 162.7, 187.3;Anal. CaldforC32H21 BrN2O2
(545.44): C, 70.47; H, 3.88; N, 5.14%. Found: C, 70.22; H, 3.70; N, 5.03%.
30. Determination of antimicrobial activity: The antibacterial activity of the
synthesized compounds (4a–m) was examined using Salmonella enterica
(SE), Micrococcus luteus (ML), Bacillus subtilis (BS) and Pseudomonas
aeruginosa (PS). All media were prepared according to manufacturers’
instructions. A colony of each test organism was subcultured from nutrient
agar plates into nutrient broth and incubated at 37 °C for 18 h. Mueller-Hinton
agar plates were prepared and four plates were inoculated with bacteria from
nutrient broth cultures. The antibacterial activity was performed by well
Bis-2-((5-bromo-1H-indol-3-yl)methyl)-1-phenyl-1H-benzo[f]chromen-3-amine
(4l). Pale brown solid; mp 290–293 °C; IR (KBr) (m
max/cmÀ1); 3418, 1634, 1516,
1439, 1230, 1185, 1094, 1022, 885, 806, 745; 1H NMR (400 MHz, DMSO-d6): dH
(ppm) 5.94 (s, 2H, CH), 6.61 (d, 4H, J = 6.8 Hz, Ar-H), 7.26 (dd, 2H, J = 8.8, 1.6 Hz,
Ar-H), 7.30–7.37 (m, 2H, Ar-H), 7.42–7.52 (m, 6H, Ar-H), 7.71 (d, 2H, J = 1.2, @CH-
NH), 7.78 (d, 4H, J = 2.0 Hz, Ar-H), 7.88–8.00 (m, 4H, Ar-H), 8.70 (br., s, 4H, NH2),
11.74 (br., s, 2H, NH); 13C NMR (100 MHz, DMSO-d6): dC; 36.9, 89.6, 113.7, 114.4,
117.0, 117.1, 120.8, 121.0, 123.1, 123.2, 124.9, 125.3, 126.9, 127.8, 127.9, 128.0,
129.0, 129.1, 130.2, 130.5, 131.2, 135.0, 144.4, 144.5, 147.7, 163.0, 163.1, 186.6;
Anal. Cald for C50H32Br2N4O4 (912.62): C, 65.80; H, 3.53; N, 6.14%. Found: C,
65.75; H, 3.59; N, 6.10%.
diffusion technique. A concentration of 100
DMSO. A sterilized glass tube (5 mm diameter) was used to aseptically scoop
out the solid medium from the plate to create wells and 40 L of the sample
solution (12 g/well) was aseptically added. The plates were incubated at 37 °C
for 24 h. After incubation, zone of inhibition was measured.
lg/ml of sample was prepared in
l
l
(3-Amino-1-(2,4-dichlorophenyl)-1H-benzo[f]chromen-2-yl)(2-methyl-1H-indol-
3-yl)methanone (4m). Pale brown solid; mp 271–273 °C; IR (KBr) (m
max/cmÀ1);
3445, 3223, 1632, 1548, 1436, 1209, 1091, 1023, 805, 742; 1H NMR (400 MHz,
DMSO-d6): dH (ppm); 2.24 (s, 3H, CH3), 6.15 (s, 1H, CH), 6.67 (t, 1H, J = 7.2 Hz, Ar-