Novel functionalized pyridoindole derivatives catalyzed by iron(III) triflate

Article abstract of DOI:10.1080/15533174.2015.1031009

A variety of novel 1H-pyrido[2,3-b]indole-3-carbonitrile derivatives have been synthesized via solvent-free one-pot cyclocondensation of substituted (triethoxymethyl)arene, 1-methyl-1H-indol-2-ol, and cyanoacetamide catalyzed by iron(III) triflate.

Full text of DOI:10.1080/15533174.2015.1031009

Synthesis and Reactivity in Inorganic, Metal-Organic, and Nano-Metal Chemistry (2015) 45, 1660–1663
Copyright © Taylor & Francis Group, LLC
ISSN: 1553-3174 print / 1553-3182 online
DOI: 10.1080/15533174.2015.1031009
Novel Functionalized Pyridoindole Derivatives Catalyzed
by Iron(III) Triflate
SAMAN DAMAVANDI1 and REZA SANDAROOS2
1Department of Chemistry, Sarvestan Branch, Islamic Azad University, Sarvestan, I. R. Iran
2Department of Chemistry, Faculty of Science, University of Birjand, Birjand, I. R. Iran
Received 7 February 2012; accepted 27 July 2013
A
variety of novel 1H-pyrido[2,3-b]indole-3-carbonitrile derivatives have been synthesized via solvent-free one-pot
cyclocondensation of substituted (triethoxymethyl)arene, 1-methyl-1H-indol-2-ol, and cyanoacetamide catalyzed by iron(III) triflate.
Keywords: pyrido[2,3-b]indole, multicomponent, catalyst
Introduction
3-carbonitrile derivatives. Herein, we report the use of Fe
(OTf)3 as an efficient catalyst for the solvent-free one-pot syn-
The indole nucleus is a ubiquitous heterocyclic structure thesis of novel 2,9-dihydro-9-methyl-2-oxo-4-aryl-1H-pyrido
found in numerous natural and synthetic compounds with a [2,3-b]indole-3-carbonitrile compounds.
wide variety of biological activities and considerable pharma-
ceutical importance.[1] The synthesis of indoles, therefore, has
attracted enormous attention from synthetic organic chemists
and a substantial number of methods for the preparation of
indoles have been developed.[2]
Experimental
Initially, the solvent-free reaction of (triethoxymethyl)ben-
zene, cyanoacetamide, and 1-methyl-1H-indol-2-ol, as the
model reaction, in the presence of 10 mol% of Fe(OTf)3 at
110ꢀC resulted in the 2,9-dihydro-9-methyl-2-oxo-4-phenyl-
1H-pyrido[2,3-b]indole-3-carbonitrile in moderate yield
(Scheme 1).
Synthesis of pyridoindole (a-carboline) derivatives has
attracted considerable interest due to the recent discoveries of
several naturally occurring compounds containing this skele-
ton.[3,4] Among these compounds, pyrido[2,3-b]indoles have
received immense attention because of their various pharma-
cological and biological activities, such as the anticancer
activity against colon and lung cancers, central nervous sys-
tem activity in mammals, and also as the biological control
agent for receptor research on bio-enzyme inhibitors (inhibi-
tion of HLE).[5–7] A few reports on synthesis of pyridoindoles
have been synthesized using the wide range of reagents and
methods.[8–11]
In contemporary organic synthesis, Lewis acid catalyzed
reactions have gained increasing interest because of the
unique reactivity and selectivity that can be achieved under
mild conditions.[12] During the past few years, the outstand-
ing potential of a variety of metal triflates (trifluoromethylsul-
fonates) has been discovered, thus triggering much research
endeavor.
General Procedure for the Synthesis of Pyrido[2,3-b]indole
Compounds 1–9
A mixture of (triethoxymethyl)arene (1 mmol), 1-methyl-1H-
indol-2-ol (1 mmol) and cyanoacetamide (1.1 mmol), in the
presence of Fe(OTf)3 (0.1 mmol) was stirred at 110ꢀC for 5–
7 h. The reaction was monitored by TLC, and after comple-
tion of the reaction, aqueous 10% Na2CO3 (10 mL) was
added and the mixture was extracted with EtOAc. The aque-
ous layer was again extracted with diethyl ether (15 mL) and
the combined organic extracts were dried over Na2SO4. Sub-
sequently, the organic solvent was evaporated and the residue
was purified by flash chromatography on silica gel (EtOAc/
hexanes, 10/90) to obtain the pure product.
Our continued interest in developing synthetic methodol-
ogy,[13–15] prompted us to investigate the one pot reactions of
substituted (triethoxymethyl)arene, 1-methyl-1H-indol-2-ol
and cyanoacetamide yielding a series of pyrido[2,3-b]indole-
2,9-dihydro-4-(4-methoxyphenyl)-9-methyl-2-oxo-1H-pyrido
[2,3-b]indole-3-carbonitrile (1)
IR (KBr, nmax, cm¡1): 3255, 3110, 2955, 2830, 2235, 1645,
1555, 1440, 1133 cm¡1 1H NMR (400 MHz, DMSO-d6):
.
Address correspondence to Saman Damavandi, Department of
Chemistry, Sarvestan Branch, Islamic Azad University, Sarvestan,
I. R. Iran. E-mail: Saman_Damavandi@yahoo.com
d D 10.85 (1H, s, -NHCO-), 7.60–7.35 (2H, m, ArH), 7.28
(2H, d, J D 7.1 Hz, ArH), 7.12 (2H, d, J D 7.4 Hz, ArH),

Novel Functionalized Pyridoindole Derivatives
1661
Sch. 1. General route to prepare pyridoindole derivatives.
6.95 (2H, d, J D 7.1 Hz, ArH), 3.80 (s, OCH3), 3.65 (3H, s, 4-(4-bromophenyl)-2,5-dihydro-2-oxo-1H-pyrido[3,2-b]
indole). 13CÀÀNMR (100 MHz, DMSO-d6): d D 165.8, indole-3-carbonitrile (4)
155.1, 150.4, 135.8, 128.2, 126.3, 124.6, 124.4, 124.2, 122.1,
IR (KBr, nmax, cm¡1): 3246, 3125, 2983, 2826, 2217, 1656,
121.4, 119.6, 115.3, 111.9, 112.6, 99.8, 55.8, 35.2. Anal.
Calcd. for C20H15N3O2: C, 72.94; H, 4.59; N, 12.76%.
Found: C, 72.56; H, 4.55; N, 12.73%.
1509, 1452 cm¡1
.
1H NMR (400 MHz, DMSO-d6): d D
10.90 (1H, s, ÀÀNHCOÀÀ), 7.57 (1H, d, J D 6.2 Hz, ArH),
7.40–7.30 (3H, m, ArH), 7.15 (2H, d, J D 6.4 Hz, ArH), 7.80
(2H, d, J D 6.4 Hz, ArH), 3.55 (s, ÀÀCH3,indole). 13C-NMR
(100 MHz, DMSO-d6): d D 168.5, 160.7, 139.2, 132.3, 129.5,
128.3, 127.9, 124.8, 124.1, 122.6, 121.8, 121.6, 117.3, 116.5,
111.3, 96.6, 32.7. Anal. Calcd. for C19H12BrN3O: C, 60.34;
H, 3.20; N, 11.11%. Found: C, 60.27; H, 3.14; N, 11.07%.
2,9-dihydro-9-methyl-2-oxo-4-phenyl-1H-pyrido[2,3-b]indole-
3-carbonitrile (2)
IR (KBr, nmax, cm¡1) 3250, 3120, 2965, 2833, 2230, 1642,
1551, 1431 cm¡1
.
1H NMR (400 MHz, DMSO-d6): d D
11.02 (1H, s, ÀÀNHCOÀÀ), 7.55 (1H, d, J D 6.3 Hz, ArH),
7.43 (1H, d, J D 6.3 Hz, ArH), 7.33–7.15 (7H, m, ArH), 3.62
(3H, s, indole). 13C-NMR (100 MHz, DMSO-d6): d D 169.3,
155.2, 138.5, 129.2, 125.5, 124.2, 123.7, 122.47 120.4, 118.5,
118.0, 117.5, 116.1, 114.6, 110.8, 96.2, 34.5. Anal. Calcd. for
C19H13N3O: C, 76.24; H, 4.38; N, 14.04%. Found: C, 75.90;
H, 4.34; N, 14.01%.
4-(2-bromophenyl)-2,5-dihydro-2-oxo-1H-pyrido[3,2-b]
indole-3-carbonitrile (5)
IR (KBr, nmax, cm¡1): 3255, 3134, 2991, 2806, 2228, 1650,
1544, 1487 cm¡1
.
1H NMR (400 MHz, DMSO-d6): d D
10.57 (1H, s, ÀÀNHCOÀÀ), 7.60 (1H, d, J D 7.0 Hz, ArH),
7.45–7.37 (2H, m, ArH), 7.22–7.14 (5H, m, ArH), 3.63 (s,
ÀÀCH3,indole). 13CÀÀNMR (100 MHz, DMSO-d6): d D
163.3, 155.2, 139.7, 135.5, 132.1, 129.8, 125.9, 125.2, 124.6,
123.3, 121.9, 121.0, 118.8, 118.6, 118.1, 115.7, 94.1, 31.6.
Anal. Calcd. for C19H12BrN3O: C, 60.34; H, 3.20; N,
11.11%. Found: C, 60.27; H, 3.13 N, 11.07%.
2,9-dihydro-9-methyl-2-oxo-4-p-tolyl-1H-pyrido[2,3-b]indole-
3-carbonitrile (3)
IR (KBr, nmax, cm¡1): 3254, 3119, 2976, 2835, 2218, 1647,
1551, 1422 cm¡1
.
1H NMR (400 MHz, DMSO-d6): d D
10.80 (1H, s, ÀÀNHCOÀÀ), 7.46 (1H, d, J D 7.1 Hz, ArH),
7.57 (1H, d, J D 7.1 Hz, ArH), 7.30–7.12 (6H, m, ArH), 3.52
(s, ÀÀCH3, indole), 2.12 (s, ÀÀCH3). 13C-NMR (100 MHz,
DMSO-d6): d D 161.9, 156.1, 139.6, 135.5, 129.3, 128.7,
127.1, 125.9, 125.3, 124.0, 121.8, 120.1, 117.8, 115.1, 112.9,
95.2, 34.6, 24.9. Anal. Calcd. for C20H15N3O: C, 76.66; H,
4.82; N, 13.41%. Found: C, 76.49; H, 4.78; N, 13.38%.
4-(4-chlorophenyl)-2,9-dihydro-9-methyl-2-oxo-1H-pyrido
[2,3-b]indole-3-carbonitrile (6)
IR (KBr, nmax, cm¡1): 3263, 3115, 2980, 2802, 2212, 1652,
1535, 1470 cm¡1
.
1H NMR (400 MHz, DMSO-d6): d D
11.02 (1H, s, ÀÀNHCOÀÀ), 7.55 (1H, d, JD 7.5 Hz, ArH),
7.46 (1H, d, J D 7.7 Hz, ArH), 7.25–7.18 (4H, m, ArH), 7.04
(2H, d, J D 7.7 Hz, ArH), 3.55 (s, ÀÀCH3,indole).
Sch. 2. General route to prepare pyridoindole derivatives.

1662
Damavandi and Sandaroos
Sch. 3. General route to prepare pyridoindole derivatives.
13CÀÀNMR (100 MHz, DMSO-d6): d D 166.4, 161.1, 138.9, All of the employed (triethoxymethyl)benzene derivatives
135.3, 129.7, 127.4, 124.93, 124.7, 123.6, 122.1, 121.5, 120.5, afforded the expected products in good to high yields, either
118.8, 116.7, 111.1, 93.6, 33.1. Anal. Calcd. for bearing electron-withdrawing groups (such as halide, nitro)
C19H12ClN3O: C, 68.37; H, 3.62; N, 12.59%. Found: C, or electron-donating groups (such as alkyl group, or alkoxyl
68.21; H, 3.58; N, 12.53%.
group) under the same reaction conditions. It was revealed
that the electronic nature as well as steric nature of the substi-
tuted groups on (triethoxymethyl)arene influenced the reac-
tion times and chemical yields.
4-(2-chlorophenyl)-2,9-dihydro-9-methyl-2-oxo-1H-pyrido
[2,3-b]indole-3-carbonitrile (7)
We proposed a three-step mechanism for one-pot synthesis
of pyrido[2,3-b]indole derivatives (Scheme 3). Cross coupling
between 1-methyl-1H-indol-2-ol and (triethoxymethyl)ben-
zene results in a,b-unsaturated compound (1), possessing eth-
oxy substituent on its b-position which can act as a leaving
group. Nucleophilic attack of cyanoacetamide on b-position
of intermediate (1) generates the intermediate (2). Condensa-
tion reaction between N-amide atom and carbonyl group on
2-position of indole furnishes the corresponding pyrido[2,3-b]
indole (3).
IR (KBr, nmax, cm¡1): 3250, 3142, 2997, 2812, 2211, 1667,
1553, 1465 cm¡1
.
1H NMR (400 MHz, DMSO-d6): d D
10.92 (1H, s, ÀÀNHCOÀÀ), 7.50 (1H, d, J D 6.5 Hz, ArH),
7.43 (1H, d, J D 6.5 Hz, ArH), 7.30–7.24 (2H, m, ArH),
7.20–7.05 (4H, m, ArH), 3.60 (s, ÀÀCH3,indole). 13CÀÀNMR
(100 MHz, DMSO-d6): d D 169.5, 158.4, 139.7, 134.4, 131.1,
128.9, 125.5, 124.2, 122.9, 122.1, 120.8, 120.1, 118.9, 118.7,
116.9, 116.3, 98.5, 34.5. Anal. Calcd. for C19H12ClN3O: C,
68.37; H, 3.62; N, 12.59%. Found: C, 68.29; H, 3.57; N,
12.54%.
2,9-dihydro-9-methyl-4-(4-nitrophenyl)-2-oxo-1H-pyrido[2,3-
b]indole-3-carbonitrile (8)
Conclusion
IR (KBr, nmax, cm¡1): 3255, 3175, 2995, 2810, 2217, 1637,
In conclusion, we have reported a new and efficient one-pot
synthesis protocol for the synthesis of novel 2,9-dihydro-2-
1552, 1516, 1481, 1345 cm¡1
.
1H NMR (400 MHz,
DMSO-d6): d D 10.85 (1H, s, -NHCO-), 8.09 (2H, d, J D
7.2 Hz, ArH), 7.65–7.50 (3H, m, ArH), 7.40 (1H, d, J D
7.5 Hz, ArH), 7.10 (2H, d, J D 7.7 Hz, ArH), 3.62 (s,
-CH3,indole). 13C-NMR (100 MHz, DMSO-d6): d D 167.7,
159.2, 154.1, 148.3, 144.4, 129.9, 127.4, 125.9, 125.2,
123.3, 122.1, 121.7, 120.4, 119.5, 115.6, 114.1, 95.5, 34.6.
Anal. Calcd. for C19H12N4O3: C, 66.28; H, 3.51; N,
16.27%. Found: C, 66.17; H, 3.45; N, 16.19%.
oxo-4-aryl-1H-pyrido[2,3-b]indole-3-carbonitriles
utilizing
iron(III) triflate. The methodology proved to tolerate a num-
ber of functional groups, allowing the synthesis of a broad set
of compounds.
References
1. Chen, Y.; Markina, N. A.; Larock, R. C. Tetrahedron 2009, 65, 8908.
2. Humphrey, G. R.; Kuethe, J. T. Chem. Rev. 2006, 106, 2875.
3. Veale, C. A.; Damewood, J. R.; Steelman, G. B.; Bryant, C.;
Gomes, B.; Williams, J. J. Med. Chem. 1995, 38, 86.
Results and Discussion
4. Menta, E.; Pescalli, N.; Spinelli, S. WO Pat 2001, 009129.
5. Ritzeler, O.; Castro, A.; Grenler, L. EP Pat 2001, 1134221 (A1).
6. Nielsch, U.; Sperzel, M.; Bethe, B.; Junge, B.; Lieb, F.; Velten, R.
DE Pat 1999, 19807993 (A1).
7. Beccalli, E. M.; Clerici, F.; Marchesini, A. Tetrahedron 2001, 57, 4787.
8. Molina, P.; Fresneda, P. M.; Sanz, M. A.; Foces, C.; Ramirez, D.
A. Tetrahedron 1998, 54, 9623.
Encouraged by this success, the methodology was then
extended to the synthesis of a variety of 2,9-dihydro-2-oxo-4-
aryl-1H-pyrido[2,3-b]indole-3-carbonitriles. We found out
that the methodology was appropriate for a wide range of
analogs and functional groups (Scheme 2). The reaction typi-
cally gave 66–80% yields of the isolated product.

Novel Functionalized Pyridoindole Derivatives
1663
9. Hostyn, S.; Tehrani, K. A.; Lemiere, F.; Smout, V.; Maes, B. U. W. 13. Damavandi, S. Heterocycl. Commun. 2011, 17, 79.
Tetrahedron 2011, 67, 655.
14. Damavandi, S.; Sandaroos, R. Heterocycl. Commun. 2011, 17, 121.
10. Ryabova, S. Y.; Alekseeva, L. M.; Granik, V. G. Chem. Heterocycl. 15. Damavandi, S. Synth. React. Inorg. Met.-Org. Nano-Met. Chem.
Compd. 2011, 37, 997.
2011, 41, 1.
11. Meyer, M.; Guyot, M. Tetrahedron Lett. 1996, 37, 4931.
12. Santelli, M.; Pons, J. M. Lewis Acids and Selectivity in Organic Syn-
thesis; CRC Press, Boca Raton, FL, 1995.
16. Heintz, R. A.; Smith, J. A.; Szalay, P. S.; Weisberger, A.; Dunbar,
K. R. In: Inorganic Syntheses, Coucouvanis D., editor. Wiley-Inter-
science: New York, 2002; Vol. 33, Chapter 2, p. 75.

Copyright of Synthesis & Reactivity in Inorganic, Metal-Organic, & Nano-Metal Chemistry
is the property of Taylor & Francis Ltd and its content may not be copied or emailed to
multiple sites or posted to a listserv without the copyright holder's express written permission.
However, users may print, download, or email articles for individual use.