Microwave-promoted efficient synthesis of benzo[ h ]quinolines by solvent-free three-component imino-diels-alder reaction under one-pot condi-tions

Article abstract of DOI:10.1055/s-0033-1339844

An one-pot, solvent-free imino Diels-Alder reaction has been developed under microwave conditions using 1-naphthylamine, aldehydes, and electron-deficient terminal alkynes in the presence of a catalytic amount of In(OTf)₃ for construction of benzo[h]quinoline derivatives in short reaction times. The method is clean and operationally simple. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0033-1339844

LETTER
▌2245
lMetteircrowave-Promoted Efficient Synthesis of Benzo[h]quinolines by Solvent-
Free Three-Component Imino-Diels–Alder Reaction under One-Pot Condi-
tions
Synthesis of Benzo[h]quinolines
Manas M. Sarmah, Debajyoti Bhuyan, Dipak Prajapati*
Medicinal Chemistry Division, CSIR-North-East Institute of Science & Technology, Jorhat, Assam-785006, India
Fax +91(376)2370011; E-mail: dr_dprajapati2003@yahoo.co.uk
Received: 25.06.2013; Accepted after revision: 22.08.2013
In continuation to our studies to develop microwave-
Abstract: An one-pot, solvent-free imino Diels–Alder reaction has
assisted methodologies for the generation of nitrogen
been developed under microwave conditions using 1-naphthyl-
heterocycles,16 we report herein an efficient solvent-free,
one-pot IDA reaction for the synthesis of benzo[h]quino-
amine, aldehydes, and electron-deficient terminal alkynes in the
presence of a catalytic amount of In(OTf)3 for construction of ben-
zo[h]quinoline derivatives in short reaction times. The method is line derivatives promoted by 10 mol% In(OTf)3 under
clean and operationally simple.
microwave irradiation.
Key words: imino-Diels–Alder reaction, metal-catalyzed multi-
component reaction, microwave-assisted organic synthesis, ben-
reaction between 1-naphthylamine (1) with 1.0 equivalent
zo[h]quinolines
Our preliminary studies were directed to investigate the
of 4-fluorobenzaldehyde (2a) and 1.2 equivalents of
methyl propiolate (3a) at 540 W in a microwave reactor in
various solvent systems. It was observed that the reaction
The imino-Diels–Alder (IDA) reaction is recognized as a
did not proceed in most solvents (e.g., methanol, ethanol,
useful approach for the construction of highly functional-
acetic acid, chloroform, dichloromethane, dimethylform-
ized heterocycles of biological and synthetic interest and
amide, dimethyl sulfoxide, nitrobenzene, toluene, and
structurally diverse molecules.1,2 During recent years,
water). However, we noticed that when the reaction was
modifications of the IDA reaction have been reported.3
performed in toluene in the presence of 5 mol% In(OTf)3
Quinolines or 1-azanaphthalenes4 are found as building the product methyl-2-(4-fluorophenyl)benzo[h]quinoline-
blocks in a wide variety of natural products that show ac- 4-carboxylate (4a) was obtained in 50% yield (Table 1,
tivities as antimalarial,5a antirheumatic,5b antiviral,5c anti- entry 1). As we are interested in utilization of solid-state
protozoal,5d antineoplastic,5e antipsychotic,5f and metal-catalyzed MAOS for the production of probable
antischizophrenic5g agents. Development of quinoline- heterocyclic compounds we performed the reaction with-
based drugs such as haplamine,6a topotecan,6b and out any solvent and found that the product was formed in
irinotecan6c has renewed interest in developing novel syn- 80% yield under microwave irradiation at 540 W and
thetic strategies for the synthesis of quinoline derivatives. 120 °C for eight minutes (Scheme 1).
A large number of methods for the synthesis of quinoline
compounds have been reported but most of them suffer
from the need for forcing reaction conditions.7
NH2
Metal-catalyzed multicomponent reactions (MCR)8,9 re-
F
duce the number of operational steps.10 Indium triflate,
1
MW, 540 W
8 min
N
In(OTf)3 is a Lewis acid catalyst that has become the fo-
cus of attention in several synthetic studies.11 Previously,
our group has established the catalytic activity of indi-
um(III) salts in a range of transformations.12
+
F
CO2Me
CO2Me
4a
3a
The growing emphasis on minimizing energy consump-
tion and elimination of harmful solvents has contributed
to the extension of the range of microwave-assisted organ-
ic synthesis (MAOS).13 Reaction under neat conditions
can result in rate enhancements along with different
selectivity14 compared to conventional methodologies.
Therefore, MAOS technology in dry reaction medium
presents a novel protocol to carry out organic reactions
which is also proved by theoretical calculations.15
CHO
2a
Scheme 1
Optimization studies under various conditions revealed
that In(OTf)3 (10 mol%) is the best catalyst with irradia-
tion at 720 W and 120 °C for eight minutes (Table 1, en-
tries 2–6) Using these optimized conditions, the feasibility
of the reaction scheme was then tested with the variation
of different aldehydes 2 and electron-deficient terminal
alkynes 3, and the results obtained are shown in Figure 1
and Scheme 2.17
SYNLETT 2013, 24, 2245–2248
Advanced online publication: 23.09.2013
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0033-1339844; Art ID: ST-2013-D0581-L
© Georg Thieme Verlag Stuttgart · New York

2246
M. M. Sarmah et al.
LETTER
Table 1 Optimization for the Synthesis of 4a under Micorwave Irra-
diationa
NH2
Entry
Solvent
Catalyst (mol%)
Yield (%)b
R1
1
N
MW, 720 W
1
2
3
4
5
6
toluene
neat
In(OTf)3 (5)
In(OTf)3 (10)
AgOTf (10)
50
90
82
84
78
79
+
R1CHO
8 min
In(OTf)3 (10 mol%)
2
CO2R2
3
CO2R2
neat
4
neat
Cu(OTf)2 (10)
Sc(OTf)3 (10)
Yb(OTf)3 (10)
Scheme 2
neat
ortho, meta, and para positions. The reaction also pro-
ceeds with benzaldehyde, cinnamaldehyde, and hetero-
aromatic aldehydes such as furfuraldehyde and
thiophene-2-carbaldehyde. There were no undesired side
reactions, and the benzo[h]quinoline derivative was ob-
tained as the only product in each instance in high yield.
However, the reaction failed when aliphatic aldehydes
were employed and only the naphthylimines were ob-
tained. Increasing the reaction time or the microwave
power resulted in decomposition. All of the products ob-
tained were characterized by IR and NMR spectroscopy
and mass spectrometry.
neat
a Reaction conditions: 1-naphthylamine (1, 1.0 mmol), 4-fluorobenz-
aldehyde (2a, 1.0 mmol), and methyl propiolate (3a, 1.2 mmol). Irra-
diation at 540 W at 120 °C for 8 min.
b Isolated yield.
The reaction conditions are tolerated by a range of differ-
ent aromatic aldehydes and electron-deficient terminal al-
kynes resulting in good to excellent yields of the desired
benzo[h]quinoline templates. It is noteworthy that alde-
hydes containing either electron-donating or electron-
withdrawing substituents on the aromatic ring underwent
the cycloaddition reaction smoothly. We also studied the
effect of the positions of substituents in the aromatic ring,
and we were gratified to find that the reaction was suc-
cessful with aromatic aldehydes having substitutions at
A reasonable mechanism for the formation of ben-
zo[h]quinolines from the three-component reaction is out-
lined in Scheme 3. The sequence starts with the formation
of an imine A from 1-naphthylamine 1 and aldehyde 2,
which then undergoes [4+2] cycloaddition with the termi-
F
F
Br
N
N
N
N
Br
CO2Me
CO2Me
CO2Me
CO2Et
4a, 90%
4b, 88%
4c, 89%
4d, 90%
OMe
N
N
N
N
Cl
CO2Me
CO2Me
CO2Me
CO2Et
4e, 87%
4f, 87%
4g, 87%
4h, 85%
CH3
Cl
N
N
N
N
CH3
Cl
CO2Me
CO2Me
CO2Me
CO2Et
4l, 84%
4i, 86%
4j, 87%
4k, 88%
O
O
S
N
N
N
N
CO2Me
4n, 83%
CO2Et
CO2Me
CO2Me
4m, 81%
4o, 82%
4p, 81%
Figure 1 Direct synthesis of a library of benzo[h]quinoline derivatives 4a–p. Reagents and conditions: 1-naphthylamine (1, 1.0 mmol), alde-
hydes 2 (1.0 mmol), and methyl propiolate/ethyl propiolate 3 (1.2 mmol), In(OTf)3 (10 mol%), irradiation in the absence of solvent at 720 W
for 8 min.
Synlett 2013, 24, 2245–2248
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of Benzo[h]quinolines
2247
R1
N
R1
NH2
N
R1CHO
In(OTf)3
[4+2] cycloaddition
+
2
CO2R2
CO2R2
A
1
3
4
Scheme 3
nal alkyne 3 in the presence of a catalytic amount of to the synthesis of a diverse range of benzo[h]quinoline
In(OTf)3 to furnish 4.
derivatives. A wide variety of substituted aromatic alde-
hydes, cinnamaldehyde, heteroaromatic aldehydes, and
electron-deficient terminal alkynes were shown to under-
go the reaction with 1-naphthylamine to give the desired
products exclusively. This methodology offers a new
route for the synthesis of benzo[h]quinolines from simple
starting materials with excellent atom-economy. This
one-pot, three-component technique is operationally sim-
ple and provides the opportunity to remove solvent from
the synthetic procedure.
To support our mechanistic postulate we performed a two-
step reaction. First we synthesized N-(3-bromobenzyli-
dene)naphthalen-1-imine (Aa) from 1-naphthylamine and
3-bromobenzaldehyde and this was then reacted with
methyl propiolate (3a) under microwave irradiation in the
presence of 10 mol% In(OTf)3 whereby product 4d was
isolated in good yield. To confirm the role of In(OTf)3 in
the cycloaddition we carried out the reaction between Aa
and 3a without catalyst and found that there was no for-
mation of the desired product even after prolonged irradi-
ation (Scheme 4). This demonstrates that the formation of
an indium alkynylide from In(III) catalyst and terminal
alkyne18 is essential for assembling benzo[h]quinoline
compounds.
Acknowledgement
We are grateful to CSIR, New Delhi for financial support to this
work. D.B. thanks UGC, NERO, for the award of a teacher fellow-
ship. We also thank the Director, CSIR-NEIST, Jorhat for his keen
interest and constant encouragement.
N
References and Notes
+
Br
CO2Me
(1) (a) Fodor, G. B.; Colasanti, B. In Alkaloids: Chemical and
Biological Perspectives; Vol. 3; Pelletier, S. W., Ed.; Wiley:
New York, 1985, 1–91. (b) Daly, J. W.; Spande, T. F. In
Alkaloids: Chemical and Biological Perspectives; Vol. 4;
Pelletier, S. W., Ed.; Wiley: New York, 1986, 1–254.
(c) Boger, D. L.; Weinreb, S. M. Hetero Diels–Alder
Methodology in Organic Synthesis; Academic Press: New
York, 1987, Chap. 2 and 9.
Aa
3a
In(OTf)3
MW, 720 W, 8 min
no catalyst
MW, 720 W, 15 min
no reaction
(2) Jørgensen, K. A. Angew. Chem. Int. Ed. 2000, 39, 3558.
(3) (a) Vicario, J.; Aparicio, D.; Palacios, F. Tetrahedron Lett.
2011, 52, 4109. (b) Tambar, U. K.; Lee, S. K.; Leighton, J.
L. J. Am. Chem. Soc. 2010, 132, 10248. (c) Costantino, U.;
Fringuelli, F.; Orru, M.; Nocchetti, M.; Piermatti, O.; Pizzo,
F. Eur. J. Org. Chem. 2009, 1214. (d) Leca, D.; Gaggini, F.;
Cassayre, J.; Loiseleur, O. J. Org. Chem. 2007, 72, 4284.
(e) Liu, H.; Cun, L.-F.; Mi, A.-Q.; Jiang, Y.-Z.; Gong, L.-Z.
Org. Lett. 2006, 8, 6023. (f) Itoh, J.; Fuchibe, K.; Akiyama,
T. Angew. Chem. Int. Ed. 2006, 45, 4796.
N
Br
CO2Me
4d
Scheme 4
We also set out to examine and compare the effect of the
nonclassical heating procedure on the outcome of this
In(III)-mediated three-component reaction. Accordingly,
a mixture of 1-naphthylamine, 4-fluorobenzaldehyde, and
methyl propiolate was refluxed in toluene in the presence
of a catalytic amount of In(OTf)3 for 10 hours to yield
methyl-2-(4-fluorophenyl)benzo[h]quinoline-4-carboxyl-
ate in 65% yield.19 Longer reaction times resulted in de-
composition. We also carried out the reaction under neat
conditions at 110 °C for 10 hours and observed that only
12% of the cyclized product was obtained.
(4) For reviews, see: (a) Balasubramanian, M.; Keay, J. G. In
Comprehensive Heterocyclic Chemistry II; Vol. 5;
Katritzky, A. R.; Rees, C. W.; Scriven, E. F. V., Eds.;
Pergamon Press: Oxford, 1996, 245. (b) Wagman, A. S.;
Wentland, M. P. In Comprehensive Medicinal Chemistry II;
Vol. 7; Taylor, J. B.; Triggle, D. J., Eds.; Elsevier: Oxford,
2006, 567–596. (c) Michael, J. P. Nat. Prod. Rep. 2008, 25,
166. (d) Michael, J. P. Nat. Prod. Rep. 2007, 24, 223.
(e) Michael, J. P. Nat. Prod. Rep. 2005, 22, 627.
(5) (a) Bray, P. G.; Ward, S. A.; O’Neil, P. M. Curr. Top.
Microbiol. Immunol. 2005, 295, 3. (b) Steere, A. C.;
Angelis, S. M. Arthritis Rheum. 2006, 54, 3079.
(c) Savarino, A.; Boelaert, J. R.; Cassone, A.; Majori, G.;
Cauda, R. Lancet Infect. Dis. 2003, 3, 722. (d) Kager, P. A.
Ned. Tijdschr. Geneeskd. 2005, 149, 51. (e) Hertzberg, R. P.;
In summary, we have demonstrated an indium triflate cat-
alyzed imino Diels–Alder reaction which efficiently leads
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 2245–2248

2248
M. M. Sarmah et al.
LETTER
Caranfa, M. J.; Holden, K. G.; Jakas, D. R.; Gallagher, G.;
Mattern, M. R.; Mong, S. M.; Bartus, J. O.; Johnson, R. K.;
Kingsbury, W. D. J. Med. Chem. 1989, 32, 715.
(f) Szmuszkovicz, J.; Darlington, W. H.; Von Voigtlander,
P. F. WO 8804292 A1, ; Chem. Abstr. 1988, 110, 75335
(g) Seeman, P.; Guan, H.-C.; Nobrega, J.; Jiwa, D.;
Markstein, R.; Balk, J.-H.; Picetti, R.; Borrelli, E.; Tol, H. H.
M. V. Synapse 1997, 25, 137.
(13) (a) Moseley, J. D.; Kappe, C. O. Green Chem. 2011, 13, 794.
(b) Lidstrom, P.; Tierney, J.; Wathey, B.; Westman, J.
Tetrahedron 2001, 57, 9225.
(14) (a) Loupy, A. C. R. Chim. 2004, 7, 103. (b) Microwaves in
Organic Synthesis; Loupy, A., Ed.; Wiley-VCH: Weinheim,
2006, 2nd ed.. (c) Strauss, C. R.; Varma, R. S. Top. Curr.
Chem. 2006, 266, 199. (d) Varma, R. S. Green Chem. Lett.
Rev. 2007, 1, 37. (e) Jeselnik, M.; Varma, R. S.; Polanc, S.;
Kocevar, M. Chem. Commun. 2001, 1716. (f) Larhed, M.;
Moberg, C.; Hallberg, A. Acc. Chem. Res. 2002, 35, 717.
(15) Rodriguez, A. M.; Prieto, P.; de la Hoz, A.; Diaz-Ortiz, A.
Org. Biomol. Chem. 2011, 9, 2371.
(16) (a) Sarmah, M. M.; Sarma, R.; Prajapati, D.; Hu, W.
Tetrahedron Lett. 2013, 54, 267. (b) Sarma, R.; Sarmah, M.
M.; Prajapati, D. J. Org. Chem. 2012, 77, 2018. (c) Lekhok,
K. C.; Bhuyan, D.; Prajapati, D.; Boruah, R. C. Mol.
Diversity 2010, 14, 841. (d) Prajapati, D.; Borah, K. J.;
Gohain, M. Synlett 2007, 595. (e) Prajapati, D.; Gohain, M.;
Thakur, A. J. Bioorg. Med. Chem. Lett. 2006, 16, 3537.
(17) General Procedure
(6) (a) Jansen, O.; Akhmedjanova, V.; Angenot, L.; Balansard,
G.; Chariot, A.; Ollivier, E.; Tits, M.; Frederich, M. J.
Ethnopharmacol. 2006, 105, 241. (b) Takimoto, C. H.;
Calvo, E. Principles of Oncologic Pharmacotherapy, In
Cancer Management: A Multidisciplinary Approach;
Pazdur, R.; Wagman, L. D.; Camphausen, K. A.; Hoskins,
W. J., Eds.; Oncology Group, CMPMedica: New York,
2008, 11 ed. (c) Wall, M. E.; Wani, M. C.; Cook, C. E.;
Palmer, K. H.; McPhail, A. I.; Sim, G. A. J. Am. Chem. Soc.
1966, 88, 3888.
(7) (a) Baruah, B.; Bhuyan, P. J. Tetrahedron 2009, 65, 7099.
(b) Kalita, P. K.; Baruah, B.; Bhuyan, P. J. Tetrahedron Lett.
2006, 47, 7779. (c) Yi, C. S.; Yun, S. Y. J. Am. Chem. Soc.
2005, 127, 17000. (d) Amii, H.; Kishikawa, Y.; Uneyama,
K. Org. Lett. 2001, 3, 1109.
(8) Kundu, D.; Majee, A.; Hajra, A. Tetrahedron Lett. 2009, 50,
2668.
(9) Prajapati, D.; Bhuyan, D.; Gohain, M.; Hu, W. Mol.
Diversity 2011, 15, 257.
(10) (a) Groebke, K.; Weber, L.; Mehlin, F. Synlett 1998, 661.
(b) Verma, R. S.; Kumar, D. Tetrahedron Lett. 1999, 40,
7665.
(11) (a) Smith, B. M.; Kubczyk, T. M.; Graham, A. E.
Tetrahedron 2012, 68, 7775. (b) Smith, B. M.; Graham, A.
E. Tetrahedron Lett. 2011, 52, 6281. (c) Golden, K. C.;
Gregg, B. T.; Quinn, J. F. Tetrahedron Lett. 2010, 51, 4010.
(d) Zhang, J.; Blazecka, P. G.; Angell, P.; Lovdahl, M.;
Curran, T. T. Tetrahedron 2005, 61, 7801. (e) Ali, T.;
Chauhan, K. K.; Frost, C. G. Tetrahedron Lett. 1999, 40,
5621. (f) Chauhan, K. K.; Frost, C. G. J. Chem. Soc., Perkin
Trans. 1 2000, 3015. (g) Cintas, P. Synlett 1995, 1097.
(h) Podlech, J.; Maier, T. C. Synthesis 2003, 633. (i) Loh, T.
P.; Chua, G. L. Chem. Commun. 2006, 2739. (j) Hoppe, H.
A. F.; Lloyd-Jones, G. C.; Murray, M.; Peakman, T. M.;
Walsh, K. E. Angew. Chem. Int. Ed. 1998, 37, 1545.
(12) (a) Lekhok, K. C.; Prajapati, D.; Boruah, R. C. Synlett 2008,
655. (b) Prajapati, D.; Gohain, M. Beilstein J. Org. Chem.
2006, 2. (c) Borah, H. N.; Prajapati, D.; Boruah, R. C. Synlett
2005, 2823. (d) Prajapati, D.; Laskar, D. D.; Gogoi, B. J.;
Devi, G. Tetrahedron Lett. 2003, 44, 8725. (e) Ilias, M.;
Barman, D. C.; Prajapati, D.; Sandhu, J. S. Tetrahedron Lett.
2002, 43, 1877.
1-Naphthylamine (1, 1.0 mmol), 4-fluorobenzaldehyde (2a,
1.0 mmol), and methyl propiolate (3a, 1.2 mmol) were
irradiated in a closed vessel with In(OTf)3 (10 mol%)
without solvent in a Synthos 3000 microwave reactor at 720
W, 120 °C, and 10 bar for 8 min. The crude product mixture
was dissolved in CHCl3 and directly purified by column
chromatography eluting with EtOAc–hexane (1:9) to obtain
pure methyl-2-(4-fluorophenyl)benzo[h]quinoline-4-
carboxylate (4a).
Compound 4a: off-white solid; mp 116–117 °C. 1H NMR
(300 MHz, CDCl3): δ = 9.32–9.37 (m, 1 H, arom), 8.64 (s, 1
H, COOCH3C=CH), 7.05–7.95 (m, 9 H, arom), 3.81 (s, 3 H,
CH3). 13C NMR (75 MHz, CDCl3): δ = 168.6, 155.5, 147.1,
138.6, 136.8, 136.7, 134.5, 131.07, 131.0, 130.9, 129.1,
128.6, 127.9, 127.3, 125.2, 124.8, 124.7, 123.9, 115.3,
115.0, 52.5. IR (CHCl3): 1726.7, 1603.3, 1589.0, 1561.0,
1512.7 cm–1. GC–MS: m/z = 331 [M]+. Anal. Calcd for
C21H14FNO2: C, 76.12; H, 4.26; F, 5.73; N, 4.23; O, 9.66.
Found: C, 76.10; H, 4.20; F, 5.69; N, 4.21; O, 9.61.
(18) Zani, L.; Bolm, C. Chem. Commun. 2006, 4263; and
references cited therein.
(19) 1-Naphthylamine (1, 1.0 mmol), 4-fluorobenzaldehyde (2a,
1.0 mmol), and methyl propiolate (3a, 1.2 mmol) were
refluxed with In(OTf)3 (10 mol%) in toluene (10 mL) under
air until completion (TLC), the solvent was distilled off
under reduced pressure, and the product was purified by
column chromatography eluting with EtOAc–hexane (1:9)
to obtain pure methyl-2-(4-fluorophenyl)benzo[h]quinoline-
4-carboxylate (4a).
Synlett 2013, 24, 2245–2248
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