Bismuth(III) bromide catalyzed synthesis of polyhydroquinoline derivatives via the Hantzsch reaction

Article abstract of DOI:10.1016/j.tetlet.2015.04.121

Abstract Bismuth(III) bromide is an efficient catalyst for the one-pot multicomponent synthesis of polyhydroquinolines via the Hantzsch reaction. The mild reaction conditions, short reaction times, high yields, and the remarkably low toxicity of bismuth c

Full text of DOI:10.1016/j.tetlet.2015.04.121

Accepted Manuscript
Bismuth(III) bromide catalyzed synthesis of polyhydroquinoline derivatives via
the Hantzsch reaction
Joshua S. Yoo, Thomas J. Laughlin, Joseph J. Krob, Ram S. Mohan
PII:
S0040-4039(15)00778-9
DOI:
http://dx.doi.org/10.1016/j.tetlet.2015.04.121
TETL 46261
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
31 March 2015
22 April 2015
29 April 2015
Please cite this article as: Yoo, J.S., Laughlin, T.J., Krob, J.J., Mohan, R.S., Bismuth(III) bromide catalyzed synthesis
of polyhydroquinoline derivatives via the Hantzsch reaction, Tetrahedron Letters (2015), doi: http://dx.doi.org/
10.1016/j.tetlet.2015.04.121
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Bismuth(III) bromide catalyzed synthesis of
polyhydroquinoline derivatives via The
Hantzsch reaction.
Leave this area blank for abstract info.
Joshua S. Yoo, Thomas J. Laughlin, Joseph J. Krob, Ram S. Mohan.*
1

Bismuth(III) bromide catalyzed synthesis of polyhydroquinoline derivatives via The
Hantzsch reaction
Joshua S. Yoo a, Thomas J. Laughlin,a Joseph J. Kroba and Ram S. Mohan.*a
aLaboratory for Environmentally Friendly Organic Synthesis, Department of Chemistry,
Illinois Wesleyan University, Bloomington, IL 61701 USA
Email: rmohan@iwu.edu
Abstract
Bismuth(III) bromide is an efficient catalyst for the one-pot multicomponent synthesis of
polyhydroquinolines via the Hantzsch reaction. The mild reaction conditions, short reaction
times, high yields and the remarkably low toxicity of bismuth compounds make this method
especially attractive.
Keywords:
Bismuth bromide, Polyhydroquinolines, Hantzsch reaction, Multicomponent reaction, Green
chemistry.
2

Bismuth(III) bromide catalyzed synthesis of polyhydroquinoline derivatives via
The Hantzsch reaction.
The synthesis of 1,4-dihydropyridine derivatives such as polyhydroquinolines (PHQ) is of
considerable interest due to their biological properties. Their derivatives such as nifedipine
are calcium channel antagonists.1 Polyhydroquinolines bearing a tetraazole moiety have been
shown to possess antimicrobial activity.2 2,4-disubstituted polyhydroquinolines also show
promise as antihyperglycemic and lipid modulating agents.3 Polyhydroquinolines have also
been shown to reduce cellular tau levels and therefore hold promise in the search for
therapies for Alzheimer’s disease.4 Many PHQ derivatives also show activity against
multidrug resistance proteins.5 Hence there has been considerable interest in methods for
their synthesis. The most common route to polyhydroquinolines 5 involves a modified
Hantzsch reaction6 involving the multi-component coupling of an aldehyde 1 with a -
ketoester (such as ethyl acetoacetate) 2, a diketone (such as dimedone) 3, and ammonium
acetate 4 (Scheme 1).
Scheme 1
Some representative examples of catalysts used for this coupling include I2,7 metal triflates,8
ceric ammonium nitrate,9 Baker’s yeast,10 organocatalysts,11 zeolites,12 Ph3P,13 GaCl3,14
thiourea dioxide,15 thiazolium ion,16 sulphamic acid,17 Al2(SO4)3,18 La2O3,19 and
nanoparticles.20 Syntheses of PHQs have also been carried out in various ionic liquids as
solvents.21 Their syntheses have also been reported under catalyst-free conditions, but the
3

methods suffer from longer reaction times.22 Solvent and catalyst-free methods involving
grinding the reaction mixtures have also been reported and are certainly attractive from a
green chemistry perspective. But these methods require the use of solvent for product
isolation and are not always amenable to scale-up.23 PHQs have also been synthesized under
microwave irradiation conditions.24 The most elegant synthesis of PHQs to date is their
enantioselective synthesis using a phosphoric acid derived organocatalyst.25
Given our continued interest in bismuth(III) salts as catalysts due to their remarkably non
toxic nature (many bismuth salts are even less toxic than NaCl) and ease of handling, we
explored the utility of bismuth bromide, BiBr3 as a catalyst for the synthesis of PHQs.26
Herein we report an efficient synthesis of a variety of polyhydroquinolines using bismuth(III)
bromide as a catalyst in ethanol as the solvent (Table 1). The reactions are fast, and product
is isolated by filtration of the reaction mixture. Hence no aqueous waste stream is generated.
In the absence of BiBr3, the reactions took a considerably longer time and lower yields were
obtained. For example, p-N,N-dimethylaminobenzaldehyde (Table 1, entry 2) yielded 61%
product (t = 23 h), and p-chlorobenzaldehyde (Table 1, entry 4) yielded 65% product (t = 7 h)
under catalyst free conditions. We found that the reaction was also efficiently catalyzed by
bismuth triflate (2.0 mol%). For example, p-tolualdehyde (Table 1, entry 1) yielded 86%
product (t = 2 h), but owing to the higher cost of bismuth triflate ($225/25 g from Acros
Organics) relative to bismuth bromide ($25/25 g) and its increased moisture sensitivity, we
chose bismuth bromide. Ytterbium triflate, Yb(OTf)3 (5.0 mol%) has been reported as a
catalyst8a for the formation of polyhydroquinolines but a higher catalyst loading (5 mol%)
and its high cost detract from its utility ($395/25 g for the anhydrous salt, and $136/25 g for
the monohydrate). Although we used anhydrous ethanol as the reaction solvent, one cannot
rule out hydrolysis of BiBr3 by adventitious water to generate HBr, which could act as a
Bronsted acid catalyst. In order to get some insight into the role of BiBr3 in the reaction, we
4

carried out the reaction (Scheme 2) of p-chlorobenzaldehyde in the presence of BiBr3 (2.0
mol%) and solid potassium carbonate (10 mol%). The pH of this reaction mixture was found
to be ~ 6-7, and yet product was obtained in 86% yield suggesting that BiBr3 is acting as a
Lewis acid and not just as a source of HBr.
Scheme 2
The mild reaction conditions with BiBr3 allow for easy scale-up as well. In summary, a mild
and efficient method for the multicomponent synthesis of polyhydroquinolines using a
relatively nontoxic and noncorrosive catalyst is reported.
5

Table 1. Synthesis of polyhydroquinolines catalyzed by BiBr3 (2.0 mol%).27
entry
1
Ar
R
Time (h)a
Yield (%)b, c
8628
p-CH3C6H4
p-NMe2C6H4
p -CH3OC6H4
p -ClCC6H4
p -NO2C6H4
m-CH3OC6H4
m-NO2C6H4
m-CH3C6H4
2-naphthyl
p-biphenyl
2-Furyl
CH2CH3
CH2CH3
CH2CH3
CH2CH3
CH2CH3
CH2CH3
CH2CH3
CH2CH3
CH2CH3
CH2CH3
CH2CH3
CH3
1.5
2.5
3
2
878a
3
8928
4
2.5
1.5
1.5
1.5
2
9320f
8720f
8929
5
6
7
7920f
8530
8
9
2.5
3
8325
10
11
12
8825
1
8728
p-CH3C6H4
1.5
9020f
aReaction progress was monitored by TLC.
bRefers to yield of isolated, purified product.
cAll products have been previously reported and were identified by comparison of melting
point and their spectral data with those reported in the literature. Superscript against yield
refers to literature reference for product.1H and 13C-NMR are provided in the SI section.
6

Acknowledgments
This material is based upon work supported by the National Science Foundation under CHE –
1229133, which funded the purchase of a 400 MHz NMR spectrometer. We also acknowledge
funding from The American Chemical Society-Petroleum Research Fund (ACS PRF# 51036-
UR1).
Supplementary Material
Although all products have been previously reported, their spectral data is not readily available.
1H and 13C spectra not previously reported are included here.
References
1. (a) L. Rosenberger and D. J. Triggle in “Calcium and Drug Action”, G. B. Weiss, Ed., Plenum
Press, New York, 1978, p 1. (b) P. A. van Zweiten and E. Schönbaum, Eds., Prog. Pharmacol.,
2(1), 39 (1978). (c) Fleckenstein, A., Annu. Rev. Pharmacol. Toxicol., 1977, 17, 149.
2. Ladani, N.K.; Mungra, D.C.; Patel, M.P.; Patel R.G. Chinese Chem. Lett. 2011, 22, 1407
3. Kumar, A.; Sharma, S.; Tripathi, V.D.; Maurya, R.A.; Srivastava, S.P.; Bhatia, G.; Tamrakar,
A.K.; Srivastava, A.K. Bioorganic & Medicinal Chemistry 2010, 18, 4138.
4. Evans, C.G.; Jinwal, U.K.; Makley, L. N.; Dickey, C. A.; Gestwicki, J. E. Chem. Commun.
2011, 47, 529.
5. Miri, R.; Mehdipour, A. Bioorg. Med. Chem. 2008, 16, 8329.
6. Hantzsch, A. Ann. 1882, 215, 1.
7. Ko, S.; Sastry, M. N. V.; Lin, C.; Yao, C-F. Tetrahedron Lett. 2005, 46, 5771.
8. (a) Yb(OTf)3: Wang, L-M.; Sheng, J.; Zhang, L.; Han, J-W.; Fan, Z-Y.; Tian, H.; Qian, C-T.
Tetrahedron 2005, 61, 1539 (b) Sc(OTf)3: Donelson, J. L.; Gibbs, R. A.; De, S. K. J. Mol. Cat.
A:Chemical 2006, 256, 309.
9. Ko, S.; Yao, C-F. Tetrahedron 2006, 62, 7293.
10. Kumar, A.; Maurya, R. A. Tetrahedron Lett. 2007, 48, 3887.
7

11. Kumar, A.; Maurya, R. A. Tetrahedron 2007, 63, 1946.
12. Gadekar, L.S.; Katkar, S.S.; Mane, S.R.; Arbad, B.R.; Lande, M.K. Bulletin Korean Chem.
Soc. 2009, 30, 2532.
13. Debache, A.; Ghalem, W.; Boulcina, R.; Belfaitah, A.; Rhouati, S.; Carboni, B. Tetrahedron
Lett. 2009, 50, 5248.
14. Patil, D.R.; Deshmukh, M.B.; Salunkhe, S.M.; Salunkhe, D. K.; Kolekar, G.B.; Anbhule,
P.V. Der Pharma Chemica 2010, 2, 342.
15. Kumar, N.; Verma, S.; Jain, S.L. Chemistry Lett. 2012, 41, 920.
16. Fatma, S.; Ankit, P.; Singh, M.; Singh, S.B.; Singh, J. Synthetic Commun. 2014, 44, 1810.
17. Lambat, T.; Deo, S.; Deshmukh, T. J. Chem. Pharm. Res. 2014, 6, 888.
18. Kulkarni, P. J. Chil. Chem. Soc. 2014, 59, 2319.
19. Tekale, S.U.; Pagore, V.P.; Kauthale, S.S.; Pawar, R.P. Chinese Chem. Lett. 2014, 25, 1149.
20. (a) Ranjbar-Karimi, R.; Hashemi-Uderji, S.; Bazmandegan-Shamili, A. Chinese J. Chem.
2011, 29, 1624. (b) Shirini, F.; Atghia, S.V.; Khoshdel, M.A. Iranian J. Catal. 2011, 1, 93. (c)
Saikia, L.; Dutta, D.; Dutta, D.K. Catal. Commun., 2012, 19, 1. (d) Vahdat, S.M.; Chekin, F.;
Hatami, M.; Khavarpour, M.; Baghery, S.; Roshan-Kouhi, Z. Chin. J. Chem. 2013, 34, 758. (e)
Kiasat, A. R.; Almasi, H.; Saghanezhad, S. J. Rev. Roum. Chim. 2014, 59, 61. (f) Nasr-Esfahani,
M.; Hoseini, S.J.; Montazerozohori, M.; Mehrabi, R.; Nasrabadi, H. J. Mol. Catal. A: Chemical
2014, 382, 99.
21. (a) Nirmal, J.P.; Dadhaniya, P.V.; Patel, M.P.; Patel, R.G. Indian Journal of Chemistry,
Section B 2010, 49B, 587. (b) Rajendran, A.; Karthikeyan, C.; Rajathi, K. International Journal
of ChemTech Research 2011, 3, 810. (c) Raghuvanshi, D.S.; Singh, K.N. Indian Journal of
8

Chemistry, Section B 2013, 52B, 1218. (d) Rostamnia, S.; Hassankhani, A. Synlett 2014, 25,
2753.
22. Undale, K. A.; Shaikh, T. S.; Gaikwad, D. S.; Pore, D. M. Comptes Rendus Chimie 2011, 14,
511.
23. (a) Arumugam, P.; Perumal, P.T. Indian Journal of Chemistry, Section B 2008, 47B, 1084.
(b) Kumar, S.; Sharma, P.; Kapoor, K.K.; Hundal, M.S. Tetrahedron 2008, 64, 536.
24. (a) Zhang, X-L.; Sheng, S-R.; Liu, X-L.; Liu, X-L. ARKIVOC 2007, xiii, 79. (b) Das, S.;
Santra, S.; Roy, A.; Urinda, S.; Majee, A.; Hajra, A. Green Chemistry Letters and Reviews 2012,
5, 97. (c) Joshi, V.M.; Pawar, R.P. European Chemical Bulletin 2013, 2, 679.
25. Evans, C.G.; Gestwicki, J.E. Org. Lett. 2009, 11, 2957.
26. For a review on the utility of bismuth compounds in organic synthesis, see: (a) Ollevier, T.
Org. Biomol. Chem. 2013,11, 2740. (b) Krabbe, S. W.; Bothwell, J. M.; Mohan, R. S. Chem.
Soc. Rev. 2011, 40, 4649. For some recent examples of the use of bismuth(III) compounds in
organic synthesis see (c) Coca, A.; Feinn, L.; Dudley, J. Synthetic Commun. 2015, 45, 1023. (d)
Sabitha, G.; Shankaraiah, K.; Sindhu, K.; Latha, B. M. Synthesis 2015, 47, 124. (e) Sheng, J.;
Wu, J. Org. Biomol. Chem. 2014, 12, 7629. (f) Moskalenko, A. I.; Boev, V. I. Russian. J. Org.
Chem. 2014, 50, 1117. (g) Nitsch, D.; Bach, T. J. Org. Chem. 2014, 79, 6372. (h) Murai, M.;
Origuchi, K.; Takai, K. Org. Lett. 2014, 16, 3828. (i) Rasmussen, M. R.; Marqvorsen, M. H. S.;
Kristensen, S. K.; Jensen, H. H. J. Org. Chem. 2014, 79, 11011. (j) Schneider, A. E.; Beisel, T.;
Shemet, A.; Manolikakes, G. Org. Biomol. Chem. 2014, 12, 2356.
27. Representative procedure: A homogeneous mixture of p-tolualdehyde (0.5000 g, 4.16 mmol),
dimedone (0.6417 g, 4.58 mmol, 1.1 equiv.), ethyl acetoacetate (0.5968 g, 0.58 mL, 4.58 mmol,
1.1 equiv.), and ammonium acetate (0.3528 g, 4.58 mmol, 1.1 equiv.) was stirred in anhydrous
9

ethanol (10.0 mL) at room temperature as BiBr3 (0.0373 g, 2.0 mol%) was added. The reaction
progress was monitored by TLC (2,4-DNP stain). After 1.5 h, the reaction mixture was poured
onto 20 g of ice and the resulting yellow precipitate was collected via suction filtration. The
crude product was recrystallized using anhydrous ethanol (approximately 30 mL) to yield 1.2694
g (86% yield) of a slightly off-white, powdery compound. Mpt: 258-259 °C (Lit: 258-259 °C).
28. Heravi, M. M.; Saeedi, M.; Karimi, N.; Zakeri, M.; Beheshtiha, Y. S.; Davoodnia, A.
Synthetic Commun. 2010, 40, 523.
29. Maleki, B.; Tayebee, R.; Kermanian, M.; Ashrafi, S. S. J. Mex. Chem. Soc. 2013, 57, 290.
30. Ghasemzadeh, M. A.; Safaei-Ghomi, H. J. Chem. Res. 2014, 38, 313.
10