An Efficient One-Pot Synthesis of 1,2,3-Triazole-Fused Chromenes/Quinolines via Oxidative [3+2] Cycloaddition followed by Reductive Cyclization

Article abstract of DOI:10.1002/adsc.201800908

A convenient and efficient one-pot synthesis of 1,2,3-triazole-fused chromenes/ quinolines is developed. The methodology is based on oxidative azide-olefin [3+2] cycloaddition followed by intramolecular reductive cyclization. This methodology affords fast and simple access to 1,2,3-triazole-fused heterocycles in good to excellent yields without necessitating chromatographic purification. (Figure presented.).

Full text of DOI:10.1002/adsc.201800908

Title: An Efficient One-Pot Synthesis of 1,2,3-Triazole-Fused
Chromenes/ Quinolines via Oxidative [3+2] Cycloaddition
followed by Reductive Cyclization
Authors: Jebamalai Elangovan, Gangaprasad D, Paul Raj J,
Karthikeyan Kesavan, and Rengasamy R
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201800908
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10.1002/adsc.201800908
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
An Efficient One-Pot Synthesis of 1,2,3-Triazole-Fused
Chromenes/ Quinolines via Oxidative [3+2] Cycloaddition
followed by Reductive Cyclization
D. Gangaprasad,a J. Paul Raj,a K. Karthikeyana, R. Rengasamyb and J. Elangovanb*
a Department of Chemistry, B. S. Abdur Rahman Crescent Institute of Science & Technology, Vandalur, Chennai -
600048, India.
b Department of Chemistry, Rajah Serfoji Government College, Thanjavur, Tamilnadu - 613204, India.
email: elangoorganic@gmail.com
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
triazoles.[11]
Abstract. A convenient and efficient one-pot synthesis of
Literature reports infer that 1,2,3-triazole-fused
heterocycles can be synthesized primarily by two
strategic approaches. First strategy involves
1,2,3-triazole-fused chromenes/ quinolines is developed.
The methodology is based on oxidative azide-olefin [3+2]
cycloaddition followed by intramolecular reductive
cyclization. This methodology affords fast and simple
access to 1,2,3-triazole-fused heterocycles in good to
excellent yields without necessitating chromatographic
purification.
intermolecular
regioselective
1,3-dipolar
cycloaddition between azide and terminal alkyne
followed by metal catalyzed arylation (coupling) of
the resulting 1,2,3-triazole (Scheme 1, A). With this
strategy Ackermann[12] synthesized 1,2,3-triazole-
fused chromenes by a click reaction then followed by
an intramolecular dehydrogenative arylation using a
Pd2+−Cu2+ catalytic system under air. More recently,
Keywords: Fused 1,2,3-Triazoles; One-Pot Synthesis;
Oxidative [3+2] Cycloaddition; Reductive Cyclization
Chromene and quinoline are two important structural
scaffolds for pharmaceutical and biologically active
natural products.[1-4] On the other hand, the 1,2,3-
triazole moiety has its own importance in synthetic,
medicinal and materials chemistry.[5-6] Especially,
1,2,3-triazole-fused heterocycles are found in a wide
spectrum of bioactive molecules and pharmaceutical
targets (Figure 1), such as benzodiazepine receptors,
chemotherapeutic,
GPR109A
agonists
and
cardiovascular agents.[7-10] Hence, new strategies to
synthesize this class of molecules are highly desirable.
In this regard, different methods have been developed
toward the synthesis of compounds containing fused
Figure 1. Pharmacologically active 1,2,3-triazole-fused
Scheme 1. Synthetic routes to access 1,2,3-triazole-fused
heterocycles.
heterocycles.
1
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10.1002/adsc.201800908
Advanced Synthesis & Catalysis
Lautens[13] developed an elegant palladium-catalyzed, were observed. The screening of solvent, azide
intramolecular cyclization of 5-iodotriazoles to afford (equiv), catalyst load (equiv) and temperature was
a number of 1,2,3-triazole-fused chromenes. Later, in also examined. However, DMF was chosen for the
2013 Wang[14] reported palladium catalyzed synthesis OAOC of 2-hydroxychalcone since it accomplished
of 1,2,3-triazole-fused chromenes/ quinolones. The higher yield (81%) of triazole 4a than toluene (Table
second strategy involves thermal or metal-catalyzed 1, entries 4-5) with azide (1.2 equiv) and CuO NPs
regioselective
cycloaddition (IAAC) of the azido-alkyne substrates
(Scheme 1, B). In this regard, Swamy[15] described a reduction cyclization of 2-hydroxychalcones and 2-
copper-catalyzed tandem, one-pot
click- nitrochalcones respectively,[25-26] prompted us to
intramolecular
azide-alkyne (20 mol%) at 100 °C.
Synthesis of flavans and quinolines through
intramolecular arylation sequence to generate several investigate the synthesis of 1,2,3-triazole-fused
1,2,3-triazole-fused chromenes. Cai and Gong heterocycles. Reduction of keto group of the triazole
reported Cu(I)-catalyzed cascade reactions of 1,1,1- (4a) was examined upon treatment with NaBH4 in
trifluoro-N-(2-iodophenyl)but-3-yn-2-imines and N- methanol at RT which affords the corresponding
(2-iodophenyl) propiolamides with sodium azide to alcohol 6a in 98% yield (Scheme 2).
achieve tricyclic 4-(trifluoromethyl)-[1,2,3]triazolo
[1,5-a]
quinoxalines
and
1,2,3-triazolo[1,5-
a]quinoxalin-4(5H)-ones through cycloaddition and
intramolecular Ullmann coupling.[16-17] In 2011, Yao
described copper-catalyzed [3+2] cycloaddition,
followed by N-arylation to access indoline- and
thiophene-fused triazolothiadiazepine 1,1-dioxide
derivatives.[18]
In continuation of our work on azide-olefin [3+2]
cycloaddition reactions,[19-22] we have developed an
alternative methodology based on oxidative azide-
olefin [3+2] cycloaddition of organic azides with 2-
hydroxychalcones (1) and 2-nitrochalcones (2)
respectively, followed by reductive cyclization
(Scheme 1, C) to access 1,2,3-triazole-fused
heterocycles. This straightforward one-pot synthesis
of 1,2,3-triazole-fused chromenes/ quinolones
constitutes an important alternative strategy to the
reported multistep route (Scheme 1, A and B).
Scheme 2. Reduction of keto group of the 1,2,3-triazole 4a.
Initially cyclization of alcohol 6a was examined
with acetic acid at 80 °C for 2 h, excellent yield of the
corresponding 1,2,3-triazole-fused chromene (7a) was
obtained (Table 2, entry 1). The effect of catalyst,
solvent and temperature were also studied (Table 2,
entries 1-6). However acetic acid was chosen for the
cyclization of alcohol 6a since it accomplished higher
yield of 7a than PTSA and HCl. It was found that the
synthesis of 4a, 6a and 7a proceeded without
necessitating the chromatographic purification.
Table 2. Optimization for the cyclization of alcohol 6a.[a]
At the outset, we have started our investigations
with 2-hydroxychalcone (1a) and benzyl azide (3a) as
model substrates for optimizing the oxidative azide-
olefin cycloaddition (OAOC) reaction by using CuO
nanoparticles (NPs) catalyst chosen from our previous
report.[19] Initially the reaction was performed with
1.0 mmol of 3a at 90 °C in DMF, producing 64%
Entry Catalyst (equiv.) Solvent T (°C) Time (h) Yield of 7a
yield of 4a (Table 1, entry 1). Exclusively, one regio-
(%)[b]
23-24]
isomeric[19,
1,2,3-triazole 4a was achieved in
1
2
3
4
5
6
AcOH
AcOH
-
80
2
0.5
0.5
1
90
90
90
83
66
78
DMF and toluene (Table 1) and no other products
-
100
100
100
100
100
AcOH
DMF
DMF
DMF
DMF
Table 1. Optimization of OAOC with 2-hydroxychalcones.[a]
PTSA (1.0)
HCl(1.0)
HCl(2.0)
5
5
[a] Reaction conditions: Alcohol 6a (1.0 mmol), acetic acid (3 mL) and
DMF (3 mL) were heated at 100 °C for 0.5h. [b] Isolated yields.
Entry
Azide
(equiv.)
1.0
CuO NPs
(mol%)
20
Solvent
T (°C) Yield of 4a
(%)[b]
With these excellent initial results in hand, a three-
step, “one-pot” procedure was attempted. Since the
oxidative [3+2] cycloaddition was carried out in DMF
solvent, we reasoned that by optimizing the second
1
2
DMF
DMF
90
90
64
70
1.2
20
3
4
5
6
7
1.0
1.2
1.2
1.2
1.5
20
20
20
15
20
DMF
DMF
100
100
100
100
100
66
81
53
72
80
Toluene
DMF
DMF
[a] Reaction conditions: 2-hydroxychalcone 1a (1.0 mmol), benzyl azide
3a (1.2mol),CuO NPs (20 mol%) and solvent (4 mL) were heated for 12h.
[b] Isolated Yields.
Scheme 3. One-pot synthesis of 1,2,3-triazole-fused
chromene 7a.
2
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10.1002/adsc.201800908
Advanced Synthesis & Catalysis
and third steps (reduction and cyclization respective-
ly) using DMF, which enables us to carry out the
substituted-1,2,3-triazole (5a) in 86% yield.
Initially reductive cyclization of triazole 5a was
entire synthetic sequence in a one-pot procedure. This examined with Iron powder (5.0 mmol), ammonium
definitely proved to be highly efficient process in our chloride (5.0 mmol) in MeOH were refluxed for 5 h,
test experiment as outlined in Scheme 3.
the corresponding 1,2,3-triazole-fused quinoline (8a)
Three step, one-pot synthesis of 1,2,3-triazole-fused was obtained in 88% yield (Table 4, entry1). The
chromene (7a) was examined from the above effect of additive (acid catalyst) and reductant was
optimized conditions. Initially OAOC was carried out also studied (Table 4, entries 1-5). However Iron
with 2-hydroxychalcone 1a (1.0 mmol) and benzyl powder and acetic acid combination was chosen for
azide 3a (1.2 mmol) using CuO NPs (20 mol%) in the reductive cyclization of triazole 5a since it
DMF (3 mL) at 90 °C for 12 h. Completion of accomplished higher yield (90%) of 8a in relatively
reaction was monitored by the TLC, NaBH4 (5.0 shorter duration than other combinations (Table 4,
mmol) was added in small portions at 0 °C and stirred entry 2).
at RT for 0.5 h to afford the corresponding alcohol 6a,
which on treatment with acetic acid (3 mL) at 100 °C, Table 4. Optimization for reductive cyclization of triazole 5a.[a]
cleanly produces the desired 1,2,3-triazole-fused
chromene (7a) in 74% overall yield (Scheme 3).
Under the optimized reaction conditions, we further
investigated the scope of the reaction (Table 3). A
wide range of 2-hydroxychalcones (1) were treated
with organic azides (3) which led to the 1,2,3-triazole-
Entry
Reductant
Fe[c]
Solvent
MeOH
AcOH
EtOH
Time (h)
Yield 29a(%)[b]
fused chromenes (7) in moderate to excellent yields in
one-pot. In all the cases single product (7) was
obtained without necessitating chromatographic
purification. Substrates bearing both electron-
donating and electron-withdrawing groups were
tolerated (Table 3, entries 7a-7s).
1
2
3
4
5
5
0.5
1
88
90
86
62
79
Fe
Fe[d]
Fe[d]
Zn
MeOH
AcOH
1
2
[a] Reaction conditions: Triazole 26a (1.0 mmol), catalyst (5.0 mmol) and
solvent (3 mL) were refluxed for particular time. [b] Isolated yields. [c]
NH4Cl (5.0 mmol). [d] Conc. HCl (1.0 mmol).
Table 3. Reaction scope for 1,2,3-triazole-fused chromenes 7.[a-b]
With these excellent initial results in hand, a two-step,
“one-pot” procedure was attempted. Since the
oxidative [3+2] cycloaddition of 2-nitrochalcone (2a)
was carried out in DMF solvent, we reasoned that by
optimizing the second step (reductive cyclization)
using DMF and acetic acid, we should be able to
carry out the entire synthetic sequence in a one-pot
procedure.
Scheme 5. One-pot synthesis of 1,2,3-triazole-fused
quinoline 8a.
Azide-olefin cycloaddition and reductive cyclization
strategy was extended for the construction of 1,2,3-
triazole-fused quinolines. With the success of triazole
(4a) derivatives in hand, the optimized reaction
condition adopted from Table 2 is applied to perform
the oxidative cycloaddition reaction of 2-
nitrochalcone (2a) with benzyl azide (3a) using CuO
NPs (20 mol%), in DMF and the reaction underwent
smooth conversion to obtain the desired 1,4,5-tri-
Two-step, one-pot synthesis of 1,2,3-triazole-fused
quinoline (8a) was examined from the above
optimized conditions. Initially OAOC was carried out
with 2-nitrochalcone 2a (1.0 mmol) and benzyl azide
3a (1.2 mmol) using CuO NPs (20 mol%) in DMF (3
mL) at 90 °C for 12 h. Completion of reaction was
monitored by the TLC, Iron powder (5.0 mmol) and
acetic acid (3 mL) were added and refluxed for 0.5 h
to afford the desired 1,2,3-triazole-fused quinolone
(8a) in 83% overall yield (Scheme 5).
Under the optimized reaction conditions, we further
investigated the scope of the reaction (Table 5). A
wide array of 2-nitrochalcones (2) reacted with
organic azides (3) which led to the 1,2,3-triazole-
fused quinolines (8) in moderate to excellent yields in
Scheme 4. OAOC of 2-nitrochalcone with benzyl azide.
3
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10.1002/adsc.201800908
Advanced Synthesis & Catalysis
one-pot without necessitating chromatographic
purification. Substrates bearing both electron-
donating and electron-withdrawing groups were
tolerated in this conversion (Table 5, entries 8a-8o).
General procedure for one-pot synthesis of 1,2,3-
triazole-fused quinolines (8a-o)
A mixture of 2-nitrochalcone 2 (1.0 mmol), organic
azide 3 (1.1 mmol), CuO NPs (20 mol%) and DMF (3
mL) were heated at 90 °C for 12 h. The completion of
the reaction was monitored by TLC, and then Iron
powder (5.0 mmol) and acetic acid (3 mL) were
added and refluxed for 0.5 h. Completion of the
reaction was monitored by TLC and the reaction
mixture was cooled to room temperature. The black
sludge was filtered through a bed of celite and washed
with DCM (20 mL). The combined filtrates were
washed with water (40 mL). The organic layer was
dried (NaSO4) and concentrated under vacuum to
afford the pure 1,2,3-triazole-fused quinolones (8a-o)
in moderate to excellent yield.
Table 5. Reaction scope for 1,2,3-triazole-fused quinolines 8.[a-b]
Acknowledgments
DG thanks the CSIR, New Delhi for Senior Research Fellowship
(09/1166(0001)/2017-EMR-I).
References
In conclusion, we have developed an easy and
efficient one-pot protocol to synthesize novel 4-aryl
substituted 1,2,3-triazole-fused chromenes and 4-aryl
substituted 1,2,3-triazole-fused quinolines via
oxidative [3+2] cycloaddition using CuO NPs,
followed by an intramolecular reductive cyclization
sequence. The precedent methods for synthesizing
1,2,3-triazole fused heterocycles often involve multi
step synthesis, utilization of costly catalysts such as
palladium and poor synthetic availability of the
starting materials. But this method affords a fast and
simple access to a diverse array of 1,2,3-triazole-
fused heterocycles in good to excellent yields without
necessitating chromatographic purification.
1. R. Prathap, V. Ji Ram, Chem. Rev. 2014, 114, 10476-10526.
2. N. Thomas, S. M. Zachariah, Asian J. Pharm. Clin. Res.
2013, 6, 11-15.
3. S. M. Prajapati, K. D. Patel, R. H. Vekariya, S. N. Panchal, H.
D. Patel, RSC Adv. 2014, 4, 24463-24476.
4. S. Kumar, S. Bawa, H. Gupta, Mini Rev. Med. Chem. 2009,
9, 1648-1654.
5. Chem. Soc. Rev. 2010, 39, 1221-1408.
6. Y. L. Angell, K. Burgess, Chem. Soc. Rev. 2007, 36, 1674-
1689.
7. G. Biagi, I. Giorgi, O. Livi, V. Scartoni, L. Betti, G.
Giannaccini, M. L. Trincavelli, Eur. J. Med. Chem. 2002,
37, 565-571.
8. L. S. Kallander, Q. Lu, W. Chen, T. Tomaszek, G. Yang, D.
Tew, T. D.Meek, G. A. Hofmann, C. K. Schulz-Pritchard,
W.W. Smith, C. A. Janson, M. D. Ryan, G.-F. Zhang, K. O.
Johanson, R. B. Kirkpatrick, T. F. Ho, P. W. Fisher, M. R.
Mattern, R. K. Johnson, M. J. Hansbury, J. D. Winkler, K.
W. Ward, D. F. Veber, S. K. Thompson, J. Med. Chem.
2005, 48, 5644-5647.
9. H. C. Shen, F. Ding, Q. Deng, L. C. Wilsie, M. L.
Krsmanovic, A. K. Taggart, E. Carballo-Jane, N. Ren, T.
Cai, T. Wu, K. K. Wu, K. Cheng, Q. Chen, M. S. Wolff, X.
Tong, T. G. Holt, M. G. Waters, M. L. Hammond, J. R.
Tata, S. L. Colletti, J. Med. Chem. 2009, 52, 2587-2602.
10. D. Niculescu-Duvaz, I. Niculescu-Duvaz, B. M. J. M.
Suijkerbuijk, D. Menard, A. Zambon, A. Nourry, L. Davies,
H. A. Manne, F. Friedlos, L. Ogilvie, D. Hedley, A. K.
Takle, D. M. Wilson, J.-F. Pons, T. Coulter, R. Kirk, N.
Cantarino, S. Whittaker, R. Marais, C. J. Springer, Bioorg.
Med. Chem. 2010, 18, 6934-6952.
Experimental Section
General procedure for one-pot synthesis of 1,2,3-
triazole-fused chromenes (7a-s)
A mixture of 2-hydroxychalcone 1 (1.0 mmol),
organic azide 3 (1.2 mmol), CuO NPs (20 mol%) and
DMF (3 mL) were heated at 90 °C for 12 h.
Completion of reaction was monitored by the TLC
and then NaBH4 (5.0 mmol) was added in small
portions at 0 °C and stirred at RT for 0.5 h to afford
the corresponding alcohol (6). Following that acetic
acid (3 mL) was added and the temperature was
gradually raised to 100 °C and then heated for 0.5 h.
The consumption of the starting materials was
monitored by TLC. The reaction mixture was cooled
to room temperature and poured into the ice water (50
mL) there by the precipitated solid was filtered and
washed with hexane (10-20 mL) and dried under
vacuum to obtain pure 1,2,3-triazole-fused chromenes
(7a-s) in moderate to excellent yield.
11. E. A. Shafran, V. A. Bakulev, Y. A. Rozin, Y. M. Shafran,
Chem. Heterocycl. Compd. 2008, 44, 1040-1069.
12. L. Ackermann, R. Jeyachandran, H. K. Potukuchi, P.
Novak, L. Buttner, Org. lett. 2010, 12, 2056-2059.
13. J. M. Schulman, A. A. Friedman, J. Panteleev, M. Lautens,
Chem. Commun. 2012, 48, 55-57.
14. C.-Y. Chen, C.-H. Yang, W.-P. Hu, J. K. Vandavasi, M.-I.
4
This article is protected by copyright. All rights reserved.

10.1002/adsc.201800908
Advanced Synthesis & Catalysis
Chung, J.-J. Wang, RSC Adv. 2013, 3, 2710-2719.
15. M. Nagarjuna Reddy, K. C. Kumara Swamy, Eur. J. Org.
Chem. 2012, 2012, 2013-2022.
16. Z. Chen, J. Zhu, H. Xie, S. Li, Y. Wu, Y. Gong, Adv. Synth.
Catal. 2010, 352, 1296-1300.
17. J. Yan, F. Zhou, D. Qin, T. Cai, K. Ding, Q. Cai, Org. Lett.
2012, 14, 1262-1265.
18. D. K. Barange, Y-C. Tu, V. Kavala, C-W. Kuo, C-F. Yao,
Adv. Synth. Catal. 2011, 353, 41-48.
19. D. Gangaprasad, J. Paul Raj, T. Kiranmye, S. SagubarSadik,
J. Elangovan, RSC Adv. 2015, 5, 63473-63477.
20. D. Gangaprasad, J. Paul Raj, T. Kiranmye, R. Sasikala, K.
Karthikeyan, S. Kutti Rani, J. Elangovan, Tetrahedron Lett.
2016, 57, 3105-3108.
21. D. Gangaprasad, J. Paul Raj, T. Kiranmye, K. Karthikeyan,
J. Elangovan, Eur. J. Org. Chem. 2016, 2016, 5642-5646.
22. J. Paul Raj, D. Gangaprasad, K. Karthikeyan, M. Vajjiravel,
J. Elangovan, J. Chem. Sci. 2018, 130, 44-49.
23. D. Janreddy, V. Kavala, C.-W. Kuo, W.-C. Chen, C.
Ramesh, T. Kotipalli, T.-S. Kuo, M.-L. Chen, C.-H. He, C.-
F. Yao, Adv. Synth. Catal. 2013, 355, 2918-2927.
24. W. Yang, T. Miao, P. Li, L. Wang, RSC Adv. 2015, 5,
95833-95839.
25. O. Mazimba, I. B. Masesane, R. R. Majinda, Tetrahedron
Lett. 2011, 52, 6716-6718.
26. W.-C. Chen, C.-C. Lin, V. Kavala, C.-W. Kuo, C.-Y. Huang
and C.-F. Yao, Molecules, 2015, 20, 22499-22519.
5
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10.1002/adsc.201800908
Advanced Synthesis & Catalysis
COMMUNICATION
An Efficient Synthesis of 1,2,3-Triazole-Fused
Chromenes/ Quinolines via Oxidative [3+2]
Cycloaddition
Cyclization
Followed
by
Reductive
Adv. Synth. Catal. Year, Volume, Page – Page
D. Gangaprasad,a J. Paul Raj,a K. Karthikeyana, R.
Rengasamyb and J. Elangovanb*
An easy and efficient one-pot synthesis of 1,2,3-triazole-fused chromenes/ quinolines is developed. The
methodology is based on oxidative azide-olefin [3+2] cycloaddition followed by intramolecular reductive
cyclization. This methodology affords fast and simple access to 1,2,3-triazole-fused heterocycles in good to
excellent yields without necessitating chromatographic purification.
6
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