An efficient and facile synthesis of novel triazole C-N linked chromone hybrids

Article abstract of DOI:10.14233/ajchem.2020.22734

A series of new C₃-N₁directly linked chromone/1,2,3-triazole molecular hybrids synthesized by adopting low cost effective CuI catalyzed azide-alkyne 1,3-dipolar cycloaddition (Cu-AAC triazole annulation) from chromone-3-aldehyde via key intermediates 3-azidochromone, synthesized from another intermediate 3-hydroxychromone. These synthetic 1,2,3-triazole embedded chromones are the new addition to the click chemistry family. The structures of final products established by IR, NMR and mass spectral analysis.

Full text of DOI:10.14233/ajchem.2020.22734

Asian Journal of Chemistry; Vol. 32, No. 7 (2020), 1806-1808
A
SIAN
J
OURNAL OF HEMISTRY
C
https://doi.org/10.14233/ajchem.2020.22734
An Efficient and Facile Synthesis of Novel Triazole C-N Linked Chromone Hybrids
*,
B. KANAKADURGA RAO and Y. JAYAPRAKASH RAO
Department of Chemistry, Osmania University, Hyderabad-500007, India
Corresponding author: E-mail: yjpr_19@yahoo.com
Received: 19 March 2020; Accepted: 4 May 2020;
*
Published online: 27 June 2020;
AJC-19952
A series of new C
3
1
-N directly linked chromone/1,2,3-triazole molecular hybrids synthesized by adopting low cost effective CuI catalyzed
azide-alkyne 1,3-dipolar cycloaddition (Cu-AAC triazole annulation) from chromone-3-aldehyde via key intermediates 3-azidochromone,
synthesized from another intermediate 3-hydroxychromone. These synthetic 1,2,3-triazole embedded chromones are the new addition to
the click chemistry family. The structures of final products established by IR, NMR and mass spectral analysis.
Keywords: 3-Hydroxychromone, 3-Azido-chromone, Aryl/alkyl acetylenes, Click cycloaddition, Chromone, 1,2,3-Triazole.
click chemistry. To the best of our knowledge there is no report
on N-heterocyclic directly linked to chromone scaffold.
INTRODUCTION
The chromone frame work is the core moiety in numerous
EXPERIMENTAL
flavonoid secondary metabolites such as flavones, flavonols
and isoflavones [1]. Natural and synthetic compounds having
chromone scaffold shows multiple biological activities, like
antitumor [1], anti-hepatotoxic, antioxidant [2], anti-inflam-
matory [3], anti-spasmolytic, estrogenic [4] and antibacterial
activities [5]. In addition 1,2,3-triazoles attracted attention in
bioconjugation, medicinal chemistry, chemical biology, organic
synthesis and material science [6-8], Furthermore, 1,2,3-triazoles
are widely used as building block for many complex chemical
compounds, such as pharmaceutical drugs like tazobactam [9].
These medicinal applications of chromone and 1,2,3-
triazole pharmacophores have stimulated an organic chemist
for the continuous synthesis of new chromones and their hetero-
cyclic hybrid derivatives to evaluate biological activity. Novel
hybrid heterocyclics containing two or more bioactive scaffolds
are expected to possess higher biological activities than parent
skeleton [10,11].
All chemicals and reagents were purchased from comm-
ercial source and used as such without further purification. Melting
points were measured on the open capillary method and are
uncorrected. IR spectra were recorded on Shimadzu-8400
FTIR spectrophotometer. H & C NMR spectra were measured
on a Bruker Avance II 400 spectrometer, operating at 400 and
100 MHz, respectively. Molecular weights were determined with
ESI Mass spectra. Reactions were monitored by thin layer
chromatography (TLC) on silica gel; plates were visualized with
ultraviolet light or iodine. Column chromatography was perf-
ormed on silica gel 60 (0.043-0.06 mm) Merck.
Synthesis: Chromone-3-aldehyde (2a) and 3-hydroxy-
chromone (3a) were synthesized according to the literature
procedure described elsewhere [15,16].
Synthesis of 4-oxo-4H-chromen-3-yl trifluoromethane
sulfonate (4a): To a solution of 3-hydroxychromone (3a) (10
mmol) in dry DCM (10 mL) triethyl amine (2.2 mmol) was
1
13
A CuI catalyzed azide-alkyne 1,3-dipolar cycloaddition
click reaction is the powerful tool for the generation of regio-
selective 1,4 disubstituted 1,2,3-triazoles and are highly tolerant
and flexible to several organic functions. In continuation of
our efforts on structural modification of chromones and 1,2,3-
triazole core to improve their pharmacological activity [12-14],
added in portions under the atmosphere of N maintaining at
2
0 ºC. After stirring the mixture at this temperature for 15 min,
triflic anhydride (2 mmol) was added and the reaction mixture
was stirred at room temperature for 3 h. After completion of
reaction quenched with water and extraction with DCM. The
combined organic layers were washed with water and dried
we have designed and synthesized new C
3
-N directly linked
1
chromone/1,2,3-triazole hybrid templates, adopting CuI-catalyzed
over conc. Na
2
SO under reduced pressure. The crude product
4
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Vol. 32, No. 7 (2020)
An Efficient and Facile Synthesis of Novel Triazole C-N Linked Chromone Hybrids 1807
was purified by column chromatography giving the desired
product 4-oxo-4H-chromen-3-yltrifluoromethane sulfonate
120.92, 122.75, 125.84, 126.24, 126.47, 127.54, 129.71, 130.92,
132.54, 134.75, 138.25, 148.09, 150.31, 155.88, 170.74; ESI-
MS: 290 [M+H] .
+
(
4a) 70-75% yield [17].
Synthesis of 3-azido-4H-chromen-4-one (5a): To a stirred
solution of 3-((trifluoromethyl)sulfonyl)-4H-chromen-4-one
4a) (1mmol), DMF (10mL) sodium azide (1.2 mmol) was
added. The reaction mixture was refluxed at 90 ºC for 3 h.After
the starting materials were consumed as judged byTLC analysis,
the reaction mixture was poured in to ice cold water; obtained
precipitate was filtered and purified by column chromato-
graphy using ethyl acetate/pet ether (2:8) to afford 3-azido-
3-(4-(4-Methoxyphenyl)-1H-1,2,3-triazol-1-yl)-4H-
chromen-4-one (6c): Light brown colour solid; yield 80%;
-1
(
m.f.: C18
H
13
N
3
O
3
; m.p.: 210-212 ºC; IR (KBr, νmax, cm ): 1728
1
(C=O); H NMR (400 MHz, CDCl ) δ ppm: 3.87 (s, 3H, OCH ),
3
3
7.00 (d, 2H, J = 8.7 Hz, Ar-H), 7.55 (t, 1H, J = 7.4 Hz, Ar-H),
7.63 (d, 1H, J = 8.5 Hz, Ar-H), 7.80 (d, 1H, J = 7.1 Hz, Ar-H),
7.86 (d, 2H, J = 8.7 Hz, Ar-H), 8.41-8.35 (m, 1H, Ar-H), 8.77
13
(s, 1H, triazole-H), 8.94 (s, 1H, C
2
-H); C NMR (100 MHz,
4
H-chromen-4-one (5a) in good yield. Light brown coloured
CDCl ) δ ppm: 57.25, 114.10, 116.76, 118.58, 122.74, 123.90,
3
solid;Yield 60%; m.f.: C ; m.p.:186-188 ºC; IR (KBr,
H N O
9 5 3 2
124.73, 127.82, 128.25, 129.65, 131.61, 130.94, 136.95, 143.25,
-1
1
+
ν
max, cm ): 1726 (C=O), 2123 (N=N=N); H NMR (400 MHz,
CDCl ) δ ppm: 7.42 (t, 1H, J = 7.5Hz, Ar-H), 7.51 (d, 1H, J =
.5 Hz, Ar-H), 7.70 (t, 1H, J = 7.8 Hz, Ar-H), 8.02 (s, 1H Ar-
148.29, 150.31, 156.78, 161.25, 170.72; ESI- MS: 320 [M+H] .
3
3-(4-(4-Fluorophenyl)-1H-1,2,3-triazol-1-yl)-4H-
8
chromen-4-one (6d): Light brown colour solid; yield 80%;
+
-1
H), 8.27 (d, 1H, J = 8.0 Hz, Ar-H); ESI-MS: 188 [M+H] .
Synthesis of 3-(4-phenyl-1H-1,2,3-triazol-1-yl)-4H-
chromen-4-on (6a-f): To a stirred solution of 3-azido-4H-
chromen-4-one (5a) (1.0 mmol) and aryl acetylenes (1.5 mmol)
in DMF (8 mL) was added a saturated CuI catalyst (0.02 mmol).
The reaction mixture was refluxed at 90 ºC for 2h. The compl-
etion of reaction examined by TLC. The reaction mixture poured
into ice cold water and extracted with ethyl acetate. The organic
C
17
H
10
N
3
O
2
F;m.p.: 210-212 ºC. IR (KBr, νmax, cm ): 1738 (C=O);
1
H NMR (400 MHz, CDCl ): 7.16 (t, 2H, J = 8.7 Hz, Ar-H),
3
7.56 (t, 1H, J = 7.9 Hz, Ar-H), 7.64 (d, 1H, J = 8.3 Hz, Ar-H),
7.81 (m 1H, Ar-H), 7.91 (dd, 2H, J = 8.8, 5.3Hz, Ar-H), 8.38 (d,
1H, J = 8.0 Hz, Ar-H), 8.83 (s, 1H, triazole-H), 8.95 (s, 1H, C -
2
1
3
H); C NMR (100 MHz, CDCl ) δ ppm: 114.11, 116.54, 116.63,
3
118.48, 121.92, 124.23, 126.02, 126.45, 126.42, 127.45, 132.74,
138.25, 148.09, 156.28, 164.54, 170.42; ESI- MS: 308 [M+H] .
+
layer separated and dried with Na
2
SO
4
and concentrated under
3-(4-Butyl-1H-1,2,3-triazol-1-yl)-4H-chromen-4-one
reduced pressure. The products purified by column chromato-
graphy to afford pure compounds (6a-f) (Scheme-I).
(6e): Light yellow colour solid; yield 75%; m.f.: C15
H
15
N
3
O ;
2
-1
1
m.p.: 218-220 ºC; IR (KBr, νmax, cm ): 1730 (C=O); H NMR
(400 MHz, CDCl ) δ ppm: 1.00-0.95 (m, 3H, CH ), 1.44 (dd,
2H, J = 14.9, 7.6 Hz, CH ), 1.74 (dt, 2H, J = 15.4, 7.6 Hz, CH ),
2.85-2.80 (m, 2H, CH ), 7.56-7.50 (m, 1H, Ar-H ),7.61 (d, 1H,
J = 8.1 Hz, Ar-H ), 7.80 (dd, 1H, J = 8.7, 7.2, 1.7 Hz, Ar-H),
3
-(4-(p-Tolyl)-1H-1,2,3-triazol-1-yl)-4H-chromen-4-
3
3
one (6a): Light brown colour solid; yield 80%; m.f.: C18
H
13
N
3
O
2
;
2
2
-1
1
m.p.: 218-220 ºC. IR (KBr, νmax, cm ): 1734 (C=O); H NMR
400 MHz, CDCl ) δ ppm: 2.41 (s, 3H, CH ), 7.28 (d, 2H, J =
.4 Hz, Ar-H), 7.55 (t, 1H, J = 7.5 Hz, Ar-H), 7.63 (d, 1H, J =
.4 Hz, Ar-H), 7.81 (t, 3H, J = 7.4 Hz, Ar-H), 8.38 (d,1H, J =
2
(
3
3
1
3
8
8
7
8.42–8.11 (m, 2H, Ar-H), 8.86 s (1H, triazole-H); C NMR
(100 MHz, CDCl
3
) δ ppm: 14.16, 22.73, 29.73, 33.86, 114.09,
13
.8 Hz, Ar-H), 8.82 (s, 1H, triazole-H), 8.95 (s, 1H, C
2
-H); C
118.54, 122.46, 126.39, 128.84, 130.9, 134.66, 139.32, 148.66,
+
3
NMR (100 MHz, CDCl ): 21.37, 114.00, 118.58, 120.90, 124.13,
150.28, 155.62, 167.74; ESI- MS: 270 [M+H] .
1
25.82, 126.25, 126.42, 127.45, 128.84, 129.61, 130.94, 134.75,
3-(4-(4-Chlorophenyl)-1H-1,2,3-triazol-1-yl)-4H-
chromen-4-one (6f): White colour solid; yield 80%; m.f.:
+
138.25, 148.09, 150.31, 155.78, 170.72; ESI- MS: 304 [M+H] .
-1
3
-(4-Phenyl-1H-1,2,3-triazol-1-yl)-4H-chromen-4-one
6b): White colour solid; yield 70%; m.f.: C17 ; m.p.:
26-228 ºC; 1730 (C=O), IR (KBr, νmax, cm ): H NMR (400
): 7.37 (t, 1H, J = 7.4 Hz, Ar-H), 7.47 (t, 2H, J = 7.5
C
17
H
10
N
3
1
O
2
Cl; m.p.: 215-218 ºC; IR (KBr, νmax, cm ): 1724
(
2
H
11
N O
3 2
(C=O); H NMR (400 MHz, CDCl ):7.44 (d, 2H, J = 8.6 Hz,
3
-1
1
Ar-H), 7.59-7.53 (m,1H, Ar-H), 7.64 (d, 1H, J = 7.9 Hz, Ar-H),
7.89-7.79 (m, 3H, Ar-H), 8.38 (dd, 1H, J = 8.0, 1.6 Hz, Ar-H),
MHz, CDCl
3
1
3
Hz,Ar-H), 7.56 (t, 1H, J = 7.5 Hz,Ar-H), 7.64 (d, 1H, J = 8.4 Hz,
Ar-H), 7.82 (t, 1H, J = 7.1 Hz, Ar-H), 7.94 (d, 2H, J = 7.3 Hz,
Ar-H), 8.38 (d, 1H, J = 6.9 Hz, Ar-H), 8.87 (s, 1H, triazole-H),
8.87 (s, 1H, triazole-H), 8.96 (s, 1H, C
CDCl
2
-H); C NMR (100 MHz,
3
) δ ppm: 114.11, 118.28, 121.92, 124.23, 126.12, 132.02,
132.90, 133.12, 134.25, 134.97, 136.74, 137.35, 148.09, 150.31,
13
+
8.96 (s, 1H, C
2
-H); C NMR (100 MHz, CDCl
3
): 114.12, 118.60,
157.02, 171.12; ESI- MS: 346 [M+Na] .
O
O
O
O
O
OH
(i)
(ii)
(iii)
(iv)
(v)
O
CF3
S
CHO
OH
O
3a
O
N3
N
N N
R
O
O
2a
O
4a
O
5a
O
O
1a
6a-f
R =
Cl
F
Br
NO2
(6g)
CH3
OCH3
(
6a)
(6b)
(6c)
(6d)
(6e)
(6f)
(6g)
Scheme-I: Synthesis of chromone-1,2,3-triazole hybrids (6a-h); Reaction conditions: (i) POCl
m-CPBA, DCM, 40 °C reflux, 24 h, yield 70%. (iii) Trifluoro methane sulfonic anhydride, triethylamine in DCM, 0 °C, room temperature, 3 h,
yield 70-75%. (iv) NaN , DMF, 90 °C, 3 h, yield 60%. (v) CuI, alkyl/aryl acetylenes, DMSO, 60 °C, 1 h, yield 80%
3
in DMF, room temperature, 24 h, yield 75-80%. (ii)
3

1
808 Rao et al.
Asian J. Chem.
O
O
3
-(4-(4-Bromophenyl)-1H-1,2,3-triazol-1-yl)-4H-
N
N
N
chromen-4-one (6g): Light white colour solid; yield 74%;
R
-1
H
[ C u L n ]
R
m.f.: C17
H
10
N O
3 2
Br; m.p.: 208-210 ºC. IR (KBr, νmax, cm ): 1728
C=O); H NMR (400 MHz, CDCl ) δ ppm: 7.48 (d, 2H, J =
.4 Hz, Ar-H), 7.55-7.52 (t, 1H, Ar-H), 7.64 (d, 1H, J = 8.1 Hz,
H +
1
(
8
3
O
O
H +
N
N
N
R
R
C u L n
O
Ar-H), 7.78-7.65 (m 3H, Ar-H), 8.39 (d, 1H, J = 8.1 Hz, Ar-
C u L n
13
N
N
H), 8.75 (s, 1H, triazole-H), 8.97 (s, 1H, C
MHz, CDCl ) δ ppm: 114.11, 116.53, 120.41, 123.12, 124.96,
24.23, 126.10, 128.25, 128.28, 129.15, 132.54, 134.25, 136.09,
2
-H); C NMR (100
N
O
3
O
O
O
L n
C u
1
1
N
N
N
+
N
48.13, 157.18, 171.42; ESI-MS: 369 [M+H] .
-(4-(4-Nitrophenyl)-1H-1,2,3-triazol-1-yl)-4H-
chromen-4-one (6h): White colour solid; yield 70%; m.f.:
O
N
R
N
C u L n
3
R
Fig. 1. Plausible mechanism of 1,3-dipolar cycloaddition of 5a to acetylenes
-1
C
17
H
10
N O
4 4
; m.p.: 220-221 ºC; IR (KBr, νmax, cm ): 1712 (C=O);
H NMR (400 MHz, CDCl ) δ ppm: 7.48 (d, 2H, J = 8.8 Hz,
Ar-H), 7.56-7.51 (m, 1H,Ar-H), 7.67 (d, 1H, J = 7.2 Hz,Ar-H),
1
ACKNOWLEDGEMENTS
3
One of the authors (BKR) thanks to the Ministry of Tribal
Affairs (NFST-RGNF), New Delhi, India for financial support
and I.I.C.T. Hyderabad and Central facilities for research &
Development, Osmania University Hyderabad, India providing
for spectral analysis.
7
1
.99-7.95 (m, 3H,Ar-H), 8.25 (dd, 1H, J = 8.1, Ar-H), 8.67 (s,
H, triazole-H), 8.98 (s, 1H, C
δ ppm: 114.56, 118.42, 122.02, 124.26, 126.22, 127.12, 132.02,
28.90, 135.02, 136.25, 138.97, 148.22, 150.41, 158.02, 172.12;
ESI-MS: 335 [M+H] .
13
2
-H); C NMR (100 MHz, CDCl )
3
1
+
CONFLICT OF INTEREST
RESULTS AND DISCUSSION
The authors declare that there is no conflict of interests
regarding the publication of this article.
The synthesis of chromone-triazole hybrids involve four-
step synthetic strategy. The regioselective Bayer-Villiger oxid-
ation of chromone-3-aldehyde with m-CPBA (2a) gave corres-
ponding 3-hydroxy-4H-chromen-4-one (3a) [15]. In order to
make hydroxy group as good leaving group subsequently 3a
converted to O-triflate (4a) by treating with triflic anhydride
O; 2.0 equiv). Compound 4a on reaction with NaN in
DMF smoothly underwent nucleophilic substitution with azide
to afford desired new key intermediate 3-azido-4H-chromen-
REFERENCES
1
2
.
.
L. Rackova, S. Firakova, D. Kostalova, M. Stefek, E. Sturdik and M.
Majekova, Bioorg. Med. Chem., 13, 6477 (2005);
https://doi.org/10.1016/j.bmc.2005.07.047
E. Csepanyi, P. Szabados-Furjesi, A. Kiss-Szikszai, L.M. Frensemeier,
U. Karst, I. Lekli, D.D. Haines, A. Tosaki and I. Bak, Molecules, 22,
5
88 (2017);
(
Tf
2
3
https://doi.org/10.3390/molecules22040588
3. S. Khadem and R.J. Marles, Molecules, 17, 191 (2012);
https://doi.org/10.3390/molecules17010191
4
5
6
7
.
.
.
.
M.E. Hegazy, H.M.A. El-Hamd, A.M. El-Halawany, P.C. Djemgou,
A.A. Shahat and P.W. Pare, J. Nat. Prod., 74, 937 (2011);
https://doi.org/10.1021/np100378d
4
-one (5a) in good yield. IR spectrum of compound 5a shows
-1
characteristic azide band appeared at 2123 cm . Initially we
tried for the generation of 3-azido chromone from 3-bromo
chromone (organoazides are generally prepared by heating
R.S.Keri, S. Budagumpi, R.K.Pai and R.G. Balakrishna, Eur. J. Med.
Chem., 78, 340 (2014);
https://doi.org/10.1016/j.ejmech.2014.03.047
M. Hanif, M. Saleem, M.T. Hussain, N.H. Rama, S. Zaib, M.A.M.
Aslam, P.G. Jones and J. Iqbal, J. Braz. Chem. Soc., 23, 854 (2012);
https://doi.org/10.1590/S0103-50532012000500010
W.T. Li, W.H. Wu, C.H. Tang, R. Tai and S.T. Chen, ACS Comb. Sci.,
on alkyl/aryl halide with NaN
3
in DMF or DMSO) by treating
with NaN in DMF. But even after long time reaction, a low
3
1
3, 72 (2011);
yield of azide intermediate 5a probably due to unactivated C-3
vinyl bromo chromone. Hence, we planned for the generation
of 3-azidochromone from chromone-3-O-triflate by treating
https://doi.org/10.1021/co1000234
8. G.O. Resende, S.F. Teixeira, I.F. Figueiredo, A.A. Godoy, D.J.F.
Lougon, B.A. Cotrim and F.C. de Souza, Int. J. Electrochem., 2019,
6
759478 (2019);
with NaN
3
. The key intermediate 5a smoothly underwent CuI
https://doi.org/10.1155/2019/6759478
9
.
J.F. Lutz, Angew. Chem. Int. Ed., 46, 1018 (2007);
https://doi.org/10.1002/anie.200604050
catalyzed 1,3-dipolar cycloaddition with variety of terminal
alkynes in DMSO and gave the exclusively 1,4-regio isomeric
triazole linked chromone hybrids in excellent yield with high
purity.
10. D. Dheer, V. Singh and R. Shankar, Bioorg. Chem., 71, 30 (2017);
https://doi.org/10.1016/j.bioorg.2017.01.010
1
1
1
1
1
1. V. Pervaram, D. Ashok, C.V.R. Reddy, M. Sarasija and A. Rao, Russ. J.
Gen. Chem., 88, 566 (2018);
https://doi.org/10.1134/S1070363218030283
2. T. Sowjanya, Y.J. Rao and N.Y.S. Murthy, Russ. J. Gen. Chem., 87, 1864
(2017);
https://doi.org/10.1134/S1070363217080357
3. Y.J. Rao, T. Sowjanya, G. Thirupathi, N.Y.S. Murthy and K.S. Sravant,
Mol. Divers., 22, 803 (2018);
1
The H NMR of compound 6a exhibited triazole charac-
teristic signals at δ8.82 (s, 1H, triazole-CH) and δ8.95 (chromone
13
C -H), Compound 6a structure supported by C NMR signals
2
δ 170.72 (carbonyl carbon), 148.09 (triazole carbon) and ESI-
MS: 304 (M+H). The plausible mechanism for 1,2,3-triazole
formation via Cu(I) catalyzed azide-alkyne [1,3]dipolar cyclo-
addition presented in Fig. 1.
https://doi.org/10.1007/s11030-018-9833-4
4. M.K. Reddy, Y.J. Rao and G.L.D. Krupadanam, J. Saudi Chem. Soc.,
19, 372 (2015);
https://doi.org/10.1016/j.jscs.2012.04.006
5. G. Madhu, M. Sudhakar, K.S. Kumar, G.R. Reddy, K. Ramakrishna,
A. Sravani and Ch. Prasad Rao, Russ. J. Gen. Chem., 87, 2421 (2017);
https://doi.org/10.1134/S1070363217100243
Conclusion
In conclusion, a simple and efficient synthesis of 1,4-di-
substituted 1,2,3-triazole C-N linked chromone hybrids via
key precursor azido chromone is developed using convenient
and highly selective Cu(I) catalyzed click reaction.
16. V. Satyanarayana, C.P. Rao, G.L.D. Krupadanam and G. Srimannarayana,
Synth. Commun., 21, 1455 (1991);
https://doi.org/10.1080/00397919108016418
1
7. Y.J. Rao, E.Y. Goud, Y. Hemasri, N. Jain and S. Gabriella, Russ. J. Gen.
Chem., 86, 184 (2016);
https://doi.org/10.1134/S1070363216010291