Cu(I) catalyzed coumarin-1,2,3-triazole hybrids: Click chemistry

Article abstract of DOI:10.14233/ajchem.2019.22183

A series of novel coumarin-1,2,3-triazole derivatives were synthesized in good yield via click chemistry using Cu(I) catalyzed intermolecular Huisgen [3+2] cycloaddition reaction. All the synthesized compounds were characterized spectroscopically. This piece of work could be helpful to develop biologically relevant coumarin analogs.

Full text of DOI:10.14233/ajchem.2019.22183

Asian Journal of Chemistry; Vol. 31, No. 11 (2019), 2543-2547
A
SIAN
J
OURNAL OF HEMISTRY
C
https://doi.org/10.14233/ajchem.2019.22183
Cu(I) Catalyzed Coumarin-1,2,3-Triazole Hybrids: Click Chemistry
RITU MAMGAIN
Department of Chemistry, Modern College of Arts, Science and Commerce, Ganeshkhind, Pune-411007, India
Corresponding author: E-mail: ritumamgain@gmail.com
Received: 6 May 2019;
Accepted: 18 June 2019;
Published online: 28 September 2019;
AJC-19584
A series of novel coumarin-1,2,3-triazole derivatives were synthesized in good yield via click chemistry using Cu(I) catalyzed intermolecular
Huisgen [3+2] cycloaddition reaction. All the synthesized compounds were characterized spectroscopically. This piece of work could be
helpful to develop biologically relevant coumarin analogs.
Keywords: Coumarin, 1,2,3-Triazoles, Hybrid molecules, Click chemistry.
hydrogen bonds, diverse non-covalent interactions and thus
shows potential biological activity such as anti-HIV [17,18],
antimicrobial [19] and selective ω-3 adrenergic receptor agonist
[20] activities. Triazoles are part of many biologically active
natural product such as vancomycin [21], syn-TZ2PA6. Triazole
is a rigid linking unit, which cannot be oxidized or reduced and
cannot be easily cleaved hydrolytically. Examples of ligation
of two different pharmacophores by 1,2,3-triazole ring are
linezolid-macrolide [22] and vancomycin-cephalosporin [23]
conjugates.
Coumarin 1,2,4 triazoles have displayed comparable or
even better antibacterial and antifungal efficacy in comparison
with reference drugs enoxacin, chloromycin and fluconazole
[24]. Few coumarin-1,2,3-triazole derivatives have been recently
reported to exhibit antimicrobial activity [25]. Owing to the
importance of hybrid molecules, we tried to incorporate both
coumarin and 1,2,3-triazole in one pharmacophore. To synthesize
a hybrid molecule click chemistry is a powerful strategy, which
relies mainly upon the construction of carbon-heteroatom bonds.
The azide-alkyne Huisgen 1,3-dipolar cycloaddition reaction
in the presence of Cu(I) catalyst leads to substituted 1,2,3-triazoles
[26]. The reaction is one pot not affected by air and water,
generates negligible inoffensive byproduct, tolerant to most
of the functionality highly regioselective and "spring loaded"
molecules [27].
INTRODUCTION
Coumarin (benzopyran-2-one or chromen-2-one) ring system
is imperative and exhibits interesting pharmacological properties
and has intrigued chemists for decades to explore its synthetic
analogs for their activities. Pharmacologically, it falls in the class
of flavonoids [1] and has widespread biological activities, affecting
many mammalian cell functions, including inhibition of mito-
chondrial enzyme systems [2]. They have a reputation for anti-
inflammatory [3,4], antiallergic, antimicrobial [5], anticancer
[6] and antihemorrhagic activities [7], novobiocin [8] and
clorobiocin [9] are coumarin antibiotics of natural origin, which
are known inhibitors of DNA gyrase and exhibit activity against
Gram-positive bacteria, including methicillin-resistant strains
of Staphylococci species [10,11].
Novobiocin has also been developed for anti-proliferative
activity against various cancer cell lines [12]. Geiparvarin has
been isolated from the leaves of Geijera parviflora Lindl [13]
and exhibit potent in vitro cytostatic activity [14]. Warfarin
exhibits anticoagulant activity and possess significant
pharmacokinetic profile [15]. Phenprocoumon and substituted
4-hydroxy-2-pyrone derivatives are considered to be the first
generation HIV-PR inhibitors [16]. Dicoumarol is another well-
known molecule developed for the management of myocardial
infarction.
Triazole is a five-membered heterocyclic compound with
three nitrogen atoms at position 1, 2 and 3. The molecule is
capable of binding with various enzymes and receptors via
The copper-catalyzed reaction is assumed to proceed in a
stepwise manner starting with the generation of copper(I)
acetylide (D) (Fig. 1). Density functional theory calculations
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2544 Mamgain
Asian J. Chem.
CuSO4
K2CO3, DMF
RT, 8-10 h
A
ROH
+
Br
OR
R1
Reducing agent
R1
5a, R = o-CHO-C6H4
5b, R = p-CHO-C6H4
5c, R = o-CH3-Pyridine
6 a, R = o-CHO-C6H4
6 b,
R = p-CHO-C6H4
6 c, R = o-CH3-Pyridine
6 d,
N
N
H
R2
N
C
[CuLn]+
5d,
R = 2-Napthalene
5e, R = OTHP
R = 2-Napthalene
6 e, R = OTHP
I
+H+
B
Scheme-I: Synthesis of required alkynes (OTHP = oxy tetrahydropyran)
-H+
Procedure for the synthesis of 4-(bromo-alkoxy)chromen-
2-one (8a-b): Solution of 4-hydroxy coumarin (7), (31 mmol)
in 20 mL dry DMF was added dropwise (0.5 h) to a magnetically
stirred suspension of 1,2-dibromoethane (111 mmol) and anhy-
drous K2CO3 (123 mmol) in dry 75 mL DMF at room temperature
and progress of reaction was monitored by thin layer chromato-
graphy. Reaction took 2-3 h to complete and after completion,
the reaction mixture was poured into ice-cold water and extracted
with CHCl3 (3 × 75 mL). Combined organic layer was washed
with water (5 × 100 mL). The chloroform layer was dried over
anhydrous Na2SO4 and excess of solvent was removed under
vacuum. The crude product thus obtained was purified over
silica gel column using EtOAc/hexane as an eluent to give
compound (8a-b) in good yield.
CuLn
R1
N
R1
CuLn
R1
N
R2
N
CuLn
N
D
H
N
R2
N
G
R2
R1
CuLn
N
N N
N
R2
N
E
N
F
Fig. 1. Catalytic cycle for azide-alkyne coupling
show a preference for the stepwise addition (D → F → G →
H) over the concerted cycloaddition (G→ H) by approximately
12 to 15 kcal mol-1 leading to the intriguing six-membered metal-
locycle G. Further rearrangement takes place G → H → I,
afforded triazole compound I.
4-(2-Bromo-ethoxy)chromen-2-one (8a): Yield: 85 %;
white solid; m.p.: 148 ºC; IR (KBr, νmax, cm-1): 3042, 1722,
1
1610, 1564, 1495, 1453, 1410, 1369, 1328, 1275; H NMR
(200 MHz, CDCl3): 3.70 (t, J = 6 Hz, 2H, CH2CH2Br), 4.39 (t,
J = 6 Hz, 2H, OCH2), 5.60 (s, 1H ), 7.23-7.28 (m, 2H), 7.46-
7.51 (m, 1H), 7.78-7.83 (m, 1H); 13C NMR (50.32 MHz, CDCl3):
27.75 (CH2), 68.53 (CH2), 90.90 (CH), 115.21 (Cquart), 116.69
(CH), 123.03 (CH), 123.99 (CH), 132.58 (CH), 153.23 (Cquart),
162.48 (Cquart), 164.83 (Cquart); HRMS calcd. for C11H9O3Br:
269.0914, found: 269.1443 (M+).
4-(3-Bromo-propoxy)chromen-2-one (8b):Yield: 75%;
white solid; m.p.: 94 ºC; IR (KBr, νmax, cm-1): 3086, 1713, 1628,
1563, 1493, 1459, 1416, 1376, 1276, 1247; 1H NMR (200 MHz,
CDCl3): 2.33-2.45 (m, 2H, CH2CH2CH2Br), 3.56 (t, J = 6 Hz,
2H, CH2CH2Br), 4.23 (t, J = 6 Hz, 2H, OCH2CH2), 5.65 (s, 1H ),
7.20-7.27 (m, 2H), 7.45-7.49 (m, 1H), 7.70-7.75 (m, 1H); 13C
NMR (50.32 MHz, CDCl3): 28.88 (CH2), 31.28 (CH2), 66.65
(CH2), 90.64 (CH), 115.37 (Cquart), 116.66 (CH), 122.72 (CH),
123.81 (CH), 132.37 (CH), 153.15 (Cquart), 162.60 (Cquart),
165.15 (Cquart); HRMS calcd. for C12H11O3Br: 283.1179,
found: 283.1256 (M+).
Procedure for the synthesis of 4-(azido-alkoxy)chromen-
2-one (9a-b):To a stirred solution of 4-(bromo-alkoxy)chromen-
2-one (8) (5.50 mmol) in 20 mL dry DMF, NaN3 (22.0 mmol)
was added at 60 °C. Progress of the reaction was observed by
a thin layer chromatography. The reaction, took 3 h to complete.
After completion of reaction water (100 mL) was added to the
reaction mixture. The crude product was extracted with CHCl3
(3 × 50 mL) and combined organic layer was washed with water
(3 × 50 mL). The chloroform layer was dried over anhydrous
Na2SO4 and excess of solvent was removed under vacuum.
The crude product (9a-b) thus obtained was purified over SiO2
using EtOAc/hexane as eluent.
EXPERIMENTAL
All the chemicals used in the synthesis were purchased
from Sigma-Aldrich and used as such. Thin layer chromato-
graphy was used to monitor the progress of the reactions. All
the compounds were purified over a silica gel column. Solvents
were distilled before for purification. Melting points were
determined on ERS automated melting point apparatus and
are uncorrected. IR (Film) and IR (KBr) spectra were obtained
using Perkin-Elmer FT-IR spectrophotometer. NMR spectra
were recorded in CDCl3 or DMSO-d6 on Brucker Spectrospin
spectrometer at 200 MHz for 1H NMR and 50.32 MHz for 13C
NMR using TMS as an internal standard. The chemical shift
values are recorded on the δ scale and the coupling constant
(J) are in Hz. Mass spectral data were recorded on a Jeol
(Japan) JMS-DX303 and micromass LCT, Mass spectrometer/
Data system.
General procedure for the synthesis of alkynes (6a-e):
A solution of propargyl bromide (2 equiv.) in dry DMF was
added dropwise to a stirred suspension of substituted phenol
(1 equiv.) and anhydrous K2CO3 (6 equiv.) in dry DMF at room
temperature for 8-10 h. The progress of the reaction was monitored
by thin layer chromatography and after completion of the
reaction; it was poured into ice-cold water (100 mL) and extracted
with chloroform (3 × 60 mL). The combined organic layer was
washed with water (5 × 100). The chloroform layer was dried
over anhydrous Na2SO4 and excess of solvent was removed
under reduced pressure. The crude product, thus obtained was
purified over a silica gel column using EtOAc/hexane as eluent
(Scheme-I).
4-(2-Azido-ethoxy)chromen-2-one (9a):Yield: 90 %; white
solid; m.p.: 175 ºC; IR (KBr, νmax, cm-1): 2946, 2125, 1741, 1610,

Vol. 31, No. 11 (2019)
Cu(I) Catalyzed Coumarin-1,2,3-Triazole Hybrids: Click Chemistry 2545
1417, 1371, 1238, 1146; 1H NMR (60 MHz, CDCl3): 3.90 (t,
2H, CH2CH2N3), 4.45 (t, 2H, OCH2), 5.80 (s, 1H), 7.40-7.60
(m, 2H), 7.70-7.90 (m, 1H), 8.01-8.15 (m, 1H); EI-MS (m/z):
231 (M+).
4-(3-Azido-propoxy)chromen-2-one (9b):Yield: 87 %;
white solid; m.p.: 142 ºC; IR (Film, νmax, cm-1): 3007, 2933,
2101, 1672, 1387, 1094; 1H NMR (200 MHz, CDCl3): 2.09-2.15
(m, 2H, CH2CH2CH2N3), 3.52 (t, J = 6 Hz, 2H, CH2CH2N3),
4.16 (t, J = 6 Hz, 2H, OCH2CH2), 5.63 (s, 1H), 7.23-7.27 (m,
2H), 7.45-7.50 (m, 1H), 7.71-7.75 (m, 1H); 13C NMR (50.32
MHz, CDCl3): 27.86 (CH2), 47.71 (CH2), 65.87 (CH2), 90.49
(CH), 115.31 (Cquart), 116.55 (CH), 122.67 (CH), 123.76 (CH),
132.3 (CH), 153.08 (Cquart), 162.50 (Cquart), 165.12 (Cquart);
EI-MS (m/z): 245 (M+).
General procedure for the synthesis of 1, 2, 3-triazole
incorporated coumarin derivatives (10a-p): To a vigorously
stirred solution of compound 9 (3.088 mmol) and respective
alkyne (12.97 mmol) in 10 mL tert-butyl alcohol, solution of
CuSO4·5H2O (0.67 mmol) and sodium ascorbate (1.23 mmol)
in 10 mL distilled water, was added. The amount of tert-butyl
alcohol and distilled water was kept 1:1. The deep yellow mixture
was stirred vigorously at 45 ºC and the progress of reaction
was monitored by thin layer chromatography. After 6 h, the
reaction was completed and crude mixture was extracted with
CHCl3 and water. The organic layer was extracted with CHCl3
(3 × 30 mL) and combined organic layer was dried over anhydrous
Na2SO4. Excess of solvent was removed under vacuum. The
crude reaction mixture was purified over SiO2 column using
MeOH:CHCl3 as an eluent (Scheme-II).
5.27 (s, 2H, OCH2), 5.94 (s, 1H, CH), 7.17-7.38 (m, 4H), 7.60-
7.83 (m, 4H), 8.44 (s, 1H), 9.82 (s, 1H, CHO). HRMS calcd.
for C21H17N3O5: 391.1168; found: 391.2938 (M+).
4-[2-(4-Hydroxymethyl-[1,2,3]triazol-1-yl)ethoxy]-
chromen-2-one (10c): IR (KBr, νmax, cm-1): 3395, 3085, 2881,
1695, 1622, 1564, 1420, 1382, 1248, 1142, 1052, 947, 851,
775; 1H NMR (300 MHz, DMSO-d6): 3.34 (brs, 1H, OH), 4.62
(t, J = 6 Hz, 2H, NCH2), 4.90 (t, J = 6 Hz, 2H, OCH2), 5.23 (d,
J = 4 Hz, 2H, CH2OH), 5.96 (s, 1H, CH), 7.32-7.38 (m, 2H),
7.64-7.71 (m, 2H), 8.74 (s, 1H, CH). Anal. calcd. (found) %
for C14H13N3O4: C, 58.53 (58.17); H, 4.56 (4.43); N, 14.63
(14.25).
4-[2-(4-Phenyl-[1,2,3]triazol-1-yl)ethoxy]chromen-2-
one (10d): IR (KBr, νmax, cm-1): 3085, 1729, 1625, 1566, 1421,
1380, 1244, 1184, 1110, 932, 843, 767; 1H NMR (300 MHz,
DMSO-d6): 4.65 (t, J = 6 Hz, 2H, NCH2), 4.94 (t, J = 6 Hz,
2H, OCH2), 5.96 (s, 1H, CH), 7.30-7.44 (m, 5H), 7.58-7.82 (m,
4H), 8.74 (s, 1H, CH);Anal. calcd. (found) % for C19H15N3O3: C,
68.46 (68.26); H, 4.54 (4.34); N, 12.61 (12.71).
4-{2-[4-(Tetrahydropyran-2-yloxymethyl)-[1,2,3]-
triazol-1-yl]ethoxy}chromen-2-one (10e): IR (KBr, νmax, cm-1):
2943, 2868, 1739, 1627, 1454, 1383, 1245, 1184, 1137, 1036,
935, 896, 771; 1H NMR (300 MHz, DMSO-d6): 1.41-1.62 (m,
6H), 3.73 (t, J = 3 Hz, 2H, OCH2), 4.48-4.52 (m, 1H, OCH),
4.62-4.69 (m, 4H, 2 × OCH2), 4.90 (s, 2H, NCH2), 5.95 (s, 1H,
CH), 7.34-7.39 (m, 2H), 7.62-7.73 (m, 2H), 8.28 (s, 1H, NCH);
13C NMR (75.5 MHz, DMSO-d6): 18.85 (CH2), 24.90 (CH2),
29.98 (CH2), 48.31 (NCH2), 59.42 (OCH2), 61.18 (OCH2),
67.81 (OCH2), 91.06 (CH), 96.92 (OCH), 114.89 (CH), 116.39
(CH), 122.72 (CH), 124.10 (CH), 124.63 (CH), 132.81 (Cquart),
144.06 (Cquart), 152.70 (Cquart), 161.38 (Cquart), 164.20 (CO);
Anal. calcd. (found) % for C19H21N3O5: C, 61.45 (61.35); H,
5.70 (5.69); N, 11.31 (11.54).
2-{1-[2-(2-oxo-2H-chromen-4-yloxy)ethyl]-1H[1,2,3]-
triazol-4-ylmethoxy}benzaldehyde (10a): IR (KBr, νmax, cm-1):
2916, 1727, 1684, 1624, 1565, 1456, 1421, 1380, 1278, 1241,
1
1186, 1156, 1113, 1042, 935, 896, 845, 753; H NMR (300
MHz, DMSO-d6): 4.62 (t, J = 6 Hz, 2H, NCH2), 4.92 (t, J = 6
Hz, 2H, OCH2), 5.36 (s, 2H, OCH2), 5.96 (s, 1H, CH), 7.05-
7.10 (m, 1H), 7.29-7.43 (m, 3H), 7.59-7.68 (m, 4H), 8.49 (s,
1H, CH), 10.31 (s, 1H, CHO); 13C (75.5 MHz, DMSO-d6):
48.48 (NCH2), 62.21 (OCH2), 67.80 (OCH2), 91.07 (CH), 114.16
(CH), 114.87 (CH), 116.41 (CH), 121.11 (CH), 122.68 (CH),
124.13 (CH), 125.35 (CH), 127.61 (CH), 124.45 (Cquart), 132.82
(Cquart), 136.28 (Cquart), 142.51 (CH), 152.69 (Cquart), 160.32
(Cquart), 161.43 (Cquart), 164.20 (CO), 189.07 (CHO); HRMS
calcd. for C21H17N3O5: 391.1168; found: 391.8978 (M+).
4-{1-[2-(2-Oxo-2H-chromen-4-yloxy)ethyl]-1H-[1,2,3]-
triazol-4-ylmethoxy}benzaldehyde (10b): IR (KBr, νmax, cm-1):
3443, 2916, 1734, 1693, 1628, 1600, 1417, 1382, 1251, 1156,
4-{2-[4-(6-Methyl-pyridin-3-yloxymethyl)-[1,2,3]-
triazol-1-yl]ethoxy}chromen-2-one (10f): IR (KBr, νmax, cm-1):
3074, 1701, 1623, 1563, 1488, 1456, 1379, 1277, 1249, 1193,
1
1141, 1027, 945, 855, 826, 772, 755; H NMR (300 MHz,
DMSO-d6): 2.35 (s, 3H, CH3), 4.61-4.64 (m, 2H, NCH2), 4.91-
4.94 (t, J = 6 Hz, 2H, OCH2), 5.19 (s, 2H, OCH2), 5.95 (s, 1H,
CH), 7.09-7.12 (m, 1H), 7.32 - 7.37 (m, 3H), 7.61-7.67 (m, 2H),
8.17 (s, 1H), 8.41 (s, 1H, NCH); HRMS calcd. for C20H18N4O4
378.1328; found: 379.5938 (M++H).
1-[3-(2-Oxo-2H-chromen-4-yloxy)-propyl]-1H-[1,2,3]-
-1
triazol-4-carboxylic acid ethyl ester (10g): IR (KBr, νmax, cm ):
2927, 1726, 1625, 1566, 1421, 1384, 1275, 1246, 1176, 1142,
1030, 932, 844, 769; 1H NMR (300 MHz, DMSO-d6): 1.00 (t,
J = 6 Hz, 3H, CH2CH3), 2.24 (m, 2H), 4.62 (t, J = 6 Hz, 2H,
NCH2), 4.91 (t, J = 6 Hz, 2H, OCH2), 5.12 (m, 2H, OCH2),
1
1054, 986, 930, 866, 749; H NMR (300 MHz, DMSO-d6):
4.61 (t, J = 6 Hz, 2H, NCH2), 4.92 (t, J = 6 Hz, 2H, OCH2),
N
n
O
N3
n
OH
O
Br
n
O
N
N
R
R
a
b
O
O
O
O
O
O
O
O
8a, n = 2
8b, n = 3
9a, n = 2
9b, n = 3
10a-h, n = 2
10i-q, n = 3
7
Scheme-II: (a) K2CO3,Br(CH2)nBr, DMF, 80 °C, 2-3 h (b) NaN3, DMF, 60 °C, 3 h, 80 % (c) CuSO4,5H2O, Sodium ascorbate, t-butanol: H2O
(1:1), 45 °C, 6 h, 80-90 %

2546 Mamgain
Asian J. Chem.
5.95 (s, 1H, CH), 7.32-7.39 (m, 2H), 7.62 - 7.72 (m, 2H), 8.32
(s, 1H, NCH);Anal. calcd. (found) % for C17H17N3O5: C, 59.47
(59.55); H, 4.99 (5.09); N, 12.24 (12.36).
4-{3-[4-(1-Hydroxy-cyclohexyl)-[1,2,3]triazol-1-yl]-
propoxy}chromen-2-one (10 n): IR (KBr, νmax, cm-1): 2932,
2856, 1717, 1622, 1565, 1451, 1417, 1379, 1274, 1240, 1186,
1141, 1109, 1058, 929, 818, 751; 1H NMR (300 MHz, DMSO-
d6): 1.23-1.83 (m, 10H), 2.40 (m, 2H, CH2CH2), 4.24 (t, J = 3
Hz, 2H, NCH2), 4.57 (t, J = 3 Hz, 2H, OCH2), 4.80 (brs, 1H,
OH), 5.87 (s, 1H, CH), 7.36-7.40 (m, 2H ), 7.64-7.82 (m, 2H),
7.95 (s, 1H, CH); HRMS calcd. for C20H23N3O4: 369.1689;
found: 369.8452 (M+).
4-{3-[4-(6-Methyl-pyridin-3-yloxymethyl)-[1,2,3]triazol-
1-yl]propoxy}chromen-2-one (10o): IR (KBr, νmax, cm-1):2928,
1718, 1622, 1567, 1493, 1381, 1272, 1239, 1185, 1141, 1109,
1029, 927, 821, 769; 1H NMR (300 MHz, DMSO-d6): 2.37 (s,
3H, CH3), 2.39-2.45 (m, 2H, CH2CH2), 4.21-4.25 (t, J = 6 Hz,
2H, NCH2), 4.61-4.65 (t, J= 6 Hz, 2H, OCH2), 5.15 (s, 2H, OCH2),
5.86 (s, 1H), 7.13-7.16 (m, 1H) 7.31-7.39 (m, 3H) 7.62 (m,
1H), 7.94 (s, 1H), 8.19 (s, 1H, CH), 8.32 (s, 1H, CH); HRMS
calcd. for C21H20N4O4: 392.1485; found: 392.1991 (M+).
4-[1-[3-(2-Oxo-2H-chromen-4-yloxy)propyl]-1H-
[1,2,3]triazol-4-ylmethoxy}-benzaldehyde (10p): IR (KBr,
4-{2-[4-(1-Hydroxy-cyclohexyl)-[1,2,3]triazol-1-yl]-
ethoxy}chromen-2-one (10h): IR (KBr, νmax, cm-1): 3439, 2937,
2855, 1689, 1627, 1607, 1567, 1452, 1381, 1252, 1156, 948,
749; 1H NMR (300 MHz, DMSO-d6): 1.22-1.85 (m, 10H), 1.89
(brs, 1H, OH), 4.64 (t, J = 6 Hz, 2H, NCH2), 4.88 (t, J = 6 Hz,
2H, OCH2), 5.94 (s, 1H), 7.31-7.39 (m, 2H), 7.62-7.71 (m, 2H),
8.05 (s, 1H); HRMS calcd. for C19H21N3O4: 355.1532; found:
355.6414 (M+).
4-[3-(4-Hydroxymethyl-{1,2,3}triazol-1-yl)propoxy]-
chromen-2-one (10i): IR (KBr, νmax, cm-1): 3422, 2929, 1714,
1621, 1415, 1380, 1274, 1240, 1109, 1029, 820, 769; 1H NMR
(300 MHz, DMSO-d6): 2.38-2.41 (m, 2H), 4.22 (m, 2H), 4.22
(t, 2H), 4.49-4.61 (s, 2H), 5.20 (brs, 1H), 5.87 (s, 1H), 7.33-7.77
(m, 4H), 8.06 (s, 1H); 13C NMR (75.5 MHz, DMSO-d6): 28.83
(CH2), 46.42 (NCH2), 55.08 (CH2OH), 66.69 (OCH2), 90.54
(CH), 115.07 (CH), 116.30 (CH), 123.01 (CH), 124.06 (Cquart),
132.69 (NCH), 152.68 (Cquart), 161.56 (Cquart), 164.74 (CO);
Anal. calcd. (found) % for C15H15N3O4: C, 59.79 (59.97); H,
5.02 (5.16); N, 13.95 (13.41).
4-[3-(4-Phenyl-[1,2,3]triazol-1-yl)propoxy]chromen-2-
one (10j): IR (KBr, νmax, cm-1): 3084, 2927, 1706, 1621, 1564,
1422, 1382, 1275, 1250, 1191, 1109, 1087, 939, 857, 764; 1H
NMR (300 MHz, DMSO-d6): 2.45-2.48 (m, 2H, CH2CH2N),
4.29 (t, J = 6Hz, 2H, NCH2), 4.66 (t, J = 6Hz, 2H, OCH2), 5.89
(s, 1H), 7.18-7.46 (m, 4H), 7.59-7.83 (m, 5H), 8.67 (s, 1H, NCH);
Anal. calcd. (found) % for C20H17N3O3: C, 69.15 (69.37); H,
4.93 (5.06); N, 12.10 (12.41).
ν
max, cm-1): 2834, 1711, 1599, 1571, 1507, 1466, 1416, 1251,
1
1160, 1110, 992, 925, 867, 807, 774; H NMR (300 MHz,
DMSO-d6): 2.40 (m, 2H, NCH2CH2), 4.20 (t, J= 6 Hz, 2H, NCH2),
4.60 (t, J = 6 Hz, 2H, OCH2), 5.21 (s, 2H, OCH2), 5.82 (s, 1H,
CH), 7.18-7.35 (m, 4H), 7.61-7.83 (m, 4H), 8.31 (s, 1H, NCH),
9.82 (s, 1H, CHO); HRMS calcd. for C22H19N3O5: 405.1325;
found: 406.7173 (M++H).
2-{1-[3-(2-Oxo-2H-chromen-4-yloxy)propyl]-1H-[1,2,3]-
triazol-4-ylmethoxy}benzaldehyde (10q): IR (KBr, νmax, cm-1):
2926, 1730, 1689, 1628, 1600, 1488, 1458, 1387, 1291, 1250,
1191, 1107, 1053, 938, 847, 748; 1H NMR (300 MHz, DMSO-
d6): 2.40 (m, 2H, CH2), 4.22 (t, J = 6 Hz, 2H, OCH2), 4.62 (t,
J = 6 Hz, 2H, NCH2), 5.30 (s, 2H, OCH2), 5.84 (s, 1H, CH),
7.07-7.41 (m, 4H), 7.61-7.73 (m, 4H), 8.37 (s, 1H, CH), 10.28
(s, 1H, CHO); HRMS calcd. for C22H19N3O5: 405.1325; found:
406.6071 (M++H).
4-{3-[4-(Tetrahydropyran-2-yloxymethyl)-[1,2,3]triazol-
1-yl]propoxy}chromen-2-one (10k): IR (KBr, νmax, cm-1): 2942,
2868, 1711, 1624, 1565, 1462, 1417, 1381, 1244, 1188, 1137,
1
1026, 927, 856, 770, 751; H NMR (300 MHz, DMSO-d6):
1.44-1.62 (m, 6H), 2.40 (m, 2H, CH2CH2N), 3.43 (d, J = 3Hz,
2H, NCH2), 3.76 (t, 2H, OCH2), 4.24 (s, 2H, OCH2), 4.47-4.67
(m, 3H, OCH2, OCH), 5.86 (s, 1H, CH), 7.33-7.39 (m, 2H), 7.63-
7.76 (m, 2H), 8.15 (s, 1H, NCH); HRMS calcd. for C20H23N3O5:
385.1638; found: 385.3630 (M+).
RESULTS AND DISCUSSION
Huisgen [3+2] cycloaddition reaction occurs between a
terminal alkyne and an azide to generate substituted 1,2,3-
triazoles.Alkynes used in the reaction (Scheme-II) were prepared
by treating various substituted phenols (5a-e) with propargyl
bromide in the presence of anhydrous K2CO3 in dry DMF at
80 ºC for 8-10 h to yield substituted alkynes (6a-e) (Scheme-
I).
The azide counterpart was synthesized by a sequence of
reactions of 4-hydroxy coumarin with 1,2-dibromoethane and
1,3-dibromopropane in the presence of K2CO3 and dry DMF
at room temperature. The corresponding 4-(2-bromo-ethoxy)-
and 4-(3-bromo-propoxy)chromen-2-one on treating with
sodium azide in DMF as a solvent at 60 ºC gave corresponding
azide [28]. In the final click reaction, the substituted coumarins
azide and above synthesized and commercially available alkynes
were treated in the presence of sodium ascorbate, CuSO4·5H2O,
t-BuOH/H2O (1:1) as solvent, leading to the formation of desired
hybrid molecules (10a-q, Table-1), in good to excellent yield
at 45 ºC (Scheme-II).All the synthesized compounds were purified
over silica gel column and characterized spectroscopically.
1-[3-(2-Oxo-2H-chromen)-4-yloxypropyl]-1H-[1,2,3]-
triazole-4-carboxylic acid ethyl ester (10l): IR (KBr, νmax
,
cm-1): 2926, 1736, 1714, 1623, 1563, 1461, 1421, 1382, 1272,
1241, 1177, 1136, 1106, 923, 845, 770; 1H NMR (300 MHz,
DMSO-d6): 1.00 (t, 3H, CH3), 2.26-2.33 (m, 2H, CH2), 2.39
(d, J = 3 Hz, 2H, CH2CH3), 4.22 (t, J = 3 Hz, 2H, NCH2), 4.60
(t, J = 3Hz, 2H, OCH2), 5.09 (m, 2H, OCH2), 5.88 (s, 1H, CH),
7.36-7.41 (m, 2H ), 7.65-7.75 (m, 2H), 8.15 (s, 1H, CH);Anal.
calcd. (found) % for C18H19N3O5: C, 60.50 (60.47); H, 5.36
(5.49); N, 11.76 (11.64).
4-{3-[4-(Napthalen-1-yloxymethyl)-[1,2,3]triazol-1-yl]-
propoxy}chromen-2-one (10m): IR (KBr, νmax, cm-1): 2944,
1715, 1625, 1565, 1468, 1413, 1378, 1273, 1236, 1216, 1184,
1
1142, 1107, 1009, 922, 839, 815, 750; H NMR (300 MHz,
DMSO-d6): 2.40 (m, 2H, NCH2CH2), 4.24 (t, J= 6 Hz, 2H, NCH2),
4.64 (t, J = 6 Hz, 2H, OCH2), 5.24 (s, 2H, OCH2), 5.86 (s, 1H,
CH), 7.32-7.45 (m, 4H, C6H4), 7.48-7.83 (m, 7H, C10H7), 8.36
(s, 1H, NCH); HRMS calcd. for C25H21N3O4: 427.1532; found:
428.7991 (M++1).

Vol. 31, No. 11 (2019)
Cu(I) Catalyzed Coumarin-1,2,3-Triazole Hybrids: Click Chemistry 2547
8. H. Hoeksema, J.L. Johnson and J.W. Hinman, J. Am. Chem. Soc., 77,
6710 (1955);
TABLE-1
SYNTHESIZED 1,2,4-TRIAZOLE-COUMARIN DERIVATIVES
WITH THEIR MELTING POINT AND YIELD
https://doi.org/10.1021/ja01629a129.
9. U. Galm, S. Heller, S. Shapiro, M. Page, S.M. Li and M. Heide, Antimicrob.
Agents Chemoth., 48, 1307 (2004);
Compd.
10a
10b
10c
10d
10e
10f
10g
10h
10i
10j
10k
10l
10m
10n
10o
10p
10q
n
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
R
m.p. (°C)
178
218
192
158
153-155
167
202
200
203
161
125
147
168
178
130
130
180
Yield (%)
72
-CH2OC6H4CHO(o)
-CH2OC6H4CHO(p)
-CH2OH
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Strohbach, S.R. Turner, C. Biles, R.R. Morge, P.D. Johnson, P.A.Aristoff,
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68
78
70
68
67
65
69
70
75
68
68
67
66
65
73
75
-C6H5
-CH2OTHP
-CH2OC5H3NCH3(p)
-CH2OCOCH2CH3
-Cyclohexanol-1
-CH2OH
-C6H5
CH2OTHP
-CH2OCOCH2CH3
-CH2OC10H7
Cyclohexanol-1
CH2OC5H3NCH3(p)
-CH2OC6H4CHO(o)
-C6H4CHO(p)
Conclusion
In summary, a series of 17 novel 1,2,3-triazole coumarin
derivatives were synthesized via effective alkyl-azide Cu(I)
catalyzed classic click reaction. All the synthesized hybrid
molecules are important biological precursors. One pot, water-
mediated click reaction was found to be a useful tool for the
regioselective synthesis of coumarin-triazole hybrid molecules.
This simple three-step synthesis resulted in good to excellent
yields of final products with high purity. The chemical structures
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1
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CONFLICT OF INTEREST
The authors declare that there is no conflict of interests
regarding the publication of this article.
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