An Efficient Synthesis of 1,2,3-Triazole Bridge-Connected Phosphonate Derivatives of Coumarin

Article abstract of DOI:10.1080/10426507.2014.979987

An efficient general synthetic approach giving the possibility of a facile access to a wide range of novel 1,2,3-triazole bridge-connected phosphonate derivatives of coumarin, based on a copper(I)-catalyzed azide-alkyne 1,3-dipolar cycloaddition, has been developed. Under the optimized conditions, a novel series of 1,2,3-triazole bridge-connected phosphonate derivatives of coumarin was synthesized in high yields, and their structures were elucidated by NMR, IR, and HR MS.

Full text of DOI:10.1080/10426507.2014.979987

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An Efficient Synthesis of 1,2,3-triazole Bridge-connected Phosphonate Derivatives of
Coumarin
Xu Li,1 Xiaolan Chen,1 Jinwei Yuan,2 Yang Liu, 1 Peipei Li, 1 Lingbo Qu,1,2* and Yufen Zhao1,3
1 Department of Chemistry, Zhengzhou University, Key Laboratory of Organic Chemistry and
Chemical Biology, Henan Province, Zhengzhou, 450052, P. R. China
2 Chemistry and Chemical Engineering School, Henan University of Technology, Henan Province,
Zhengzhou 450001, P. R. China
3 Department of Chemistry, Xiamen University, Xiamen, 361005, P. R. China
ABSTRACT: An efficient general synthetic approach giving the possibility of a facile access to
a wide range of novel 1,2,3-triazole bridge-connected phosphonate derivatives of coumarin,
based on a copper(I)-catalyzed azide-alkyne 1,3-dipolar cycloaddition, has been developed.
Under the optimized conditions, a novel series of 1,2,3-triazole bridge-connected phosphonate
derivatives of coumarin was synthesized in high yields, and their structures were elucidated by
NMR, IR and HR MS.
 Corresponding author. Tel.: +86-371-67767051; Fax:+86-371-67767051; E-mail: chenxl@zzu.edu.cn
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KEYWORDS: 1,2,3-triazole, phosphonate, coumarin, 1,3-dipolar cycloaddition
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INTRODUCTION
Coumarin is an important constituent of many bioactive natural products that are of wide
interest because of their diverse biological and clinical applications. Coumarin derivatives have
multiple
biological
activities
including
antimicrobial,1
anticancer,2,3
anti-HIV,4
anti-inflammatory,5 anticoagulation,6 anti-hypertension properties.7 Two representative natural
coumarin derivatives are shown in Figure 1. Isolated from Callophyllum cordato-oblongum,
compound A showed potent inhibitory activity against HIV-1 replication in a novel green
fluorescent protein-based reporter cell assay.4a Compound B, a dihydroseselin-type angular
pyranocoumarin isolated from Lomatium suksdorfii, suppressed viral replication in eleven
separate acute HIV-1 infections of H9 lymphocyte cells with an average EC50 value of 2.6 mM,
and also suppressed acute HIV-1 infections in fresh peripheral blood mononuclear cells,
monocyte/macrophages and U-937 cells, a promonocytic cell line.4b Phosphate ester as an
organophosphorus compound plays an important role in life process, and many endogenous
active substances contain a phosphate ester unit,8,9 such as DNA, RNA, ATP, cell membrane and
some enzymes.10 Moreover, inserting a phosphate ester group into molecule can not only
significantly change the physical and chemical properties of parent molecule, but also bring
fundamental changes in the intermolecular forces and molecular polarity. In the pharmaceutical
industry, phosphate esters are usually used as pro-drugs to increase the water solubility and
hence bio-availability of the agent.11,12
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[Insert Figure 1]
In recent years, 1,2,3-triazole moiety, as an important pharmacophore,13-17 synthesized by
copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC reaction),18-21 was widely introduced
into DNA, RNA, peptides and carbohydrates and so on.22-23 Substituted 1,2,3-triazoles, which
can connect two different moieties to give innovative bifunctional molecules,24 have become
increasingly useful and important in constructing bioactive molecules. However, little attention
has been paid to the introduction of 1,2,3-triazole and phosphonate scaffolds into coumarin
derivatives. In order to search new coumarin drugs with higher biological activity and lower
toxicity, we designed a simple and highly efficient method to introduce 1,2,3-triazole and
phosphonate groups into coumarin and its derivatives (Scheme 1). Novel 1,2,3-triazole
bridge-connected phosphonates of coumarin derivatives were synthesized through CuAAC
cycloaddition reaction of azidoalkyl phosphonates and different propargylated coumarins
derivatives, and their structures were elucidated by NMR, HR MS and IR. Furthermore, the
CuAAC cycloaddition reaction condition has also been optimized. The result showed that the
reaction could smoothly occur under mild conditions, using DMSO/H2O (v/v, 1:1) as the
co-solvent, CuSO4·5H2O (10 mol%) and sodium ascorbate (20 mol%) as the catalyst at 45 C,
for 1 h with the help of the ultrasound irradiation, affording the title compounds in high yields.
[Insert Scheme 1]
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RESULT AND DISCUSSION
Diethyl 2-bromoethylphosphonate (1) was synthesized by Michaelis-Arbuzov rearrangement
reaction of triethyl phosphite with 1,2-dibromoethane under refluxing conditions without
external solvent.25 Diethyl 2-azidoethylphosphonate (2) was obtained by traditional substitution
of an appropriate leaving group with an azidating agent. The bromine atom of (1) was easily
substituted by N3 group of NaN3 through SN2 substitution reaction in co-solvent of H2O and
DMF at room temperature for 48 h, and the process was monitored by 31P NMR spectrum.26
Propargylated coumarin derivatives (4) were synthesized from corresponding
hydroxyl-contained coumarins (3) and propargyl bromide under basic condition (K2CO3) at 65
C for 24 h. The title compounds (5) were synthesized using (2) and (4) by the 1,3-dipolar
cycloaddition reaction, which is the key step in the pathway for preparation of the target
molecules (5). To obtain the optimal yield, the reaction conditions (the solvent, amount of
catalyst, reaction temperature, etc) were investigated. The 1,3-dipolar cycloaddition reaction
between 2-azidoethyl phosphonate (2) and 4a was chosen as a model reaction (Scheme 2).
[Insert Scheme 2]
For the 1,3-dipolar cycloaddition reaction, CuSO4·5H2O/sodium ascorbate, which was
commonly used in CuAAC reaction and could, in situ, generate the active Cu(I) ion, was selected
as the catalyst system. As the CuAAC reaction can be notably improved in rate and yield under
the ultrasound irradiation,23 this reaction was carried out at 45 C for 1 h under ultrasound
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irradiation with CuSO4·5H2O/sodium ascorbate as the catalyst system. Initially, the effect of
solvent was taken into consideration. As could be seen in Table 1, the results showed that the
yields of product in water/organic co-solvents (Table 1, entry 11-17) were obviously higher than
in pure organic solvents (Table 1, entry 1-9) or water (Table 1, entry 10). The data suggested that
the solubility of reactants and catalyst in different solvents was of great importance. Among the
co-solvents, DMSO/H2O (1:1, v/v) (Table 1, entry12) gave the best result for the reaction.
Therefore, DMSO/H2O (1:1, v/v) was chosen as the reaction solvent.
As to the catalyst, Various of Cu(II) and Cu(I) salts (10 mol%) were selected to investigate
the catalytic ability in DMSO/water (1:1 v/v) under ultrasound irradiation for 1 h at 45 C. As
shown in Figure 2, the product was obtained in a very low yield in the presence of Cu(II) salts
with copper wire (column 1 and 2) or Cu(I) salts only (column 5-8). However, using a Cu(II) salt
in the presence of a reducing agent (sodium ascorbate), the catalyst system showed the efficient
catalysis (column 3 and 4). CuSO4·5H2O/sodium ascorbate was chosen as the catalyst system for
the 1,3-dipolar cycloaddition.
[Insert Figure 2]
At present, heavy metal pollution has become a major environmental problem. In order to
reduce the environmental pollution of copper salts, the amount of the catalyst was examined
(Figure 3). The molar ratio of CuSO4·5H2O and sodium ascorbate was 1:2, and the optimum
CuSO4·5H2O loading was found to be 10 mol % (entry 3). When the amount of CuSO4·5H2O
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was increased to 20 mol % and 15 mol % (entry 1 and 2), the yield showed almost no change.
However, when decreased to 2 mol % or 5 mol % (entry 4 and 5), the production rate dropped
significantly.
[Insert Figure 3]
Finally, the effect of the reaction temperature was also investigated. This model reaction was
carried out with CuSO4·5H2O (10 mol%)/sodium ascorbate (20 mol%) as the catalyst system
under ultrasound irradiation (150 W) for 1 h. As shown in Figure 4, raising the reaction
temperature from 25 C to 45 C, the yield of the product had an obvious increase. From 45 C
to 65 C, there was almost no change. However, when the temperature was raised to 75 C, a
slight drop in the yield of the product was observed. The reason may be that high temperature
caused side reaction, such as trinitride disintegrate or alkyne coupled reaction.
[Insert Figure 4]
With the optimized reaction conditions, the title compounds 5a-5g were synthesized using
DMSO/H2O (v/v, 1/1) as co-solvent, CuSO4·5H2O (10 mol%) and sodium ascorbate (20
mol%)as the catalyst system, under the ultrasound irradiation at 45 C for 1 h. Their structures
were elucidated by 1H, 13C, and 31P NMR, as well as IR and HR MS spectra.
CONCLUSION
In summary, an efficient synthetic methodology has been carried out to construct
novel 1,2,3-triazole bridge-connected phosphonate derivatives of coumarin via a 1,3-dipolar
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cycloaddition reaction under the ultrasound irradiation in high yields.
EXPERIMENTAL
General information: Solvents were freshly distilled from respective drying agents before
use. All other reagents were distilled when necessary. TLC was performed on silica gel plates
1
13
31
and preparative chromatograph on columns of silica gel (200-300 mesh). H, C, and P NMR
spectra were recorded with a Bruker Avance 400 MHz spectrometer operating at 400.13, 100.61,
13
31
and 161.98 MHz, respectively, with C and P NMR spectra being recorded with broad band
proton decoupled. All NMR spectra were recorded in CDCl3 at room temperature (20 ± 3 C). 1H
31
and 13C chemical shifts are quoted in parts per million downfield from TMS. P chemical shifts
are quoted in parts per million relative to 85% H3PO4 as an external standard. High resolution
mass spectra (HR MS) were obtained with a Waters Micromass Q-Tof Micro instrument using
the ESI technique. IR spectra were recorded on Shimadzu IR-408 fourier transform infrared
spectrophotometer using a thin film supported on KBr pellets. Sonication was performed in
Kunshan KQ-250B ultrasonic cleaner with a frequency of 40 kHz and a power of 150 W.
Coumarin was purchased from Aladdin and used without further purification, and coumarin
1
derivatives (3c-3g) were obtained according to the known process.27 Selected H, 13C and 31P
NMR spectra for products 5a – 5g are presented in the Supplemental Materials (Figures S 1 – S
21)
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Preparation of propargylated coumarin derivatives (4)
7-Hydroxycoumarin derivatives (10.0 mmol), K2CO3 (1.38 g, 10.0 mmol) and anhydrous
acetone (30 mL) were put into a 100 mL three-necked flask. Propargyl bromide (1.18 g, 10.0
mmol) was added under stirring at room temperature. The reaction mixture was refluxed at 65 C
for 24 h. This process was monitored by TLC (thin-layer chromatography). After the reaction
was finished, the solution was cooled to room temperature. The solvent was removed by rotary
evaporation. Then water (30 mL) was added, and the resulting mixture was extracted with
dichloromethane (3 × 30 mL). The combined organic phase was dried over Na2SO4, filtered, and
evaporated under vacuum, and the crude compound was purified by column chromatography on
silica gel with methanol as eluent to give pure 4a-4g .
1
7-(prop-2-yn-1-yloxy)-2H-chromen-2-one (4a): White solid, yield 75%. M.p. 104-106 C. H
NMR (CDCl3)  = 7.55 (d, J =8.0 Hz, 1H, 4-H), 6.98 (s, 1H, 8-H), 6.96 (d, J = 8.0 Hz, 1H, 5-H),
6.20 (s, 1H, 6-H), 4.81 (s, 1H, 3-H), 2.61 (s, 2H, -CH2-), 1.62 (s, 1H, CH). 13C NMR (CDCl3) 
= 161.1(2-C), 160.4(7-C), 155.1(9-C), 152.5(4-C), 125.6(5-C), 114.3(3-C), 112.7(10-C),
112.5(6-C), 102.2(8-C), 77.4(-CH2-C-), 76.5(-CH), 56.2(-CH2-). HRMS: calcd for C12H8O3
[M+H]+ 201.0546, found 201.0548.
4-methyl-7-(prop-2-yn-1-yloxy)-2H-chromen-2-one (4b): White solid, yield 73%. M.p.
1
103-105 C. H NMR (CDCl3)  = 7.56 (d, J =8.0 Hz, 1H, 5-H), 6.96 (s, 1H, 8-H), 6.95 (d, J =
8.0 Hz, 1H, 6-H), 6.19 (s, 1H, 3-H), 4.79 (s, 2H, -CH2-), 2.60 (s, 1H, -CH), 2.43 (s, 3H, -CH3).
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13C NMR (CDCl3)  = 161.1(2-C), 160.4(7-C), 155.1(9-C), 152.4(4-C), 125.6(5-C), 114.3(3-C),
112.7(10-C), 112.5(6-C), 102.2(8-C), 77.4(-CH2-C-), 76.5(-CH-), 56.2(-CH2-), 18.7(-CH3).
HRMS: calcd for C13H10O3 [M+H]+ 215.0703, found 215.0701.
8-((diethylamino)methyl)-4-methyl-7-(prop-2-yn-1-yloxy)-2H-chromen-2-one (4c): White
solid, yield 75%. M.p. 112-114 C. 1H NMR (CDCl3) δ = 7.40 (d, J = 8.0 Hz, 1H, 5-H), 6.74 (d,
J = 8.0 Hz, 1H, 6-H), 6.05 (s, 1H, 3-H), 4.11 (s, 2H, -CH2-C-), 3.66 (s, 2H, -CH2-N-), 3.32(s, 1H,
-CH), 2.72 (m, 4H, -CH2CH3), 2.38 (s, 3H, -CH3), 1.17 (t, J = 8.0 Hz, 6H, -CH2CH3). 13C NMR
(CDCl3)  = 163.6(2-C), 161.4(7-C), 153.4(4-C), 152.4(9-C), 124.4(5-C), 113.5(8-C), 111.8(3-C),
110.3(10-C),
108.1(6-C),
77.3(-CH2-C-CH),
76.7(-CH2-C-CH),
50.1(-CH2-C-CH),
49.0(-CH2CH3)46.8(-CH2-N-), 18.8(-CH3), 11.1(-CH2CH3). HRMS: calcd for C18H21NO3
[M+H]+ 300.1594, found 300.1595.
8-((dipropylamino)methyl)-4-methyl-7-(prop-2-yn-1-yloxy)-2H-chromen-2-one (4d): White
solid, yield 80%. M.p. 116-118 C. 1H NMR (CDCl3) δ = 7.61 (d, J = 8.0 Hz, 1H, 4-H), 7.25 (d,
J = 8.0 Hz, 1H, 5-H), 6.71 (d, J = 8.0 Hz, 1H, 6-H), 6.16 (d, J = 8.0 Hz, 1H, 3-H), 4.08 (s, 2H,
-CH2-C-CH), 3.56 (s, 2H, -CH2-N-), 3.32(s, 1H, -CH2-C-CH), 2.57 (t, J = 8.0 Hz, 4H,
13
-CH2CH2CH3), 1.62 (m, 4H, -CH2CH2CH3), 0.92 (t, J = 8.0 Hz, 6H, -CH2CH2CH3). C NMR
(CDCl3)  = 160.8(2-C), 159.9(7-C), 154.0(9-C), 143.6(4-C), 127.7(5-C), 123.3(10-C),
113.4(3-C), 113.1(8-C), 108.9(6-C), 77.4(-CH2-C-CH), 76.5(-CH2-C-CH), 62.7(-CH2CH2CH3),
55.9(-CH2-C-CH), 44.8(-CH2-N-), 19.6(-CH2CH2CH3), 11.9(-CH2CH2CH3). HRMS: calcd for
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C19H23NO3 [M+H]+ 314.1751, found 314.1752.
8-((diisopropylamino)methyl)-7-(prop-2-yn-1-yloxy)-2H-chromen-2-one (4e): White solid,
yield 70%. M.p. 115-116 C. 1H NMR (CDCl3) δ = 7.64 (d, J = 8.0 Hz, 1H, 4-H), 7.36 (d, J = 8.0
Hz, 1H, 5-H), 6.97 (d, J = 8.0 Hz, 1H, 6-H), 6.28 (d, J = 8.0 Hz, 1H, 3-H), 4.81 (s, 2H,
-CH2-C-CH), 3.87 (s, 2H, -CH2-N-), 3.32(s, 1H, -CH2-C-CH), 2.99 (m, 2H, -CH(CH3)2), 1.11 (d,
J = 8.0 Hz, 12H, -CH3). 13C NMR (CDCl3)  = 160.0(2-C), 159.4(7-C), 154.2(9-C), 143.5(4-C),
127.0(5-C),
118.6(8-C),
113.6(3-C),
113.4(10-C),
109.2(6-C),
78.0(-CH2-C-CH),
75.8(-CH2-C-CH), 56.6(-CH2-C-CH), 47.0(-CH(CH3)2), 36.2(-CH2-N-), 20.7(-CH3). HRMS:
calcd for C19H23NO3 [M+H]+ 314.1751, found 314.1749.
8-((dibutylamino)methyl)-7-(prop-2-yn-1-yloxy)-2H-chromen-2-one (4f): White solid, yield
78%. M.p. 118-120 C. 1H NMR (CDCl3) δ = 7.66 (d, J = 8.0 Hz, 1H, 4-H), 7.40 (d, J = 8.0 Hz,
1H, 5-H), 6.99 (d, J = 8.0 Hz, 1H, 6-H), 6.30 (d, J = 8.0 Hz, 1H, 3-H), 4.84 (s, 2H, -CH2-C-CH),
3.86 (s, 2H, -CH2-N-), 3.32(s, 1H, -CH2-C-CH), 2.54 (t, J = 8.0 Hz, 4H, -N-CH2-), 1.57 (m, 4H,
-CH2CH2CH2CH3), 1.31 (m, 4H, -CH2CH2CH2CH3), 0.91 (t, J = 8.0 Hz, 6H, -CH2CH2CH2CH3).
13C NMR (CDCl3)  = 160.8(2-C), 159.2(7-C), 154.0(9-C), 143.6(4-C), 132.8(5-C), 127.5(8-C),
121.1(3-C), 113.5(10-C), 109.0(6-C), 77.4(-CH2-C-CH), 76.5(-CH2-C-CH), 57.1(-CH2-C-CH),
53.5(-CH2CH2CH2CH3), 44.4(-CH2-N-), 32.9(-CH2CH2CH2CH3), 20.4(-CH2CH2CH2CH3),
13.5(-CH2CH2CH2CH3). HRMS: calcd for C21H27NO3 [M+H]+ 342.2064, found 342.2063.
8-((diisobutylamino)methyl)-7-(prop-2-yn-1-yloxy)-2H-chromen-2-one (4g): White solid,
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yield 70%. M.p. 116-118 C. 1H NMR (CDCl3) δ = 7.66 (d, J = 8.0 Hz, 1H, 4-H), 7.40 (d, J = 8.0
Hz, 1H, 5-H), 7.01 (d, J = 8.0 Hz, 1H, 6-H), 6.29 (d, J = 8.0 Hz, 1H, 3-H), 4.82 (s, 2H,
-CH2-C-CH), 3.32(s, 1H, -CH2-C-CH), 3.79 (s, 2H, -CH2-N-), 2.14 (d, J = 7.2 Hz, 4H, -N-CH2-),
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1.82 (m, 2H, -CH(CH3)2), 0.80 (d, J = 6.4 Hz, 12H, -CH3). C NMR (CDCl3)  = 160.9(2-C),
159.2(7-C), 154.0(9-C), 143.5(4-C), 127.3(5-C), 116.8(8-C), 113.5(3-C), 113.2(10-C),
108.6(6-C), 77.9(-CH2-C-CH), 76.0(-CH2-C-CH), 63.9(-CH2CH(CH3)2), 56.1(-CH2-C-CH),
46.0(-CH2-N-), 26.5(-CH2CH(CH3)2), 20.8(-CH2CH(CH3)2). HRMS: calcd for C21H27NO3
[M+H]+ 342.2064, found 342.2065.
General procedure for synthesis of 1,2,3-triazole bridge-connected phosphonate derivatives
of coumarin (5a-5g)
Diethyl 2-azidoethylphosphonate (1.0 g, 5.0 mmol) and propargylated coumarin derivatives
(5.0 mmol) were added into DMSO/H2O (V/V=1:1, 30 mL) in a 50 mL flask followed by
CuSO4·5H2O (125 mg, 0.5 mmol) and sodium ascorbate (216 mg, 1.0 mmol). The mixture was
sonicated for 1 h in ultrasonic cleaning bath, and the temperature of water bath was 45 C. After
completion of the reaction, the reaction mixture was diluted with water (20 mL), extracted with
dichloromethane (3×30 mL) and combined organic phase was washed with saturated ammonium
chloride (3×30 mL ). The crude product was purified by column chromatography on silica gel to
give pure 5a-5g.
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Diethyl(2-(4-(((2-oxo-2H-chromen-7-yl)oxy)methyl)-1H-1,2,3-triazol-1-yl)ethyl)phosphonat
e (5a): faint yellow oil, yield 85%. IR (KBr) (cm-1) = 2985, 2929 (-CH3, -CH2), 1728 (C=O),
1620, 1556, 1516 (C=C), 1245 (P=O), 1043 (PO).1H NMR (CDCl3)  = 7.78 (s, 1H,
5-triazol-H), 7.56 (d, J = 9.5 Hz, 1H, 4-H), 7.32 (d, J = 8.5 Hz, 1H, 5-H), 6.82 (dd, J = 8.5 Hz, J
= 2.3 Hz, 1H, 6-H), 6.78 (d, J = 2.3 Hz, 1H, 8-H), 6.13 (d, J = 9.5 Hz, 1H, 3-H), 5.16 (s, 2H,
-O-CH2-), 4.57 (dt, J = 7.5 Hz, J = 12.8 Hz, 2H, -CH2CH2-P-), 3.98 (m, 4H, -CH2CH3), 2.36 (dt,
J = 7.5 Hz, J = 18.4 Hz, 2H, -CH2CH2-P-), 1.19 (t, J = 7.0 Hz, 6H, -CH3). 13C NMR (CDCl3)  =
161.2(2-C),
160.9(7-C),
155.5(9-C),
143.4(4-C),
142.7(4-triazol-C),
128.9(5-C),
123.8(5-triazol-C), 113.2(3-C), 112.8(010-C, 112.6(6-C), 101.8(8-C), 62.2(-O-CH2-), 62.0 (d, J
= 4.8 Hz, -O-CH2CH3), 44.6 (d, J = 1.7 Hz, -CH2CH2-P-), 27.7 (d, J = 140.4 Hz, -CH2CH2-P-),
16.3 (d, J = 6.0 Hz, -O-CH2CH3). 31P NMR (CDCl3) δ = 25.3. HRMS calcd for C18H22N3O6P [M
+ H]+ 408.1319, found 408.1320.
Diethyl(2-(4-(((4-methyl-2-oxo-2H-chromen-7-yl)oxy)methyl)-1H-1,2,3-triazol-1-yl)ethyl)ph
o-sphonate (5b): faint yellow oil, yield 86%. IR (KBr) (cm-1) = 2985, 2935 (-CH3, -CH2), 1725
1
(C=O), 1625, 1556, 1516 (C=C), 1235 (P=O), 1028 (PO). H NMR (CDCl3)  = 7.77 (s, 1H,
5-triazol-H), 7.51 (d, J = 9.6 Hz, 1H, 5-H), 6.95 (d, J = 9.6 Hz, 1H, 6-H), 6.92 (s, 1H, 8-H),
6.15(s, 1H, 3-H), 5.26 (s, 2H, -O-CH2-C-), 4.65(dt, J = 7.5 Hz, J = 12.2 Hz, 2H, -CH2CH2-P-),
4.10 (m, 4H, -CH2CH3), 2.47(m, 2H, -CH2CH2-P-), 2.40(s, 3H, 4-CH3), 1.31 ( t, J = 7.0 Hz, 6H,
-CH2CH3). 13C NMR (CDCl3)  = 161.1(2-C), 161.0(7-C), 155.1(9-C), 152.4(4-C),
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143.0(4-trizol-C), 125.7(5-trizol-C), 123.5(5-C), 114.1(3-C), 112.4(10-C), 112.3(6-C),
102.1(8-C), 72.3(-O-CH2-C-), 62.2(-CH2CH3), 44.7 (d, J =2.2 Hz, -CH2CH2-P-), 27.2 (d, J
31
=140.7 Hz, -CH2CH2-P-), 18.7(4-CH3), 16.4 (d, J = 6.0 Hz, (-CH2CH3). P NMR (CDCl3) δ =
25.3. HRMS calcd for C19H24N3O6P [M + H]+ 422.1475, found 422.1477.
Diethyl(2-(4-(((8-((diethylamino)methyl)-4-methyl-2-oxo-2H-chromen-7-yl)oxy)methyl)-1H-
1,2,3-triazol-1-yl)ethyl)phosphonate (5c): faint yellow oil, yield 86%. IR (KBr) (cm-1) = 2985,
1
2931 (-CH3, -CH2), 1665 (C=O), 1616, 1556, 1516 (C=C), 1238 (P=O), 1043 (PO). H NMR
(CDCl3)  = 8.04 (s, 1H, 5-triazol-H), 7.55 (d, J = 8.8 Hz, 1H, 5-H), 7.08 (d, J = 8.8 Hz, 1H,
6-H), 6.15 (s, 1H, 3-H), 5.38 (s, 2H, -O-CH2-C-), 4.62 (m, 2H, -CH2CH2-P-), 4.10 (m, 4H,
-O-CH2CH3), 3.97 (s, 2H, -CH2-N-), 2.76 (m, 4H, -N-CH2CH3), 2.45 (m, 2H, -CH2CH2-P-), 2.40
13
(s, 3H, 4-CH3), 1.31 (t, J = 7.0 Hz, 6H, -O-CH2CH3), 1.15 (t, J = 7.0 Hz, 6H, -N-CH2CH3). C
NMR (CDCl3)  = 160.5(2-C), 159.9(7-C), 153.4(9-C), 152.6(4-C), 143.4(4-trizol-C),
125.5(5-trizol-C),
124.2(5-C),
114.2(3-C),
112.3(10-C),
108.6(6-C),
102.1(8-C),62.7(-O-CH2-C-), 62.2 (d, J = 6.4 Hz, -CH2CH2-P-), 46.9(-O-CH2CH3),
44.7(-N-CH2CH3), 27.2 (d, J = 140.5 Hz, -CH2CH2-P-), 18.8(4-CH3), 16.4 (d, J = 6.0 Hz,
-O-CH2CH3), 10.4(-N-CH2CH3). 31P NMR (CDCl3)  = 25.3. HRMS calcd for C24H35N4O6P [M
+ H]+ 507.2367, found 507.2371.
Diethyl(2-(4-(((8-((dipropylamino)methyl)-2-oxo-2H-chromen-7-yl)oxy)methyl)-1H-1,2,3-tri
azol-1-yl)ethyl)phosphonate (5d): faint yellow oil, yield 87%. IR (KBr) (cm-1) = 2978, 2915
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(-CH3, -CH2), 1725 (C=O), 1625, 1546, 1520 (C=C), 1245 (P=O), 1048 (PO). H NMR
(CDCl3)  = 7.78 (s ,1H, 5-triazol-H), 7.63 (d, J = 9.6 Hz, 1H, 4-H), 7.37 (d, J = 8.8 Hz, 1H,
5-H), 7.03 (d, J = 8.8 Hz, 1H, 6-H), 6.25 (d, J = 9.6 Hz, 1H, 3-H), 5.34 (s, 2H, -O-CH2-C-), 4.62
(m, 2H, -CH2CH2-P-), 4.09 (m, 4H, -O-CH2CH3), 3.82 (s, 2H, -CH2-N-), 2.46 (m, 4H,
-N-CH2CH2CH3), 2.39 (m, 2H, -CH2CH2-P-), 1.51 (m, 4H, -N-CH2CH2CH3), 1.31 (t, J = 7.2 Hz,
13
6H, -O-CH2CH3) 0.78 (t, J = 7.2 Hz, 6H, -N-CH2CH2CH3). C NMR (CDCl3)  = 160.9(2-C),
159.9(7-C), 154.1(9-C), 143.7(4-C), 143.6(4-triazol-C), 127.7(5-C), 123.4(5-triazol-C),
117.3(8-C), 113.4(3-C), 113.2(10-C), 108.9(6-C), 62.7(-O-CH2-C-), 62.2 (d, J = 6.5 Hz,
-O-CH2-CH3), 55.9(-N-CH2CH2CH3), 44.8 (d, J = 8.2 Hz, -CH2CH2-P-), 27.2 (d, J = 140.6 Hz,
-CH2CH2-P-), 19.6(-N-CH2CH2CH3), 16.4 (d, J = 5.9 Hz, -O-CH2-CH3), 11.9(-N-CH2CH2CH3).
31P NMR (CDCl3) δ = 25.2. HRMS calcd for C25H38N4O6P [M + H]+ 521.2523, found 521.2570.
Diethyl(2-(4-(((8-((diisopropylamino)methyl)-2-oxo-2H-chromen-7-yl)oxy)methyl)-1H-1,2,3
-triazol-1-yl)ethyl)phosphonate (5e): faint yellow oil, yield 84%. IR (KBr) (cm-1) = 2980,
1
2919 (-CH3, -CH2), 1728 (C=O), 1620, 1556, 1516 (C=C), 1246 (P=O), 1038 (PO). H NMR
(CDCl3)  = 7.71 (s ,1H, 5-triazol-H), 7.53 (d, J = 9.6 Hz, 1H, 4-H), 7.24 (d, J = 8.4 Hz, 1H,
5-H), 6.92 (d, J = 8.4 Hz, 1H, 6-H), 6.13 (d, J = 9.6 Hz, 1H,3-H), 5.25 (s, 2H, -O-CH2-C-), 4.55
(dt, J = 8.0 Hz, J = 11.2 Hz, 2H, -CH2CH2-P-), 4.01 (m, 4H, -O-CH2CH3), 3.75 (s, 2H, -CH2-N-),
2.87 ( m, 2H, -N-CH(CH3)2), 2.37 (dt, J = 8.0 Hz, J = 18.4 Hz, 2H, -CH2CH2-P-), 1.22 ( t, J =
7.2 Hz, 6H, -O-CH2CH3), 0.95 (d, J = 6.8 Hz, 12H, -N-CH(CH3)2). 13C NMR (CDCl3)  =
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160.9(2-C),
159.8(7-C),
154.2(9-C),
143.6(4-C),
143.5(4-triazol-C),
127.3(5-C),
123.2(5-triazol-C), 117.7(8-C), 113.2(3-C), 112.9(10-C), 108.8(6-C), 62.4((-O-CH2-C-)), 62.1
(d, J = 6.4 Hz,), 46.9(-N-CH(CH3)2), 44.6(-CH2-N-), 36.2(-CH2CH2-P-), 27.1 (d, J = 140.6 Hz,
-CH2CH2-P-), 20.7(-N-CH(CH3)2), 16.3(d, J = 5.9 Hz, -O-CH2CH3). 31P NMR (CDCl3)  = 25.3.
HRMS calcd for C25H37N4O6P [M + H]+ 521.2523, found 521.2530.
Diethyl(2-(4-(((8-((dibutylamino)methyl)-2-oxo-2H-chromen-7-yl)oxy)methyl)-1H-1,2,3-tria
zol-1-yl)ethyl)phosphonate (5f): faint yellow oil, yield 86%. IR (KBr) (cm-1) = 2938, 2933
(-CH3, -CH2), 1726 (C=O), 1620, 1558, 1508 (C=C), 1244 (P=O), 1043 (PO).1H NMR (CDCl3)
 = 7.78 (s ,1H, 5-triazol-H), 7.63 (d, J = 9.6 Hz, 1H, 4-H), 7.36 (d, J = 8.8 Hz, 1H, 5-H), 7.04
(d, J = 8.8 Hz, 1H, 5-H), 6.26 (d, J = 9.6 Hz, 1H, 3-H), 5.34 (s, 2H, -O-CH2-C-), 4.62 (dt, J = 8.0
Hz, J = 11.2 Hz, 2H, -CH2CH2-P-), 4.12 (m, 4H, -O-CH2CH3), 3.81 (s, 2H,-CH2-N-), 2.48 (m,
4H, -N-CH2CH2CH2CH3), 2.41 (m, 2H, -CH2CH2-P-), 1.48 ( m, 4H, -N-CH2CH2CH2CH3), 1.31
(t, J = 7.2 Hz, 6H, -O-CH2CH3), 1.21 (m, 4H, -N-CH2CH2CH2CH3), 0.83 (t, J = 7.2 Hz, 6H,
-N-CH2CH2CH2CH3). 13C NMR (CDCl3)  = 160.9(2-C), 159.9(7-C), 154.0(9-C), 143.7(4-C),
143.6(4-triazol-C), 127.7(5-C), 123.3(5-triazol-C), 116.5(8-C), 113.4(3-C), 113.1(10-C),
108.9(6-C), 62.7(-O-CH2-C-), 62.2 (d, J = 6.5 Hz, -O-CH2CH3), 53.5(-N-CH2CH2CH2CH3),
44.8(-CH2-N-), 44.7(-N-CH2CH2CH2CH3), 28.6(-CH2CH2-P-), 27.9 (d, J = 140.6 Hz,
-CH2CH2-P-),20.7(-N-CH2CH2CH2CH3),16.4(d,
J
=
6.0
Hz,
-O-CH2CH3),
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14.0(-N-CH2CH2CH2CH3). 31P NMR (CDCl3)  = 25.3. HRMS calcd for C27H41N4O6P [M + H]+
549.2836, found 549.2841.
Diethyl(2-(4-(((8-((diisobutylamino)methyl)-2-oxo-2H-chromen-7-yl)oxy)methyl)-1H-1,2,3-t
riazol-1-yl)ethyl)phosphonate (5g): faint yellow oil, yield 86%. IR (KBr) (cm-1) = 2945, 2936
1
(-CH3, -CH2), 1726 (C=O), 1625, 1555, 1512 (C=C), 1244 (P=O), 1043 (PO). H NMR
(CDCl3)  = 7.69 (s ,1H, 5-triazol-H), 7.63 (d, J = 9.6 Hz, 1H,4-H), 7.36 (d, J = 8.8 Hz, 1H,
5-H), 7.05 (d, J = 8.8 Hz, 1H, 6-H), 6.26 (d, J = 9.6 Hz, 1H, 3-H), 5.33 (s, 2H, -O-CH2-C-), 4.66
(m, 2H, -CH2CH2-P-), 4.10 (m, 4H, -O-CH2CH3), 3.76 (s, 2H, -CH2-N-), 2.43 (dt, J = 8.0 Hz, J =
18.4 Hz, 2H, -CH2CH2-P-), 2.09 ( d, J = 8.0 Hz, 4H, -N-CH2CH(CH3)2), 1.75 (m, 2H,
-N-CH2CH(CH3)2), 1.31 (t, J = 6.4 Hz, 6H, -O-CH2CH3), 0.74 (t, J = 6.4 Hz, 12H,
-N-CH2CH(CH3)2). 13C NMR (CDCl3)  = 160.9(2-H), 159.9(7-C), 154.1(9-C), 143.7(4-C),
143.6(4-triazol-C), 127.6(5-C), 123.2(5-triazol-C), 116.4(8-C), 113.4(3-C), 113.0(10-C),
108.6(6-C), 63.9(-N-CH2CH(CH3)2), 62.5(-O-CH2-C-), 62.2 (d, J = 6.4 Hz, -OCH2CH3),
46.3(-CH2-N-),
44.7(-CH2CH2-P-),
27.9
(d,
J
=
140.0
Hz,
-CH2CH2-P-),
26.5(-N-CH2CH(CH3)2), 20.8(-N-CH2CH(CH3)2), 16.4 (d, J = 5.9 Hz, -OCH2CH3). 31P NMR
(CDCl3)  = 25.3. HRMS calcd for C27H41N4O6P [M + H]+ 549.2836, found 549.2841.
ACKNOWLEDGEMENTS
Financial support from The National Natural Science Foundation of China (No. 21072178),
Innovation Specialist Projects of Henan Province (No. 114200510023), Technology and Science
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talent Cultivation Project in Zhengzhou City (No. 112PLJRC359), The Special Fund for the
Doctoral Program of Higher Education (No. 20124101110003), Foundational and Frontier
Technology Research Foundation of Henan Province for their financial support (No.
132300410027).
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Table 1. Screening for the reaction solvent
Entry Solvent Yield (%) Entry
Solvent
H2O
Yield (%)
1
2
3
4
5
6
7
8
9
EtOH
DMSO
THF
13
12
10
11
12
13
14
15
16
17
18
33
56
EtOH+H2O
DMSO+H2O
THF+H2O
Trace
11
91
DMF
52
t-BuOH
CH3CN
CHCl3
Acetone
Toluene
13
DMF + H2O
t-BuOH+H2O
CHCl3+H2O
Acetone+H2O
Toluene+H2O
74
Trace
Trace
Trace
41
83
45
44
Trace
Reaction conditions: co-solvent (1:1 v/v), CuSO4·5H2O (10 mol%)/sodium ascorbate
(20 mol%) as the catalyst, ultrasound irradiation (US, 150W), 45 C, 1h.
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Scheme 1. Synthesis of 1,2,3-triazole bridge-connected phosphonates of coumarin derivatives
Reaction conditions: a) No solvent, reflux; b) NaN3, H2O and DMF, rt, 48h; c) Propargyl
bromide, K2CO3, acetone, 65 C, 24h; d) CuSO4·5H2O (10 mol%) and sodium ascorbate (20
mol%), DMSO/H2O (1:1 v/v), ultrasound irradiation (US), 45 C, 1h.
Scheme 2. Model reaction for optimizing reaction conditions.
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Figure 1. Two examples illustrating the importance of coumarin derivatives
Figure 2. Screening of catalyst for the synthesis of compound 5a in DMSO/H2O (1:1, v/v)
under ultrasound irradiation (150 W) for 1 h at 45 C.
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Figure 3. Screening of catalyst loading for the synthesis of compound 5a in DMSO/H2O
(1:1 v/v) under ultrasound irradiation (150 W) for 1 h at 45 C.
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90
85
80
75
70
65
20
30
40
50
60
70
80
Reaction temperature(C)
Figure 4. Screening of reaction temperature for the synthesis of Compound 5a in
DMSO/H2O (1:1 v/v) under ultrasound irradiation (150 W) for 1 h.
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