Synthesis of novel phosphorylated chrysin derivatives by 1, 3-dipolar cycloaddition reaction

Article abstract of DOI:10.1080/10426507.2016.1223076

Through 1,3-dipolar cycloaddition reaction, 1,4,5-trisubstituted-1,2,3-triazole and phosphate-containing chrysin derivatives were synthesized with high yields. The target compounds were characterized by¹H,³¹P,¹³C NMR spect

Full text of DOI:10.1080/10426507.2016.1223076

Phosphorus, Sulfur, and Silicon and the Related Elements
ISSN: 1042-6507 (Print) 1563-5325 (Online) Journal homepage: http://www.tandfonline.com/loi/gpss20
Synthesis of Novel Phosphorylated Chrysin
Derivatives by 1, 3-Dipolar Cycloaddition Reaction
Shaohua Zhu, Yan Zhang, Peipei Li, Wenzhu Bi, Xiaolan Chen & Yufen Zhao
To cite this article: Shaohua Zhu, Yan Zhang, Peipei Li, Wenzhu Bi, Xiaolan Chen & Yufen
Zhao (2016): Synthesis of Novel Phosphorylated Chrysin Derivatives by 1, 3-Dipolar
Cycloaddition Reaction, Phosphorus, Sulfur, and Silicon and the Related Elements, DOI:
10.1080/10426507.2016.1223076
To link to this article: http://dx.doi.org/10.1080/10426507.2016.1223076
Accepted author version posted online: 17
Aug 2016.
Published online: 17 Aug 2016.
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Date: 19 September 2016, At: 08:15

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Synthesis of Novel Phosphorylated Chrysin Derivatives by 1, 3-Dipolar Cycloaddition
Reaction
1
1
1
1
1,*
1,2
Shaohua Zhu, Yan Zhang, Peipei Li, Wenzhu Bi, Xiaolan Chen, and Yufen Zhao
1
2
College of Chemistry and Molecular Engineering, Zhengzhou University, Zhengzhou, 450001,
China
Department of Chemistry, Xiamen University, Xiamen, 361000, China
Corresponding author. Tel.: +86-371-67767051; Fax:+86-371-67767051; E-mail:
chenxl@zzu.edu.cn
Abstract
Through 1,3-dipolar cycloaddition reaction, 1,4,5- trisubstituted-1,2,3-triazole and
phosphate contained chrysin derivatives were synthesized with high yields. The target
1
31
13
compounds were characterized by H, P, C NMR spectroscopy and HRMS.
Keywords
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Chrysin; 1,4,5-trisubstituted-1,2,3-triazole; phosphate; 1,3-dipolar cycloaddition.
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Introduction
Chrysin, namely 5,7-dihydroxyflavone, as shown in Figure 1, is a naturally occurring
flavone and exists in the passion flowers Passiflora caerulea and Passiflora incarnata, and in
1
Oroxylum indicum. It is also found in chamomile, in the mushroom Pleurotus ostreatus ,and in
honeycomb. Because of its extensive pharmacological activities, chrysin has been widely used in
the process of new drug development research for antioxidation, antitumor, cancer, high blood
2
-3
pressure, diabetes, allergy . However, chrysin has little or no absorption in the intestine and its
rapid metabolism (carbonylation thereby rapidly react with common carbohydrate, aldehyde and
4
acid) significantly reduces its activity and thereby limits its application in a clinical setting. To
obtain more efficient and less harmful lead compounds, making appropriate modifications to
chrysin has been an important research field. In recent years, through methylation, acetoxylation,
nitration and halogenation (Scheme 1, (I), (II)), many chemists are constantly expanding the
applicable scope of chrysin and its derivatives, with a hope to develop new drugs of clinical
5
-10
value . By the use of the Atherton-Todd reaction, our group synthesized a series of phosphorus
acylation chrysin derivatives (Scheme 1, (III)), which showed stronger inhibitory effects on
1
1-13
HeLa cells compared with the chrysin itself
.
1
,2,3-triazoles, a class of nitrogen containing heterocycles, display a broad spectrum of
biological activities and exist in a fairly large proportion of the clinical use drugs for
1
4-18
antibacterium, HIV, malignant tumor
. Therefore, based on the prodrug principle of drug
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molecules design, we designed a simple and effective method to introduce 1,2,3- triazole and
phosphate groups onto chrysin by 1,3-dipolar cycloadditionof
7
-(3-azidopropoxy)-5-hydroxy-flavone and dialkyl alkynylphosphonates. With the optimized
reaction conditions, 14 novel 1,4,5-trisubstituted-1,2,3-triazole and phosphate contained chrysin
1
derivatives were synthesized with high yields. The target compounds were characterized by H,
3
1
13
P, C NMR spectroscopy and HRMS.
Results and discussion
The 1, 3-dipolar cycloaddition, also called Huisgen reaction, refers to a chemical reaction
between the 1, 3-dipoleswhich have internal octet stabilization and the dipolarophile (unsaturated
1
9
compounds) to form a five-membered ring . This process is an important route to the synthesis
of five-membered heterocycles and their ring-opened acyclic derivatives. In recent years, the 1,
3
3
-dipolar cycloaddition is often used in the synthesis and modification of natural products.
Initially, we started with a variety of experiment to find the optimal conditions for the 1,
-dipolar cycloaddition of 7-(3-azidopropoxy)-5-hydroxy-flavone and dialkyl
alkynylphosphonates. The screening results are summarized in Table 1. The effect of solvents on
the model reaction was first investigated (Table 1, entries 1 - 5). A relatively higher yield was
obtained when toluene was used as a solvent (92%) (Table 1, entry 5). Other solvents resulted in
lower yields: i.e. DMF (42%), DMSO (30%), Ac O (30%), and NMP (65%). It is worth noting
2
4
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that the yield was also relatively high when the reaction occurred under solvent-free conditions
(
Table 1, entry 6). So, the influence of temperature was investigated under solvent-free
conditions (Table 1, entries 7 - 8). The yield increased over the temperature range of 90 -
30°C, from 82% to 97%. When the temperature reached 150 - 160°C, the reaction still brought
1
about a satisfactory yield in a relatively short reaction time (Table 1, entries 9 - 10).
With the optimized reaction conditions (Table 1, entry 10), the 1, 3-dipolar cycloaddition
of 7-(3-azidopropoxy)-5-hydroxy-flavone and dialkyl alkynylphosphonates proceeded
satisfactorily, giving the resulting chrysin derivatives in moderate to good yields from 78% to
9
5% (Table 2). It is worth noting that the stereoselectivity was impacted by the steric hindrance
of the substituent groups of the corresponding dialkyl alkynylphosphonates.
1
D and 2D NMR spectra data were used to identify the structures of the two isomers.
1
Compound 6a and 6b were taken as examples for structural identification (Figure 2). In the H
NMR spectrum, compound 6a exhibited singlet at δ 5.53 ppm assigned to the methylene protons
1
3
(
5-H) and triplet at δ 4.80 ppm assigned to the methylene protons (12-H). In the C NMR of
compound 6a, two doublets are observed at 134.7 and 138.2 ppm due to the consequence of
2
3
coupling of phosphorus atom, while the coupling constant J (3-C) and J (4-C) are 233.0
PC
PCC
3
Hz and 35.0 Hz separately. In the HMBC spectrum diagram, the J correlations were shown in
CH
grey. At this point, it was noted that the trisubstituted-triazole isomer with coupling constant
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3
JPCC (4-C) 35.0 Hz was presumed to be the configuration of 6a and the isomer with coupling
2
constant J (3-C) 216.0 Hz should be the configuration of 6b.
PC
Conclusion
In summary, based on the prodrug principle of drug molecules design, 14 novel 1,4,5-
trisubstituted-1,2,3-triazole and phosphate contained chrysin derivatives were synthesized
1
31
13
through 1,3-dipolar cycloaddition reaction, and their structures were investigated by H, P, C
NMR spectroscopy and HRMS. The research progress of their biological activities are ongoing.
Experimental Section
All the chemicals were obtained from Hangzhou HC Pharm & Chem Co., Ltd., Tianjin
Kermel Chemical Reagent Co., Ltd., and Shanghai Aladdin Bio-Chem Technology Co., Ltd.,
1
13
31
and used as received. H, C, and P NMR spectra were recorded with a Bruker Avance 400
1
3
31
MHz spectrometer operating at 400.13, 100.61, and 161.98 MHz, respectively, with C and P
NMR spectra being recorded with broad band proton decoupled. All NMR spectra were
1
13
recorded in CDCl at room temperature (20 ± 3 C). H and C chemical shifts are quoted in
3
3
1
parts per million downfield from TMS. P chemical shifts are quoted in parts per million
relative to 85% H PO as an external standard. High resolution mass spectra (HRMS) were
3
4
obtained with a Waters Micromass Q-Tof Micro instrument using the ESI technique. IR spectra
were recorded on Shimadazu IR-408 Fourier Transform infrared spectrophotometer using a thin
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13
31
film supported on KBr pellets. The Supplemental Materials contains sample H, C and P
NMR spectra of products 6 and 7 (Figures S 1 -- S 48)
General procedure
2
0
Synthesis of dialkyl alkynylphosphonates
Terminal alkynes (0.006 mol), dialkyl H-phosphonates (5 mmol), CuSO ·5H O (20 mmol%) and
4
2
Et N (35 mmol%) were dissolved in DMF (60 mL) in a 250 mL 3-neck round bottom flask at
3
3
1
5
5°C. The reaction was tracked by P NMR. After completion of the reaction, the mixture was
extracted by CH Cl (3 × 30 mL). The combined organic layer was washed with saturated
2
2
ammonium chloride aqueous solution and dried over anhydrous Na SO . The solvent was
2
4
removed in vacuum and the brown oily crude product was purified by column chromatography
on silica gel (petroleum ether : ethyl acetate = 1 : 1, v : v).
Synthesis of phosphorylated chrysin derivatives
7
-(3-azidopropoxy)-5-hydroxy-flavone (0.6 mmol) and dialkyl alkynylphosphonates (0.5 mmol)
were mixed in a 100 mL bottom flask. The reaction mixture was heated at 160°C for 0.5 h, then
mixture was cooled to room temperature, diluted with water and extracted by CH Cl (3 × 30
2
2
mL). The combined organic layer was dried over anhydrous Na SO . The solvent was removed
2
4
in vacuo and the two isomers were obtained by column chromatography on silica gel (petroleum
ether : ethyl acetate = 1 : 2, v : v).
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Diethyl
(5-cyclopropyl-1-(3-((5-hydroxy-4-oxo-2-phenyl-4H-chromen-7-yl)oxy)propyl)-1H-1,2,3-tri
azol-4-yl)phosphonate (1a)
3
1
1
Isolated Yield 53%. Brown solid. mp: 100-102 ꢀꢁ . P NMR(161 MHz, CDCl ) : 7.9. H
3
NMR (400 MHz, CDCl ) :1.20 (m,4H), 1.32 (t,J = 7.2 Hz, 6H),1.73(m, 1H), 2.46(m, 2H),4.05
3
(t,J = 4.8 Hz, 2H), 4.17 (m, 4H,), 4.61 (t, J = 6.4 Hz, 2H), 6.28(s, 1H), 6.42(s, 1H), 6.62(s, 1H),
1
3
7
8
9
1
.48(m, 3H), 7.83(d, J = 6.8 Hz, 2H), 12.69(s, 1H). C NMR(100 MHz, CDCl ) : 6.6(5-C),
3
.8(6,7-C), 16.2(d, J = 7.0 Hz, 1-C), 29.6(9-C), 47.5(8-C), 63.0(d, J = 5.0 Hz, 2-C), 65.4(10-C),
3.0(16-C), 98.6(12 -C),105.8(14-C),105.9(18-C), 120.6(d, J = 220.0 Hz, 3-C), 126.2(22, 14-C),
29.0(21, 25-C),131.2(23-C), 131.8(20-C), 156.3(d, J = 21.0 Hz, 4-C), 157,7(16-C), 162.1(13
1
-
C), 163.9(15-C), 164.5(19-C), 182.4(17-C).IR (KBr) max(cm ): 3150(-OH), 3000(Ar-H),
1
7
660(-C = O), 1580, 1550, 1460(Ar-C = C), 1465(-CH ), 1380(-CH ), 1245(P = O), 1020(C-O),
2 3
+
50 (-CH ). HRMS (ESI-Q-TOF): [M+H] , Cal.: 556.2207, found: 556.2207.
2
8
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Diethyl
(4-cyclopropyl-1-(3-((5-hydroxy-4-oxo-2-phenyl-4H-chromen-7-yl)oxy)propyl)-1H-1,2,3-tri
azol-5-yl)phosphonate (1b)
3
1
1
Isolated Yield 42%. Brown solid. mp: 126-128 ꢀꢁ . P NMR(161 MHz, CDCl ) δ: 5.5. H
3
NMR (400 MHz, CDCl ) :1.03 (m, 2H), 1.14(m, 2H), 1.35 (t, J = 7.2 Hz, 6H), 2.26(m, 1H),
3
2
3
1
9
.45(m, 2H), 4.10(m, 6H), 4.80(t, J = 6.8 Hz, 2H), 6.31(s,1H), 6.46(s, 1H), 6.66(s, 1H), 7.52(m,
1
3
H), 7.87(d, J = 6.4 Hz, 2H), 12.69(s, 1H). C NMR(100 MHz, CDCl ) : 4.0(5-C), 6.7(6,7-C),
3
6.3(d, J = 7.0 Hz, 1-C), 29.1(9-C), 44.7(8-C), 62.8(d, J = 5.0 Hz, 2-C), 64.8(10-C), 92.7(16-C),
8.5(12- C), 105.8(14-C), 105.9(18-C), 126.2(21, 25-C), 129.0(22, 24-C), 131.1(23-C), 131.9
(20-C), 133.4(d, J = 239.0 Hz, 3-C), 144.1(d, J = 33.0 Hz, 4-C), 157.7(13-C), 162.1(15 -C),

1
1
1
64.0(11-C), 164.2(19-C), 182.3(17-C). IR(KBr) max(cm ): 3200(-OH), 3050 (Ar-H),
650(-C = O), 1600, 1545, 1450(Ar-C = C), 1472(-CH ), 1383(-CH ), 1245(P = O), 1026 (C-O).
2
3
+
HRMS (ESI-Q-TOF): [M+H] , Cal.: 556.2207, found: 556.2205.
9
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Diethyl
(
1-(3-((5-hydroxy-4-oxo-2-phenyl-4H-chromen-7-yl)oxy)propyl)-5-(p-tolyl)-1H-1,2,3-triazol
4-yl)phosphonate (2a)
-
3
1
1
Isolated Yield 45%. Brown solid. mp:134-135
ꢀꢁ . P NMR(161 MHz, CDCl ) δ: 7.5. H
3
NMR (400 MHz, CDCl ) :1.17(t, J = 7.2 Hz, 6H), 2.31(m, 5H), 3.89 (t, J = 6.4 Hz,2H),
3
4
.03(m, 4H), 4.47(t, J = 6.4 Hz, 2H), 6.09(s, 1H), 6.28(s, 1H), 6.62(s, 1H), 7.21(d, J = 8.0
1
3
Hz,4H), 7.48(m, 3H), 7.83(d, J = 7.2 Hz, 2H), 12.64(s, 1H). C NMR(100 MHz, CDCl )
3

6
9
1
1
1
1
:16.0(d, J = 6.0 Hz,1-C), 21.3(11-C), 29.3 (13-C), 44.7(12-C), 62.8(d, J = 6.0 Hz, 2-C),
4.4(14-C), 92.6(16-C), 98.6(23-C), 105.7(18, 20-C), 122.3(27-C), 126.2(26, 28-C), 129.0(7,
-C), 129.4(6, 10-C), 129.5 (25, 29-C), 131.1(24-C), 131.9(8-C), 134.3(d, J = 229.0 Hz, 3-C),
40.4(5-C), 143.2(d, J = 33.0 Hz, 4-C), 157.6(15-C), 161.9(17-C), 163.9(22-C), 164.1 (21-C),

1
82.3 (19-C). IR(KBr) max(cm ): 3215(-OH), 3012(Ar-H), 2925(-CH -), 1675(-C = O), 1593,
2
583, 1497, 1443(Ar-C = C), 1472(-CH ), 1380, 1370(-CH ), 1245(P = O), 1030(C-N),
2
3
+
028(C-O). HRMS (ESI-Q-TOF): [M+H] , Cal.: 590.2051, found: 590.2050.
1
0
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Diethyl
(
1-(3-((5-hydroxy-4-oxo-2-phenyl-4H-chromen-7-yl)oxy)propyl)-4-(p-tolyl)-1H-1,2,3-triazol
5-yl)phosphonate (2b)
-
3
1
1
Isolated Yield 43%. Brown solid. mp: 147-149
ꢀC . P NMR(161 MHz, CDCl ) δ: 4.2. H
3
NMR (400 MHz, CDCl ) :1.14(t, J = 7.2 Hz, 6H), 2.37(s, 3H), 2.51 (t, J = 6.4 Hz, 2H), 3.90(m,
3
6
7
H), 4.17(t, J = 6.4 Hz, 2H), 6.30(s, 1H), 6.43(s, 1H), 6.62(s, 1H), 7.21(d, J = 7.2 Hz, 2H),
1
3
.46(m, 3H), 7.63(d, J = 8.0 Hz, 2H), 7.82(d, J = 6.8 Hz, 2H), 12.67(s, 1H). C NMR(100
MHz, CDCl ) :15.9(d, J = 6.0 Hz,1-C), 21.3(11-C), 30.0 (13-C), 48.1(12-C), 63.1(d, J = 6.0
3
Hz, 2-C), 65.5(14-C), 93.0(16-C), 98.5(23-C), 105.7(18, 20-C), 120.7(d, J = 219.0 Hz,3-C),
1
1
1
1
1
26.2(26, 28-C), 127.1(27-C), 128.8(25, 29-C), 129.0(6, 10-C), 129.1(7, 9-C), 131.1(24-C),
31.8(5-C), 138.9(8-C), 153.2(d, J = 19.0 Hz, 4-C), 157.6(15-C), 162.0(17-C), 163.8(22-C),

1
64.5(21-C), 182.3 (19-C). IR(KBr) max(cm ): 3200(-OH), 3025(Ar-H), 2938(-CH -),
2
670(-C = O), 1600, 1583, 1500, 1450(Ar-C = C), 1470(-CH ), 1385, 1377(-CH ), 1243(P = O),
2
3
+
033(C-N), 1020(C-O). HRMS (ESI-Q-TOF): [M+H] , Cal.: 590.2051, found: 590.2051.
1
1
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Diethyl
(5-(4-ethylphenyl)-1-(3-((5-hydroxy-4-oxo-2-phenyl-4H-chromen-7-yl)oxy)pro-pyl)-1H-1,2,
3
-triazol-4-yl)phosphonate (3a)
31
Isolated Yield 47%. Faint yellow solid. mp: 103-105 ꢀꢁ . P NMR(161 MHz, CDCl ) δ: 7.5.
3
1
H NMR (400 MHz, CDCl ) :1.55(t, J = 7.2 Hz, 6H), 2.33(m, 2H), 2.63 (dd, J = 7.6 Hz, 2H),
3
3
.90(t, J = 5.6 Hz, 2H), 4.05(m, 2H), 4.48(t, J = 5.6 Hz, 2H), 6.10(s, 1H), 6.28(s, 1H), 6.62(s,
H), 7.24(d, J = 8.0 Hz, 4H), 7.27(d, J = 8.0 Hz, 4H), 7.48(m, 3H), 7.83 (d, J = 6.8 Hz, 2H),
1
1
2
2
1
1
3
1
6
1
3
2.64(s, 1H). C NMR(100 MHz, CDCl ) :15.2(12-C), 16.0(d, J = 7.0 Hz, 1-C), 28.6 (14-C),
3
9.3(11-C), 44.7(13-C), 62.7(d, J = 5.0 Hz, 2-C), 64.4(15-C), 92.6(17-C), 98.5(24-C), 105.6(19,
1-C), 122.5(28-C), 126.1(27, 29-C), 128.2(26, 30-C), 129.0(7, 9-C), 129.5(6, 10-C),
31.0(25-C), 133.3(d, J = 242.0Hz, 3-C), 143.2(d, J = 21.0 Hz, 4-C), 146.5(5-C), 157.5(16-C),

1
61.9(18-C), 163.8(23-C), 164.0(22-C), 182.3(20-C). IR(KBr) max(cm ): 3200(-OH),
017(Ar-H), 2920(-CH -), 1686(-C = O), 1604, 1580, 1493, 1445(Ar-C = C), 1475(-CH ),
2
2
+
378(-CH ), 1247(P = O), 1030(C-N), 1017(C-O). HRMS (ESI-Q-TOF): [M+H] , Cal.:
3
04.2207, found: 604.2212.
1
2
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Diethyl
(4-(4-ethylphenyl)-1-(3-((5-hydroxy-4-oxo-2-phenyl-4H-chromen-7-yl)oxy)pro-pyl)-1H-1,2,
3
-triazol-5-yl)phosphonate (3b)
31
Isolated Yield 42%. Faint yellow solid. mp:112-114 ꢀꢁ . P NMR(161 MHz, CDCl ) δ: 4.7.
3
1
H NMR (400 MHz, CDCl ) :1.55(t, J = 7.2 Hz, 6H), 2.33(m, 2H), 2.63 (dd, J = 7.6 Hz,2H),
3
3
.90(t, J = 5.6 Hz, 2H), 4.05(m, 2H), 4.48(t, J = 5.6 Hz, 2H), 6.10(s, 1H), 6.28(s, 1H), 6.62(s,
H), 7.24(d, J = 8.0 Hz, 4H), 7.27(d, J = 8.0 Hz, 4H), 7.48(m, 3H), 7.83 (d, J = 6.8 Hz, 2H),
1
1
3
2
1
1
3
1
6
1
3
2.64(s, 1H). C NMR(100 MHz, CDCl ) :15.5(12-C), 15.8(d, J = 7.0 Hz, 1-C), 28.6 (14-C),
3
0.0 (11-C), 48.1(13-C), 63.1(d, J = 5.0 Hz, 2-C), 65.5(15-C), 93.0(17-C), 98.5(24-C), 105.6(19,
1-C), 120.4(d, J = 219.0 Hz, 3-C), 126.1(27, 29-C), 127.3(28 -C), 127.6(26, 30-C), 129.0(6,
0-C), 129.2(7, 9 -C), 131.0(25-C), 131.8(8-C), 145.2 (5-C), 153.2(d, J = 20.0 Hz, 4-C),
1
57.5(16-C), 162.0(18-C), 163.8(23-C), 164.4(22-C), 182.3(20-C).IR (KBr) max(cm ):
207(-OH), 3010(Ar-H), 2917(-CH -), 1680(-C = O), 1600, 1490, 1458(Ar-C = C), 1470(-CH ),
2
2
+
383(-CH ), 1241 (P = O), 1038(C-N), 1020(C-O). HRMS (ESI-Q-TOF): [M+H] , Cal.:
3
04.2207, found: 604.2211.
1
3
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Diethyl
(
1-(3-((5-hydroxy-4-oxo-2-phenyl-4H-chromen-7-yl)oxy)propyl)-5-phenoxy-1H-1,2,3-triazol
4-yl)phosphonate (4a)
-
3
1
1
Isolated Yield 61%. Yellow solid. mp: 123-125
ꢀꢁ . P NMR(161 MHz, CDCl ) δ: 6.1. H
3
NMR (400 MHz, CDCl ) :1.32 (t,J = 6.4 Hz, 6H), 2.53(m, 2H), 4.19 (m, 6H),4.70(t,J = 6.8 Hz,
3
2
7
6
9
1
2
H), 5.50(s, 2H),6.25(s, 1H),6.37(s, 1H), 6.65(s, 1H), 7.00(m, 3H), 7.29(d, J = 8.0 Hz, 2H),
1
3
.53(m, 3H), 7.86(d, J = 8.0 Hz, 2H), 12.70(s, 1H). C NMR(100 MHz, CDCl ) :16.2(d, J =
3
.0 Hz, 1-C), 29.3(13-C), 46.0 (12-C), 57.5(5-C), 63.2(d, J = 6.0 Hz, 2-C), 64.9(14-C),
3.0(20-C), 98.4(16-C), 105.8(18-C), 114.8(21-C),122.1(27-C), 126.2(26, 28-C),129.1(7, 11-C),
29.7(8, 10, 26, 28-C), 131.1(24-C), 131.9(9, 27-C), 134.5(d, J = 234.0 Hz, 3-C), 139.4(d, J =
0.0 Hz, 4-C), 157.2(17-C), 157.6(6-C), 162.1(15-C), 163.9(19-C), 164.2(20-C), 182.4(22 -C).

1
IR(KBr) max(cm ): 3200(-OH), 3013(Ar-H), 2900(-CH -), 1680(-C = O), 1600, 1553,
2
+
1
6
500(Ar-C = C), 1375(-CH ), 1244(P = O), 1027(C-O). HRMS (ESI-Q-TOF): [M+H] , Cal.:
3
06.2000, found: 606.2000.
1
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Diethyl
(
1-(3-((5-hydroxy-4-oxo-2-phenyl-4H-chromen-7-yl)oxy)propyl)-4-phenoxy-1H-1,2,3-triazol
5-yl)phosphonate (4b)
-
3
1
1
Isolated Yield 30%. Yellow solid. mp: 120-123
ꢀꢁ . P NMR(161 MHz, CDCl ) δ: 3.5. H
3
NMR (400 MHz, CDCl ) :1.30 (t,J = 7.2 Hz, 6H), 2.54(m, 2H), 4.16 (m, 6H),4.90(t,J = 6.8Hz,
3
2
7
6
9
2
1
3
1
H), 5.29(s, 2H),6.34(s, 1H),6.49(s, 1H), 6.68(s, 1H), 6.96(m, 3H), 7.03(d, J = 8.0 Hz, 2H),
1
3
.54(m, 3H), 7.89(d, J = 8.0 Hz, 2H), 12.22(s, 1H). C NMR(100 MHz, CDCl ) :16.2(d, J =
3
.0 Hz, 1-C), 29.7(13-C), 47.9 (12-C), 61.0(5-C), 63.5(d, J = 5.0 Hz, 2-C), 65.4(14-C),
3.1(16-C), 98.4(29-C), 105.8(18-C), 114.8(22-C),121.2(23-C), 126.1(24, 28-C),129.0(8, 10, 25,
7-C), 129.4(d, J = 181.0 Hz, 3-C), 131.8(23-C), 149.3(d, J = 20.0 Hz, 4-C), 157.7(17-C),
1
58.4(6-C), 162.2(15-C), 164.0(19-C), 164.4(20-C), 182.4(21-C). IR(KBr) max(cm ):
200(-OH), 3050(Ar-H), 2917(-CH -), 1678(-C = O), 1600, 1540, 1506(Ar-C = C), 1377(-CH ),
2
3
+
242(P = O), 1027(C-O). HRMS (ESI-Q-TOF): [M+H] , Cal.: 606.2000, found: 606.2003.
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Diethyl
(5-(4-formylphenoxy)-1-(3-((5-hydroxy-4-oxo-2-phenyl-4H-chromen-7-yl)oxy)-propyl)-1H-
1
,2,3-triazol-4-yl)phosphonate (5a)
3
1
1
Isolated Yield 63%. Brown solid. mp: 110-113 ꢀꢁ . P NMR(161 MHz, CDCl ) δ: 7.6. H
3
NMR (400 MHz, CDCl ) δ:132 (t,J = 7.2 Hz, 6H), 2.53(m, 2H), 4.10 (m, 6H), 4.70(t,J = 6.0 Hz,
3
2
7
H), 5.58(s, 2H), 6.20(s, 1H), 6.34(s, 1H), 6.62(s, 1H), 7.13 (d, J = 6.8 Hz, 2H), 7.51(m, 3H),
1
3
.79(d, J = 8.8 Hz, 2H), 7.82(d, J = 7.2 Hz, 2H), 9.84(s, 1H), 12.68(s, 1H). C NMR(100 MHz,
CDCl ) δ:16.2(d, J = 7.0 Hz, 1-C), 29.3(14-C), 45.9(13-C), 57.6(15-C), 63.3(d, J = 6.0 Hz, 2-C),
3
6
2
1
1
2
1
4.7(5-C), 93.0(17-C), 98.3(21-C), 105.9(19-C), 115.0(23-C),126.2 (26, 28, 30-C), 129.1(27,
9-C), 131.0(25-C), 131.1(9-C), 131.9(8, 10-C), 132.0(7, 11-C), 134.8(d, J = 233.0 Hz, 3-C),
38.2(d, J = 25.0 Hz, 4-C), 157.6(16-C), 161.9(18-C), 162.2(20-C), 163.9(24-C), 164.0(6-C),

1
82.4(22-C), 190.5 (12-C). IR(KBr) max(cm ): 3170(-OH), 3107(Ar-H), 2960 (-CH -), 2820,
2
730(H-C = O), 1720(C = O), 1596, 1550, 1446(Ar-C = C), 1375(-CH ), 1245(P = O),
3
+
014(C-O). HRMS (ESI-Q-TOF): [M+H] , Cal.: 634.1949, found: 634.1948.
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Diethyl
(4-(4-formylphenoxy)-1-(3-((5-hydroxy-4-oxo-2-phenyl-4H-chromen-7-yl)oxy)-propyl)-1H-
1
,2,3-triazol-5-yl)phosphonate (5b)
3
1
1
Isolated Yield 19%. Brown solid. mp: 112-114 ꢀꢁ . P NMR(161 MHz, CDCl ) δ: 5.8. H
3
NMR (400 MHz, CDCl ) :1.29 (t,J = 7.2 Hz, 6H), 2.50(m, 2H), 4.12 (m, 6H),4.84(t,J = 6.8 Hz,
3
2
7
2
1
1
1
H), 5.38(s, 2H),6.29(s, 1H),6.45(s, 1H), 6.63(s, 1H), 7.12(d, J = 8.4 Hz, 2H), 7.47(m, 3H),
1
3
.81(m, 4H), 9.86(s, 1H), 12.69(s, 1H). C NMR(100 MHz, CDCl ) :16.2(d, J = 6.0 Hz, 1-C),
3
9.6(13-C), 47.9(12-C), 61.2(14-C), 63.6(d, J = 6.0 Hz, 2-C), 65.3(5-C), 92.9(20-C), 98.5(16-C),
05.8(18-C), 115.0(22-C),124.2 (d, J = 218.0 Hz, 3-C), 126.4(26, 28-C), 129.0(25, 27, 29-C),
30.1(9-C), 131.1(23-C), 131.8(7, 11, 24-C), 131.9(8, 10-C), 148.6(d, J = 21.0 Hz, 4-C),
57.7(15-C), 162.1(19-C), 163.3(17-C), 164.0(23-C), 164.3(6-C), 182.4 (21-C), 190.7(30-C).

1
IR(KBr) max(cm ): 3150(-OH), 3102(Ar-H), 2973(-CH -), 2824, 2722(H-C = O), 1722(C =
2
O), 1600, 1543, 1455(Ar-C = C), 1390(-CH ), 1242(P = O), 1020(C-O). HRMS (ESI-Q-TOF):
3
+
[
M+H] , Cal.: 634.1949, found: 634.1952.
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Diethyl
(5-(2,4-dichlorophenoxy)-1-(3-((5-hydroxy-4-oxo-2-phenyl-4H-chromen-7-yl)-oxy)propyl)-1
H-1,2,3-triazol-4-yl)phosphonate (6a)
3
1
1
Isolated Yield 33%. Yellow oily liquid. P NMR(161 MHz, CDCl ) δ: 5.8. H NMR (400
3
MHz, CDCl ) :1.27 (t,J = 7.2 Hz, 6H), 2.45(m, 2H), 4.08 (m, 6H),4.80(t,J = 6.8 Hz, 2H),
3
5
3
1
9
2
.30(s, 2H),6.22(s, 1H),6.38(s, 1H), 6.56(s, 1H), 7.13(m, J = 8.0 Hz, 2H), 7.25(s, 1H), 7.40(m,
1
3
H), 7.76(d, J = 7.2 Hz, 2H), 12.64(s, 1H). C NMR(100 MHz, CDCl ) :16.1(d, J = 7.0 Hz,
3
-C), 29.2(13-C), 46.0(12-C), 58.6(5-C), 63.3(d, J = 6.0 Hz, 2-C), 64.9(14-C), 92.8(16-C),
8.3(20-C), 105.7(18-C), 115.3(22-C),123.7(27-C), 123.7(27-C), 126.2(9, 26, 28-C), 127.3(25,
9-C), 127.8(9-C), 129.0(8, 11-C), 130.0(7-C), 131.0(24-C), 131.8(10-C), 134.7(d, J = 233.0
Hz,3-C), 138.2(d, J = 35.0 Hz, 4-C), 151.4(15-C), 157.5(19-C), 162.0(6-C), 163.8(23-C),

1
1
64.0(17-C), 182.2(21-C). IR(KBr) max(cm ): 3200(-OH), 3135(Ar-H), 2974(-CH -), 1664
2
(
Ar-C = O), 1625, 1543, 1487,1448(Ar-C = C), 1465(-CH ), 1378(-CH ), 1240(P = O),
2 3
+
1
166(C-O -C), 1045(C-N).HRMS (ESI-Q-TOF): [M+H] , Cal.: 674.1220, found: 674.1220.
1
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Diethyl
(4-(2,4-dichlorophenoxy)-1-(3-((5-hydroxy-4-oxo-2-phenyl-4H-chromen-7-yl)-oxy)propyl)-1
H-1,2,3-triazol-5-yl)phosphonate (6b)
3
1
1
Isolated Yield 50%. Yellow solid. mp: 151-153 ꢀꢁ . P NMR(161 MHz, CDCl ) δ: 3.3. H
3
NMR (400 MHz, CDCl ) :1.29 (t,J = 7.2 Hz, 6H), 2.53(t,J = 6.0 Hz, 2H), 4.09(m, 6H),4.75(t, J
3
=
=
6.0Hz, 2H), 5.53(s, 2H),6.18(s, 1H),6.31(s, 1H), 6.59(s, 1H), 7.11(d, J = 8.8Hz, 1H), 7.16(d, J
1
3
8.8 Hz, 1H), 7.26(s, 1H), 7.67(m, 3H), 7.80(d, J = 6.4 Hz, 2H), 12.65(s, 1H). C NMR(100
MHz, CDCl ) :29.6(13-C), 47.9(12-C), 62.1(14-C), 63.7(d, J = 6 Hz, 2-C), 65.3(5-C),
3
9
3
1
1
1
2.9(14-C), 98.4(20-C), 105.6(18-C), 114.8(22-C),123.6(27-C), 124.3(d, J = 216 Hz,
-C),126.1(9, 26, 28-C), 127.6(25, 29-C), 129.0(8, 11-C), 129.9(7-C), 130.9(24-C), 131.8(10-C),
48.5(d, J = 21 Hz, 4-C), 152.7(15-C), 157.5(19-C), 161.9(23-C), 163.8(17-C), 164.3(6-C),

1
82.2(21-C). IR(KBr) max(cm ): 3175(-OH), 3120(Ar-H), 2920(-CH -), 1685 (-C = O), 1600,
2
545, 1520, 1460(Ar-C = C), 1470(-CH ), 1375(-CH ), 1245(P = O), 1120(C-O -C), 1055(C-N).
2
3
+
HRMS (ESI-Q-TOF): [M+H] , Cal.: 674.1220, found: 674.1223.
1
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Diisopropyl
(5-(4-formylphenoxy)-1-(3-((5-hydroxy-4-oxo-2-phenyl-4H-chromen-7-yl)-oxy)propyl)-1H-
1
,2,3-triazol-4-yl)phosphonate (7a)
31
Isolated Yield 27%. Faint yellow solid. mp: 121-123 ꢀꢁ . P NMR(161 MHz, CDCl ) δ:
3
1
3
2
7
1
1
9
1
1

.7. H NMR (400 MHz, CDCl ) ::1.28(d, J = 6.4 Hz, 6H), 1.33(d, J = 6.4 Hz, 6H), 2.51(m,
3
H), 4.08(t, J = 6.4 Hz, 2H), 4.69(m, 4H), 5.58(s, 2H), 6.20(s, 1H), 6.33(s, 1H), 6.61(s, 1H),
.13(d, J = 8.4 Hz, 2H), 7.50(m, 3H), 7.78(d, J = 8.8 Hz, 2H), 7.82(d, J = 8.0 Hz, 2H), 9.84 (s,
1
3
H), 12.67(s, 1H). C NMR(100 MHz, CDCl ) : :23.7(d, J = 5.0 Hz,1-C), 23.9(d, J = 4.0 Hz,
3
’-C), 29.3(14-C), 45.8(13-C), 57.7(15-C), 64.7(5-C), 72.2(d, J = 6.0 Hz, 2-C), 92.9(17-C),
8.3(24-C), 105.7(19, 21-C), 115.0(7, 11-C), 126.2(26, 30-C), 129.1(27, 29-C), 130.9 (28-C),
31.0(25-C), 131.9(8, 10-C), 135.9(d, J = 184.0 Hz, 3-C), 137.8(d, J = 15.0 Hz, 4-C),
57.6(16-C), 162.0(18-C), 162.1(6, 23-C), 164.0(9, 22-C), 182.4 (20-C), 190.7(12 -C). IR(KBr)

1
max(cm ): 3200(-OH), 3125(Ar-H), 2972(-CH -), 1723(-C = O), 1600, 1585, 1540, 1503
2
(Ar-C = C), 1374, 1368(-CH(CH ) ), 1247(P = O), 1040(C-N), 1022(C-O). HRMS
3 2
+
(
ESI-Q-TOF): [M+H] , Cal.: 662.6455, found: 662.6445.
2
0
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Diisopropyl
(4-(4-formylphenoxy)-1-(3-((5-hydroxy-4-oxo-2-phenyl-4H-chromen-7-yl)-oxy)propyl)-1H-
1
,2,3-triazol-5-yl)phosphonate (7b)
3
1
1
Isolated Yield 45%. Yellow solid. mp: 113-11ꢂ ꢀꢁ . P NMR(161 MHz, CDCl ) δ: 0.7. H
3
NMR (400 MHz, CDCl ) : 1.25(t, J = 6.4 Hz, 6H), 1.37(t, J = 6.4 Hz, 6H), 2.52(m, 2H),
3
4
1
.16(m, 2H), 4.78(t, J = 6.4 Hz,2H), 4.84(t, J = 6.4 Hz, 2H), 5.43(s, 2H), 6.32(s, 1H), 6.48(s,
H), 6.66(s, 1H), 7.14(d, J = 8.8 Hz, 2H), 7.49(m, 3H), 7.82(d, J = 8.4 Hz, 2H), 7.86(d, J = 6.8
1
3
Hz, 2H), 9.88 (s, 1H), 12.70(s, 1H). C NMR(100 MHz, CDCl ) : 23.7(d, J = 5.0 Hz, 1-C),
3
2
2
1
1
1
2
3.9(d, J = 4.0 Hz, 1’-C), 29.6(14-C), 47.8(13-C), 61.1(15-C), 65.4(5-C), 73.1(d, J = 6.0 Hz,
-C), 92.9(17-C), 98.6(24-C), 105.8(19, 21-C), 115.0(7, 11-C), 123.4(d, J = 223.0 Hz, 3-C),
26.2(26, 30-C), 127.5(27, 29-C), 129.0(28-C), 130.2(25-C), 131.1(9-C), 131.8(8, 10-C),
48.3(d, J = 22.0 Hz, 4-C), 157.7(16-C), 162.1(18-C), 163.4(23-C), 164.0(22- C), 164.4(6-C),

1
82.4(20-C), 190.7(12-C). IR(KBr) max(cm ): 3200(-OH), 3107(Ar-H), 2972(-CH -), 2822,
2
717(H-C = O), 1720(C = O), 1596, 1576, 1550, 1443(Ar-C = C), 1385, 1373(-CH(CH ) ), 1240
3
2
+
(
P = O), 1024(C-O).HRMS (ESI-Q-TOF): [M+H] , Cal.: 662.6455, found: 662.6455.
Acknowledgements
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Financial support from The National Natural Science Foundation of China (No. 21072178),
Innovation Specialist Projects of Henan Province (No. 114200510023), Technology and Science
talent Cultivation Project in Zhengzhou City (No. 112PLJRC359).
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a
Table 1. Optimization of the reaction conditions
a
Reaction conditions: flavone (0.5 mmol), phosphonates (0.6 mmol), solvent (10
mL)
b13
P NMR yields.
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a
Table 2. Scope of 1,3-dipolar cycloadditions
a
Reaction conditions: flavone (0.5 mmol) and phosphonates (0.6 mmol)
under solvent free conditions for 0.5 h
b13
P NMR yields.
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Figure 1. The structure of chrysin
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Figure 2. Structural characterization and HMBC spectrum diagram of 6a (left) and 6b (right).
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