Synthesis of Coumarin-4-Ylmethyl Phosphonic Acids

Article abstract of DOI:10.1007/s10600-019-02766-9

New coumarin-4-ylmethylphosphonates and coumarin-4-ylmethylphosphonic acids were synthesized and tested for antiviral activity.

Full text of DOI:10.1007/s10600-019-02766-9

DOI 10.1007/s10600-019-02766-9
Chemistry of Natural Compounds, Vol. 55, No. 4, July, 2019
SYNTHESIS OF COUMARIN-4-YLMETHYL PHOSPHONIC ACIDS
1*
2
2
K. M. Kondratyuk, V. A. Dluzhevskii, S. P. Bondarenko,
1
1
V. S. Brovarets, and M. S. Frasinyuk
New coumarin-4-ylmethylphosphonates and coumarin-4-ylmethylphosphonic acids were synthesized and
tested for antiviral activity.
Keywords: coumarin, phosphonate, phosphonic acid, antiviral activity.
Coumarins are representative of broadly distributed natural O-containing heterocycles and a promising platform for
medicinal chemistry. Natural coumarins and their synthetic derivatives are well known for their valuable antimicrobial,
antiviral, anti-inflammatory, anticoagulant, antitumor pharmacological properties and their ability to inhibit enzymes [1–4].
Coumarin is recognized as a preferred scaffold for drug design because the benzopyrone core can be modified to produce
valuable biologically active compounds and can be synthetically transformed into a large variety of functionalized derivatives
[5, 6].
Previously, we developed new synthetic methods for various N-containing coumarin derivatives and condensed
heterocyclic systems using 4-chloromethylcoumarins as universal starting compounds [7–11]. Herein, a synthetic method for
coumarin-4-ylmethylphosphonic acids is developed. This is interesting with respect to not only expanding the synthetic
applications of 4-chloromethylcoumarins but also the ability of the phosphonic acid to bind uniquely to biological targets [12].
Dialkylphosphonates produced using Arbuzov reactions were used as intermediates in the simplest method of
introducing the phosphonic acid [12].
Diethyl (coumarin-4-ylmethyl)phosphonates were produced via bromination of 4-methylcoumarin derivatives using
N-bromosuccinimide followed by reaction of the synthesized 4-bromomethylcoumarins with triethylphosphite [13].
In our opinion, 4-chloromethylcoumarins are synthetically more attractive for preparing diethyl (coumarin-4-
ylmethyl)phosphonates because they are easily and simply prepared. Thus, starting 4-chloromethylcoumarins 1a–k were
synthesized using Pechmann reactions of the corresponding phenols and 4-chloroacetoacetic ester in H SO .
2
4
R
2
O
O
R
2
O
O
a
R
1
R
1
O
Cl
P
OR
RO
1a-k
2a-k; 3a-k
2a-k: R = Et
b
3a-k: R = H
a: R = OH, R = H; b: R = OMe, R = H; c: R = Me, R = H
1
2
1
2
1
2
d: R = Et, R = H; e: R = i-Pr, R = H; f: R = t-Bu, R = H
1
2
1
2
2
g: R = H, R = OMe; h: R = H, R = Me; i: R = OH, R = OMe
1
2
1
2
1
2
j: R = OH, R = Me; k: R = OH, R = Ph
1
2
1
2
a. P(OEt) , diglyme, 155°C, 2–16 h; b. H O, HCl, AcOH, reflux, 30–40 h
3
2
1) V. P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry, National Academy of Sciences of Ukraine,
1 Murmanskaya St., 02094 Kiev, Ukraine, e-mail: kondratyuk_km@ukr.net; 2) National University of Food Technologies,
68 Vladimirskaya St., 01601 Kiev, Ukraine. Translated from Khimiya Prirodnykh Soedinenii, No. 4, July–August, 2019,
pp. 544–548. Original article submitted January 29, 2019.
©
632
0009-3130/19/5504-0632 2019 Springer Science+Business Media, LLC

An important task of our research was to find suitable conditions for the phosphorylation because the Arbuzov
reaction requires the substrate and dialkylphosphonate to be heated at high temperature although substituted
4-chloromethylcoumarins tend to be poorly soluble in triethylphosphite.
The best results were obtained using the dimethyl ether of diethylene glycol (diglyme) as the solvent. Our research
showed that the optimal reaction temperature was 155°C. These conditions favor nucleophilic attack of the substrate by the
P(OEt) P atom, avoid competition between P(OEt) and ethyl chloride formed in the reaction because the latter is removed
3
3
from the reaction mixture, and provide a homogeneous medium for the reaction.
The structures of synthesized diethylphosphonates 2a–k were confirmed by NMR spectroscopic data. PMR spectra
contained resonances for coumarin protons although the H-3 resonance was observed as a doublet at 6.28–6.59 ppm with
4
SSCC J = 4.3–4.8 Hz because of its proximity to the P atom. Furthermore, the 2H singlet for CH Cl at 4.91–5.10 ppm was
HP
2
missing. A2H doublet for CH Pwas observed at 3.25–3.78 ppm with SSCC 22.8–23.5 Hz and multiplets for diethylphosphonate
2
13
31
protons at 1.18–1.35 ppm (CH ) and 3.99–4.25 ppm (OCH ) were also observed. C NMR, P NMR, and IR spectra agreed
3
2
fully with the structures of 2a–k.
The corresponding phosphonic acids were prepared by hydrolyzing 2a–k. The most suitable reaction conditions
were heating the diethylphosphonates in a mixture of AcOH and HCl.
Me
O
O
O
O
Me
a
OH
O
O
P
Cl
OR
11
4,5
4: R = Et
b
5: R = H
a. P(OEt) , diglyme, 155°C, 120 h; b. H O, HCl, AcOH, reflux, 32 h
3
2
The structures of phosphonic acids 3a–k were confirmed by IR and NMR spectroscopic data and LC-MS analysis.
13
PMR and C NMR spectra displayed all resonances corresponding to the coumarin core and phosphonic acid.
The reaction of 5-hydroxy-7-methyl-4-chloromethylcoumarin 11 with triethylphosphite in diglyme did not stop at
formation of the corresponding diethylphosphonate. Prolonged heating of the reaction mixture induced intramolecular cyclization
to form the new heterocyclic framework 2,3-dihydro-5H-[1,2]oxaphosphinino[4,5,6-de]chromen-5-one 2-oxide (4).
Compound 4 was hydrolyzed with heating in AcOH and HCl to give 2-hydroxy-8-methyl-2,3-dihydro-5H-
[1,2]oxaphosphinino[4,5,6-de]chromen-5-one 2-oxide (5).
Antiviral activity of the synthesized compounds against Varicella-Zoster virus (VZV) strain Ellen was assessed at the
USA National Institute ofAllergy and Infectious Diseases. The tests were conducted in vitro in HFF cells using CellTiter-Glo
analysis and acyclovir reference drug. The concentration range of the control and tested compounds was 0.048–150 μM.
Phosphonic acid 3c turned out to have antiviral activity against VZV. Its concentration reducing virus replication by
50% (EC ) was <0.05 μM. Moreover, the concentration of 3c reducing cell survival by 50% (CC ) was >150.00 μM.
50
50
The selectivity index (SI ) was calculated as the ratio CC /EC and was >3125 for 3c. In addition, reference drug acyclovir
50
50
50
gave EC = 7.55 μM and CC = 150.00 M with SI = 20.
50
50
50
The biological test results indicated that the search for antiviral agents among coumarin derivatives modified at C-4
was promising.
EXPERIMENTAL
®
The course of reactions and purity of products were monitored by TLC on ALUGRAM Xtra SIL G/UV254 plates
(Germany) using mixtures of hexane–EtOAc (80:20) and CH Cl –MeOH (50:50) as eluents. IR spectra were recorded from
2
2
KBr pellets on a Vertex 70 spectrometer. NMR spectra were measured in DMSO-d or CDCl on a Varian Unity plus-400
6
3
1
1
31
13
( H, 400 MHz) or Bruker Avance DRX-500 instrument ( H, 500 MHz; P, 202 MHz; C, 125 MHz). Chemical shifts were
given vs. TMS (internal standard) or 85% H PO (external standard) on the δ-scale. Mass spectra were measured using an
3
4
Agilent 1100 system (chemical ionization at atmospheric pressure, APCI). Melting points were determined on a Fisher-Johns
apparatus. Elemental analyses of all compounds agreed with those calculated.
633

General Method for Synthesizing Diethyl (Coumarin-4-ylmethyl)phosphonates 2a–k. A solution of 1a–k
(10 mmol) in diglyme (20 mL) was treated with P(OEt) (2.49 g, 15 mmol), refluxed under Ar on an oil bath at 155°C for
3
2–16 h, cooled, and evaporated to dryness in vacuo. Compounds 2c–f and 2h were crystallized from C H ; 2a, b, g, and i–k,
6
6
from dioxane.
Diethyl [(6-Hydroxy-2-oxo-2H-chromen-4-yl)methyl]phosphonate (2a). Yield 1.87 g (60%), C H O P,
14 17
6
–1
mp 199–200°Ñ. IR spectrum (KBr, ν, cm ): 3235, 3072, 2989, 1719, 1582, 1455, 1270, 1243, 1225, 1199, 1168, 1060, 1019,
+ 1
982, 943. LC/MS (APCI): 313.2 [M + H] . Í NMR spectrum (400 MHz, CDCl , δ, ppm, J/Hz): 1.31 (6H, t, J = 7.1, 2OCH CH ),
3
2
3
3.29 (2H, d, J = 23.2, PCH ), 4.14 (4H, m, 2OCH ), 6.35 (1H, d, J = 4.6, H-3), 6.89 (1H, dd, J = 9.0, 2.7, H-8), 7.11 (1H, d,
2
2
13
J = 9.0, H-7), 7.19 (1H, d, J = 2.8, Í-5), 7.36 (1H, s, OÍ). C NMR spectrum (125 MHz, CDCl , δ, ppm, J/Hz): 16.12 (d,
3
J = 5.8), 28.99 (d, J = 132.6, PCH ), 62.03 (d, J = 6.5), 111.00, 116.51 (d, J = 8.5), 117.28, 119.26 (d, J = 3.7), 120.05, 146.38,
2
31
148.07 (d, J = 9.3), 153.60, 159.67 (d, J = 3.2). P NMR spectrum (202 MHz, CDCl , δ, ppm): 23.24.
3
Diethyl [(6-Methoxy-2-oxo-2H-chromen-4-yl)methyl]phosphonate (2b). Yield 3.06 g (94%), C H O P,
15 19
6
–1
mp 141–142°Ñ. IR spectrum (KBr, ν, cm ): 3088, 3069, 2990, 2963, 2944, 2904, 2844, 1715, 1679, 1573, 1497, 1466, 1436,
1426, 1382, 1288, 1261, 1249, 1227, 1208, 1171, 1153, 1057, 1043, 1027, 969, 937, 926. LC/MS (APCI): 327.2 [M + H] .
Í NMR spectrum (400 MHz, CDCl , δ, ppm, J/Hz): 1.23 (6H, t, J = 7.0, 2OCH CH ), 3.26 (2H, d, J = 23.2, PCH ), 3.82 (3H,
+
1
3
2
3
2
s, OCH ), 4.00–4.11 (4H, m, 2OCH ), 6.36 (1H, d, J = 4.5, H-3), 7.07 (1H, dd, J = 9.0, 2.9, H-7), 7.16 (1H, d, J = 2.9, H-5),
3
2
13
7.21 (1H, d, J = 9.0, H-8). C NMR spectrum (125 MHz, CDCl , δ, ppm, J/Hz): 16.38 (d, J = 6.0), 30.65 (d, J = 137.5, PCH ),
3
2
55.93, 62.82 (d, J = 6.8), 108.46, 117.48 (d, J = 8.7), 118.07, 119.25 (d, J = 3.7), 119.53, 146.86 (d, J = 9.4), 148.11, 155.94,
31
160.34 (d, J = 3.2). P NMR spectrum (202 MHz, CDCl , δ, ppm): 23.00.
3
Diethyl [(6-Methyl-2-oxo-2H-chromen-4-yl)methyl]phosphonate (2c). Yield 2.85 g (92%), C H O P,
15 19
5
–1
mp 114–115°Ñ. IR spectrum (KBr, ν, cm ): 3063, 2985, 2940, 2904, 1716, 1572, 1268, 1255, 1219, 1197, 1064, 1052, 1026,
962, 940. LC/MS (APCI): 311.0 [M + H] (100%). Í NMR spectrum (400 MHz, CDCl , δ, ppm, J/Hz): 1.22 (6H, t, J = 7.0,
+
1
3
2OCH CH ), 2.38 (3H, s, CH ), 3.26 (2H, d, J = 23.1, PCH ), 4.00–4.11 (4H, m, 2OCH ), 6.34 (1H, d, J = 4.5, H-3), 7.17 (1H,
2
3
3
2
2
13
d, J = 8.2, H-8), 7.29 (1H, dd, J = 8.2, 2.1, H-7), 7.45 (1H, d, J = 2.1, H-5). C NMR spectrum (125 MHz, CDCl , δ, ppm,
3
J/Hz): 16.32 (d, J = 6.1), 21.00, 30.31 (d, J = 137.6, PCH ), 62.73 (d, J = 6.8), 116.90, 117.03 (d, J = 8.5), 118.50 (d, J = 3.7),
2
31
125.28, 133.12, 133.80, 146.97 (d, J = 9.3), 151.90, 160.29 (d, J = 3.4). P NMR spectrum (202 MHz, CDCl , δ, ppm): 22.38.
3
Diethyl [(6-Ethyl-2-oxo-2H-chromen-4-yl)methyl]phosphonate (2d). Yield 3.05 g (94%), C H O P,
16 21
5
–1
mp 123–124°Ñ. IR spectrum (KBr, ν, cm ): 3061, 2971, 2935, 2903, 2878, 2860, 1717, 1621, 1571, 1380, 1290, 1269, 1254,
1234, 1218, 1195, 1063, 1051, 1025, 960, 940. LC/MS (APCI): 325.0 [M + H] (100%). Í NMR spectrum (400 MHz,
+
1
CDCl , δ, ppm, J/Hz): 1.27 (9Í, m, 2OCH CH , CH ), 2.73 (2H, q, J = 7.6, CH ), 3.32 (2H, d, J = 23.1, PCH ), 4.04–4.16
3
2
3
3
2
2
(4H, m, 2OCH ), 6.40 (1H, d, J = 4.5, H-3), 7.26 (1H, d, J = 8.4, H-8), 7.38 (1H, dd, J = 8.5, 2.0, H-7), 7.52 (1H, d, J = 2.0,
2
13
H-5). C NMR spectrum (125 MHz, CDCl , δ, ppm, J/Hz): 15.86, 16.49 (d, J = 6.0), 28.59, 30.53 (d, J = 137.9, PCH ), 62.89
3
2
31
(d, J = 6.8), 91.42, 117.13, 117.21 (d, J = 2.8), 118.69 (d, J = 3.4), 124.29, 132.17, 140.35, 147.21, 152.19. P NMR spectrum
(202 MHz, CDCl , δ, ppm): 23.09.
3
Diethyl [(6-Isopropyl-2-oxo-2H-chromen-4-yl)methyl]phosphonate (2e). Yield 3.17 g (94%), C H O P,
17 23
5
–1
mp 93–94°Ñ. IR spectrum (KBr, ν, cm ): 3055, 2965, 2936, 2904, 2874, 1719, 1619, 1570, 1389, 1266, 1220, 1203, 1054,
1024, 939, 957. LC/MS (APCI): 339.1 [M + H] (100%). Í NMR spectrum (400 MHz, CDCl , δ, ppm, J/Hz): 1.19–1.36
+
1
3
(12H, m, 2OCH CH , CH(CH ) ), 3.00 (1H, hept, J = 6.9, CH(CH ) ), 3.33 (2H, d, J = 23.1, PCH ), 4.03–4.18 (4H, m, 2OCH ),
2
3
3 2
3 2
2
2
13
6.40 (1H, d, J = 4.4, H-3), 7.28 (1H, d, J = 8.0, H-8), 7.43 (1H, dd, J = 8.0, 2.1, Í-7), 7.54 (1H, d, J = 2.1, Í-5). C NMR
spectrum (125 MHz, CDCl , δ, ppm, J/Hz): 16.37 (d, J = 5.9), 24.07, 30.37 (d, J = 137.6, PCH ), 33.83, 62.75 (d, J = 6.8),
3
2
31
116.98 (d, J = 8.5), 117.06, 118.50 (d, J = 3.7), 122.88, 130.58, 144.84, 147.18 (d, J = 9.5), 152.06, 160.38 (d, J = 3.3). P NMR
spectrum (202 MHz, CDCl , δ, ppm): 23.16.
3
Diethyl [(6-tert-Butyl-2-oxo-2H-chromen-4-yl)methyl]phosphonate (2f). Yield 2.61 g (74%), C H O P,
18 25
5
–1
mp 100–101°Ñ. IR spectrum (KBr, ν, cm ): 3064, 2969, 2943, 2906, 2867, 1722, 1255, 1228, 1210, 1059, 1044, 1028, 974,
944. LC/MS (APCI): 353.1 [M + H] (100%). Í NMR spectrum (500 MHz, CDCl , δ, ppm, J/Hz): 1.26 (6H, t, J = 7.1,
+
1
3
2OCH CH ), 1.37 (9H, s, Ñ(ÑH ) ), 3.34 (2H, d, J = 23.1, PCH ), 4.05–4.15 (4H, m, 2OCH ), 6.40 (1H, d, J = 4.6, H-3), 7.28
2
3
3 3
2
2
13
(1H, d, J = 8.8, H-8), 7.60 (1H, dd, J = 8.8, 2.3, H-7), 7.70 (1H, d, J = 2.3, H-5). C NMR spectrum (125 MHz, CDCl , δ, ppm,
3
J/Hz): 16.52 (d, J = 5.8), 30.63 (d, J = 137.5, PCH ), 31.54, 34.89, 62.89 (d, J = 6.8), 116.90, 117.11 (d, J = 9.3), 118.24 (d,
2
31
J = 3.5), 121.86, 129.92, 147.31, 147.49 (d, J = 9.4), 151.91, 160.60. P NMR spectrum (202 MHz, CDCl , δ, ppm): 23.22.
3
Diethyl [(7-Methoxy-2-oxo-2H-chromen-4-yl)methyl]phosphonate (2g). Yield 2.38 g (73%), C H O P,
15 19
6
–1
mp 78–79°Ñ. IR spectrum (KBr, ν, cm ): 3079, 2982, 2928, 2841, 1720, 1618, 1392, 1268, 1244, 1208, 1138, 1067, 1024,
634

+
1
962. LC/MS (APCI): 327 [M + H] (100%). Í NMR spectrum (400 MHz, CDCl , δ, ppm, J/Hz): 1.25 (6H, t, J = 7.3,
3
2OCH CH ), 3.25 (2H, d, J = 23.2, PCH ), 3.85 (3H, s, OCH ), 4.06 (4H, m, 2OCH ), 6.22 (1H, d, J = 4.4, H-3), 6.80 (1H, s,
2
3
2
3
2
13
H-8), 6.86 (1H, d, J = 9.1, H-6), 7.63 (1H, d, J = 9.1, H-5). C NMR spectrum (125 MHz, CDCl , δ, ppm, J/Hz): 16.45 (d,
3
J = 6.0), 30.69 (d, J = 137.3, PCH ), 55.90, 62.90 (d, J = 6.9), 101.09, 112.44, 112.51 (d, J = 3.4), 113.85 (d, J = 8.3), 126.66,
2
31
147.25 (d, J = 9.2), 155.71, 160.74 (d, J = 3.2), 163.07. P NMR spectrum (202 MHz, CDCl , δ, ppm): 23.16.
3
Diethyl [(7-Methyl-2-oxo-2H-chromen-4-yl)methyl]phosphonate (2h). Yield 3.01 g (97%), C H O P,
15 19
5
–1
mp 87–88°Ñ. IR spectrum (KBr, ν, cm ): 3084, 2983, 2961, 2912, 1731, 1712, 1621, 1393, 1244, 1142, 1067, 1044, 1020,
968. LC/MS (APCI): 311.1 [M + H] (100%). Í NMR spectrum (400 MHz, CDCl , δ, ppm, J/Hz): 1.25 (6H, t, J = 7.2,
+
1
3
2OCH CH ), 2.42 (3H, s, CH ), 3.27 (2H, d, J = 23.2, PCH ), 4.07 (4H, m, 2OCH ), 6.32 (1H, d, J = 4.5, H-3), 7.03–7.17 (2H,
2
3
3
2
2
13
m, Í-6, 8), 7.60 (1H, d, J = 8.1, H-5). C NMR spectrum (125 MHz, CDCl , δ, ppm, J/Hz): 16.44 (d, J = 6.1), 21.69, 30.51
3
(d, J = 137.4, PCH ), 62.84 (d, J = 6.8), 116.04 (d, J = 8.5), 116.50 (d, J = 3.6), 117.42, 125.25, 125.48, 143.56, 147.16 (d,
2
31
J = 9.3), 153.92, 160.54 (d, J = 3.3). P NMR spectrum (202 MHz, CDCl , δ, ppm): 23.08.
3
Diethyl [(6-Hydroxy-7-methoxy-2-oxo-2H-chromen-4-yl)methyl]phosphonate (2i). Yield 2.83 g (83%),
–1
C H O P, mp 140–141°Ñ. IR spectrum (KBr, ν, cm ): 3239, 3079, 2988, 2925, 1709, 1623, 1557, 1514, 1446, 1385, 1366,
15 19
7
+
1
1290, 1237, 1204, 1157, 1057, 1041, 1022, 999, 951, 936 . LC/MS (APCI): 343 [M + H] (100%). Í NMR spectrum
(400 MHz, DMSO-d , δ, ppm, J/Hz): 1.17 (3H, t, J = 6.2, 2OCH CH ), 3.46 (2H, d, J = 23.1, PCH ), 3.87 (3H, s, OCH ),
6
2
3
2
3
3.93–4.11 (4H, m, 2OCH ), 6.24 (1H, d, J = 2.7, H-3), 7.02 (1H, d, J = 1.6, H-8), 7.21 (1H, d, J = 1.6, H-5), 9.32 (1H, s, J = 9.1, ÎÍ).
2
13
C NMR spectrum (125 MHz, CDCl , δ, ppm, J/Hz): 16.59 (d, J = 6.0), 29.66 (d, J = 132.5, PCH ), 56.63, 62.42 (d, J = 6.4),
3
2
100.37, 110.98, 111.96 (d, J = 3.6), 113.48 (d, J = 8.3), 143.67, 148.41, 148.77 (d, J = 9.0), 152.28, 160.59 (d, J = 3.2).
31
P NMR spectrum (202 MHz, DMSO-d , δ, ppm): 23.73.
6
Diethyl [(6-Hydroxy-7-methyl-2-oxo-2H-chromen-4-yl)methyl]phosphonate (2j). Yield 2.71 g (83%), C H O P,
15 19
6
–1
mp 211–213°Ñ. IR spectrum (KBr, ν, cm ): 3164, 3060, 2992, 2924, 1704, 1620, 1567, 1457, 1425, 1408, 1282, 1253, 1222,
1199, 1166, 1057, 1027, 984, 973, 943. LC/MS (APCI): 327.0 [M + H] (100%). Í NMR spectrum (400 MHz, CDCl , δ,
+
1
3
ppm, J/Hz): 1.32 (6H, t, J = 7.1, 2OCH CH ), 2.19 (3H, s, CH ), 3.27 (2H, d, J = 23.2, PCH ), 4.04–4.26 (4H, m, 2OCH ),
2
3
3
2
2
13
6.28 (1H, d, J = 4.7, H-3), 7.05 (1H, s), 7.15 (1H, s), 7.97 (1H, br.s, OH). C NMR spectrum (125 MHz, CDCl , δ, ppm, J/Hz):
3
16.48, 16.55 (d, J = 3.6), 30.52 (d, J = 137.6, PCH ), 63.58 (d, J = 7.0), 109.02, 116.09 (d, J = 8.7), 117.04 (d, J = 3.3), 118.81,
2
31
131.78, 146.33 (d, J = 9.6), 147.50, 152.07, 161.05 (d, J = 3.4). P NMR spectrum (202 MHz, CDCl , δ, ppm): 23.51.
3
Diethyl [(6-Hydroxy-7-phenyl-2-oxo-2H-chromen-4-yl)methyl]phosphonate (2k). Yield 2.41 g (62%), C H O P,
20 21
6
–1
mp 172–173°Ñ. IR spectrum (KBr, ν, cm ): 3125, 2975, 2938, 2907, 1708, 1555, 1421, 1384, 1366, 1292, 1250, 1231, 1211,
1184, 1158, 1132, 1045, 1022, 973, 941. LC/MS (APCI): 389.0 [M + H] (100%). Í NMR spectrum (400 MHz, DMSO-d ,
+
1
6
δ, ppm, J/Hz): 1.20 (6H, t, J = 7.0, 2OCH CH ), 3.49 (2H, d, J = 23.0, PCH ), 3.98–4.12 (4H, m, 2OCH ), 6.45 (1H, d, J = 4.5,
2
3
2
2
13
H-3), 7.28–7.40 (3H, m), 7.44 (2H, t, J = 7.6), 7.64 (2H, d, J = 7.6), 10.00 (1H, s, ÎÍ). C NMR spectrum (125 MHz,
DMSO-d , δ, ppm, J/Hz): 16.16 (d, J = 5.8), 29.12 (d, J = 133.1, PCH ), 62.13 (d, J = 6.5), 111.50, 116.32 (d, J = 8.6), 117.46,
6
2
31
118.29 (d, J = 3.5), 127.64, 128.13, 129.23, 132.55, 136.74, 146.61, 147.55 (d, J = 9.4), 150.70, 159.72 (d, J = 3.4). P NMR
spectrum (202 MHz, DMSO-d , δ, ppm): 23.94.
6
General Method for Synthesizing (Coumarin-4-ylmethyl)phosphonic Acids 3a–k. A solution of 2a–k (1 mmol)
in HCl (conc., 2 mL) and AcOH (2 mL) was refluxed for 30–40 h (end of reaction determined by TLC) and evaporated to
dryness in vacuo. The solid was crystallized from aqueous dioxane.
[(6-Hydroxy-2-oxo-2H-chromen-4-yl)methyl]phosphonic Acid (3a). Yield 0.166 g (65%), C H O P,
10
9 6
–1
mp 244–245°Ñ. IR spectrum (KBr, ν, cm ): 3448, 3086, 1669, 1571, 1445, 1231, 1215, 1186, 1147, 1125, 1001, 978, 948,
938. LC/MS (APCI): 257.0 [M + H] (100%). Í NMR spectrum (500 MHz, DMSO-d , δ, ppm, J/Hz): 3.19 (2H, d, J = 22.6,
PCH ), 6.32 (1H, d, J = 4.3, H-3), 7.03 (1H, dd, J = 8.9, 2.6, Í-7), 7.24–7.14 (2H, m, Í-5, 8). C NMR spectrum (125 MHz,
+
1
6
13
2
DMSO-d , δ, ppm, J/Hz): 32.23 (d, J = 126.4, PCH ), 111.47, 116.32 (d, J = 8.2), 117.58, 120.06, 120.27, 146.85, 150.14 (d,
6
2
31
J = 6.7), 153.96, 160.34. P NMR spectrum (202 MHz, DMSO-d , δ, ppm): 17.90.
6
[(6-Methoxy-2-oxo-2H-chromen-4-yl)methyl]phosphonic Acid (3b). Yield 0.186 g (69%), C H O P,
11 11
6
–1
mp 228–229°Ñ. IR spectrum (KBr, ν, cm ): 3087, 2844, 1668, 1571, 1428, 1248, 1197, 1182, 1029, 1007, 970, 931. LC/MS
+
1
(APCI): 271.0 [M + H] (100%). Í NMR spectrum (500 MHz, DMSO-d , δ, ppm, J/Hz): 3.33 (2H, d, J = 22.8, PCH ), 3.81
6
2
(3H, s, CH ), 6.37 (1H, d, J = 4.2, H-3), 7.22–7.17 (1H, m, H-8), 7.32 (1H, d, J = 9.0, Í-6), 7.38 (1H, s, Í-5), 7.32 (2H, s, ÎÍ).
3
13
C NMR spectrum (125 MHz, DMSO-d , δ, ppm, J/Hz): 32.50 (d, J = 126.8, PCH ), 56.17, 116.64 (d, J = 8.4), 117.78, 119.64,
6
2
31
119.95 (d, J = 3.4), 147.91, 150.42, (d, J = 9.0), 155.71, 160.24 (d, J = 3.0). PNMR spectrum (202 MHz, DMSO-d , δ, ppm): 18.33.
6
635

[(6-Methyl-2-oxo-2H-chromen-4-yl)methyl]phosphonic Acid (3c). Yield 0.173 g (68%), C H O P,
11 11
5
–1
mp 235–236°Ñ. IR spectrum (KBr, ν, cm ): 3329, 2931, 2266, 1721, 1680, 1609, 1566, 1494,1279, 1237, 1180, 1181, 1159,
1078, 1023, 965, 947. LC/MS (APCI): 255.0 [M + H] (100%). Í NMR spectrum (400 MHz, DMSO-d , δ, ppm, J/Hz): 2.37
+
1
6
(3H, s, CH ), 3.30 (2H, d, J = 22.8, PCH ), 6.36 (1H, d, J = 4.2, H-3), 7.28 (1H, d, J = 8.4, H-8), 7.42 (1H, d, J = 8.3, H-7), 7.70
3
2
13
(1H, s, H-5). C NMR spectrum (125 MHz, DMSO-d , δ, ppm, J/Hz): 20.57, 31.66 (d, J = 126.8, PCH ), 115.78 (d, J = 8.1),
116.20, 118.72 (d, J = 3.7), 126.40, 132.84, 133.27, 149.98 (d, J = 9.0), 151.36, 159.82, (d, J = 3.2). P NMR spectrum
6
2
31
(202 MHz, DMSO-d , δ, ppm): 18.42.
6
[(6-Ethyl-2-oxo-2H-chromen-4-yl)methyl]phosphonic Acid (3d). Yield 0.185 g (69%), C H O P, mp 233–234°Ñ.
12 13
5
–1
IR spectrum (KBr, ν, cm ): 2972, 2936, 1669, 1617, 1602, 1570, 1434, 1387, 1285, 1255, 1241, 1199, 1146, 1011, 963, 928.
LC/MS (APCI): 269.0 [M + H] (100%). Í NMR spectrum (500 MHz, DMSO-d , δ, ppm, J/Hz): 1.12–1.32 (3H, m, CH CH ),
+
1
6
2
3
2.66 (2H, q, J = 7.6, CH CH ), 3.32 (2H, d, J = 22.8, PCH ), 6.36 (1H, d, J = 4.3, H-3), 7.16–7.36 (1H, m, H-8), 7.44 (1H, dd,
2
3
2
13
J = 8.3, 2.2, H-7), 7.58–7.82 (1H, m, H-5), 9.49 (2H, s, ÎÍ). C NMR spectrum (125 MHz, DMSO-d , δ, ppm, J/Hz): 15.75,
6
27.78, 31.79 (d, J = 127.0, PCH ), 115.79 (d, J = 8.2), 116.26, 118.76 (d, J = 3.5), 125.48, 131.72, 139.61, 150.08 (d, J = 9.0),
2
31
151.51, 159.85 (d, J = 3.2). P NMR spectrum (202 MHz, DMSO-d , δ, ppm): 18.52.
6
[(6-Isopropyl-2-oxo-2H-chromen-4-yl)methyl]phosphonic Acid (3e). Yield 0.172 g (61%), C
mp 238–239°Ñ. IR spectrum (KBr, ν, cm ): 2956, 1675, 1606, 1567, 1386, 1281, 1252, 1227, 1189, 1135, 1003, 957, 927. LC/MS
(APCI): 283.0 [M + H] (100%). Í NMR spectrum (500 MHz, DMSO-d , δ, ppm, J/Hz): 1.24 (6H, d, J = 7.0, CH(CH ) ),
H O P,
13 15 5
–1
+
1
6
3 2
2.88–3.09 (1H, m, CH(CH ) ), 3.32 (2H, d, J = 22.6, PCH ), 6.37 (1H, s, H-3), 7.29 (1H, s, J = 8.5, Í-7), 7.49 (1H, s, J = 8.2,
3 2
2
13
Í-8), 7.75 (1H, s, Í-5). C NMR spectrum (125 MHz, DMSO-d , δ, ppm, J/Hz): 23.80, 31.90 (d, J = 127.1, PCH ), 33.05, 115.71
(d, J = 8.3), 116.15, 118.64, 124.23, 130.14, 144.07, 150.20 (d, J = 9.0), 151.46, 159.79. P NMR spectrum (202 MHz,
6
2
31
DMSO-d , δ, ppm): 18.38.
6
[(6-tert-Butyl-2-oxo-2H-chromen-4-yl)methyl]phosphonic Acid (3f). Yield 0.249 g (84%), C
mp 224–225°Ñ. IR spectrum (KBr, ν, cm ): 2963, 2909, 2869, 1683, 1616, 1604, 1567, 1379, 1258, 1216, 1196, 1010, 965,
931. LC/MS (APCI): 297.0 [M + H] (100%). Í NMR spectrum (400 MHz, DMSO-d , δ, ppm, J/Hz): 1.32 (9H, s, C(CH ) ),
H O P,
14 17 5
–1
+
1
6
3 3
3.35 (2H, d, J = 22.7, PCH ), 6.36 (1H, d, J = 4.3, H-3), 7.25–7.36 (1H, m, H-8), 7.65 (1H, d, J = 8.9, H-7), 7.89 (1H, s, Í-5).
2
13
C NMR spectrum (125 MHz, DMSO-d , δ, ppm, J/Hz): 31.10, 32.22 (d, J = 126.6, PCH ), 34.48, 115.77 (d, J = 12.4),
118.20 (d, J = 3.5), 123.29, 129.35, 146.31, 150.50 (d, J = 9.1), 151.18, 159.85. P NMR spectrum (202 MHz, DMSO-d , δ,
6
2
31
6
ppm): 18.34.
[(7-Methoxy-2-oxo-2H-chromen-4-yl)methyl]phosphonic Acid (3g). Yield 0.149 g (55%), C H O P,
11 11
6
–1
mp 203–204°Ñ. IR spectrum (KBr, ν, cm ): 3095, 2980, 2940, 2845, 1671, 1613, 1549, 1394, 1300, 1214, 1154, 1137, 993,
933. LC/MS (APCI): 271 [M + H] (100%). Í NMR spectrum (400 MHz, DMSO-d , δ, ppm, J/Hz): 3.26 (2H, d, J = 22.8,
+
1
6
PCH ), 3.85 (3H, s, OCH ), 5.94 (2H, br.s, ÎÍ), 6.19 (1H, d, J = 4.2, H-3), 7.02–6.89 (2H, m, Í-6, 8), 7.79 (1H, d, Í-5).
2
3
13
C NMR spectrum (125 MHz, DMSO-d , δ, ppm, J/Hz): 32.38 (d, J = 126.5, PCH ), 56.37, 101.05, 112.20, 112.87 (d,
J = 7.7), 112.98 (d, J = 2.6), 128.24, 150.70 (d, J = 8.6), 155.44, 160.46, 162.78. P NMR spectrum (202 MHz, DMSO-d , δ,
6
2
31
6
ppm): 17.40–19.00.
[(7-Methyl-2-oxo-2H-chromen-4-yl)methyl]phosphonic Acid (3h). Yield 0.188g (74%), C
H O P,
11 11 5
–1
mp 196–197°Ñ. IR spectrum (KBr, ν, cm ): 3491, 3364, 1729, 1675, 1619, 1588, 1549, 1450, 1393, 1249, 1224, 1192, 1137,
+
1
1020, 936. LC/MS (APCI): 255 [M + H] (100%). Í NMR spectrum (400 MHz, DMSO-d , δ, ppm, J/Hz): 2.40 (3H, s, CH ),
6
3
13
3.27 (2H, d, J = 22.7, PCH ), 6.29 (1H, s, H-3), 7.25–7.08 (2H, m, Í-6, 8), 7.76 (1H, d, J = 8.1, Í-5). C NMR spectrum (125 MHz,
2
DMSO-d , δ, ppm, J/Hz): 21.43, 32.25 (d, J = 126.5, PCH ), 115.03 (d, J = 8.0), 116.78, 117.07, 125.54, 126.82, 143.18, 150.60,
6
2
31
153.67, 160.27. P NMR spectrum (202 MHz, DMSO-d , δ, ppm): 24.35.
6
[(6-Hydroxy-7-methoxy-2-oxo-2H-chromen-4-yl)methyl]phosphonicAcid (3i). Yield 0.246 g (86%), C H O P,
11 11
7
–1
mp 255–256°Ñ. IR spectrum (KBr, ν, cm ): 3428, 3112, 2988, 2935, 1669, 1651, 1619, 1601, 1561, 1438, 1388, 1294, 1217,
1201, 1160, 1138, 1022, 1001, 957, 945. LC/MS (APCI): 287 [M + H] (100%). Í NMR spectrum (400 MHz, DMSO-d , δ,
+
1
6
ppm, J/Hz): 3.16 (2H, d, J = 22.6, PCH ), 3.87 (3H, s, CH ), 4.41 (2H, br.s, ÎÍ), 6.16 (1H, s, H-3), 7.01 (1H, s, Í-8), 7.19 (1H,
2
3
13
s, Í-5), 9.30 (1H, s, OH). C NMR spectrum (125 MHz, DMSO-d , δ, ppm, J/Hz): 32.03 (d, J = 127.1, PCH ), 56.17, 110.62,
111.91 (d, J = 3.3), 112.52 (d, J = 7.9), 143.15, 147.97, 149.96 (d, J = 8.6), 151.69, 160.37 (d, J = 3.2). P NMR spectrum
6
2
31
(202 MHz, DMSO-d , δ, ppm): 17.54 (td, J = 22.7, 4.2).
6
[(6-Hydroxy-7-methyl-2-oxo-2H-chromen-4-yl)methyl]phosphonic Acid (3j). Yield 0.135 g (50%), C H O P,
11 11
6
–1
mp 273–274°Ñ. IR spectrum (KBr, ν, cm ): 3450, 3067, 2968, 2927, 1670, 1601, 1561, 1519, 1461, 1427, 1394, 1381, 1282,
1236, 1213, 1176, 1054, 1012, 987, 964, 930. LC/MS (APCI): 271.0 [M + H] (100%). Í NMR spectrum (400 MHz,
+
1
636

DMSO-d , δ, ppm, J/Hz): 2.22 (3H, s, CH ), 3.15 (2H, d, J = 22.5, PCH ), 6.27 (1H, d, J = 4.2, H-3), 7.12 (1H, s), 7.18 (1H, s), 7.64
6
3
2
13
(3H, s, ÎÍ). C NMR spectrum (125 MHz, DMSO-d , δ, ppm, J/Hz): 16.70, 32.16 (d, J = 127.6, PCH ), 110.16, 115.16 (d,
J = 7.9), 117.74, 118.15, 130.89, 146.88, 149.96 (d, J = 8.8), 152.25, 160.50 (d, J = 3.2). P NMR spectrum (202 MHz, DMSO-d ,
6
2
31
6
δ, ppm): 18.07.
[(6-Hydroxy-7-phenyl-2-oxo-2H-chromen-4-yl)methyl]phosphonic Acid (3k). Yield 0.196 g (59%), C H O P,
16 13
6
–1
mp 268–269°Ñ. IR spectrum (KBr, ν, cm ): 3240, 3063, 2975, 1691, 1618, 1578, 1549, 1419, 1295, 1239, 1213, 1153, 1038,
1078, 1038, 1002, 942. LC/MS (APCI): 333.0 [M + H] (100%). Í NMR spectrum (500 MHz, DMSO-d , δ, ppm, J/Hz):
+
1
6
3.21 (2H, d, J = 22.5, PCH ), 6.35 (1H, d, J = 4.5, H-3), 7.30 (1H, s), 7.37 (2H, m), 7.44 (2H, t, J = 6.8), 7.63 (2H, d, J=6.8), 9.99
2
13
(1H, br.s, ÎH). C NMR spectrum (125 MHz, DMSO-d , δ, ppm, J/Hz): 31.79 (d, J = 127.3, PCH ), 111.64, 115.71 (d, J = 8.0),
6
2
117.31, 118.71 (d, J = 3.1), 127.58, 128.11, 129.21, 132.27, 136.83, 146.65, 149.26 (d, J = 9.2), 150.63, 159.94 (d, J = 2.9).
31
P NMR spectrum (202 MHz, DMSO-d , δ, ppm): 17.84.
6
2,3-Dihydro-8-methyl-2-ethoxy-5H-[1,2]oxaphosphinino[4,5,6-de]chromen-5-one 2-Oxide (4). A solution of
4-chloromethylcomarin (11, 2.24 g, 10 mmol) in diglyme (20 mL) was treated with P(OEt) (2.49 g, 15 mmol), refluxed under
3
Ar on an oil bath at 155°C for 120 h (end of reaction determined by TLC), cooled, and evaporated to dryness in vacuo.
The solid was triturated with hexane (20 mL). The resulting precipitate was filtered off and crystallized from dioxane. Yield
–1
1.21 g (43%), C H O P, mp 157–158°Ñ. IR spectrum (KBr, ν, cm ): 3055, 2978, 2900, 1734, 1630, 1617, 1371, 1292,
15 19
7
+
1
1230, 1074, 1036, 1009, 975, 946. LC/MS (APCI): 281 [M + H] (100%). Í NMR spectrum (400 MHz, CDCl , δ, ppm,
3
J/Hz): 1.25 (3H, t, J = 7.1, 2OCH CH ), 2.40 (3H, s, CH ), 3.13–3.37 (2H, m, PCH ), 4.08–4.13 (4H, m, 2OCH ), 6.15 (1H, s,
2
3
3
2
2
13
H-3), 6.76 (1H, s, H-8), 6.89 (1H, s, J = H-6). C NMR spectrum (125 MHz, CDCl , δ, ppm, J/Hz): 16.25 (d, J = 5.3), 21.95,
3
27.71 (d, J = 133.1, PCH ), 63.36 (d, J = 6.9), 105.36 (d, J = 12.0), 113.03, 114.38 (d, J = 14.9), 148.79 (d, J = 8.4), 145.10,
2
31
149.48 (d, J = 6.7), 153.69, 159.42 (d, J = 2.5). P NMR spectrum (202 MHz, CDCl , δ, ppm): 16.49.
3
2-Hydroxy-2,3-dihydro-8-methyl-5H-[1,2]oxaphosphinino[4,5,6-de]chromen-5-one 2-Oxide (5). A solution of
4 (0.280 g, 1 mmol) in HCl (conc., 2 mL) and AcOH (2 mL) was refluxed for 32 h (end of reaction determined by TLC),
cooled, and evaporated to dryness in vacuo. The solid was crystallized from aqueous dioxane. Yield 0.202 g (80%), C H O P,
11 11
7
–1
mp 217–218°Ñ. IR spectrum (KBr, ν, cm ): 3189, 3064, 3014, 1689, 1625, 1599, 1511, 1425, 1409, 1394, 1332, 1286, 1255,
+
1
1188, 1127, 1094, 1003, 958, 931. LC/MS (APCI): 253 [M + H] (100%). Í NMR spectrum (400 MHz, DMSO-d , δ, ppm,
6
13
J/Hz): 2.26 (3H, s, ÑÍ ), 3.63 (2H, d, J = 23.5, PCH ), 6.07 (1H, d, J = 4.5, Í-3), 6.55 (1H, s, Í-8), 6.62 (1H, s, Í-6). C NMR
3
2
spectrum (125 MHz, DMSO-d , δ, ppm, J/Hz): 21.52, 34.64 (d, J = 126.4, PCH ), 106.93 (d, J = 3.7), 108.37, 113.28, 113.85 (d,
6
2
31
J = 8.0), 143.19, 150.93 (d, J = 9.2), 155.35, 156.71, 160.12 (d, J = 3.5). P NMR spectrum (202 MHz, DMSO-d , δ, ppm): 15.73.
6
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