5-Fluorouracil derivatives containing α-hydroxy phosphonates

Article abstract of DOI:10.1080/10426500600919975

In order to find high acitivity and low toxicity antitumor drug-lead compounds, 13 novel N¹-(2-furanidyl)-N³-(O,O- dialkylphosphonyl aryl (alkyl)methoxy-carbonylmethyl)-5-fluorouracils were synthesized via phase-transferred catalytic reactions of chloroacetyloxyalkyl phosphonates 2 with N¹-(2-furanidyl)-5-fluorouracil. The structures of the products were confirmed by ¹H NMR, ³¹P NMR, IR, and MS spectra and elemental analyses. The results of preliminary bioassay showed that the new compounds possess some extent of inhibitory effect against HCT-8 and Bel-7402 cell lines and good fungicidal activities. Copyright Taylor & Francis Group, LLC.

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Phosphorus, Sulfur, and Silicon
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5-Fluorouracil Derivatives
Containing α-Hydroxy
Phosphonates
De-Qing Shi a , Xiao-Ju Li a & Jia Wei a
a Key Laboratory of Pesticide and Chemical Biology
of Ministry of Education, College of Chemistry ,
Central China Normal University , Wuhan, P. R.
China
Published online: 18 Feb 2007.
To cite this article: De-Qing Shi , Xiao-Ju Li & Jia Wei (2007) 5-Fluorouracil
Derivatives Containing α-Hydroxy Phosphonates, Phosphorus, Sulfur, and Silicon and
the Related Elements, 182:2, 405-412, DOI: 10.1080/10426500600919975
To link to this article: http://dx.doi.org/10.1080/10426500600919975
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Phosphorus, Sulfur, and Silicon, 182:405–412, 2007
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500600919975
5-Fluorouracil Derivatives Containing α-Hydroxy
Phosphonates
De-Qing Shi
Xiao-Ju Li
Jia Wei
Key Laboratory of Pesticide and Chemical Biology of Ministry of
Education, College of Chemistry, Central China Normal University,
Wuhan, P. R. China
In order to find high acitivity and low toxicity antitumor drug-lead compounds,
13 novel N1 -(2-furanidyl)-N3 -(O,O-dialkylphosphonyl aryl (alkyl)methoxy-
carbonylmethyl)-5-fluorouracils were synthesized via phase-transferred catalytic
reactions of chloroacetyloxyalkyl phosphonates
2
with N1 -(2-furanidyl)-5-
fluorouracil. The structures of the products were confirmed by 1H NMR, 31P NMR,
IR, and MS spectra and elemental analyses. The results of preliminary bioassay
showed that the new compounds possess some extent of inhibitory effect against
HCT-8 and Bel-7402 cell lines and good fungicidal activities.
Keywords α-hydroxy phosphonates; fungicidal activities; N1-(2-furanidyl)-5-
fluorouracil
INTRODUCTION
N1-(2-furanidyl)-5-fluorouracil (Tegafur) is a potent inhibitor of mam-
malian cell growth in clinical use. However, undesirable side ef-
fects such as hot sensation and pollakiuria syndrome1 and low
selectivity between normal cells and cancer cells has attracted in-
terests of many medical and chemical scientists to develop bet-
ter, new antitumor drugs. There are many reports on synthesizing
Received June 26, 2006; accepted July 11, 2006.
We are thankful to the Key Project of Science and Technology of Ministry of Education
of China (02140) and the Dawn Plan of Science and Technology for Young Scientists of
Wuhan city (2002501024) for financial support. We are also indebted to Prof. Guanhua
Du, who works at Beijing Institute of Medicine in Academy of Medical Sciences of China
for the antitumor activities test.
Address correspondence to De-Qing Shi, Key Laboratory of Pesticide and Chemical
Biology of Ministry of Education, College of Chemistry, Central China Normal University,
Wuhan, 430079 P. R. China. E-mail: chshidq@yahoo.com.cn
405

406
De-Qing Shi et al.
O
R2CHP(O)(OR1)2
OCOCH2Cl
ClCH2COCl
NEt3
Cat.
R2CHP(O)(OR1)2
OH
R2CHO
HP(OR1)2
+
2
1
O
O
O
2
F
F
(R1O)2P CHOCOCH2N
HN
R2
O
N
PTC
O
N
O
O
3
R =CH3; R2=CH3, Ph, 2-ClPh, 2-CH3OPh, 4-ClPh, 4-CH3OPh, 3, 4-Cl2Ph
R1=C2H5; R2= Ph, 4-ClPh, 4-CH3OPh, 2-furyl, 2, 4-Cl2Ph, 3, 4-Cl2Ph
1
SCHEME 1
5-fluorouracil derivatives containing α-hydroxy phosphonates, phos-
phonopeptides, and cyclic thiophosphonates.2−5 As a mimic of α-
hydroxy acids, α-hydroxy phosphonates and their derivatives represent
an important class of organophosphorus compounds that continue to at-
tract considerable attention due to their wide biological activities and
extensive applications in organic and medical chemistry. In an attempt
to search for novel high activities and low-toxicity anti-tumor drug-lead
compounds, we designed and synthesized a type of N1-(2-furanidyl)-
5-fluorouracil derivatives containing α-hydroxy phosphonates 3. The
synthetic route is shown in Scheme 1.
The results of preliminary biological bioassay show that some of these
new compounds have certain selective anti-tumor activities and good
fungicidal activities.
RESULTS AND DISCUSSION
Synthesis and Structure of the Title Compounds
The title compounds 3 were synthesized by the multistep route
outlined in Scheme 1. For converting aldehydes to α-hydroxy
alkyl(aryl)methylphosphonates 1, both a solid base (1:1 KF/Al2O3) and
an organic base (such as triethylamine) were used as the catalyst.
When KF/Al2O3 was used, compounds 1 were given in better yields
than triethylamine. Moreover, the addition reaction was affected by
the inductive effect of the carbonyl compounds as well as the stereo-
hindered effect. For example, aromatic aldehydes gave a better yield
than aliphatic aldehydes. In the same substituent, the yields decreased
according to the order of para, meta, and ortho one. Moreover, the yields

5-Fluorouracil Derivatives Containing α-Hydroxy Phosphonates
407
were better using O,O–dimethyl phosphite as the starting material
than O,O–diethyl phosphite.
We tried to prepare the target compounds 3 in a homogeneous reac-
tion condition (KOH/DMF, 50–55◦C), but the yield of the product was
very low. However, improving the reaction temperature led to cleavage
of the furanyl ring from N1-(2-furanidyl)-5-fluorouracil. It is notewor-
thy that the reaction took place smoothly under the two-phase catalytic
system of chloroform and water using tetrabutyl ammonium bromide
as the phase-transferred catalyst, and the target compounds 3 were
obtained in better yields without byproducts being detected by TLC.
All the products 3 were purified by flash column chromatography on
silica gel with a mixture of ethyl acetate and petroleum ether as the
eluent. The structures of compounds 3 were confirmed by 1H NMR, 31
P
NMR, IR, and MS spectra and elemental analyses.
1
In H NMR spectra, the uracil ring proton exhibited a doublet due
to coupling with the fluorine atom. 5-position furanyl protons (5ꢀ-H)
appeared multiplet because of their different magnetic surroundings.
It is noteworthy that the methylene proton adjacent to the phosphonyl
group displayed a doublet because of coupling with the phosphorus atom
with the coupling constant of 13 Hz. Moreover, the methylene proton
appeared in downfield when linking with an aromatic group relative to
an aliphatic one. In 31P NMR spectra, the phosphorus atom of all com-
pounds displayed a singlet with the chemical shifts in 14–17. IR spectra
of all compounds showed normal stretching absorption bands indicating
the existence of the P O (∼1260 cm−1), C O (1680∼1710 cm−1), and
P O C (∼1000 cm−1) moiety. EI mass spectra of compound 3 revealed
that the existence of molecular ion peaks and fragmentation peaks were
in accordance with the given structures of products 3.
Biological Activities
The cell toxicity experiments (in vitro) indicated that some of the title
compounds had some extent of inhibitory effect against HCT-8 and Bel-
7402 cell lines. For example, the inhibitory ratios against HCT-8 cell
lines of compounds 3b and 3e were, respectively, 38.0% and 40.1% at the
concentration of 5.0 × 10−6; the inhibitory ratios of Bel-7402 cell lines of
compounds 3f and 3g were 39.8% and 54.4% at the same concentration,
respectively. However, cell toxicity experiments showed that the title
compounds had little inhibitory effect against A-549 cell lines.
Moreover, the preliminary fungicidal activities of title compounds
3 were evaluated against Fusarium oxysporium, Gibberella zeae,
Botryosphaeria berengeriana, Rhizoctonia solani, and Cercospora beti-
cola by the classic plate method6 at a the concentration of 0.005%. The

408
De-Qing Shi et al.
results indicated that most of compounds 3 had significant inhibitory
activities against the five fungi. The relative inhibitory ratios against
the five fungi were in the range 60–100%; for example, compound 3j
had 100% relative ratios of the inhibition against these five fungi.
EXPERIMENTAL
Instruments
1H NMR and 31P NMR spectra were recorded with VARIAN MERCURY-
PLUS400 400 MHz spectrometer with TMS and 85% H3PO4 as the in-
ternal and external reference, respectively, and CDCl3 as the solvent,
while mass spectra were obtained with a Finnigan TRACEMS2000
spectrometer using the EI method. IR spectra were measured by
a NICOLET NEXUS470 spectrometer. Elemental analyses was per-
formed with an ELEMENTAR Vario EL III CHNSO elementary ana-
lyzer. Melting points were determined with a WRS-1B digital melting
point apparatus, and the thermometer was uncorrected.
Reagents and solvents were available commercially and pu-
rified according to conventional methods before use. α-hydroxy
alkyl(aryl)methylphosphonates 1 were synthesized by addition re-
actions of aldehydes with dialkyl phosphites according to the
literature.7,8 Chloroacetyloxyalkyl phosphonates 2 were prepared
by condensation reactions of chloroacetyl chloride with α-hydroxy
alkyl(aryl)methylphosphonates in the presence of triethylamine accord-
ing to the literature.9
General Procedure for the Synthesis of
N 1-(2-furanidyl)-N 3-(O,O-dialkylphosphonyl Aryl
(Alkyl)methoxy-carbonylmethyl)-5-fluorouracil
Ten milliliter of water, 15 mL chloroform, 0.97 g (3 mmol) tetrabutyl
ammonium bromide, and 10 mmol compounds 2 were added into a 100-
mL three-necked flask; 2.0 g (10 mmol) N1-(2-furanidyl)-5-fluorouracil
(Tegafur) dissolved in 15 mL 0.8mol/L of sodium hydroxide solution
was added dropwise at r.t. After the addition was complete, the mix-
ture was stirred vigorously at 50∼55◦C for about 10 h until the re-
action was complete (monitored by TLC). The workup involved phase
separation, washing with aqueous sodium hydroxide (removal of excess
N1-(2-furanidyl)-5-fluorouracil) and drying over anhydrous magnesium
sulphate, filtration, and evaporation. The crude product was purified by
flash column chromatography on silica gel using petroleuom ether and
acetone (1:1 v/v) as an eluant, giving compounds 3a–m, yield: 48–77%.

5-Fluorouracil Derivatives Containing α-Hydroxy Phosphonates
409
3a (R1 = CH3, R2 = CH3): light yellow solid, m.p. 74–76◦C, yield 70%;
1H NMR δ = 1.45 (q, 3H, CH-CH3), 1.82–2.50 (m, 4H, 3ꢀ, 4ꢀ-H), 3.82
(2d,3 JP-H = 10.6 Hz, 6H, 2OCH3), 3.90–4.05 (m, 1H, 5ꢀ-H), 4.20–4.30 (m,
1H, 5ꢀ-H), 4.78 (s, 2H, NCH2C O), 5.28–5.40 (m, 1H, PCH), 6.00 (d, br,
3
1H, 2ꢀ-H), 7.55 (d, JH-F = 6.2 Hz, 1H, FC CH); IR (KBr) (υmax/cm−1
)
1761, 1716 and 1683 (C O), 1261 (P O), 1050(P O C); EI-MS, m/z
(%) 395 (M+1, 52), 324 (92), 171 (78), 142 (90), 109 (87), 71 (100); anal.
calcd. for C14H20O8N2FP (394): C, 42.64; H, 5.08; N, 7.11. Found: C,
42.35; H, 4.86; N, 6.75.
3b (R1 = C2H5, R2 = Ph): colorless crystal, m.p. 93–94◦C, yield 67%;
1H NMR δ = 1.20 (2t, 6H, 2OCH2CH3), 1.80–2.45 (m, 4H, 3ꢀ, 4ꢀ-H),
3.90–4.25 (m, 6H, 2OCH2CH3, 5ꢀ-H), 4.78 (s, 2H, NCH2C O), 5.95 (d,
br, 1H, 2ꢀ-H), 6.16 (d, JH-P = 12.6 Hz, 1H, PCH), 7.30–7.52 (m, 6H,
2
C6H5, FC CH); IR (KBr) (υmax/cm−1) 1763, 1720 and 1655 (C O),
1254 (P O), 1044 (P O C); EI-MS, m/z (%) 484 (M+, 15.5), 171 (46),
143 (76), 109 (27), 71 (100); anal. calcd. for C21H26O8N2FP (484): C,
52.07; H, 5.37; N, 5.79. Found: C, 52.05; H, 5.50; N, 5.44.
3c (R1 = C2H5, R2 = 2,4-Cl2Ph): light yellow syrup, yield: 75%; H
1
NMR δ = 1.26 (2t, 6H, 2OCH2CH3), 1.92–2.40 (m, 4H, 3ꢀ, 4ꢀ-H), 3.85–
4.20 (m, 6H, 2OCH2CH3, 5ꢀ-H), 4.81 (s, 2H, NCH2C O), 5.87 (d,
br, 1H, 2ꢀ-H), 6.21 (d, JH-P = 13.0 Hz, 1H, PCH), 7.35–7.80 (m, 4H,
2
C6H3Cl2, FC CH); IR (KBr) (υmax/cm−1) 1764, 1720 and 1650 (C O),
1260 (P O), 1047(P O C); EI-MS, m/z (%) 553 (M+, 11), 556 (4), 483
(5), 449 (24), 314 (36), 244 (26), 138 (51), 71 (100); anal. calcd. for
C21H24O8N2Cl2FP (553): C, 45.57; H, 4.34; N, 5.06. Found: C, 45.45;
H, 4.30; N, 4.98.
3d (R1 = C2H5, R2 = 4-CH3OPh): colorless solid, m.p. 96–98◦C, yield
52%; 1H NMR δ = 1.23 (2t, 6H, 2OCH2CH3), 1.84–2.44 (m, 4H, 3ꢀ, 4ꢀ-H),
3.80 (s, 3H, ArOCH3), 3.84–4.26 (m, 6H, 2OCH2CH3, 5ꢀ-H), 4.82 (s, 2H,
NCH2C O), 5.95 (d, br, 1H, 2ꢀ-H), 6.09 (d, JH-P = 12.8 Hz, 1H, PCH),
2
3
6.88 (d, JH−H = 8.1 Hz, 2H, Ar-H), 7.40–7.46(m, 3H, Ar-H, FC CH);
31P NMR δ = 16.69; IR (KBr) (υmax/cm−1) 1755, 1719 and 1659 (C O),
1258 (P O), 1026 (P O C); EI-MS, m/z (%) 514 (M+, 17), 444 (32), 257
(100), 229 (30), 171 (65), 142 (28), 109 (25), 71 (100); anal. calcd. for
C22H28O9N2FP (514): C, 51.36; H, 5.45; N, 5.45. Found: C, 51.20; H,
5.66; N, 5.38.
3e (R1 = C2H5, R2 = 2-furyl): yellow crystal, m.p. 101–102◦C, yield
48%; H NMR δ = 1.28 (2t, 6H, 2OCH2CH3), 1.82–2.45 (m, 4H, 3ꢀ, 4ꢀ-
1
H), 3.92–4.30 (m, 6H, 2OCH2CH3, 5ꢀ-H), 4.80 (s, 2H, NCH2C O), 5.98
(d, br, 1H, 2ꢀ-H), 6.28 (d, 2 JH-P = 14.8 Hz, 1H, PCH), 6.40 (s, 1H, Fu-H),
6.64(s, 1H, Fu-H), 7.40–7.50(m, 2H, Fu-H, FC CH); 31P NMR δ = 14.04;
IR (KBr) (υmax/cm−1) 1764, 1720 and 1656 (C O), 1265 (P O), 1023
(P O C); EI-MS, m/z(%) 475 (M+1, 26), 404 (43), 233 (42), 217 (100),

410
De-Qing Shi et al.
189 (47), 171 (52), 143 (33), 71 (95); anal. calcd. for C19H24O9N2FP (474):
C, 48.10; H, 5.06; N, 5.91. Found: C, 47.99; H, 5.13; N, 5.08.
3f (R1 = C2H5, R2 = 3,4-Cl2Ph): white syrup, yield 61%; 1H NMR
δ = 1.28 (2t, 6H, 2OCH2CH3), 1.82–2.40 (m, 4H, 3ꢀ, 4ꢀ-H), 3.90–4.25 (m,
6H, 2OCH2CH3, 5ꢀ-H), 4.80 (s, 2H, NCH2C O), 5.97 (d, br, 1H, 2ꢀ-H),
6.20 (d, 2 JH-P = 13 Hz, 1H, PCH), 7.35–7.90 (m, 4H, C6H3Cl2, FC CH);
IR (KBr) (υmax/cm−1) 1761, 1722 and 1683 (C O), 1261 (P O), 1026
(P O C); EI-MS, m/z (%) 553 (M+, 31), 555 (M+2, 20.5), 557 (M+4, 5),
483 (22.33), 485 (14.1), 487 (2.7), 295 (36.8), 297 (24.7), 299 (4.78), 251
(19.2), 171 (51.78), 138 (58.26), 114 (46.2), 109 (19.8), 71 (100); anal.
calcd. for C21H24O8N2Cl2FP (553): C, 45.57; H, 4.34; N, 5.06. Found: C,
45.86; H, 4.42; N, 5.27.
3g (R1 = CH3, R2 = 2-ClPh): yellow syrup, yield 53%; 1H NMR
3
δ = 1.82–2.45 (m, 4H, 3ꢀ, 4ꢀ-H), 3.72 (2d, JP-H = 10.8 Hz, 6H, 2OCH3),
3.92–4.05 (m, 1H, 5ꢀ-H), 4.20–4.30 (m, 1H, 5ꢀ-H), 4.80 (s, 2H,
2
NCH2C O), 5.92 (d, br, 1H, 2ꢀ-H), 6.67 (d, JH-P = 13.2 Hz, 1H, PCH),
7.23–7.50 (m, 4H, Ar-H), 7.65 (d, 3 JH−F = 7.6 Hz, 1H, FC CH); IR (KBr)
(υmax/cm−1) 1770, 1716 and 1652 (C O), 1261 (P O), 1061 (P O C);
EI-MS, m/z (%) 491(M+, 4), 421 (20), 385 (43), 233 (43), 171 (55), 143 (58),
114 (57), 109 (44), 71 (100); anal. calcd. for C19H21O8N2ClFP (490.5): C,
46.48; H, 4.28; N, 5.71. Found: C, 46.56; H, 4.09; N, 5.96.
3h (R1 = CH3, R2 = Ph): light yellow crystal, m.p. 152–153◦C, yield
58%; 1H NMR δ = 1.82–2.40 (m, 4H, 3ꢀ, 4ꢀ-H), 3.70 (2d, 3 JP-H = 10.8 Hz,
6H, 2OCH3), 3.99–4.03 (m, 1H, 5ꢀ-H), 4.22–4.24 (m, 1H, 5ꢀ-H), 4.83 (s,
2
2H, NCH2C O), 5.96 (d, br, 1H, 2ꢀ-H), 6.19 (d, JH-P = 13.2 Hz, 1H,
PCH), 7.32–7.49 (m, 6H, Ar-H, FC CH); IR (KBr) (υmax/cm−1) 1770,
1723 and 1658 (C O), 1259 (P O), 1065 (P O C); EI-MS, m/z (%)
457(M+1, 3), 386 (56), 215 (18), 171 (45), 143 (61), 109 (48), 77 (38),
71 (100); anal. calcd. for C19H22O8N2FP (456): C, 50.00; H, 4.82; N,
6.14. Found: C, 49.87; H, 4.47; N, 6.30.
3i (R1 = CH3, R2 = 4-CH3OPh): colorless solid, m.p. 138–140◦C, yield
70%; 1H NMR δ = 1.90–2.40 (m, 4H, 3ꢀ, 4ꢀ-H), 3.66–3.78 (m, 9H,
ArOCH3, 2OCH3), 3.99–4.01 (m, 1H, 5ꢀ-H), 4.23–4.24 (m, 1H, 5ꢀ-H), 4.82
2
(s, 2H, NCH2C O), 5.95 (d, br, 1H, 2ꢀ-H), 6.13 (d, JH-P = 13.6 Hz, 1H,
PCH), 7.35–7.48 (m, 5H, Ar-H, FC CH); IR (KBr) (υmax/cm−1) 1774,
1721 and 1655 (C O), 1253 (P O), 1061 (P O C); EI-MS, m/z (%) 486
(M+, 25), 215 (7), 171 (85), 109 (37), 77 (55), 71 (100); anal. calcd. for
C20H24O9N2FP (486): C, 49.38; H, 4.94; N, 5.76. Found: C, 49.74; H,
5.06; N, 5.49.
3j (R1 = CH3, R2 = 2-CH3OPh): yellow syrup, yield 54%; 1H NMR
3
δ = 1.93–2.44 (m, 4H, 3ꢀ, 4ꢀ-H), 3.74 (2d, JP-H = 11.0 Hz, 6H, 2OCH3),
3.88 (s, 3H, CH3OAr), 3.98–4.00 (m, 1H, 5ꢀ-H), 4.22–4.28 (m, 1H, 5ꢀ-H),

5-Fluorouracil Derivatives Containing α-Hydroxy Phosphonates
411
4.79 (s, 2H, NCH2C O), 5.95 (d, br, 1H, 2ꢀ-H), 6.76 (d, 2 JH-P = 12.8 Hz,
1H, PCH), 6.88–7.00 (m, 2H, Ar-H), 7.28–7.46 (m, 2H, Ar-H), 7.54 (d,
3 JH-F = 7.6 Hz, 1H, FC CH); IR (KBr) (υmax/cm−1) 1762, 1723 and
1671 (C O), 1265 (P O), 1033 (P O C); EI-MS, m/z(%) 486 (M+, 7), 215
(59), 171 (77), 109 (43), 77 (89), 71 (100); anal. calcd. for C20H24O9N2FP
(486): C, 49.38; H, 4.94; N, 5.76. Found: C, 49.29; H, 4.97; N, 5.62.
3k (R1 = CH3, R2 = 4-ClPh): white wax, yield 69%; 1H NMR δ = 1.91–
2.40 (m, 4H, 3ꢀ, 4ꢀ-H), 3.71 (2d, 3 JP-H = 10.8 Hz, 6H, 2OCH3), 3.98–4.00
(m, 1H, 5ꢀ-H), 4.21–4.24 (m, 1H, 5ꢀ-H), 4.81 (s, 2H, NCH2C O), 5.95 (d,
br, 1H, 2ꢀ-H), 6.13 (d, 2 JH-P = 13.2 Hz, 1H, PCH), 7.35–7.43 (m, 4H, Ar-
H), 7.47 (d, 3 JH-F = 6.0 Hz, 1H, FC CH); IR (KBr) (υmax/cm−1) 1762,
1719 and 1656 (C O), 1252 (P O), 1029 (P O C); EI-MS, m/z (%) 491
(M+, 26), 422 (33), 385 (43), 233 (69), 171 (75), 143 (67), 138 (57), 109
(52), 71 (100); anal. calcd. for C19H21O8N2ClFP (490.5): C, 46.48; H,
4.28; N, 5.71. Found: C, 46.60; H, 4.46; N, 5.83.
3l (R1 = C2H5, R2 = 4-ClPh): yellow solid, m.p. 133–135◦C yield 77%;
1H NMR δ = 1.30 (2t, 6H, 2OCH2CH3), 1.85–2.40 (m, 4H, 3ꢀ, 4ꢀ-H),
3.80–4.20 (m, 6H, 2OCH2CH3, 5ꢀ-H), 4.80 (s, 2H, NCH2C O), 5.81 (d,
2
br, 1H, 2ꢀ-H), 6.34 (d, JH-P = 13.6 Hz, 1H, PCH), 7.40–7.55 (m, 6H,
C6H5, FC CH); IR (KBr) (υmax/cm−1) 1764, 1721 and 1656 (C O),
1265 (P O), 1031(P O C); EI-MS, m/z (%) 519 (M+, 8), 448 (41), 277
(55), 233 (60), 171 (65), 142 (28), 109 (25), 71 (100); anal. calcd. for
C21H25O8N2ClFP (518.5): C, 48.60; H, 4.82; N, 5.40. Found: C, 48.26; H,
4.90; N, 5.72.
3m (R1 = CH3, R2 = 3, 4-Cl2Ph): colorless syrup, yield 55%; 1H NMR
3
δ = 1.82–2.40 (m, 4H, 3ꢀ, 4ꢀ-H), 3.60–3.80 (2d, JP-H = 10.8 Hz, 6H,
2OCH3), 3.82–3.90 (m, 1H, 5ꢀ-H), 3.96–4.00 (m, 1H, 5ꢀ-H), 4.40 (s, 2H,
2
NCH2C O), 5.87 (d, br, 1H, 2ꢀ-H), 6.46 (d, JH-P = 13.4 Hz, 1H, PCH),
7.40–7.55 (m, 4H, Ar-H, FC CH); IR (KBr) (υmax/cm−1) 1761, 1721
and 1683 (C O), 1261 (P O), 1026 (P O C); EI-MS, m/z (%) 529, 527,
525 (M+, 18), 171 (48), 143 (34), 114 (62), 109 (88), 71 (100); anal. calcd.
for C19H20O8N2Cl2FP (525): C, 43.43; H, 3.81; N, 5.33. Found: C, 43.53;
H, 3.92; N, 5.27.
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