One-pot syntheses of novel pyrazole-containing bisphosphonate esters at room temperature

Article abstract of DOI:10.1039/c2ob25889g

An efficient general synthetic approach has been developed to synthesize pyrazole-containing bisphosphonate (N-BPs) esters from chromenone derivatives via a sequential two-step reaction in one pot at ambient temperature in good to excellent yields. This protocol provides a new convenient method to prepare lipophilic bisphosphonate precursors with potential activities. The Royal Society of Chemistry 2012.

Full text of DOI:10.1039/c2ob25889g

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PAPER
One-pot syntheses of novel pyrazole-containing bisphosphonate esters at room
temperature†
Haoyue Xiang,a Xueyu Qi,a,b Yuyuan Xie,a Guangyu Xub and Chunhao Yang*a
Received 9th May 2012, Accepted 29th July 2012
DOI: 10.1039/c2ob25889g
An efficient general synthetic approach has been developed to synthesize pyrazole-containing
bisphosphonate (N-BPs) esters from chromenone derivatives via a sequential two-step reaction in one pot
at ambient temperature in good to excellent yields. This protocol provides a new convenient method to
prepare lipophilic bisphosphonate precursors with potential activities.
Introduction
Bisphosphonates (BPs) have been reported to exhibit important
bioactive properties and are widely used in pharmaceuticals and
agrochemicals, such as for the treatment of hypercalcemia1 and
chronic kidney disease,2 as anti-cancer agents3 and inhibitors of
plant glutamine synthetase,4 and especially as powerful inhibi-
tors of bone resorption.5 So far, most of the highly potent third-
generation BP drugs against bone resorption contain a nitrogen
heterocycle in the molecule, such as risedronate and zoledronate
(Fig. 1).6 These nitrogen-containing bisphosphonates are cur-
rently clinically applied widely to treat osteoporosis6a,7 and
Paget’s disease,8 and are the only clinically validated drugs tar-
geting hFPPS.9 More importantly, N-BPs also display direct
anti-tumor activity in vivo by inhibiting cancer growth through
anti-angiogenic, anti-invasive, and immunomodulatory actions.10
Recently lipophilic bisphosphonates have attracted more atten-
Fig. 1
tion because they display potent activities as γδ T cell stimu-
lators,11 anti-malarial agents,12,13 anti-infective agents,13 and
anti-cancer agents14 with improved cell penetration ability. Pyra-
In addition, high throughput screening (HTS) plays an impor-
zole is one important scaffold in medicinal chemistry due to its
tant role in medicinal chemistry, especially in the hit-to-lead
potential biological activity. Pyrazole derivatives are powerful
process. HTS has seldom been used in bisphosphonate screening
inhibitors of COX-2,15 CDK16 and Hsp90.17 For example,
due to lack of diversified libraries.12 Although many ways have
VER-49009 and CCT018159 (Fig. 1) are potent inhibitors of
been reported to construct bisphosphonates,18 it is still an urgent
Hsp90. Therefore, a quick method to a larger number of hybrids
task to develop a simple synthetic method for the facile gener-
containing both bisphosphonates and pyrazole groups would be
ation of high-quality libraries of bisphosphonates or their
very useful.
precursors.
Recently, chromone-3-carboxaldehyde and chromen-4-one
have attracted lots of interest due to their strong electrophilic
centres.19 Several papers have reported the synthesis of o-hydro-
aState Key Laboratory of Drug Research, Shanghai Institute of Materia
Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road,
Shanghai, 201203, P. R. China. E-mail: chyang@mail.shcnc.ac.cn;
xyphenyl pyrazole through a reaction between chromone and
hydrazine.17a,20 To the best of our knowledge, the synthetic
chemistry and biochemistry of chromenone BPs have not been
explored. Herein, this work provides a convenient method to
prepare lipophilic pyrazole-containing bisphosphonate esters
from chromenone derivatives with excellent yields in one pot at
ambient temperature.
Fax: +86-21-50806770; Tel: +86-21-50806770
bCollege of Chemistry and Chemical Engineering, Hunan Normal
University, Changsha, 410081, China
†Electronic supplementary information (ESI) available: The 1H
NMR,13C NMR and 31P NMR spectra for the final products. See DOI:
10.1039/c2ob25889g
7730 | Org. Biomol. Chem., 2012, 10, 7730–7738
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Scheme 1 Model reaction for optimization of reaction conditions.
Table 1 Optimization of reaction conditionsa Table 2 Reaction of 1a with various hydrazinesa
Entry
Solvent
Base (equiv.)
Temperature
Yieldb (%)
Entry
Hydrazine
Product
Yieldb (%)
1
2
3
4
5
6
7
8
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
CH2Cl2
DMF
DME
EtOH
EtOH
NaOAc (2)
K2CO3 (2)
NaHCO3 (2)
Et3N (2)
NaOAc (1.2)
None
NaOAc (2)
NaOAc (2)
NaOAc (2)
NaOAc (1.2)
NaOAc (1.2)
r.t
r.t
r.t
r.t
r.t
r.t
r.t
r.t
85
73
70
79
85
Trace
68
71
75
1
2
3
4
5
6
7
8
2a
2b
2c
2d
2e
2f
2g
3h
2i
2j
2k
2l
2m
2n
2o
2p
2q
2r
2s
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
4r
4s
60
72
84
85
89
80
94
92
83
90
88
76
85
89
90
80
61
79
81
9
10
11
r.t
45
Reflux
9
85
75
10
11
12
13
14
15
16
17
18
19
a Reaction conditions: 1a (0.2 mmol), p-tolylhydrazine hydrochloride
(2d) (0.2 mmol), solvent (5 mL), base, NaBH4 (0.6 mmol). b Isolated
yield.
Results and discussion
a Reaction conditions: compound 1a (0.2 mmol), hydrazine or hydrazine
hydrochloride 2 (0.2 mmol), EtOH (5 mL), NaOAc (0.24 mmol) NaBH4
(0.6 mmol) at room temperature. b Isolated yield.
At the outset of our study, the reaction of tetraethyl 2-(4-oxo-4H-
chromen-3-yl)ethene-1,1-diyldiphosphonate
(1a)
prepared
according to the literature21 and p-tolylhydrazine hydrochloride
(2d) (Scheme 1) was used to optimize the reaction conditions
(Table 1). Initially, the effect of base was taken into
consideration.
benzene ring were well tolerated. As a result, we found that
hydrazine with electron-withdrawing or electron-donating substi-
tuents gave higher yields than hydrazinobenzene without any
substituent (Table 2, entry 1). However, too strong electron-with-
drawing (entries 16, 18) and electron-donating (entry 6) substitu-
ents decreased the yields of the desired products slightly.
Obviously, the position of the substituents on the phenyl group
of hydrazine had a considerable effect on the yield. Compared
with the phenyl groups substituted at the meta-, or para-position,
the ortho-position substituted phenylhydrazines gave lower
yields (entry 2 versus 4; 9 versus 11; 12 versus 14 and 16 versus
17), which may be due to the steric hindrance effect of substi-
tuted group at the ortho-position. Heteroaryl hydrazines such as
5-bromo-2-hydrazinopyridine also reacted smoothly with com-
pound 1a in good yield (entry 19).
We found that both organic base and inorganic base gave the
desired product with moderate to good yield (entries 1–4).
NaOAc was chosen as the best base for further reactions with
consideration of the cost of base and yield of product. The
amount of the base was also varied, which indicated that the
reaction was not influenced by decreasing the amount of base to
1.2 equivalents (entry 5). Nevertheless, only a trace product was
obtained without base (entry 6). After examining the solvents,
we found that albeit the effect of solvents for this reaction is
subtle, EtOH gave better yield than others (entries 5, 7–9).
Then, the effect of the reaction temperature was investigated.
Raising the reaction temperature to 45 °C, the yield of product
was almost equivalent to the output at room temperature. Even
when the temperature was increased to boiling point, the yield
decreased a little bit (entry 11).
After that, the scope of compounds 1 was extended in this
methodology by reaction with 2o. The results are summarized in
Table 3. Compared with entry 1, an electron-donating group
(–Me) or withdrawing group (Cl) on the chromone moiety at the
6-position almost gave the same yield (entries 2–3). A hydroxyl group
on the chromone provided a much lower yield (entry 4 versus 3).
Having the optimized reaction conditions (1.2 eq NaOAc,
EtOH, r.t. entry 5), we investigated various hydrazines reacting
with compound 1a (Table 2) (Fig. 2). As illustrated in Table 2,
aromatic hydrazines with electron-withdrawing or electron-
donating substituents at the ortho-, meta-, or para position of the
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Fig. 3 Reaction with amidine.
To our surprise, when we treated compound 1a with 4-tolu-
amidine hydrochloride under the optimized conditions, compound
3w without a bisphosphonate group was detected instead of the
expected compound 3t (Fig. 3), which may be due to the differ-
ence of nucleophilic ability of amidine and hydrazine or the pre-
ferred attack of amidine to the olefin carbon rather than the
carbonyl carbon for steric reasons after attacking the α-carbon.
Fig. 2 The various hydrazines investigated.
Conclusions
Table 3 The scope of compounds 1a
In summary, we have developed an efficient and useful synthetic
method via a sequential two-step one-pot reaction to construct
various pyrazole-bisphosphonate esters in good to excellent
yields. Moreover, the reaction occurred in green solvent under
mild conditions with wide scope and high functional tolerance,
and the starting materials are readily commercially available and
cheap. Further studies of biological activities of these com-
pounds are in progress.
Entry
1
Compounds 1
Product
Yieldb (%)
85
4o
2
3
4t
87
84
Experimental
General information
4u
Unless otherwise noted, all solvents and other reagents are com-
mercially available and used without further purification. H 13C
1
and 31P NMR spectra were recorded on Varian Mercury-300/400
and Varian Mercury-400/500 spectrometers. MS and HRMS
spectra were performed on a Finnigan MAT 95 spectrometer.
Melting points were measured by Büchi 510 melting point
apparatus without further correction.
4
4v
60
Preparation of the starting material substituted 3-formyl-4-
chromenones22
a Reaction conditions: compound 1 (0.2 mmol), 4-(trifluoromethoxy)-
phenylhydrazine hydrochloride 2o (0.2 mmol), EtOH (5 mL), NaOAc
(0.24 mmol), NaBH4 (0.6 mmol) at room temperature. b Isolated yield.
Dimethylformamide (6.0 mL) was cooled in an ice-cold water
bath and 2-hydroxyacetophenone (0.01 mmol) was added to this
7732 | Org. Biomol. Chem., 2012, 10, 7730–7738
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with vigorous stirring; phosphorus oxychloride (2.0 mL) was
slowly added into the solution. The pink colour thick mass was
kept overnight at room temperature. The mixture was then
decomposed by cold water and extracted by EtOAc (3 ×
100 mL). Concentrated under reduced pressure, the crude
product was further purified by column chromatography (PE :
EtOAc 10 : 1).
(20 mL) twice. The combined the organic layer was dried over
anhydrous Na2SO4 and concentrated under reduced pressure, the
crude product was obtained and further purified by column
chromatography (CH2Cl2 : MeOH 100 : 0–30 : 1).
Tetraethyl 2-(4-oxo-4H-chromen-3-yl)ethene-1,1-
diyldiphosphonate (1a)
Yellow solid (56%). Mp 75–76 °C. 1H NMR (300 MHz, CDCl3)
δ 8.90 (s, 1H), 8.42–8.13 (m, 2H), 7.71 (ddd, 1H, J = 8.6, 7.2,
1.7 Hz), 7.55–7.38 (m, 2H), 4.26–4.05 (m, 8H), 1.38 (t, 6H, J =
7.1 Hz), 1.25 (t, 6H, J = 7.1 Hz). 13C NMR (126 MHz, CDCl3)
δ 175.59, 157.80, 156.07, 151.16 (d, J = 3.0 Hz, PCCH),
134.24, 126.07, 125.88, 123.78, 122.95 (t, J = 166.8 Hz, PC),
119.74 (dd, J = 21.2, 8.4 Hz, PCCHC), 118.40, 62.91 (d, J =
5.7 Hz POCH2), 62.88 (d, J = 5.5 Hz POCH2), 16.35 (d, J =
6.5 Hz, POCH2CH3), 16.21 (d, J = 6.4 Hz, POCH2CH3). 31P
NMR (243 MHz, CDCl3) δ 32.86 (d, J = 50.1 Hz), 29.72 (t, J =
50.1 Hz). IR (KBr) 3068, 2983, 2904, 1651, 1616, 1581, 1568,
1463, 1245, 1033, 956, 846, 769, 659, 528 cm−1. m/z (EI): 444
(M+, 4), 307 (100), 171 (22). calcd for C19H26O8P2, 444.1103;
found 444.1103.
6-Methyl-4-oxo-4H-chromene-3-carbaldehyde
Yellow solid (64%). Mp 164–166 °C. 1H NMR (300 MHz,
CDCl3) δ = 10.38 (s, 1H), 8.52 (s, 1H), 8.07 (s, 1H), 7.55 (d,
1H, J = 8.6 Hz), 7.42 (d, 1H, J = 8.6 Hz), 2.48 (s, 3H). IR (KBr)
3082, 2856, 1695, 1655, 1616, 1485, 949, 891, 825, 773, 545,
486 cm−1
.
6-Chloro-4-oxo-4H-chromene-3-carbaldehyde
Yellow solid (89%). Mp 94–96 °C. 1H NMR (300 MHz, CDCl3)
δ = 10.36 (s, 1H), 8.54 (s, 1H), 8.25 (d, 1H, J = 2.6 Hz), 7.70
(dd, 1H, J = 8.9, 2.6 Hz), 7.51 (d, 1H, J = 8.9 Hz). IR (KBr)
3074, 2977, 2881, 1651, 1623, 1604, 1568, 1463, 1443, 1388,
1338, 1307, 1089, 1049, 997, 923, 842, 636, 543 cm−1
.
Tetraethyl 2-(6-methyl-4-oxo-4H-chromen-3-yl)ethene-1,1-
diyldiphosphonate (1b)
6-Chloro-7-hydroxy-4-oxo-4H-chromene-3-carbaldehyde
Yellow solid (86%). Mp > 300 °C. 1H NMR (300 MHz, DMSO-
d6) δ = 11.69 (s, 1H), 8.18 (s, 1H), 7.93 (s, 1H), 7.04 (s, 1H),
5.55 (s, 1H). IR (KBr) 3116, 2974, 1635, 1585, 1567, 1388,
Yellow solid (52%). Mp 88–90 °C. 1H NMR (300 MHz, CDCl3)
δ 8.88 (s, 1H), 8.28 (dd, 1H, J = 47.8, 28.4 Hz), 8.01 (s, 1H),
7.50 (dd, 1H, J = 8.5, 1.7 Hz), 7.38 (d, 1H, J = 8.6 Hz),
4.28–4.14 (m, 4H), 4.16–4.04 (m, 4H), 2.46 (s, 3H), 1.38 (t, 6H,
J = 7.1 Hz), 1.24 (t, 6H, J = 7.1 Hz). 13C NMR (126 MHz,
CDCl3) δ 175.64, 157.76, 154.35, 151.41 (d, J = 3.0 Hz,
PCCH), 135.98, 135.44, 125.38, 122.56 (t, J = 167.3 Hz, PC),
123.44, 119.55 (dd, J = 21.2, 8.4 Hz, PCCHC), 118.13, 62.87
(d, J = 6.0 Hz, POCH2), 62.85 (d, J = 5.8 Hz, POCH2), 21.00,
16.35 (d, J = 6.6 Hz, POCH2CH3), 16.20 (d, J = 6.0 Hz,
POCH2CH3). 31P NMR (243 MHz, CDCl3) δ 32.98 (d, J =
50.4 Hz), 29.82 (d, J = 50.4 Hz). IR (KBr) 3060, 2981, 2900,
1651, 1618, 1579, 1568, 1481, 1230, 1059, 964, 794, 669,
560 cm−1. m/z (EI): 458 (M+, 4), 321 (100), 247 (22) 185(23).
calcd for C20H28O8P2, 458.1259; found 458.1265.
1307, 1253, 1097, 1049, 921, 842, 642 cm−1
.
General procedure for the syntheses of compounds 1a–1d
Firstly, 100 mL of dry THF was placed in a 250 mL flask and
cooled to 0 °C under nitrogen and 3-formylchromone (4 mmol),
titanium tetrachloride (1.97 g, 10.4 mmol), tetraethyl methylene-
bisphosphonate (1.16 g, 10.4 mmol) and N-methylmorpholine
(2.1 g, 20.8 mmol) were added successively. Then the mixture
was partitioned between EtOAc (100 mL) and H2O and extracted
by EtOAc (100 mL) twice after stirring for 3–4 h at room temp-
erature. The combined the organic layers were washed with
aqueous NaHCO3 to neutral, dried over anhydrous Na2SO4, and
evaporated to dryness under reduced pressure, and then the
crude product was further purified by column chromatography
(CH2Cl2 : MeOH 100 : 0–40 : 1).
Tetraethyl 2-(6-chloro-4-oxo-4H-chromen-3-yl)ethene-1,1-
diyldiphosphonate (1c)
Yellow solid (52%). Mp 64–65 °C. 1H NMR (300 MHz, CDCl3)
δ 8.88 (s, 1H), 8.23 (ddd, 1H, J = 48, 30, 0.9 Hz), 8.19 (d, 1H,
J = 2.6 Hz) 7.64 (dd, 1H, J = 8.9, 2.6 Hz), 7.46 (d, 1H, J =
8.9 Hz), 4.28–4.04 (m, 8H), 1.38 (t, 6H, J = 7.1 Hz), 1.26 (t,
6H, J = 7.1 Hz). 13C NMR (126 MHz, CDCl3) δ 174.47,
157.73, 154.39, 150.62 (d, J = 3.0 Hz, PCCH), 134.45, 131.92,
125.49, 124.70, 123.84 (t, J = 166.7 Hz, PC), 120.15, 119.82
(dd, J = 21.4, 8.4 Hz, PCCHC), 62.95 (t, J = 6.6 Hz, POCH2),
16.36 (d, J = 6.5 Hz, POCH2CH3), 16.23 (d, J = 6.4 Hz,
POCH2CH3). 31P NMR (243 MHz, CDCl3) δ 32.57 (d, J =
49.0 Hz), 29.49 (d, J = 49.0 Hz). IR (KBr) 2987, 2906, 1651,
General procedure for the syntheses of compounds 4a–4v
Compound 1 (0.2 mmol), NaOAc (0.24 mmol), and hydrazine
hydrochloride 2 (0.2 mmol, when free hydrazine used, NaOAc
was not necessary) were dissolved in EtOH (5 mL) and the
mixture was stirred at room temperature for 2–12 hours until the
starting materials disappeared, (monitored by TLC). NaBH4
(0.6 mmol) was added, after compound 1 was completely con-
verted to the intermediate. Then, the ethanol was evaporated
under reduced pressure after stirring at room temperature for
another 3 hours. The residue was partitioned between 1 N HCl
and EtOAc (20 mL). HCl layer was extracted with ethyl acetate
1614, 1589, 1566, 1465, 1439, 1247, 1028, 980, 665 544 cm−1
.
This journal is © The Royal Society of Chemistry 2012
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m/z (EI): 478 (M+, 4), 341 (100), 343 (36) 267 (12) 205 (18).
calcd for C19H25ClO8P2, 478.0713; found 478.0710.
Tetraethyl 2-(5-(2-hydroxyphenyl)-1-m-tolyl-1H-pyrazol-4-yl)
ethane-1,1-diyldiphosphonate (4c)
1
White solid (84%). Mp 92–94 °C. H NMR (300 MHz, CDCl3)
δ 8.02 (br s, 1H), 7.68 (s, 1H), 7.29–7.20 (m, 1H), 7.17 (s, 1H),
7.08–7.03 (m, 1H), 7.01–6.90 (m, 4H), 6.83 (td, 1H, J = 7.4,
1.1 Hz), 4.18–3.92 (m, 8H), 3.24–2.84 (m, 2H), 2.73–2.49 (m,
1H), 2.23 (s, 3H), 1.35–1.15 (m, 12H). 13C NMR (101 MHz,
CDCl3) δ 155.32, 139.97, 139.82, 138.55, 137.02, 128.21,
127.62, 124.49, 120.62, 120.33, 119.30 (dd, J = 10.2, 7.8 Hz,
PCHCH2C), 118.12, 118.06, 63.01–62.36 (m, POCH2), 37.14 (t,
J = 132.7 Hz, PCH), 21.20, 20.54 (t, J = 4.3 Hz, PCHCH2),
16.21 (dd, J = 9.9, 5.1 Hz, POCH2CH3). 31P NMR (243 MHz,
CDCl3) δ 40.17, 40.13.
Tetraethyl 2-(6-chloro-7-hydroxy-4-oxo-4H-chromen-3-yl)-
ethene-1,1-diyldiphosphonate (1d)
Yellow solid (47%). Mp 184–185 °C. 1H NMR (300 MHz,
CDCl3) δ 9.99 (br s, 1H), 8.62 (s, 1H), 8.26 (dd, 1H, J = 48.9,
27.5 Hz), 8.12 (s, 1H), 6.99 (s, 1H), 4.32–4.08 (m, 8H), 1.40 (t,
6H, J = 7.1 Hz), 1.31 (t, 6H, J = 7.1 Hz). 13C NMR (101 MHz,
CDCl3) δ 173.75, 158.54, 156.31, 155.79, 152.82 (d, J =
2.4 Hz, PCCH), 126.75, 119.47 (dd, J = 20.8, 8.3 Hz, PCCHC),
116.88, 103.68, 63.68 (d, J = 6.4 Hz, POCH2), 63.14 (d, J =
6.0 Hz, POCH2), 16.31 (d, J = 6.4 Hz, POCH2CH3), 16.14 (d,
J = 6.6 Hz, POCH2CH3). 31P NMR (243 MHz, CDCl3) δ 32.15
(d, J = 50.5 Hz), 29.91 (d, J = 50.5 Hz). IR (KBr) 3068, 2989,
2941, 1645, 1625, 1604, 1587, 1496, 1456, 1251, 1214, 1010,
787, 677, 538 cm−1. m/z (EI): 494 (M+, 4), 385 (44), 387(16)
357(100) 359(100) 221 (22). calcd for C19H25ClO9P2, 494.0662;
found 494.0667.
IR (KBr) 3417, 3155, 2981, 1612, 1592, 1496, 1446, 1369,
1261, 1027, 971, 760, 526 cm−1. m/z (EI): 550 (M+, 12), 413 (100),
261(14). calcd for C26H36N2O7P2, 550.1998; found 550.1985.
Tetraethyl 2-(5-(2-hydroxyphenyl)-1-p-tolyl-1H-pyrazol-4-yl)
ethane-1,1-diyldiphosphonate (4d)
Yellow solid (85%). Mp 101–102 °C; 1H NMR (400 MHz,
CDCl3) δ 7.92 (br s, 1H), 7.68 (s, 1H), 7.24 (m, 1H), 7.15 (d,
2H, J = 8.3 Hz), 7.01 (d, 2H, J = 8.2 Hz), 6.94 (m, 2H), 6.85 (t,
1H, J = 7.4 Hz), 4.19–3.95 (m, 8H), 3.22–3.04 (m, 1H), 2.94 (tt,
1H, J = 23.8, 11.9 Hz), 2.61 (tt, 1H, J = 24.4, 7.4 Hz), 2.26 (s,
3H), 1.34–1.19 (m, 12H). 13C NMR (126 MHz, CDCl3) δ
155.35, 139.86, 137.59, 136.95, 136.75, 131.68, 130.92, 129.23,
123.71, 120.51, 118.44, 119.22–119.37 (m, PCHCH2C), 118.28,
63.16–62.31 (m, POCH2), 37.26 (t, J = 133.1 Hz, PCH), 20.99,
20.62 (t, J = 4.3 Hz, PCHCH2), 16.58–15.89 (m, POCH2CH3).
31P NMR (243 MHz, CDCl3) δ 40.14, 40.09. IR (KBr) 3145,
2981, 2929, 1614, 1590, 1519, 1471, 1444, 1392, 1255, 1018,
966, 823, 532 cm−1. m/z (EI): 550 (M+, 12), 413 (100). calcd for
C26H36N2O7P2, 550.1998; found 550.1995.
Tetraethyl 2-(5-(2-hydroxyphenyl)-1-phenyl-1H-pyrazol-4-yl)-
ethane-1,1-diyldiphosphonate (4a)
Yellow solid (60%). Mp 90–92 °C. 1H NMR (300 MHz, CDCl3)
δ 8.09 (s, 1H), 7.69 (s, 1H), 7.30–7.25 (m, 2H), 7.25–7.23 (m,
1H), 7.22–7.11 (m, 3H), 7.00–6.89 (m, 2H), 6.83 (t, 1H, J =
7.4 Hz), 4.22–3.84 (m, 8H), 3.28–2.80 (m, 2H), 2.77–2.41 (tt,
1H, J = 24.1, 7.4 Hz), 1.33–1.15 (m, 12H). 13C NMR
(126 MHz, CDCl3) δ 155.45, 140.18, 140.05, 137.19, 131.66,
130.92, 128.60, 126.89, 123.83, 120.39, 119.44 (t, J = 8.8 Hz,
PCHCH2C), 118.20 (d, J = 6.3 Hz, PCHCH2CCH), 118.10 (d,
J = 2.5 Hz, PCHCH2CC), 62.86 (dd, J = 20.2, 6.1 Hz, POCH2),
62.66 (dd, J = 20.2, 6.1 Hz, POCH2), 37.25 (t, J = 132.3 Hz,
PCH), 20.59, 16.25 (m, PCHCH2). 31P NMR (243 MHz,
CDCl3) δ 40.14. IR (KBr) 3151, 2981, 1612, 1599, 1502, 1446,
1392, 1244, 1219, 1019, 985, 761, 524 cm−1. m/z (EI): 536
(M+, 19), 399 (100), 247 (12). calcd for C25H34N2O7P2,
536.1841; found 536.1857.
Tetraethyl 2-(1-(3,5-dimethylphenyl)-5-(2-hydroxyphenyl)-1H-
pyrazol-4-yl)ethane-1,1-diyldiphosphonate (4e)
White solid (90%). Mp 118–120 °C. 1H NMR (300 MHz,
CDCl3) δ 8.07 (br s, 1H), 7.74 (s, 1H), 7.35–7.29 (m, 1H),
7.04–7.02 (m, 2H), 6.95 (s, 2H), 6.91 (td, 1H, J = 8.1, 0.9 Hz),
6.86 (s, 1H), 4.27–3.98 (m, 8H), 3.30–2.98 (m, 2H), 2.70 (tt,
1H, J = 23.1, 7.5 Hz), 2.23 (s, 6H), 1.41–1.25 (m, 12H). 13C
NMR (101 MHz, CDCl3) δ 155.42, 139.92, 139.82, 138.23,
137.03, 131.70, 130.91, 128.62, 121.52, 120.42, 119.29 (dd, J =
10.1, 8.0 Hz, PCHCH2C), 118.24, 118.17, 63.18–62.49 (m,
POCH2), 37.26 (t, J = 132.8 Hz, PCH), 21.20, 20.66 (t, J =
4.2 Hz, PCHCH2), 16.32 (dd, J = 10.0, 5.3 Hz, POCH2CH3).
31P NMR (243 MHz, CDCl3) δ 40.19, 40.14. IR (KBr) 3154,
2983, 2943, 1616, 1597, 1510, 1444, 1373, 1251, 1221, 1000,
972, 848, 755, 528 cm−1. m/z (EI): 564 (M+, 12), 427 (100),
275 (8). calcd for C27H38N2O7P2, 564.2154; found 564.2153.
Tetraethyl 2-(5-(2-hydroxyphenyl)-1-o-tolyl-1H-pyrazol-4-yl)-
ethane-1,1-diyldiphosphonate (4b)
Colorless oil (72%). 1H NMR (300 MHz, CDCl3) δ 8.14 (s, 1H),
7.70 (s, 1H), 7.17–7.10 (m, 4H), 7.07–6.98 (m, 1H), 6.90 (dd,
1H, J = 7.6, 1.6 Hz), 6.85 (d, 1H, J = 8.2 Hz), 6.75 (td, 1H, J =
7.4, 0.8 Hz), 4.20–3.94 (m, 8H), 3.28–2.85 (m, 2H), 2.65 (tt,
1H, J = 23.5, 7.6 Hz), 2.09 (s, 3H), 1.40–1.13 (m, 12H). 13C
NMR (126 MHz, CDCl3) δ 155.26, 139.59, 138.84, 138.54,
135.74, 131.54, 130.68, 130.60, 128.50, 127.73, 125.77, 119.99,
118.23, 118.05–117.74 (m, PCHCH2C), 117.53, 62.78 (t, J =
14.4 Hz, POCH2), 37.29 (t, J = 132.9 Hz, PCH), 20.69 (t, J =
4.3 Hz, PCHCH2), 17.59, 16.57–15.97 (m, POCH2CH3). 31P
NMR (243 MHz, CDCl3) δ 40.25. IR (KBr) 3394, 3187, 2919,
2740, 2601, 1645, 1614, 1500, 1446, 1386, 1259, 1022, 798,
532 cm−1. m/z (EI): 550 (M+, 10), 413 (100). calcd for
C26H36N2O7P2, 550.1998; found 550.2007.
Tetraethyl 2-(5-(2-hydroxyphenyl)-1-(4-methoxyphenyl)-1H-
pyrazol-4-yl)ethane-1,1-diyldiphosphonate (4f)
Yellow solid (80%). Mp 120–122.5 °C. 1H NMR (400 MHz,
CDCl3) δ 7.91 (s, 1H), 7.67 (s, 1H), 7.27 (m, 1H), 7.22–7.17
7734 | Org. Biomol. Chem., 2012, 10, 7730–7738
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(m, 2H), 6.96–6.93 (m, 2H), 6.85 (t, 1H, J = 7.4 Hz), 6.77–6.69
(m, 2H), 4.18–3.96 (m, 8H), 3.74 (s, 3H), 3.23–3.05 (m, 1H),
3.00–2.84 (m, 1H), 2.62 (tt, 1H, J = 25.6, 7.6 Hz), 1.36–1.18
(m, 12H). 13C NMR (126 MHz, CDCl3) δ 158.40, 155.39,
139.61, 137.04, 133.33, 131.70, 130.94, 125.36, 120.53,
119.32–118.83 (m, PCHCH2C), 118.59, 118.33, 113.75,
63.08–62.31 (m, POCH2), 55.33, 37.32 (J = 133.6 Hz, PCH),
20.63 (t, J = 4.1 Hz, PCHCH2), 16.27 (m, POCH2CH3). 31P
NMR (243 MHz, CDCl3) δ 40.15, 40.09. IR (KBr) 3141, 2981,
2931, 2738, 1730, 1614, 1589, 1518, 1468, 1446, 1369, 1251,
1016, 966, 850, 777, 659, 532 cm−1. m/z (EI): 566 (M+, 12),
429 (100), 167 (26), 149 (68). calcd for C26H36N2O8P2,
566.1947; found 566.1952.
6.86 (d, 1H, J = 7.3 Hz), 6.76 (td, 1H, J = 7.5, 1.1 Hz),
4.17–3.95 (m, 8H), 3.31–2.86 (m, 2H), 2.66 (tt, 1H, J = 23.6,
7.5 Hz), 1.36–1.17 (m, 12H). 13C NMR (101 MHz, CDCl3) δ
155.24, 140.24, 139.07, 138.79, 133.06, 131.63, 130.95, 130.24,
129.93, 127.62, 122.2, 120.11, 118.56–118.27 (m, PCHCH2C),
118.24, 117.11, 62.84, 37.28 (t, J = 132.9 Hz, PCH), 20.67 (t,
J = 4.2 Hz, PCHCH2), 16.40. 31P NMR (243 MHz, CDCl3) δ
40.14. IR (KBr) 3417, 3157, 2983, 2931, 2740, 1614, 1589,
1493, 1444, 1390, 1259, 1018, 758, 524 cm−1. m/z (EI): 616
(M+, (Br81), 12), 616 (M+, (Br79), 12), 479 (100), 477(100), 327
(10). 325 (10). calcd for C25H33BrN2O7P2, 614.0946; found
614.0940.
Tetraethyl 2-(1-(3-bromophenyl)-5-(2-hydroxyphenyl)-1H-
Tetraethyl 2-(1-(4-fluorophenyl)-5-(2-hydroxyphenyl)-1H-
pyrazol-4-yl)ethane-1,1-diyldiphosphonate (4j)
pyrazol-4-yl)ethane-1,1-diyldiphosphonate (4g)
White solid (90%). Mp 107–108 °C. 1H NMR (300 MHz,
CDCl3) δ 8.09 (br s, 1H), 7.70 (s, 1H), 7.55 (t, 1H, J = 1.9 Hz),
7.33–7.27 (m, 2H), 7.16–7.09 (m, 1H), 7.04 (t, 1H, J = 8.0 Hz),
7.0–6.95 (m, 2H), 6.93–6.85 (m, 1H), 4.19–3.94 (m, 8H), 3.04
(m, 2H), 2.72–2.47 (m, 1H), 1.36–1.15 (m, 12H). 13C NMR
(101 MHz, CDCl3) δ 155.34, 140.99, 140.48, 137.33, 131.47,
131.25, 129.79, 129.72, 126.79, 122.08, 121.85, 120.70,
120.05–119.52 (m, PCHCH2C), 118.79, 117.96, 62.77 (m,
POCH2), 37.18 (t, J = 133.1 Hz, PCH), 20.47 (t, J = 4.1 Hz,
PCHCH2), 16.22 (dd, J = 11.5, 5.3 Hz, POCH2CH3). 31P NMR
(243 MHz, CDCl3) δ 40.01, 39.95. IR (KBr) 3133, 2981, 1591,
1579, 1491, 1444, 1387, 1263, 1223, 1028, 970, 850, 789,
526 cm−1. m/z (EI): 616 (M+, (Br81), 12), 616 (M+, (Br79), 12),
479 (100), 477(100), 327 (9). 325 (9). calcd for
C25H33BrN2O7P2, 614.0946; found, 614.0944 [M+].
Yellow solid (94%). Mp 64–65 °C. 1H NMR (300 MHz, CDCl3)
δ 8.09 (br s, 1H), 7.68 (s, 1H), 7.30–7.21 (m, 3H), 6.99–6.83
(m, 5H), 4.20–3.94 (m, 8H), 3.26–2.81 (m, 2H), 2.73–2.47 (m,
1H), 1.32–1.18 (m, 12H). 13C NMR (126 MHz, CDCl3) δ
161.36 (d, J = 246.7 Hz, FArC), 155.45, 140.05, 137.4, 136.17,
131.61, 131.14, 125.70 (d, J = 8.6 Hz, ArCCHCH), 120.63,
119.47 (dd, J = 10.7, 7.6 Hz, PCHCH2C), 118.78, 118.16,
115.47 (d, J = 22.8 Hz, ArCCH), 63.22–62.37 (m, POCH2),
37.31 (t, J = 133.2 Hz, PCH), 16.45–16.05 (m, POCH2CH3).
31P NMR (243 MHz, CDCl3) δ 40.05, 40.00. IR (KBr) 3138,
2923, 2850, 1616, 1517, 1467, 1446, 1396, 1365, 1245, 1219,
1029, 966, 850, 760, 532 cm−1. m/z (EI): 554 (M+, 9), 417
(100), 265 (11). calcd for C25H33FN2O7P2, 554.1747; found
554.1743.
Tetraethyl 2-(1-(3-fluorophenyl)-5-(2-hydroxyphenyl)-1H-
Tetraethyl 2-(1-(4-bromophenyl)-5-(2-hydroxyphenyl)-1H-
pyrazol-4-yl)ethane-1,1-diyldiphosphonate (4h)
pyrazol-4-yl)ethane-1,1-diyldiphosphonate (4k)
Yellow solid (92%). Mp 92–93 °C. 1H NMR (300 MHz, CDCl3)
δ 8.07 (br s, 1H), 7.70 (s, 1H), 7.39–7.27 (m, 1H), 7.22–6.94
(m, 5H), 6.91–6.84 (m, 2H), 4.20–3.91 (m, 8H), 3.26–2.81 (m,
2H), 2.69–2.49 (m, 1H), 1.35–1.15 (m, 12H). 13C NMR
(101 MHz, CDCl3) δ 162.34 (d, J = 246.3 Hz, FC), 155.34,
141.30 (d, J = 10.3 Hz, FCCHC), 140.46, 137.31, 131.44,
Yellow solid (88%). Mp 123–124 °C. 1H NMR (300 MHz,
CDCl3) δ 8.13 (br s, 1H), 7.69 (s, 1H), 7.36–7.29 (m, 2H),
7.28–7.25 (m, 1H), 7.18–7.11 (m, 2H), 7.00–6.91 (m, 2H), 6.87
(td, 1H, J = 7.4, 1.1 Hz), 4.21–3.89 (m, 8H), 3.25–2.79 (m, 2H),
2.72–2.46 (m, 1H), 1.33–1.17 (m, 12H). 13C NMR (126 MHz,
CDCl3) δ 155.41, 140.44, 139.10, 137.30, 131.74, 131.55,
131.22, 125.18, 120.72, 120.52, 119.87 (dd, J = 10.5, 7.3 Hz,
PCHCH2C), 118.77, 118.08, 62.82 (m, POCH2), 37.25 (t, J =
133.1 Hz, PCH), 20.53 (t, J = 4.2 Hz, PCHCH2), 16.66–16.01
(m, POCH2CH3). 31P NMR (243 MHz, CDCl3) δ 40.02, 39.97.
IR (KBr) 3143, 2980, 1614, 1591, 1495, 1467, 1444, 1390,
1257, 1226, 1045, 1014, 964, 852, 764, 532 cm−1. m/z (EI): 616
(M+, (Br81), 14), 616 (M+, (Br79), 14), 479 (100), 477(100), 327
(10), 325 (10). calcd for C25H33BrN2O7P2, 614.0946; found
614.0952.
131.18, 129.67 (d,
J = 9.0 Hz, FCCHCH), 120.63,
120.00–119.70 (m, PCHCH2CH), 118.99 (d, J = 2.8 Hz,
FCCHCH), 118.63, 117.95, 113.67 (d, J = 21.0 Hz, FCCH),
111.07 (d, J = 25.3 Hz, FCCH), 64.94–60.29 (m, POCH2),
37.15 (t, J = 133.0 Hz, PCH), 20.45 (t, J = 4.1 Hz, PCHCH2),
16.20 (dd, J = 11.1, 5.3 Hz, POCH2CH3). 31P NMR (243 MHz,
CDCl3) δ 40.02, 39.96. IR (KBr) 3133, 2985, 2910, 1610, 1600,
1508, 1496, 1496, 1441, 1388, 1367, 1246, 1029, 972, 873,
798, 762, 534 cm−1. m/z (EI): 554(M+, 10), 417 (100), 265 (10).
calcd for C25H33FN2O7P2, 554.1747; found 554.1763.
Tetraethyl 2-(1-(2-chlorophenyl)-5-(2-hydroxyphenyl)-1H-
Tetraethyl 2-(1-(2-bromophenyl)-5-(2-hydroxyphenyl)-1H-
pyrazol-4-yl)ethane-1,1-diyldiphosphonate (4l)
pyrazol-4-yl)ethane-1,1-diyldiphosphonate (4i)
1
Colorless oil (76%). H NMR (300 MHz, CDCl3) δ 8.06 (br s,
1
Colorless oil (83%). H NMR (300 MHz, CDCl3) δ 8.10 (br s,
1H), 7.75 (s, 1H), 7.35 (m, 2H), 7.25–7.10 (m, 3H), 7.03–6.94
(m, 1H), 6.86 (d, 1H, J = 8.2 Hz), 6.77 (td, 1H, J = 7.5, 1.1 Hz),
4.22–3.93 (m, 8H), 3.03 (m, 2H), 2.78–2.52 (tt, 1H, J = 23.4,
1H), 7.74 (s, 1H), 7.50 (dd, 1H, J = 7.8, 1.5 Hz), 7.36 (dd, 1H,
J = 7.7, 1.6 Hz), 7.16 (m, 3H), 7.01 (dd, 1H, J = 7.6, 1.6 Hz),
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7.5 Hz), 1.38–1.15 (m, 12H). 13C NMR (126 MHz, CDCl3) δ
155.21, 140.37, 138.93, 137.49, 132.27, 131.49, 130.92, 129.94,
129.89, 129.74, 126.94, 120.09, 118.40–118.33 (m, PCHCH2C),
118.23, 117.11, 62.82 (t, J = 15.6 Hz, POCH2), 37.26 (t, J =
133.0 Hz, PCH), 20.63 (t, J = 4.3 Hz, PCHCH2), 16.32. 31P
NMR (243 MHz, CDCl3) δ 40.13. IR (KBr) 3392, 3165, 2983,
2931, 2740, 1614, 1591, 1495, 1446, 1390, 1249, 1163, 1028,
966, 758, 532 cm−1. m/z (EI): 572 (M+, (Cl37), 5), 570
(M+, (Cl35) 17), 435 (34), 433 (100), 281 (11). calcd for
C25H33ClN2O7P2, 570.1452; found, 570.1444.
258.6 Hz, CF3), 120.16–119.40 (m, PCHCH2C), 118.81,
118.04, 62.78 (m, POCH2), 37.21 (t, J = 133.1 Hz, PCH), 20.50
(t, J = 4.2 Hz, PCHCH2), 16.23 (dd, J = 11.5, 5.2 Hz,
POCH2CH3). 31P NMR (243 MHz, CDCl3) δ 40.01, 39.96. IR
(KBr) 3133, 2987, 1616, 1593, 1516, 1467, 1449, 1394, 1371,
1267, 1222, 1165, 1020, 964, 860, 750, 530 cm−1. m/z (EI): 620
(M+, 11), 483 (100), 331 (11). calcd for C26H33F3N2O8P2,
620.1664; found 620.1668.
Tetraethyl 2-(5-(2-hydroxyphenyl)-1-(4-(trifluoromethyl)-
phenyl)-1H-pyrazol-4-yl)ethane-1,1-diyldiphosphonate (4p)
Tetraethyl 2-(1-(3-chlorophenyl)-5-(2-hydroxyphenyl)-1H-
pyrazol-4-yl)ethane-1,1-diyldiphosphonate (4m)
White solid (80%). Mp 142–142.5 °C. 1H NMR (300 MHz,
CDCl3) δ 8.24 (br s, 1H), 7.73 (s, 1H), 7.47 (d, 2H, J = 8.7 Hz),
7.39 (d, 2H, J = 8.5 Hz), 7.29 (ddd, 1H, J = 8.2, 7.2, 1.9 Hz),
7.02–6.94 (m, 2H), 6.89 (td, 1H, J = 7.4, 1.1 Hz), 4.20–3.91 (m,
8H), 3.18–2.85 (m, 2H), 2.73–2.45 (m, 1H), 1.32–1.13 (m,
12H). 13C NMR (126 MHz, CDCl3) δ 155.42, 142.80, 140.97,
137.53, 131.49, 131.36, 128.47 (q, J = 32.8 Hz, CF3ArC),
125.87–125.82 (m, CF3ArCH), 123.88 (q, J = 272.1 Hz, CF3),
123.30, 120.82 (s, 19H), 120.36 (dd, J = 10.6, 7.3 Hz,
PCHCH2C), 118.83, 118.03, 63.20–62.23 (m, POCH2), 38.27,
37.21, 36.15, 20.49 (t, J = 4.3 Hz, PCHCH2), 16.62–16.05 (m,
POCH2CH3). 31P NMR (243 MHz, CDCl3) δ 39.97, 39.92. IR
(KBr) 3100, 2987, 1616, 1593, 1523, 1448, 1390, 1326, 1251,
1226, 1201, 1163, 1066, 1024, 962, 845, 754, 532 cm−1. m/z
(EI): 604 (M+, 9), 467 (100), 315 (14). calcd for
C26H33F3N2O7P2, 604.1715; found 604.1715.
White solid (85%). Mp 104–106 °C. 1H NMR (300 MHz,
CDCl3) δ 8.08 (br s, 1H), 7.70 (s, 1H), 7.39–7.38 (m, 1H),
7.35–7.26 (m, 1H), 7.18–7.05 (m, 3H), 7.0–6.95 (m, 2H), 6.89
(td, 1H, J = 7.4, 1.0 Hz), 4.21–3.93 (m, 8H), 3.24–2.85 (m, 2H),
2.71–2.48 (m, 1H), 1.36–1.16 (m, 12H). 13C NMR (126 MHz,
CDCl3) δ 155.43, 141.02, 140.53, 137.40, 134.27, 131.55,
131.31, 129.52, 126.96, 124.02, 121.51, 120.77, 119.97 (dd, J =
10.8, 7.1 Hz, PCHCH2C), 118.89, 118.09, 63.37–62.27 (m,
POCH2), 37.28 (t, J = 133.2 Hz, PCH), 20.54 (t, J = 4.3 Hz,
PCHCH2), 16.28 (m, POCH2CH3). 31P NMR (243 MHz,
CDCl3) δ 40.02, 39.94. IR (KBr) 3158, 2981, 1614, 1595, 1487,
1446, 1369, 1251, 1220, 1022, 970, 842, 783, 757, 522 cm−1
.
m/z (EI): 572 (M+, (Cl37), 5), 570 (M+, (Cl35) 13), 435 (36), 433
(100), 281 (12). calcd for C25H33ClN2O7P2, 570.1452; found
570.1451.
Tetraethyl 2-(5-(2-hydroxyphenyl)-1-(2-(trifluoromethyl)-
phenyl)-1H-pyrazol-4-yl)ethane-1,1-diyldiphosphonate (4q)
Tetraethyl 2-(1-(4-chlorophenyl)-5-(2-hydroxyphenyl)-1H-
pyrazol-4-yl)ethane-1,1-diyldiphosphonate (4n)
White solid (61%). Mp 125–126 °C. 1H NMR (300 MHz,
CDCl3) δ 8.25 (s, 1H), 7.72 (s, 1H), 7.69–7.61 (m, 1H),
7.44–7.35 (m, 3H), 7.22–7.12 (m, 1H), 6.95–6.84 (m, 2H), 6.77
(t, 1H, J = 7.4 Hz), 4.23–3.94 (m, 8H), 3.30–2.83 (m, 2H),
2.78–2.53 (m, 1H), 1.41–1.17 (m, 12H). 13C NMR (101 MHz,
CDCl3) δ 155.36, 140.08, 138.88, 137.28, 131.93, 131.61,
130.92, 129.70, 128.81, 127.18, 120.28, 119.00–118.61 (m,
PCHCH2C), 118.54, 117.36, 62.78 (t, J = 16.5 Hz, POCH2),
37.17 (t, J = 133.4 Hz, PCH), 20.55 (t, J = 4.2 Hz, PCHCH2),
16.26. 31P NMR (243 MHz, CDCl3) δ 40.11. IR (KBr) 3165,
2985, 1608, 1589, 1510, 1458, 1389, 1321, 1233, 1159, 1036,
964, 860, 754, 536 cm−1. m/z (EI): 604 (M+, 11), 467 (100), 315
(10). calcd for C26H33F3N2O7P2, 604.1715; found 604.1720.
Yellow solid (89%). Mp 105–108 °C. 1H NMR (300 MHz,
CDCl3) δ 8.14 (s, 1H), 7.69 (s, 1H), 7.28 (t, 1H, J = 7.2 Hz),
7.25–7.13 (m, 4H), 7.01–6.92 (m, 2H), 6.87 (t, 1H, J = 7.4 Hz),
4.05 (m, 8H), 3.26–2.81 (m, 2H), 2.59 (tt, 1H, J = 7.4 Hz),
1.36–1.14 (m, 12H). 13C NMR (126 MHz, CDCl3) δ 155.43,
140.37, 138.60, 137.34, 132.53, 131.56, 131.20, 128.77, 124.91,
120.69, 119.80 (dd, J = 10.7, 7.3 Hz, PCHCH2C), 118.76,
118.10, 62.81 (m, POCH2), 37.28 (t, J = 133.6 Hz, PCH), 20.54
(t, J = 4.4 Hz, PCHCH2), 16.63–16.02 (m, POCH2CH3). 31P
NMR (243 MHz, CDCl3) δ 40.02, 39.97. IR (KBr) 3143, 2981,
2734, 1616, 1593, 1498, 1469, 1444, 1390, 1369, 1257, 1226,
1167, 1016, 964, 852, 764, 532 cm−1. m/z (EI): 572 (M+, (Cl37)
5), 570 (M+, (Cl35), 13), 435 (37), 433 (100), 281 (12). calcd for
C25H33ClN2O7P2, 570.1452; found 570.1448.
Tetraethyl 2-(1-(4-cyanophenyl)-5-(2-hydroxyphenyl)-1H-
pyrazol-4-yl)ethane-1,1-diyldiphosphonate (4r)
Tetraethyl 2-(5-(2-hydroxyphenyl)-1-(4-(trifluoromethoxy)-
phenyl)-1H-pyrazol-4-yl)ethane-1,1-diyldiphosphonate (4o)
Yellow solid (79%). Mp 121–122 °C. 1H NMR (300 MHz,
CDCl3) δ 8.23 (br, 1H), 7.75 (s, 1H), 7.56–7.46 (m, 2H),
7.42–7.36 (m, 2H), 7.36–7.28 (m, 1H), 6.98 (m, 2H), 6.93 (m,
1H), 4.26–3.84 (m, 8H), 3.25–2.82 (m, 2H), 2.57 (ddd, 1H, J =
23.5, 19.3, 6.0 Hz), 1.35–1.14 (m, 12H). 13C NMR (126 MHz,
CDCl3) δ 155.39, 143.45, 141.41, 137.71, 132.771, 131.59,
131.39, 123.36, 121.04, 120.90–120.76 (m, PCHCH2C), 119.19,
118.44, 118.07, 110.00, 62.95 (dd, J = 15.1, 6.3 Hz POCH2),
62.79 (dd, J = 17.6, 6.3 Hz POCH2), 37.20 (t, J = 133.4 Hz,
White solid (90%). Mp 102–104 °C. 1H NMR (300 MHz,
CDCl3) δ 8.13 (s, 1H), 7.70 (s, 1H), 7.37–7.26 (m, 3H), 7.06 (d,
2H, J = 8.5 Hz), 6.96 (dd, 2H, J = 7.3, 2.2 Hz), 6.88 (t, 1H, J =
7.2 Hz), 4.21–3.92 (m, 8H), 3.26–2.80 (m, 2H), 2.60 (tdd, 1H,
J = 23.4, 8.4, 6.1 Hz), 1.37–1.15 (m, 12H). 13C NMR
(101 MHz, CDCl3) δ 155.39, 147.52, 140.39, 138.46, 137.34,
131.52, 131.23, 124.88, 121.02, 120.70, 120.28 (q, J =
7736 | Org. Biomol. Chem., 2012, 10, 7730–7738
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PCH), 20.42 (m, PCHCH2), 16.73–16.06 (m, 4C). 31P NMR
(243 MHz, CDCl3) δ 39.85, 39.79. IR (KBr) 3163, 2989, 2898,
2227, 1606, 1513, 1444, 1392, 1290, 1225, 1108, 1018, 987,
877, 852, 754, 658, 538, 482 cm−1. m/z (EI): 561 (M+, 13), 424
(100), 272 (14). calcd for C26H33N3O7P2, 561.1794; found
561.1795.
119.97, 63.21–62.64 (m, POCH2), 37.40 (t, J = 133.4 Hz, PCH),
20.49 (t, J = 4.4 Hz, PCHCH2), 16.27 (dd, J = 13.6, 6.0 Hz,
POCH2CH3). 31P NMR (243 MHz, CDCl3) δ 39.81, 39.78. IR
(KBr) 3073, 2985, 1608, 1516, 1467, 1444, 1408, 1394, 1263,
1223, 1162, 1022, 968, 837, 651 cm−1. m/z (EI): 656
(M+, (Cl37), 4), 654 (M+, (Cl35), 12), 519 (37), 517 (100), 463
(35). calcd for C26H32ClF3N2O8P2, 654.1275 found 654.1269.
Tetraethyl 2-(1-(5-bromopyridin-2-yl)-5-(2-hydroxyphenyl)-1H-
pyrazol-4-yl)ethane-1,1-diyldiphosphonate (4s)
Tetraethyl 2-(5-(5-chloro-2,4-dihydroxyphenyl)-1-
(4-(trifluoromethoxy)phenyl)-1H-pyrazol-4-yl)ethane-
1,1-diyldiphosphonate (4v)
White solid (81%). Mp 104–105 °C. 1H NMR (300 MHz,
CDCl3) δ 8.28 (d, 1H, J = 2.3 Hz), 8.14 (s, 1H), 7.80 (dd, 1H,
J = 9, 3 Hz), 7.77 (s, 1H), 7.46 (d, J = 8.8 Hz, 1H), 7.31 (t, J =
8.4 Hz, 1H), 7.04–7.00 (m, 2H), 6.93 (t, 1H, J = 7.3 Hz),
4.16–3.90 (m, 8H), 3.19–2.86 (m, 2H), 2.49 (tt, 1H, J = 23.1,
7.5 Hz), 1.31–1.17 (m, 12H). 13C NMR (126 MHz, CDCl3) δ
155.40, 150.82, 148.64, 142.08, 141.1, 137.7, 131.45, 130.98,
121.23, 120.85, 119.40, 119.19, 118.53, 118.24, 62.71 (m,
POCH2), 37.24 (t, J = 133.1 Hz, PCH), 20.46, 16.28 (m,
PCH2CH3). 31P NMR (243 MHz, CDCl3) δ 39.91, 39.66. IR
(KBr) 3140, 2987, 1614, 1593, 1577, 1506, 1475, 1400, 1290,
1255, 1203, 1157, 1026, 964, 845, 752, 532 cm−1. m/z (EI): 617
(M+, (Br81), 13), 615 (M+, (Br79), 13), 480 (100), 478 (100).
calcd for C24H32BrN3O7P2, 615.0899; found 615.0903.
White solid (60%). Mp 156–158 °C. 1H NMR (300 MHz,
CDCl3) δ 8.76 (br s, 1H), 8.21 (br s, 1H), 7.64 (s, 1H),
7.40–7.32 (m, 2H), 7.13 (s, 1H), 7.10 (d, 2H, J = 8.2 Hz), 6.87
(s, 1H), 4.18–3.80 (m, 8H), 3.13–2.92 (m, 2H), 2.68 (tt, 1H, J =
24.0, 7.1 Hz), 1.30 (td, 6H, J = 7.1, 4.4 Hz), 1.22 (td, 6H, J =
7.0, 4.4 Hz). 13C NMR (101 MHz, CDCl3) δ 155.31, 154.85,
147.52, 140.78, 138.49, 136.82, 131.27, 124.82, 121.14,
119.80–119.54 (m, PCHCH2C), 111.61, 109.06, 105.33,
63.09–62.88 (m, POCH2), 37.10 (t, J = 133.6 Hz, PCH), 20.67,
16.37–15.92 (m, POCH2CH3). 31P NMR (243 MHz, CDCl3) δ
39.69 (s), 39.54 (s). IR (KBr) 3219, 2989, 1621, 1603, 1514,
1423, 1392, 1261, 1225, 1166, 1024, 979, 850, 810, 531 cm−1
.
m/z (EI): 672 (M+, (Cl37), 4), 670 (M+, (Cl35), 12), 535 (33), 533
(100), 345 (16). calcd for C26H32ClF3N2O9P2, 670.1224; found
670.1217.
Tetraethyl 2-(5-(2-hydroxy-5-methylphenyl)-1-
(4-(trifluoromethoxy)phenyl)-1H-pyrazol-4-yl)ethane-
1,1-diyldiphosphonate (4t)
1
Tetraethyl 2-(5-(2-hydroxyphenyl)-1-(4-(trifluoromethyl)
phenyl)-1H-pyrazol-4-yl)ethene-1,1-diyldiphosphonate (3p)
White solid (87%). Mp 90–91 °C. H NMR (300 MHz, CDCl3)
δ 7.86 (s, 1H), 7.69 (s, 1H), 7.34 (d, 2H, J = 9.0 Hz), 7.10–7.08
(d, 3H, J = 3.8 Hz), 6.87 (d, 1H, J = 8.3 Hz), 6.76 (s, 1H),
4.22–3.91 (m, 8H), 3.28–2.79 (m, 2H), 2.71–2.44 (m, 1H), 2.21
(s, 3H), 1.27 (tt, 12H, J = 20.2, 7.1 Hz). 13C NMR (126 MHz,
CDCl3) δ 153.10, 147.55, 140.34, 138.61, 137.58, 131.95,
131.59, 130.07, 124.84, 121.06, 120.35 (q, J = 257.9 Hz,
OCF3), 119.78 (dd, J = 10.9, 7.0 Hz, PCHCH2C), 118.95,
118.12, 63.03–62.55 (m, POCH2), 37.27 (t, J = 133.1 Hz, PCH),
20.56 (t, J = 4.1 Hz, PCHCH2), 20.36, 16.44–16.09 (m,
POCH2CH3). 31P NMR (243 MHz, CDCl3) δ 40.07 (d, J =
4.3 Hz,), 39.92 (d, J = 4.1 Hz). IR (KBr) 3141, 2987, 1617,
1513, 1475, 1392, 1263, 1223, 1165, 1165, 1016, 968, 837, 796,
1
Yellow solid. Mp 91–92 °C. H NMR (300 MHz, DMSO-d6) δ
9.99 (s, 1H), 8.72 (s, 1H), 7.75 (d, 2H, J = 8.5 Hz), 7.53 (dd,
1H, J = 46.2, 29.1 Hz), 7.47 (d, 2H, J = 8.5 Hz,), 7.35 (t, 1H,
J = 7.8 Hz), 7.15 (d, 1H, J = 7.5 Hz,), 6.98–6.83 (m, 2H),
4.20–3.80 (m, 8H), 1.30–1.17 (m, 6H), 1.13 (t, 6H, J = 7.0 Hz).
IR (KBr) 3427, 2916, 1610, 1628, 1576, 1513, 1486, 1442,
1385, 1336, 1246, 1178, 935, 798, 756, 677 cm−1
.
(2-Hydroxyphenyl)(2-p-tolylpyrimidin-5-yl)methanone (3w)
1
+
522 cm−1. m/z (EI): 634 (M , 14), 497 (100), 345 (16). calcd
Yellow solid. Mp 154–156 °C. H NMR (300 MHz, CDCl3) δ
11.81 (s, 1H), 9.09 (s, 2H), 8.44 (d, 2H, J = 8.2 Hz), 7.59 (t, 2H,
J = 8.7 Hz), 7.35 (d, 2H, J = 8.3 Hz), 7.12 (d, 1H, J = 8.7 Hz),
6.96 (t, 1H, J = 7.6 Hz), 2.46 (s, 3H). 13C NMR (126 MHz,
CDCl3) δ 197.02 166.58, 163.26, 157.64, 142.61, 137.34,
133.77, 132.55, 129.65, 128.92, 128.55, 119.33, 118.95, 118.91,
21.65. IR (KBr) 3423, 3131, 2988, 1616, 1589, 1522, 1469,
1448, 1392, 1367, 1325, 1213, 1166, 1128, 1063, 1022, 962,
845, 757, 613, 532 cm−1. m/z (EI): 290 (M+, 100), 272 (32%).
calcd for C18H14N2O2, 290.1055; found 290.1054.
for C27H35F3N2O8P2, 634.1821; found 634.1827.
Tetraethyl 2-(5-(5-chloro-2-hydroxyphenyl)-1-
(4-(trifluoromethoxy)phenyl)-1H-pyrazol-4-yl)ethane-
1,1-diyldiphosphonate (4u)
White solid (84%). Mp 124–126 °C. 1H NMR (300 MHz,
CDCl3) δ 8.47 (br s, 1H), 7.69 (s, 1H), 7.37–7.27 (m, 2H), 7.25
(dd, 1H, J = 8.8 2.7 Hz), 7.10 (d, 2H, J = 8.2 Hz), 6.96 (d, 1H,
J = 2.6 Hz), 6.92 (d, 1H, J = 8.8 Hz), 4.08 (dtd, 8H, J = 14.2,
7.1, 2.1 Hz), 3.27–3.01 (m, 1H), 3.00–2.79 (m, 1H), 2.58 (tdd,
1H, J = 23.5, 9.2, 5.9 Hz), 1.40–1.18 (m, 12H). 13C NMR
(126 MHz, CDCl3) δ 154.46, 147.83, 140.37, 138.28, 136.21,
131.24, 130.94, 125.35, 125.07, 121.19, 120.63, 120.34 (q, J =
258.3 Hz, OCF3), 120.12 (dd, J = 11.0, 6.7 Hz, PCHCH2C),
Acknowledgements
This work was financially supported by the “Interdisciplinary
Cooperation Team” Program for Science and Technology Inno-
vation of the Chinese Academy of Sciences, the National
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 7730–7738 | 7737

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