Facile solid-phase synthesis of cycloalkylphosphonates and 1-cycloalkenylphosphonates using polymer-supported phenylsulfonylmethylphosphonates

Article abstract of DOI:10.1080/00397910600978515

A facile procedure for the solid-phase synthesis of cycloalkylphosphonates and 1-cycloalkenylphosphonates in good yields and high purities using polystyrene-supported phenylsulfonylmethylphosphonates with traceless sulfone linker strategy is described. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910600978515

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Facile Solid‐Phase Synthesis of
Cycloalkylphosphonates and
1‐Cycloalkenylphosphonates
Using Polymer‐Supported
Phenylsulfonylmethylphosphonates
Xiao‐Ling Liu a , Shou‐Ri Sheng a , Wei Zhou a , Qin‐Ying Wang a , Xiao‐Lan
Zhang a & Bin Gong a
a College of Chemistry and Chemical Engineering, Jiangxi Normal University,
Nanchang, China
Version of record first published: 25 Jul 2007.
To cite this article: Xiao‐Ling Liu , Shou‐Ri Sheng , Wei Zhou , Qin‐Ying Wang , Xiao‐Lan Zhang & Bin Gong
(2007): Facile Solid‐Phase Synthesis of Cycloalkylphosphonates and 1‐Cycloalkenylphosphonates Using
Polymer‐Supported Phenylsulfonylmethylphosphonates, Synthetic Communications: An International Journal
for Rapid Communication of Synthetic Organic Chemistry, 37:1, 119-127
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Synthetic Communicationsw, 37: 119–127, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910600978515
Facile Solid-Phase Synthesis of
Cycloalkylphosphonates and
1-Cycloalkenylphosphonates Using
Polymer-Supported
Phenylsulfonylmethylphosphonates
Xiao-Ling Liu, Shou-Ri Sheng, Wei Zhou, Qin-Ying Wang,
Xiao-Lan Zhang, and Bin Gong
College of Chemistry and Chemical Engineering, Jiangxi Normal
University, Nanchang, China
Abstract: A facile procedure for the solid-phase synthesis of cycloalkylphosphonates
and 1-cycloalkenylphosphonates in good yields and high purities using polystyrene-
supported phenylsulfonylmethylphosphonates with traceless sulfone linker strategy
is described.
Keywords: 1-cycloalkenylphosphonate, cycloalkylphosphonate, polymer-supported
phenylsulfonylmethylphosphonate, solid-phase organic synthesis
Fueled by a rapidly growing interest in combinatorial chemistry, solid-phase
organic synthesis (SPOS) is of current interest.[1] SPOS enjoys several
advantages over solution-phase synthesis, such as easy manipulation and puri-
fication of the organic products, greatly simplified through the use of polymer-
bound reagents. Phosphonate derivatives are important biologically active
compounds[2] and synthetic intermediates, which can he converted into a
variety of other organophosphorus compounds using well-established
protocols.[3] Solution-phase synthetic methods for cycloalkylphosphonates[4]
and 1-cycloalkenylphosphonates[5] are well documented; however, efforts
Received in R.O.C. March 18, 2006
Address correspondence to Shou-Ri Sheng, College of Chemistry and Chemical
Engineering, Jiangxi Normal University, Nanchang 330027, China. E-mail:
shengsr@jxnu.edu.cn
119

120
X.-L. Liu et al.
are continuing for the development of more efficient, simple methods. To our
knowledge, they have not been prepared via SPOS. Recently, several groups
have developed the traceless sulfone linker, which was shown to be a robust
and versatile tether that offers various resin functionalizations or cleavage
with additional changes.[6] In continuation of our interest in SOPS with
sulfone linker,[7] we herein report the extension of this sulfone-based
chemistry to a convenient, traceless, solid-phase synthesis of cycloalkylpho-
sphonates and 1-cycloalkenylphosphonates using polystyrene-supported
phenylsulfonylmethylphosphonate. The procedure for the synthesis of target
compounds from polystyrene/1% divinylbenzene sodium phenylsulfinate
(1) include (a) sulfinate S-alkylation, (b) the sulfonyl anion bis-alkylations
with dihaloalkanes, and (c) traceless product release by desulfonation
(Scheme 1).
The polystyrene-supported diethyl (phenylsulfonyl)methylphosphonate
2a (R ¼ Et) and diisopropyl (phenylsulfonyl)methylphosphonate 2b
(R ¼ i-Pr) were easily accessible, both in 95% yield, by the reaction of a
THF-swollen suspension of resin 1 with diethyl iodomethylphosphonate and
diisopropyl iodomethylphosphonate, respectively, at 808C for 12 h. The
FT-IR spectrum of resin 2a–2b with a loading of 0.86 and 0.84 mmol P/g
determined by elemental analysis exhibited characteristic absorptions near
1240 cm21 and 1150 cm21 due to a P55O double bond and the sulfone
groups, respectively. Moreover, resin 2 can be stored at room temperature
for a long time without diminution of capacity. With the resin 2 in hand,
the sulfonyl anion bis-alkylation with dihaloalkanes, the key step for the
Scheme 1. Reagents and conditions: (a) ICH2PO(OR)2, THF/DMF (2/1), 808C,
12 h; (b) (i) n-BuLi, 2788C, THF, 30 min; (ii) X (CH2)n X (3a–3e), THF, 2788C,
1 h, then rt, 10 h; (c) Mg/HgCl2, EtOH/THF, rt, 16 h; (d) Et3N, CH2Cl2, rt, 10 h.

Cycloalkylphosphonates
121
success of this protocol, was investigated. Apparently, previous solution-
phase studies[4f] with aqueous sodium hydroxide solution as a base and dode-
cyltrimethylammounium chloride as phase-transfer catalyst could not survey
this SPOS reaction. Here, we started optimization of solution-phase bis-alky-
lation reaction conditions by treatment of diethyl (phenylsulfonyl) methylpho-
sphonate 7 with v-dibromopentane 3c using different bases (Scheme 2,
Table 1). As shown in Table 1 (Entry 4), the bis-alkylation product 8 was
obtained in high yield (95%) when n-BuLi was used as base at 2788C for
1 h and then at room temperature for 10 h.
Subsequent solid-phase bis-alkylation of resin 2 with dihaloalkanes using
the similar solution-phase methodology generated the corresponding resin 4 in
good yields (94–96%). Because this transformation exhibited no reliably
diagnostic absorption peaks in the single-bead FTIR spectrum, the final
cleavage of 4 was carried out directly. The resin 4ac was further employed
as a model to investigate the cleavage conditions. When using the classical
one-electron reducing agent Na/Hg[8] in MeOH/DMF in the presence of
[9]
Na2HPO4 at room temperature for 18 h, SmI2 in MeOH/THF at 2788C
or 08C, 5ac was produced via concomitant linker cleavage in 60–70%
overall yield from starting resin 1. Furthermore, the residual resin still
exhibited a weak P55O absorption near 1240 cm21 in FT-IR, which
indicated the cleavage was not complete. To our delight, when magnesium
power with a catalytic amount of HgCl2 in EtOH/THF[10] was adopted at
room temperature for 16 h, 5ac was obtained in 90% yield with 95% purity.
The optimized synthetic strategy was applied to the preparation of 5aa–
5bd, and the results are summarized in Table 2. This protocol gave the
crude products in good yields (82–90%) with high purity (.92% by HPLC
analysis).
Finally, we switched to another cleavage strategy wherein the polymeric
sulfone 4 was treated with an excess of triethylamine[7] at room temperature
for 12 h to give the 1-cycloalkenylphosphonates 6 in good yields and
purities. Several typical examples are described in Table 3.
In summary, we have developed a novel method for the solid-phase
synthesis of cycloalkylphosphonates and 1-cycloalkenylphosphonates in
good yields and purities using a sulfone-linker strategy. This methodology
is applicable for combinatorial library preparation.
Scheme 2.

122
X.-L. Liu et al.
Table 1. Solution-phase bis-alkylation of 7 with v-dibromopentane
Entry
Basea
Temp./time
Yield of 8b (%)
1
2
3
4
5
6
7
8
LDA
LDA
2308C/1 h
2788C/1 h
68
70
80
95
90
78
85
80
LDA
2788C/1 h to rt/10 h
2788C/1 h to rt/10 h
2788C/1 h to rt/10 h
rt/10 h
08C/1 h to rt/10 h
08C/1 h to rt/10 h
n-BuLi
n-BuLi
n-BuLi
t-BuOK
NaH
aFour equiv of base and 8 equiv of v-dibromopentane.
bIsolated yield.
EXPERIMENTAL
Melting points were determined on an X4 melting-point apparatus and are
uncorrected. 1H NMR (400 MHz) spectra were recorded on a Bruker
Avance (400-MHz) spectrometer, using CDCl3 as the solvent and TMS as
internal standard. FT-IR spectra were taken on a Perkin–Elmer SP One FT-
IR spectrophotometer. Microanalyses were performed with a PE 2400
elemental analyzer. All final products are known, and their spectra (1H
NMR and IR) were compared with authentic samples. Polystyrene (100–
200 mesh, cross-linked with 1% divinylbenzene) sodium sulfinate was
purchased from Tianjin Nankai Hecheng Science and Technology Co.
Table 2. Yields and purities of cycloalkylphosphonates 5
Yielda Purityb
Entry
Dihaloalkane
R
Product
(%)
(%)
1
2
3
4
5
6
7
8
9
Br (CH2)3 Br (3a) Et
Cl (CH2)4 Cl (3b) Et
Br (CH2)5 Br (3c) Et
Br (CH2)6 Br (3d) Et
Br (CH2)7 Br (3e) Et
Br (CH2)3 Br (3a) i-Pr
Cl (CH2)4 Cl (3b) i-Pr
Br (CH2)5 Br (3c) i-Pr
Br (CH2)6 Br (3d) i-Pr
5aa
5ab
5ac
5ad
5ae
5ba
5bb
5bc
5bd
83
84
90
82
83
84
86
90
87
93
94
95
94
95
92
95
96
94
aOverall yield based on the loading of the resin 1.
bPurity determined by HPLC of crude cleavage product.

Cycloalkylphosphonates
Table 3. Yields and purities of 1-cycloalkenylphosphonates 6
123
Yielda
(%)
Purityb
(%)
Entry
Resin 4 (n)
R
Product
1
2
3
4
4aa (n ¼ 3)
4ab (n ¼ 4)
4ac (n ¼ 5)
4ad (n ¼ 6)
Et
Et
Et
Et
6aa
6ab
6ac
6ad
80
95
94
90
90
96
94
95
aOverall yield based on the loading of the resin 1.
bPurity determined by HPLC of crude cleavage product.
(catalog no. HC8201-1). All chemicals were obtained from commercial
suppliers and used without purification.
General Procedure for the Preparation of Polystyrene-Supported
Phenylmethylsulfone 2
Polystyrene/1% divinyl benzene sodium sulfinate 1 (1.0 g, 2.1 mmol) was
swollen under nitrogen in THF/DMF (2 : 1, 15 mL). Either diethyl iodo-
methylphosphonate (4.0 mmol) or diisopropyl iodomethylphosphonate
(4.0 mmol) was added, and the reaction mixture was stirred at 808C for
12 h, after which the reaction mixture was cooled to room temperature,
quenched with water, and filtered. The resin was washed successively with
THF/H2O (2 : 1, 3 ꢀ 10 mL), THF (2 ꢀ 5 mL), CH2Cl2 (2 ꢀ 5 mL), and
ether (2 ꢀ 5 mL) and then dried under vacuum overnight to afford the pale
yellow resin 2. 2a: FT-IR (single bead reflection) 1600, 1495, 1452, 1313,
1240, 1150, 1025 cm21, Anal. P, 2.67% (0.86 m equiv/g); 2b: FT-IR
(single bead reflection) 1600, 1498, 1450, 1315, 1242, 1151, 1026 cm21
,
anal. P, 2.60% (0.84 mequiv/g).
General Procedure for the Preparation of Cycloalkylphosphonates
(5aa–5bd)
A suspension of polymer 2 (1.0 mmol) in THF (8 mL) at 2788C was treated with
a solution of n-BuLi in hexane (1.6 M, 2.5 mL, 4.0 mmol) under nitrogen. After
stirring for 30 min, a solution of dihaloalkane (8.0 mmol) in THF (5.0 mL) was
added dropwise. The mixture was stirred for another 1 h at 2788C and then at
room temperature for 10 h. The reaction was quenched with 10% HCl (aq.)
after 10 min, and the resin was filtered, washed successively with H2O
(3 ꢀ 10 mL), THF (3 ꢀ 5 mL), and CH2Cl2 (3 ꢀ 5 mL), and dried in a
vacuum to afford resin 4 as pale yellow beads. Subsequently the resin 4 was
swollen in THF (8 mL) and treated with Mg (0.24 g, 10 mmol, powder, 50
mesh) and a catalytic amount of HgCl2 in EtOH–THF (3 : 1, 12 mL) under

124
X.-L. Liu et al.
nitrogen. The mixture was stirred at room temperature for 16 h. Then the reaction
mixture was added with cold 0.5 N HCl solution and stirred for 10 min. The
residual resin was collected by filtration and washed with Et2O (3 ꢀ 10 mL).
The organic extracts were washed with saturated aqueous NaHCO3 solution,
dried over anhydrous MgSO4, and concentrated to afford crude product 5aa–
5bd with 92–96% purity as determined by HPLC, which was further purified
by flash-column chromatography using petroleum ether–ethyl acetate (1: 1) as
an eluent, affording the pure products for their structure analysis, if necessary.
Data
O,O-Diethyl cyclobutylphosphonate (5aa): Colorless oil (lit.[4d] oil); 1H
NMR: d ¼ 4.06–4.02 (m, 4H), 2.71–2.68 (m, 1H) 2.50–1.96 (m, 6H), 1.31
(t, J ¼ 7.1 Hz, 6H); IR (film): 2930, 1385, 1240, 1160, 1040 cm21. Anal.
calcd. for C8H17O3P: C, 50.00; H, 8.92. Found: C, 49.96; H, 8.99.
O,O-Diethyl cyclopentylphosphonate (5ab): Colorless oil (lit.[4d] oil); 1H
NMR: d ¼ 4.12–4.08 (m, 4H), 2.19–1.46 (m, 9H), 1.31 (t, J ¼ 7.1 Hz,
6H); IR (film): 2928, 1384, 1238, 1155, 1040 cm21. Anal. calcd. for
C9H19O3P: C, 52.42; H, 9.29. Found: C, 52.45; H, 9.36.
O,O-Diethyl cyclohexylphosphonate (5ac): Colorless oil (lit.[4d] oil); 1H
NMR: d ¼ 4.07–4.02 (m, 4H), 2.12–1.43 (m, 11H), 1.30 (t, J ¼ 7.0 Hz,
6H); IR (film): 2931, 1385, 1235, 1158, 1036 cm21. Anal. calcd. for
C10H21O3P: C, 54.53; H, 9.61. Found: C, 54.60; H, 9.72.
O,O-Diethyl cycloheptylphosphonate (5ad): Colorless oil (lit.[4d] oil); 1H
NMR: d ¼ 4.02–3.98 (m, 4H), 2.18–1.33 (m, 13H), 1.29 (t, J ¼ 7.0 Hz,
6H); IR (film): 2933, 1385, 1241, 1162, 1042 cm21. Anal. calcd. for
C11H23O3P: C, 56.40; H, 9.90. Found: C, 56.47; H, 9.97.
O,O-Diethyl cyclooctylphosphonate (5ae): Colorless oil; 1H NMR: d ¼ 4.13–
3.05 (m, 4H), 1.98–1.54 (m, 15H), 1.31 (t, J ¼ 6.8 Hz, 6H); IR (film): 2932,
1386, 1239, 1162, 1045 cm21. Anal. calcd. for C12H25O3P: C, 58.05; H,
10.15. Found: C, 58.12; H, 10.26; EIMS: m/z: 248 (Mþ).
1
O,O-Diisopropyl cyclobutylphosphonate (5ba): Colorless oil (lit.[4d] oil); H
NMR: d ¼ 4.70–4.62 (m, 2H), 2.60–2.48 (m, 1H), 2.37–1.91 (m, 6H), 1.21
(d, J ¼ 6.1 Hz, 12H); IR (film): 2927, 1383, 1375, 1237, 1160, 1046, 988
cm21. Anal. calcd. for C10H21O3P: C, 54.53; H, 9.61. Found: C, 54.61; H, 9.73.
O,O-Diisopropyl cyclopentylphosphonate (5bb): Colorless oil (lit.[4d] oil); 1H
NMR: d ¼ 4.45–4.38 (m, 2H), 1.24–1.20 (m, 9H), 1.21 (d, J ¼ 6.0 Hz, 12H);
IR (film): 2930, 1385, 1376, 1240, 1164, 1050, 985 cm21. Anal. calcd. for
C11H23O3P: C, 56.40; H, 9.90. Found: C, 56.49; H, 9.99.

Cycloalkylphosphonates
125
1
O,O-Diisopropyl cyclohexylphosphonate (5bc): Colorless oil (lit.[4d] oil); H
NMR: d ¼ 4.66–4.61 (m, 2H), 1.27–1.22 (m, 11H), 1.25 (d, J ¼ 6.1 Hz,
12H); IR (film): 2935, 1385, 1375, 1238, 1162, 1045, 986 cm21. Anal.
calcd. for C12H25O3P: C, 58.05; H, 10.15. Found: C, 58.15; H, 10.24.
O,O-Diisopropyl cycloheptylphosphonate (5bd): Colorless oil (lit.[4d] oil); 1H
NMR: d ¼ 4.60–4.52 (m, 2H), 1.35–2.01 (m, 13H), 1.23 (d, J ¼ 6.0 Hz,
12H); IR (film): 2934, 1383, 1374, 1240, 1160, 1044, 990 cm21. Anal.
calcd. for C13H27O3P: C, 59.54; H, 10.38. Found: C, 59.62; H, 10.46.
General Procedure for the Preparation of
1-Cycloalkenylphosphonates (6aa–6bd)
The resin 4 was swollen in CH2Cl2 (10 mL) and treated with triethylamine
(5.0 mmol) at room temperature for 12 h. The residual resin was collected by
filtration and washed with CH2Cl2 (2 ꢀ 3 mL). The organic extracts were
washed with water, dried over anhydrous MgSO4, and concentrated to afford
crude product 6 with 90–96% purity determined by HPLC, which was further
purified by silica-gel chromatographic column (hexane–ethyl acetate ¼ 1 : 1),
affording the pure products for their structure analysis, if necessary.
Data
1
O,O-Diethyl cyclobutenylphosphonate (6aa): Colorless oil (lit.[5a] oil); H
NMR: d ¼ 6.72 (ddt, J ¼ 21.6, 17.0, 6.6, 1H), 4.06–4.02 (m, 4H), 2.19–
2.23 (m, 2H), 1.87–1.96 (m, 2H), 1.31 (t, J ¼ 7.1 Hz, 6H); IR (film): 2895,
1620, 1386, 1241, 1160, 1053, 1027 cm21; anal. calcd. for C8H15O3P: C,
50.53; H, 7.95. Found: C, 50.62; H, 8.03.
1
O,O-Diethyl cyclopentenylphosphonate (6ab): Colorless oil (lit.[5a] oil); H
NMR: d ¼ 6.75 (ddt, J ¼ 22, 17.1, 6.7, 1H), 4.10–4.06 (m, 4H), 2.18–2.22
(m, 2H), 1.87–1.95 (m, 2H), 1.25–1.40 (m, 2H), 1.31 (t, J ¼ 7.1 Hz, 6H);
IR (film): 2892, 1618, 1385, 1239, 1160, 1053, 1027, 821 cm21. Anal.
calcd. for C9H17O3P: C, 52.94; H, 8.39. Found: C, 52.99, H, 8.48.
1
O,O-Diethyl cyclohexenylphosphonate (6ac): Colorless oil (lit.[5b] oil); H
NMR: d ¼ 6.74 (ddt, J ¼ 21.8, 17.2, 6.7, 1H), 4.12–4.07 (m, 4H), 2.19–
2.22 (m, 2H), 1.83–1.93 (m, 2H), 1.22–1.41 (m, 4H), 1.30 (t, J ¼ 7.1 Hz,
6H); IR (film): 2893, 1621, 1387, 1240, 1159, 1052, 1028 cm21. Anal.
calcd. for C10H19O3P: C, 55.04; H, 8.78. Found: C, 55.15; H, 8.86.
1
O,O-Diethyl cycloheptenylphosphonate (6ad): Colorless oil (lit.[5a] oil); H
NMR: d ¼ 6.72 (ddt, J ¼ 21.9, 17.0, 6.6, 1H), 4.11–4.08 (m, 4H), 2.17–

126
X.-L. Liu et al.
2.20 (m, 2H), 1.82–1.91 (m, 2H), 1.20–1.39 (m, 6H), 1.30 (t, J ¼ 7.1 Hz, 6H);
IR (film): 2895, 1619, 1388, 1241, 1160, 1054, 1025 cm21. Anal. calcd. for
C11H21O3P: C, 56.88; H, 9.11. Found: C, 56.98; H, 9.23.
ACKNOWLEDGMENT
We gratefully acknowledge financial support from the National Natural
Science Foundation of China (No. 20562005) and Natural Science Foundation
of Jiangxi Province.
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