Synthesis and application of N-tosyl piperidinyl-containing α-aminophosphonates

Article abstract of DOI:10.1080/10426507.2012.729236

A series of novel (4′-tosyl) piperidin-4-yl containing α-aminophosphonates were synthesized by a one-pot reaction, efficiently catalyzed by magnesium perchlorate, under solvent-free conditions from 1-tosylpiperidin-4-one, substituted aromatic amines, and diethyl phosphite (DEP). The synthesized compounds were characterized by IR, ¹H NMR, ¹³C NMR, ³¹P NMR, and HRMS spectroscopy. A single-crystal X-ray structure of diethyl 4-(2-chlorophenyl) amino-1-(4-methylbezenesulfonyl) piperidin-4-yl-phosphonate (2a) was obtained, and some of the title compounds displayed insecticidal activities against Plutella xylostella. Supplementary materials are available for this article. Go to the publisher's online edition of Phosphorus, Sulfer, and Silicon and the Related Elements for the following free supplemental files: Additional figures and tables.

Full text of DOI:10.1080/10426507.2012.729236

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Synthesis and Application of N-
Tosyl Piperidinyl-Containing α-
Aminophosphonates
Zhifu Jiang a , Jian Zhao a , Beibei Gao a , Shuo Chen a , Wenyan Qu a
, Xiangdong Mei a , Changhui Rui a , Jun Ning a & Dongmei She a
a Key Laboratory of Pesticide Chemistry and Application, MOA,
Institute of Plant Protection, Chinese Academy of Agricultural
Sciences , Beijing , China
Accepted author version posted online: 05 Oct 2012.
To cite this article: Zhifu Jiang , Jian Zhao , Beibei Gao , Shuo Chen , Wenyan Qu , Xiangdong Mei ,
Changhui Rui , Jun Ning & Dongmei She (2013) Synthesis and Application of N-Tosyl Piperidinyl-
Containing α-Aminophosphonates, Phosphorus, Sulfur, and Silicon and the Related Elements, 188:8,
1026-1037, DOI: 10.1080/10426507.2012.729236
To link to this article: http://dx.doi.org/10.1080/10426507.2012.729236
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Phosphorus, Sulfur, and Silicon, 188:1026–1037, 2013
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426507.2012.729236
SYNTHESIS AND APPLICATION OF N-TOSYL
PIPERIDINYL-CONTAINING α-AMINOPHOSPHONATES
Zhifu Jiang, Jian Zhao, Beibei Gao, Shuo Chen, Wenyan Qu,
Xiangdong Mei, Changhui Rui, Jun Ning, and Dongmei She
Key Laboratory of Pesticide Chemistry and Application, MOA, Institute of Plant
Protection, Chinese Academy of Agricultural Sciences, Beijing, China
GRAPHICAL ABSTRACT
Abstract A series of novel (4ꢁ-tosyl) piperidin-4-yl containing α-aminophosphonates were syn-
thesized by a one-pot reaction, efficiently catalyzed by magnesium perchlorate, under solvent-
free conditions from 1-tosylpiperidin-4-one, substituted aromatic amines, and diethyl phosphite
(DEP). The synthesized compounds were characterized by IR, 1H NMR, 13C NMR, 31P NMR,
and HRMS spectroscopy. A single-crystal X-ray structure of diethyl 4-(2-chlorophenyl) amino-
1-(4’-methylbezenesulfonyl) piperidin-4-yl-phosphonate (2a) was obtained, and some of the
title compounds displayed insecticidal activities against Plutella xylostella.
Supplementary materials are available for this article. Go to the publisher’s online edition of
Phosphorus, Sulfer, and Silicon and the Related Elements for the following free supplemental
files: Additional figures and tables.
Keywords Tosyl; piperidine; magnesium perchlorate; α-aminophosphonates; synthesis; crystal
structure
INTRODUCTION
Due totheir diverseandinterestingbiological and biochemical properties, aminophos-
phonates are of considerable current interest. This class of compounds is mainly applied
as plant growth regulators, herbicides, fungicidal, antiplant virus, enzyme inhibitors, and
anticancer agents.1 Such an impressive array of applications has recently stimulated a
growing amount of research on the synthesis of α-aminophosphonates and rendered the
Received 12 July 2012; accepted 9 September 2012.
The authors thank Prof. Liang Xiao-Mei for NMR measurements and Prof. Zhang Wen-Xiong for X-ray
diffraction analysis. Financial support by the “Eleventh Five-Year Plan” technology support project of China
(No. 2009BAK61B04) and Gong Yi Hang Ye Zhuan Xiang (Nong Ye) 200903054, is gratefully acknowledged.
Address correspondence to Dongmei She, Key Laboratory of Pesticide Chemistry and Application, MOA,
Institute of Plant Protection, Chinese Academy of Agricultural Sciences, Yuanmingyuan West Road 2, Beijing
100193, China. E-mail: dmshe2000@yahoo.com.cn
1026

N-TOSYL PIPERIDINYL-CONTAINING α-AMINOPHOSPHONATES
1027
α-aminophosphonate moiety the status of a novel pharmacophore in the context of drug
design.1,2
The N-substitutent piperidine moiety is a key ingredient, as it appears in the structure
of many alkaloid natural products and drugs.3 In addition, cyclic or heterocyclic rings
introduced into the molecular skeleton increase their rigidity and modify electronic effects.4
Therefore, many cyclic α-amino-phosphonates or -phosphonic acids have been prepared,
such as derivatives of α-amino(4-piperidine)phosphonic acid, as well as their 4-pyran,
4-thiopyran, 3-piperidine,4 and cycloalkyl analogues.5 However, very few examples of
N-substitutent piperidine α-aminophosphonic acids or the corresponding phosphonates
have been reported in the literature; only N-Me, -Boc, -allyl, -Bn, and -Cbz piperidine
α-aminophosphonates are described.4,6 In the synthetic approach to the N-Boc example,
the Kabachnick-Fields reaction was used from N-Boc piperidone, benzylamine and diethyl
phosphite (DEP), to provide α-aminophosphonate with 99% yield, but the metal tetra(tert-
butyl)phthalocyanine complex tPcAlCl as catalyst is not easily accessible.
N-tosyl piperidinyl-containing heterocycles are subunits of many biologically active
pharmaceuticals and reported to exhibit a wide range of bioactivities, including nervous
system agents, cardiovascular agents, antitumor, anti-infective, and anti-inflammatory ac-
tivities.7
Magnesium perchlorate has been shown to be very active in promoting a variety of
reactions.8 In 2007, it was reported as an extremely efficient catalyst for the formation of α-
aminophosphonate by a one-pot, three-component reaction under solvent-free conditions.9
In this paper, magnesium perchlorate is explored as catalyst and the reaction involving
1-tosylpiperidine-4-one, aromatic amines with an electron-donating or –withdrawing sub-
stituent, and DEP are carried out under solvent-free conditions. Thus, compounds 1–6 were
synthesized and a single crystal structure of compound 2a was obtained. All the novel
compounds were analyzed by IR, 1H NMR, 13C NMR, 31P NMR, and HRMS spectroscopy.
Preliminary tests showed that some of these compounds, to some extent, have insecticidal
activities against Plutella xylostella. The synthetic route of novel compounds is shown in
Scheme 1.
Scheme 1
RESULTS AND DISCUSSION
To determine the best operative experimental conditions, the reaction of 1-
tosylpiperidine-4-one (A), 4-nitroaniline (B) as an electron-deficient amine, DEP was
considered as the model (Table 1). The best reaction conditions required the use of a
◦
5% mol Mg(ClO4)2 and a 2 equivalent of DEP at 80 C to obtain a good conversion
in the desired product without any traces of byproducts. For the same substituent, the
yield is not obviously dependent on the position on the benzene ring of the aromatic

1028
Z. JIANG ET AL.
Table 1 Reaction of A, B, and DEP under various conditionsa
Entry
Catalyst
Solvent
T(◦C)
Time(h)
Yieldb,c (%)
1
2
3
4
neat
neat
neat
neat
rt
80
rt
4
2
4
2
nild
nild
nild
77
Mg(ClO4)2
Mg(ClO4)2
80
aA (2.5 mmol) was treated with B (2.5 mmol) and DEP (5.0 mmol) in the presence of the catalyst (5 mol%)
(except for entries 1 and 2) under solvent-free conditions. bYield of the isolated and purified 6c. cThe product was
characterized by the IR, 1H, 13C and 31P NMR, and HRMS. dThe unreacted starting materials remained unchanged
(TLC) and A was still solid (except for entry 2).
amine. But it is affected by the electronic effect of the substituent, and the presence of an
electron-withdrawing substituent decreases nucleophilicity, then leading to lower reactivity
and yield (Supplemental Materials). We tried to extend the procedure to 2,4-dinitroaniline
(pKa = −4.30), but unfortunately the corresponding aminophosphonate was not obtained.
The IR spectra of 1–6 contained absorption bands at 3400–3250 cm−1 assigned to the
N–H group, at 1240–1220 cm−1 corresponding to the P O group and at 1170–1160 cm−1
attributed to the S O group.
The structural parameters of compound 2a are presented in Table 2. The molecular
structure of the title compound 2a is shown in Figure 1. The conformation with the N-tosyl
group being equatorial dominates. Selected bond lengths (Å) and torsional angles (◦) are
Table 2 Crystal structure and data refinement parameters for 2a
Compound
2a
Empirical formula
C22H30ClN2O5PS
Formula weight
Crystal system/Space group
500.96
Monoclinic/P2(1)/n
14.011(3)
a / Å
b / Å
c / Å
α / ◦
β / ◦
γ / ◦
V / Å3
Z
11.191(2)
17.736(4)
90
111.07(3)
90
2595.2(9)
4
Dcalc (g cm−3
μ (mm−1
)
1.282 × 10−9
)
0.323
Crystal size (mm)
Color/Shape
0.40 × 0.40 × 0.20
Colorless
Temp (K)
293(2)
Theta range for collection
Reflections collected
Independent reflections
Data/restraints/parameters
Goodness of fit on F2
Final R indices [I > 2σ(I)]
R indices (all data)
2.20◦ to 27.24◦
5709
5709 [R(int) = 0.0502]
5709/0/293
1.024
R1 = 0.0637, wR2 = 0.1701
R1 = 0.0922, wR2 = 0.1886
0.685 and –0.514 e. Å−3
Largest difference peak/hole

N-TOSYL PIPERIDINYL-CONTAINING α-AMINOPHOSPHONATES
1029
Figure 1 X-ray diffraction analysis of compound 2a.
P1–C3 1.875(3), C1–N1 1.498(3), C5–N1 1.487(3), N1–S1 1.669(2), and C1 C2 C3 P1
–174.94(18), C2 C1 N1 S1 164.28(17), while in a similar structure in the literature these
are P–C3 1.816(2), N–C1 1.436(3), N–C5 1.455(3), N–S 1.621(2), P C3 C4 C5 –95.0, and
S N C5 C4 148.5.10
1
The H NMR spectra of 1–6 show signals for chemically nonequivalent piperidine
ring. The signals for the methylene protons at C2 and C6 position appear at δ 2.64–2.72
(m) and 3.61 (br d); the complex multiplets for the methylene protons at C3 and C5
position appear at δ 2.15–2.22. A broad singlet at δ 2.50–4.00 corresponds to the amino
group.
The 13C NMR spectra of 1–6 show signals at δ 29–31 (2JPC = 1–3 Hz), 40–42 (3JPC
= 10–13 Hz), 54–56 (1JPC = 155–175 Hz) for the piperidine ring at C3 or C5, C2 or C6,
and C4, respectively. Signals for the nonisochronous ethoxy groups appear as two doublets
at δ 16 (3JPC = 5–6 Hz, CH3) and doublets at δ 62–63 (2JPC = 7–8 Hz, OCH2). The other
1
signals in the H and 13C NMR spectra of α-aminophosphonates are consistent with the
carbon framework structures of the starting ketones. The 31P NMR spectra of 1–6 exhibit
signals at 23.75–28.27 relating to the diethyl phosphonate group.
As indicated in Supplemental Materials, some of the title compounds displayed
insecticidal activities against Plutella xylostella. But the activities of these compounds
were much lower than Fipronil. Thus, different substituents in each series did not have
great impact on the activity. The main reason was probably due to the weak interaction
with three binding subsites in the GABA receptor: a hydrophobic site, a hydrogen binding
site, and a pi bonding site.11

1030
Z. JIANG ET AL.
CONCLUSIONS
In conclusion, a novel series of N-tosyl piperidine-containing α-aminophosphonates
were synthesized in high yields by solvent-free Kabachnik-Fields reaction catalyzed by
magnesium perchlorate. The catalyst is commercially available, and the reaction conditions
are mild. The insecticidal activities against Plutella xylostella were evaluated. The results
indicated some of the compounds showed certain levels of insecticidal activity.
EXPERIMENTAL
Infrared spectra (νmax, cm−1) were recorded in potassium bromide disks on a Thermo
1
Nicolet 6700 FTIR spectrophotometer; the H NMR, 13C, and 31P NMR spectra were
recorded on a Bruker DPX 300 MHz NMR spectrometer; chemical shifts values are given
in ppm relative to TMS in CDCl3; chemical shifts of 31P NMR (121.5 MHz) were referenced
to 85% H3PO4; HRMS was performed on a Bruker Apex IV FTMS; melting points were
measured on a Yu Hua X-4 microscopic melting point apparatus which was uncorrected.
All reagents were commercial products of analytical grade and were used directly without
additional purification.
Procedure for the Synthesis of 1-tosylpiperidin-4-one
To a slurry of K2CO3 (8.9 g, 64 mmol) and 4-piperidone monohydrate hydrochloride
(3.8 g, 25 mmol) in H2O (30 mL)/CHCl3 (30 mL), was added 4-tolylsulfonyl chloride
(7.4 g, 39 mmol). The reaction mixture was then stirred at room temperature for 10 h, and
quenched by the addition of saturated aqueous NaHCO3. The aqueous layer was separated
and extracted with CH2Cl2 (3 × Vol). The combined CH2Cl2 extracts were dried (Na2SO4)
and concentrated under reduced pressure. Chromatography (Petroleum ether/EtOAc:2/3)
or recrystallization (Petroleum ether/EtOAc:15/1) afforded 1-tosylpiperidin-4-one (6.0 g,
95%) as a white solid.12
Procedure for the Synthesis of N-Tosyl Piperidinyl-Containing
α-Amino-phosphonates
A mixture of 1-tosylpiperidin-4-one (1.27 g, 5 mmol), Mg(ClO4)2 (56 mg, 5 mol%),
◦
aniline (0.46 g, 5 mmol), and DEP (1.40 g, 10 mmol) was stirred at 80 C for 2 h. The
reaction mixture was dissolved in EtOAc and dried over anhydrous Na2SO4. The solvent
was removed under reduced pressure. The residue was washed with ethyl ether and then
purified by a column of silica gel (Petroleum ether/EtOAc:3/2) to give the title compound 1.
X-Ray Crystallographic Studies of 2a
A single crystal of 2a was obtained as colorless crystals from a petroleum ether and
◦
EtOAc (1:15, v/v). Data collection was performed at 20 C on a Rigaku RAXIS RAPID
IP diffractometer, using graphite-monochromated Mo Kα radiation (λ = 0.71073 Å). The
determination of crystal class and unit cell parameters was carried out by the Rapid-
AUTO (Rigaku 2000) program package. The raw frame data were processed using crystal
structure (Rigaku/MSC 2000) to yield the reflection data file. The structure was solved by
use of SHELXTL program. Refinement was performed on F2 anisotropically for all the

N-TOSYL PIPERIDINYL-CONTAINING α-AMINOPHOSPHONATES
1031
nonhydrogen atoms by the full-matrix least-squares method. The hydrogen atoms were
placed at the calculated positions and were included in the structure calculation without
further refinement of the parameters. CCDC 857571 (2a) contains the supplementary
crystallographic data for this paper. These data can be obtained free of charge via www.
ccdc.cam.ac.uk/retrieving.html (or from the Cambridge Crystallographic Data Centre, 12,
Union Road, Cambridge, B2 1EZ, UK; fax +44 1223 336033; or deposit@ccdc.cam.ac.uk).
Chemical Data
Diethyl 4-phenylamino-1-(4ꢁ-methylbezenesulfonyl) piperidin-4-yl-phosphonate (1):
1.94 g (83%), a pale yellow solid: mp 159◦C–160◦C. Rf = 0.30 (Petroleum ether/EtOAc:2/3)
IR (KBr) ν: 3338, 2980, 2853, 1600, 1498, 1341, 1224 (P O), 1170 (S O), 1067, 1045,
1
1027 (P O), 972, 934, 727 (C S), 596, 549 cm−1. H NMR (CDCl3, 300 MHz) δ:
1.17 (t, J = 7.1 Hz, 6H, CH3 CH2O), 2.15–2.21 (m, 4Hcyclc), 2.43 (s, 3H, CH3 C6H4),
2.64–2.72 (m, 2Hcyclc, 1H C2 and 1H C6), 3.15 (br s, 1H, NH), 3.61 (br d, J = 11.2 Hz,
2Hcyclc, 1H C2 and 1H C6), 3.84–4.04 (m, 4H, CH2OP), 6.81–6.86 (m, 3H, C6H5 NH),
ꢁ
ꢁ
7.08–7.13 (m, 2H, C6H5 NH), 7.27–7.31 (m, 2H, 1H C3 and 1H C5 ), 7.59–7.62 (m,
2H, 1H C2 and 1H C6 ). 13C NMR (CDCl3, 75.5 MHz) δ: 16.3 (d, JPC = 5.6 Hz,
3
ꢁ
ꢁ
2
3
CH3 CH2O), 21.4 (CH3 C6H4), 30.0 (d, JPC = 2.2 Hz, C3 or C5), 40.5 (d, JPC
=
1
2
11.4 Hz, C2 or C6), 54.8 (d, JPC = 161.6 Hz, C4), 62.2 (d, JPC = 7.8 Hz, CH2OP),
[12 arom C: 119.8 (d, J = 1.1 Hz, 2C), 120.7 (1C), 127.5 (2C), 128.7 (2C, C6H5 NH),
129.6 (2C), 133.0 (1C), 143.5 (1C, tosyl), 144.9 (1C)]. 31P NMR (CH3OH, 121.5 MHz) δ:
27.95. HRMS (ESI, m/z): calcd mass for C22H31N2NaO5PS, [M+Na]+: 489.15835. Found:
489.15881.
Diethyl 4-(2-chlorophenyl) amino-1-(4ꢁ-methylbezenesulfonyl) piperidin-4-yl-phos-
phonate (2a): 1.85 g (74%), a white solid: mp 124◦C–125◦C. Rf = 0.60 (Petroleum
ether/EtOAc:1/4) IR (KBr) ν: 3367, 2980, 1595, 1470, 1344, 1327, 1227 (P O), 1170
(S O), 1066, 1040, 1025 (P-O), 965, 922, 727 (C S), 650 (C Cl), 597, 550 cm−1. H
1
NMR (CDCl3, 300 MHz) δ: 1.29 (t, J = 7.0 Hz, 6H, CH3 CH2O), 2.19–2.40 (m, 6Hcyclc
,
4Hcyclc and 1H C2 and 1H C6), 2.44 (s, 3H, CH3 C6H4), 3.56 (br d, J = 11.7 Hz,
2Hcyclc, 1H C2 and 1H C6), 3.69 (br d, J = 7.9 Hz, 1H, NH), 4.04–4.17 (m, 4H, CH2OP),
ꢁ
6.68–6.74 (m, 1H, C6H4 NH), 7.07–7.12 (m, 2H, C6H4 NH), 7.27–7.31 (m, 2H, 1H C3
and 1H C5 ), 7.54–7.57 (m, 2H, 1H C2 and 1H C6 ), 7.66–7.69 (m, 1H, C6H4 NH). 13
C
ꢁ
ꢁ
ꢁ
3
NMR (CDCl3, 75.5 MHz) δ: 16.4 (d, JPC = 5.4 Hz, CH3 CH2O), 21.4 (CH3 C6H4),
2
3
1
29.0 (d, JPC = 1.7 Hz, C3 or C5), 40.2 (d, JPC = 11.7 Hz, C2 or C6), 54.2 (d, JPC
=
172.1 Hz, C4), 62.8 (d, 2JPC = 7.6 Hz, CH2OP), [12 arom C: 119.2 (d, J = 1.7 Hz, 1C),
120.1 (1C), 122.2 (d, J = 2.0 Hz, 1C), 127.4 (1C, C6H5 NH), 127.6 (2C), 128.8 (1C,
C6H5 NH), 129.5 (2C), 132.2 (1C), 139.8 (1C), 143.5 (1C, tosyl)]. 31P NMR (CHCl3,
121.5 MHz) δ: 24.94. HRMS (ESI, m/z): calcd mass for C22H30ClN2NaO5PS, [M+Na]+:
523.11938. Found: 523.11989.
Diethyl 4-(3-chlorophenyl) amino-1-(4ꢁ-methylbezenesulfonyl) piperidin-4-yl-phos-
phonate (2b): 2.00 g (80%), a white solid: mp 171◦C–172◦C. Rf = 0.50 (Petroleum
ether/EtOAc:1/4) IR (KBr) ν: 3299, 2983, 1595, 1483, 1351, 1327, 1223 (P O), 1168
1
(S O), 1066, 1041, 1019 (P-O), 967, 935, 720 (C S), 649 (C Cl), 600, 549 cm−1. H
NMR (CDCl3, 300 MHz) δ: 1.22 (t, J = 7.0 Hz, 6H, CH3 CH2O), 2.18 (br d, J = 4.2 Hz,
4Hcyclc), 2.43 (s, 3H, CH3 C6H4), 2.52–2.60 (m, 2Hcyclc, 1H C2 and 1H C6), 2.82–3.39
(br, 1H, NH), 3.59 (br d, J = 11.6 Hz, 2Hcyclc, 1H C2 and 1H C6), 3.92–4.10 (m, 4H,
CH2OP), 6.76–6.78 (m, 3H, C6H4 NH), 7.01 (t, J = 8.3 Hz, 1H, C6H4 NH), 7.28–7.32

1032
Z. JIANG ET AL.
(m, 2H, 1H C3 and 1H C5 ), 7.60 (d, J = 8.2 Hz, 2H, 1H C2 and 1H C6 ). 13C NMR
(CDCl3, 75.5 MHz) δ: 16.3 (d, 3JPC = 5.6 Hz, CH3 CH2O), 21.5 (CH3 C6H4), 29.7 (d,
2JPC = 2.1 Hz, C3 or C5), 40.3 (d, 3JPC = 11.3 Hz, C2 or C6), 54.5 (d, 1JPC = 164.1 Hz,
ꢁ
ꢁ
ꢁ
ꢁ
2
C4), 62.5 (d, JPC = 7.9 Hz, CH2OP), [12 arom C: 117.2 (d, J = 1.3 Hz, 2C), 118.8
(d, J = 1.7 Hz, 1C), 120.2 (1C), 127.6 (2C), 129.7 (d, J = 5.7 Hz,2C), 132.8 (1C, tosyl),
134.3 (1C), 143.7 (1C, tosyl), 146.1 (1C)]. 31P NMR (CHCl3, 121.5 MHz) δ: 26.95. HRMS
(ESI, m/z): calcd mass for C22H30ClN2NaO5PS, [M+Na]+: 523.11938. Found: 523.11986.
Diethyl 4-(4-chlorophenyl) amino-1-(4ꢁ-methylbezenesulfonyl) piperidin-4-yl-phos-
phonate (2c): 1.99 g (80%), a white solid: mp 157◦C–159◦C. Rf = 0.50 (Petroleum
ether/EtOAc:1/4) IR (KBr) ν: 3302, 2983, 1597, 1492, 1346, 1327, 1229 (P O), 1170
(S O), 1065, 1043, 1019 (P O), 970, 917, 820, 727 (C S), 650 (C Cl), 602, 551 cm−1
.
1H NMR (CDCl3, 300 MHz) δ: 1.20 (t, J = 7.1 Hz, 6H, CH3 CH2O), 2.16 (br t, J =
3.7 Hz, 4Hcyclc), 2.43 (s, 3H, CH3 C6H4), 2.58–2.62 (m, 2Hcyclc, 1H C2 and 1H C6),
3.60 (br d, J = 11.3 Hz, 2Hcyclc, 1H C2 and 1H C6), 3.89–4.05 (m, 4H, CH2OP), 4.2–4.9
ꢁ
ꢁ
(br, 1H, NH), 6.77 (dd, J1 = 2.1 Hz, J2 = 4.6 Hz, 1H C2 and 1H C6 ), 7.04 (dd, J1 =
ꢁ
ꢁ
ꢁ
ꢁ
2.2 Hz, J2 = 4.5 Hz, 1H C3 and 1H C5 ), 7.28–7.32 (m, 2H, 1H C3 and 1H C5 ), 7.60
(dd, J1 = 1.6 Hz, J2 = 5.0 Hz, 2H, 1H C2 and 1H C6 ). 13C NMR (CDCl3, 75.5 MHz)
ꢁ
ꢁ
δ: 16.3 (d, 3JPC = 5.5 Hz, CH3 CH2O), 21.4 (CH3 C6H4), 29.7 (d, 2JPC = 2.0 Hz, C3 or
3
1
2
C5), 40.4 (d, JPC = 11.4 Hz, C2 or C6), 54.7 (d, JPC = 163.0 Hz, C4), 62.6 (d, JPC
=
7.9 Hz, CH2OP), [12 arom C: 120.6 (2C), 125.5 (1C), 127.5 (2C), 128.6 (2C, C6H5 NH),
129.6 (2C), 132.9 (1C), 143.3 (1C, tosyl), 143.6 (1C)]. 31P NMR (CHCl3, 121.5 MHz) δ:
26.50. HRMS (ESI, m/z): calcd mass for C22H31ClN2O5PS, [M+H]+: 501.13743. Found:
501.13784.
Diethyl 4-(2-fluorophenyl) amino-1-(4ꢁ-methylbezenesulfonyl) piperidin-4-yl-phos-
phonate (3a): 1.70 g (70%), a white solid: mp 141◦C–142◦C. Rf = 0.50 (Petroleum
ether/EtOAc:2/3) IR (KBr) ν: 3354, 2979, 1614, 1491, 1344, 1227 (P O), 1171 (S O),
1098 (C F), 1066, 1047, 1025 (P O), 962, 918, 757, 724 (C S), 650, 599, 550 cm−1. 1H
NMR (CDCl3, 300 MHz) δ: 1.25 (t, J = 7.1 Hz, 6H, CH3 CH2O), 2.18–2.23 (m, 4Hcyclc),
2.44−2.51 (m, 5H, 3CH3 C6H4 and 1H C2 and 1H C6), 3.10–3.82 (br, 1H, NH), 3.57
(br d, J = 11.5 Hz, 2Hcyclc, 1H C2 and 1H C6), 4.00–4.13 (m, 4H, CH2OP), 6.72–6.87
ꢁ
(m, 2H, C6H4 NH), 6.94 (t, J = 7.6 Hz, 1H, C6H4 NH), 7.30 (d, J = 8.5 Hz, 2H, 1H C3
ꢁ
ꢁ
and 1H C5 ), 7.41 (t, J = 8.5 Hz, 1H, C6H4 NH), 7.58 (d, J = 8.2 Hz, 2H, 1H C2 and
1H C6 ). 13C NMR (CDCl3, 75.5 MHz) δ: 16.4 (d, JPC = 5.5 Hz, CH3 CH2O), 21.4
3
ꢁ
(CH3 C6H4), 29.4 (d, 2JPC = 2.0 Hz, C3 or C5), 40.3 (d, 3JPC = 11.5 Hz, C2 or C6), 54.6
(d, 1JPC = 168.5 Hz, C4), 62.7 (d, 2JPC = 7.7 Hz, CH2OP), [12 arom C: 114.3 (d, 2JCF
=
20.2 Hz, 1C), 120.1 (d, 3JCF = 7.5 Hz, 1C, C6H5 NH), 120.3 (1C, C6H5 NH), 124.1 (d,
4JCF = 3.8 Hz, 1C, C6H5 NH), 127.5 (2C), 129.5 (2C), 132.5 (d, JCF = 10.3 Hz, 1C,
2
C6H5 NH), 132.6 (1C), 143.6 (1C, tosyl), 153.3 (d, 1JCF = 238.7 Hz, 1C, C6H5 NH)]. 31
P
NMR (CHCl3, 121.5 MHz) δ: 25.19. HRMS (ESI, m/z): calcd mass for C22H30FN2NaO5PS,
[M+Na]+: 507.14893. Found: 507.14917.
Diethyl 4-(3-fluorophenyl) amino-1-(4ꢁ-methylbezenesulfonyl) piperidin-4-yl-phos-
phonate (3b): 2.03 g (84%), a brown solid: mp 156◦C–157◦C. Rf = 0.30 (Petroleum
ether/EtOAc:2/3) IR (KBr) ν: 3342, 2986, 1615, 1495, 1339, 1224 (P O), 1169 (S O),
1095 (C F), 1068, 1043, 1025 (P O), 966, 943, 913, 760, 726 (C S), 650, 594, 549 cm−1
.
1H NMR (CDCl3, 300MHz) δ: 1.22 (t, J = 7.1Hz, 6H, CH3 CH2O), 2.14–2.21 (m, 4Hcyclc),
2.43 (s, 3H, CH3 C6H4), 2.57 (t, J = 11.0 Hz, 2H, 1H C2 and 1H C6), 3.60 (br d, J =
11.3 Hz, 2Hcyclc, 1H C2 and 1H C6), 3.91–4.08 (m, 4H, CH2OP), 4.22–5.01 (br, 1H, NH),

N-TOSYL PIPERIDINYL-CONTAINING α-AMINOPHOSPHONATES
1033
6.46–6.59 (m, 3H, C6H4 NH), 6.98–7.06 (m, 1H, C6H4 NH), 7.28–32 (m, 2H, 1H C3
and 1H C5 ), 7.60 (d, J = 8.4 Hz, 2H, 1H C2 and 1H C6 ). 13C NMR (CDCl3, 75.5 MHz)
ꢁ
ꢁ
ꢁ
δ: 16.3 (d, 3JPC = 5.5 Hz, CH3 CH2O), 21.4 (CH3 C6H4), 29.7 (d, 2JPC = 1.9 Hz, C3 or
3
1
2
C5), 40.3 (d, JPC = 11.4 Hz, C2 or C6), 54.6 (d, JPC = 163.7 Hz, C4), 62.6 (d, JPC
=
2
2
7.9 Hz, CH2OP), [12 arom C: 105.8 (d, JCF = 25.4 Hz, 1C), 106.8 (d, JCF = 21.4 Hz,
1C), 114.6 (1C), 127.6 (2C), 129.6 (2C), 129.8 (d, 3JCF = 10.0 Hz, 1C, C6H5 NH), 132.8
(1C, tosyl), 143.7 (1C, tosyl), 146.6 (d, 3JCF = 10.4 Hz, 1C, C6H5 NH), 163.2 (d, 1JCF
=
243.8 Hz, 1C, C6H5 NH)]. 31P NMR (CHCl3, 121.5 MHz) δ: 25.51. HRMS (ESI, m/z):
calcd mass for C22H30FN2NaO5PS, [M+Na]+: 507.14893. Found: 507.14910.
Diethyl 4-(4-fluorophenyl) amino-1-(4ꢁ-methylbezenesulfonyl) piperidin-4-yl-phos-
phonate (3c): 1.82 g (75%), a white solid: mp 153◦C–154◦C. Rf = 0.30 (Petroleum
ether/EtOAc:2/3) IR (KBr) ν: 3308, 2982, 1596, 1508, 1345, 1229 (P O), 1170 (S O),
1095 (C F), 1065, 1043, 1019 (P O), 966, 920, 821, 781, 724 (C S), 650, 602, 550 cm−1
.
1H NMR (CDCl3, 300 MHz) δ: 1.18 (t, J = 7.0 Hz, 6H, CH3 CH2O), 2.04–2.21 (m,
4Hcyclc), 2.44 (s, 3H, CH3 C6H4), 2.68 (t, J = 9.6 Hz, 2H, 1H C2 and 1H C6), 3.60
(br d, J = 11.4 Hz, 2Hcyclc, 1H C2 and 1H C6), 3.87–4.02 (m, 4H, CH2OP), 4.18–5.16
ꢁ
(br, 1H, NH), 6.81 (d, J = 6.6 Hz, 4H, C6H4 NH), 7.30 (t, J = 7.5 Hz, 2H, 1H C3 and
1H C5 ), 7.62 (d, J = 8.1 Hz, 2H, 1H C2 and 1H C6 ). 13C NMR (CDCl3, 75.5 MHz)
ꢁ
ꢁ
ꢁ
3
2
δ: 16.3 (d, JPC = 5.5 Hz, CH3 CH2O), 21.4 (CH3 C6H4), 29.8 (d, JPC = 2.4 Hz,
3
1
C3 or C5), 40.5 (d, JPC = 11.2 Hz, C2 or C6), 55.1 (d, JPC = 160.2 Hz, C4), 62.4
2
2
(d, JPC = 7.9 Hz, CH2OP), [12 arom C: 115.2 (d, JCF = 22.2 Hz, 2C), 122.2 (d,
4
3JCF = 6.5 Hz, 2C), 127.6 (2C), 129.6 (2C), 132.2 (1C), 140.7 (d, JCF = 2.2 Hz, 1C,
1
C6H5 NH), 143.6 (1C, tosyl), 158.0 (d, JCF = 240.2 Hz, 1C, C6H5 NH)]. 31P NMR
(CHCl3, 121.5 MHz) δ: 25.82. HRMS (ESI, m/z): calcd mass for C22H30FN2NaO5PS,
[M+Na]+: 507.14893. Found: 507.14907.
Diethyl 4-(2-methylphenyl) amino-1-(4ꢁ-methylbezenesulfonyl) piperidin-4-yl-pho-
sphonate (4a): 2.05 g (85%), a white solid: mp 156◦C–158◦C. Rf = 0.50 (Petroleum
ether/EtOAc:2/3) IR (KBr) ν: 3367, 2979, 1602, 1481, 1345, 1234 (P O), 1170 (S O),
1
1064, 1044, 1026 (P O), 968, 923, 753, 725 (C-S), 600, 545 cm−1. H NMR (CDCl3,
300MHz) δ: 1.22 (t, J = 7.1 Hz, 6H, CH3 CH2O), 1.84 (s, 3H, CH3 C6H4 NH),
2.16–2.33 (m, 4Hcyclc), 2.43−2.52 (m, 5H, CH3 C6H4, 1H C2 and 1H C6), 2.88 (d,
J = 3.8 Hz, 1H, NH), 3.57 (br d, J = 11.3 Hz, 2Hcyclc, 1H C2 and 1H C6), 3.92–4.09 (m,
4H, CH2OP), 6.71 (t, J = 7.2 Hz, 1H, C6H4 NH), 6.94 (d, J = 7.3 Hz, 1H, C6H4 NH),
ꢁ
ꢁ
7.01–7.07 (m, 1H, C6H4 NH), 7.27–7.32 (m, 3H, C6H4 NH, 1H C3 and 1H C5 ),7.58
(d, J = 8.2 Hz, 2H, 1H C2 and 1H C6 ). 13C NMR (CDCl3, 75.5 MHz) δ: 16.3 (d, 3JPC
=
ꢁ
ꢁ
5.5 Hz, CH3 CH2O), 17.5 (CH3 C6H4 NH), 21.4 (CH3 C6H4), 29.7 (d, 2JPC = 2.6 Hz,
3
1
C3 or C5), 40.4 (d, JPC = 11.2 Hz, C2 or C6), 55.4 (d, JPC = 165.2 Hz, C4), 62.5 (d,
2JPC = 7.7 Hz, CH2OP), [12 arom C: 117.7 (d, J = 1.7 Hz, 1C), 119.6 (1C), 125.1 (d,
J = 1.4 Hz, 1C), 126.6 (1C), 127.6 (2C), 129.6 (d, J = 5.7 Hz, 2C), 130.3 (1C), 132.4 (1C),
142.2 (1C), 143.6 (1C, tosyl)]. 31P NMR (CHCl3, 121.5 MHz) δ: 27.42. HRMS (ESI, m/z):
calcd mass for C23H33N2NaO5PS, [M+Na]+: 503.17400. Found: 503.17405.
Diethyl 4-(3-methylphenyl) amino-1-(4ꢁ-methylbezenesulfonyl) piperidin-4-yl-pho-
sphonate (4b): 1.89 g (79%), a yellow solid: mp 155◦C–157◦C. Rf = 0.50 (Petroleum
ether/EtOAc:2/3) IR (KBr) ν: 3311, 2928, 1592, 1485, 1234 (P O), 1169 (S O), 1063,
1045, 1016 (P O), 966, 910, 794, 723 (C S), 600, 550 cm−1 1H NMR (CDCl3,
.
300 MHz) δ: 1.18 (t, J = 7.1 Hz, 6H, CH3 CH2O), 2.16–2.18 (m, 4Hcyclc), 2.20 (s, 3H,
CH3 C6H4 NH), 2.43 (s, 3H, CH3 C6H4), 2.60–2.68 (m, 2H, 1H C2 and 1H C6), 3.10
(br s, 1H, NH), 3.59 (br d, J = 11.3 Hz, 2Hcyclc, 1H C2 and 1H C6), 3.86–4.05 (m, 4H,

1034
Z. JIANG ET AL.
CH2OP), 6.63–6.67 (m, 3H, C6H4 NH), 6.99 (d, J = 7.7 Hz, 1H, C6H4 NH), 7.27–7.31
(m, 2H, 1H C3 and 1H C5 ), 7.61 (d, J = 8.3 Hz, 2H, 1H C2 and 1H C6 ). 13C NMR
ꢁ
ꢁ
ꢁ
ꢁ
3
(CDCl3, 75.5 MHz) δ: 16.3 (d, JPC = 5.7 Hz, CH3 CH2O), 21.3 (CH3 C6H4 NH),
21.4 (CH3 C6H4), 30.0 (d, 2JPC = 2.2 Hz, C3 or C5), 40.5 (d, 3JPC = 12.7 Hz, C2 or C6),
54.7 (d, 1JPC = 162.6 Hz, C4), 62.2 (d, 2JPC = 7.9 Hz, CH2OP), [12 arom C: 116.9 (1C),
120.5 (1C), 127.6 (2C), 128.6 (1C), 129.6 (2C), 133.0 (1C), 138.5 (1C), 143.5 (1C, tosyl),
144.7 (1C)]. 31P NMR (CHCl3, 121.5 MHz) δ: 25.96. HRMS (ESI, m/z): calcd mass for
C23H33N2NaO5PS, [M+Na]+: 503.17400. Found: 503.17530.
Diethyl 4-(4-methylphenyl) amino-1-(4ꢁ-methylbezenesulfonyl) piperidin-4-yl-ph-
osphonate (4c): 1.73 g (72%), a pale yellow solid: mp 151◦C–153◦C. Rf = 0.40 (Petroleum
ether/EtOAc:2/3) IR (KBr) ν: 3301, 2978, 1616, 1512, 1350, 1228 (P O), 1170 (S O),
1
1066, 1038, 1019 (P O), 974, 934, 815, 721 (C S), 599, 561 cm−1. H NMR (CDCl3,
300 MHz) δ: 1.17 (t, J = 7.1 Hz, 6H, CH3 CH2O), 2.12–2.16 (m, 4Hcyclc), 2.22 (s, 3H,
CH3–C6H4 NH), 2.43 (s, 3H, CH3 C6H4), 2.65–2.74 (m, 2H, 1H C2 and 1H C6),
2.91 (br s, 1H, NH), 3.59 (br d, J = 11.1 Hz, 2Hcyclc, 1H C2 and 1H C6), 3.84–4.10
(m, 4H, CH2OP), 6.71–6.75 (m, 2H, C6H4 NH), 6.91 (d, J = 8.0 Hz, 2H, C6H4 NH),
7.28–7.31 (m, 2H, 1H C3 and 1H C5 ), 7.59–7.63 (m, 2H, 1H C2 and 1H C6 ). 13C
NMR (CDCl3, 75.5 MHz) δ: 16.3 (d, 3JPC = 5.6 Hz, CH3 CH2O), 20.4 (CH3 C6H4 NH),
21.4 (CH3 C6H4), 30.0 (d, 2JPC = 2.6 Hz, C3 or C5), 40.6 (d, 3JPC = 11.2 Hz, C2 or C6),
54.9 (d, 1JPC = 160.6 Hz, C4), 62.2 (d, 2JPC = 7.8 Hz, CH2OP), [12 arom C: 120.4 (d, J
= 1.4 Hz, 1C), 127.6 (2C), 129.2 (1C), 129.6 (1C), 130.4 (1C), 133.1 (1C), 142.2 (1C),
143.5 (1C)]. 31P NMR (CHCl3, 121.5 MHz) δ: 27.51. HRMS (ESI, m/z): calcd mass for
C23H34N2O5PS, [M+H]+: 481.19206. Found: 481.19240.
ꢁ
ꢁ
ꢁ
ꢁ
Diethyl 4-(2-methoxyphenyl) amino-1-(4ꢁ-methylbezenesulfonyl) piperidin-4-yl-ph-
osphonate (5a): 1.99 g (80%), a white solid: mp 154◦C–156◦C. Rf = 0.50 (Petroleum
ether/EtOAc:2/3) IR (KBr) ν: 3387, 2986, 2932, 1598, 1516, 1345, 1225 (P O), 1167
(S O), 1066, 1041, 1024 (P O), 963, 925, 729 (C S), 598, 550 cm−1. 1H NMR (CDCl3,
300 MHz) δ: 1.27 (t, J = 7.1 Hz, 6H, CH3 CH2O), 2.15–2.39 (m, 6H, 4Hcyclc and 1H C2
and 1H C6), 2.42 (s, 3H, CH3 C6H4), 3.43 (s, 3H, CH3O C6H4), 3.54 (br d, J = 11.6 Hz,
2Hcyclc, 1H C2 and 1H-C6), 3.78 (br d, J = 9.8 Hz, 1H, NH), 4.02–4.16 (m, 4H, CH2OP),
ꢁ
6.60–6.63 (m, 1H, C6H4 NH), 6.71–6.83 (m, 2H, C6H4 NH), 7.27–7.30 (m, 2H, 1H C3
ꢁ
and 1H C5 ), 7.49 (dd, J1 = 1.4 Hz, J2 = 6.4 Hz, 1H, C6H4 NH), 7.57 (dd, J1 = 1.7 Hz,
J2 = 4.9 Hz, 2H, 1H C2 and 1H C6 ). 13C NMR (CDCl3, 75.5 MHz) δ: 16.4 (d, 3JPC
=
ꢁ
ꢁ
5.5 Hz, CH3-CH2O), 21.4 (CH3 C6H4), 29.1 (d, 2JPC = 1.9 Hz, C3 or C5), 40.3 (d, 3JPC
= 11.9 Hz, C2 or C6), 53.9 (d, 1JPC = 172.4 Hz, C4), 55.2 (OCH3), 62.7 (d, 2JPC = 7.6 Hz,
CH2OP), [12 arom C: 109.5 (1C), 118.5 (d, J = 1.8 Hz, 1C), 119.5 (1C), 120.9 (1C), 127.7
(2C), 129.4 (2C), 133.0 (1C, tosyl), 133.6 (1C), 143.3 (1C), 148.5 (d, J = 0.9 Hz, 1C)]. 31P
NMR (CHCl3, 121.5 MHz) δ: 25.59. HRMS (ESI, m/z): calcd mass for C23H33N2NaO6PS,
[M+Na]+: 519.16892. Found: 519.16789.
Diethyl 4-(3-methoxyphenyl) amino-1-(4ꢁ-methylbezenesulfonyl) piperidin-4-yl-ph-
osphonate (5b): 1.78 g (72%), a white solid: mp 154◦C–156◦C. Rf = 0.30 (Petroleum
ether/EtOAc:3/1.5) IR (KBr) ν: 3311, 2984, 2866, 1601, 1498, 1350, 1233, 1168 (S O),
1036 (P O), 966, 943, 718 (C S), 695, 600, 549 cm−1. 1H NMR (CDCl3, 300 MHz) δ:
1.20 (t, J = 7.1 Hz, 6H, CH3 CH2O), 2.15–2.22 (m, 4Hcyclc), 2.43 (s, 3H, CH3 C6H4),
2.61–2.64 (m, 2H, 1H C2 and 1H C6), 3.15 (br d, J = 3.9 Hz, 1H, NH), 3.60 (br d, J
= 11.2 Hz, 2Hcyclc, 1H C2 and 1H C6), 3.72 (s, 3H, CH3O C6H4), 3.89–4.07 (m, 4H,
CH2OP), 6.36–6.41 (m, 2H, C6H4 NH), 6.48 (t, J = 2.3 Hz, 1H, C6H4 NH), 6.99 (t,
ꢁ
ꢁ
J = 8.1 Hz, 1H, C6H4 NH), 7.27–7.31 (m, 2H, 1H C3 and 1H C5 ), 7.58–7.62 (m,

N-TOSYL PIPERIDINYL-CONTAINING α-AMINOPHOSPHONATES
1035
3
2H, 1H C2 and 1H C6 ). 13C NMR (CDCl3, 75.5 MHz) δ: 16.4 (d, JPC = 5.6 Hz,
ꢁ
ꢁ
2
3
CH3 CH2O), 21.4 (CH3 C6H4), 30.0 (d, JPC = 2.2 Hz, C3 or C5), 40.5 (d, JPC
=
11.3 Hz, C2 or C6), 54.7 (d, 1JPC = 163.2 Hz, C4), 55.1 (OCH3), 62.3 (d, 2JPC = 7.8 Hz,
CH2OP), [12 arom C: 105.5 (1C), 105.9 (1C), 112.1 (2C), 127.6 (2C), 129.5 (d, J = 14.9 Hz,
2C), 132.9 (1C), 143.6 (1C), 146.1 (1C), 160.2 (1C)]. 31P NMR (CHCl3, 121.5 MHz) δ:
25.84. HRMS (ESI, m/z): calcd mass for C23H34N2O6PS, [M+H]+: 497.18697. Found:
497.18759.
Diethyl 4-(4-methoxyphenyl) amino-1-(4ꢁ-methylbezenesulfonyl) piperidin-4-yl-ph-
osphonate (5c): 1.87 g (75%), a brown solid: mp 132◦C–134◦C. Rf = 0.30 (Petroleum
ether/EtOAc:3/2) IR (KBr) ν: 3302, 3065, 2982, 1509, 1250, 1236 (P O), 1169 (S O),
1066, 1043, 1020 (P O), 972, 935, 721 (C S), 600, 561 cm−1. 1H NMR (CDCl3, 300 MHz)
δ: 1.16 (t, J = 7.1 Hz, 6H, CH3 CH2O), 2.04–2.16 (m, 4Hcyclc), 2.43 (s, 3H, CH3 C6H4),
2.75 (t, J = 10.7 Hz, 2H, 1H C2 and 1H C6), 2.98 (br s, 1H, NH), 3.58 (br d, J = 11.2 Hz,
2Hcyclc, 1H C2 and 1H C6), 3.73 (s, 3H, CH3O C6H4), 3.84–4.03 (m, 4H, CH2OP), 6.68
(dd, J1 = 2.3 Hz, J2 = 4.3 Hz, 2H, C6H4 NH), 6.80 (dd, J1 = 2.3 Hz, J2 = 4.3 Hz, 2H,
ꢁ
ꢁ
3
ꢁ
C6H4 NH), 7.28–7.32 (m, 2H, 1H C3 and 1H C5 ), 7.61–7.64 (m, 2H, 1H C2 and
1H C6 ). 13C NMR (CDCl3, 75.5 MHz) δ: 16.3 (d, JPC = 5.6 Hz, CH3 CH2O), 21.4
ꢁ
(CH3 C6H4), 29.9 (d, 2JPC = 2.5 Hz, C3 or C5), 40.6 (d, 3JPC = 11.2 Hz, C2 or C6), 55.2
1
2
(d, JPC = 158.6 Hz, C4), 55.4 (OCH3), 62.1 (d, JPC = 7.9 Hz, CH2OP), [12 arom C:
114.02 (2C), 123.0 (d, J = 1.7 Hz, 2C), 127.6 (2C), 129.6 (2C), 133.0 (1C), 137.8 (1C),
143.5 (1C), 154.9 (1C)]. 31P NMR (CH3OH, 121.5 MHz) δ: 28.27. HRMS (ESI, m/z): calcd
mass for C23H34N2O6PS, [M+H]+: 497.18697. Found: 497.18735.
Diethyl 4-(2-nitrophenyl) amino-1-(4ꢁ-methylbezenesulfonyl) piperidin-4-yl-phosp-
honate (6a): 1.41 g (55%), a yellow solid: mp 161◦C–162◦C. Rf = 0.60 (Petroleum
ether/EtOAc:1/4) IR (KBr) ν: 3414, 2980, 1612, 1505, 1347 (N O), 1239 (P O), 1171
(S O), 1063, 1037, 1021 (P O), 963, 923, 718 (C S), 604, 565 cm−1. 1H NMR (CDCl3,
300 MHz) δ: 1.29 (t, J = 7.1 Hz, 6H, CH3 CH2O), 2.23–2.40 (m, 6H, 4Hcyclc and 1H C2
and 1H C6), 2.44 (s, 3H, CH3 C6H4), 3.61 (br d, J = 6.5 Hz, 2Hcyclc, 1H C2 and
1H C6), 4.06–4.17 (m, 4H, CH2OP), 6.75 (t, J = 7.5 Hz, 1H, NH), 7.27 (d, J = 8.3 Hz,
ꢁ
ꢁ
ꢁ
2H, 1H C3 and 1H C5 ), 7.39–7.45 (m, 1H, C6H4 NH), 7.52 (d, J = 8.2 Hz, 2H, 1H C2
ꢁ
and 1H C6 ), 7.63 (d, J = 6.2 Hz, 1H, C6H4 NH), 7.82 (d, J = 8.7 Hz, 1H, C6H4 NH),
8.04 (dd, J1 = 1.6 Hz, J2 = 7.0 Hz, 1H, C6H4 NH). 13C NMR (CDCl3, 75.5 MHz) δ: 16.4
3
3
(d, JPC = 5.4 Hz, CH3 CH2O), 21.4 (CH3 C6H4), 29.4 (s, C3 or C5), 40.1 (d, JPC
=
11.1 Hz, C2 or C6), 54.6 (d, 1JPC = 168.3 Hz, C4), 63.1 (d, 2JPC = 7.6 Hz, CH2OP), [12
arom C: 117.8 (1C), 119.4 (d, J = 2.0 Hz, 1C), 126.5 (1C), 127.4 (2C), 129.6 (2C), 131.8
(1C, C6H5 NH), 134.2 (1C, tosyl), 135.7 (1C, C6H5 NH), 142.6 (1C, tosyl), 144.1 (1C,
C6H5 NH)]. 31P NMR (CHCl3, 121.5 MHz) δ: 23.75. HRMS (ESI, m/z): calcd mass for
C22H30N3NaO7PS, [M+Na]+: 534.14343. Found: 534.14359.
Diethyl 4-(3-nitrophenyl) amino-1-(4ꢁ-methylbezenesulfonyl) piperidin-4-yl-phosp-
honate (6b): 1.41 g (55%), a luminous yellow solid: mp 173◦C–175◦C. Rf = 0.20 (Petroleum
ether/EtOAc:2/3) IR (KBr) ν: 3420, 2984, 1623,1527, 1382 (N O), 1223 (P O), 1167
(S O), 1066, 1040, 1017 (P O), 971, 937, 822, 716 (C S), 650, 603, 549 cm−1. 1H NMR
(CDCl3, 300 MHz) δ: 1.25 (t, J = 7.1 Hz, 6H, CH3 CH2O), 2.18–2.24 (m, 4Hcyclc), 2.42 (s,
3H, CH3 C6H4), 2.55 (t, J = 10.8 Hz, 2H, 1H C2 and 1H C6), 3.61 (br d, J = 11.7 Hz,
2Hcyclc, 1H C2 and 1H C6), 3.95 4.12 (m, 5H, 4CH2OP and 1NH), 7.19–7.29 (m, 4H,
ꢁ
ꢁ
ꢁ
2 C6H4 NH and 1H C3 and 1H C5 ), 7.57–7.61 (m, 4H, 2 C6H4 NH and 1H C2 and
1H C6 ). 13C NMR (CDCl3, 75.5 MHz) δ: 16.4 (d, JPC = 5.4 Hz, CH3 CH2O), 21.4
3
ꢁ
2
3
(CH3 C6H4), 29.5 (d, JPC = 1.9 Hz, C3 or C5), 40.2 (d, JPC = 11.2 Hz, C2 or C6),

1036
Z. JIANG ET AL.
54.5 (d, 1JPC = 165.3 Hz, C4), 62.8 (d, 2JPC = 7.8 Hz, CH2OP), [12 arom C: 112.1 (1C),
114.2 (1C), 123.7 (d, J = 1.1 Hz, 1C), 127.5 (2C), 129.4 (1C, C6H5 NH), 129.6 (2C,
tosyl), 132.8 (1C), 143.8 (1C, tosyl), 145.9 (1C, C6H5 NH), 148.7 (1C, C6H5 NH)]. 31
P
NMR (CHCl3, 121.5 MHz) δ: 25.14. HRMS (ESI, m/z): calcd mass for C22H30N3NaO7PS,
[M+Na]+: 534.14343. Found: 534.14322.
Diethyl 4-(4-nitrophenyl) amino-1-(4ꢁ-methylbezenesulfonyl) piperidin-4-yl-phosp-
honate (6c): 1.97 g (77%), a pale yellow solid: mp 219◦C–220◦C. Rf = 0.60 (Petroleum
ether/EtOAc:1/4) IR (KBr) ν: 3309, 2987, 1598, 1505, 1320 (N O), 1222 (P O), 1169
(S O), 1067, 1041, 1019 (P O), 971, 936, 718 (C S), 596, 548 cm−1. 1H NMR (CDCl3,
300 MHz) δ: 1.26 (t, J = 7.1 Hz, 6H, CH3 CH2O), 2.22–2.30 (m, 4Hcyclc), 2.43 (s, 3H,
CH3 C6H4), 2.50 (t, J = 11.1 Hz, 2H, 1H C2 and 1H C6), 3.64 (br d, J = 11.7 Hz,
2Hcyclc, 1H C2 and 1H C6), 3.99–4.13 (m, 5H, 4CH2OP and 1NH), 7.19–7.29 (m, 4H,
ꢁ
ꢁ
ꢁ
2 C6H4 NH and 1H C3 and 1H C5 ), 7.57–7.61 (m, 4H, 2 C6H4 NH and 1H C2
and 1H C6 ). 13C NMR (CDCl3, 75.5 MHz) δ: 16.5 (d, JPC = 5.4 Hz, CH3 CH2O),
3
ꢁ
3
1
21.5 (CH3 C6H4), 29.9 (C3 or C5), 40.2 (d, JPC = 10.9 Hz, C2 or C6), 54.6 (d, JPC
=
165.9 Hz, C4), 62.9 (d, 2JPC = 7.7 Hz, CH2OP), [12 arom C: 115.7 (2C), 125.5 (2C), 127.6
(2C), 129.8 (2C), 133.0 (1C), 139.8 (1C), 143.9 (1C, tosyl), 150.8 (1C)]. 31P NMR (CHCl3,
121.5 MHz) δ: 24.33. HRMS (ESI, m/z): calcd mass for C22H30N3NaO7PS, [M+Na]+:
534.14343. Found: 534.14348.
REFERENCES
1. (a) Kafarski, P.; Lejczak, B. Phosphorus, Sulfur Silicon 1991, 63, 193–215; (b) Peyman, A.;
Buidt, K.-H.; Spanig, J.; Ruppert, D. Angew. Chem. Int. Ed. Engl. 1993, 32, 1720–1722; (c)
Chen, R.-Y.; Dai, Q. Sci. China, Ser.B 1995, 25, 591–595 (in Chinese); (d) Wang, H.-L.; Zhou,
J.; Qiu, Y.-G.; Feng, K.-S.; Chen, R.-Y. Phosphorus, Sulfur Silicon 1995, 104, 135–141; (e)
Kukhar, V. P.; Hudson, H. R. Aminophosphonic and Aminophosphinic Acids: Chemistry and
Biological Activity, Wiley: Chichester, NY, 2000; (f) Liu, X.-J.; Chen, R.-Y.; Yang, Y.-Y. Chem.
J. Chin. Univ. 2002, 23, 1299–1293 (in Chinese); (g) Lang, S.-Y.; Yue, F.; Cao, L.-H. Phosphorus,
Sulfur Silicon Relat. Elem. 2012, 187, 461–467.
2. (a) Dhawan, B.; Redmore, D. Phosphorous Sulfur 1987, 32, 119–144; (b) Kukhar, V.P.;
Soloshonok, V.A.; Solodenko, V.A. Phosphorus, Sulfur Silicon Relat. Elem. 1994, 92, 239–264;
(c) Bennani, Y.L.; Hanessian, S. Chem. Rev. 1997, 97, 3161–3196; (d) Kolodiazhnyi, O.I. Tetra-
hedron: Asymmetry 1998, 9, 1279–1332; (e) Mikolajczyk, M. J. Organomet. Chem. 2005, 690,
2488–2496; (f) Ma, J.A. Chem. Soc. Rev. 2006, 35, 630–636; (g) Zhang, J.-F.; Cui, Z.-W.;
Miao, Z.-W.; Chen, R.-Y. Chin. J. Org. Chem. 2008, 28, 956–953 (in Chinese); (h) Bhagat,
S.; Chakraborti, A.K. J. Org. Chem. 2008, 73, 6029–6032; (i) Lang, S.-Y.; Yue, F.; Cao, L.-H.
Phosphorus, Sulfur Silicon Relat. Elem. 2012, 187, 461–467; (j) Sundar, C.S.; Srinivasulu, D.;
Nayak, S.K.; Reddy, C.S. Phosphorus, Sulfur Silicon Relat. Elem. 2012, 187, 523–534.
3. (a) Bailey, P.D.; Millwood, P.A.; Smith, P.D. Chem. Commun. 1998, 633–640; (b) Laschat, S.;
Dickner, T. Synthesis 2000, 1781–1813; (c) Mitchinson, A.; Nadin, A. J. Chem. Soc., Perkin
Trans. 1 2000, 2862–2892; (d) Weintraub, P.M.; Sabol, J.S.; Kane, J.M.; Borcherding, D.R.
Tetrahedron 2003, 59, 2953–2989; (e) Maxime, G.P. B. Tetrahedron 2004, 60, 1701–1729.
4. Rabasso, N.; Louaisil, N.; Fadel, A. Tetrahedron 2006, 62, 7445–7454.
5. (a) Gue´guen, C.; About-Jaude, E.; Collignon, N.; Savignac, P. Synth. Commun. 1996, 26,
4131–4143; (b) Stoikov, I.I.; Repejkov, S.A.; Antipin, I.S.; Konovalov, A.I. Heteroat. Chem
2000, 11, 518–527; (c) Wieczorek, J.S.; Gancarz, R.; Bielecki, K.; Grzys´, E.; Sarapuk, J. Phos-
phorus, Sulfur Silicon Relat. Elem. 2000, 166, 111–123; (d) Wieczorek, J.S.; Gancarz, R.;
Bielecki, K.; Grzys´, E.; Sarapuk, J. Phosphorus, Sulfur Silicon Relat. Elem. 2001, 174, 119–128;

N-TOSYL PIPERIDINYL-CONTAINING α-AMINOPHOSPHONATES
1037
(e) Yadav, J.S.; Subba Reddy, B.V.; Madan, C. Synlett 2001, 2001, 1131–1133; (f) Ranu, B.C.;
Hajra, A. Green Chem. 2002, 4, 551–554.
6. (a) Dzhiembaev, B.Z.; Abiyurov, B.D.; Zaporozhskaya, N.I.; Minbaev, B.U. Zh. Obshch. Khim.
1989, 59, 77–80; (b) Gancarz, R.; Latajka, R.; Halama, A.; Kafarski, P. Magn. Reson. Chem.
2000, 38, 867–871; (c) Matveeva, E.; Podrugina, T.; Prisyajnoy, M.; Zefirov, N. Russ. Chem. Bull.
2006, 55, 1209–1214; (d) Louaisil, N.; Rabasso, N.; Fadel, A. Tetrahedron 2009, 65, 8587–8595.
7. (a) Barton, P.J.; Jewsbury, P.J.; Pease, J.E. WO2004033427A1, 2004; (b) Leo´n, L.G.; Carballo,
R.M.; Vega-Herna´ndez, M.C.; Mart´ın, V.S.; Padro´n, J.I.; Padro´n, J.M. Bioorg. Med. Chem. Lett.
2007, 17, 2681–2684; (c) Matsumura, A.; Mikamiyama, H.; Tsuno, N.; Kyle, D.J.; Shao, B.; Yao,
J. WO2008008398A2, 2008; (d) Shah, U.; Boyle, C.D.; Chackalamannil, S. WO2009023180A1,
2009; (e) Wilckens, T.; Weber, L. EP2243494A1, 2010.
8. (a) Chakraborti, A.K.; Sharma, L.; Gulhane, R.; Shivani Tetrahedron 2003, 59, 7661–7668; (b)
Chakraborti, A.K.; Bhagat, S.; Rudrawar, S. Tetrahedron Lett. 2004, 45, 7641–7644; (c) Bartoli,
G.; Babiuch, K.; Bosco, M.; Carlone, A.; Galzerano, P.; Melchiorre, P.; Sambri, L. Synlett 2007,
2897–2901; (d) Bartoli, G.; Locatelli, M.; Melchiorre, P.; Sambri, L. Eur. J. Org. Chem. 2007,
2037–2049; (e) Khatik, G.L.; Kumar, R.; Chakraborti, A.K. Synthesis 2007, 541–546; (f) Bartoli,
G.; Bosco, M.; Carlone, A.; Dalpozzo, R.; Galzerano, P.; Melchiorre, P.; Sambri, L. Tetrahedron
Lett. 2008, 49, 2555–2557.
9. Bhagat, S.; Chakraborti, A.K. J. Org. Chem. 2007, 72, 1263–1270.
10. Haase, M.; Gu¨nther, W.; Go¨rls, H.; Anders, E. Synthesis 1999, 1999, 2071–2081.
11. Sammelson, R.E.; Caboni, P.; Durkin, K.A.; Casida, J.E. Bioorg. Med. Chem. 2004, 12,
3345–3355.
12. Engler, T.A.; Wanner, J. J. Org. Chem. 2000, 65, 2444–2457.