Synthesis and spectroscopic characterization of some new piperazine phosphoramide derivatives of 4-hydroxycoumarin

Article abstract of DOI:10.1080/10426507.2011.597799

A series of new piperazine phosphoramide derivatives of 4-hydroxycoumarin were synthesized through a facile phosphorylating reaction starting from 4-hydroxycoumarin and various phosphorylating agents. The title compounds were characterized by IR, NMR, ele

Full text of DOI:10.1080/10426507.2011.597799

Phosphorus, Sulfur, and Silicon, 187:245–254, 2012
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426507.2011.597799
SYNTHESIS AND SPECTROSCOPIC CHARACTERIZATION
OF SOME NEW PIPERAZINE PHOSPHORAMIDE
DERIVATIVES OF 4-HYDROXYCOUMARIN
Xiaolan Chen,1 Jinwei Yuan,2 Lingbo Qu,1,2 Zhibo Qu,1
Shaohua Xu,1 Fujun Wang,1 and Yufen Zhao1,3
1Key Laboratory of Organic Chemistry and Chemical Biology, Department
of Chemistry, Zhengzhou University, Henan Province, Zhengzhou, P. R. China
2Chemistry and Chemical Engineering School, Henan University of Technology,
Henan Province, Zhengzhou, P. R. China
3Department of Chemistry, Xiamen University, Xiamen, P. R. China
GRAPHICAL ABSTRACT
Abstract A series of new piperazine phosphoramide derivatives of 4-hydroxycoumarin were
synthesized through a facile phosphorylating reaction starting from 4-hydroxycoumarin and
various phosphorylating agents. The title compounds were characterized by IR, NMR, electro-
spray ionization-mass spectrometry, and high-resolution mass spectrometry, and their spectro-
scopic data were further analyzed to feature the related spectroscopic characteristics of the
compounds of this class.
Keywords 4-Hydroxycoumarin; phosphoramide; phosphorylating reaction; piperazine
INTRODUCTION
4-Hydroxycoumarin is an important component of many synthetic and natural
products with a wide range of biological activities, which include antipyretic,1 anti-
inflammatory,2 antibacterical,3 anticancer,4 anticoagulant, and HIV protease inhibition ef-
fects.5 The special properties have stimulated considerable interest in this class of com-
pounds and led to the synthesis of various derivatives of 4-hydroxycoumarin,6,7 based on the
Received 23 February 2011; accepted 27 May 2011.
The authors would like to thank the National Natural Science Foundation of China (No. 20472076, 21072178)
and Innovation Specialist Projects of Henan Province for their financial support.
Address correspondence to Xiaolan Chen, Key Laboratory of Organic Chemistry and Chemical Biology,
Department of Chemistry, Zhengzhou University, Henan Province, Zhengzhou 450052, P. R. China. E-mail:
chenxl@zzu.edu.cn
245

246
X. CHEN ET AL.
fact that a number of comparative pharmacological investigations of 4-hydroxycoumarin
derivatives have shown good activities combined with low side effects and little toxicity.8
A wide range of biologically active compounds incorporating piperazine structures
has shown different therapeutic activities, such as antibacterial,9 HIV protease inhibitor,10
and antitumor activity.11 Phosphoramide mustards, representing one of the earliest designed
strategies in cancer chemotherapy, are usually used as antineoplastic agents.12 Meanwhile,
phosphates and phosphoramides have been proven to be exceedingly important agents
for anticancer and antiviral therapy and therefore are widely used as prodrug moieties to
enhance therapeutic potential of a parent drug or water solubility.13,14 The insertion of
different biologically active groups into a single molecule is already an important strategy
to find new medicinal preparations. We have previously reported the synthesis of coumarin-
7,8-cyclophosphoramide derivatives using a facial method by introducing the functional
group of cyclophosphoramide into 7-hydroxycoumarin, a natural product occurring in the
essential oils in a large number of plants.15 Here, we describe a synthetic method to form a
novel type of piperazine phosphoramide derivatives of 4-hydroxycoumarin. By this method,
two pharmacologically active groups—the piperazine group and the mustard group—were
smoothly coupled with 4-hydroxycoumarin as shown in Scheme 1. The structures of the
new compounds are elucidated by NMR spectroscopy, electrospray ionization-mass spec-
trometry (ESI-MS), IR, and high-resolution mass spectrometry (HRMS). Furthermore, their
spectroscopic data were analyzed in order to obtain their spectral features.
Scheme 1
RESULTS AND DISCUSSION
The synthesis of piperazine phosphoramide derivatives 4 of 4-hydroxycoumarin in
a two-step process is shown in Scheme 1. Phosphorodichloridate 1 first reacts with N-
substituted piperazine hydrochloride 2 in dichloromethane to give the phosphochloridates
3. When the reaction was complete, the solvent was evaporated and anhydrous diethyl ether
was added to dissolve the intermediate phosphochloridate, while the undissolved triethy-
lamine hydrochloride was separated by filtration. The crude phosphochloridate obtained by
evaporation of the diethyl ether was used without further purification in the second step to
react with 4-hydroxycoumarin and yield products 4.
It must be mentioned that the final yield of the products 4 is substantially affected
by several crucial factors such as reaction temperature, molar ratio of the reactants, and
sequence of addition of reactants. For example, the temperature during the first step was
kept at −78 ◦C and powder of the N-substituted piperazine hydrochloride 2 was added to
the dichloromethane solution of phosphorodichloridate 1 in small portions with constant
stirring until a 1:1 molar ratio of the two reactants was reached. The amounts of disubstituted
phosphine amide or phosphinate byproducts, formed by nucleophilic substitution between
the very reactive phosphorodichloridate 1 and the N-substituted piperazine hydrochloride

PIPERAZINE PHOSPHORAMIDE DERIVATIVES OF 4-HYDROXYCOUMARIN
247
Table 1 Piperazine phosphoramide derivatives of 4-hydroxycoumarin 4a–h
4
R1
R2
Yield (%)
4a
4b
4c
4d
4e
4f
C6H5O
C6H5O
C6H5O
C6H5O
(ClCH2CH2)2N
(ClCH2CH2)2N
(ClCH2CH2)2N
(ClCH2CH2)2N
p
p
CH3
CH3 C6H4
Cl C6H4
85
85
80
83
83
85
87
84
(CH3)3C O CO
p
p
CH3
(CH3)3C
CH3 C6H4
Cl C6H4
4g
4h
O CO
2, were decreased to a great extent by choosing suitable reaction conditions. The reaction
between phosphochloridates 3 and 4-hydroxycoumarin in the second step was carried out
in the presence of triethylamine at room temperature, forming a series of novel piperazine
phosphoramide derivatives 4 of 4-hydroxycoumarin as shown in Table 1.
A strong absorption band in the region 1240–1290 cm−1 present in the IR spectra
of piperazine phosphoramide derivatives of 4-hydroxycoumarin 4a–h is ascribed to P O
stretching vibration. An absorption band in the region 1105–1138 cm−1 is assigned to P O
stretching vibration and a strong absorption band of 1701–1731 cm−1 corresponds to the
C O stretching vibration of coumarin. The absorption band for O−H (at about 3389 cm−1),
typical for 4-hydroxycoumarin, is not observed in the IR spectra of piperazine phospho-
ramide derivatives of 4-hydroxycoumarin 4a–h. The IR spectra support the presence of the
corresponding functional groups in the products.
Several characteristic resonances are observed in the 13C NMR spectra of compounds
4a–h. The NMR signals of C-3, C-4, and C-10 are split into doublet by coupling with
phosphorus, indicating that phosphorylation has occurred at C-4 of the 4-hydroxycoumarin
moiety. As an example in the case of 4a, doublets are observed for C-3 at δ = 101.1 (d, J =
3.0 Hz), for C-4 at δ = 158.8 (d, J = 6.0 Hz), and for C-10 at δ = 115.4 (J = 9.0 Hz) and
also applies for the resonance signals of C-11(13), C-12(14), C-1ꢁ, C-2ꢁ(6ꢁ), and C-15(17)
in 4a–h as shown in Table 2.
2
3
The values of the coupling constants JPC and JPC in compounds 4a–d (Figure 1)
2
3
3
decrease in the order: 3JP,C-10 > JP,C-4 > JP,C-3 ; 2JP,C-1 > JP,C-2 (6 ). The coupling constants
ꢁ
ꢁ
ꢁ
Figure 1 The structure of compounds 4a–d.

248

PIPERAZINE PHOSPHORAMIDE DERIVATIVES OF 4-HYDROXYCOUMARIN
249
Figure 2 The structure of compounds 4e–h.
2JP,C and 3JP,C in compounds 4e–h (Figure 2) are found to decrease in the order: 3JP,C-12(14)
>
2JP,C-11(13), 2JP,C-15(17) > 2JP,C-11(13). Interestingly, the 13C NMR signals of C-11(13) and C-
12(14) in compounds 4d and 4h, in which a tert-butoxy- carbonyl (t-BOC) group is attached
to the nitrogen atom of piperazine moiety, do not show a coupling to phosphorus. The 31P
NMR signals of 4a–d appear in the region δ = −2.7 to −3.0 and those of 4e–h in the
region δ = 11.7–11.9, which is in good agreement with reference data.16,17
The nature of the fragments observed in the mass spectrum often provides a clue to the
molecular structure. The fragmentation pathways of 4a–h were studied in detail by tandem
ESI-MSn in positive mode to unambiguously identify the structure of products 4a–h. The
fragmentation pathways of compounds 4a and 4e are discussed as representative examples
in detail and are shown in Figures 3 and 4. The fragmentation pathways of compounds
4a–d and 4e–h are similar. The ESI-MS of 4a shows a molecular ion peak [M + H]+
at m/z 477 (100%). The ESI-MS2 of the ion at m/z 477 shows three product ions, one at
Figure 3 Fragmentation pathway of compound 4a by ESI-MSn.

250
X. CHEN ET AL.
Figure 4 Fragmentation pathway of compound 4e by ESI-MSn.
m/z 315 corresponding to [M + H − C9H6O3]+, one at m/z 221 corresponding to [M +
H − C9H6O3 − C6H6O]+, and one at m/z 175 corresponding to [M + H − C9H6O3 −
C6H5O2P]+. The two product ions at m/z 175 and m/z 221 were proved to be produced
from the parent ion at m/z 315 by ESI-MS3. The ion at m/z 175 is formed through a 1,2
hydride shift by loss of a molecule of C6H5O2P according to path 1, while the ion at m/z
221 is formed through a three-membered ring as transition state by loss of a molecule of
phenol according to path 2, as shown in Figure 3.
The ion at m/z 315 is produced by loss of a molecule of 4-hydroxycoumarin, indicating
the relatively low stability of the P O bond to the 4-hydroxycoumarin part, in comparison
with that of the P N bond or the P O bond to phenol part. The ESI-MS of 4e gives a
molecular ion peak [M + H]+ at m/z 524 (100%). Further fragmentation of the molecular
ion peak [M + H]+ at m/z 524 is shown in Figure 4 and proceeds according to path 1
and path 2. The ion at m/z 362 [M + H − C9H6O3]+ is formed by loss of a molecule of
4-hydroxycoumarin, while the ion [M + H − C9H6O3 − C4H9Cl2N]+ at m/z 221 is formed
through a three-membered ring as transition state by loss of a molecule of mustard from
the ion at m/z 362 following path 1. The ion [M + H − C4H9Cl2N]+ at m/z 383 is formed
by loss of a molecule of mustard and the ion at m/z 175 is formed through a 1,2 hydride
shift by loss of a molecule of C9H5O4P following path 2.
CONCLUSION
A series of piperazine phosphoramide derivatives of 4-hydroxycoumarin (4a–h) have
been synthesized through a convenient phosphorylating reaction. Careful analysis of the
spectral data (IR, NMR, and ESI-MS) of 4a–h reveals spectral features, which may be
considered as characteristic for this class of compounds.

PIPERAZINE PHOSPHORAMIDE DERIVATIVES OF 4-HYDROXYCOUMARIN
251
EXPERIMENTAL
All experiments involving water-sensitive compounds were conducted under scrupu-
lously dry conditions. The solvents were dried by appropriate methods. IR spectra were
recorded with a Shimadazu IR-408 spectrophotometer. 1H, 13C, and 31P NMR spectra were
recorded with a Bruker Avance 400 MHz spectrometer operating at 400.13, 100.61, and
161.98 MHz, respectively, with the 13C and 31P NMR spectra being recorded with broad-
band proton decoupling. All NMR spectra were recorded in CDCl3 at room temperature
◦
1
(20 3 C). H and 13C chemical shifts are quoted in parts per million downfield from
tetramethylsilane. 31P chemical shifts are quoted in parts per million relative to 85% H3PO4
as an external standard. Thin layer chromatography was performed on silica gel plates, and
for preparative chromatography, columns of silica gel (200–300 mesh) were used. ESI-MS
spectra were recorded with a Bruker Esquire 3000. High-resolution mass spectra were
obtained with a Waters Micromass Q-Tof Micro instrument using the ESI technique.
Synthesis of Phosphodichloridates 1: General Procedure
Phosphodichloridates 1 were prepared according to the refs. 16 and 18.
Synthesis of N-Substituted Piperazine Hydrochlorides 2:
General Procedure
N-Substituted piperazine hydrochlorides 2a–d were synthesized following the pro-
cedures described in refs. 17–20.
Synthesis of Phosphochloridates 3a–h: General Procedure
N-Substituted piperazine hydrochloride 2 (5.0 mmol) was slowly added to 30 mL
of anhydrous dichloromethane solution of phosphorodichloridate 1 (1.05 g, 5.0 mmol)
with constant stirring. Anhydrous triethylamine (1.4 mL, 10.0 mmol) was then added
dropwise at −78 ◦C within 20 min and the reaction mixture was left to warm up to ambient
temperature while stirring during 8 h. The solvent was evaporated under reduced pressure,
and the residue was washed with anhydrous ether and separated by filtration. The filtrate
was evaporated to dryness under reduced pressure. The crude phosphochloridates 3a–h
thus obtained were used without further purification.
Synthesis of Piperazine Phosphoramide Derivatives 4a–h:
General Procedure
Anhydrous triethylamine (0.4 mL, 3 mmol) was added dropwise to a solution of
the respective phosphorochloridate 3a–h (2.7 mmol) and 4-hydroxycoumarin (0.5 g, 1.8
mmol) in anhydrous acetone at ambient temperature. The reaction mixture was stirred
at ambient temperature for 3–4 h. The precipitated triethylamine hydrochloride salt was
filtered off and the filtrate was evaporated under reduced pressure to give compounds 4a–h
as yellow powders. The crude product was purified by column chromatography on silica
gel (cyclohexane:AcOEt = 1:2) to give pure products 4a–h.
4a: White solid, mp 105 ◦C–107 ◦C. IR (KBr) v (cm−1): 1725 (C O), 1271 (P O),
1128 (P O). ESI-MS m/z: 477 [M + H]+, 953 [2M + H]+. HRMS m/z: 477.1575

252
X. CHEN ET AL.
1
[M + H]+ (calcd. for C25H24N2O5P 477.1579). H NMR (CDCl3): δ = 7.66 (dd, J =
7.9, 1.3 Hz, 1H, 5H), 7.61 (td, J = 8.5, 1.3 Hz, 1H, 7H), 7.42–7.18 (m, 7H, 6H, 8H,
arom-H), 7.09 (d, J = 8.4 Hz, 2H), 6.82 (d, J = 8.4 Hz, 2H), 6.56 (s, 1H, 3H), 3.56–3.45
(m, 4H, 12H, 14H), 3.14–3.00 (m, 4H, 11H, 13H), 2.28 (s, 3H, CH3). 13C NMR (CDCl3):
δ = 161.4 (C-2), 158.8 (d, JPC = 6.5 Hz, C-4), 153.7 (C-9), 150.1 (d, JPC = 7.1 Hz), 148.9,
133.0, 130.5, 130.1, 129.8, 125.7, 124.4, 122.6, 120.0 (d, JPC = 5.1 Hz), 117.2, 117.0,
115.4 (d, JPC = 8.7 Hz), 101.1 (d, JPC = 3.5 Hz), 50.3 (d, JPC = 5.2 Hz), 44.8 (d, JPC
1.4 Hz), 20.4 (CH3). 31P NMR (CDCl3): δ = −2.8.
=
4b: White solid, mp 152 ◦C–154 ◦C. IR (KBr) v (cm−1): 1725 (C O), 1272 (P O),
1108 (P O). ESI-MS m/z: 497 [M + H]+, 993 [2M + H]+. HRMS m/z: 497.1029 [M +
H]+ (calcd. for C25H23ClN2O5P 497.1033). 1H NMR (CDCl3): δ = 7.63 (dd, J = 7.9, 1.3
Hz, 1H, 5H), 7.58 (td, J = 7.4, 1.2 Hz, 1H, 7H), 7.42–7.24 (m, 7H, 6H, 8H, arom-H),
7.21 (d, J = 8.9 Hz, 2H), 6.81 (d, J = 8.9 Hz, 2H), 6.55 (s, 1H, 3H), 3.55–3.51 (m, 4H,
12H, 14H), 3.12–3.09 (m, 4H, 11H, 13H). 13C NMR (CDCl3): δ = 161.4 (C-2), 158.7 (d,
JPC = 6.1 Hz, C-4), 153.7 (C-9), 150.1 (d, JPC = 6.7 Hz), 149.6, 133.1, 130.1, 129.1, 125.8
(d, JPC = 4.6 Hz), 124.4, 122.6, 119.9 (d, JPC = 5.0 Hz), 118.1, 117.1, 115.4 (d, JPC
=
8.4 Hz), 101.1 (d, JPC = 3.5 Hz), 49.7 (d, JPC = 5.2 Hz), 44.7 (d, JPC = 1.7 Hz). 31P NMR
(CDCl3): δ = −3.0.
4c: Colorless oil, IR (KBr) v (cm−1): 1701 (C O), 1290 (P O), 1105 (P O). ESI-
MS m/z: 401 [M + H]+, 423 [M + Na]+. HRMS m/z: 401.1265 [M + H]+ (calcd. for
1
C20H22N2O5P 401.1266). H NMR (CDCl3): δ = 7.57 (dd, J = 7.9, 1.3 Hz, 1H, 5H),
7.52 (td, J = 8.5, 1.3 Hz, 1H, 7H), 7.35–7.15 (m, 7H, 6H, 8H, arom-H), 6.46 (s, 1H, 3H),
3.38–3.34 (m, 4H, 11H, 13H), 2.38–2.35 (m, 4H, 12H, 14H), 2.24 (s, 3H, CH3). 13C NMR
(CDCl3): δ = 161.4 (C-2), 158.8 (d, JPC = 6.3 Hz, C-4), 153.5 (C-9), 150.1 (d, JPC = 7.2
Hz), 133.0, 130.0, 129.8, 125.7, 124.4, 122.6, 119.9 (d, JPC = 5.1 Hz), 116.9, 115.3 (d,
JPC = 8.6 Hz), 100.9 (d, JPC = 3.5 Hz), 54.5 (d, JPC = 5.3 Hz), 46.0 (CH3), 44.4 (d, JPC
1.6 Hz). 31P NMR (CDCl3): δ = −2.7.
=
4d: Colorless oil, IR (KBr) v (cm−1): 1731 (C O), 1282 (P O), 1138 (P O). ESI-
MS m/z: 487 [M + H]+, 509 [M + Na]+. HRMS m/z: 509.1450 [M + Na]+ (calcd. for
C24H27N2O7PNa 509.1454). 1H NMR (CDCl3): δ = 7.62–7.56 (m, 2H, 5H, 7H), 7.40–7.23
(m, 7H, 6H, 8H, arom-H), 6.50 (s, 1H, 3H), 3.40–3.38 (m, 4H, 12H, 14H), 3.34–3.30 (m,
4H, 11H, 13H), 1.44 (s, 9H, CH3). 13C NMR (CDCl3): δ = 161.3 (C-2), 158.6 (d, JPC = 6.4
Hz, C-4), 154.3 (C O), 153.6 (C-9), 150.0 (d, JPC = 6.8 Hz), 133.1, 130.1, 125.8, 124.4,
122.6, 119.9 (d, JPC = 5.1 Hz), 117.1, 115.3 (d, JPC = 8.4 Hz), 101.0 (d, JPC = 3.6 Hz),
80.5 (OC(CH3)3), 44.6 (C-11, C-12, C-13, C-14), 28.3 (OC(CH3)3). 31P NMR (CDCl3):
δ = −2.8.
4e: White solid, mp 103 ◦C–105 ◦C. IR (KBr) v (cm−1): 1718 (C O), 1240 (P O),
1138 (P O). ESI-MS m/z: 524 [M + H]+. HRMS m/z: 524.1270 [M + H]+ (calcd. for
C24H29Cl2N3O4P 524.1273). 1H NMR (CDCl3): δ = 7.72 (dd, J = 7.0, 1.3 Hz, 1H, 5H),
7.60 (td, J = 8.6, 1.3 Hz, 1H, 7H), 7.36–7.32 (m, 2H, 6H, 8H), 7.06 (d, J = 8.5 Hz,
2H, arom-H), 6.80 (d, J = 8.5 Hz, 2H, arom-H), 6.67 (s, 1H, 3H), 3.74–3.51 (m, 8H,
N(CH2CH2Cl)2), 3.50–3.41 (m, 4H, 12H, 14H), 3.16–3.08 (m, 4H, 11H, 13H), 2.26 (s,
3H, CH3). 13C NMR (CDCl3): δ = 161.4 (C-2), 158.9 (d, JPC = 5.5 Hz, C-4), 153.6 (C-9),
148.8, 133.0, 130.4, 129.8, 124.5, 122.3, 117.2, 117.1, 115.4 (d, JPC = 8.3 Hz), 100.8 (d,
JPC = 3.4 Hz), 50.4 (d, JPC = 5.7 Hz), 49.1 (d, JPC = 4.4 Hz), 45.0 (d, JPC = 1.3 Hz), 41.9
(d, JPC = 1.0 Hz), 20.4 (s, CH3). 31P NMR (CDCl3): δ = 11.8.
4f: White solid, mp 145 ◦C–147 ◦C. IR (KBr) v (cm−1): 1722 (C O), 1241 (P O),
1108 (P O). ESI-MS m/z: 544 [M + H]+. HRMS m/z: 544.0723 [M + H]+ (calcd. for

PIPERAZINE PHOSPHORAMIDE DERIVATIVES OF 4-HYDROXYCOUMARIN
253
C23H26Cl3N3O4P 544.0727). 1H NMR (CDCl3): δ = 7.72 (dd, J = 7.9, 1.4 Hz, 1H, 5H),
7.60 (td, J = 8.0, 1.4 Hz, 1H, 7H), 7.38–7.34 (m, 2H, 6H, 8H), 7.20 (dd, J = 6.8, 2.1 Hz,
2H, arom-H), 6.81 (dd, J = 6.8, 2.1 Hz, 2H, arom-H), 6.66 (s, 1H, 3H), 3.74–3.52 (m, 8H,
N(CH2CH2Cl)2), 3.50–3.42 (m, 4H, 12H, 14H), 3.16–3.11 (m, 4H, 11H, 13H). 13C NMR
(CDCl3): δ = 161.4 (C-2), 158.9 (d, JPC = 5.4 Hz, C-4), 153.6 (C-9), 149.5, 133.1, 129.1,
125.7, 124.5, 122.3, 118.0, 117.3, 115.3 (d, JPC = 8.4 Hz), 100.8 (d, JPC = 3.3 Hz), 49.9
(d, JPC = 5.7 Hz), 49.1 (d, JPC = 4.6 Hz), 44.9 (d, JPC = 1.5 Hz), 41.9. 31P NMR (CDCl3):
δ = 11.7.
4g: Colorless oil, IR (KBr) v (cm−1): 1718 (C O), 1240 (P O), 1138 (P O). ESI-
MS m/z: 448 [M + H]+. HRMS m/z: 448.0958 [M + H]+ (calcd. for C18H25Cl2N3O4P
1
448.0960). H NMR (CDCl3): δ = 7.57 (dd, J = 8.4, 1.6 Hz, 1H, 5H), 7.44 (td, J =
8.4, 1.6 Hz, 1H, 7H), 7.20–7.16 (m, 2H, 6H, 8H), 6.46 (s, 1H, 3H), 3.57–3.51 (m,
4H, N(CH2CH2Cl)2), 3.49–3.32 (m, 4H, N(CH2CH2Cl)2, 3.18–3.11 (m, 4H, 11H, 13H),
2.28–2.22 (m, 4H, 12H, 14H), 2.11 (s, 3H, CH3). 13C NMR (CDCl3): δ = 161.4 (C-2),
158.9 (d, JPC = 5.7 Hz, C-4), 153.4 (C-9), 132.9, 124.4, 122.4, 116.9, 115.3 (d, JPC
=
8.6 Hz), 100.5 (d, JPC = 3.2 Hz), 54.7 (d, JPC = 5.7 Hz), 48.9 (d, JPC = 4.4 Hz), 46.0
(CH3), 44.6 (d, JPC = 1.3 Hz), 41.8. 31P NMR (CDCl3): δ = 11.9.
4h: Colorless oil, IR (KBr) v (cm−1): 1731 (C O), 1282 (P O), 1138 (P O–C).
ESI-MS m/z: 534 [M + H]+, 556 [M + Na]+. HRMS m/z: 556.1145 [M + Na]+ (calcd.
for C22H30Cl2N3O6PNa 556.1147). 1H NMR (CDCl3): δ = 7.66 (dd, J = 8.0, 1.2 Hz, 1H,
5H), 7.56 (td, J = 8.4, 1.2 Hz, 1H, 7H), 7.32–7.27 (m, 2H, 6H, 8H), 6.59 (s, 1H, 3H),
3.68–3.59 (m, 4H, N(CH2CH2Cl)2), 3.57–3.45 (m, 4H, N(CH2CH2Cl)2), 3.40–3.33 (m,
4H, 12H, 14H), 3.28–3.17 (m, 4H, 11H, 13H), 1.39 (s, 9H, CH3). 13C NMR (CDCl3): δ =
161.3 (C-2), 158.8 (d, JPC = 5.5 Hz, C-4), 154.3 (C O), 153.5 (C-9), 133.1, 124.5, 122.2,
117.2, 115.3 (d, JPC = 8.6 Hz), 100.6 (d, JPC = 3.3 Hz), 80.3 (OC(CH3)3), 60.3, 48.9 (d,
JPC = 4.4 Hz), 44.7, 41.8, 28.2 (OC(CH3)3). 31P NMR (CDCl3): δ = 11.7.
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