Synthesis and characterization of phosphoramide piperazine analogs of paeonol

Article abstract of DOI:10.1080/10426507.2014.965822

Based on the phosphorylated reaction, an efficient general synthetic approach that provide facile, rapid and cheap access to a wide range of novel phosphoramide derivatives of paeonol has been developed. These analogues of paeonol are synthesized in high

Full text of DOI:10.1080/10426507.2014.965822

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Phosphorus, Sulfur, and Silicon and the Related
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Synthesis and Characterization of Phosphoramide
Piperazine Analogues of Paeonol
Xu Lia, Xiaolan Chena, Jinwei Yuanb, Lingbo Quab, Haisheng Zhua, Wenzhu Bia & Yufen Zhaoac
a College of Chemistry and Molecular Engineering, Zhengzhou University, Zhengzhou,
450001, China
b School of Chemistry & Chemical Engineering, Henan University of Technology, Zhengzhou
450001, China
c Department of Chemistry, Xiamen University, Xiamen, P. R. China
Accepted author version posted online: 09 Mar 2015.
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To cite this article: Xu Li, Xiaolan Chen, Jinwei Yuan, Lingbo Qu, Haisheng Zhu, Wenzhu Bi & Yufen Zhao (2015): Synthesis
and Characterization of Phosphoramide Piperazine Analogues of Paeonol, Phosphorus, Sulfur, and Silicon and the Related
Elements, DOI: 10.1080/10426507.2014.965822
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ACCEPTED MANUSCRIPT
Synthesis and Characterization of Phosphoramide Piperazine Analogues of Paeonol
Xu Li,1 Xiaolan Chen, 1, Jinwei Yuan,2 Lingbo Qu 1,2 Haisheng Zhu 1, Wenzhu Bi, 1 Yufen
Zhao1,3
1 College of Chemistry and Molecular Engineering, Zhengzhou University, Zhengzhou, 450001,
China
2 School of Chemistry & Chemical Engineering, Henan University of Technology, Zhengzhou
450001, China
3 Department of Chemistry, Xiamen University, Xiamen, P. R. China
Abstract: Based on the phosphorylated reaction, an efficient general synthetic approach that
provide facile, rapid and cheap access to a wide range of novel phosphoramide derivatives of
paeonol has been developed. These analogues of paeonol are synthesized in high yields and
elucidated by IR, HR MS and NMR.
R2
N
R1
N
O
OH
O
P
P
R1
N
N R2
O
NEt3, K2CO3
acetone, r.t.
O
O
H3C
Cl
OCH3
H3C
OCH3
Keywords: paeonol, piperazine, phosphoramide, synthesis
 Corresponding author.
E-mail address: chenxl@zzu.edu.cn (X. L. Chen)
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INTRODUCTION
Paeonol, 2-hydroxyl-4-methoxyacetophenone (Fig. 1), is one of the main components of
Moutan Cortex. It is a traditional Chinese medicine with analgesic,1 antiallergic,2 antioxidative,3
Antitumor,4,5 anti-inflammatory and antimicrobial6 properties and has been used as a remedy for
cardiovascular and female genital diseases.7, 8 But the nature of water insolubility and volatility
of paeonol makes it difficult to exert its efficiency sufficiently. The impressive wide range of
biological activities of paeonol has generated great research interest in the synthesis of various
paeonol derivatives.9, 10
The piperazine scaffold has been classified as a privileged structure and is frequently found in
biologically active compounds across a number of different therapeutic areas. Some of these
therapeutic areas include antifungal, HIV protease inhibitor,11 antitumor,12 and antiviral
therapy.13 N-substituted piperazine pharmacophores are found in numerous drug molecules.
Furthermore, an alkylating nitrogen mustard, representing one of the earliest design strategies in
cancer chemotherapy, is usually used as an antineoplastic agent.14 Phosphates and
phosphoramidates were widely used as prodrug moieties to enhance desired biological activities
and have proven to be exceedingly important agents for anticancer and antiviral therapy.15,16
Moreover, the introduction of a phosphate group essentially changes the physical and chemical
properties of the parent molecule, resulting in changes to the polarization and intermolecular
bonding characteristics of that molecule.17
The insertion of different biologically active groups into a single molecule already became an
important strategy in finding new medicinal preparations. We have previously reported the
synthesis of phosphoramide derivatives of coumarin18 and quinoline,19 etc. To the best of our
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knowledge, there are no reports concerning phosphoramide derivatives of paeonol. As a
continuation of our previous work, we reported here the synthesis of a novel type of
phosphoramide piperazine derivatives of paeonol, in which two pharmic groups, piperazine and
mustard were smoothly coupled with paeonol (Scheme 1), to improve their desirable
physicochemical and biological properties. The structures of compounds 4a-h are elucidated by
IR, HR MS and NMR for the first time.
RESULT AND DISCUSSION
The title compounds were synthesized using a facile phosphorylated reaction, and the
synthetic procedure was shown in Scheme 1. First, phosphorodichloridates 1 reacted with N-
substituted piperazine hydrochlorides 2 in dichloromethane at low temperature to give
phosphochloridates 3, which were used without further purification in the following step to
couple with paeonol at room temperature and yielded products 4. It should be mentioned that the
overall yield of the reaction was substantially affected by several factors, such as reaction
temperature, molar ratio of the related reactants and their addition sequence. The results showed
that for the first step, the temperature need to be kept at a relatively low temperature (-78 C),
and meanwhile the molar equivalent N-substituted piperazine hydrochlorides 2 must be added to
the dichloromethane solution of phosphorodichloridates 1 in small portions with constant
stirring. The byproducts (disubstituted phosphinamides or phosphinates) formation were
therefore inhibited effectively by choosing a suitable reaction condition. For the second step,
when the crude phosphochloridates 3 were couple with paeonol in the presence of triethylamine
at room temperature, no products 4 were obtained. Increasing the reaction temperature to reflux
condition or prolong the reaction time to 48 h afforded a small amount of products 4 . In the
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structure of paeonol, there is an intramolecular hydrogen bond between H atom of hydroxyl and
O atom of carbonyl, making the nucleophilic substitution reaction between the
phosphochloridates 3 and paeonol difficult to occur. To obtain the products 4, addition of a small
amount of potassium carbonate was necessary. The results showed that the reaction between
phosphochloridates 3 and paeonol proceeded successfully in the presence of triethylamine and
potassium carbonate at room temperature, producing a series of novel phosphoramide piperazine
derivatives of paeonol 4 as shown in Table 1.
IR spectra of phosphoramide piperazine derivatives of paeonol 4a-h show a strong absorption
band in the region 1252-1268 cm-1, which are ascribed to P=O stretching vibrations. The
absorption bands in the region 1021-1039 cm-1 could be assigned to PO stretching vibrations.
One strong absorption band of 1677-1696 cm-1 corresponds to the C=O stretching vibrations of
paeonol group. The typical absorption band for OH (at about 3400 cm-1) group of paeonol is
not observed in the IR spectra of phosphoramide piperazine derivatives of paeonol 4a-h, which
indicates that the hydroxyl group of paeonol was phosphorylated.
Several characteristic resonances are appeared in the NMR spectra of 4a-h. The chemical shift
of 31P NMR in compounds 4a-e (Fig. 2a) is -1.97  -4.80 ppm, and that of compound 4f-h (Fig.
2b) is about 10.5 ppm. 13C NMR signals of C-1, C-2, C-6, C-10(12), C-11(13), C-14 and C-
15(15) for compound 4a-h are split into doublet by the nearby phosphorus atom, and the values
of these signal peaks and coupling constants are shown in Table 2. The result gave a decisive
conclusion that the phosphorylation reaction occurred at 1-OH of paeonol. Notably different 2JP-C
and 3JP-C coupling constants of carbon atoms were shown. 2J(P, C) and 3J(P, C) coupling constants
for the aryl carbon atoms are 2J(P, C-1)  3J(P, C-6) > 3J(P, C-2); 2J(P, C-14) > 3J(P, C-15(15)). On the
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contrary, 2J(P, C) and 3J(P, C) coupling constants for heterocyclic piperazine carbon atoms coupled
with phosphorus atom are 3J(P, C-11(13)) > 2J(P, C-10(12)). Interestingly, the signals of C-11(13) for
compound 4b and 4g is distinctive. The chemical shifts of 4b and 4g shift to high-field, and the
coupling constants of the peaks decrease or the split is not observed. It can be attributed to the
existence of the strong electron-withdrawing (CH3)3C-O-CO group.
CONCLUSION
In summary, a highly efficient synthesis of phosphoramide derivatives of paeonol has been
developed using a facile phosphorylated reaction. A novel series of phosphoramide piperazine
analogues of paeonol are synthesized in high yields and their structures are elucidated by IR, HR
MS and NMR. The research progress of their biological activities are ongoing.
EXPERIMENTAL
All experiments involving water-sensitive compounds were conducted under scrupulously dry
conditions. 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 13C and 31P NMR spectra being recorded
with broad band proton decoupled. All NMR spectra were recorded in CDCl3 at room
temperature (20 ± 3 C). 1H and 13C chemical shifts are quoted in parts per million downfield
from TMS. 31P chemical shifts are quoted in parts per million relative to 85% H3PO4 as an
external standard. J values refer to coupling constants, and signal splitting patterns are described
as singlet (s), doublet (d), triplet (t), quartet (q), multiplet (m), or combinations thereof. TLC was
performed on silica gel plates and preparative chromatograph on columns of silica gel (200-300
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mesh). High resolution mass spectra (HR MS) were obtained with a Waters Micromass Q-Tof
Micro instrument using the ESI technique.
General Procedure
Synthesis of Phosphodichloridates 1
Phosphodichloridates 1 were prepared according to the literature.18,19
Synthesis of N-substituted Piperazine Hydrochlorides 2
N-substituted piperazine hydrochlorides 2a-e were synthesized following the procedures.18,20
Synthesis of Phosphorochloridates 3a-h
N-substituted piperazine hydrochloride salt 2 (2.0 mmol) was added to anhydrous
dichloromethane (30 mL) solution of phosphodichloridate 1 (2.0 mmol) with constant stirring.
Anhydrous triethylamine (1.4 mL, 10.0 mmol) was then added dropwise at -78 C for 10 min,
and the reaction mixture was left to warm up to room temperature. After 8 h, the solvent was
evaporated under reduced pressure, and the residue was washed with anhydrous ether and was
filtered. The filtrate was evaporated to dryness under reduced pressure. The crude
phosphochloridates 3a-h were obtained and used without further purification.
Synthesis of Phosphoramide Piperazine Analogues of paeonol (4)
The solution of phosphorochloridate 3a-h (2 mmol) in 5 mL anhydrous acetone was added
dropwise to a solution of paeonol (0.332 g, 2 mmol), anhydrous triethylamine (0.3 mL, 2.0
mmol), and potassium carbonate (0.276 g, 2mmol) in anhydrous acetone (20 mL) at room
temperature. The reaction mixture was stirred for 20 h. The precipitation was filtered off, and the
filtrate was evaporated under reduced pressure to give the residues as the yellow liquid. The
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crude products were purified by column chromatography on silica gel (petroleum ether : ethyl
acetate = 2 : 1, v : v). The phosphoramide piperazine analogues of paeonol 4a-h were obtained.
Compound 4a: Light yellow liquid, IR(KBr), (cm-1): 1679 (C=O), 1604, 1455 (Ar), 1268
(P=O), 1027 (P-O). 1H NMR (CDCl3) δ: 7.72 (d, J = 8.8 Hz, 1H, 5-H), 7.29 (t, J = 7.8 Hz, 2H,
16, 16′-H), 7.21 (d, J = 7.8 Hz, 2H, 15, 15′-H), 7.13 (t, J = 7.6 Hz, 1H, 17-H), 7.08 (s, 1H, 2-H),
6.70 (d, J = 8.8 Hz, 1H, 4-H), 3.79 (s, 3H, 9-H), 3.29 (m, 4H, 10, 12-H), 2.51 (s, 3H, 8-H), 2.23
(m, 4H, 11, 13-H), 2.17 (s, 3H, NCH3). 13C NMR (CDCl3) δ: 196.3 (7-C), 163.5 (3-C), 151.1 (d,
J = 7.1 Hz, 1-C), 150.4 (d, J = 6.5 Hz, 14-C), 132.1 (5-C), 129.7 (16, 16′-C), 125.0 (17-C), 123.1
(d, J = 7.0 Hz, 6-C), 119.9 (d, J = 5.1 Hz, 15, 15′-C), 110.6 (4-C), 106.0 (d, J = 2.8 Hz, 2-C),
55.6 (9-C), 54.5 (d, J = 5.6 Hz, 11, 13-C), 46.1 (NCH3), 44.4 (d, J = 1.9 Hz, 10, 12-C), 30.7 (8-
C). 31P NMR (CDCl3) δ: -1.9. HR MS 405.1570 [M+H]+ (calculated for C20H26N2O5P 405.1574).
Compound 4b: Light yellow liquid, IR(KBr), (cm-1): 1696 (C=O), 1606, 1448 (Ar), 1263
(P=O), 1027 (P-O). 1H NMR (CDCl3) δ: 7.72 (d, J = 8.8 Hz, 1H, 5-H), 7.30 (m, 2H, 16, 16′-H),
7.20 (d, J = 8.8 Hz, 2H, 15, 15′-H), 7.14 (t, J = 7.2 Hz, 17-H), 7.06 (d, J = 1.2 Hz, 1H, 2-H), 6.71
(dd, J = 8.8, 1.6 Hz, 1H, 4-H), 3.79 (s, 3H, 9-H), 3.24 (m, 8H, 10, 11, 12, 13-H), 2.51 (s, 3H, 8-
H), 1.39 (s, 9H, -C(CH3)3). 13C NMR (CDCl3) δ: 196.5 (7-C), 163.6 (3-C), 154.4 (-
COOC(CH3)3), 151.0 (d, J = 6.9 Hz, 1-C), 150.4 (d, J = 6.4 Hz, 14-C), 132.2 (5-C), 129.8 (16,
16′-C), 125.2 (17-C), 123.1 (d, J = 7.0 Hz, 6-C), 119.9 (d, J = 5.2 Hz, 15, 15′-C), 110.7 (4-C),
106.3 (d, J = 2.8 Hz, 2-C), 80.1 (-COOC(CH3)3), 55.7 (9-C), 44.4 (d, J = 1.7 Hz, 10,12-C), 44.3
(d, J = 2.8 Hz, 11,13-C), 30.6 (8-C), 28.3 (-COOC(CH3)3). 31P NMR (CDCl3) δ: -2.2. HR MS
491.1939 [M+H]+ (calculated for C24H32N2O7P 491.1942).
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Compound 4c: Colorless liquid, IR(KBr), (cm-1): 1677 (C=O), 1604, 1450 (Ar), 1264 (P=O),
1029 (P-O). 1H NMR (CDCl3) δ: 7.77 (dd, J = 8.8, 1.0 Hz, 1H, 5-H), 7.35 (t, J = 8.0 Hz, 2H, 16,
16′-H), 7.26 (d, J = 7.2 Hz, 2H), 7.20 (m, 3H, 15, 15′, 17-H ), 7.14 (dd, J = 2.2, 1.0 Hz, 1H, 2-H),
6.79 (d, J = 8.6 Hz, 2H), 6.76 (dd, J = 8.8, 2.2 Hz, 1H, 4-H), 3.85 (s, 3H, 9-H), 3.47 (m, 4H, 11,
13-H), 3.01 (t, J = 4.8 Hz, 4H, 10, 12-H), 2.57 (s, 3H, 8-H). 13C NMR (CDCl3) δ: 196.6 (7-C),
163.7 (3-C), 151.1 (d, J = 7.0 Hz, 1-C), 150.5 (d, J = 6.5 Hz, 14-C), 149.8, 132.2 (5-C), 129.9
(16, 16′-C), 129.0, 125.4 (17-C), 125.3, 123.2 (d, J = 6.8 Hz, 6-C), 120.0 (d, J = 5.1 Hz, 15, 15′-
C), 117.9, 110.7 (4-C), 106.4 (d, J = 2.7 Hz, 2-C), 55.8 (9-C), 49.6 (d, J = 5.4 Hz, 11, 13-C),
44.5 (d, J = 1.9 Hz, 10, 12-C), 30.7 (8-C). 31P NMR (CDCl3) δ: -2.4. HR MS 501.1338 [M+H]+
(calculated for C25H27ClN2O5P 501.1341).
Compound 4d: Light yellow liquid, IR(KBr), (cm-1): 1681 (C=O), 1603, 1482 (Ar), 1265
(P=O), 1021 (P-O). 1H NMR (CDCl3) δ: 7.78 (d, J = 8.8 Hz, 1H, 5-H), 7.35 (t, J = 8.2 Hz, 2H,
16,16-H), 7.26 (m, 5H), 7.15 (m, 3H), 6.76 (dd, J = 8.8, 2.0 Hz, 1H, 4-H), 3.85 (s, 3H, 9-H),
3.77 (s, 3H, OCH3), 3.49 (bs, 4H, 11,13-H), 2.96 (bs, 4H, 10,12-H), 2.58 (s, 3H, 8-H). 13C NMR
(CDCl3) δ: 196.6 (7-C), 163.7 (3-C), 154.5, 151.2 (d, J = 7.2 Hz, 1-C), 150.5 (d, J = 6.3 Hz, 14-
C), 132.2 (5-C), 129.8 (16, 16′-C), 125.4 (17-C), 125.2, 123.2 (d, J = 7.0 Hz, 6-C), 120.0 (d, J =
5.1 Hz, 15,15′-C), 119.0, 114.5, 110.8 (4-C), 106.3 (d, J = 2.7 Hz, 2-C), 55.8 (9-C), 55.5
(OCH3), 51.1 (d, J = 5.1 Hz, 11,13-C), 44.7 (10,12-C), 30.7 (8-C). 31P NMR (CDCl3) δ: -2.2. HR
MS 497.1838 [M+H]+ (calculated for C26H30N2O6P 497.1836).
Compound 4e: Colorless liquid, IR(KBr), (cm-1): 1677 (C=O), 1604, 1450 (Ar), 1264 (P=O),
1029 (P-O). 1H NMR (CDCl3) δ: 7.78 (d, J = 8.8 Hz, 1H, 5-H), 7.36 (t, J = 7.9 Hz, 2H, 16, 16′-
H), 7.27 (m, 5H), 7.16 (m, 3H), 6.76 (dd, J = 8.8, 2.4 Hz, 1H, 4-H), 3.85 (s, 3H, 9-H), 3.78 (s,
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3H, OCH3), 3.47 (bs, 4H, 11,13-H), 3.05 (bs, 4H, 10,12-H), 2.58 (s, 3H, 8-H). 13C NMR (CDCl3)
δ: 196.6 (7-C), 163.7 (3-C), 160.6, 151.2 (d, J = 7.0 Hz, 1-C), 150.5 (d, J = 6.2 Hz, 14-C), 132.2
(5-C), 130.9, 129.8 (16, 16′-C), 128.8, 125.2 (17-C), 123.2 (d, J = 7.1 Hz, 6-C), 120.0 (d, J = 5.1
Hz, 15, 15′-C), 110.7 (4-C), 109.3, 106.3 (d, J = 2.7 Hz, 2-C), 103.2, 55.8 (9-C), 55.2 (OCH3),
49.5 (d, J = 4.3 Hz, 11,13-C), 44.6 (10,12-C), 30.8 (8-C). 31P NMR (CDCl3) δ: -4.8. HR MS
497.1839 [M+H]+ (calculated for C26H30N2O6P 497.1836).
Compound 4f: Light yellow liquid, IR(KBr), (cm-1): 1679 (C=O), 1606, 1458 (Ar), 1255
(P=O), 1028 (P-O). 1H NMR (CDCl3) δ: 7.69 (d, J = 8.8 Hz, 1H, 5-H), 7.28 (d, J = 2.4 Hz, 1H,
2-H), 6.70 (dd, J = 8.8, 2.4 Hz, 1H, 4-H), 3.84 (s, 3H, 9-H), 3.63 (m, 4H, 15, 17-H), 3.50 (m, 4H,
14, 16-H), 3.26 (m, 4H, 11,13-H), 2.54 (s, 3H, 8-H), 2.31 (m, 4H, 12, 14-H), 2.24 (s, 3H, NCH3).
13C NMR (CDCl3) : 196.5 (7-C), 163.5 (3-C), 151.2 (d, J = 6.4 Hz, 1-C), 132.3(5-C), 122.5 (d,
J = 6.8 Hz, 6-C), 110.3 (4-C), 106.4 (d, J = 3.0 Hz, 2-C), 55.8 (9-C), 55.0 (d, J = 5.8 Hz, 11, 13-
C), 49.5 (d, J = 4.4 Hz, 14, 16-C), 46.2 (NCH3), 44.6 (d, J = 1.7 Hz, 10, 12-C), 42.2 (15, 17-C),
29.8 (8-C). 31P NMR (CDCl3) : 10.9. HR MS 452.1263 [M+H]+ (calculated for
C18H29Cl2N3O4P 452.1267).
Compound 4g: Light yellow liquid, IR(KBr), (cm-1): 1686 (C=O), 1605, 1456 (Ar), 1252
(P=O), 1029 (P-O). 1H NMR (CDCl3) δ: 7.69 (d, J = 8.8 Hz, 1H, 5-H), 7.31 (dd, J = 2.4, 0.8 Hz,
1H, 2-H), 6.72 (dd, J = 8.8, 2.4 Hz, 1H, 4-H), 3.85 (s, 3H, 9-H), 3.62 (m, 4H, 15,17-H), 3.42 (m,
4H, 14,16-H), 3.30 (m, 4H, 11,13-H), 3.20 (m, 4H, 12,14-H), 2.55 (s, 3H, 8-H), 1.44 (s, 9H, -
C(CH3)3). 13C NMR (CDCl3) : 196.5 (7-C), 163.5 (3-C), 154.5 (-COOC(CH3)3), 151.2 (d, J =
6.4 Hz, 1-C), 132.4 (5-C), 122.3 (d, J = 6.6 Hz, 6-C), 110.2 (4-C), 106.5 (d, J = 2.9 Hz, 2-C),
80.1 (-C(CH3)3), 55.8 (9-C), 49.4 (d, J = 4.4 Hz, 14,16-C), 44.5 (d, J = 1.9 Hz, 10,12-C), 44.3
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(11,13-C), 42.2 (15,17-C), 29.8 (8-C), 28.3 (-C(CH3)3). 31P NMR (CDCl3) : 10.5. HR MS
538.1631 [M+H]+ (calculated for C22H35Cl2N3O6P 538.1635).
Compound 4h: Light yellow liquid, IR(KBr), (cm-1): 1680 (C=O), 1602, 1452 (Ar), 1256
(P=O), 1039 (P-O). 1H NMR (CDCl3) δ 7.69 (d, J = 8.8 Hz, 1H, 5-H), 7.33 (dd, J = 2.4, 0.8 Hz,
1H, 2-H), 6.71 (dd, J = 8.8, 2.4 Hz, 1H, 5-H), 3.85 (s, 3H, 9-H), 3.78 (s, 3H, OCH3), 3.72 (m,
4H, 15,17-H), 3.52 (m, 4H, 14,16-H), 3.42 (m, 4H, 11,13-H), 3.05 (m, 4H, 12,14-H), 2.56 (s, 3H,
8-H). 13C NMR (CDCl3) : 196.6 (7-C), 163.6 (3-C), 160.5, 152.5, 151.2 (d, J = 6.5 Hz, 1-C),
132.4 (5-C), 129.9, 122.5 (d, J = 6.7 Hz, 6-C), 110.2 (4-C), 109.2, 106.5 (d, J = 3.0 Hz, 2-C),
105.2, 102.9, 55.8 (9-C), 55.2 (OCH3), 49.7 (d, J = 5.8 Hz, 11,13-C), 49.4 (d, J = 4.4 Hz, 14,16-
C), 44.7 (d, J = 2.1 Hz,10,12-C), 42.3 (15,17-C), 29.8 (8-C). 31P NMR (CDCl3) : 10.6. HR MS
544.1527 [M+H]+ (calculated for C24H33Cl2N3O5P 544.1529).
ACKNOWLEDGEMENTS
Financial support from The National Natural Science Foun-dation of China (No. 21072178),
Innovation Specialist Projects of Henan Province (No. 114200510023), Technology and Science
talent Cultivation Project in Zhengzhou City (No. 112PLJRC359), The Special Fund for the
Doctoral Program of Higher Education (No. 20124101110003), Foundational and Frontier
Technology Research Foundation of Henan Province for their financial support(No.
132300410027).
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Table 1 Phosphoramide piperazine derivatives of paeonol
Entry
4a
R1
R2
Yield (%)
C6H5O
C6H5O
CH3
80
78
4b
(CH3)3COCO
p-ClC6H4
p-CH3OC6H4
m-CH3OC6H4
CH3
C6H5O
C6H5O
71
77
4c
4d
C6H5O
71
80
79
4e
4f
(ClCH2CH2)2N
(ClCH2CH2)2N
4g
(CH3)3COCO
m-CH3OC6H4
(ClCH2CH2)2N
86
4h
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Table 2. The data of 31P NMR and partial 13C NMR split by phosphor atom for 4a-h
13C NMR
31P
Entr
y
C-1
C-2
C-6
C-10(12) C-11(13)
C-14
C-15, 15
NMR
2J(Hz) 3J(Hz) 3J(Hz) 2J(Hz) 3J(Hz) 2J(Hz) 3J(Hz)
151.1
7.1
106.0
2.8
123.1
7.0
44.4
1.9
54.5
5.6
150.4
6.5
119.9
5.1
4a
4b
4c
4d
4e
4f
-1.9
-2.2
-2.4
-2.2
-4.8
10.9
10.5
10.6
151.0
6.9
106.3
2.8
123.1
7.0
44.4
1.7
44.3
2.8
150.4
6.4
119.9
5.2
151.1
7.0
106.4
2.7
123.2
6.8
44.5
1.9
49.6
5.4
150.5
6.5
120.0
5.1
151.2
7.2
106.3
2.7
123.2
7.0
44.7
/
51.1
5.1
150.5
6.3
120.0
5.1
151.2
7.0
106.3
2.7
123.2
7.1
44.6
/
49.5
4.3
150.5
6.2
120.0
5.1
151.2
6.4
106.4
3.0
122.5
6.8
44.6
1.7
55.0
5.8
49.5
4.4
/
/
/
151.2
6.4
106.5
2.9
122.3
6.6
44.5
1.9
44.3
/
49.4
4.4
4g
4h
151.2
6.5
106.5
3.0
122.5
6.7
44.7
2.1
49.7
5.8
49.4
4.4
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H3C
O
OH
OCH3
Fig. 1. The structure of paeonol
R2
N
O
OH
R1
N
H3C
R2
P
O
P
O
P
O
O
O
NEt3
OCH3
R2
N
R1
R1
HCl
HN
+
Cl
N
N
CH2Cl2,-78℃
NEt3, K2CO3
acetone, r.t.
H3C
Cl
Cl
OCH3
2
3
4
1
Scheme 1 Synthesis of phosphoramide piperazine analogues of paeonol 4a-h
Cl
14
N P
11
N R2
11
N R2
10
10
O
O
P
15
17
15
N
O
N
14
16
17
16
12
13
12
O
6
O
13
Cl
1
1
15'
2
2
9
9
7
8
7
8
O
O
16'
3
3
6
O
O
5
4
5
4
a
b
Fig. 2. The structures of compounds 4a-e (a) and 4f-h (b)
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