A convenient synthesis of novel phosphoramide mustard analogues of 2-arylquinolone

Article abstract of DOI:10.1080/10426500802625529

A series of novel phosphoramide mustard analogues of 2-arylquinolones are synthesized through a convenient and facile phosphorylated reaction, and their structures are elucidated by NMR, IR, and HR MS. The amino acid esters and phosphoryl nitrogen mustard are linked to 2-arylquinolone to improve their undesirable physicochemical and biological properties.

Full text of DOI:10.1080/10426500802625529

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A Convenient Synthesis of
Novel Phosphoramide Mustard
Analogues of 2-Arylquinolone
Jinwei Yuan a , Xiaolan Chen a , Lingbo Qu a b
,
Shouren Zhang a , Jiansha Lu a & Yufen Zhao a c
a Key Laboratory of Organic Chemistry and Chemical
Biology, Henan Province, Department of Chemistry,
Zhengzhou University, Zhengzhou, P. R. China
b Henan University of Technology, Henan Province,
Zhengzhou, P. R. China
c Key Laboratory for Bioorganic Phosphorus
Chemistry and Chemical Biology, Ministry of
Education, Department of Chemistry, School of
Life Sciences and Engineering, Tsinghua University,
Beijing, P. R. China
Published online: 03 Nov 2009.
To cite this article: Jinwei Yuan , Xiaolan Chen , Lingbo Qu , Shouren Zhang ,
Jiansha Lu & Yufen Zhao (2009): A Convenient Synthesis of Novel Phosphoramide
Mustard Analogues of 2-Arylquinolone, Phosphorus, Sulfur, and Silicon and the Related
Elements, 184:11, 2936-2944
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Phosphorus, Sulfur, and Silicon, 184:2936–2944, 2009
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500802625529
A Convenient Synthesis of Novel Phosphoramide
Mustard Analogues of 2-Arylquinolone
Jinwei Yuan,1 Xiaolan Chen,1 Lingbo Qu,1,2
Shouren Zhang,1 Jiansha Lu,1 and Yufen Zhao1,3
1Key Laboratory of Organic Chemistry and Chemical Biology, Henan
Province, Department of Chemistry, Zhengzhou University, Zhengzhou,
P. R. China
2Henan University of Technology, Henan Province, Zhengzhou,
P. R. China
3Key Laboratory for Bioorganic Phosphorus Chemistry and Chemical
Biology, Ministry of Education, Department of Chemistry, School of Life
Sciences and Engineering, Tsinghua University, Beijing, P. R. China
A series of novel phosphoramide mustard analogues of 2-arylquinolones are synthe-
sized through a convenient and facile phosphorylated reaction, and their structures
are elucidated by NMR, IR, and HR MS. The amino acid esters and phosphoryl
nitrogen mustard are linked to 2-arylquinolone to improve their undesirable physic-
ochemical and biological properties.
Keywords Amino acid ester; 2-arylquinolone; phosphoramide mustard
INTRODUCTION
2-Arylquinolones are a class of molecules used as aza analogues of
flavones (Figure 1). Over the last 10 years, 2-arylquinolones and related
compounds have been the subject of extensive studies as potent cyto-
toxic antimitotic agents,1,2 antibacterial agents, anti-platelet agents,
and as cardiovascular protectors.3,4,5 Moreover, 2-arylquinolones have
been the subject of investigations as a new class of antitumor agents.
With the goal of enhancing their pharmacological and biological activ-
ity, several 2-arylquinolone derivatives have been synthesized previ-
ously, and their biological activities have also been studied.6,7,8,9
Glyciphosphoramide, N,N-bis(chloroethyl)-Nꢀ,Nꢀꢀ-bis-(carbethoxy-
methyl)phosphoric triamide (Figure 2 is a synthetic anticancer agent
Received 12 September 2008; accepted 13 November 2008.
Address correspondence to Xiaolan Chen and Yufen Zhao, Department of Chemistry,
Zhengzhou University, 75 Daxue Road, Henan Province, Zhengzhou 450052, P.R. China.
E-mail: chenxl@zzu.edu.cn
2936

Phosphoramide Mustard Analogues of 2-Arylquinolone
2937
FIGURE 1 X = O: flavone; X = N: 2-phenyl-4-quinolone.
used against a broad spectrum of tumor in animal tests and has been
undergoing evaluation in China for some time. Glyciphosphoramide
is activated in the presence of plasma or serum. This unique prop-
erty of glyciphosphoramide makes the compound a useful agent for
topical use in the treatment of cancerous ulceration and malignant
tumors.10–12 Within the pharmaceutical industry, several candidates
belonging to this structural class have been synthesized as potential
antitumor agents.13,14 In the hope of increasing the biological speci-
ficity of these compounds, the phosphoramide mustard group has been
linked to various carrier molecules such as carbohydrates.15,16
Our interest was in synthesizing a series of amino acid esters and
phosphoryl nitrogen mustard linked 2-arylquinolone derivatives to im-
prove their undesirable physicochemical and biological properties as
potential antitumor agents. In the work described in this article, novel
phosphoramide mustard analogues of 2-arylquinolone 4a–g are synthe-
sized through a convenient and facile phosphorylated reaction (Scheme
1). The structures of compounds 4a–g have been elucidated by NMR,
IR, and HR MS for the first time.
FIGURE 2 Glyciphosphoramide.

2938
J. Yuan et al.
SCHEME 1 Synthesis of phosphoramide mustard analogues of 2-aryl-
quinolone 4a–g.
RESULTS AND DISCUSSION
In the synthesis of phosphoramide mustard analogues of 2-
arylquinolone (4) (Scheme 1), bis-(β-chloroethyl)-amine hydrochloride
was first reacted with phosphorus oxychloride at reflux temperature
to give di-(2-chloroethyl)-phosphoramidic dichloride (1). Then it was
coupled with different L-amino acid esters hydrochloride salts at low
temperature to achieve N,N-bis(2-chloroethyl) phosphonamidic chlo-
rides (2), which were not purified further by the chromatography. 2-
Arylquinolone (3) was reacted with N,N-bis(2-chloroethyl) phospho-
namidic chloride (2) in THF by a convenient and facile phosphorylation
reaction to form phosphoramide mustard analogues of 2-arylquinolone
(4) in the presence of triethylamine at low temperatures. The yields of
the final purified compounds were in the range 30–49%. The structures
of all the newly synthesized 2-arylquinolone derivatives were confirmed
by NMR, IR, and HR MS.

Phosphoramide Mustard Analogues of 2-Arylquinolone
2939
2-Arylquinolones can be synthesized by several pathways.2,3 The
degree of unsaturation in the C-ring causes it to exist in tautomeric
equilibriums, 2-arylquinolone and 2-aryl-4-hydroquinoline isomer. 2-
Arylquinolones are found to exist exclusively in solution phase and
solid state.17 The experimental results show that the final product is
compound (4). This conclusion was confirmed by 13C NMR. For exam-
ple, 13C NMR of compound 4a showed 3-C at δ 109.01(3JP-C = 2.83
Hz), 4-C at δ 154.82(2JP-C = 7.38 Hz), and 10-C at δ 108.57(3JP-C
=
5.00 Hz) were split into doublet, respectively. The reason is because the
phosphorus atom makes the surrounding carbon atoms split. We spec-
ulate that 2-arylquinolone (3) first undergoes a tautomeric change to
become 2-aryl-4-hydroquinoline (3ꢀ), and then reacts with N, N-bis(2-
chloroethyl) phosphonamidic chloride (2) to obtain the final product
(4).
NMR spectra of 4a, 4d, 4e, 4f, and 4g show only a group of signals
because these compounds are formed by a pair of enantiomers, respec-
tively. However, two groups of signals could be found from NMR spectra
of 4b and 4c. The reason is due to the chirality at the phosphorus center
and L-amino acid esters. Each of compound 4b and 4c includes two iso-
mers (Sp and Rp), and the confirmation of the presence of two isomers
is shown by 31P NMR. Separation of the diastereoisomers by column
chromatography has been difficult and problematic. By using 31P NMR,
we were able to approximately determine the ratios of each isomer. It is
interesting to note that in the case of the L-alanine methylester isomer
(4b and 4c), a ratio of approximately 20% of isomer | and 80% isomer
|| can be obtained. This indicates that the approach of 2-arylquinolone
in the final segment of the synthesis is affected by the configuration at
the amino acid terminal of the phosphorochloridate.
In summary, novel phosphoramide mustard analogues of 2-
arylquinolone 4a–g have been synthesized through a versatile method.
Work is in progress in our laboratory to further evaluate the biological
activity of these analogues as potential antitumor prodrugs.
EXPERIMENTAL
All experiments involving water-sensitive compounds were conducted
under scrupulously dry conditions. The solvents were dried by appro-
priate methods.18 IR spectra were recorded on a Shimadazu IR-408. 1H,
13C, and 31P NMR spectra were recorded on a Bruker Avance DPX spec-
trometer operating at 400.13, 100.61, and 161.98 MHz, respectively,
with 13C and 31P spectra being recorded as proton-decoupled. All NMR
spectra were recorded in CDCl3 at room temperature (20◦C 3◦C). 1H

2940
J. Yuan et al.
and 13C chemical shifts are quoted in parts per million downfield from
TMS. 31P chemical shifts are quoted in parts per million relative to an
external 85% H3PO4 standard. J values refer to coupling constants,
and signal splitting patterns are described as singlet (s), broad singlet
(bs), doublet (d), triplet (t), quartet (q), multiplet (m), or combinations
thereof. TLC was performed on silica gel plates and preparative chro-
matograph on columns of silica gel (200–300 mesh). TOF MS were
recorded on Q-Tof Micro.
Di-(2-chloroethyl)-phosphoramidic Dichloride (1)
A suspension of bis-(β-chloroethyl)-amine hydrochloride (40 g, 0.23
mol) in distilled phosphorus oxychloride (174 mL, 1.78 mol, b.p.
105.5–107.5◦C) was refluxed for 24 h until complete solution resulted.
The excess phosphorus oxychloride was removed by distillation, and
the residue was crystallized from acetone-petroleum ether, yielding the
desired product, mp 55–57◦C.19
General Procedure to Prepare N,N-Bis(2-chloroethyl)
Phosphonamidic Chloride (2a–g)
Di-(2-chloroethyl)-phosphoramidic dichloride (5 g, 19.5 mmol) and the
appropriate L-amino acid ester hydrochloric salt (19.5 mmol) were sus-
pended in anhydrous dichloromethane. Anhydrous triethylamine (2.7
mL, 19.5 mmol) was added dropwise at –78◦C, and after 2 h, the re-
action was left to warm to room temperature. The formation of N,N-
bis(2-chloroethyl) phosphonamidic chloride was monitored by 31P NMR.
After 6–15 h, the solvent was removed under reduced pressure, and the
solid obtained was washed with anhydrous ether (2 × 20 mL), filtered,
and the filtrate was concentrated to dryness to give the crude products
(2), which were used without further purification.
General Procedure to Prepare Phosphoramide Mustard
Analogues of 2-Arylquinolone (4a–g)
A solution of 2-arylquinolone (1.8 mmol) and the appropriate N, N-
bis(2-chloroethyl) phosphonamidic chloride (2) (2.0–3.0 mol) in anhy-
drous tetrahydrofuran was stirred at –40◦C for 30 min, and anhydrous
triethylamine (0.3 mL, 2.0 mmol) was added dropwise to the solution
over a period of 30 min. After 1 h, the reaction was left to warm to
room temperature and stirred for a further 10–24 h. The solution was
filtered, and the filtrate was evaporated to dryness to give the residues

Phosphoramide Mustard Analogues of 2-Arylquinolone
2941
as yellow oils. The residues were purified by column chromatography
on silica gel (cyclohexane:ethyl acetate, 3:1).
Compound 4a (C24H28Cl2N3O6P)
Mp: 165–166◦C, Yield: 49%. HR MS 556.1170 [M + H]+ (calculated
for C24H28Cl2N3O6PH 556.1171); IR(KBr) ν(cm−1): 3408 (N-H), 2926,
2854 (-CH3, -CH2), 1748 (C = O), 1619 (heterocycle), 1584 (C = N),
1374 (P = O), 1212 (P-O-Ar), 772 (C-Cl); 1H NMR(CDCl3) δ: 7.77 (d, 1H,
4
4JP-H = 1.68 Hz, 3-H), 6.59 (d, 1H, JH-H = 2.24 Hz, 6-H), 7.16 (d, 1H,
3
4JH-H = 2.08 Hz, 8-H), 8.12 (d, 2H, JH-H = 8.12 Hz, 2ꢀ6ꢀ-H), 7.47 (m,
3H, 3ꢀ4ꢀ5ꢀ-H), 4.08 (s, 3H, 5-OCH3), 4.03 (s, 3H, 7-OCH3), 3.73 (m, 8H,
NCH2CH2Cl), 3.70 (s, 3H, OOCH3); 13C NMR(CDCl3) δ: 158.94 (2-C),
109.01 (d, 3JP-C = 2.83 Hz, 3-C), 154.82 (d, 2JP-C = 7.38 Hz, 4-C), 155.73
(5-C), 99.70 (6-C), 161.19 (7-C), 101.38 (8-C), 153.52 (9-C), 108.57 (d,
3JP-C = 5.00 Hz, 10-C), 138.64 (C-1ꢀ), 128.73 (2ꢀ6ꢀ-C), 127.55 (3ꢀ5ꢀ-C),
2
129.64 (4ꢀ-C), 55.68 (5-OCH3), 56.28 (7-OCH3), 49.21 (d, JP-C = 4.57
Hz, NCH2), 42.24 (CH2Cl), 42.06 (d, 2JP-C = 3.42 Hz, -CH2), 171.37 (d,
3JP-C = 9.40 Hz, C = O), 52.43 (OOCH3); 31P NMR(CDCl3) δ: 11.00.
Compound 4b (C25H30Cl2N3O6P)
Mp: 155–157◦C, Yield: 36%. HR MS 570.1320 [M + H]+ (calculated
for C25H30Cl2N3O6PH 570.1328); IR(KBr) ν(cm−1): 2929, 2851 (-CH3,
-CH2), 1743 (C = O) 1636(heterocycle), 1609 (C = N), 1374 (P = O),
1
4
1213 (P-O-Ar), 772 (C-Cl); H NMR(CDCl3) δ: 7.81, 7.79 (d, 1H, JP-H
4
= 1.56 Hz, 3-H), 6.60, 6.59 (d, 1H, JH-H = 2.24Hz, 6-H), 7.17, 7.16 (d,
1H, JH-H = 2.04 Hz, 8-H), 8.14, 8.11 (d, 2H, JH-H = 8.36 Hz, 2ꢀ6ꢀ-H),
7.47, 7.47 (m, 3H, 3ꢀ4ꢀ5ꢀ-H), 4.07, 4.03 (s, 3H, 5-OCH3), 3.96, 3.96 (s,
3H, 7-OCH3), 3.68, 3.52 (m, 8H, NCH2CH2Cl), 4.10, 4.10 (m, 1H, -CH),
4
3
4
1.44, 1.26 (d, 3H, JP-H = 6.72 Hz, -CH3), 3.74, 3.60 (s, 3H, OOCH3);
13C NMR(CDCl3) δ: 158.94, 158.86 (2-C), 108.65, 108.57 (d, 3JP-C = 2.78
Hz, 3-C), 154.92, 154.85 (d, 2JP-C = 6.91 Hz, 4-C), 155.93, 155.73 (5-C),
99.68, 99.60 (6-C), 161.22, 161.19 (7-C), 101.38, 101.26 (8-C), 153.49,
3
153.49 (9-C), 109.17, 109.14 (d, JP-C = 3.03 Hz, 10-C), 138.67, 138.63
(C-1ꢀ), 128.75, 128.75 (2ꢀ6ꢀ-C), 127.54, 127.54 (3ꢀ5ꢀ-C), 129.66, 129.63
(4ꢀ-C), 56.33, 56.15 (5-OCH3), 55.71, 55.68 (7-OCH3), 49.49, 49.17 (d,
2JP-C = 4.56 Hz, NCH2), 42.20, 42.20 (CH2Cl), 49.74, 49.71 (d, JP-C
=
2
3
3.20 Hz, -CH), 21.57, 20.83 (d, JP-C = 3.72 Hz, -CH3), 174.49, 174.05
(d, 3JP-C = 8.58 Hz, C = O), 52.57, 52.48 (OOCH3); 31P NMR(CDCl3) δ:
9.76, 9.56.
Compound 4c (C26H32Cl2N3O6P)
Mp: 167–169◦C, Yield: 40%. HR MS 584.1480 [M + H]+ (calculated
for C26H32Cl2N3O6PH 584.1484); IR(KBr) ν(cm−1): 3399 (N-H), 2930,

2942
J. Yuan et al.
2852 (-CH3, -CH2), 1740 (C = O), 1626 (heterocycle), 1285 (P = O),
1
4
1213 (P-O-Ar), 776 (C-Cl); H NMR(CDCl3) δ: 7.82, 7.79 (d, 1H, JP-H
= 1.48 Hz, 3-H), 6.60, 6.58 (d, 1H, J = 2.16Hz, 6-H), 7.17, 7.16 (d,
1H, JH-H = 1.96 Hz, 8-H), 8.14, 8.12 (d, 2H, JH-H = 8.00 Hz, 2ꢀ6ꢀ-H),
7.47, 7.47 (m, 3H, 3ꢀ4ꢀ5ꢀ-H), 4.07, 4.03 (s, 3H, 5-OCH3), 3.96, 3.96 (s,
3H, 7-OCH3), 3.60, 3.60 (m, 8H, NCH2CH2Cl), 4.05, 4.05 (m, 1H, -CH),
4
4
3
3
1.44, 1.28 (d, 3H, JH-H = 6.88 Hz, -CH3), 4.18, 4.18 (q, 2H, JH-H
=
7.36 Hz, OOCH2), 1.26, 1.15 (t, 3H, JH-H = 7.16 Hz, OOCCH3); 13C
3
3
NMR(CDCl3) δ: 158.94, 158.87 (2-C), 108.68, 108.64 (d, JP-C = 3.56
Hz, 3-C), 154.94, 154.87 (d, 2JP-C = 7.13 Hz, 4-C), 155.93, 155.76 (5-C),
99.66, 99.58 (6-C), 161.21, 161.18 (7-C), 101.37, 101.25 (8-C), 153.50,
3
153.50 (9-C), 109.17, 109.13 (d, JP-C = 3.09 Hz, 10-C), 138.67, 138.65
(C-1ꢀ), 128.75, 128.75 (2ꢀ6ꢀ-C), 127.54, 127.54 (3ꢀ5ꢀ-C), 129.65, 129.61
(4ꢀ-C), 56.34, 56.14(5-OCH3), 55.71, 55.68 (7-OCH3), 49.51, 49.20 (d,
2JP-C = 4.49 Hz, NCH2), 42.21, 42.21 (CH2Cl), 49.77, 49.74 (d, 2JP-C
=
3.32 Hz, -CH), 21.63, 20.88 (d, 3JP-C = 3.52 Hz, -CH3), 174.03, 173.57 (d,
3JP-C = 8.84 Hz, C = O), 61.65, 61.57 (OOCH2), 14.16, 14.00 (OOCCH3);
31P NMR(CDCl3) δ: 9.81, 9.58.
Compound 4d (C24H27Cl3N3O6P)
Mp: 80–81◦C, Yield: 30%. HR MS 590.0780 [M + H]+ (calculated
for C24H27Cl3N3O6PH 590.0781); IR(KBr) ν(cm−1): 3411 (N-H), 2954,
2926, 2854 (-CH3, -CH2), 1748 (C = O), 1619 (heterocycle), 1577 (C =
N), 1279 (P = O), 1211 (P-O-Ar), 752 (C-Cl); 1H NMR(CDCl3) δ: 7.74 (d,
4
4
1H, JP-H = 1.52 Hz, 3-H), 6.60 (d, 1H, JH-H = 2.24Hz, 6-H), 7.13 (d,
1H, 4JH-H = 2.20 Hz, 8-H), 8.08 (d, 2H, 3JH-H = 8.68 Hz, 2ꢀ6ꢀ-H), 7.44 (d,
2H, 3JH-H = 8.60 Hz, 3ꢀ5ꢀ-H), 4.08 (s, 3H, 5-OCH3), 3.96 (s, 3H, 7-OCH3),
3.71 (m, 8H, NCH2CH2Cl), 3.52 (m, 2H, -CH2), 3.71 (s, 3H, OOCH3); 13
C
3
NMR(CDCl3) δ: 157.60 (2-C), 108.63 (d, JP-C = 2.88 Hz, 3-C), 155.00
(d, 2JP-C = 7.11 Hz, 4-C), 155.74 (5-C), 99.91 (6-C), 161.35 (7-C), 101.34
(8-C), 153.52 (9-C), 108.72 (d, JP-C = 3.62 Hz, 10-C), 137.08 (C-1ꢀ),
3
128.84 (2ꢀ6ꢀ-C), 128.92 (3ꢀ5ꢀ-C), 135.85 (4ꢀ-C), 55.72 (5-OCH3), 56.34 (7-
OCH3), 49.20 (d, 2JP-C = 4.59 Hz, NCH2), 42.23 (CH2Cl), 42.05 (d, 2JP-C
3
= 3.44 Hz, -CH2), 171.38 (d, JP-C = 9.40 Hz, C = O), 52.48 (OOCH3);
31P NMR(CDCl3) δ: 11.05.
Compound 4e (C25H30Cl2N3O7P)
Mp: 105–106◦C, Yield: 39%. HR MS 586.1272 [M + H]+ (calculated
for C25H30Cl2N3O7PH 586.1277); IR(KBr) ν(cm−1): 3422 (N-H), 2958,
2926, 2853 (-CH3, -CH2), 1747 (C = O), 1616 (heterocycle), 1375 (P =
1
4
O), 1212 (P-O-Ar), 832 (C-Cl); H NMR(CDCl3) δ: 7.72 (d, 1H, JP-H
=
=
4
4
1.52 Hz, 3-H), 6.56 (d, 1H, JH-H = 2.20Hz, 6-H), 7.13 (d, 1H, JH-H

Phosphoramide Mustard Analogues of 2-Arylquinolone
2943
3
3
2.08 Hz, 8-H), 8.10 (d, 2H, JH-H = 8.84 Hz, 2ꢀ6ꢀ-H), 7.00 (d, 2H, JH-H
= 8.88 Hz, 3ꢀ5ꢀ-H), 4.05 (s, 3H, 5-OCH3), 3.95 (s, 3H, 7-OCH3), 3.87(s,
3H, 4ꢀ-OCH3), 3.72(m, 8H, NCH2CH2Cl), 3.51(m, 2H, -CH2), 3.72(s,
3H, OOCH3); 13C NMR(CDCl3) δ: 158.49 (2-C), 108.45 (d, JP-C = 2.78
3
2
Hz, 3-C), 154.70 (d, JP-C = 7.35 Hz, 4-C), 155.74 (5-C), 99.37 (6-C),
3
161.16 (7-C), 101.24 (8-C), 153.50 (9-C), 108.22 (d, JP-C = 4.87 Hz,
10-C), 128.84 (C-1ꢀ), 128.95 (2ꢀ6ꢀ-C), 114.09 (3ꢀ5ꢀ-C), 161.07 (4ꢀ-C), 55.39
(5-OCH3), 56.27 (7-OCH3), 55.68 (4ꢀ-OCH3), 49.22 (d, JP-C = 4.56 Hz,
2
NCH2), 42.25 (CH2Cl), 42.07 (d, 2JP-C = 3.35 Hz, -CH2), 171.40 (d, 3JP-C
= 9.28 Hz, C = O), 52.44 (OOCH3); 31P NMR(CDCl3) δ: 11.00.
Compound 4f (C25H30Cl2N3O6P)
Mp: 77–78◦C, Yield: 36%. HR MS 570.1322 [M + H]+ (calculated for
C25H30Cl2N3O6PH 570.1328); IR(KBr) ν(cm−1): 3442 (N-H), 2927, 2856
(-CH3, -CH2), 1744 (C = O), 1634 (heterocycle), 1374 (P = O), 1212
1
4
(P-O-Ar), 771 (C-Cl); H NMR(CDCl3) δ: 7.73 (d, 1H, JP-H = 1.68 Hz,
4
4
3-H), 6.58 (d, 1H, JH-H = 2.28Hz, 6-H), 7.13 (d, 1H, JH-H = 2.28 Hz,
8-H), 8.01 (d, 2H, 3JH-H = 8.20 Hz, 2ꢀ6ꢀ-H), 7.27 (d, 2H, 3JH-H = 8.00 Hz,
3ꢀ5ꢀ-H), 4.06 (s, 3H, 5-OCH3), 3.96 (s, 3H, 7-OCH3), 2.41 (s, 3H, 4ꢀ-CH3),
3.75 (m, 8H, NCH2CH2Cl), 3.51 (m, 2H, -CH2), 3.75 (s, 3H, OOCH3); 13
C
NMR(CDCl3) δ: 158.96 (2-C), 108.79 (d, 3JP-C = 2.90 Hz, 3-C), 154.67 (d,
2JP-C = 8.18 Hz, 4-C), 155.71 (5-C), 99.54 (6-C), 161.13 (7-C), 101.41 (8-
C), 153.58 (9-C), 108.45 (d, 3JP-C = 4.97 Hz, 10-C), 135.83 (C-1ꢀ), 127.40
(2ꢀ6ꢀ-C), 129.46 (3ꢀ5ꢀ-C), 139.79 (4ꢀ-C), 55.69 (5-OCH3), 56.28 (7-OCH3),
21.36 (4ꢀ-CH3), 49.24 (d, 2JP-C = 4.50 Hz, NCH2), 42.24 (CH2Cl), 42.07
2
3
(d, JP-C = 3.33 Hz, -CH2), 171.39 (d, JP-C = 9.28 Hz, C = O), 52.45
(OOCH3); 31P NMR(CDCl3) δ: 10.93.
Compound 4g (C26H32Cl2N3O6P)
Mp: 85–86◦C, Yield: 32%. HR MS 584.1485 [M + H]+ (calculated for
C26H32Cl2N3O6PH 584.1484); IR(KBr) ν(cm−1): 3402 (N-H), 2925, 2848
(-CH3, -CH2), 1744 (C = O), 1619 (heterocycle), 1591 (C = N), 1350 (P
1
4
= O), 1210 (P-O-Ar), 829 (C-Cl); H NMR(CDCl3) δ: 7.75 (d, 1H, JP-H
= 1.52 Hz, 3-H), 6.58 (d, 1H, 4JH-H = 2.16Hz, 6-H), 7.14 (d, 1H, 4JH-H
=
2.16 Hz, 8-H), 8.02 (d, 2H, JH-H = 8.16 Hz, 2ꢀ6ꢀ-H), 7.28 (d, 2H, JH-H
= 8.16 Hz, 3ꢀ5ꢀ-H), 4.06 (s, 3H, 5-OCH3), 3.96 (s, 3H, 7-OCH3), 2.41 (s,
3H, 4ꢀ-CH3), 3.71 (m, 8H, NCH2CH2Cl), 3.51 (m, 2H, -CH2), 4.18 (q, 2H,
3
3
3JH-H = 2.12 Hz, OOCH2), 1.25 (t, 3H, 3JH-H = 2.36 Hz, -OOCCH3); 13
C
NMR(CDCl3) δ: 158.96 (2-C), 108.82 (d, 3JP-C = 3.02 Hz, 3-C), 154.73 (d,
2JP-C = 7.35 Hz, 4-C), 155.74 (5-C), 99.52 (6-C), 161.12 (7-C), 101.39 (8-
C), 153.58 (9-C), 108.48 (d, 3JP-C = 5.07 Hz, 10-C), 135.87 (C-1ꢀ), 127.42
(2ꢀ6ꢀ-C), 129.46 (3ꢀ5ꢀ-C), 139.77 (4ꢀ-C), 55.69 (5-OCH3), 56.29 (7-OCH3),

2944
J. Yuan et al.
49.28 (d, 2JP-C = 4.75 Hz, NCH2), 42.27 (CH2Cl), 42.21 (d, 2JP-C = 3.05
3
Hz, -CH2), 170.96 (d, JP-C = 9.69 Hz, C = O), 61.65 (OOCH2), 14.14
(-OOCCH3); 31P NMR(CDCl3) δ: 10.97.
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