Synthesis and characterization of bidentate cyclotriphosphazene derivatives

Article abstract of DOI:10.1080/10426507.2011.583617

Three novel cyclotriphosphazene derivatives were designed. Title compounds were synthesized by the reaction of the dichlorocyclotriphosphazene derivative [N₃P₃Cl₂(O₂C₁₂H ₈)₂] wit

Full text of DOI:10.1080/10426507.2011.583617

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Phosphorus, Sulfur, and Silicon and the
Related Elements
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Synthesis and Characterization of
Bidentate Cyclotriphosphazene
Derivatives
Rui Han a , Xue-lin Ren b , Di Zhang a , Min Wang a , Jun-liang Yang a
Yong Ye a & Yufen Zhao a c
,
a Phosphorus Chemical Engineering Research Center of Henan
Province, Key Laboratory of Chemical Biology and Organic
Chemistry of Henan Province, Department of Chemistry , Zhengzhou
University , Zhengzhou, China
b School of Pharmaceutical Science , Zhengzhou University , Ke Xue
Da Dao 100, Zhengzhou, P. R. China
c Department of Chemistry and Key Laboratory for Chemical Biology
of Fujian Province , Xiamen University , Xiamen, China
Published online: 31 Oct 2011.
To cite this article: Rui Han , Xue-lin Ren , Di Zhang , Min Wang , Jun-liang Yang , Yong Ye & Yufen
Zhao (2011) Synthesis and Characterization of Bidentate Cyclotriphosphazene Derivatives, Phosphorus,
Sulfur, and Silicon and the Related Elements, 186:11, 2202-2207, DOI: 10.1080/10426507.2011.583617
To link to this article: http://dx.doi.org/10.1080/10426507.2011.583617
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Phosphorus, Sulfur, and Silicon, 186:2202–2207, 2011
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426507.2011.583617
SYNTHESIS AND CHARACTERIZATION OF BIDENTATE
CYCLOTRIPHOSPHAZENE DERIVATIVES
Rui Han,1 Xue-lin Ren,2 Di Zhang,1 Min Wang,1
Jun-liang Yang,1 Yong Ye,1 and Yufen Zhao1,3
1Phosphorus Chemical Engineering Research Center of Henan Province, Key
Laboratory of Chemical Biology and Organic Chemistry of Henan Province,
Department of Chemistry, Zhengzhou University, Zhengzhou, China
2School of Pharmaceutical Science, Zhengzhou University, Ke Xue Da Dao 100,
Zhengzhou, P. R. China
3Department of Chemistry and Key Laboratory for Chemical Biology of Fujian
Province, Xiamen University, Xiamen, China
GRAPHICAL ABSTRACT
CH2R
CHO
NaBH
O
4
O
O
O
N
P
N
P
P
P
O
P
P
O
PBr
3
CH2R
O
N
N
CHO
O
N
N
HR
O
O
O
O
1
4a-c: R=cyclen, imdazolyl, morpholino
Abstract Three novel cyclotriphosphazene derivatives were designed. Title com-
pounds were synthesized by the reaction of the dichlorocyclotriphosphazene derivative
[N3P3Cl2(O2C12H8)2] with the potassium salt of 4-hydroxybenzaldehyde, and subsequent
reduction of aldehyde groups to alcohol groups using sodium borohydride. The bromination
reaction was carried out using PBr3 to give N3P3(O2C12H8)2 (OC6H4-p-CH2Br)2. This
compound was employed in reactions with macrocyclic polyamide, imidazole, or morpholine
to produce title compounds. The target compounds were characterized using 1H NMR, 31P
NMR, 13C NMR, IR, and electrospray ionization mass spectra (ESI-MS).
[Supplemental materials are available for this article. Go to the publisher’s online edition of
Phosphorus, Sulfur, and Silicon and the Related Elements for the following free supplemental
resource: Figures S1–S6.]
Keywords Macrocyclic polyamide; cyclotriphosphazene derivatives; imidazole; morpholine
Received 17 March 2011; accepted 20 April 2011.
We all thank the financial supports from the NSFC (Nos. 20602032, 20732004, and 20972143).
Address correspondence to Yong Ye, Phosphorus Chemical Engineering Research Center of Henan Province,
Key Laboratory of Chemical Biology and Organic Chemistry of Henan Province, Department of Chemistry,
Zhengzhou University, Zhengzhou 450052, China. E-mail: yeyong03@mail.nankai.edu.cn
2202

CYCLOTRIPHOSPHAZENE DERIVATIVES
2203
INTRODUCTION
The phosphodiester bonds of DNA are remarkably resistant to hydrolysis under
physiological conditions.1–3 Although many types of enzymes have been harnessed for use
in the laboratory, there is a great deal of interest in the design of artificial nucleases, small
molecular scissors that can cleave DNA hydrolytically. Therefore, designing new ligands
suitable for cleaving DNA under hydrolytic conditions is of considerable importance.
Cyclotriphosphazenes have received considerable interest, not only because of their
wide spectra of chemical and physical properties but also for their importance in synthetic
chemistry. Different side-group structures affect the chemical and physical properties of the
ring systems.4–11 Recently, we reported some polydentate cyclotriphosphazene ligands,12–14
which showed good nuclease activity with a hydrolytic cleavage mechanism. In this work,
we synthesized three bidentate cyclotriphosphazene derivatives in order to obtain more
insight into the selective recognization and efficient cleavage of DNA by different metal
complexes of the cyclotriphosphazene. Their synthetic route is outlined in Scheme 1.
RESULTS AND DISCUSSION
Compound 1 was synthesized according to a modified procedure reported by Carriedo
et al.15 The reaction of [N3P3Cl6] with 2 equiv. of HOC6H4C6H4OH and K2CO3 in acetone
gave the known spiro derivatives [N3P3Cl2(O2C12H8)2], and the dichloro derivative reacted
directly with parasubstituted phenol HOC6H4CHO and NaH in tetrahydrofuran (THF) to
give the compound 1. We found that the reactant ratio had an important effect on the
yield of compound 1 by following the reaction using 31P NMR tracking. Consequently,
a satisfactory yield of the expected compounds can be obtained when an optimum 2.1:1
NaOPhCHO: N3P3Cl2(O2C12H8)2 ratio was used.
The aldehyde group of compound 1 was easily reduced to an alcohol by sodium
borohydride in THF/MeOH. The process was monitored by TLC. Several reagents were
available for converting alcohols to alkyl bromides. Bromination reagents based on hydro-
bromic acid–sulfuric acid were found unemployable, as the reaction was hard to control and
formed insoluble intermediates through reaction with the hydroxyl groups of compound
2. The bromination reaction was achieved using PBr3. Compound 3 was characterized by
1H NMR, 31P NMR, and electrospray ionization mass spectra (ESI-MS). 1H NMR spectra
showed that both the hydroxyl groups were replaced by bromo groups. Two doublet peaks
for aromatic ring protons appeared at 7.03 and 7.43 ppm, and a single peak for bromomethyl
group protons was observed at 4.51 ppm.
Compound 4a was first synthesized from compound 3 in CHCl3/Et3N or
THF/Na2CO3. However, as indicated by the 31P NMR spectra, compound 3 did not
completely disappear. In addition, there were four spots in the TLC, which were very
close. After further optimization, pure compound 4a was obtained in good yield (77%)
when Na2CO3 was selected as the base in CH3CN and the reaction time prolonged to 48
h. The trifluoroacetic acid (TFA) salts of 5a were obtained by deprotection of 4a with a
solution of TFA in dichloromethane at room temperature. Subsequent basification with
1
NaOH gave the free compound 5a which was characterized by H NMR, 31P NMR, 13C
NMR, and ESI-MS.
Similar to 4a, compounds 4b and 4c were produced in 59.6% and 62.0% yield,
respectively. The target compounds 4b and 4c were characterized by 1H NMR, 31P NMR,
13C NMR, HRMS, and ESI-MS spectra. ESI mass spectra for all compounds showed

2204
R. HAN ET AL.
CH2OH
CHO
O
O
O
O
PBr3
THF
NaBH4
N
P
N
P
P
P
P
P
O
O
CH2OH
O
CHO
O
N
N
N
N
THF/CH3OH
O
O
O
O
2
1
CH2R
CH2Br
O
O
O
O
HR
N
P
P
N
O
P
P
CH2R
O
O
N
N
Na2CO3
CH2Br
O
P
N
N
P
O
O
O
O
4
3
4a-c: R= Boc3-cyclen, imdazolyl, morpholino
N
N
H
Boc
H2C
N
H2C
N
BocN
Boc
N
HN
H
N
CF3COOH
O
O
O
O
N
N
P
P
N
O
H2
C
P
P
N
H
O
H2
C
Boc
N
O
N
N
N
O
BocN
N
N
HN
Boc
P
H
N
P
N
O
O
O
O
4a
5a
Scheme 1
[M+H]+ ion. Their structures were similar and 4b was chosen as a sample to explain. In
1H NMR spectra, two doublet peaks at 7.03 and 7.51 ppm were assigned to the protons on
the benzene ring due to their interaction with each other. A single peak at 5.13 ppm was
assigned to methylene group protons between benzene and imidazole. Three singlet peaks
for imidazole group protons were observed at 6.91, 7.1, and 7.58 ppm, respectively.
The 31P NMR spectra of compounds 1–5 are similar. It shows that the two phosphorus
nuclei are chemically equivalent, and their chemical shifts are recorded as doublets (2JPP
=
93 Hz) at low magnetic fields around 25 ppm. The only explanation for the coupling split
is that the two phosphorus nuclei are substituted by diphenol groups. A triplet peak at high
magnetic fields, observed around 9 ppm, was assigned to the phosphorus nuclei which were
substituted by two phenol groups.

CYCLOTRIPHOSPHAZENE DERIVATIVES
2205
CONCLUSION
Three novel bidentate cyclotriphosphazene derivatives were synthesized from spiro
derivatives [N3P3Cl2(O2C12H8)2]. The title compounds were obtained through subsequent
reduction of aldehyde groups, bromination reaction of alcohol groups, and substitution
reactions with macrocyclic polyamide, imidazole, or morpholine. The target compounds
were characterized using IR, 1H NMR, 31P NMR, 13C NMR, and mass spectrometry. The
DNA cleavage activity of the title compounds is currently being examined.
EXPERIMENTAL
General
1H NMR and 31P NMR spectra were measured by using a Bruker AC-P400 spectrom-
eter with TMS and 85% H3PO4 as the internal and external reference, respectively, and with
CDCl3 or DMSO as the solvent. Mass spectra were acquired in positive ion mode using
a Bruker ESQUIRE-LCTM ion trap spectrometer equipped with a gas nebulizer probe,
capable of analyzing ions up to m/z 20,000. The high-resolution mass spectral data for 4b
was recorded on a Bruker APEXII Fourier transform ion cyclotron resonance (FTICR) MS
instrument with an external ion source and analyzed using liquid secondary ion (LSI) MS
with a Cs ion gun in the positive ion mode. Solvents were purified and dried by standard
procedures.
Preparation of 1,1,3,3-Tetraphenylyloxy-5,5,-Bikis(4-Hydroxylmethyl
phenoxy)Cyclotri- Phosphazene (2)
To a solution of 1 (0.75 g, 1 mmoL) in THF/MeOH (20:10 mL) was added sodium
◦
borohydride (0.12 g) at 0 C under N2. The reaction mixture was stirred for 5 h at room
temperature. After removal of the solvent under reduced pressure, the pure solid was
obtained by recrystallized from ethanol. Yield 85%, mp: 112–114 ◦C; 31P NMR (CDCl3):
δ 24.7 (d,-P(O2C12H8)2, J = 93.9 Hz), 8.8 (t, P(-O-C6H4-)2, J = 92.3 Hz); ESI-MS: m/z
750 [M+H]+, m/z 772 [M+Na]+, m/z 788 [M+K]+.
Preparation of 1,1,3,3-Tetraphenylyloxy-5,5,-Bikis(4-Bromomethyl
phenoxy)Cyclotri- Phosphazene (3)
Compound 2 (1.49 g, 2 mmol) was placed into a 100 mL round-bottom flask with
THF (30 mL) under an argon atmosphere. Then, phosphorus tribromide (1.1 mL) in THF
(10 mL) was added dropwise at 0 ◦C and the mixture was stirred 5 h. The organic solvent
was removed under reduced pressure and the residue was dissolved in CHCl3. The residue
washed with aq. K2CO3, extracted with CHCl3 (3 × 10 mL). The organic layer was
dried over Na2SO4 and the evaporated under reduced pressure. The remaining residue was
purified by silica gel column chromatography (CH2Cl2/petroleum ether) to provide 3 as a
◦
◦
1
colorless solid. Yield 72.4%, mp 219 C–221 C; H NMR (CDCl3): δ 7.49 (d, 4H, J =
7.6 Hz), 7.43 (d, 4H, J = 8.2 Hz), 7.39–7.25 (m, 12H), 7.03 (d, 4H, J = 8.2 Hz), 4.51
(s, 4H, -CH2-Ph-); 13C NMR (CDCl3): δ 150.6, 148.0, 134.8, 130.4, 129.7, 129.5, 128.6,
126.0, 121.8, 121.5, 32.8; 31P NMR (CDCl3): δ 25.3 (d, -P(O2C12H8)2, J = 92.7 Hz), 9.8
(t, P(-O-C6H4-)2, J = 93.6 Hz); ESI-MS: m/z 876 [M+H]+.

2206
R. HAN ET AL.
Preparation of 4
Imidazole, Boc-cyclen, or morpholine (10 mmoL) and compound 3 (10 mmol) were
placed into a 50 mL round-bottom flask with CH3CN (30 mL) and Na2CO3 (0.5 g). The
reaction mixture was allowed to warm to reflux and stirred 48 h under Ar. The solvent was
removed by rotary evaporation and the residue was chromatographed on a silica gel column
(petroleum ether:AcOEt = 1:1.5) to give pure title compound 4.
1,1,3,3-tetraphenylyloxy-5,5,-bikis[4-(1,4,7,10-(1,4,7-tricarboxylic acid tri-tert-
butyl)- tetraazacyclododecanyl)methylphenoxy]cyclotriphosphazene (4a): yield 77%;
1H NMR (CDCl3): δ 7.49 (dd, 4H, -C6H4, J = 7.6 Hz), 7.39 (t, 4H, -C12H8, J = 6.8 Hz),
7.33–7.28 (m, 12H, -C12H8), 7.08 (d, 4H, -C6H4, J = 8.0 Hz), 3.77 (s, 4H, -CH2-Ph), 3.57
(s, 8H, -CH2-cyclen), 3.39–3.17 (m, 16H, -CH2-cyclen) 2.69 (s, 8H, -CH2-cyclen), 1.43 (t,
54H, -CH3, J = 11.6 Hz); 13C NMR (CDCl3): δ 156.1, 155.6, 155.2, 150.0, 148.0, 133.8,
131.3, 129.7, 129.5, 128.7, 126.0, 121.7, 120.9, 120.8, 79.5, 79.4, 79.2, 56.3, 55.9, 55.3,
50.0, 48.7, 48.0, 47.5, 47.2, 28.6, 28.4; 31P NMR (CDCl3): δ 25.6 (d, -P(O2C12H8)2, J =
92.7 Hz), 9.2 (t, P(-O-C6H4-)2, J = 92 Hz); ESI-MS: m/z 1681 [M+Na]+.
1,1,3,3-tetraphenylyloxy-5,5,-bikis(4-imdazolylmethylphenoxy)cyclotriphospha
1
zene (4b): yield 59.6%; H NMR (CDCl3): δ 7.58 (s, 2H, -N-CH N-), 7.51 (dd, 4H,
-C6H4, J = 7.4 Hz), 7.38–7.29 (m, 12H, -C12H8), 7.18 (d, 4H, -C12H8, J = 8.4Hz), 7.10
(s, 2H, CH-N ), 7.03 (d, 4H, -C6H4, J = 8.0 Hz), 6.91 (s, 2H, -N-CH2 = C-), 5.13
(s, 4H, -CH2-Ph); 13C NMR (CDCl3): δ 150.5, 147.9, 137.3, 133.2, 129.9, 129.7, 129.6,
128.6, 128.5, 126.1, 121.7, 121.6, 119.1; 31P NMR (CDCl3): δ 25.3 (d, P(O2C12H8)2, J =
93.2 Hz); 9.5 (t, P(-O-C6H4-)2, J = 92.3 Hz); ESI-MS: m/z 850 [M+H]+; HR-MS: m/z
found 850.1866 (calcd. 850.1862) [M+H]+.
1,1,3,3-tetraphenylyloxy-5,5-bikis(4-morpholinomethylphenoxy)cyclotriphosph
azene (4c): yield 62.0%; 1H NMR (CDCl3): δ7.51 (dd, 4H, -C6H4, J = 7.6 Hz), 7.40–7.29
(m, 16H, -C12H8), 7.07 (d, 4H, -C6H4, J = 7.6 Hz), 3.69 (t, 8H, CH2-O-, J = 4.4 Hz),
3.51 (s, 4H, -CH2-Ph), 2.54 (t, 8H, N-CH2-C-, J = 4.4 Hz); 13C NMR (CDCl3): δ149.9,
148.0, 134.7, 130.2, 129.5, 128.7, 126.0, 121.0, 121.0, 120.9, 66.9, 62.8, 53.5; 31P NMR
(CDCl3): δ 25.6 (d, -P(O2C12H8)2, J = 92.3 Hz), 9.7 (t, P(-O-C6H4-)2, J = 92.3 Hz);
ESI-MS: m/z 888 [M+H]+, m/z 910 [M+Na]+.
Preparation of 5a
◦
To a solution of 4a (1.68 g, 1 mmol) in dry CH2Cl2 (50 mL) at 0 C, CF3COOH
(15 mL) was added dropwise under N2. The mixture was stirred for 7 h at room temperature.
After removal of the solvent, the residue was adjusted to pH 14 by NaOH aqueous solution,
and extracted with CHCl3 (5 × 15 mL). The organic phase was collected and dried over
Na2SO4. After removal of the solvent, the desired colorless solid was obtained in 95.4%
yield.
1,1,3,3-tetraphenylyloxy-5,5,-bikis[4-(1,4,7,10-tetraazacyclododecanyl)methylph
enoxy]cyclotriphosphazene (5a): 1H NMR (CDCl3): δ 7.45 (dd, 4H, -C6H4, J = 7.6 Hz),
7.38 (m, 4H, -C12H8), 7.29 (m, 12H, -C12H8), 7.10 (d, 4H, -C6H4, J = 7.6 Hz), 3.67 (s,
4H, -CH2-Ph), 2.78 (t, 8H, -CH2-cyclen, J = 4.4 Hz), 2.66 (d, 8H, -CH2-cyclen, J = 5.6
Hz), 2.62 (d, 8H, -CH2-cyclen, J = 5.6 Hz), 2.56 (t, 8H, -CH2-cyclen, J = 5.2 Hz); 13C
NMR (CDCl3): δ 149.9, 148.3, 135.7, 130.1, 129.6, 129.5, 128.7, 126.0, 121.8, 121.0,
58.9, 51.4, 47.6, 46.3, 45.7; 31P NMR (CDCl3): δ 25.6 (d, -P(O2C12H8)2, J = 91.5 Hz),
9.2 (t, P(-O-C6H4-)2, J = 89.3 Hz); ESI-MS: m/z 1058 [M+H]+.

CYCLOTRIPHOSPHAZENE DERIVATIVES
2207
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