Synthesis of 3,7-Dihydroxy-3,7-dioxopenhydro-1,5,3,7-diazadiphosphocines with Various Amines

Article abstract of DOI:10.14233/ajchem.2014.15550

As a part of a research program related to the synthetic study of pharmacologically interesting compounds and good chelating agent for transition metal ion, we here report the synthesis of an unusual medium-sized ring heterocyclic ligand with mixed carboxylic-aminophosphonic donating groups. We have synthesized 1,5-diphenyl-3,7-dihydroxy-3,7-dioxoperhydro-1,5,3,7- diazadiphosphocine (4a), 1,5-di(2-ethaneamine)yl-3,7-dihydroxy-3,7- dioxoperhydro-1,5,3,7-diazadiphosphocine (4b), 1,5-dibenzoic acid-yl-3,7-dihydroxy-3,7-dioxoperhydro-1,5,3,7-diazadiphosphocine (4c), 1,5-difurfuryl-3,7-dihydroxy-3,7-dioxoperhydro-1,5,3,7-diazadiphosphocine (4d), 1,5-di[thiophene-2ylmethyl]-3,7-dihydroxy-3,7-dioxoperhydro-1,5,3, 7-diazadiphosphocine (4e), 1,5-di[thiophene-2yl]-3,7-dihydroxy-3,7- dioxoperhydro-1,5,3,7-diazadiphosphocine (4f), 1,5-dipyridin-4-yl-3,7-dihydroxy- 3,7-dioxoperhydro-1,5,3,7-diazadiphosphocine (4g), 3,7-dihydroxy-3,7- dioxoperhydro-1,5,3,7-diazadiphosphocine-1,5-diacetic acid (4h), 2-[5-(1,2-dicarboxyethyl-3,7-dihydroxy-3,7,dioxo-315.715-[1,5,3,7] diazadiphosphocan-1-yl]-succinic acid (4i) and 3,7-Dihydroxy-3,7-dioxoperhydro- 1,5,3,7-diazadiphosphocine-1,5-di-(2-glutaric acid) (4j).

Full text of DOI:10.14233/ajchem.2014.15550

Asian Journal of Chemistry; Vol. 26, No. 3 (2014), 805-808
http://dx.doi.org/10.14233/ajchem.2014.15550
Synthesis of 3,7-Dihydroxy-3,7-dioxopenhydro-1,5,3,7-diazadiphosphocines with Various Amines
1
1
1
2
Y.G. LEE , U.S. LEE , J.W. YANG , D.I. JUNG1,* and J.T. HAHN
1Department of Chemistry, Dong-A University, Busan 604741, Republic of Korea
2Department of Beautycare, Youngdong University, Youngdong 370701, Republic of Korea
*Corresponding author: Fax: +82 51 2007259; Tel: +82 51 2007249; E-mail: dijung@dau.ac.kr
Received: 29 March 2013;
Accepted: 4 June 2013;
Published online: 30 January 2014;
AJC-14642
As a part of a research program related to the synthetic study of pharmacologically interesting compounds and good chelating agent for
transition metal ion, we here report the synthesis of an unusual medium-sized ring heterocyclic ligand with mixed carboxylic-amino-
phosphonic donating groups. We have synthesized 1,5-diphenyl-3,7-dihydroxy-3,7-dioxoperhydro-1,5,3,7-diazadiphosphocine (4a),
1,5-di(2-ethaneamine)yl-3,7-dihydroxy-3,7-dioxoperhydro-1,5,3,7-diazadiphosphocine (4b), 1,5-dibenzoic acid-yl-3,7-dihydroxy-3,7-
dioxoperhydro-1,5,3,7-diazadiphosphocine (4c), 1,5-difurfuryl-3,7-dihydroxy-3,7-dioxoperhydro-1,5,3,7-diazadiphosphocine (4d), 1,5-
di[thiophene-2ylmethyl]-3,7-dihydroxy-3,7-dioxoperhydro-1,5,3,7-diazadiphosphocine (4e), 1,5-di[thiophene-2yl]-3,7-dihydroxy-3,7-
dioxoperhydro-1,5,3,7-diazadiphosphocine (4f), 1,5-dipyridin-4-yl-3,7-dihydroxy-3,7-dioxoperhydro-1,5,3,7-diazadiphosphocine (4g),
3,7-dihydroxy-3,7-dioxoperhydro-1,5,3,7-diazadiphosphocine-1,5-diacetic acid (4h), 2-[5-(1,2-dicarboxyethyl-3,7-dihydroxy-3,7,dioxo-
315.715-[1,5,3,7]diazadiphosphocan-1-yl]-succinic acid (4i) and 3,7-Dihydroxy-3,7-dioxoperhydro-1,5,3,7-diazadiphosphocine-1,5-di-
(2-glutaric acid) (4j).
Keywords: 1,5,3,7-Diazadiphosphocine, Chelating agent, Magnetic resonance imaging, Amines.
already reported the synthesis of 1,5,3,7-diazadiphosphocine-
1,5-dicarboxylic acid and their esterifications9.
INTRODUCTION
In the last few years, great efforts have been devoted to
the development of efficient ligands for transition metal ions,
in order to obtain complexes whose stability, physical properties
and biodistribution could make them suitable for application
as contrast agents for magnetic resonance imaging (MRI)1,
diagnostic-therapeutic radiopharmaceuticals2 or fluorecent
bioassay.3
As a part of a research program related to the synthetic
study of pharmacologically interesting compounds and good
chelating agent for transition metal ion, we here report the
synthesis of an unusual medium-sized ring heterocyclic ligand
with mixed carboxylic-amino-phosphonic donating groups.
EXPERIMENTAL
Most of these ligands belong to the huge class of poly-
aminopolycarboxylic acids as diethylenetriamine-pentaacetic
acid (DTPA), 1,4,7,10-tetra-azacyclododecane-1,4,7,10-
tetraacetic acid(DOTA) and the great array of their substituted
or modified derivatives4-6. But there is still a great effort in
synthesizing new products with improved properties and for
specific applications. An urgent and specific medical need
is represented by the imaging of the cardiovascular system7,8.
To perform a magnetic resonance angiography (MRA) the
administered contrast agent must stay in the blood stream for
a long time and three main differents ptrategies have been
proposed. It is important to synthesize new bioactive comp-
ounds and contrast agents. To the best of our knowledge, there
are few reports involving the reaction of hypophosphorous
(wheady) acid with formaldehyde and aromatic amines. We
Melting points were determined on an electrothermal
capillary melting point apparatus and uncorected. TLC was
performed on glass plates coated with silicon oxide (silica-gel
60 F254) and compounds were visualized using a UV lamp. 1H
and 13C NMR spectra were obtained with brukerAC2000 (200
MHz) and varian Gemini (200 or 300 MHz) spectrometers.
Mass spectra were measured with HP 5890 GC/MASS (70 eV,
EI). The organic solvents and chemicals were obtained from
commercial products and purified by the appropriate methods
before use. Except where noted, all starting amterials were
purchased from Aldrich, Fluka, Fisher, Lancaster or TCI
Chemical Companies and used as received. The following
known compounds were prepared by literature procedures11:
ethanol, DMSO, hexane, chloroform, water, butanol, propanol,

806 Lee et al.
H2N R
Asian J. Chem.
NMR (D2O, pH 10, 200 MHz) δ: 3.59-3.78 (m, 8H), 5.55-
5.61 (d, 4H), 7.20-8.28 (m, 6H); 13C NMR (D2O, pH 10, 300
MHz) δ: 59.8, 124.3, 132.4, 157.4, 179.8; MS (MOLDI-TOP),
m/z 374 (Anal. calcd. (%) for C, 44.93; H, 5.39; N, 7.48; P,
16.55 found : C, 45.12; H, 5.31; N, 7.59; P, 17.00) 1,5-di[thio-
phene-2ylmethyl]-3,7-dihydroxy-3,7-dioxoperhydro-1,5,3,7-
diazadiphosphocine (4e); m.p.: sticky oil; IR (KBr, νmax, cm-1):
3015, 2847, 2657, 1586, 1486, 1323; 1H NMR (D2O, pH, 200
MHz) δ: 3.70-3.73 (d, 8H), 5.60-5.65 (m, 4H), 6.92-8.37 (m,
6H); 13C NMR (D2O, pH 10, 300 MHz) δ: 59.7, 63.4, 123.7,
138.9, 142.1, 157.0; MS (MOLDI-TOP), m/z 406 (Anal. calcd.
(%) for C, 41.38; H, 4.69; N, 6.89; P, 15.24; S, 15.78 Found :
C, 41.36; H, 4.88; N, 6.99; P, 15.12; s, 15.65). 1,5-di[thiophene-
2yl]-3,7-dihydroxy-3,7-dioxoperhydro-1,5,3,7-diazadi-
phosphocine (4f); m.p.: sticky oil; IR (νmax, KBr, cm-1): 3013,
1 a-g
O
OH
N
+
P
CH2O
2
R
N
R
P
+
H3PO2
3
HO
O
4
R
S
N
4a
b
c
4f
g
h
i
(CH2)2NH2
N
1
2646, 1524, 1423, 1311, 1245; H NMR (D2O, pH 10, 200
O
COH
MHz) δ 3.17-3.18 (d, 8H), 7.06-7.56 (m, 4H); 13C NMR (D2O,
300 MHz) δ 62.7, 101.3, 131.1, 162.9; MS (MOLDI-TOP),
m/z 380 (Anal. calcd. (%) for C, 31.58; H, 3.71; N, 14.73; P,
16.29; S, 16.86 Found : C, 31.49; H, 3.80; N, 14.81; P, 16.22;
S, 16.93). 1,5-dipyridin-4-yl-3,7-dihydroxy-3,7-dioxoperhydro-
1,5,3,7-diazadiphosphocine (4g); m.p.: sticky oil; IR (KBr,
CH2COOH
COOH
d
e
CH2
CHCH2COOH
O
COOH
j
CH2
CH(CH2)2COOH
S
1
νmax, cm-1): 3077, 3017, 2612, 1674, 1507, 1311; H NMR
and methanol. Known compounds prepared by modified proce-
dures have been included in the supplemental information.
General procedure for the preparation of 4a-g: A
mixture of aniline (0.93 g, 0.01 mol), hypophosphorous acid
(0.55 mL, 0.01 mol), paraformaldehyde (1.8 g, 0.02 mol) and
6M HCl (10 mL) was stirred for 0.5 h. And then the clear
solution was left standing for 3 days. The physical data of all
the synthesized compounds 4a-g are given in Table-1.
(D2O, pH 10, 200 MHz) δ: 3.78-3.80 (m, 8H), 6.80-8.19 (m,
8H); 13C NMR (D2O, pH, 300 MHz) δ: 61.7, 108.6, 157.6,
161.4; MS (MOLDI-TOP), m/z 368 (Anal. calcd. (%) for C,
45.66; H, 4.93; N, 15.21; P, 16.82 Found : C, 45.62; H, 5.01;
N, 15.25; P, 16.63). 3,7-Dihydroxy-3,7-dioxoperhydro-1,5,3,7-
diazadiphosphocine-1,5-diacetic acid (4h):A mixture of glycine
(0.75 g, 0.01 mol), hypophosphorous acid (0.55 mL, 0.01 mol),
paraformaldehyde (1.8 g, 0.02 mol) and 6 M HCl (10 mL)
was stirred for 0.5 h and then the clear solution was left standing
3 days. A white solid product (0.26 g, yield 8 %), was then
collected by filteration, washed with a small amount of cold
water, ethanol and dried in vacuo. Unreacted starting materials
remained in solution.: m.p. 273-275 °C; IR (KBr, νmax, cm-1):
3445 (OH), 2999,1718 (C=O), 1652; 1H NMR (D2O, PH 10,
200 MHz) δ: 3.87(s, 4H), 3.50 (d, J = 9.3 Hz, 8H); 13C NMR
(D2O), pH 10, 50 MHz) δ: 178.5, 59.2, 55.6; MS (MOLDI-
TOF), m/z 331 (Anal. calcd. for C, 26.24; H, 5.50; N,7.65; P,
16.92 Found; C, 26.50; H, 5.53; N, 7.36; P,16.71). 2-[5-(1,2-
Dicarboxyethyl-3,7-dihydroxy-3,7,dioxo-315.715-[1,5,3,7]-
diazadiphosphocan-1-yl]-succinic acid (4i): A mixture of
L-aspartic acid (1.33 g, 0.01 mol), hypophosphorous acid
(0.55 mL, 0.01 mol), paraformaldehyde (1.8 g, 0.02 mol) and
6 M HCl (10 mL) was stirred for 0.5 h. And then the clear
solution was left standing 3 days. And then mixture was added
ether, another separated with H2O, dried in vacuo. A white
solid product (0.17 g, yield 7.8 %) was then collected: m.p.
238-240 °C; IR (KBr, νmax, cm-1) 3445 (OH), 2999, 1718
(C=O), 1652; 1H NMR (D2O, pH 10, 200 MHz) δ: 4.24 (t, J =
6.9 MHz, 2H), 3.48 (d, J = 9.2 MHz, 8H), 3.34 (m, 4H); 13C
NMR (D2O, pH 10, 50 MHz) δ: 174.1, 173.4, 52.1, 50.8, 48.5.
3,7-Dihydroxy-3,7-dioxoperhydro-1,5,3,7-diazadiphos-
phocine-1,5-di-(2-glutaric acid) (4j):A mixture of L-glutamic
acid (1.47 g, 0.01 mol), hypophosphorous acid (0.55 mL, 0.01
mol), paraformaldehyde (1.8 g, 0.02 mol) and 6 M HCl
A brown solid product (9.6 %) 4a, was then collected by
filteration, washed with a small amount of cold water, ethanol
and dried in vacuo. Unreacted starting materials remained in
solation. 1,5-Diphenyl-3,7-dihydroxy-3,7-dioxoperhydro-
1,5,3,7-diazadiphosphocine (4a), m.p 273-274 °C; IR (KBr,
νmax, cm-1): 3011, 1321, 1100; 1H NMR (D2O, pH 10, 200 MHz)
δ: 3.17-3.21 (d, 8H), 7.18-7.35 (m, 10H); 13C NMR (D2O,
pH 10, 300 MHz) δ: 53.2, 130.8, 131.9, 142.1, 148.5; MS
(MOLDI-TOP), m/z 336 (Anal. calcd. (%) for C, 52.46; H,
5.50; N, 7.65; P, 16.91 found; C, 52.82; H, 5.36; N, 7.57; P,
16.69). 1,5-Di(2-ethaneamine)yl-3,7-dihydroxy-3,7-dioxo-
perhydro-1,5,3,7-diazadiphosphocine (4b), m.p.: sticky oil; IR
(KBr, νmax, cm-1): 3421, 3055, 1378, 1180; 1H NMR (D2O, pH
10, 200 MHz) δ: 3.09 (s, 8H), 3.31-3.39 (t, 4H), 3.51-3.59 (t,
4H); 13C NMR (D2O, pH 10, 300 MHz) δ: 47.3, 48.1, 58.7;
MS (MOLDI-TOP), m/z 300 (Anal. calcd. (%) for C, 32.00;
H, 7.39; N, 18.66; P, 20.63 found; C, 32.32; H, 7.46; N, 18.51;
P, 20.87) 1,5-dibenzoicacid-yl-3,7-dihydroxy-3,7-dioxo-
perhydro-1,5,3,7-diazadiphos-phocine (4c); m.p.: 232-233 °C;
IR (KBr, νmax, cm-1): 3454, 3010, 2699, 1378; 1H NMR (D2O,
pH 10, 200 MHz) δ: 3.28 (s, 8H), 7.13-7.46 (m, 8H); 13C NMR
(D2O, pH 10, 300 MHz) δ: 59.8, 124.3, 128.7, 132.4, 157.4,
179.8; MS (MOLDI-TOP), m/z 454 (Anal. calcd. (%) for C,
47.59; H, 4.44; N, 6.17; P, 13.64 found (%): C, 46.98; H, 4.67;
N, 6.29; P, 13.65) 1,5-difurfuryl-3,7-dihydroxy-3,7-dioxo-
perhydro-1,5,3,7-diazadiphosphocine (4d); m.p.: sticky oil;
IR (KBr, νmax, cm-1): 3027, 2646, 1547, 1324, 1151, 1001; 1H

Vol. 26, No. 3 (2014)
Synthesis of 3,7-Dihydroxy-3,7-dioxopenhydro-1,5,3,7-diazadiphosphocines with Various Amines 807
TABLE-1
PHYSICAL DATA OF PRODUCTS 4a-j
Entry
1
Product
m.p. (°C)
273-274
Yielda (%)
O
OH
P
N
N
9.6
4a
4b
P
HO
O
O
OH
P
H2N(H2C)2
N
N
(CH2)2NH2
2
-
7.4
P
P
P
P
P
P
HO
O
O
OH
O
COH
HOC
O
N
N
3
4
4c
232-233
5.2
5.6
HO
O
O
OH
O
N
N CH2
CH2
4d
-
O
HO
O
O
OH
S
N
N CH2
CH2
5
6
7
8
4e
4f
-
6.1
6.8
8.7
8.0
S
P
P
HO
O
O
OH
N
S
N
N
N
-
S
P
P
P
HO
O
O
OH
N
N
N
N
4g
4h
-
HO
O
O
OH
P
P
P
N
CH2COOH
HOOCH2C
N
273-274
HO
O
O
OH
COOH
HOOCH2CHC
HOOC
N
N
CHCH2COOH
9
4i
4j
150-152
304-305
7.8
6.8
P
P
P
HO
O
O
OH
COOH
HOOC(H2C)2HC
HOOC
N
N
CH(CH2)2COOH
10
HO
O
aIsolated yield
(20 mL) was stirred for 0.5 h. And then the clear solution was
left standing 3 days. In order to precipitate solid, the clear
solution in refrigerator was kept for 24 h. After filtering
precipitated solid, it was washed by hexane and chloroform.
A white solid product (0.32 g, yield 6.8 %) was then collected:
m.p. 304-306 °C; IR (KBr, νmax, cm-1) 3448 (OH), 2956, 1731
1
(C=O), 1655; H NMR (D2O, pH 10, 200 MHz) δ: 4.27 (s,
2H) 3.50 (d, J = 9.3 Hz, 8H), 2.42 (t, J = 6.9 Hz, 4H), 2.08 (m.
4H); 13C NMR (D2O, pH 10, 50 MHz) δ: 173.0, 172.6, 170.4,
169.7, 52.3, 51.5, 48.9, 25.8.

808 Lee et al.
Asian J. Chem.
molecules, representing a formal '1+1+1+1+ 1+1+1+1'
cyclocondensation. The yield is satisfactory despite the number
of elemental steps involved in the overall transformation and
of the ring size, usually unfavorable for entropic reasons. In
case of aspartic acid with paraformaldehyde and H3PO2 we
could obtain 2-[5-(1,2-dicarboxyethyl)-3,7-dihydroxy-3,7-
dioxo-315.715-[1,5,3,7]diazadiphosphocan-1-yl]-succinic
acid (4i). Work-up step to get 4i is very different and difficult
than those of 4h and 4j. We remarked work-up step to get 4i at
the experimental section. The reaction of glutamic acid with
paraformaldehyde and H3PO2 gave 3,7-dihydroxy-3,7-dioxo-
perhydro-1,5,3,7-diazadiphosphocine-1,5-di-(2-glutaric acid)
(4j).
RESULTS AND DISCUSSION
As a part of research program related to the synthetic study
of pharmacologically interesting compounds and good chelating
agents for transition metal ions, we here report the synthesis
of an unusual medium signed ring heterocyclic ligand with
mixed aminophosphonic donating group. In order to synthesize
1,5-di(2-ethaneamine)-yl-3,7-dihydroxy-3,7-dioxoperhydro-
1,5,3,7-diazadiphosphocine (4a), 1,5-di(2-ethaneamine)-yl-
3,7-dihydroxy-3,7-dioxoperhydro-1,5,3,7-diazadiphosphocine
(4b), 1,5-dibenzoicacid-4-yl-3,7-dihydroxy-3,7-dioxoperhydro-
1,5,3,7-diazadiphosphocine (4c), 1,5-difurfuryl-3,7-dihydroxy-
3,7-dioxoperhydro-1,5,3,7-diazadiphosphocine (4d), 1,5-
di[thiophene-2-ylmethyl]-3,7-dihydroxy-3,7-dioxoperhydro-
1,5,3,7-diazadiphosphocine (4e), 1,5-di[thiazol-2-yl]-3,7-
dihydroxy-3,7-dioxoperhydro-1,5,3,7-diazadiphosphocine
(4f), 1,5-dipyridin-4-yl-3,7-dihydroxy-3,7-dioxoperhydro-
1,5,3,7-diazadiphosphocine (4g), 3,7-dihydroxy-3,7-dioxo-
perhydro-1,5,3,7-diazadi-phosphocine-1,5-diaceticacid (4h),
2-[5-(1,2-dicarboxyethyl)-3,7-dihydroxy-3,7-dioxo-3[1,5,3,7]-
diazadiphosphocan-1-yl]-succinic acid (4i), and 3,7-dihydroxy-
3,7-dioxoperhydro-1,5,3,7-diazadiphosphocine-1,5-di-(2-
glutaric acid) (4j). These reactions were then performed, adop-
ting various aromatic groups and aminoethyl group with glycine
in aq. HCl.
The relative position of the functional groups is particulary
interesting in view of the possible application of carboxylic
acid (4h) as ligand for metal ions. The N-CH2COOH and N-
CH2-P(O)OH-CH2-N moieties are known to chelate efficiently
through formation of five-membered rings with the metal atom.
Furthermore, the latter is embraced by the six donor atoms in
a nearly ideal octahedral arrangement, highly advantageous
for the complexation of the hexacoordinated transition metal
ions. Hence we will start a preliminary investigation on the
binding properties of carboxylic acid (4h) towards Mn2+ and
Gd3+, two paramagnetic ions of choice in the design of contrast
agents for MRI, with different chemical behaviors and whose
magnetic features help in the investigation of the solution
structures of the corresponding adducts.
The strongly acidic medium is required to promote the
second reaction of H3PO2 and to avoid the side reactions of
the iminium ion such as the reduction by means of formaldehyde
to N-methyl derivatives. The reaction was found to be highly
dependent on the experimental conditions employed. High
concentrations of the reactant, heat and very long reaction times
led to extensive formation of polymeric products; conversely,
low acidity (pH > 1) and low reactant concentrations gave rise
to complex mixtures.A clean reaction was effected dissolving
glycine and H3PO2 in 6 M HCl to obtain a 1.0 M solution in
both reagents and adding paraformaldehyde in slight excess
(3 equiv.) in one portion. Complete dissolution was achieved
by stirring for 3 days. A white solid product was then collected
by filtration, washed with a small amount of cold water, ethanol
and dried in vacuo. NMR analysis of the product showed a
ACKNOWLEDGEMENTS
This work was supported by the grant from Dong-A
University (2013).
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highly symmetrical molecule, (two signals in H NMR and
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