1
482 Lee et al.
Asian J. Chem.
MHz) and varian Gemeni (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 amterial
were purchased fromAldrich, Fluka, Fisher, Lancaster or TCI
chemical companies and used as received. The following known
compounds were prepared by literature procedures : ethanol,
DMSO, hexane, chloroform, water, butanol, propanol and meta-
hanol. Known compounds prepared by modified procedures
have been included in the supplemental information.
NMR (D
52.3, 51.5, 48.9, 25.8.
2
O, pH 10, 50 MHz) δ: 173.0, 172.6, 170.4, 169.7,
RESULTS AND DISCUSSION
As a part of existing study 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 to synthesize 3,7-
dihydroxy-3,7-dioxoperhydro-1,5,3,7-diazadiphosphocine-
7
a
1
3
,5-diacetic acid (4a),2-[5-(1,2-dicarboxylethyl)-3,7-dihydroxy-
,7-dioxoperhydro-diazadiphosphocan-1-yl]succinic acid (4b)
H2N
R
and 3,7-dihydroxy-3,7-dioxoperhydro-1,5,3,7-diazaphos phocine-
,5-di-(2-glutaric acid) (4c). These reactions were then performed,
R: a= -CH COOH
1
a-c
O
OH
N
2
1
P
COOH
adopting various aromatic groups and aminoethyl group with
glycine in aq. HCl.
The strongly acidic medium is required to promote the
second reaction of H
the iminium ion such as the reduction by means of formal-
dehyde to N-methyl derivatives. The reaction was found to be
highly dependent on the experimental conditions employed.
High concentration of the reactant, heat and long reaction times
led to expensive formation of polymeric product; conversely,
low acidity (pH > 1) and low reactant concentrations gave rise
to complex mixtures.A clean reaction was effected dissolving
R
N
R
b=-CHCH
COOH
c=-CH(CH ) COOH
COOH
CH O
2
2
2
P
4
HO
O
3
PO and to avoid the side reactions of
2
2 2
H
3
PO
2
3
3,7-Dihydroxy-3,7-dioxoperhydro-1,5,3,7-diazadiphos
phonic-1,5-diacetic acid (4a):A mixture of glycine (1a) (0.75
g, 0.01 mol), hypophosphorous acid (0.55 mL, 0.01 mol), para-
formaldehyde (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
glycine and H
3
PO
2
in 6 M HCl to obtain a 1 M solution in both
3
days. A white solid product (0.26 g, yield 8 %), was then
reagents and adding para-formaldehyde in slight excess
collected by filteration, washed with a small amount of cold
(
3 equiv.) in one portion.
water, ethanol and dried in vacuo. Unreacted starting materials
-1
Complete dissolution was achived by stirring for 3 days.
remained in olution: m.p. 273-275 °C; IR (KBr, νmax, cm ):
1
A white solid product was then collected by filteration, washed
with a small amount of cold water, ethanol and dried in vacuo.
NMR analysis of the product showed a highly symmetrical
molecule, (two signals in H NMR and three signals in the C
NMR) with a molecular weight of 330 a.m.u characterized as
3
2
445 (OH), 2999, 1718 (C=O), 1652; H NMR (D O, PH 10,
2
13
00 MHz) δ; 3.87 (s, 4H), 3.50 (d, J = 9.3 Hz, 8H); C NMR
O), pH 10, 50 MHz) δ; 178.5, 59.2, 55.6; MS (MOLDI-
TOF), m/z 331 (Anal. Calcd. C, 26.24; H, 5.50; N, 7.65; P,
6.92; Found; C, 26.50; H, 5.53; N, 7.36; P, 16.71).
-[5-(1,2-Dicarboxylethyl-3,7-dihydroxy-3,7-dioxo-
perhydro-[1,5,3,7]-diazadiphosphocan-1-yl]-succinic acid
4b): A mixture of L-aspartic acid (1.33 g, 0.01 mol), hypo-
(
D
2
1
13
1
3,7-dihydroxy-3,7-dioxoperhydro-1,5,3,7-diazadiphos phocine-
2
1,5-diaceticacid (4a). This heterocyclic ligand results from the
assembly of two molecules of glycine, two molecules of H
3
PO
2
(
and four molecules of formaldehyde; its striking feature is
that each atom of this eightmembered ring is originated from
eight single different molecules, representing a formal
phosphorus acid (0.55 mL, 0.01 mol), para-formaldehyde (1.8
g, 0.02 mol) and 6 M HCl (10 mL) was stirred for 0.5 h. The
clear solution was left standing 3 days. And then mixture was
‘
1+1+1+1+1+1+1+1’ cyclocondensation. The yield is satis-
2
added ether, another separated with H O, dried in vacuo. A
factory despite the number of elemental steps involved in the
overall transformation and of the ring size, usually unfavor-
able for entropic reasons. In case of aspartic acid with para-
white solid product (0.17 g yield 7.8 %) was then collected:
-1
m.p. 238-240 °C; IR (KBr, νmax, cm ) 3445 (OH), 2999, 1718
1
(
6
C=O), 1652; H NMR (D
2
O, pH 10, 200 MHz) δ: 4.24 (t, J =
13
formaldehyde and H
3
PO , we could obtain 2-[5-(1,2-dicarboxy-
2
.9 MHz, 2H), 3.48 (d, J = 9.2 MHz, 8H), 3.34 (m, 4H); C
ethyl)-3,7-dihydroxy-3,7-dioxoperhydro[1,5,3,7]diazadiphos-
phocan-1-yl]succinic acid (4b). Work-up step to get 4b is very
different and difficult than those of 4a and 4c.
NMR (D O, pH 10, 50 MHz) δ: 174.1, 173.4, 52.1, 50.8, 48.5.
2
3
,7-Dihydroxy-3,7-dioxoprehydro-1,5,3,7-diazadi-
phosphocine-1,5-di-(2-glutaric acid)(4c): A mixture of L-
glutamic acid (1.47 g, 0.01 mol), hypophophrous acid (0.55
mL, 0.01 mol), para-formaldehyde (1.8 g 0.02 mol) and 6 M
HCl (20 mL) was stirred for 0.5 h. The clear solution was left
standing 3 days. In order to precipitate solid, the clear solution
in refrogerator 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-
The reaction of glutamic acid with para-formaldehyde
and H
3
PO gave 3,7-dihydroxy-3,7-dioxoperhydro-1,5,3,7-
2
diazaphosphocine-1,5-di-(2-glutaric acid) (4c). The relative
position of the fuctional group is particulary interesting in view
of the possible application of carboxylic acid (4a) as ligand
for metal ions. The N-CH
2
COOH and N-CH
2
-P(O)OH-CH -
2
N moieties are known to chelate efficiently through formation
of five-membered rings with the metal atom. Furthermore, the
latter is embraced by six donor atoms in a nearly ideal octahedral
arrangement, highly advantageous for the complexation of the
-
1
3
1
(
06 °C; IR (KBr, νmax, cm ) 3448 (OH), 2956, 1731 (C=O),
1
655; H NMR (D O, 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); C
2
13