Paper
Dalton Transactions
Compound 6 (118.1 mg, 0.46 mmol) was dissolved in ethanol
2,2′-((2-((Hydroxy(methyl)phosphoryl)methoxy)phenyl)aza-
(20 mL). Palladium on charcoal (10 wt%, 51.6 mg, 0.03 mmol) nediyl) diacetic acid, APDAP.
was added and the reaction mixture was stirred at room temp-
erature for 2 h under an atmosphere of hydrogen. After
this time, the reaction mixture was filtered through a
Celite plug. The solvent was removed under reduced pressure
to form a pale yellow oil (104 mg, 96%). Compound 7 was used
in subsequent steps without any additional purification.
1
3
4
5
3
H NMR (600 MHz, CDCl ) 6.86–6.82 (2 H, m, H , H , H or
The tris-ester 8 (82.6 mg, 0.21 mmol) was dissolved in CD OD
3
6
3
4
5
6
H ), 6.74–6.70 (2 H, m, H , H , H or H ), 4.29–4.07 (4 H, m,
(
2
4 mL) and NaOD (0.4 M in D O, 1.4 mL). The pale yellow solu-
7
9
8
10
H and H ), 1.64 (3 H, d, J 14.6, H ), 1.34 (3 H, t, J 7, H );
tion was stirred under an inert atmosphere of argon at room
temperature for 20 h. Hydrolysis of the ethyl esters was moni-
3
1
1
13
1
P{ H} NMR (162 MHz, CDCl
3
) + 47.4; C{ H} (151 MHz,
1
2
3
4
5
6
CDCl
1
C
1
3
) 146.3 (d, J 11.9, C ), 136.4 (C ), 122.8 (C , C , C or C ),
1
31
tored by H NMR spectrometry, P NMR spectrometry and
ESI-LRMS. The solution was lyophilized to form the title com-
3
4
5
6
3
4
5
6
3
4
18.5 (C , C , C or C ), 115.7 (C , C , C or C ), 112.2 (C , C ,
or C ), 64.6 (d, J 111, C ), 61.0 (d, J 7, C ), 16.6 (s, C ),
5
6
7
9
10
pound as an off-white solid in almost quantitative yield
8
+
2.6 (d, J 98, C ); ESI-LRMS [C10
H
16NO
3
+
P] (+) m/z 230.6;
1
(
62 mg, 93%). H NMR (600 MHz, D
2
O) 6.95 (1 H, dd, J 1.8, 8,
ESI-HRMS calculated for [C H NO P] 230.0946 found
6
4
5
3
1
0
16
3
H ), 6.83 (2 H, m, H and H ), 6.78 (1 H, br m, H ), 3.93 (2 H,
d, J 9, H ), 3.71 (4 H, s, H ), 1.29 (3 H, d, J 14, H ); P{ H}
NMR (283 MHz, D O) + 36.54; C{ H} NMR (176 MHz, D O)
2 2
79.1 (C ), 150.6 (C ) 139.4 (C ), 121.6 (C or C ), 118.5 (C or
C ), 118.1 (C ), 113.4 (C ), 56.5 (C ), 14.2 (d, J 95, C ); reverse
phase HPLC (0%–100%–0% CH CN in ammonium bicarbon-
2
30.0949.
Diethyl 2,2′-((2-((ethoxy(methyl)phosphoryl)methoxy)phenyl)
7
9
8
31
1
13
1
azanediyl) diacetate, 8.
10
1
2
4
5
4
1
5
3
6
9
8
3
ate buffer (25 mM), t = 1.2 min).
R
Conflicts of interest
N,N-Diisopropylamine (410 μL, 2.36 mmol) and ethyl bromo-
acetate (158 μL, 1.42 mmol) were added to a solution of 7
There are no conflicts to declare.
(107.5 mg, 0.46 mmol) and sodium iodide (125.6 mg,
0
.97 mmol) in anhydrous acetonitrile. The reaction was heated
for 2 d at 85 °C under an inert atmosphere of argon before the Acknowledgements
addition of further N,N-diisopropylamine (120 μL, 0.69 mmol)
We thank Durham University and EPSRC for support.
and ethyl bromoacetate (50 μL, 0.45 mmol). The reaction
mixture was stirred at 85 °C for a further 2 d, before being
cooled and diluted with ethyl acetate (10 mL). Inorganic impu-
rities were removed by filtration before the organic filtrate was
washed with water (10 mL) and brine (10 mL). Organic extracts
References
were combined and dried over MgSO
removed under reduced pressure to form a pale brown residue.
Purification by silica gel column chromatography (gradient
4
, and the solvent was
1 R. D. Hancock and A. E. Martell, Chem. Rev., 1989, 89,
1875.
2 D. L. Wright, J. H. Holloway and C. N. Reilley, Anal. Chem.,
1965, 37, 884.
3 J. R. Hart, J. Chem. Educ., 1984, 61, 1060; J. R. Hart,
J. Chem. Educ., 1985, 62, 75; O. J. Grundler, A. T. M. van der
Steen and J. Wilmot, in Overview of the European Risk
Assessment on EDTA, ACS Symposium Series, 2005, ch. 21.
4 R. Y. Tsien, Biochemistry, 1980, 19, 2396.
5 R. Y. Tsien, Fluorescent Chemosensors for Ion and Molecule
Recognition, ed. A. W. Czarnik, American Chemical Society,
Washington DC, 1993, ch. 9.
6 B. Raju, E. Murphy, L. A. Levy, R. D. Hall and R. E. London,
Am. J. Physiol., 1989, 256, C540.
7 B. Morelle, J. M. Salmon, J. Vigo and P. Viallet, Anal.
Biochem., 1994, 218, 170.
8 For example: C. A. Reid, R. Fabian-Fine and A. Fine,
J. Neurosci., 2001, 21, 2206.
1
: 1 hexane/ethyl acetate to 100% ethyl acetate) formed the
1
title compound as a pale brown oil (97.3 mg, 53%). H NMR
3
4
5
6
(
6
700 MHz, CDCl ) 6.95–6.93 (3 H, m, H , H , H or H ),
3
3
4
5
6
7
.90–6.88 (1 H, m, H , H , H or H ), 4.32–4.05 (14 H, m, H ,
9
11
13
8
10
H , H and H ), 1.66 (3 H, d, J 15, H ), 1.33 (3 H, t, J 7, H ),
1
4
31
1
1
.23 (6 H, t, J 7, H ); P{ H} NMR (283 MHz, CDCl ) + 48.3;
3
1
3
1
12
C{ H} NMR (176 MHz, CDCl
3
,) 170.9 (s, C ), 150.9 (d, J 11,
1
2
3
4
5
6
3
4
5
C ), 139.4 (s, C ), 122.9 (s, C , C , C or C ), 122.7 (s, C , C , C
or C ), 120.8 (s, C , C , C or C ), 117.4 (s, C , C , C or C ),
6
5
C ); ESI-LRMS [C H NO P] (+) m/z 402.6; ESI-HRMS calcu-
lated for [C18
phase HPLC (0%–100%–0% CH
6
3
4
5
6
3
4
5
6
7
9
7
9
11
13
4.8 (d, J 6, C or C ), 60.9 (d, J 7, C or C ), 60.7 (s, C or C ),
1
1
13
10
14
3.2 (s, C or C ), 16.5 (d, J 6, C ), 14.2 (s, C ), 12.5 (d, J 97,
8
+
1
8
29
7
+
H
29NO
7
P] 402.1682 found 402.1694; reverse
CN in ammonium bicarbon-
3
ate buffer (25 mM), t = 9.6 min).
R
Dalton Trans.
This journal is © The Royal Society of Chemistry 2018