Synthesis of meta and para-substituted aromatic sulfonate derivatives of polydentate phenylazaphosphinate ligands: Enhancement of the water solubility of emissive europium(III) EuroTracker dyes

Article abstract of DOI:10.1039/c4ob01143k

The synthesis is described of a series of meta and para-substituted phenylsulfonate derivatives of very bright Eu(III) complexes with arylphosphinate groups and strongly absorbing arylalkynylpyridine moieties. The synthetic route involved the early introduction of trifluoroethyl esters to protect the sulfonic acid group, withstanding the use of reagents including acetyl bromide and mCPBA, and tolerating acid-catalysed esterification and Sonogashira reaction conditions. The Eu(III) complexes exhibit enhanced water solubility; their photophysical properties are not perturbed significantly by introduction of the anionic sulfonate groups.

Full text of DOI:10.1039/c4ob01143k

Organic &
Biomolecular Chemistry
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Synthesis of meta and para-substituted aromatic
sulfonate derivatives of polydentate
phenylazaphosphinate ligands: enhancement of
the water solubility of emissive europium(III)
EuroTracker® dyes†
Cite this: Org. Biomol. Chem., 2014,
12, 8061
Martina Delbianco,a Laurent Lamarqueb and David Parker*a
The synthesis is described of a series of meta and para-substituted phenylsulfonate derivatives of very
bright Eu(III) complexes with arylphosphinate groups and strongly absorbing arylalkynylpyridine moieties.
The synthetic route involved the early introduction of trifluoroethyl esters to protect the sulfonic acid
group, withstanding the use of reagents including acetyl bromide and mCPBA, and tolerating acid-cata-
lysed esterification and Sonogashira reaction conditions. The Eu(III) complexes exhibit enhanced water
solubility; their photophysical properties are not perturbed significantly by introduction of the anionic sul-
fonate groups.
Received 3rd June 2014,
Accepted 21st August 2014
DOI: 10.1039/c4ob01143k
www.rsc.org/obc
bearing three electron-rich alkyne and phenylphosphinate
ester groups. The sulfonate group has been introduced in the
Introduction
Aromatic sulfonation is an excellent method for enhancing the meta and para-positions of the phenylphosphinate moiety, and
water solubility of lipophilic aromatic compounds, and has is released in a final base hydrolysis step that also unmasks
been applied to create water soluble dyes and polymers,1–3 and the phosphinate anion. The Eu(III) complexes show good water
to enhance prototropic exchange in various solid-state ionic solubility and possess a brightness, B (340 nm) in water of
materials.4 Classically, aryl sulfonation occurs under forcing between 17 and 20 mM−1 m−1, making them amongst the
electrophilic conditions and the methods used for CH functio- most emissive europium complexes in aqueous solution.13–15
nalisation are generally not suitable for multifunctional com-
pounds with electron-rich or nucleophilic groups.5 Therefore,
various strategies have been devised to create suitable sulfo-
nate protecting groups, typically using electron poor or steri-
Results and discussion
cally hindered sulfonate esters (e.g. CH2CX3, X = F, Cl;
The target complexes (Fig. 1) include three strongly absorbing
neopentyl) to suppress the nucleophilic substitution reaction
and equivalent chromophores, in which there is meta or para-
that may cleave the C–O bond. Examples have been reported in
sulfonic acid substituent in the phenyl ring of the phosphinate
which de-protection occurs using either base, acid or enzy-
matic-catalysis,6–12 allowing the release of the sulfonate group
moiety. The sulfonation of this position was not expected to
perturb the chromophore characteristics significantly, as the
in a final reaction step. The protected intermediates are stable
phosphorus oxygen bond and the aryl groups to which it is
to conventional chromatographic separation and so avoid
attached are not strongly conjugated, unlike a trigonal amide
handling the anionic systems, for which reverse-phase HPLC
or carboxylate substituent. Previous X-ray analysis studies of
offers the main practicable method of purification.
these phenylphosphinate lanthanide complexes have revealed
In this work, we have applied the use of trifluoroethyl sulfo-
nate esters, brought to prominence by the work of Miller,6a to
that the phenyl rings are oriented in the same direction, away
from the plane of the 9-N3 ring, and with the same relative
the synthesis of a set of very emissive Eu(III) complexes,
configuration at phosphorus.13,15,16 These structural studies
also confirmed that the phosphorus–oxygen double bond lies
out of the plane of the aryl rings. A simple retrosynthetic analy-
sis suggests the intermediacy of a 2,4,6-trisubstituted pyridine,
with a 4-Br group, allowing a Sonogashira coupling reaction to
an arylalkyne in a final ligand assembly step.
aDepartment of Chemistry, Durham University, South Road, Durham DH1 3LE, UK.
E-mail: david.parker@dur.ac.uk
bCisbio Bioassays, Parc Marcel Boiteux, BP 84175 30200 Codolet, France
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
c4ob01143k
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Fig. 1 Structures of the sulfonated trianionic Eu(III) complexes. The unsubstituted complexes ([Eu·L1] and [Eu·L3] exist as racemic mixtures of Δ and
Λ isomers with SSS and RRR configurations at the P centres respectively, as deduced by X-ray and CD studies on related systems.13–16
Scheme 1
In order to form the C–P bond, a palladium-catalysed reac- alcohols 11 and 12. The introduction of the aryl-alkynyl moiety
tion was envisaged, allowing insertion of a 2-pyridyl group into by a Sonogashira coupling reaction proceeded smoothly and
the P–H bond of a phenylphosphinic ester, bearing a suitably mesylation of the primary alcohol was effected in near quanti-
protected sulfonate group. Following the studies of Miller,6a tative yield, to furnish, for example, the triesters, 13 and 14,
the behaviour of the trifluoroethyl and phenylsulfonate esters with a 4-methoxy-2-methylphenyl substituent. In a similar
as protecting groups for the sulfonic acid moiety was exam- manner, the triester 15 was prepared, with a simple 4-OMe
ined; each ester was derived from 3 or 4-bromo-phenylsulfonyl aryl group. The introduction of the methyl group shifts the
chloride (Scheme 1). Palladium-catalysed coupling between absorption wavelength of the conjugated chromophore by
the aryl bromide and anilinium hypophosphite proceeded in 7–10 nm to the red.14,20
70% yield for the trifluoroethyl ester, but failed with the
Trialkylation of 1,4,7-triazacyclononane (9-N3) with the
phenyl ester, probably due to competitive insertion into the appropriate mesylates afforded the neutral intermediates
O–Ph bond. In this reaction, the added aminopropyltriethoxy- which were purified by column chromatography. Treatment
silane serves as a base in the Pd-catalysed reaction, and with aqueous base (NaOH in water–methanol) hydrolysed the
enables the esterification of the phosphinic acid in situ.17–19
phosphinate and the sulfonate esters. In the latter case, hydro-
The di-esters 3 and 4 were used in coupling reactions with lysis of the sulfonated occurred at a similar rate to the phos-
2-bromo-4-nitro-6-methyl pyridine in degassed toluene using phinate cleavage reaction and was conveniently monitored by
Cl2Pd[bis(diphenylphosphino)ferrocene] as the catalyst to give observing formation of trifluoroethanol by 19F NMR spec-
the phosphinate esters 5 and 6 (Scheme 2). Bromination with troscopy. Complexation of the ligand in aqueous methanol at
neat acetyl bromide followed by re-esterification of the phos- pH 6 gave the Eu(III) complexes which were purified by reverse
phinic acid group with HC(OEt)3 allowed the isolation of inter- phase HPLC in the presence of triethylammonium acetate and
mediates 7 and 8 in 77 and 81% yield respectively. Treatment isolated as their triethylammonium salts (Scheme 3). Ion-pair
of the 4-bromo-pyridyl esters with mCPBA in CHCl3 gave the adducts of the ammonium salts were identified by ESMS (see
corresponding N-oxides 9 and 10. Activation of the proximate ESI†) to confirm the constitution of the isolated salt.
methyl group occurred following treatment with (CF3CO)2O,
The C-substituted complex with a 4-aminobutyl substituent
in a Boekelheide rearrangement; subsequent hydrolysis of on the 9-membered ring, [Eu·L2]2− was formed via alkylation
the trifluoroacetate esters in situ, using wet ethanol, gave the of the Boc-protected amine, S-16,21 and the Boc group was
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Scheme 2
Scheme 3 The meta-sulfonated isomer, [Eu·L3]3− and the ring C-substituted derivative, [Eu·L2]2−, were made analogously.
subsequently removed with TFA at room temperature, prior to Comparison of the photophysical properties of the four euro-
base hydrolysis and europium complexation. In each case, the pium complexes (Table 1) shows that they possess similar
four Eu(III) complexes showed good water solubility (e.g. allow- optical properties (λ, ε, τ, ϕ) to each other and to the parent
ing 1 mM solutions to be made up readily), contrasting with phenylphosphinate complexes that were examined in aqueous
the behaviour of the parent P-phenyl analogues lacking the methanol,13,20 consistent with the absence of perturbation of
anionic groups, where water solubility was very low, even when the sensitiser excited state energies or the coordination
oxyethylene chains replaced the 4-methoxy group on the environment around the Eu(III) centre. Their relative hydrophi-
remote aryl rings.13
licity was assessed by measuring log P values, measuring the
partition coefficient between water and 1-octanol. The intro-
duction of the methyl group in the three phenyl rings led to a
decrease in log P, and the meta-sulfonated complex, rather sur-
prisingly had a higher negative log P value than the para-
substituted isomer (compare [Eu·L1a]3− and [Eu·L3]3−).
The complex [Eu·L2]2− is derived from S-lysine, and as
shown very recently, the stereogenic centre at carbon directs
the formation of a single complex enantiomer with >98%
stereoselectivity, as deduced by chiral HPLC and NMR ana-
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Table 1 Photophysical and log P dataa for europium(III) complexes,
−
[Eu·Ln] (n = 1–3; 295 K, H2O; [Eu·L3]3− possesses a meta-SO3 group,
and the other three examples have para-substituted sulfonate groups)
log P ( 0.05)
λabs
ε ( 0.5)
ϕem
τ
Eu (ms)
Complex
[Eu·L1a 3−
(octanol–water) (nm) mM−1 cm−1 (%) ( 3) ( 0.03)
]
−0.7
−0.1
n.d.
332
340
333
340
58
58.5
58
31
32
31
33
1.11
1.09
1.10
1.12
[Eu·L1b 3−
]
[Eu·L2]2−
[Eu·L3]3−
−1.4
58.5
a The neutral complex analogues lacking the sulphonated groups
have log P values of >+2; the neutral PMe analogue of [Eu·L1a 3−
has a
log P value of +1.4.
]
lyses.22,24 For the europium complex derived from S-Lys, the
configuration at each P centre is the same (RRR) and the metal
coordination helicity is Λ (or M).22–24 The complex gave rise to
a very strong circularly polarized luminescence (CPL) spectrum
in water (Fig. 2), with emission dissymmetry factors (gem) in
the range 0.05 to 0.25. These values lie in the expected range
for chiral complexes of this type.24,25 Despite several attempts,
the anionic complex was found not to be amenable to analysis
by chiral HPLC under the experimental conditions (aqueous
methanol gradients) that had been used to analyse the ana-
logue, [Eu·L4]. For this neutral complex, chiral HPLC had
showed that a sample could be isolated with >98% enantio-
meric purity. However, the enantiomeric purity (% ee) of
[Eu·L2]2− can also be estimated by comparing gem values for
the same transitions, as the g value scales directly with percen-
tage enantiomeric purity.24
Fig. 2 Total emission (top) and CPL spectrum (bottom) for S-RRR-Λ-
[Eu·L2]2− (295 K, water, pH 6; 2 μM solution; 20 min spectral acquisition;
gem (λ) values were as follows: +0.10(591); −0.10 (595.5); −0.10(598);
−0.015(615); +0.18(654); −0.10(702.5); +0.25(708). Experimental errors
in g values are 0.01 (standard deviation on 5 consecutive measure-
ments of the CPL spectrum).
anionic sulfonated europium complexes with enhanced water
solubility. The synthetic route undertaken required that the
sulfonate group would withstand some vigorous reaction con-
ditions, including treatment with an acyl bromide, mCPBA oxi-
dation, acid-catalysed trans-esterification and palladium
catalysed coupling reactions. The release of the trifluoroethyl
ester under basic conditions in the final step permitted
standard normal phase chromatography separations and
purifications.
Thus, this work emphasizes the scope and utility of the syn-
thetic approach in more complex examples than those pre-
viously examined, and allows the synthesis of highly water
soluble Eu(III) complexes, in which the relatively hydrophobic
aryl groups are screened by the presence of the sulfonate moi-
eties, leading to enhanced water solubility. Such features
should also suppress non-specific binding to hydrophobic
pockets in proteins and suppress interactions with cell mem-
branes where anionic head groups, e.g. phospholipids are
abundant.
The gem values obtained for transitions at 654 and 598 nm
were +0.18 and −0.10; given that the sample of [Eu·L2]2− gave
corresponding values of +0.17 and −0.10,24 it seems reason-
able to assume that the CPL spectrum and gem values refer to a
sample of >95% ee.
Summary and conclusions
Experimental
The use of a trifluoroethyl ester protecting group for an aro- Details of instrumentation, general methods of analysis and
matic sulfonic acid has facilitated the synthesis of a series of purification methods are given in the ESI.† Further detailed
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syntheses, spectral and HPLC data are also given in the ESI.† 2,2,2-Trifluoroethyl 4-(ethoxyhydrophosphoryl)benzene-
Isolated yields for the Eu(III) complexes are based on the sulfonate, 3
measured absorbance as the isolated amount of material was
small and the extinction coefficients are particularly high and
were assumed to be the same for the protonated precursor
ligand and the complex in the same solvent. Such behaviour
To
a suspension of anilinium hypophosphite (1.00 g,
has been observed previously for related series of complexes
with strong ICT bands, ε = 55 to 60 000 M−1 cm−1 in water and
MeOH).14,20
6.29 mmol) in dry toluene was added 2,2,2-trifluoroethyl
4-bromobenzenesulfonate (1.60 g, 5.02 mmol). Argon was
bubbled through the solution for 30 min, then aminopropyl-
triethoxysilane (1.48 mL, 6.30 mmol) was added, and Argon
was bubbled through the solution for additional 30 min.
PdCl2(dppf)·CH2Cl2 (220 mg, 0.27 mmol) was added, and the
mixture stirred at 100 °C for 45 min under argon. The reaction
was monitored by 31P-NMR [δP(reactant) = 7.4, δP(product) =
20.8, δP(diaryl phosphinate) = 25.5]. The solvent was removed
under reduced pressure, 1 M HCl (10 mL) was added and the
mixture extracted with EtOAc (3 × 20 mL). The organic frac-
tions were combined, dried over MgSO4 and concentrate to
give a pale orange oil. The product was used in the next step
without further purification; δH (CDCl3) 8.03 (4H, m, H2–3),
Emission spectra were recorded using an ISA Jobin-Yvon
Spex Fluorolog-3 luminescence spectrometer. Lifetime
measurements were carried out with a Perkin Elmer LS55
spectrometer using FL Winlab software. Errors in the lifetime
values are given as the standard deviation for the 10 measure-
ments of the observed lifetime, examining emission at
620 nm, following excitation at the maximum absorption wave-
length, typically around 330–340 nm. Quantum yield measure-
ments were measured using an integrating sphere or were
2+
calculated by comparison with Ru(bpy)3 as standard (ϕ =
0.028 in aerated water)27 as a standard. For the standards and
each of the unknowns, five solutions with absorbance values
between 0.05 and 0.1 were used. The quantum yield was calcu-
lated according to the equation:
7.76 (1H, d, JP–H 576 Hz, PH), 4.43 (2H, q, JF–H 10 Hz, H7),
1
3
4.21 (2H, m, H5), 1.40 (3H, t, JH–H 7.0 Hz, H6); δF (CDCl3)
3
−74.2 (t, JF–H 8 Hz); δP (CDCl3) +20.8; m/z (HRMS+) 333.0167
3
2
[M + H]+ (C10H13O5SF3P requires 333.0173).
Ar Ex Ir ηx
Ax Er Ix ηr
Φx ¼ Φr
2
2,2,2-Trifluoroethyl 4-(ethoxy(6-methyl-4-nitropyridin-2-yl)-
phosphoryl)benzenesulfonate, 5
where r and x refer to reference and unknown respectively; A is
the absorbance at λex, which equals 340, 333 or 332 nm accord-
ing to the nature of the complex (Table 1); E is the corrected
integrated emission intensity; I is the corrected intensity of
excitation light; η is the refractive index of solution. Errors in
quantum yield are given as the standard deviation from the 5
separate measurements.
2,2,2-Trifluoroethyl 4-bromobenzenesulfonate, 1
2,2,2-Trifluoroethyl 4-(ethoxyhydrophosphoryl)benzenesulfo-
nate (1.60 g, 4.82 mmol) was added to degassed toluene
4-Bromobenzenesulfonyl chloride (3.00 g, 11.7 mmol) was dis- (40 mL), followed by 2-bromo-6-methyl-4-nitropyridine (1.00 g,
solved in DCM (20 mL) and trifluoroethanol (840 μL, 4.61 mmol) and freshly distilled triethylamine (2.30 mL,
11.7 mmol) was added. A solution of DABCO (1.50 g, 16.8 mmol). Argon was bubbled through the yellow solution
13.4 mmol) in DCM (10 mL) was added resulting in precipitate for 30 min, then PdCl2(dppf)·CH2Cl2 (110 mg, 0.13 mmol) was
formation. The reaction was stirred for 1 h at RT, after which added, and the mixture stirred at 120 °C for 2 h under argon,
time a solution of 1 M NaOH (3 mL) was added. The reaction during which time the mixture turned brown. The solvent was
was diluted in EtOAc (100 mL) and washed with 0.5 M removed under reduced pressure, with purification of the
NaHCO3, 0.1 M HCl, water and brine. The organic layer was resulting black oil by column chromatography (silica, EtOAc–
dried over MgSO4 and the solvent removed under reduced n-hexane 1 : 3 to 1 : 1) giving a colourless oil (902 mg, 40%);
pressure to give a white solid (3.40 g, 91%); m.p. 105–107 °C. δH (CDCl3) 8.63 (1H, dd, JH–P 6.5 JH–H 1.5 Hz, H4), 8.24 (2H,
3
4
3
3
3
Found: C, 29.8; H, 2.05%. C8H6F3BrO3S requires: C, 30.1; H, dd, JH–P 11.5 Hz, JH–H 8.5 Hz, H11), 8.02 (2H, dd, JH–H
1.88%. δH (CDCl3) 7.77 (4H, m, H2-3), 4.40 (2H, q, JH–F 8 Hz, 8.5 Hz, JH–P 3 Hz, H12), 7.79 (1H, s, H2), 4.42 (2H, q, JF–H
3
4
3
H5); δC (CDCl3) 134.1 (C1), 133.1 (C3), 130.3 (C4), 129.7 (C2), 8 Hz, H6), 4.27–4.09 (2H, m, H7), 2.74 (3H, s, H9), 1.40 (3H, t,
122.0 (q, 1JC–F 278 Hz, CF3), 65.0 (q, 2JC–F 38 Hz, C5); δF (CDCl3) 3JH–H 7.0 Hz, H8); δC (CDCl3) 163.5 (d, JC–P 21.5 Hz, C1),
5
−74.2 (t, JF–H 7.0 Hz); m/z (HRMS+) 340.9077 [M + Na]+ 156.5 (d, 1JC–P 171 Hz, C5), 154.2 (d, 3JC–P 13.5 Hz, C3), 138.9 (d,
3
(C8H6O3S79BrF3Na requires 340.9071); Rf = 0.58 (silica, EtOAc– 5JC–P 3.5 Hz, C13), 136.5 (d, JC–P 138 Hz, C10), 133.7 (d, JC–P
1
2
n-hexane 2 : 8).
10 Hz, C11), 127.7 (d, 3JC–P 13.5 Hz, C12), 122.1 (q, 1JC–F 281 Hz,
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CF3), 118.2 (s, C2), 118.0 (d, JC–P 9 Hz, C4), 64.8 (q, chromatography (silica, CH2Cl2–1CH3OH) to yield a yellow oil
3
2JC–F 38.5 Hz, C6), 62.9 (d, 2JC–P 6.5 Hz, C7), 24.8 (s, C9), 16.5 (d, (530 mg, 81% over two steps); δH (CDCl3) 8.22 (2H, dd, JH–P
3
3
3
4
3JC–P 6 Hz, C8); δF (CDCl3) −74.2 (t, JF–H 7 Hz); δP (CDCl3) + 11.5 Hz, JH–H 8.5 Hz, H11), 8.11 (1H, dd, JH–P 6.5, JH–H
3
4
20.7; m/z (HRMS+) 469.0444 [M
+
H]+ (C16H17N2O7SF3P 1.5 Hz, H4), 8.00 (2H, dd, JH–H 8.5 Hz, JH–P 3 Hz, H12), 7.45
3
requires 469.0446); Rf = 0.70 (silica, EtOAc–n-hexane 2 : 1).
(1H, s, H2), 4.40 (2H, q, JF–H 8 Hz, H6), 4.23–4.08 (2H, m, H7),
2.54 (3H, s, H9), 1.37 (3H, t, 3JH–H 7.0 Hz, H8); δC (CDCl3) 161.3
(d, JC–P 22 Hz, C1), 153.8 (d, JC–P 169 Hz, C5), 138.5 (d, JC–P
5
1
5
4-Bromo-6-methylpyridin-2-yl(4-(2,2,2-trifluoroethoxysulfonyl)-
phenyl)phosphinic acid
3 Hz, C13), 137.3 (d, JC–P 136 Hz, C10), 133.7 (s, C3), 133.6 (d,
1
2JC–P 10 Hz, C11), 129.2 (s, 4JC–P 3 Hz, C2), 129.0 (d, 2JC–P 24 Hz,
C4), 127.5 (d, JC–P 13 Hz, C12), 121.7 (q, JC–F 278 Hz, CF3),
3
1
64.8 (q, 2JC–F 38.5 Hz, C6), 62.6 (d, 2JC–P 6.5 Hz, C7), 24.3 (s, C9),
16.4 (d, JC–P 6.5 Hz, C8); δF (CDCl3) −74.2 (t, JF–H 7 Hz);
3
3
δP (CDCl3)
+ +
21.5; m/z (HRMS+) 501.9690 [M H]+
(C16H17NO5F3PS79Br requires 501.9701); Rf = 0.50 (silica,
DCM–MeOH 96 : 4).
4-Bromo-2-(ethoxy(4-(2,2,2-trifluoroethoxysulfonyl)phenyl)-
phosphoryl)-6-methylpyridine 1-oxide
2,2,2-Trifluoroethyl 4-(ethoxy(6-methyl-4-nitropyridin-2-yl)phos-
phoryl)benzenesulfonate (600 mg, 1.28 mmol) was dissolved
in CH3COBr (3.0 mL, 39 mmol) and the mixture stirred at
70 °C for 16 h under argon. The brown solution was dropped
cautiously into CH3OH (30 mL) stirred at 0 °C. The solvent was
removed under reduced pressure to yield a pale brown solid.
The resulting material, containing unidentified contaminants,
was used without further purification, assuming quantitative
conversion to the p-bromo-phosphinic acid; δH (CDCl3) 8.42
3
3
(1H, d, JH–P 7, H4), 8.31 (1H, s, H2), 8.24 (2H, dd, JH–P
3
3
4
12.5 Hz, JH–H 8.5 Hz, H11), 8.09 (2H, dd, JH–H 8.5 Hz, JH–P
2 Hz, H12), 4.66 (2H, q, JF–H 8 Hz, H6), 2.81 (3H, s, H9); δC
3
(CDCl3) 158.0 (d, JC–P 8 Hz, C1), 151.0 (d, JC–P 134 Hz, C5),
5
1
3
1
143.5 (d, JC–P 10.5 Hz, C3), 138.9 (s, C13), 138.8 (d, JC–P 155
2,2,2-Trifluoroethyl 4-((4-bromo-6-methylpyridin-2-yl)(ethoxy)-
phosphoryl)benzenesulfonate (530 mg, 1.06 mmol) was dis-
solved in CHCl3 (15 mL). 3-Chloroperbenzoic acid (345 mg,
2.01 mmol) was added and the solution stirred at 65 °C for
16 h. The solvent was then removed under reduced pressure,
with the resulting material being re-dissolved in CH2Cl2
(15 mL), and washed with NaHCO3(aq) (0.5 M, 10 mL). The
aqueous layer was re-extracted with CH2Cl2 (3 × 10 mL), the
organic extracts combined, dried over MgSO4, and the
solvent removed under reduced pressure to afford a yellow
Hz, C10), 133.4 (s, C2), 133.3 (d, 2JC–P 11 Hz, C11), 131.5 (d, 2JC–P
12 Hz, C4), 128.0 (d, JC–P 14 Hz, C12), 122.2 (q, JC–F 277 Hz,
3
1
CF3), 65.1 (q, JC–F 37.5 Hz, C6), 19.0 (s, C9); δF (CDCl3) −76.0
2
(t, 3JF–H 7 Hz); δP (CDCl3) + 8.1; m/z (HRMS+) 473.9389 [M + H]+
(C14H13NO5F3PS79Br requires 473.9388).
2,2,2-Trifluoroethyl 4-((4-bromo-6-methylpyridin-2-yl)(ethoxy)-
phosphoryl)benzenesulfonate, 7
3
3
oil (475 mg, 91%); δH (CDCl3) 8.25 (2H, dd, JH–P 13 Hz, JH–H
8.5 Hz, H11), 8.12 (1H, dd, JH–P 8, JH–H 3 Hz, H4), 7.99 (2H,
3
4
dd, JH–H 8.5 Hz, JH–P 3 Hz, H12), 7.55 (1H, d, JH–P 2.5 Hz,
3
4
5
H2), 4.40 (2H, q, JF–H 8 Hz, H6), 4.26–4.16 (2H, m, H7),
3
2.37 (3H, s, H9), 1.40 (3H, t, JH–H 7.0 Hz, H8); δC (CDCl3)
3
150.9 (s, C1), 142.8 (d, JC–P 153 Hz, C5), 138.7 (s, C13), 136.3
1
(d, JC–P 151 Hz, C10), 134.2 (d, JC–P 11.5 Hz, C11), 133.2 (d,
1
2
2JC–P 11 Hz, C4), 132.7 (s, C2), 127.4 (d, JC–P 14.5 Hz,
3
C12), 124.1 (s, C3), 121.6 (q, JC–F 274 Hz, CF3), 64.8
1
4-Bromo-6-methylpyridin-2-yl(4-(2,2,2-trifluoroethoxysulfonyl)- (q, JC–F 38.5 Hz, C6), 63.0 (d, JC–P 6 Hz, C7), 17.2 (s, C9),
2
2
phenyl)phosphinic acid (606 mg, 1.28 mmol) was added to 16.5 (d, JC–P 6 Hz, C8); δF (CDCl3) −74.2 (t, JF–H 8 Hz);
3
3
HC(OCH2CH3)3 (25 mL) and the mixture stirred at 140 °C for δP (CDCl3)
+ +
17.2; m/z (HRMS+) 517.9650 [M H]+
16 h under argon. The solvent was removed under reduced (C16H17NO6PS79BrF3 requires 517.9650); Rf = 0.49 (silica,
pressure and the resulting residue was purified by column DCM–MeOH 96 : 4).
8066 | Org. Biomol. Chem., 2014, 12, 8061–8071
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Paper
2,2,2-Trifluoroethyl-4-((4-bromo-6-(hydroxymethyl)pyridin-
2-yl)(ethoxy)phosphoryl)benzenesulfonate, 11
was dissolved in dry THF (2.5 mL) and the solution was
degassed (freeze–thaw cycle) three times. 4-Ethynylanisole
(76 mg, 0.57 mmol) and NEt3 (1.0 mL) were added and the
solution degassed once more. [1,1′-Bis(diphenylphosphino)-
ferrocene]palladium(II) chloride (45 mg, 55 μmol) and CuI
(7 mg, 37 μmol) were added and the solution was degassed a
further three times. The solution was stirred at 65 °C under
argon for 16 h, solvent was removed under reduced pressure
and the crude material purified by column chromatography
(silica, CH2Cl2–CH3OH 0–2%) to give a pale orange oil
3
(153 mg, 69%); δH (CDCl3) 8.19 (2H, d, JH–H 8.5 Hz, H11), 8.10
3
(1H, s, H4), 8.01 (2H, d, JH–H 7 Hz, H12), 7.47 (3H, m, H17 and
3
H2), 6.90 (2H, d, JH–H 8.5 Hz, H18), 4.78 (2H, s, H9), 4.40 (2H,
Trifluoroacetic anhydride (2.5 mL) was added to a solution
of 4-bromo-2-(ethoxy(4-(2,2,2-trifluoroethoxysulfonyl)phenyl)-
phosphoryl)-6-methylpyridine 1-oxide (475 mg, 0.91 mmol) in
dry CHCl3 (20 mL). The reaction mixture was heated to 60 °C
for 3 h under argon. The solvent was removed under reduced
pressure and the resulting oil was dissolved in EtOH (15 mL)
and H2O (15 mL) and stirred for 1 h. After this time the solu-
tion was concentrated (ca. 15 mL) and extracted with CH2Cl2
(3 × 30 mL). The organic extracts were combined, dried over
MgSO4, and the solvent removed under reduced pressure,
giving a clear oil (430 mg, 91%); δH (CDCl3) 8.19–8.13 (3H, m,
3
q, JF–H 7.5 Hz, H6), 4.17 (2H, m, H7), 3.84 (3H, s, OMe), 3.52
(1H, br, OH), 1.39 (3H, t, 3JH–H 6.5 Hz, H8); δC (CDCl3) 161.2 (s,
1
C1), 160.7 (s, C19), 151.0 (d, JC–P 183 Hz, C5), 138.6 (s, C13),
1
137.4 (d, JC–P 136 Hz, C10), 133.7 (s, C17), 133.5 (s, C3), 133.4
2
4
(d, JC–P 9 Hz, C11), 128.9 (s, C4), 127.7 (d, JC–P 12.5 Hz, C12),
124.4 (s, C2), 121.7 (q, JC–F 327 Hz, CF3), 114.3 (s, C18), 113.5
1
(s, C16), 96.7 (s, C15), 85.0 (s, C14), 64.9 (q, 2JC–F 38 Hz, C6), 64.1
(s, C9), 62.6 (s, C7), 55.4 (s, OMe), 16.5 (s, C8); δF (CDCl3) −74.2
3
(t, JF–H 8 Hz); δP (CDCl3) + 22.5; m/z (HRMS+) 570.0973
[M + H]+ (C25H24F3NO7PS requires 570.0963); Rf = 0.61 (silica,
DCM–MeOH 95 : 5).
3
4
H4-11), 8.00 (2H, dd, JH–H 8.5 Hz, JH–P 2.5 Hz, H12), 7.72 (1H,
s, H2), 6.83 (1H, br, OH), 4.76 (2H, s, H9), 4.41 (2H, q, JF–H
3
8 Hz, H6), 4.29–4.04 (2H, m, H7), 1.37 (3H, t, JH–H 7 Hz, H8);
3
2,2,2-Trifluoroethyl-4-(ethoxy(4-((4-methoxyphenyl)ethynyl)-
6-((methylsulfonyloxy)methyl)pyridin-2-yl)phosphoryl)-
benzenesulfonate, 15
5
1
δC (CDCl3) 163.1 (s, JC–P 20.5 Hz, C1), 152.8 (d, JC–P 169 Hz,
C5), 139.0 (d, JC–P 3 Hz C13), 136.2 (d, JC–P 138.5 Hz, C10),
4
1
134.6 (d, 3JC–P 15 Hz, C3), 133.5 (d, 2JC–P 10.5 Hz, C11), 130.3 (d,
2JC–P 23.5 Hz, C4), 127.8 (d, JC–P 13.5 Hz, C12), 126.8 (d, JC–P
3
4
1
2
3 Hz, C2), 122.8 (q, JC–F 274 Hz, CF3), 64.9 (q, JC–F 38.5 Hz,
C6), 64.0 (s, C9), 63.2 (d, JC–P 6.5 Hz, C7), 16.4 (d, JC–P 6 Hz,
2
3
C8); δF (CDCl3) −74.2 (t, JF–H 8 Hz); δP (CDCl3) + 22.1; m/z
3
(HRMS+) 517.9647 [M + H]+ (C16H17NO6PS79BrF3 requires
517.9650); Rf = 0.56 (silica, DCM–MeOH 96 : 4).
2,2,2-Trifluoroethyl-4-(ethoxy(6-(hydroxymethyl)-4-
((4-methoxyphenyl)ethynyl)pyridin-2-yl)phosphoryl)-
benzenesulfonate
2,2,2-Trifluoroethyl-4-(ethoxy(6-(hydroxymethyl)-4-((4-methoxy-
phenyl)ethynyl)pyridin-2-yl)phosphoryl)benzenesulfonate (93 mg,
0.16 mmol) was dissolved in anhydrous THF (4 mL) and NEt3
(0.07 mL, 0.50 mmol) was added. The mixture was stirred at
5 °C and methanesulfonyl chloride (19 μL, 0.24 mmol) was
added. The reaction was monitored by TLC (silica; CH2Cl2: 5%
CH3OH, Rf(product) = 0.75, Rf(reactant) = 0.61) and stopped
after 30 min. The solvent was removed under reduced pressure
and the residue dissolved in CH2Cl2 (15 mL) and washed with
NaCl solution (saturated, 10 mL). The aqueous layer was re-
2,2,2-Trifluoroethyl-4-((4-bromo-6-(hydroxymethyl)pyridin-2-yl)- extracted with CH2Cl2 (3 × 10 mL) and the organic layers com-
(ethoxy)phosphoryl)benzenesulfonate (200 mg, 0.39 mmol) bined, dried over MgSO4 and the solvent removed under
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reduced pressure to afford a colourless oil (95 mg, 92%); δH 22.5; m/z (HRMS+) 1783.362 [M + H]+ (C81H79F9N6O18P3S3
3
3
(CDCl3) 8.22 (2H, dd, JH–P 11.5 Hz, JH–H 8.5 Hz, H11), 8.17 requires 1783.368).
(1H, d, JH–H 6.5 Hz, H4), 8.02 (2H, dd, JH–H 8.5 Hz, JH–P 2.5
3
3
4
Hz, H12), 7.62 (1H, s, H2), 7.50 (2H, d, JH–H 9 Hz, H17), 6.91
3
(2H, d, JH–H 9 Hz, H18), 5.32 (2H, m, H9), 4.42 (2H, q, JF–H
3
3
8 Hz, H6), 4.18 (2H, m, H7), 3.85 (3H, s, OMe), 3.08 (3H, s, Ms),
Eu(III) complex of 6,6′,6″-(1,4,7-triazacyclononane-1,4,7-triyl)-
tris(methylene)tris(4-((4-methoxyphenyl)ethynyl)pyridine-
6,2-diyl)tris(4-(hydroxyphosphoryl benzenesulfonate),
[Eu·L1a]3−
1.40 (3H, t, JH–H 7 Hz, H8); δF (CDCl3) −74.1 (t, JF–H 8 Hz);
3
3
δP (CDCl3)
+ +
21.9; m/z (HRMS+) 648.0728 [M H]+
(C26H26F3NO9PS2 requires 648.0739); Rf = 0.75 (silica, DCM–
MeOH 95 : 5).
2,2,2-Trifluoroethyl 6,6′,6″-(1,4,7-triazacyclononane-1,4,7-triyl)-
tris(methylene)tris(4-((4-methoxyphenyl)ethynyl)pyridine-6,2-
diyl)tris(4-(ethoxyphosphoryl benzenesulfonate)
2,2,2-Trifluoroethyl-6,6′,6″-(1,4,7-triazacyclononane-1,4,7-triyl)-
tris(methylene)tris(4-((4-methoxyphenyl)ethynyl)pyridine-6,2-
diyl)tris(4-(ethoxyphosphoryl benzenesulfonate) (3.0 mg,
1.7 μmol) was dissolved in CD3OD (1 mL) and a solution of
0.1 M NaOH in D2O (0.5 mL) was added. The mixture was
heated to 60 °C under argon and monitored with 19F-NMR
1,4,7-Triazacyclononane hydrochloride salt (2.5 mg, 10 μmol) [δF(reactant) = −76.0, (δF(product, trifluoroethanol) = −78.0]
and 2,2,2-trifluoroethyl
4-(ethoxy(4-((4-methoxyphenyl)- and 31P-NMR [δP(reactant) = +23.1, (δP(product) = +14.9]. After
ethynyl)-6-((methylsulfonyloxy)methyl)pyridin-2-yl)phosphoryl)- 3 h the solution was cooled to RT and the pH was adjusted to
benzenesulfonate (20 mg, 29 μmol) were dissolved in anhy- 7 with HCl. Eu(Cl)3·6H2O (0.7 mg, 1.7 μmol) was added and
drous CH3CN (1 mL) and K2CO3 (8.0 mg, 58 μmol) was added. the mixture heated to 65 °C overnight under argon. The
The mixture was stirred under argon at 60 °C for 16 h. The solvent was removed under reduced pressure and the product
reaction was cooled and the solution decanted from excess purified by HPLC ((XBridge C18 column, 19 × 100 mm, i.d.
potassium salts. The solvent was removed under reduced 5 μm) flow rate of 17 mL min−1 with H2O (25 mM triethyl-
pressure and the crude product purified by HPLC ((XBridge ammonium acetate buffer, pH = 7) – 2% CH3CN) as eluents
C18 column, 19 × 100 mm, i.d. 5 μm) flow rate of 17 mL min−1 (3 min) [linear gradient to 40% MeOH (15 min), linear gradi-
with H2O (0.1% formic acid) – 40% MeOH (0.1% formic acid) ent to 100% MeOH (3 min)], tR = 17.7 min) giving the triethyl-
as eluents (3 min) [linear gradient to 100% MeOH (15 min)], ammonium salt as a white solid (2.0 mg, 60%); (HRMS−)
tR = 12.6 min) to give a pale yellow oil (7.5 mg, 42%); δH 1599.146
[Eu·L1aH2]−
(CDCl3) 8.18 (6H, dd, JH–P 11.5 Hz, JH–H 8.5 Hz, H11), 8.05 1599.146); τH2O = 1.11 ms; λmax = 332 nm. Evidence for the
(C69H59151EuN6O18P3S3
requires
3
3
3
3
4
(3H, d, JH–H 6 Hz, H4), 7.97 (6H, dd, JH–H 8.5 Hz, JH–P 2 Hz, presence of the triethylammonium cation in the isolated
H12), 7.62 (3H, s, H2), 7.45 (6H, d, 3JH–H 9 Hz, H17), 6.88 (6H, d, salt was provided by examination of the positive ion
3JH–H 9 Hz, H18), 4.40 (6H, q, 3JF–H 8 Hz, H6), 4.20–4.06 (6H, m, channel (Et3NH+ observed at 102) and by the observation
H7), 3.87 (6H, s, H9), 3.82 (9H, s, OMe), 2.81 (12H, br, 9N3), in negative ion mode of the ion-pair adducts with one and
3
1.34 (9H, t, JH–H 7 Hz, H8); δC (CDCl3) 160.9 (s, C1), 160.7 (s, two triethylammonium ions at 102 and 204 mass units
1
1
C19), 153.0 (d, JC–P 184 Hz, C5), 138.4 (s, C13), 137.4 (d, JC–P above the major species (see ESI†). The isolated yield here is
138 Hz, C10), 133.6 (s, C17), 133.5 (d, JC–P 9.5 Hz, C11), 128.1 an estimate ( 10%, depending on the degree of hydration of
2
(d, JC–P 12 Hz, C4), 128.2 (s, C3), 127.5 (d, JC–P 13.5 Hz, C12), the product), deduced by measuring the absorbance of a
2
4
127.0 (s, C2), 121.7 (q, JC–F 329 Hz, CF3), 114.3 (s, C18), 113.5 weighed sample of the HPLC-purified europium complex,
1
(s, C16), 96.3 (s, C15), 85.0 (s, C14), 64.8 (q, 2JC–F 37 Hz, C6), 62.9 assuming that the extinction coefficient was the same as that
(s, C9), 62.3 (d, JC–P 14 Hz, C7), 55.5 (OMe), 55.2–54.5 (br, of the protonated ligand chromophore, in the same solvent
2
9N3), 16.5 (s, C8); δF (CDCl3) −74.1 (t, JF–H 8 Hz); δP (CDCl3) + (Table 1).
3
8068 | Org. Biomol. Chem., 2014, 12, 8061–8071
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(S)-tert-Butyl 4-(1,4,7-triazacyclononane-2-yl)butylcarbamate
(S)-tert-Butyl
4-(1,4,7-triazacyclononane-2-yl)butylcarbamate
(15 mg, 0.05 mmol) and 2,2,2-trifluoroethyl-4-(ethoxy(4-((4-
methoxyphenyl)ethynyl)-6-((methylsulfonyloxy)methyl)pyridin-
2-yl)phosphoryl)benzenesulfonate (95 mg, 0.15 mmol), were
dissolved in anhydrous CH3CN (2 mL) and K2CO3 (21 mg,
0.15 mmol) was added. The mixture was stirred under argon at
60 °C for 16 h. The reaction was cooled and the solution de-
canted from excess potassium salts. The solvent was removed
under reduced pressure and the crude product purified by
HPLC ((XBridge C18 column, 19 × 100 mm, i.d. 5 μm) flow rate
of 17 mL min−1 with H2O (0.1% formic acid) – 30% MeOH
(0.1% formic acid) as eluents (3 min) [linear gradient to 100%
MeOH (15 min)], tR = 14.1 min) to give a pale yellow oil
(32 mg, 33%); δH (CDCl3) 8.18 (6H, m, H4), 8.04 (3H, m, H3),
7.96 (6H, m, H5), 7.48 (3H, m, H2), 7.44 (6H, m, H6), 6.88 (6H,
The tetrahydrochloride salt of (S)-4-(1,4,7-triazacyclononane-2-
yl)butan-1-amine21 was converted into the free tetra-amine
(66 mg, 0.33 mmol) by anion exchange chromatography using
DOWEX 1 × 2–200 resin (hydroxide form). The free amine was
dissolved in MeOH (4 mL) and CuCl2·H2O (56 mg, 1.33 mmol)
was added, resulting in an intense green mixture. The mixture
was stirred at RT under argon for 2 h, after which the solvent
was removed and the green solid was dissolved in H2O (2 mL).
A solution of BOC-anhydride (140 mg, 0.66 mmol) in dioxane
(2 mL) was added and the solution was stirred at RT. After 3 h
another equivalent of BOC-anhydride (70 mg) was added and
the reaction was stirred for 16 h. At this time, LC-MS revealed
complete consumption of starting material. The blue solution
was treated with H2S over 5 min and the mixture was centri-
fuged to remove the dark precipitate. The supernatant was
washed with DCM and the pH was adjusted to 11 before extract-
ing repeatedly with DCM. The organic layer was concentrated to
give a colourless oil (54 mg, 55%); δH (CDCl3): 6.46 (1H, br,
CONH), 3.13 (2H, m, H13), 2.89–2.47 (10H, m, H3-5-6-8-9), 2.79
(1H, m, H2), 2.35 (3H, br, NH), 1.47 (9H, s, CH3(Boc)), 1.49–1.35
(6H, m, H10-11-12); δC (CDCl3): 156.3 (CO), 79.3 (C(Boc)), 55.2
(C2), 49.9, 46.2, 45.3, 44.3, 40.6 (C3-5-6-8-9), 40.3(C13), 33.9, 30.4,
23.7, (C10-11-12), 28.6 (CH3(Boc)); (HRMS+) 301.2603 [M + H]+
(C15H33N4O2 requires 301.2604). Analysis of the enantiomeric
purity of this amine by 1-H NMR using R-O-acetyl mandelic
acid (CDCl3, 500 MHz, 295 K) as a chiral solvating agent26 con-
firmed the enantiomeric purity to be >97%.22,24
3
m, H7), 5.08 (1H, br, CONH), 4.40 (6H, q, JF–H 7.5 Hz, H8),
4.14 (6H, m, P–OCH2), 3.83 (15H, m, H1 and OMe), 3.00–2.56
(13H, m, 9N3 ring protons and H11), 1.38 (9H, s, Boc),
1.45–1.30 (6H, m, H10-9-8), 1.35 (9H, m, CH3(Et)); δF (CDCl3)
3
−74.2 (t, JF–H 8 Hz); δP (CDCl3) + 22.6; m/z (HRMS+) 977.7515
[M + 2H]2+ (C90H97F9N7O20P3S3 requires 977.7510).
2,2,2-Trifluoroethyl-6,6′,6″-((S)-2-(4-aminobutyl)-1,4,7-
triazacyclononane-1,4,7-triyl)tris(methylene)tris(4-((4-
methoxyphenyl)ethynyl)pyridine-6,2-diyl)tris(4-(ethoxy
phosphoryl benzenesulfonate)
tert-Butyl-4-((S)-1,4,7-tris((6-(ethoxy(4-(2,2,2-trifluoroethyl)phos-
phoryl benzenesulfonate)-4-((4-methoxyphenyl)ethynyl)pyridin-2-
yl)methyl)-1,4,7-triazacyclononane-2-yl)butylcarbamate
tert-Butyl 4-((S)-1,4,7-tris((6-(ethoxy(4-(2,2,2-trifluoroethyl)phos-
phoryl benzenesulfonate)-4-((4-methoxyphenyl)ethynyl)pyridin-
2-yl)methyl)-1,4,7-triazacyclononane-2-yl)butylcarbamate (30 mg,
15 μmol) was dissolved in dry DCM (1.8 mL). Argon was
bubbled for 10 min after which time TFA (0.2 mL) was added.
The solution was stirred for 20 min and the solvent was
removed under reduced pressure to give a yellow oil (16 mg,
60%); δH (CD3OD) 8.11 (6H, m, H4), 8.04 (3H, m, H3), 8.01 (6H,
m, H5), 7.61 (3H, m, H2), 7.57 (6H, m, H6), 6.93 (6H, m, H7),
4.65 (6H, m, H6), 4.17 (6H, m, P–OCH2), 3.96 (15H, m, H1 and
OMe), 3.82–3.60 (13H, m, 9N3 and H11), 1.61–1.47 (6H, m,
H10-9-8), 1.46 (9H, m, CH3(Et)); δF (CD3OD) −76.0 (br); δP
(CD3OD) + 23.6; m/z (HRMS+) 1854.437 [M + H]+ (C85H88N7O18-
F9P3S3 requires 1854.442).
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Eu(III) complex of 6,6′,6″-((S)-2-(4-aminobutyl)-1,4,7-
triazacyclononane-1,4,7-triyl)tris(methylene)tris(4-((4-
methoxyphenyl)ethynyl)pyridine-6,2-diyl)tris(4-
(hydroxyphosphoryl benzenesulfonate), [Eu·L2]2−
2 M. T. Morgan, P. Bagchi and C. J. Fahrni, J. Am. Chem. Soc.,
2011, 133, 15906.
3 S. L. Niu, G. Ulrich, R. Ziessel, A. Kiss, P.-Y. Renard and
A. Romieu, Org. Lett., 2009, 11, 2049.
4 E. Montoneri, G. Viscardi, S. Bottigliengo, R. Gobetto,
M. R. Chierotti, R. Busciano and P. Quagliotto, Chem.
Mater., 2007, 19, 2671.
5 (a) W. R. Reynolds, P. M. Liu, G. Kociok-Kohn and
C. G. Frost, Synlett, 2013, 2687; (b) O. Saidi, J. Marafie,
A. E. W. Ledger, P. M. Liu, M. F. Mahon, G. Kociok-Köhn,
M. K. Whittlesey and C. G. Frost, J. Am. Chem. Soc., 2011,
133, 19298.
6 (a) S. C. Miller, J. Org. Chem., 2010, 75, 4632; (b) A. M. Ali,
B. Hill and S. D. Taylor, J. Org. Chem., 2009, 74,
3583.
7 S. M. Pauff and S. C. Miller, J. Org. Chem., 2013, 78,
711.
8 L. Rusha and S. C. Miller, Chem. Commun., 2011, 47,
2038.
2,2,2-Trifluoroethyl-6,6′,6″-((S)-2-(4-aminobutyl)-1,4,7-triazacyclo-
nonane-1,4,7-triyl)tris(methylene)tris(4-((4-methoxyphenyl)-
ethynyl)pyridine-6,2-diyl)tris(4-(ethoxy phosphoryl benzenesul-
9 T. W. Greene and P. G. M. Wuts, Protective Groups
in Organic Synthesis, John Wiley and Sons, New York, NY,
3rd edn, 1999.
fonate) (5.0 mg, 2.7 μmol) was dissolved in CD3OD (1 mL) and 10 J. C. Roberts, H. Gao, A. Gopalsamy, A. Kongsjahju and
a solution of 0.1 M NaOH in D2O (0.5 mL) was added. The
R. J. Patch, Tetrahedron Lett., 1997, 38, 355.
mixture was heated to 60 °C under argon and monitored with 11 S. Seeberger, R. J. Griffin, I. R. Hardcastle and
19F-NMR [δF(reactant) = −76.0, (δF(product, trifluoroethanol) =
B. T. Golding, Org. Biomol. Chem., 2007, 5, 132.
−77.7] and 31P-NMR [δP(reactant) = +23.6, (δP(product) = 12 B. Musicki and T. S. Widlanski, J. Org. Chem., 1990, 55,
+15.1]. After 3 h the solution was cooled to RT and the pH was
4231.
adjusted to 7 with dilute HCl. Eu(Cl)3·6H2O (1.0 mg, 2.7 μmol) 13 J. W. Walton, A. Bourdolle, S. J. Butler, M. Soulie,
was added and the mixture heated to 65 °C overnight under
argon. The solvent was removed under reduced pressure and
the product purified by HPLC ((XBridge C18 column, 19 ×
M. Delbianco, B. K. McMahon, R. Pal, H. Puschmann,
J. M. Zwier, L. Lamarque, O. Maury, C. Andraud and
D. Parker, Chem. Commun., 2013, 49, 1600.
100 mm, i.d. 5 μm) flow rate of 17 mL min−1 with H2O (25 mM 14 S. J. Butler, L. Lamarque, R. Pal and D. Parker, Chem. Sci.,
triethylammonium acetate buffer, pH = 7) – 2% CH3CN) as
eluents (3 min) [linear gradient to 40% MeOH (15 min), linear 15 E. R. Neil, A. M. Funk, D. S. Yufit and D. Parker, Dalton
gradient to 100% MeOH (3 min)], tR = 16.1 min) giving the
Trans., 2014, 43, 5490.
2014, 5, 1750.
triethylammonium salt as a white solid (2.8 mg, 54%); 16 J. W. Walton, R. Carr, N. H. Evans, A. M. Funk,
(HRMS−) 1671.237 [EuL1bH2]− (C73H68151EuN7O18P3S3 requires
A. M. Kenwright, D. Parker, D. S. Yufit, M. Botta, S. De
1671.238); τH2O = 1.13 ms; λmax = 332 nm. As this highly
Pinto and K. L. Wong, Inorg. Chem., 2012, 51, 8042.
charged complex was not amenable to chiral HPLC analysis in 17 J. L. Montchamp and Y. R. Dumond, J. Am. Chem. Soc.,
the same manner as the uncharged analogues reported earlier,
2001, 123, 510.
an estimation of the enantiomeric purity of the product was 18 K. B. Altamirano, Z. Huang and J. L. Montchamp, Tetra-
made by comparing the CPL gem values at 654 and 598 nm
hedron, 2005, 6315.
(see main text).
19 Y. R. Dumond, R. L. Baker and J.-L. Montchamp, Org. Lett.,
2000, 2, 3341.
20 M. Soulié, F. Latzko, E. Bourrier, V. Placide, S. J. Butler,
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Acknowledgements
We thank the ERC (FCC 266804), Cisbio Bioassays (MD) and
the EPSRC for support.
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