1,2,4-Triazine method of bipyridine ligand synthesis for the preparation of new luminescent Eu(III) complexes

Article abstract of DOI:10.1016/j.tet.2010.11.058

The 'triazine' methodology for the synthesis of functionalized bipyridine ligands proved to be a convenient method for the preparation of luminescent Eu(III) complexes. The approach allows flexible construction of chromophore and coordination sphere with control of photophysical properties. Europium(III) complexes [Eu1]-[Eu5] prepared in this way exhibit intense long-life metal-centered luminescence in aqueous media. The aromatic substituent in the position 5 of bipyridine has a significant influence on luminescence parameters and is used to introduce functionality for bioconjugation. The complexes [Eu4] and [Eu5] bearing primary amine groups are ready-to-go luminescent 'tags' for peptide labeling.

Full text of DOI:10.1016/j.tet.2010.11.058

Tetrahedron 67 (2011) 597e607
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journal homepage: www.elsevier.com/locate/tet
1,2,4-Triazine method of bipyridine ligand synthesis for the preparation of new
luminescent Eu(III) complexes
,
b
a
c
c
Anton M. Prokhorov a , Valery N. Kozhevnikov , Dmitry S. Kopchuk , Helene Bernard , Nathalie Le Bris ,
*
ꢀ ꢁ
c
c
d
a,e
€
Raphael Tripier , Henri Handel , Burkhard Koenig , Dmitry N. Kozhevnikov
a Ural Federal University, Mira 19, Ekaterinburg 620002, Russia
b Northumbria University, Newcastle-upon-Tyne, NE1 8ST, UK
c
ꢀ
UMR CNRS 6521, Universite de Brest, 6 Avenue Victor Le Gorgeu, 29200 Brest, France
d
€
€
Institut fur Organische Chemie, Universitat Regensburg, D-93040 Regensburg, Germany
e I. Postovsky Institute of Organic Synthesis, Ekaterinburg 620990, Russia
a r t i c l e i n f o
a b s t r a c t
Article history:
The ‘triazine’ methodology for the synthesis of functionalized bipyridine ligands proved to be a conve-
nient method for the preparation of luminescent Eu(III) complexes. The approach allows flexible con-
struction of chromophore and coordination sphere with control of photophysical properties. Europium
(III) complexes [Eu1]e[Eu5] prepared in this way exhibit intense long-life metal-centered luminescence
in aqueous media. The aromatic substituent in the position 5 of bipyridine has a significant influence on
luminescence parameters and is used to introduce functionality for bioconjugation. The complexes [Eu4]
and [Eu5] bearing primary amine groups are ready-to-go luminescent ‘tags’ for peptide labeling.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 9 September 2010
Received in revised form 22 October 2010
Accepted 16 November 2010
Available online 24 November 2010
1. Introduction
The ‘1,2,4-triazine’ methodology for the synthesis of pyridines8
has proved to be an effective approach toward various functional-
Luminescent complexes of trivalent lanthanide cations are of
great interest because of their applications as molecular probes in
biomedical,1 sensing2 or imaging areas,3 as light emitting devices.4
In particular, Eu(III) complexes, possessing long-life (milliseconds)
intense luminescence in aqueous solutions, have been widely used
as luminescent labels for time-resolved immunoassays.5 In this
case, the structure of a ligand plays a key role since the Eu(III) cation
itself cannot be effectively excited by light in the visible or long-
wave UV region (e.g., at 395 nm, generated by cheap LED lasers) and
cannot be attached to a biomolecular substrate. The synthesis of
such a polyfunctionalized ligand is not a trivial task: the ligand has
to form a stable complex with Eu(III) in aqueous media; nine co-
ordination sites of the metal should be occupied by a multidentate
ligand to exclude water coordination resulting in non-radiative
decay of the excited state, and the ligand should bear appropriate
linker for bioconjugation.6 The choice of a chromophore, that is,
capable of transferring its excited state energy to the encapsulated
Eu(III) ion, is a very important step in the ligand design. The energy
transfer from ligand to metal is most efficient when the chromo-
phore is integrated into the coordination sphere and directly
participates in metal ion binding.7 From this point of view, oligo-
pyridines (bi- and ter-pyridines, phenanthroline) are the most
suitable bases for desired ligands.
ized polypyridine ligands.9e11 This method includes the synthesis
of properly substituted 1,2,4-triazines followed by their trans-
formation to the targeted substituted pyridines in reactions with
dienophiles (enamines, enols, 2,5-norbornadiene, substituted
acetylene, allylcarborane).12e17 The main advantage of this strategy
is the control of particular properties of metal complexes through
structural variety of ligands: from photophysical to liquid crystal
properties.18e22 Herein we describe the design and synthesis of
new luminescent Eu(III) complexes, which can potentially be used
as luminescent labels for bioassays.
2. Results and discussion
2.1. Ligand design and synthesis
The design of ligands is the crucial point in the preparation of
luminescent europium labels.7 The correct choice of a chromo-
phore, connected with appropriate construction of the co-
ordination sphere, provides desired chemical and photophysical
properties of the target complex. We chose 5-aryl-2,20-bipyridines
as chromophore units for our systems. This is because bipyridines
were successfully used previously for the creation of luminescent
europium(III) complexes and proved an efficient sensitization and
energy transfer to the emitting metal center.23 Introduction of ar-
omatic substituents at position 5 of bipyridine is an effective tool
* Corresponding author. Tel.: þ79122805967; e-mail address: aprohor@yandex.ru
(A.M. Prokhorov).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.11.058

598
A.M. Prokhorov et al. / Tetrahedron 67 (2011) 597e607
for fine-tuning of photophysical properties of the chromophore:
decreasing the energy of the excited state (red-shift of absorption
and emission maxima) and increasing the extinction co-
efficient.24,25 In addition, the aryl ring allows the introduction of
functionalities to expedite binding to biological targets and acts as
a linker keeping the emissive center away from the biomolecular
substrate. We exemplify it here by introducing an amino group,
which can further be transformed into isothiocyanate to provide
amino reactive luminescent dye.
In order to strongly bind the Eu(III) ion we chose three types of
widely used poly(aminoacetate) moieties: (1) 1,4,7-tris(carbox-
ymethyl)-1,4,7,10-tetraazacylodecane (DO3A), attached to position
60 of 2,20-bipyridine; (2) diethylenetriamine N,N,N00N00-tetraacetate
(DTTA), attached the same way; (3) two iminodiacetates (IDA) in
the 6 and 60 positions of 2,20-bipyridine. In this way, poly(amino-
bipyridines and the methyl or ester group are transformed into
bromomethyl group. The later is then used in alkylation of the
polyiminoacetate and gives the desired ligand.
Among the various possible pathways26 for formation of the
1,2,4-triazine ring only the three following could give the desired
configuration of the substituents. Two methods involve cyclization
of isonitrosoacetophenone hydrazone with aldehyde to give 1,2,4-
triazines22 or 1,2,4-triazine 4-oxides27 depending on conditions. The
third method is the cyclization of a-bromoacetophenone with aro-
matic hydrazide.28 The last one was found to be ineffective for the
synthesis of pyridyltriazinecarboxylate 1 (Scheme 2). The cycliza-
tion of 2-bromo-40-methoxyacetophenone 2a with monohydrazide
of 2,6-pyridinedicarboxylic acid 3 gave methoxyphenyltriazine 1a in
low (22%) yield and needed a double excess of not easily accessible
monohydrazide 3. On the contrary, the reaction of readily available
methyl 6-formylpyridine-2-carboxylate 4 or 6-methylpyridine-2-
carboxaldehyde 5 with hydrazones of isonitrosoacetophenones 6
afforded desired methoxycarbonyl(methyl)pyridyltriazines 1 or 7 in
43e62% yields (Scheme 2). Reflux of triazines 1 and 7 with 2,5-
norbornadiene in xylene gave methoxycarbonyl(methyl)-2,20-
bipyridines 8 and 9 in 70e90% yields. Reduction of the ester group of
8 gave hydroxymethylbipyridine 10, which was transformed to
bromomethylbipyridine 11. At the same time, direct bromination of
the methyl group of 9 was not so successful and afforded 11 only in
20e38% yield. An alternative pathway from methylbipyridine 9 to
acetate) connected to bipyridine at the a-positions to the nitrogen
atoms through methylene bridges binds the Eu(III) ion strongly and
includes bipyridine into the coordination sphere, which is impor-
tant in achieving effective energy transfer from the light-absorbing
bipyridine chromophore to the emissive metal center.
Scheme 1 illustrates the retrosynthetic path toward the target
Eu-complexes. The key step is the synthesis of 3-pyridyl-1,2,4-tri-
azine, which contains aryl as well as a methyl or ester group
at desired positions. The following DielseAlder reaction of 1,2,4-
triazines with 2,5-norbornadiene gives corresponding 2,20-
X
X
X
N
N
X
N
N
N
N
N
N
N
N
N
N
Eu
R
Br
O
OH
N
R = Me or COOMe
HN
N
O
O
OBu
X = auxochrome and/or
linker
n
N
n
O
n
Scheme 1. Retrosynthetic path for synthesis of new Eu-complexes.
Ar
Ar
O
iv
N
N
i
Ar
N
Me
N
5
N
11a-c
H
N
20-38%
70-80%
N
50-62%
AcOH
N
9a-c
N
Me
7a-c
Br
iii
Ar
N
N
Me
NH2
v, vi
56%
60%
OH
Ar
6a-c
Ar
Ar
N
N
O
N
N
4
COOMe
i
ii
N
N
H
N
N
70%
66-80%
N
43-60%
AcOH
1a,c
COOMe
HO
COOMe
8a,c
10a,c
Ar = 4-MeOPh (a),
Ph (b),
22%
Ar
O
3-NO2Ph (c)
+
H
N
H2N
N
COOMe
Br
O
2a
3
Scheme 2. Reagents and conditions: (i) 2,5-norbornadiene, o-xylene, reflux, 24 h; (ii) NaBH4, EtOH, 20e78 ꢀC, 4 h; (iii) PBr3, CH2Cl2, 40 ꢀC, 5 h; (iv) NBS, CCl4, 77 ꢀC, 7 h; (v) SeO2,
pyridine, 115 ꢀC, 20 h; (vi) SOCl2, 76 ꢀC, 6 h, then MeOH, 65 ꢀC, 1 h.

A.M. Prokhorov et al. / Tetrahedron 67 (2011) 597e607
599
bromomethylbipyridine 11 was the synthesis through ester 8 (oxi-
dation of the methyl group with SeO2 and esterification). However,
the overall yield for the three steps proved to be nearly the same.
1,2,4-Triazine methodology allows introduction of two bromo-
methyl groups in both rings of 2,20-bipyridine. In this case, the
starting heterocyclic system, pyridyl-1,2,4-triazine 4-oxide 12, was
obtained by oxidative cyclization of hydrazone 6 and aldehyde 4
(Scheme 3). The presence of the N-oxide group provides easy access
Bipyridine bearing two bromomethyl groups has advantages
over monosubstituted bipyridine, since two small and readily
available aminoacetate fragments, such as iminodiacetate
(IDA), can be used for chelating system formation. Indeed,
reaction of bis(bromomethyl)bipyridine 18 with IDA dimethyl
ester resulted in the formation of bipyridinetetraacetate 29
(Scheme 6). Consecutive nitration of 29, Pd/C-catalyzed hydro-
genation of the nitroester 30, and basic hydrolysis of the
O
N
4
COOMe
Tol
Tol
Tol
NC
N
N
N
iii
H
N
Tol
N
N
N
ii
NH2
i
NC
N
N+
O
N
89%
N
95%
Pb3O4/AcOH
45%
85%
N
N
OH
6
COOMe
14
13
COOMe
12
COOMe
Tol
ROOC
Tol
Tol
vi
v
N
N
N
83%
OH
17
N
75%
Br
N
Br
COOR
15 (R = H)
18
HO
iv
87%
16 (R = Me)
Scheme 3. (i) acetone cyanohydrin, NEt3, rt; (ii) 2,5-norbornadiene, toluene, reflux, 6 h; (iii) H2SO4 (50%), 120 ꢀC, 15 h; (iv) SOCl2, reflux, 1 h, then MeOH, reflux, 1 h; (v) NaBH4,
EtOH, rt, 20 h; (vi) PBr3, CH2Cl2, 40 ꢀC, 2 h.
to corresponding 5-cyano-1,2,4-triazines by direct substitution of
Ph
hydrogen under mild conditions.27 Thus, the reaction of 12 with
acetone cyanohydrin in the presence of a weak base (triethylamine)
N
Ar = 4-MeOPh (a), Ph (b)
gave pyridyltriazine 13 bearing ester and nitrile groups. Further
reaction of cyanotriazine 13 with 2,5-norbornadiene is facilitated
by the presence of electron withdrawing cyano group and pro-
ceeded smoothly to give cyanobipyridine 14 (Scheme 3). The nitrile
and ester groups were then easily transformed to bromomethyl
groups by standard methods to provide strategically important bis
(bromomethyl)arylbipyridine 18 (Scheme 3).
N
O
N
OR
O
N
N
OR
OH
O
RO
O
The next part of the synthesis was the construction of the
coordination sphere by combining bromomethyl building blocks
with the poly(aminoacetates). Reaction of bromomethylbipyr-
idines 11 with tetra-tert-butyl ester or tri-tert-butyl ester in the
presence of K2CO3 led, respectively, to the esters 19 and 20, which
gave, after a further acidic hydrolysis, the new ligands 21 and 22
as hydrochloride salts (Scheme 4). The acetate arms of 20 could
also be grafted to the cyclic ligand by in an alternative way,
starting from bis-aminal protected cyclen 23.29 This compound 23
was easily prepared as previously described and was then alky-
lated to give the quaternary salt 24, which was deprotected in
hydrazine hydrate30 with formation of monoalkylated cyclen 25.
Alkylation of the cyclic pro-ligand 25 by bromoacetate afforded
ester 20 in 36% total yield for the three steps. In practice, this way
is much more appropriate when compared with the direct al-
kylation of tri-tert-butyl ester because of the complicated syn-
thesis of the latter.
The suggested method for synthesis of the bipyridine chromo-
phore allows variation of the aromatic substituents. This helps to
form linker for proteins binding by introducing special groups in the
early steps. One of them is the amino group, which can be used in
several protocols for protein labeling.31 Here we illustrate this using
nitroacetophenone as starting material. Nitrophenylbipyridine
building block 11c, obtained as described above, was involved in the
reaction with tetra-tert-butyl ester to give nitroester 26 (Scheme 5).
The nitro group was reduced by Pd/C-catalyzed hydrogenation,
while hydrolysis of the resulting aminoester 27 gave ligand 28
bearing the amino group at the appropriate position.
t
19b (R = Bu)
iii
21b (R = H)
Ar
45%
N
i
N
N
O
OR
Ar
N
N
N
N
N
ii
70%
11a,b
RO
O
O
OR
Br
t
20a,b (R = Bu)
N
N
N
iii
22a,b (R = H)
N
80%
v
23
65%
Ar
Ar
N
N
N
N
iv
70%
H
N
N
N
N
N+
N
N
N
Br
25a
24a
H
H
Scheme 4. Construction of coordination site. Reagents and conditions: (i) DTTA tetra-
tert-butyl ester, K2CO3, CH3CN, 82 ꢀC; (ii)DO3A tri-tert-butyl ester, K2CO3, CH3CN,
82 ꢀC; (iii) HCl (5 M), 20 ꢀC; (iv) N2H4, H2O, 100 ꢀC; (v) BrCH2COOtBu, K2CO3, MeCN.

600
A.M. Prokhorov et al. / Tetrahedron 67 (2011) 597e607
H2N
O2N
ii
i
18
ii
N
N
N
i
86%
85%
11c
MeOOC
N
N
N
N
RO
O
O
t-BuO
O
50%
O
35%
COOMe
N
N
N
N
N
N
RO
t-BuO
MeOOC
COOMe
NH2
N
RO
t-BuO
NO2
29
26
O
O
O
OR
O
t-BuO
iii
27 (R = But)
iii
87%
80%
N
28 (R = H)
N
MeOOC
N
N
ROOC
N
N
Scheme 5. (i) DTTA tetra-tert-butyl ester, K2CO3, CH3CN, 82 ꢀC; (ii) H2, Pd/C, MeOH,
20 ꢀC, 6 h; (iii) HCl, 20 ꢀC, 12 h.
COOMe
COOR
N
N
MeOOC
30
COOMe
ROOC
COOR
aminoester 31 gave the octadentate amino-ligand 32 for syn-
thesis of potential Eu-label.
31 (R = Me)
32 (R = Na)
iv
97%
Finally, we prepared three types of ligands: nonadentate 22
bearing triple negative ionic charge (macrocyclic DO3A de-
rivatives); nonadentate 21 and 28 with quadruple negative ionic
charge (open-chain DTTA derivatives); and octadentate 32 with
quadruple ionic charge (open-chain bis-IDA).
Scheme 6. Construction of coordination site. Reagents and conditions: (i) IDA di-
methyl ester, K2CO3, CH3CN, 82 ꢀC; (ii) 65% HNO3, 30 min, 0 ꢀC; (iii) H2, Pd/C, EtOH,
60 h, 15 atm; (iv) NaOH (1 equiv)/water.
2.2. Complex preparation and photophysical properties
O
H N
2
O
O
O
O
N
N
N
N
O
O
N
N
N
N
O
O
N
N
N
N
O
O
N
N
N
N
Eu
Eu
N
Eu
Eu
N
O
O
N
N
O
O
N
N
O
O
O
O
O
O
O
O
O
O
O
O
O
O
[Eu4]
[Eu1]
[Eu2]
[Eu3]
H N
2
N
N
N
N
Eu
O
O
O
O
O
O
O
[Eu5]
O
Eu(III) complexes [Eu1]e[Eu5] were prepared according to
a standard procedure upon treatment of corresponding sodium salts
of ligands 22b, 22a, 21b, 28, 32 with 1 equiv of europium chloride
(III). All complexes were formed with ligand to metal ratio as 1:1.
Complexes [Eu1]e[Eu4] have nine-coordinated Eu(III) ions, and
[Eu5] has an eight-coordinated one with one unoccupied co-
ordination site open to interaction with water molecules. The
complexes [Eu1] and [Eu2] are neutral, while [Eu3], [Eu4], and [Eu5]
are mononegatively charged and have a Naþ ion as counterion.
All complexes were isolated and the structures proved by mi-
croanalysis and ESI mass-spectroscopy. A single crystal was grown
and X-ray structure was obtained for the complex [Eu2] (Fig. 1). The
structure proved that the metal cation is nine-coordinated by the
two nitrogen atoms of the bipyridine, the four nitrogen atoms and
the three carboxylic groups of the macrocycle. The distances be-
tween nitrogen atoms of bipyridine and europium center are 2.65
ꢂ
and 2.58 A, and this is nearly the same distances as between eu-
ropium and nitrogen atoms of macrocycle. The structure indicates
that the bipyridine moiety is strongly distorted from planarity: the
torsion between pyridine rings is 8ꢀ and that between pyridine and
aromatic substituent is 19ꢀ. Moreover, the lateral pyridine ring is
distorted from planarity itself and the nitrogen atom is out of the
ring plane, obviously, because of strains related to metal co-
ordination. The nitrogen atoms and the oxygen atoms form N4 and

A.M. Prokhorov et al. / Tetrahedron 67 (2011) 597e607
601
Table 1
Photophysical parameters of [Eu1]e[Eu5]
labs
e
FEM
sH2O
ms
,
sD2O
ms
,
q
(nm)
(dm3molꢁ1 cmꢁ1
)
[Eu1]
[Eu2]
[Eu3]
[Eu4]
[Eu5]
325
341
327
325
328
7505
8091
12,015
10,080
9012
0.073
0.011
0.093
0.006
0.002
1.00
0.27
0.80
0.60
0.17
1.10
0.30
1.30
0.70
0.21
ꢁ0.19
0.15
0.27
ꢁ0.01
1.05
exhibits the most red-shifted absorption (341 nm) because of the
electron-donating effect of the methoxy group reducing the energy
gap between ligand ground and single exited states. The absorption
bands of the complexes are 30e40 nm red-shifted in comparison
with free 5-aryl-2,20-bipyridines,22 confirming direct coordination
of bipyridine nitrogen atoms to the Eu3þ cation.
Upon excitation into low energy absorbance bands, the euro-
pium complexes displayed the luminescence typical for Eu-com-
plexes as a series of sharp emission bands due to transitions from
the 5D0 excited state of Eu(III) ion. The emission spectra of all
complexes [Eu1]e[Eu5] are quite similar (Fig. 3). Some differences
were observed for the bands at 680e710 nm, which correspond to
5D0/7F4 transition. The structure and intensity of this band is
known to be very sensitive to ligand environment. Indeed, we can
see the complexes [Eu1] and [Eu2] with the same coordination
sphere have the similar band profiles. The same is true for the pair
[Eu3] and [Eu4]. As we can see, chromophore type has a slight
influence on the profile of emission spectrum. On the other hand,
acting as ‘antenna’ chromophore strongly enhance the overall
emission efficiency, which depends on the efficiencies of ISC and ET
processes of the ligand.
Fig. 1. Molecular structure of [Eu2].
O3 bases that are planar and nearly parallel. The angle between the
planes is less than 1ꢀ. The europium ion lies between these planes,
but is closer to the O3 base. The twist angles of the bases around the
local fourfold axis (as counted for nonequivalent pendant arms) is
between 23ꢀ and 30ꢀ. Thus, the arrangement should be termed as
a twisted-square antiprism, so the DO3A complex is present in the
solid state as the twisted square-antiprismatic (TSAP) isomer.
The absorption spectra of the complexes [Eu1]e[Eu4] in water
solution are shown in Fig. 2 and the wavelengths and extinction
coefficients are given in Table 1. The two peaks in the UV region at
270 and 330 nm are assigned to the ligand-centered transition
of the 5-aryl-2,20-bipyridine system. The 4-methoxy derivative
1000
[Eu1]
[Eu2]
[Eu3]
[Eu4]
[Eu5]
800
600
400
200
0
580
600
620
640
660
680
700
720
Wavelength (nm)
[Eu1]
[Eu2]
[Eu3]
[Eu4]
0,6
0,4
0,2
0,0
Fig. 3. The emission spectra of [Eu1]e[Eu5].
The overall quantum yields of luminescence of new complexes
in water solution are given in Table 1. The highest efficiency was
observed for [Eu1] and [Eu3] with the same chromophore unit, 5-
phenyl-2,20-bipyridine. For other complexes, which are bearing
electron-donating group on aromatic substituent the quantum
yields are lower. This can be explained by dependence of ligand-to-
metal energy transfer (ET) efficiency on the energy gap
D
E between
ligand triple state and europium emissive state 5D0. The higher
DE,
the greater the ET efficiency or, in other words, lower energy of
ligand triplet state causes less effective luminescence. Electron-
donating groups of the ligand 22b, 28, 32 decrease the triplet state
energy decreasing the quantum yields of the complexes [Eu2],
[Eu4], and [Eu3]. In the case of amino-substituted derivatives,
photo-induced electron transfer can also be responsible for low
quantum yields of the complexes.
250
300
350
400
Wavelength (nm)
Fig. 2. The absorption spectra of [Eu1]e[Eu4].

602
A.M. Prokhorov et al. / Tetrahedron 67 (2011) 597e607
As was shown, for the complexes [Eu1]e[Eu4] with nine-co-
the described method,32 using as standard [Ru(bpy)3]2 in aerated
water and corrected for the refractive index of the solvent.
ordinated Eu(III) ion, the luminescence efficiency depends mostly on
aromatic system and is rather independent of the binding poly(ami-
noacetate) structure. This is not true for [Eu5] with eight-coordinated
metal ion, where an unprotected coordination site is accessible for
interaction with water molecules. Interaction with OH oscillators
result in excited state non-radiative deactivation and luminescence
quenching. In this regard, comparison of luminescence lifetimes
obtained in water and deuterated water solutions allows the assess-
mentofwaterbindingtoEu(III)center.32 Thiscanbedonebyusingthe
following equations where q is the number of coordinated water
4.2. Methyl 6-(6-aryl-1,2,4-triazin-3-yl)picolinates (1)
4.2.1. Via cyclization of 2-bromoacetophenone with hydrazide. 2-
Bromo-40-methoxyacetophenone 2a (12.85 g, 56.11 mmol), mon-
ohydrazide 3 (21.89 g, 112.25 mmol), and sodium acetate (5.06 g,
61.7 mmol) were stirred at 50 ꢀC in mixture ethanol/acetic acid
(4:1) (280 mL) during 15 h. Solids were filtered off, solvents re-
moved in vacuum. Ethanol was added to residue, after 3 h crystals
of 1a were filtered off, washed with water and ethanol, dried and
then passed for the next step without further purification.
molecules (uncertainty ꢂ0.5) and lifetimes (s) are in ms.
À
Á
q ¼ 1:2 1=sH O ꢁ 1=sD O ꢁ 0:25
(1)
2
2
4.2.2. Via cyclization of isonitrosoacetophenone hydrazone with al-
dehyde. Mixture of corresponding hydrazone 1 (33.65 mmol) and
monoaldehyde 4 (5.55 g, 33.65 mmol) was solved in ethanol
(150 mL). Reaction mass was kept at rt for 8 h. The resulting pre-
cipitate was filtered off and suspended in acetic acid (100 mL).
Suspension was heated to reflux two times. Solvent was removed in
vacuum. Residue was treated by ethanol. Crystals of 1 were filtered
off, washed by ethanol, dried and then passed for the next step
without further purification.
The obtained lifetimes and calculated numbers of water mole-
cules in the Eu(III) inner coordination sphere are given in Table 1. As
expected, q ∼0 for [Eu1]e[Eu4] where the metal ion is nine-co-
ordinated and q¼1 for eight-coordinated [Eu5]. So, we can say that
binding poly(aminoacetate) is responsible only for complex sta-
bility and luminescence quenching protection.
3. Conclusions
In conclusion, the proposed ‘1,2,4-triazine’ method for bipyr-
idine ligands synthesis is a useful tool for the preparation of lu-
minescent Eu(III) complexes. The approach makes possible an
aromatic chromophore design for tuning photophysical properties,
it allows a flexible construction of a coordination sphere for Eu(III)
binding and provides the possibility to introduce suitable func-
tionality for binding to biomolecules. Here we described five new
luminescent europium complexes, and two of them [Eu4] and
[Eu5] with primary amine group are ‘ready-to-go’ luminescent
labels. They exhibit intense long-life luminescence, can be excited
with available 337 nm laser light, are water-soluble, and can be
used for further conjugation to peptides. The other three com-
plexes [Eu1]e[Eu3] are ‘model’ compounds and designed to show
an influence of aromatics and coordinating poly(aminoacetate) on
photophysical properties.
4.2.3. Methyl 6-(6-phenyl-1,2,4-triazin-3-yl)picolinates (1a). Yield
3.94 g (12.2 mmol, 22%) via path 4.2.1. and 6.14 g (19.00 mmol, 56%)
via path 4.2.2. Mp: 222e224 ꢀC. 1H NMR (400 MHz, DMSO-d6)
d: 3.89
(s, 3H, OMe), 3.96 (s, 3H, COOMe), 7.21 (m, 2H, CeHarom), 8.24e8.32
(m, 4H, CeHarom, H-40,50), 8.70 (d,1H, J¼7.8 Hz, H-30), 9.56 (s,1H, H-5).
4.2.4. Methyl 6-(6-(3-nitrophenyl)-1,2,4-triazin-3-yl)picolinates (1c).
Yield 6.24 g (18.51 mmol, 55%) via path 4.2.2. Mp: 244e246 ꢀC. 1H
NMR (400 MHz, DMSO-d6) d: 3.97 (s, 3H, COOMe), 7.97 (dd, 1H,
J¼8.2, 8.0 Hz, H-500), 8.25e8.35 (m, 2H, H-40,50), 8.49 (m, 1H, H-600),
8.76 (m, 2H, H-30,400), 9.12 (d, 1H, J¼2.0 Hz, H-200), 9.77 (s, 1H, H-5).
4.3. 6-Aryl-3-(6-methylpyridine-2-yl)-1,2,4-triazines (7)
A corresponding hydrazone 6 (20 mmol) and 6-methylpyridine-
2-carbaldehyde 5 (2.42 g, 20 mmol) were solved in ethanol (50 mL).
Reaction mass was kept for 5 h at rt. Solids were filtered and sus-
pended in glacial acetic acid (50 mL). Mixture was heated at 90 ꢀC in
30 min, and allowed to cool to rt. Solvent was removed in vacuum,
residue was treated with ethanol. Crystals of 7 were filtered,
washed with ethanol and dried.
4. Experimental
4.1. General methods
Manipulations were performed under an atmosphere of dry
argon using vacuum-line and standard Schlenk techniques. Sol-
vents were dried by standard methods and distilled under nitrogen
before use. Commercially available chemicals were reagent grade
and were used without further purification. The following com-
pounds were prepared as described in the literature: 3,33 4,34 6,27
23,29 tetra-tert-butyl diethylenetriamine N,N,N00N00-tetraacetate
(tetra-tert-butyl DTTA).35 Thin-layer chromatography was per-
formed on Merck silica plates with a fluorescence indicator. TLC
spots were visualised by irradiation with UV light or by exposure to
iodine vapors (Rf values refer to relative mobilities on TLC plates).
Column chromatography was carried out on silica gel (Merck,
4.3.1. 6-(4-Methoxyphenyl)-3-(6-methylpyridine-2-yl)-1,2,4-triazine
(7a). Yield 3.45 g (12.4 mmol, 62%). Mp: 188e190 ꢀC (from etha-
nol). 1H NMR (400 MHz, DMSO-d6)
d: 2.64 (s, 3H, Me), 3.89 (s, 3H,
OMe), 7.12 (m, 2H, CeHarom), 7.40 (d, 1H, J¼7.5 Hz, H-50), 7.87 (d, 1H,
J¼7.5 Hz, H-40), 8.23e8.27 (m, 3H, CeHarom, H-30), 9.39 (s, 1H, H-5).
Anal. Calcd for C16H14N4O: C 69.05, H 5.07, N 20.13. Found: C 68.67,
H 5.03, N 20.29.
4.3.2. 6-Phenyl-3-(6-methylpyridine-2-yl)-1,2,4-triazine (7b). Yield
2.48 g (10 mmol, 50%). Mp: 175e177 ꢀC (from ethanol). 1H NMR
60e200 mm, porosity 60 A). Melting points are uncorrected.
(400 MHz, DMSO-d6)
d
: 2.66 (s, 3H, Me), 7.40 (d, 1H, J¼7.0 Hz, H-50),
ꢂ
Magnetic resonance spectra (1H NMR and 13C NMR) were recorded
at 400 MHz on a Bruker Avance 400 MHz spectrometer. Elemental
analyses were carried out by the Elemental Analysis Group in
Postovsky Institute of Organic Synthesis (Ekaterinburg) on Per-
kineElmer 2400 elemental analyzer. Absorption measurements
were done with a PerkineElmer Lambda 45 spectrophotometer.
The Eu(III) luminescence emission and luminescence lifetimes
were recoded and calculated using a Varian Cary Eclip spectroflu-
orimeter. The luminescence quantum yields were determined by
7.59 (m, 3H, Ph), 7.88 (dd,1H, J¼7.0, 6.8 Hz, H-40), 8.29 (m, 3H, Ph, H-
30), 9.43 (s, 1H, H-5). Anal. Calcd for C15H12N4: C 72.56, H 4.87, N
22.57. Found: C 72.31, H 4.81, N 22.70.
4.3.3. 6-(3-Nitrophenyl)-3-(6-methylpyridine-2-yl)-1,2,4-triazine
(7c). Yield 3.28 g (11.2 mmol, 56%). Mp: 206e208 ꢀC (from etha-
nol). 1H NMR (400 MHz, DMSO-d6)
d: 2.67 (s, 3H, Me), 7.44 (d, 1H,
J¼7.6 Hz, H-50), 7.91 (m, 2H, H-40,500), 8.35 (d, 1H, J¼7.6 Hz, H-30),
8.43 (m, 1H, H-400), 8.75 (m, 1H, H-600), 9.14 (d, 1H, J¼2.0 Hz, H-200),

A.M. Prokhorov et al. / Tetrahedron 67 (2011) 597e607
603
9.67 (s, 1H, H-5). Anal. Calcd for C15H11N5O2: C 61.43, H 3.78, N
23.88. Found: C 61.18, H 3.59, N 23.71.
DMSO-d6)
d
: 2.60 (s, 3H, Me), 7.23 (d, 1H, J¼7.8 Hz, H-50), 7.35e7.56
(m, 3H, Ph), 7.65e7.80 (m, 3H, Ph, H-40), 8.10 (dd, 1H, J¼8.3, 2.3 Hz,
H-4), 8.23 (d, 1H, J¼7.8 Hz, H-30), 8.49 (d, 1H, J¼8.3 Hz, H-3), 8.90 (d,
1H, J¼2.3 Hz, H-6). Anal. Calcd for C17H14N2: C 82.90, H 5.73, N 11.37.
Found: C 82.55, H 5.74, N 11.37.
4.4. 5-Aryl-60-methoxycarbonyl-2,20-bipyridines (8)
4.4.1. Starting from corresponding 1,2,4-triazine 1. A corresponding
1,2,4-triazine 1 (5 mmol) was suspended in o-xylene (50 mL), 2,5-
norbornadiene (2.55 mL, 25 mmol) was added and the mixture was
refluxed during 24 h with addition of 2,5-norbornadiene (1.53 mL,
15 mmol) every 5 h. The solvent was removed in vacuum, and the
residue was treated by methanol. The resulting crystals of 8 were
filtered, washed with methanol and dried.
4.5.3. 5-(3-Nitrophenyl)-60-methyl-2,20-bipyridine (9c). Yield 5.46 g
(18.75 mmol, 75%). Mp: 152e154 ꢀC (from methanol). 1H NMR
(400 MHz, DMSO-d6)
d
: 2.61 (s, 3H, Me), 7.25 (d, 1H, J¼7.6 Hz, H-50),
7.79 (m, 2H, H-40,500), 8.21 (m, 1H, H-400), 8.26 (m, 3H, H-4,30,60),
8.50e8.69 (m, 2H, H-3,200), 9.00 (d,1H, J¼7.6 Hz, H-6). Anal. Calcd for
C17H13N3O2: C 70.09, H 4.50, N 14.42. Found: C 69.81, H 4.34, N 14.40.
4.4.2. Starting from 60-methyl-2,20-bipyridines 9. Mixture of 60-
methyl-2,20-bipyridines 9a (1.28 g, 4.63 mmol) and SeO2 (2.06 g,
18.53 mmol) was refluxed in dry pyridine (25 mL) for 2 days. Solids
were filtered off, and solvent was removed in vacuum. The residue
was treated with water solution of NaOH (1 M) and heated to 80 ꢀC.
Solids were filtered off, and HCl (11 M) was added to adjust pH¼2.
The precipitate of 6-(4-methoxyphenyl)-2,20-bipyridine-20-car-
boxylic acid was filtered off, washed by water and dried. Then it was
suspended in SOCl2 (25 mL) and stirred under reflux for 6 h. Solvent
was removed, methanol (20 mL) was added and the mixture was
reflux for 1 h. Solvent was removed in vacuum, and the residue was
treated by methanol. The resulting precipitate of 8a was filtered off,
washed with methanol, and dried.
4.6. 5-(4-Methoxyphenyl)-60-hydroxymethyl-2,20-bipyridine
(10a)
The ester 8a (1 g, 3.13 mmol) was suspended in ethanol
(100 mL), NaBH4 (480 mg, 12.52 mmol) was added and the mixture
was refluxed during 2 h. An additional portion of NaBH4 (240 mg,
6.26 mmol) was added and the mixture was refluxed for another
2 h. Water (200 mL) was added and the product was extracted with
methylene chloride (3ꢃ50 mL). The extract was dried on anhydrous
sodium sulfate, and the solvent was removed in vacuum to give
a crude 10a, which was used for next step without further purifi-
cation. Yield 0.73 g (2.5 mmol, 80%). Mp: 136e138 ꢀC. 1H NMR
(400 MHz, DMSO-d6)
d
: 3.83 (s, 3H, OMe), 4.68 (d, 2H, J¼5.6 Hz,
CH2OH), 5.51 (t, 1H, J¼5.6 Hz, CH2OH), 7.09 (m, 2H, CeHarom), 7.53
(d, 1H, J¼7.6 Hz, H-50), 7.77 (m, 2H, CeHarom), 7.95 (dd, 1H, J¼7.8,
7.6 Hz, H-40), 8.18 (dd, 1H, J¼8.4, 2.4 Hz, H-4), 8.27 (d, 1H, J¼7.8,
7.6 Hz, H-30), 8.43 (d, 1H, J¼8.4 Hz, H-3), 8.97 (d, 1H, J¼2.4 Hz, H-6).
4.4.3. 5-(4-Methoxyphenyl)-60-methoxycarbonyl-2,20-bipyridine
(8a). Yield 1.12 g (3.5 mmol, 70%) via path 4.4.1. and 0.81 g
(2.53 mmol, 81%) via path 4.4.2. Mp: 142e144 ꢀC (from methanol).
1H NMR (400 MHz, DMSO-d6)
d: 3.84 (s, 3H, OMe), 3.96 (s, 3H,
COOMe), 7.10 (m, 2H, CeHarom), 7.79 (m, 2H, CeHarom), 8.11 (d, 1H,
J¼8.0 Hz, H-30), 8.17 (dd, 1H, J¼8.0, 7.8 Hz, H-40), 8.26 (dd, 1H, J¼8.0,
2.4 Hz, H-4), 8.47 (d, 1H, J¼8.0 Hz, H-3), 8.63 (d, 1H, J¼8.0 Hz, H-50),
9.02 (d, 1H, J¼2.4 Hz, H-6). Anal. Calcd for C19H16N2O3: C 71.24, H
5.03, N 8.74. Found: C 71.01, H 4.88, N 8.49.
4.7. 5-(3-Nitrophenyl)-60-hydroxymethyl-2,20-bipyridine (10c)
The ester 8c (2 g, 5.97 mmol) was dissolved in ethanol (150 mL),
NaBH4 (680 mg, 17.91 mmol) was added and the mixture was
stirred at rt with cooling in water bath for 2 h. An additional portion
of NaBH4 (450 mg, 11.94 mmol) was added and the mixture was
stirred for another 2 h. Water (200 mL) was added and the product
was extracted by methylene chloride (3ꢃ70 mL). The extract was
dried on anhydrous sodium sulfate, and the solvent was removed in
vacuum to give a crude 10c, which was used for next step without
further purification. Yield 1.21 g (3.94 mmol, 66%). Mp: 126e128 ꢀC.
4.4.4. 5-(3-Nitrophenyl)-60-methoxycarbonyl-2,20-bipyridine
(8c). Yield 1.17 g (12.59 mmol, 70%). Mp: 187e189 ꢀC (from
methanol). 1H NMR (400 MHz, DMSO-d6)
d: 3.97 (s, 3H, COOMe),
7.85 (dd, 1H, J¼8.2, 8.0 Hz, H-500), 8.15 (d, 1H, J¼7.6 Hz, H-30), 8.20
(dd, 1H, J¼7.6, 7.6 Hz, H-40), 8.32 (m, 2H, H-400,600), 8.46 (dd, 1H,
J¼8.4, 2.4 Hz, H-4), 8.55 (d, 1H, J¼8.4 Hz, H-3), 8.63 (dd, 1H,
J¼2.0 Hz, H-200), 8.67 (d,1H, J¼7.6 Hz, H-50), 9.17 (d, 1H, J¼2.4 Hz,
H-6). Anal. Calcd for C18H13N3O4: C 64.48, H 3.91, N 12.53. Found: C
64.31, H 3.80, N 12.32.
1H NMR (400 MHz, DMSO-d6)
d
: 4.68 (d, 2H, J¼5.2 Hz, CH2OH), 5.31
(t, 1H, J¼5.2 Hz, OH), 7.54 (d, 1H, J¼8.0 Hz, H-50), 7.79 (dd, 1H, J¼8.0,
7.8 Hz, H-500), 7.89 (dd, 1H, J¼8.0, 7.8 Hz, H-40), 8.20 (dd, 1H, J¼8.0,
2.0 Hz, H-4), 8.25 (m, 2H, H-400,600), 8.30 (d, 1H, J¼8.0 Hz, H-30),
8.47e8.62 (m, 2H, H-3,200), 9.00 (d, 1H, J¼2.0 Hz, H-6).
4.5. 5-Aryl-60-methyl-2,20-bipyridine (9)
A corresponding 1,2,4-triazine 7 (25 mmol) was suspended in o-
xylene (100 mL). 2,5-Norbornadien (7.58 mL, 75 mmol) was added
and the mixture was refluxed during 24 h with addition of 2,5-
norbornadien (7.58 mL, 75 mmol) after 9 h. Solvent was removed in
vacuum, and the residue was treated by methanol. The resulting
crystals of 9 were filtered off, washed with methanol, and dried.
4.8. 5-Aryl-60-bromomethyl-2,20-bipyridines (11)
4.8.1. Starting from hydroxymethyl derivative 10. A corresponding
hydroxymethyl derivative 10 (5 mmol) was dissolved in methylene
chloride (150 mL), and PBr3 (0.94 mL, 10 mmol) was added. The
resulting mixture was stirred for 3 h at rt, and then for another 5 h
under reflux. The reaction mixture was washed with an aqueous
solution of sodium carbonate, and the product was extracted with
methylene chloride (3ꢃ100 mL). The organic layer was dried on
anhydrous sodium sulfate, and solvent was removed in vacuum to
give 11 as white solids.
4.5.1. 5-(4-Methoxyphenyl)-60-methyl-2,20-bipyridine
5.73 g (20.8 mmol, 83%). Mp: 132e134 ꢀC (from methanol). 1H NMR
(9a). Yield
(400 MHz, DMSO-d6) d: 2.58 (s, 3H, Me), 3.83 (s, 3H, OMe), 7.10 (m,
2H, CeHarom), 7.32 (d, 1H, J¼7.6 Hz, H-50), 7.76 (m, 2H, CeHarom),
7.84 (dd, 1H, J¼7.6, 7.6 Hz, H-40), 8.19 (m, 2H, H-30,4), 8.43 (d, 1H,
J¼8.3 Hz, H-3), 8.97 (d, 1H, J¼1.8 Hz, H-6). Anal. Calcd for
C18H16N2O: C 78.24, H 5.84, N 10.14. Found: C 77.81, H 5.70, N 10.28.
4.8.2. Starting from 60-methyl-2,20-bipyridines 9. A mixture of 60-
methylbipyridine 9 (4 mmol), NBS (710 mg, 4 mmol), and benzoic
peroxide (in catalytic quantity) was refluxed in dry CCl4 (100 mL)
during 7 h under light radiation. Solids were filtered off, and solvent
was removed in vacuum. The product was isolated by column
4.5.2. 5-Phenyl-60-methyl-2,20-bipyridine (9b). Yield 4.49 g (18.3
mmol, 73%). Mp: 92e94 ꢀC (from methanol). 1H NMR (400 MHz,

604
A.M. Prokhorov et al. / Tetrahedron 67 (2011) 597e607
chromatography and passed for the next step without further
purification.
4.11. 6-Cyano-5-(4-methylphenyl)-60-methoxycarbonyl-2,20-
bipyridine (14)
4.8.3. 5-(4-Methoxyphenyl)-60-bromomethyl-2,20-bipyridine
(11a). Yield 0.91 g (2.55 mmol, 51%) via path 4.8.1. and 500 mg
(1.4 mmol, 35%) via path 4.8.2. Mp: 166e168 ꢀC (from ethanol). 1H
5-Cyano-1,2,4-triazine 13 (1.51g, 5.1 mmol) and bicyclo[2.2.1]
hepta-2,5-diene (2.19 mL, 20.4 mmol) in toluene (20 mL) were
stirred under reflux for 6 h. Then solvent was removed and the
residue was recrystallized from ethanol to give colorless crystals of
14. Yield 1.45 g (4.9 mmol, 95%). Mp: 123e125 ꢀC (from ethanol). 1H
NMR (400 MHz, CDCl3) d: 3.89 (s, 3H, OMe), 4.66 (s, 2H, CH2Br), 7.05
(m, 2H, CeHarom), 7.48 (d,1H, J¼8.0 Hz, H-50), 7.61 (m, 2H, CeHarom),
7.84 (dd, 1H, J¼8.0, 7.8 Hz, H-40), 7.99 (dd, 1H, J¼8.4, 2.4 Hz, H-4),
8.36 (d, 1H, J¼7.8 Hz, H-30), 8.51 (d, 1H, J¼8.4 Hz, H-3), 8.90 (d, 1H,
J¼2.4 Hz, H-6).
NMR (400 MHz, CDCl3)
d
: 2.42 (s, 3H), 7.42 (d, 2H, J¼8.0 Hz), 7.64 (d,
2H, J¼8.0 Hz), 8.17 (dd,1H, 3J¼7.7Hz, 4J¼2.2 Hz), 8.21 (dd,1H, 3J¼7.7,
6.9 Hz), 8.30 (d, 1H, 3J¼8.5 Hz), 8.60 (dd, 1H, 3J¼6.9 Hz, 4J¼2.2 Hz),
8.86 (d, 1H, 3J¼8.5 Hz). 13C NMR (100 MHz, CDCl3)
d: 20.76, 117.22,
4.8.4. 5-Phenyl-60-bromomethyl-2,20-bipyridine (11b). Yield 490 mg
(1.52 mmol, 38%) via path 4.8.2. Mp: 132e134 ꢀC (from ethanol). 1H
123.82, 124.60, 125.57, 128.70, 129.46, 130.31, 131.81, 139.18, 139.29,
139.49, 141.57, 148.14, 152.99, 154.27, 165.64. Anal. Calcd for
C20H15N3O2: C 72.94, H 4.59, N 12.76. Found: C 72.63, H 4.17, N 12.39.
NMR (400 MHz, CDCl3) d: 4.66 (s, 2H, CH2Br), 7.40e7.55 (m, 4H, Ph,
H-50), 7.66 (m, 2H, Ph), 7.84 (dd, 1H, J¼8.0, 7.8 Hz, H-40), 8.03 (dd,
1H, J¼8.4, 2.4 Hz, H-4), 8.36 (d, 1H, J¼7.8 Hz, H-30), 8.54 (d, 1H,
J¼8.4 Hz, H-3), 8.92 (d, 1H, J¼2.4 Hz, H-6).
4.12. 5-(4-Methylphenyl)- 2,20-bipyridine-6,60-dicarboxylic
acid (15)
4.8.5. 5-(3-Nitrophenyl)-60-bromomethyl-2,20-bipyridine
(11c). Yield 1.11 g (3 mmol, 60%) via path 4.8.1. and 300 mg
(0.8 mmol, 20%). Mp: 133e135 ꢀC (from ethanol). 1H NMR
A solution of compound 14 (1.45 g, 4.9 mmol) in the mixture of
ethanol (10 mL), 1 M NaOH (50 mL), and THF (20 mL) was stirred
under reflux for 2 h. Then solvent was removed and the resulting
residue of sodium salt of monocarboxylic acid was dissolved in 50%
H2SO4 (15 mL). The resulted mixture was stirred at 120 ꢀC for 15 h.
Then water (30 mL) was added to give a precipitate of 15, which
was separated by filtration and washed with water. Then the
product was passed for the next step without further purification.
(400 MHz, CDCl3)
d
: 4.67 (s, 2H, CH2Br), 7.53 (d, 1H, J¼7.6 Hz, H-50),
7.72 (dd, 1H, J¼7.6, 7.6 Hz, H-40), 7.89 (dd, 1H, J¼8.0 Hz, H-500), 8.00
(d, 1H, J¼7.6 Hz, H-30), 8.12 (dd, 1H, J¼8.2, 2.6 Hz, H-4), 8.31 (m, 1H,
H-600), 8.43 (m, 1H, H-400), 8.53 (dd, 1H, J¼2.0 Hz, H-50), 8.64 (d, 1H,
J¼8.2 Hz, H-3), 8.98 (d, 1H, J¼2.6 Hz, H-6).
Yield 1.46 g (4.36 mmol, 89%). 1H NMR (400 MHz, CDCl3)
d: 2.37 (s,
3H), 7.31 (d, 2H, J¼8.0 Hz), 7.41 (d, 2H, J¼8.0 Hz), 8.10 (d, 1H,
3J¼8.2 Hz), 8.13 (dd, 1H, 3J¼7.9 Hz, 4J¼1.9 Hz), 8.18 (dd, 1H, 3J¼7.9,
7.1 Hz), 8.61 (dd, 1H, 3J¼7.1 Hz, 4J¼1.9 Hz), 8.69 (d, 1H, 3J¼8.2 Hz).
4.9. 3-(6-Methoxycarbonyl-pyrid-2-yl)-6-(4-methylphenyl)-
1,2,4-triazine-4-oxide (12)
13C NMR (100 MHz, CDCl3)
d: 20.66, 121.90, 123.68, 125.03, 128.00,
A solution of the hydrazone 6 (2.58 g, 14.6 mmol) in acetic acid
(20 mL) was added to solution of the aldehyde 4 (2.41 g, 14.6 mmol)
in acetic acid (20 mL) at 0 ꢀC, and the mixture was stirred at rt
overnight. Then powder of red lead oxide Pb3O4 (10 g, 14.6 mmol)
was added as five separate portions of 2 g at 30 min intervals. After
Pb3O4 had been dissolved, water (80 mL) was added, and resulting
precipitate of crude 12 was separated by filtration and washed with
ethanol. The product was purified by recrystallization from DMF to
give colorless crystals of 12. Yield 2.1 g (7.14 mmol) 45%. Mp:
129.19, 134.20, 134.83, 137.70, 138.86, 139.34, 148.03, 150.08, 152.20,
154.08, 165.82, 168.27.
4.13. Dimethyl 5-(4-methylphenyl)-2,20-bipyridine-6,60-
dicarboxylate (16)
Dicarboxylic acid 15 (1.46g, 4.36 mmol) was stirred under reflux
in SOCl2 (20 mL) for 1 h until a clear solution was obtained. Then
excess of SOCl2 was removed in vacuum to reduce the reaction
mixture volume to 3 mL. This was added dropwise to 50 mL of
methanol and then stirred under reflux for 1 h. Solids were filtered
off and resulted solution was condensed in vacuum to give crude
16, which was purified by crystallization from methanol. Yield
167e168 ꢀC (from DMF). 1H NMR (400 MHz, CDCl3)
3.93 (s, 3H), 7.43 (d, 2H, J¼8.0 Hz), 8.15 (d, 2H, J¼8.0 Hz), 8.24e8.29
(m, 3H), 9.41 (s, 1H). 13C (100 MHz, CDCl3)
: 20.93, 52.53, 126.14,
d: 2.42 (s, 3H),
d
127.16, 128.93, 129.05, 129.78, 132.36, 138.16, 141.74, 147.53, 148.28,
155.11, 156.92, 164.62. Anal. Calcd for C17H14N4O3: C 63.35, H 4.38, N
17.38. Found: C 63.03, H 4.70, N 17.61.
1.37 g, (3.8 mmol, 87%). 1H NMR (400 MHz, CDCl3)
d: 2.37 (s, 3H),
3.74 (s, 3H), 3.95 (s, 3H), 7.31 (d, 2H, J¼8.0 Hz), 7.33 (d, 2H,
J¼8.0 Hz), 8.15 (dd, 1H, 3J¼7.8 Hz, 4J¼2.1 Hz), 8.16 (d, 1H, 3J¼8.2 Hz),
8.18 (dd, 1H, 3J¼7.8, 7.0 Hz), 8.58 (dd, 1H, 3J¼7.0 Hz, 4J¼2.1 Hz), 8.59
4.10. 5-Cyano-(6-methoxycarbonyl-pyrid-2-yl)-6-(4-
methylphenyl)-3-1,2,4-triazine (13)
(d, 1H, 3J¼8.2 Hz). 13C NMR (100 MHz, CDCl3)
d: 20.66, 52.36, 52.52,
122.22, 123.92, 125.36, 127.79, 129.35, 133.80, 135.59,137.89, 138.96,
139.58, 147.26, 148.51, 152.39, 154.06, 164.90, 167.16.
Acetone cyanohydrin (1.095 mL, 12 mmol) and triethylamine
(0.84 mL, 6 mmol) were added to solution of 1,2,4-triazine-4-ox-
ide 12 (1.76 g, 6 mmol) in DCM (30 mL) and the mixture was
stirred under reflux for 30 min. Then solvent was removed and
diethyl ether (10 mL) was added to the residue to form a yellow
precipitate of 5-cyano-1,2,4-triazine 13, which was filtered off and
washed with another portion of diethyl ether. Yield 1.51 g
(5.1 mmol, 85%). Mp: 113e114 ꢀC (from 2-propanol). 1H NMR
4.14. 6,60-Di(hydroxymethyl)-5-(4-methylphenyl)- 2,20-
bipyridine (17)
Compound 17 (1 g, 2.76 mmol) was suspended in ethanol (50 mL)
and NaBH4 (250 mg, 6.7 mmol) was added. The mixture was stirred
for 20 h at rt. The solvent was removed, water (5 mL) was added, and
mixture was heated to boil for 5 min. Then the solution was cooled
and extracted with chloroform (5ꢃ100 mL), the organic layer was
separated and dried with anhydrous potassium sulfate. The solvent
was removed and boiling ethanol (20 mL) was added to the residue.
The hot solution was separated from solids and the solvent was re-
moved to give product 17, which was passed for the next step
without further purification. Yield 0.63 g (2.07 mmol, 75%). 1H NMR
(400 MHz, CDCl3)
d: 2.47 (s, 3H), 3.97 (s, 3H), 7.53 (d, 2H,
3J¼8.0 Hz), 8.02 (d, 2H, 3J¼8.0 Hz), 8.33 (d, 1H, 3J¼4.4 Hz), 8.33 (d,
1H, 3J¼4.9 Hz), 8.77 (dd, 1H, J¼4.9, 4.4 Hz). 13C NMR (100 MHz,
CDCl3)
d: 21.00, 52.62, 115.33, 126.97, 127.20, 128.78, 129.07,
129.63, 133.91, 139.37, 141.84, 146.30, 151.14, 156.92, 159.56, 164.76.
Anal. Calcd for C18H13N5O2: C 65.25, H 3.95, N 21.14. Found: C
65.21, H 4.17, N 21.36.

A.M. Prokhorov et al. / Tetrahedron 67 (2011) 597e607
605
(400 MHz, CDCl3)
d
: 2.38 (s, 3H), 4.57 (d, 2H, 3J¼5.5 Hz), 4.68 (d, 2H,
The mixture was refluxed for 2 days. Then solids were filtered off
and washed with MeCN. Combined filtrates were condensed in
vacuo to dryness to give brown oil of crude product. It was dis-
solved in boiling hexane (40 mL), insoluble impurities were filtered
off. Hexane solution was evaporated to dryness and the residue was
again recrystallized from hexane to give pure product as white
crystals. Yield 220 mg (0.29 mmol, 70%). Mp 70 ꢀC. 1H NMR
3J¼5.5 Hz), 5.23 (t,1H, 3J¼5.5 Hz), 5.53 (t,1H, 3J¼5.5 Hz), 7.30 (d, 2H,
3J¼8.0 Hz), 7.43 (d, 2H, 3J¼8.0 Hz), 7.55 (d,1H, 3J¼6.9 Hz), 7.83 (d,1H,
3J¼8.1 Hz), 7.97 (dd, 1H, 3J¼6.9, 7.4 Hz), 8.36 (d, 1H, 3J¼8.1 Hz), 8.43
(d, 1H, 3J¼7.4 Hz). 13C NMR (100 MHz, CDCl3)
d: 20.67, 62.51, 64.33,
118.77, 119.10, 120.45, 128.79, 128.96, 135.09, 135.84, 137.09, 137.56,
138.59, 147.26, 153.13, 156.13, 151.58.
(400 MHz, CDCl3) d
: 1.41 (s, 18H, tBu), 1.46 (s, 9H, tBu), 2.74 (m, 4H,
4.15. 6,60-Di(bromomethyl)-5-(4-methylphenyl)- 2,20-
bipyridine (18)
CH2), 2.87 (m, 12H, CH2), 3.24 (s, 4H, CH2), 3.34 (s, 2H, CH2), 3.83 (s,
2H, CH2), 7.50 (m, 3H, Ph), 7.66 (m, 3H, PhþPy), 7.79 (dd, 1H, J¼7.8,
7.8 Hz, Py), 8.00 (dd, 1H, J¼8.2, 1.8 Hz, Py), 8.26 (d, 1H, J¼8.2 Hz, Py),
8.48 (d, 1H, J¼7.8 Hz, Py), 8.91 (d, 1H, J¼1.8 Hz, Py). 13C NMR
Compound 17 (0.49 g, 1.6 mmol) was mixed with DCM (25 mL)
and phosphorus tribromide (0.5 mL, 4.8 mmol) was added at ꢁ10 ꢀC.
The mixture was stirred under reflux for 2 h. Then an aqueous so-
lution of 5% NaHCO3 (50 mL) was added and the mixture was
extracted with chloroform (2ꢃ50 mL). The organic layer was sepa-
rated and evaporated to give colorless solid of 18. Yield 0.57 g
(400 MHz, CDCl3) d: 28.19, 51.94, 52.36, 52.71, 52.84, 55.42, 56.56,
61.60, 80.66, 118.90, 119.12, 121.00, 127.05, 128.10, 129.09, 135.15,
136.21, 137.70, 147.54, 154.84, 155.26, 159.70, 159.80, 171.05.ESI-MS,
m/z: found 759.4800 (MþH)þ, calcd 759.4809.
(1.33 mmol, 83%). Mp: 143 ꢀC. 1H NMR (400 MHz, CDCl3)
d
: 2.40 (s,
4.18. Compound 24a
3H), 4.69 (s, 2H), 4.81 (s, 2H), 7.35 (d, 2H, 3J¼8.1 Hz), 7.44 (d, 2H,
3J¼8.1 Hz), 7.66 (dd,1H, 3J¼7.5 Hz, 4J¼1.0 Hz), 7.87 (d,1H, 3J¼8.2 Hz),
8.02 (dd, 1H, 3J¼7.5, 7.5 Hz), 8.35 (dd, 1H, 3J¼7.5 Hz, 4J¼1.0 Hz), 8.38
Compound 11a (1 mmol, 355 mg) and cyclene/glyoxal 23
(1 mmol, 194 mg) were mixed in 20 mL of acetonitrile and stirred
at 60 ꢀC for 24 h. During the reaction, a precipitate was formed.
The reaction mixture was evaporated to dryness and the residue
was treated with THF (20 mL). The resulting salt 24a was filtered
off as a white solid, and then passed for the next step without
further purification. Yield 440 mg (0.80 mmol, 80%). 1H NMR
(d, 1H, 3J¼8.2 Hz). 13C NMR (100 MHz, CDCl3)
d: 20.71, 33.72, 34.78,
119.89, 120.29, 124.16, 128.45, 129.25, 134.83, 137.11, 137.56, 138.56,
139.58, 152.91, 153.57, 154.28, 156.49. Anal. Calcd for C19H16Br2N2: C
52.81, H 3.73, N 6.48. Found: C 52.66, H 3.41, N 6.30.
4.16. Compounds 19b and 26
(400 MHz, D2O) d: 2.50 (m, 2H), 2.81 (m, 2H), 2.98 (m, 2H),
3.10e3.22 (m, 4H), 3.50 (m, 6H), 3.59 (s, 3H, Me), 3.68 (br s, 1H),
4.08 (br s, 1H), 4.35 (m, 1H), 4.60 (m, 1H), 6.63 (m, 2H, Ph), 7.17 (m,
2H, Ph), 7.49 (d, 1H, J¼8.0 Hz, Py), 7.59 (dd, 1H, J¼8.0, 8.0 Hz, Py),
7.75 (d, 1H, J¼8.0 Hz, Py), (m, 2H, Py), 8.22 (d, 1H, J¼2.0 Hz, Py). 13C
Compound 11b or 11c (2 mmol) correspondingly, DTTA tetra-
tert-butyl ester (1.18 g, 2.1 mmol), and anhydrous potassium car-
bonate (1.38 g,10 mmol) were mixed in dry acetonitrile (90 mL). The
mixture was stirred under reflux for 48 h under argon atmosphere.
Then solvent was removed in vacuum and water (30 mL) was added,
the product was extractedbychloroform (2ꢃ35mL). The chloroform
extract was dried with anhydrous sodium sulfate and solvent was
removed in vacuum. The product (19b or 26 correspondingly) was
isolated by column chromatography (eluentdacetonitrile, Rf¼0.2)
as a yellow oil and passed for next step without further purification.
NMR (100 MHz, CDCl3) d: 44.11, 48.50, 48.53, 49.24, 52.17, 55.45
(2C), 59.26, 60.50, 62.17, 72.35, 82.74, 114.73, 120.77, 122.09,
128.20, 129.57, 134.80, 136.77, 139.02, 143.00, 147.50, 148.55,
153.02, 156.34, 160.10.
4.19. Compound 25a
Compound 24a (440 mg, 0.80 mmol) was suspended in 30 mL of
hydrazine hydrate and stirred at 120 ꢀC overnight. A precipitate was
formed. The mixture was cooled down and white crystals of product
25a were filtered off and washed with water. The product was
passed for the next step without further purification. Yield 250 mg
4.16.1. Compound 19b. Yield 0.72 g (0.9 mmol, 45%). 1H NMR
t
(400 MHz, CDCl3)
d
: 1.42 (s, 36H, Bu), 2.75 (t, 4H, J¼7.0 Hz, bipy-
CH2NCH2CH2), 2.92 (t, 4H, J¼7.0 Hz, bipy-CH2NCH2CH2), 3.45 (s, 8H,
CH2COOtBu), 3.93 (s, 2H, bipy-CH2), 7.42 (m,1H, Ph), 7.51 (m, 3H, Ph,
H-50), 7.66 (m, 2H, Ph), 7.77 (dd, 1H, J¼8.0, 7.8 Hz, H-40), 8.00 (dd,
1H, J¼8.2, 2.2 Hz, H-4), 8.28 (d, 1H, J¼7.8 Hz, H-30), 8.51 (d, 1H,
J¼8.4 Hz, H-3), 8.91 (d, 1H, J¼2.4 Hz, H-6). 13C NMR (100 MHz,
(0.56 mmol, 70%). Mp 153 ꢀC.1H NMR (400 MHz, CDCl3)
d: 2.32e3.00
(br s, 3H, NH), 2.57 (m, 4H), 2.71 (m, 8H), 2.81 (m, 4H), 3.86 (s, 3H,
CH3), 3.88 (s, 2H, CH2). 7.03 (d, 2H, Ph), 7.40 (d,1H, J¼7.8 Hz, Py), 7.57
(d, 2H, Ph), 7.78 (dd,1H, J¼7.8, 7.8 Hz, Py), 7.93 (dd,1H, J¼7.8, 2.0 Hz,
Py), 8.26 (d, 1H, J¼7.8 Hz, Py), 8.50 (d, 1H, J¼7.8 Hz, Py), 8.86 (d, 1H,
CDCl3) d: 28.16, 52.17, 53.27, 56.16, 60.63, 80.82, 119.07, 121.18,
122.98, 127.08, 128.12, 129.12, 135.17, 136.25, 137.24, 137.80, 147.52,
150.53, 154.92, 160.36, 170.72. ESI-MS, m/z: found 804.4811
(MþH)þ, calcd 804.4833.
J¼2.0 Hz, Py). 13C NMR (100 MHz, CDCl3)
d: 45.18, 46.47, 47.17, 51.57,
55.42, 60.77, 114.61, 119.20, 121.15, 122.86, 128.18, 130.17, 134.51,
135.91, 137.39, 147.17, 154.50, 155.30, 158.92, 159.84.
4.16.2. Compound 26. Yield 0.59 g (0.7 mmol, 35%). 1H NMR
t
(400 MHz, CDCl3)
d
: 1.43 (s, 36H, Bu), 2.76 (t, 4H, J¼7.0 Hz, bipy-
4.20. Compound 20a
CH2NCH2CH2), 2.92 (t, 4H, J¼7.0 Hz, bipy-CH2NCH2CH2), 3.45 (s, 8H,
CH2COOtBu), 3.94 (s, 2H, bipy-CH2), 7.54 (d, 1H, J¼8.0 Hz, H-50), 7.70
(dd, 1H, J¼8.0, 8.0 Hz, H-40), 7.79 (dd, 1H, J¼7.4, 7.2 Hz, H-500), 7.98
(d, 1H, J¼8.0 Hz, H-30), 8.06 (dd, 1H, J¼8.2, 2.4 Hz, H-4), 8.30 (m, 2H,
H-400,600), 8.52 (d, 1H, J¼1.8 Hz, H-200), 8.59 (d, 1H, J¼8.2 Hz, H-3),
8.94 (d, 1H, J¼2.4 Hz, H-6).ESI-MS, m/z: found 849.4667 (MþH)þ,
calcd 849.4684.
Compound 25a (250 mg, 0.56 mmol) was dissolved in dry ace-
tonitrile (20 mL) and potassium carbonate (2.24 mmol) and tert-
butyl bromoacetate (1.85 mmol) were added. The mixture was
refluxed for 2 days. Then solids were filtered off and washed with
MeCN. Combined filtrates were condensed in vacuo to dryness to
give a brown oil of crude product. It was dissolved in boiling hexane
(40 mL), insoluble impurities were filtered off. Hexane solution was
evaporated to dryness and the residue was again recrystallized from
hexane to give pure product as white crystals. Yield 265 mg
4.17. Compound 20b
Compound 11b (136 mg, 0.42 mmol) and tri-tert-butyl ester
(216 mg, 0.42 mmol) were dissolved in dry acetonitrile (20 mL) at
60 ꢀC and potassium carbonate (230 mg, 1.70 mmol) was added.
(0.37 mmol, 65%). Mp 79 ꢀC.1H NMR (400 MHz, CDCl3)
d: 1.41 (s,18H,
t
tBu), 1.45 (s, 9H, Bu), 2.62e2.80 (m, 4H, CH2), 2.82e2.90 (m, 12H,
CH2), 3.23 (s, 4H, CH2), 3.33 (s, 2H, CH2), 3.82 (s, 2H, CH2), 3.86 (s, 3H,

606
A.M. Prokhorov et al. / Tetrahedron 67 (2011) 597e607
CH3), 7.01 (m, 2H, Ph), 7.60 (m, 2H, Ph), 7.67 (d,1H, J¼7.8 Hz, Py), 7.77
(dd, 1H, J¼7.8, 7.8 Hz, Py), 7.94 (dd, 1H, J¼8.2, 1.8 Hz, Py), 8.25 (d, 1H,
J¼8.2 Hz, Py), 8.46 (d,1H, J¼7.8 Hz, Py), 8.86 (d,1H, J¼1.8 Hz, Py). 13C
(634 mg, 4.6 mmol) were mixed in dry acetonitrile (25 mL) and
stirred under reflux for 24 h. Then water (100 mL) was added and
product was extracted with DCM (3ꢃ25 mL). Solvent was re-
moved to give product 29 as a white solid. The product was
passed for the next step without further purification. Yield
NMR (100 MHz, CDCl3) d: 28.24, 52.17, 52.49, 52.59, 52.84, 55.42,
56.61, 61.79, 80.64, 114.61, 118.93, 121.08, 123.27, 129.06, 130.19,
134.62, 135.85, 137.22, 147.19, 154.84, 154.93, 159.74, 159.83,
171.17.ESI-MS, m/z: found 799.4967 (MþH)þ, calcd 789.4915.
231 mg (0.39 mmol, 85%). Mp 89 ꢀC. 1H NMR (400 MHz, CDCl3)
d:
2.38 (s, 3H), 3.49 (s, 6H), 3.61 (s, 6H), 3.62 (s, 4H), 3.64 (s, 4H),
3.95 (s, 2H), 4.06 (s, 2H), 7.29 (d, 2H, 3J¼8.0 Hz), 7.51 (d, 2H,
3J¼8.0 Hz), 7.57 (dd, 1H, 3J¼7.5 Hz, 4J¼0.8 Hz),7.82 (d, 1H,
3J¼8.1 Hz), 7.97 (dd, 1H, 3J¼7.5, 7.1 Hz), 8.24 (dd, 1H, 3J¼7.1 Hz,
4.21. Compound 27
Compound 26 (440 mg, 0.52 mmol) and Pd/C (10%) (138 mg) in
absolute ethanol (50 mL) were stirred at rt in hydrogen atmosphere
(P¼3.5 atm) for 6 h. Then the catalyst was filtered off, solvent was
removed in vacuum. The product 27 was isolated by column
4J¼0.8 Hz), 8.30 (d, 1H, 3J¼8.1 Hz). 13C NMR (100 MHz, CDCl3)
d:
20.68, 50.91, 51.10, 54.10, 54.13, 56.68, 59.15, 118.67, 118.93,
122.95, 128.79, 129.06, 135.66, 136.90, 137.60, 137.71, 138.86,
152.79, 153.96, 154.11, 158.26, 170.97, 171.08.
chromatography. Yield 200 mg (0.24 mmol, 48%). 1H NMR
t
(400 MHz, CDCl3)
d
: 1.42 (s, 36H, Bu), 2.75 (t, 4H, J¼7.0 Hz, bipy-
4.27. Compound 30
CH2NCH2CH2), 2.91 (t, 4H, J¼7.0 Hz, bipy-CH2NCH2CH2), 3.44 (s, 8H,
CH2COOtBu), 3.81 (br s., 2H, NH2), 3.92 (s, 2H, bipy-CH2), 6.74 (m,
1H, H-600), 6.95 (dd, 1H, J¼2.0 Hz, H-200), 7.04 (m, 1H, H-400), 7.28 (dd,
1H, J¼8.0, 7.8 Hz, H-500), 7.50 (d, 1H, J¼8.0 Hz, H-50), 7.77 (dd, 1H,
3J¼8.0, 8.0 Hz, H-40), 7.97 (dd, 1H, J¼8.2, 2.4 Hz, H-4), 8.26 (d, 1H,
J¼8.0 Hz, H-30), 8.47 (d, 1H, J¼8.2 Hz, H-3), 8.87 (d, 1H, J¼2.4 Hz, H-
6). ESI-MS, m/z: found 819.5047 (MþH)þ, calcd 819.5020.
A concentrated sulfuric acid (5 mL) was added to compound 29
(190 mg, 0.32 mmol) at 0 ꢀC and stirred until solution became
clear. Then 65% nitric acid (0.025 mL, 0.35 mmol) was added. The
mixture was stirred at rt for 30 min and poured on ice. The mix-
ture was neutralised with saturated solution of potassium
hydrocarbonate and extracted with DCM (3ꢃ25 mL). Solvent was
removed to give product 30 as a brown solid. The product was
passed for the next step without further purification. Yield 179 mg
4.22. Ligand 21b
(0.28 mmol, 86%). 1H NMR (400 MHz, CDCl3)
d: 2.61 (s, 3H), 3.50 (s,
The tert-butyl ester 19b (120 mg, 0.15 mmol) was dissolved and
stirred in 6 M water solution of HCl (40 mL) at rt overnight. Then acid
was evaporated to dryness, and residue was treated with dry
acetonitrile to give yellow crystals of 21b in form of pentahydro-
chloride trihydrate. Yield 100 mg (0.12 mmol, 82%). Anal. Calcd for
C29H44Cl5N5O11: C 42.69, H 5.44, N 8.58. Found: C 42.34, H 5.11, N 8.61.
6H), 3.64 (s, 6H), 3.67 (s, 4H), 3.69 (s, 4H), 3.99 (s, 2H), 4.11 (s, 2H),
7.59 (d, 1H, 3J¼6.5 Hz), 7.61 (d, 1H, 3J¼8.0 Hz), 7.90 (dd, 1H,
3J¼6.5 Hz, 4J¼1.6 Hz), 7.96 (d, 1H, 3J¼8.0 Hz), 8.01 (dd, 1H, 3J¼8.0,
7.4 Hz), 8.29 (d, 1H, 3J¼7.4), 8.37 (d, 1H, 3J¼8.0 Hz), 8.41 (d, 1H,
4J¼1.6 Hz). 13C NMR (100 MHz, CDCl3)
d: 19.07, 50.91, 51.12, 54.02,
54.13, 57.27, 59.07, 118.90, 119.24, 123.23, 124.83, 131.85, 132.62,
133.77, 135.65, 137.52, 137.75, 139.19, 148.86, 153.33, 153.66,
153.87, 158.23, 170.87, 171.03.
4.23. Ligand 22a
The tert-butyl ester 20a (265 mg, 0.33 mmol) was dissolved and
stirred in 6 M water solution of HCl (40 mL) at rt overnight. Then
acid was evaporated to dryness, and residue was treated with dry
acetonitrile to give yellow crystals of 22a in form of tetrahydro-
chloride trihydrate. Yield 245 mg, 90%. Anal. Calcd for
C32H50Cl4N6O10: C 46.84, H 6.14, N 10.24. Found: C 46.63, H 6.28, N
10.12.
4.28. Compound 31
Compound 30 (150 mg, 0.24 mmol) and Pd/C (10%) (100 mg) in
absolute ethanol (30 mL) were stirred at rt in hydrogen atmosphere
(P¼15 atm) for 60 h. Catalyst was filtered off, solvent was removed
in vacuum to give product 31. Yield 128 mg (0.21 mmol, 87%). 1H
NMR (400 MHz, CDCl3) d: 2.21 (s, 3H), 3.61 (s, 6H), 3.66 (s, 6H), 3.68
(s, 4H), 3.69 (s, 4H), 4.04 (s, 2H), 4.11 (s, 2H), 6.77 (dd, 1H, 3J¼7.5 Hz,
4J¼1.6 Hz), 7.03 (d, 1H, 4J¼1.6 Hz), 7.10 (d, 1H, 3J¼7.5 Hz), 7.53 (d, 1H,
3J¼8.5 Hz), 7.72 (d, 1H, 3J¼8.0 Hz), 7.82 (dd, 1H, 3J¼8.5, 8.5), 8.30 (d,
4.24. Ligand 22b
The tert-butyl ester 20b (200 mg, 0.26 mmol) was dissolved and
stirred in 6 M water solution of HCl (20 mL) at rt overnight. Then acid
was evaporated to dryness, and residue was treated with dry ace-
tonitrile to give yellow crystals of 22b in form of tetrahydrochloride
trihydrate. Yield 165 mg, 79%. Anal. Calcd for C31H48Cl4N6O9: C 47.10,
H 6.12, N 10.63. Found: C 46.91, H 6.05, N 10.47.
1H, 3J¼8.5 Hz), 8.33 (d, 1H, 3J¼8.0 Hz). 13C NMR (100 MHz, CDCl3)
d:
17.30, 51.66, 51.82, 54.60, 55.07, 57.82, 60.42, 116.28, 119.54, 119.70,
122.06, 123.42, 130.62, 137.80, 138.25, 139.16, 145.37, 153.96, 154.68,
155.66,158.62,171.97, 172.22.ESI-MS, m/z: found 608.2790 (MþH)þ,
calcd 608.2720.
4.25. Ligand 28
4.29. Ligand 32
The tert-butyl ester 27 (120 mg, 0.15 mmol) was dissolved and
stirred in 6 M water solution of HCl (40 mL) at rt overnight. Then
acid was evaporated to dryness, and residue was treated with dry
acetonitrile to give yellow crystals of 21b in form of pentahydro-
chloride trihydrate. Yield 98 mg (0.12 mmol, 80%). Anal. Calcd for
C29H44N5O11Cl5: C 42.38, H 5.51, N 10.23, Cl 20.28. Found: C 42.06, H
5.42, N 11.12, Cl 20.45.
Compound 31 (100 mg, 0.165 mmol) was dissolved in methanol
(50 mL) and 1 N NaOH water solution (0.66 mL, 0.66 mmol) was
added.Themixturewasstirredfor2hatrt. Thensolventwasremoved
and the residue was dissolved in water (10 mL). Insolubles were fil-
tered off and ethanol was added to the clear solution. The precipitate
of sodium salt of ligand 32 was filtered off and dried in vacuum. Yield
87 mg (0.16 mmol, 97%).1H NMR (400 MHz, CDCl3)
d: 2.04 (s, 3H), 3.66
3
(s, 8H), 4.49 (s, 4H), 6.62 (dd, 1H, J¼7.3 Hz, 4J¼1.6 Hz), 6.66 (d, 1H,
4J¼1.6 Hz), 7.06 (d, 1H, 3J¼7.3 Hz), 7.39 (d, 1H, 3J¼7.5 Hz), 7.80 (d, 1H,
3J¼8.0 Hz), 7.95 (dd,1H, 3J¼7.5, 7.5 Hz), 8.39 (d, 1H, 3J¼7.5 Hz), 8.46 (d,
1H, 3J¼8.0 Hz). Anal. Calcd for C27H25N5Na4O8: C 50.71, H 3.94, N
10.95. Found: C 50.55, H 3.71, N 10.66.
4.26. Compound 29
Compound 18 (200 mg, 0.46 mmol), dimethyl iminodiacetate
(IDA dimethyl ester) (198 mg, 1 mmol), and potassium carbonate

A.M. Prokhorov et al. / Tetrahedron 67 (2011) 597e607
607
4.30. Complex [Eu1]
4.34. Complex [Eu5]
1 M NaOH aqueous solution (0.5 mL, 0.5 mmol) was added to
a solution of ligand 22b tetrahydrochloride trihydrate (60 mg,
0.072 mmol) in water (10 mL) and then a solution of EuCl3$6H2O
(26.50 mg, 0.072 mmol) in water (10 mL) was added. Then mixture
was stirred under reflux for 10 min. Solvent was removed and
methanol (10 mL) was added. Insolubles were filtered off and sol-
vent was removed to give a white powder of the complex [Eu1].
Yield 50 mg (0.065 mmol, 91%). Anal. Calcd for C32H37EuN6O7: C,
46.03; H, 3.49; N, 9.73%. Found: C, 46.36; H, 3.60; N, 10.01%. Crys-
tallography data: A single crystal of [Eu1] polyhydrate was obtained
by slow evaporation of a saturated water solution of [Eu1].
A solution of EuCl3$6H2O (28.55 mg, 0.078 mmol) in water
(10 mLL) was added to a solution of ligand 32 sodium salt (50 mg,
0.078 mmol) in water (10 mL). Then the mixture was stirred under
reflux for 10 min. Solvent was removed and methanol (10 mL) was
added. Insolubles were filtered off and solvent was removed to give
white powder of the complex [Eu2]. Yield 50 mg (0.069 mmol,
89%). Anal. Calcd for C27H25EuN5O8Na: C 44.89, H 3.49, N 9.69.
Found: C 44.56, H 3.60, N 9.51.
Acknowledgements
C32H49EuN6O13, FW¼865.64, monoclinic, a¼15.1841(8), b¼15.4329
This work was supported by Russian Foundation for Basic
Research (grant 08-03-00585-a).
¼90.00ꢀ,
b
¼98.146(7)ꢀ,
g
¼90.00ꢀ, V¼3969.1
ꢂ
(18), c¼17.1105(18) A,
a
3
ꢂ
(7) A , T¼295(2) K, space group P2(1)/c, Z¼4, 7719 reflections
measured, 43,894 unique (Rint¼0.0467), which were used in all
calculations. R1¼0.0414, wR2¼0.1062. Crystallographic data have
been deposited with Cambridge Crystallographic Data Center as
supplementary publication number CCDC 791942. These data can
be obtained free of charge from The Cambridge Crystallographic
Data Center via www.ccdc.cam.au.uk/data_request/cif.
References and notes
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ꢁ
3. Weibel, N.; Charbonniere, L. J.; Guardigli, M.; Roda, A.; Ziessel, R. J. Am. Chem.
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4.31. Complex [Eu2]
1 N NaOH aqueous solution (0.44 mL, 0.44 mmol) was added to
a solution of ligand 22a tetrahydrochloride trihydrate (50 mg,
0.063 mmol) in water (10 mL) and then a solution of EuCl3$6H2O
(23.20 mg, 0.063 mmol) in water (10 mL) was added. Then mixture
was stirred under reflux for 10 min. Solvent was removed and
methanol (10 mL) was added. Insolubles were filtered off and sol-
vent was removed to give a white powder of the complex [Eu2].
Yield 40 mg (0.054 mmol, 86%). Anal. Calcd for C31H35EuN6O6: C,
50.34; H, 4.77; N, 11.36. Found: C, 50.08; H, 4.80; N, 11.32.
8. Joule, J. A.; Mills, K. Heterocyclic Chemistry; Blackwell Science: Oxford, 2000,
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€
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4.32. Complex [Eu3]
16. Diring, S.; Retailleau, P.; Ziessel, R. J. Org. Chem. 2007, 72, 10181e10193.
17. Stanforth, S. P.; Tarbit, B.; Watson, M. D. Tetrahedron Lett. 2002, 43, 6015e6017.
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NaOH (1 N) aqueous solution (0.37 mL, 0.37 mmol) was added to
a solution of ligand 21b pentahydrochloride trihydrate (43 mg,
0.053 mmol) in water (10 mL) and then a solution of EuCl3$6H2O
(19.31 mg, 0.063 mmol) in water (10 mL) was added. Then mixture
was stirred under reflux for 10 min. Solvent was removed and
methanol (10 mL) was added. Insolubles were filtered off and sol-
vent was removed to give a white powder of the complex [Eu3].
Yield 31 mg (0.043 mmol, 78%). Anal. Calcd for C29H29EuN5O8Na: C,
46.41; H, 3.89; N, 9.33%. Found: C, 46.08; H, 3.75; N, 9.38%. ESI-MS,
m/z (Irel (%)). Found: 741.13 (87), 742.13 (28), 743.13 (100), 744.13
(34), 745.14 (7.5) (MꢁNa)ꢁ; calcd: 741.13 (85.8), 742.13 (29.4),
743.13 (100), 744.14 (33.1), 745.14 (7).
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4.33. Complex [Eu4]
NaOH (1 N) aqueous solution (0.84 mL, 0.84 mmol) was added to
a solution of ligand 28 pentahydrochloride trihydrate (98 mg,
0.12 mmol) in water (10 mL) and then a solution of EuCl3$6H2O
(43.92 mg, 0.12 mmol) in water (10 mL) was added. Then mixture
was stirred under reflux for 10 min. Solvent was removed and
methanol (10 mL) was added. Insolubles were filtered off and sol-
vent was removed to give a white powder of the complex [Eu4] as
trihydrate. Yield 71 mg (0.091 mmol, 76%). Anal. Calcd for
C29H29EuN5O8Na: 42.96, H 4.52, N 10.01. Found: 42.50, H 4.43, N
10.25. ESI-MS, m/z (Irel (%)). Found: 726.12 (87.5), 727.12 (30), 728.12
(100), 729.12 (34.1), 730.13 (7.7) (MꢁNa)ꢁ; calcd: 726.12 (85.9),
727.12 (29.09), 728.12 (100), 729.13 (32.74), 730.13 (6.88).
ꢀ
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