New synthons for the synthesis of lanthanide containing macrocyclic schiff bases featuring substituents available for tethering

Article abstract of DOI:10.1016/S0040-4020(00)00104-6

2,6-Diacetylpyridine substituted with amine or alcohol groups in the 4- position have been prepared from chelidamic acid. The key 4-chloro derivative was synthesized in high yield via a diazo intermediate and was protected as a bis-1,3-dioxane before substitution with various amino alcohol groups. Lanthanide macrocyclic tetra-imine complexes were obtained by a template procedure that leads to stable paramagnetic and/or fluorescent derivatives with anchor groups available for linkage to macromolecules. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4020(00)00104-6

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 2043±2052
New Synthons for the Synthesis of Lanthanide
Containing Macrocyclic Schiff Bases Featuring Substituents
Available for Tethering
*
Arnaud Dumont, Vincent Jacques and Jean F. Desreux
Á Á
Coordination and Radiochemistry, University of Liege, Sart Tilman (B6), B-4000 Liege, Belgium
Received 22 July 1999; accepted 2 February 2000
AbstractÐ2,6-Diacetylpyridine substituted with amine or alcohol groups in the 4-position have been prepared from chelidamic acid. The
key 4-chloro derivative was synthesized in high yield via a diazo intermediate and was protected as a bis-1,3-dioxane before substitution with
various amino alcohol groups. Lanthanide macrocyclic tetra±imine complexes were obtained by a template procedure that leads to stable
paramagnetic and/or ¯uorescent derivatives with anchor groups available for linkage to macromolecules. q 2000 Elsevier Science Ltd. All
rights reserved.
Introduction
formed by pentadentate porphyrin-like ligands.8
Finally, inert complexes have been obtained by template
reactions leading to the formation of imine or hydrazone-
type bonds around a central lanthanide ion in a macrocyclic
unit.6
Over the last decade, the sustained research activity devoted
to the lanthanide ions and their complexes has stemmed in
part from the successful applications of these compounds in
medicine and in biology. Because of its high magnetic
moment and its long NMR relaxation times, gadolinium is
currently used in hospitals to improve the contrast of
magnetic resonance images (MRI).1 Moreover, the long
excited-state lifetimes of some lanthanides allow time-
gated measurements of the luminescence of ions such as
Eu31 and Tb31 without interferences from biological
molecules. Time-resolved ¯uoroimmunoassays2 are
commonplace in laboratories and applications in cell sorting
have been reported.3 Finally, lanthanide ions are effective
catalysts for the hydrolytic cleavage of RNA.4 Catalysis
becomes highly selective after coupling of a lanthanide to
an antisense oligonucleotide.5,6 All these applications
require that the lanthanide ions be used as stable chelates
and ligands featuring anchor groups are preferred to ensure
that the metal ions always remain tethered to a biologically
active macromolecule. In most cases, macrocyclic ligands
are preferred to linear ligands because their metal
complexes are usually more stable and kinetically more
inert. A relatively small number of macrocyclic units
are known to form suf®ciently stable lanthanide
derivatives. The 1,4,7,10-tetraazacyclododecane cycle has
been substituted by carboxylic acid, alcohol or amide
functions to obtain some of the most stable lanthanide
chelates known.1,7 Highly stable derivatives are also
It is against this background that we decided to synthesize a
series of synthons for the preparation of polyimine or poly-
hydrazone macrocyclic complexes by a template reaction in
the presence of a lanthanide ion. These synthons feature
alcohol or amine substituents that are available for tethering
as shown in Scheme 1 (letters a±h are used throughout with
the same meaning). The corresponding lanthanide Schiff
bases have also been prepared.
Results and Discussion
All the syntheses reported herein lead to synthons and
hexaaza lanthanide complexes derived from 2,6-diacetyl-
pyridine substituted in the 4 position. The synthesis and
the chemistry of 4-substituted pyridine rings have been
much less explored than that of the more accessible 2- or
3- substituted derivatives, but this molecular arrangement
was preferred as it leads to only one isomer position in the
®nal compounds. Moreover, the acetyl group was preferred
to the 2,6-diformylpyridine moiety as it seems to form
kinetically more inert lanthanide Schiff bases.9
The present work was ®rst aimed at preparing a synthon
with a simple methylamino function directly grafted onto
the pyridine ring despite the risk that this substituent could
be poorly reactive because of the electron-withdrawing
character of the diacetylpyridine group. As indicated in
Keywords: imines; templates; lanthanides; amino ketones.
* Corresponding author. Tel.: 132-4-366-3501; fax: 132-4-366-4736;
e-mail: jf.desreux@ulg.ac.be
0040±4020/00/$ - see front matter q 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00104-6

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A. Dumont et al. / Tetrahedron 56 (2000) 2043±2052
Scheme 1. Substituted polyimine lanthanide macrocyclic complexes.
Scheme 2, 4-(methylamino)pyridine-2,6-dicarboxylic acid,
2, was obtained in high yields after heating an aqueous
solution of methylamine and chelidamic acid, 1, at 1708C
in an autoclave according to a known procedure.10 In our
hands, the reaction gave a mixture of the sought compound
and of the corresponding bis-N-methylamide, but a treat-
ment with sodium peroxide directly on the reaction mixture
transformed the bis-amide into the diacid 2.
ester intermediate in the Claisen condensation did not
prove fruitful. For instance, using the dianion of acetic
acid12 led to the complete decomposition of the pyridine
ring. Similarly, a reaction with the dimethylsulfoxide
anion13 followed by a treatment of the b-ketosulfoxide
with a zinc amalgam caused a partial decomposition of
diester 3. Finally, treating ester 3 with methylmagnesium
iodide and triethylamine14 yielded the sought compound
although in poor yield (18%). It should be noted here that
the approach presented in Scheme 2 gives excellent results
in the case of the diester of pyridine-2,6-dicarboxylic acid15
but that similar dif®culties have been reported recently.16
The methylamino group of 3 is probably the site of side
reactions that might be avoided after protection of its nitro-
gen atom. However, as feared, this group was found to be
nearly totally unreactive toward substitution. Only 27% of
the starting amine was reacted after 24 h in an excess of hot
acetyl chloride. The diketone 4 and its derivatives are thus
not suited for tethering to other molecules and it was desir-
able to ®nd more reactive substituents and more practical
synthetic schemes for the preparation of substituted diketo
pyridines.
Pyridine mono- and dicarboxylic acids are known to form
esters only with great dif®culty11 and the bis-ester 3 was
synthesized by forming a silver salt of 2 that was reacted
with ethyl iodide. This tedious but classical approach can be
replaced in this particular case by a treatment with thionyl
chloride and ethanol at the cost of a lower yield (68%)
because the methylamino group is quite unreactive as will
be shown below. The diketone 4 needed for the template
reactions in the presence of a lanthanide ion was prepared
by a Claisen condensation leading to the b-keto ester that
was subsequently hydrolyzed. This procedure proved poorly
reproducible and allowed only unsatisfactory yields (37%
at best). Various other attempts at obtaining the b-keto
Scheme 2. (a) 1: CH3NH2, autoclave, 2: Na2O2 (85%); (b) i: NH4OH, AgNO3 (82%), ii: CH3CH2I, C6H6 (80%); (c) i: CH3CH2Ona, ethyl acetate, iii: HCl
(35%).

A. Dumont et al. / Tetrahedron 56 (2000) 2043±2052
2045
Scheme 3. (a) SOCl2, DMF (86%); (b) CH2N2 (68%); (c) HI (99%).
It was decided to use a protected derivative of 4-chloro-2,6-
diacetylpyridine as the starting material for the synthesis of
various synthons featuring aliphatic substituents in the 4
position. This approach appeared to have the advantage of
versatility but it requested the selection of the proper
protecting group and an effective route for the preparation
of the diketone. As shown in Scheme 3, chelidamic acid, 1,
was reacted with thionyl chloride in the presence of
dimethylformamide in order to avoid auto-quaternization
reactions. This led to the acid dichloride 5 in better yield
(86%) and more easily than with older procedures.17,18 The
acid dichloride 5 was transformed into the bis-diazoketone
derivative 6 (yield 68%), which yielded quantitatively the
sought diketone 7 by reaction with hydrogen iodide.
Compound 7 was recently obtained16 in 56% yield by
reacting 5 with Meldrum's acid followed by an hydrolysis
with aqueous acetic acid.
Scheme 3 proved extremely valuable in the present work.
Pyridine tetraketones were also obtained in quantitative
yields from the corresponding tetracarboxylic acids.19 As
shown in Scheme 4, adding an amino group on 4-chloro-
2,6-diacetylpyridine, 7, required the prior protection of the
ketone groups to avoid formation of imines. Compound 7
was quantitatively converted into the corresponding bis-1,3-
dioxolane derivative 11 by reaction with a large excess of
1,2-ethanediol. A high temperature (1708C) condensation of
11 with an excess of N, N0-dimethyl-1,2-diaminoethane in
an autoclave allowed the substitution of the chlorine atom
with an amino group in good yields (12f, 70%) but the
Scheme 4. (a) ethylene glycol, toluene, p-toluene sulfonic acid (99%); (b) 1,2-propanediol, toluene, pˆsulfonic acid (90%); (c) ethyl orthoformate, EtOH
(88%); (d) 12a: CH3±HN±CH2±CH2±OH (50%), 12f: CH3±NH±CH2±CH2±NH±CH3(70%); (e) 9a: NaH, HO±CH2±CH2±NH±CH3, 9b: NaH, HO±CH2±
CH2±NH2, 9c: NaH, HO±CH2±CH2±NH±CH3; (f) 2 M HCl 10a (69%), 10b (81%), 10c (45%); (g) (BOC)2O, MeOH, 10d (97%), 10e (98%).

2046
A. Dumont et al. / Tetrahedron 56 (2000) 2043±2052
protecting dioxolane groups could not be removed with
classical reagents such as silica gel, MgSO4 or even concen-
trated acids at elevated temperature during several days.
Transacetalization was also ineffective. Similarly, removing
the dioxolane groups of 4-(2-(N-methylamino)ethoxy)-2,6-
bis(2-methyl(1,3-dioxolan-2-yl))pyridine, 12a, could only
be performed with dif®culty in 6 M HCl.20 More easily
removable protecting groups were obviously needed. The
bis-1,3-dioxane 8 and the corresponding bis-ethyl ketal 13
were obtained respectively in 97% and 88% yields by elimi-
nating water either with a Dean±Stark trap or with triethyl
orthoformate. However, the substitution of these two
compounds with N,N0-dimethyl-1,2-diaminoethane at
elevated temperature in sealed glass tubes led only to their
complete decomposition. The aminodiketones derived from
7 thus remained elusive either because the protecting
group of the ketone functions could not be removed or
because the secondary amine substituent could not be
added to the pyridine ring without side reactions. In keeping
with these dif®culties, a few examples in the literature
mention the inertness of the 1,3-dioxolane moiety especially
in the presence of an amine function. For example, the
deprotection of a piperidine dioxolane derivative required
6 h of re¯ux in a 6 M HCl solution.15 The synthesis of 10a,b,
d±e with one oxygen atom directly bonded to the pyridine
ring instead of one nitrogen atom was then attempted
from 8.
For the preparation of the alcohol substituted 10c, the dipro-
tected chloropyridine diketone 8 was added to a xylene
solution of 2-(methylamino)ethanol treated with two
equivalents of sodium hydride. The amide anion exclusively
reacts with 8 to give 9c. However, the yield of this reaction
did not exceed 50% and the separation of 8 and 9c was not
attempted. Instead, removal of the 1,3-dioxane groups was
performed immediately with 2 M HCl with an overall yield
of 45% in the ®nal compound 10c after puri®cation. It
should be noted here that an interesting comparison of the
advantages and drawbacks of the ketal protecting groups
can be made since a variety of protected derivatives have
been synthesized in the present work. It appears that the
removal of the ketal functions is less effective and requires
longer reaction times and more drastic conditions if the side
chains contain an amine group and/or if 1,3-dioxolane is the
protecting group. Complete deprotection of 8 and 11 was
achieved with 1 M HCl in less than 10 and 15 min respec-
tively. About 2 days were needed when 9a±c were treated
with 2 M HCl and 12a required 5 days in 6 M HCl to reach a
68% yield. Finally, 12f could not be deprotected with 12 M
HCl even after 5 days.
All lanthanide complexes 14a±g were prepared in anhydrous
methanol by re¯uxing during several hours stoichiometric
amounts of a substituted diketone, of distilled 1,2-di-
aminoethane and of a lanthanide tris-acetate (see Scheme
5). Yields ranged between 70 and 90% depending on the
lanthanide ion. As noted earlier,21 the lanthanide complexes
exhibit the unusual property of being soluble in water,
methanol and chlorinated organic solvents such as chloro-
form. Cleavage of the tert-butoxycarbonyl protective
groups of 14d,e was achieved quantitatively with trimethyl-
silyl iodide in less than 45 min without any reaction with the
ether functions. Iodide ions are liberated in this procedure
and the hydrolysis of the trimethylsilyl iodide in excess
by methanol produces hydrogen iodide. The acetate ions
coordinated to the lanthanides are replaced by iodide ions
and the amine groups are protonated. Complete replacement
of the iodide ions by acetate ions was carried out by elution
on a DOWEX 1£2 200 quaternary ammonium ion
exchanger in the acetate form.
The protected chlorodiketal 8 was reacted in hot xylene with
the sodium salt of 2-(methylamino)ethanol. The reaction led
exclusively and in high yields to the formation of the
2-(methylamino)ethoxy group in 9a (yield: 90% provided
diketal 8 has been thoroughly puri®ed). Xylene was
preferred as a solvent over dimethylformamide as the yields
were found to be higher. Hydrolysis of the ketal functions
by 2 M HCl was complete within two days (yields: 88%).
Compound 10a can be kept unaltered during several weeks
as a solid at 08C but as expected, it degrades rapidly in
solution. The methylamine function was easily protected
with di-tert-butyl dicarbonate to prevent reactions between
the ketone and amine groups (yield 97%). The tert-butoxy-
carbonyl group in 10d was selected for the protection step
since it is easily removed in mild conditions by trimethyl-
silyl iodide after the template reactions have been carried
out as shown below. The diketone synthon 10e derived from
10b and featuring a protected primary amine function was
prepared according to the strategy already used for 10d.
Very similar yields were achieved but the intermediate
10b was used immediately without puri®cation for the
template synthesis of hexaaza lanthanide complexes.
The formation of the lanthanide tetra±imine complexes
14a±f is readily observed by various spectroscopic tech-
niques. The assignment of the NMR peaks listed in the
experimental section are based on the shifts and relative
areas of the 1H peaks and on COSY and 13C±1H correlation
2D spectra. Paramagnetic shifts are induced by lanthanide
ions and are useful to unravel the solution structures
Scheme 5. 14c±g: 1,2-ethylenenediamine, lanthanide tris(acetate), MeOH (70±90%); 14a±b:i: 1,2-ethylenediamine, lanthanide tris(acetate), MeOH (70±
90%), ii: (CH)3SiI, Dowex 1£2 200 in acetate form (97%).

A. Dumont et al. / Tetrahedron 56 (2000) 2043±2052
2047
provided the interactions between the ligand nuclei and the
metal ions are of purely dipolar origin and provided all
complexes are isostructural.22 Previous analyses23 of the
spectra of unsubstituted lanthanide macrocyclic tetra±
imine complexes 14h and of cryptate and aza crown imines
clearly showed that these two conditions are not met and we
made no attempt at interpreting quantitatively the NMR
spectra that were used only for identi®cation purposes. Elec-
trospray and fast atom bombardment mass spectra also
clearly showed the formation of the lanthanide complexes.
As expected, the ultra-violet peak with the highest wave-
length undergoes a red-shift when amino groups are added
to the unsubstituted Eu31 complex 14f: from lˆ303 nm and
eˆ9200 for 14e to lˆ319 nm and eˆ16000 for 14g and to
lˆ329 nm and eˆ18800 for 14c. Substitution with amino
groups has a marked effect on the ¯uorescence intensity of
the 5D0±7F2 europium peak (lemissionˆ622 nm) that also
increases in the sequence 14e, 14g, 14c with relative inten-
sities ,5, 79 and 126 and becomes very high in the presence
of 4,4,4-tri¯uoro-1(2-thienyl)butane-1,3-dione (relative
intensity 345±360 for all complexes).
heated in an autoclave at 1708C during 24 h. After cooling
to room temperature, the solvents were removed on a
rotatory evaporator leaving a brown solid. This solid was
dissolved in 40 mL of water and the solution was brought to
boiling. Sodium peroxide was added cautiously until no
basic vapor could be detected. The solution turned green
during this process. The reaction mixture was cooled to
08C and the pH was lowered to 2.5. The nearly white
crystals which formed were collected by ®ltration, and
washed with cold water. Yield: 85% (5 g, 25.5 mmol);
mp 255±2608C (decomp., lit.10 245±2558). 1H NMR
(D2O/NaOD): dˆ2.91 (s, 3 H, CH3N), 7.22 (s, 2 H,
Hpy); 13C NMR (D2O/NaOD): dˆ31.34, 110.61, 155.60,
159.46, 175.81; ES/MS (CH3CN/H2O 50/50): m/zˆ197
(M1H)1, m/zˆ195 (M2H)2. Anal calcd for C8H8N2O4:
C, 48.98; H, 4.11; N, 14.28. Found: C, 48.87; H, 4.21; N,
14.33.
Diethyl 4-(methylamino)pyridine-2,6-dicarboxylate, 3.
Compound 2 (4 g, 20 mmol) was dissolved in 40 mL of
conc. ammonium hydroxide. The solution was brought to
dryness in a rotatory evaporator and the remaining solid was
dissolved in 200 mL of hot water. In a dark room, a solution
of silver nitrate (10.4 g, 60 mmol) in 65 mL water was
added under stirring. The solution was chilled in an ice
bath to precipitate the silver salt of 2 that was collected by
®ltration, washed with ethanol and dried under vacuum. The
silver salt and freshly distilled ethyl iodide (10.4 mL,
19.5 mmol) were added to 50 mL of dried benzene. The
mixture was re¯uxed in the dark for 8 h. After cooling,
the precipitated silver iodide was ®ltered off and washed
with benzene. The ®ltrate and the washes were evaporated
and the remaining yellow oil solidi®ed after several days.
In conclusion, we propose herein an approach for the
synthesis of synthons featuring anchor groups from which
stable macrocyclic polyimine or polyhydrazone lanthanide
complexes can be prepared. These complexes feature amino
or alcohol groups that can be linked to macromolecules by
classical procedures. Derivatives with either one or two
anchor groups are available depending on the approach
selected for the synthesis of the macrocyclic unit, either a
direct condensation between identical units as reported
herein or a stepwise approach or a dihydrazone.6 The
synthesis of these new synthons required the careful selec-
tion of appropriate conditions and protecting groups but
leads to macrocycles in high yields with no ambiguities
due to regioisomers as found if the anchor groups are
added to the ±CH2±CH2± side-chains of 14h.3
1
Yield: 80% (4.0 g, 16 mmol); mp 61.3±62.78C. H NMR
(CDCl3): dˆ1.39 (t, Jˆ7.1 Hz, 6 H, CH3), 2.93 (d,
Jˆ4.2 Hz, 3 H, CH3N), 4.40 (q, Jˆ7.1 Hz, 4 H, CH2O),
5.18 (broad, 1 H, NH), 7.39 (s, 2 H, Hpy); 13C NMR
(CDCl3): dˆ14.97, 30.46, 66.35, 111.60, 149.71, 156.74,
162.94; ES/MS (CH3CN/H2O 50/50): m/zˆ253 (M1H)1.
Anal calcd for C12H16N2O4: C, 57.13; H, 6.39; N, 11.10.
Found: C, 57.46; H, 6.48; N, 11.23.
Experimental
General
4-(Methylamino)-2,6-diacetylpyridine, 4. The diester 3
(3.72 g, 15 mmol) and ethyl acetate (3.12 mL, 32 mmol)
were added to 95 mL of xylene previously dried over
CaH2. The solution was added dropwise to 1.13 g
(49 mmol) of freshly prepared solid sodium ethoxide. The
reaction mixture was re¯uxed under nitrogen during 40 h.
After cooling, conc. HCl (37 mL) and water (18 mL) were
added and re¯ux was carried out for a total of 5 h with
violent stirring. All solvents were eliminated under vacuum
and 20 mL of conc. HCl in 4 mL of water were added to the
remaining material. After re¯uxing the mixture for 5 h, the
solution was brought to dryness, taken up with 25 mL of
water and slowly basi®ed with solid Na2CO3. The resulting
precipitate was ®ltered, washed with water and dried under
vacuum. Yield: 35% (1.0 g, 5.3 mmol); mp 147.2±148.68C.
1H NMR (CDCl3): dˆ2.71 (s, 6 H, CH3CvO), 2.93 (d,
Jˆ4.9 Hz, 3 H, CH3N), 4.67 (broad, 1 H, NH), 7.30 (s, 2
H, Hpy); 13C NMR (CDCl3): dˆ26.51, 30.55, 108.23,
154.30, 156.52, 201.46; ES/MS (CH3CN/H2O 50/50):
m/zˆ193 (M1H)1.
All solvents were dried using common techniques and all
reactions were carried out under N2. Chemicals were
purchased from Aldrich Chemical Co and used without
further puri®cation. 4-Hydroxypyridine-2,6-dicarboxylic
acid (chelidamic acid) was obtained from 4-oxo-4H-
pyrane-2,6-dicarboxylic acid.24 Melting points are uncor-
rected. Mass spectra were obtained on a Fisons VGA
Platform (electrospray, ES) or a Fisons Autospec mass spec-
trometer (fast atom bombardment, FAB, in 3-nitrobenzyl
1
alcohol, NOBA, or in glycerol). H and 13C one and two
dimensional spectra (COSY, 13C±1H correlation) were
acquired on a Bruker AM 400 spectrometer at 400 and
100.6 MHz, respectively as reported elsewhere.25 Chemical
shifts (d) are reported in parts per million (ppm) relative to
tetramethylsilane. Splitting patterns are described as singlet
(s), doublet (d), triplet (t), quartet (q), multiplet (m).
4-(Methylamino)pyridine-2,6-dicarboxylic acid, 2. Cheli-
damic acid, 1, (6 g, 30 mmol) was added to 50 mL of a 40%
aqueous solution of methylamine. The reaction mixture was

2048
A. Dumont et al. / Tetrahedron 56 (2000) 2043±2052
4-Chloro-2,6-pyridinedicarboxylic dichloride, 5. Our
procedure is adapted from the method of Robison18 using
thionyl chloride instead of phenylphosphonic dichloride.
Thionyl chloride (10 mL) was added dropwise to 4 mL of
dimethylformamide in a three-neck round-bottom ¯ask
equipped with a nitrogen inlet. After agitating the mixture
briskly for 5 min, chelidamic acid, 1, (2.01 g, 11 mmol)
was slowly added in portions and agitation was maintained
until complete dissolution. The reaction mixture was
re¯uxed during 2 h. After cooling, the excess thionyl
chloride was eliminated under vacuum. The remaining
solid was dissolved in 10 mL of dry benzene and the solvent
was removed by evaporation. This treatment was repeated
twice to eliminate the last traces of thionyl chloride. The
remaining orange paste was extracted four times with
25 mL of dry ethyl ether. The combined organic phases
were brought to dryness yielding a beige solid that was
used without any further puri®cation. Yield 86% (2.25 g,
(54 mmol) and p-toluenesulfonic acid (40 mg) in 40 mL
of toluene was re¯uxed under nitrogen for 50 h while elimi-
nating water with a Dean±Stark trap. Evaporation of the
solvent gave a yellow glassy solid. This solid was taken
up with 5% aqueous sodium carbonate (10 mL). The
resulting solution was extracted with dichloromethane
(3£20 mL). After drying (MgSO4), the organic solution
was evaporated to yield a 4-chloro-2,6-diacetyl ketal that
was puri®ed by column chromatography (silica kept over-
night in ethyl acetate, dichloromethane/methanol 98:2).
4-Chloro-2,6-bis(2-methyl-(1,3-dioxan-2-yl))pyridine, 8.
Yield: 90% (1.04 g, 3.24 mmol); mp 93.1±94.78C. 1H
NMR (CDCl3): d 1.37 (m, 2 H, CH2), 1.54 (s, 6 H,
CH3CO2), 2.04 (m, 2 H, CH2), 3.75 (m, 4 H, CH2O), 3.94
(m, like d of t), 4 H, CH2O), 7.46 (s, 2 H, Hpy); 13C NMR
(CDCl3): dˆ25.04, 28.51, 61.28, 99.71, 120.95, 145.23,
162.21; ES/MS (CH3CN/H2O 50/50): m/zˆ314 (M1H)1.
Anal calcd for C15H20ClNO4: C, 57.42; H, 6.42; N, 4.46.
Found: C, 57.44; H, 6.40; N, 4.51.
1
9.5 mmol). H NMR (CDCl3): dˆ8.16 (s, 2 H, Hpy); 13C
NMR (CDCl3): dˆ123.58, 150.33, 157.91, 167.95.
4-Chloro-2,6-bis-(diazoacetyl)pyridine, 6. In an atmosphere
of nitrogen, using predried glassware, 200 mL of dry diethyl
ether containing approximately 3 g of diazomethane
(71 mmol) were cooled to 08C. A solution of 5 (2.25 g,
9.4 mmol) in 100 mL of dry diethyl ether was added drop-
wise. The reaction ¯ask was agitated manually during the
addition to disperse the thick yellow precipitate that formed
rapidly. The reaction mixture was stirred manually during 1 h
after completing the addition. The precipitate was collected
by ®ltration and washed with 20 mL of ethyl ether. A second
crop of the title compound was obtained by reducing the
volume of the ®ltrate to 15 mL. The resulting pale yellow
powder was dried under vacuum and kept in the absence of
light. Yield: 68% (1.6 g, 6.4 mmol); mp 135±1388C
(decomp.). 1H NMR (CDCl3): dˆ6.58 (s, 2 H, CHN2), 8.20
(s, 2 H, Hpy); 13C NMR (CDCl3): dˆ55.19, 125.16, 148.26,
153.42, 184.17; FAB/MS (NOBA): m/zˆ250 (M1H)1.
4-Chloro-2,6-bis(2-methyl-(1,3-dioxolan-2-yl))pyridine, 11.
Yield: 99%, (1.02 g, 3.56 mmol); oil. H NMR (CDCl3):
1
dˆ1.71 (s, 6 H, CH3CO2), 3.90 (m, 4 H, CH2O), 4.06 (m,
4 H, CH2O), 7.46 (s, 2 H, Hpy); 13C NMR (CDCl3):
dˆ25.39, 65.90, 109.05, 119.94, 145.72, 163.06; ES/MS
(CH3CN/H2O 50/50): m/zˆ286 (M1H)1. Anal calcd for
C13H16ClNO4: C, 54.65; H, 5.64; N, 4.90. Found: C,
54.48; H, 5.71; N, 4.88.
4-Chloro-2,6-bis(1,1-diethoxyethyl)pyridine, 13. 4-Chloro-
2,6-diacetylpyridine, 7, (0.2 g, 1 mmol), triethyl ortho-
formate (1.6 mL, 10 mmol) and 10 mg of p-toluenesulfonic
acid were added to 2 mL of ethanol. The reaction mixture
was re¯uxed under nitrogen during 20 h. The solvent was
eliminated under vacuum and the remaining yellow oil was
triturated with 10 mL of a 5% Na2CO3 aqueous solution.
The mixture was extracted with 3£20 mL of dichloro-
methane. The organic extracts were dried over MgSO4,
the solvent was evaporated and the remaining viscous oil
was dried in vacuum at 808C. Yield: 88% (0.3 g,
4-Chloro-2,6-diacetylpyridine, 7. A solution of 6 (1.6 g,
6.41 mmol) in 160 mL of dichloromethane was added drop-
wise to a briskly agitated mixture of 40 mL of dichloro-
methane and 10.8 g of a 47% aqueous solution of
hydrogen iodide. Stirring was continued for a further 48 h
whereupon the reaction mixture turned deep brown and then
black. Water (80 mL) was added and the organic phase was
decanted off. The aqueous phase was extracted four times
with dichloromethane (40 mL). The combined organic
phases were treated with a 10% aqueous solution of sodium
thiosulfate, washed with water (50 mL), dried over MgSO4
and brought to dryness in a rotatory evaporator at room
temperature. The remaining yellow solid was dried under
vacuum. Yield: 99% (1.26 g, 6.37 mmol); mp 72.8±74.28C
(lit.16 648C). 1H NMR (CDCl3): dˆ2.72 (s, 6 H, CH3CvO),
8.10 (s, 2 H, Hpy); 13C NMR (CDCl3): dˆ25.50, 124.80,
146.78, 153.77, 197.96; ES/MS (CH3CN/H2O 50/50):
m/zˆ198 (M1H)1. Anal calcd for C9H8ClNO2: C, 54.70;
H, 4.08; N, 7.09. Found: C, 54.72; H, 4.30; N, 7.18.
1
0.88 mmol). H NMR (CDCl3): dˆ1.16 (t, Jˆ7 Hz, 12 H,
CH3), 1.62 (s, 6 H, CH3CO2), 3.29 (m, 4 H, CH2O), 3.48
(m, 4 H, CH2O), 7.61 (s, 2 H, Hpy); 13C NMR (CDCl3):
dˆ16.09, 25.09, 57.75, 112.19, 121.42, 144.78, 163.01; ES/
MS (CH3CN/H2O 50/50): m/zˆ346 (M1H)1.
General procedure for the synthesis of 4-substituted-2,6-
diacetylpyridines
With a glass syringe, the appropriate aminoalcohol or diol
(previously dried over KOH and distilled under vacuum)
was added under nitrogen to a vigorously stirred suspension
of sodium hydride in dry xylene. A solution of 8 or 11 in dry
xylene was added into the reaction ¯ask once the evolution
of hydrogen had ceased. The resulting brown mixture was
1
re¯uxed overnight. As determined from the 400 MHz H
NMR spectrum, the reaction solution consisted of a mixture
of the starting material and of the 4-substituted ketal. No
puri®cation of the substituted ketal was attempted. The
solvent was immediately evaporated and the residue was
dissolved in dichloromethane. A 2 M HCl aqueous solution
(about 15 mL) was added and stirring was continued during
General procedure for the synthesis of 4-chloro-2,6-
diacetylpyridine ketals
A solution of 7 (0.72 g, 3.6 mmol), the appropriate diol

A. Dumont et al. / Tetrahedron 56 (2000) 2043±2052
2049
48 h. The organic phase was decanted and the aqueous
phase was extracted with dichloromethane (15 mL). The
unreacted 8 was totally found in the organic extract. The
aqueous phase was basi®ed with 2 M NaOH and extracted
with dichloromethane (3£15 mL). The combined organic
layers were washed with water and dried over sodium
sulfate. The solvent was eliminated and the remaining
solid was dried under vacuum.
4-(2-(N-methylamino)ethoxy)-2,6-bis(2-methyl-(1,3-
dioxolan-2-yl))pyridine, 12a. As described above, freshly
distilled 2-(methylamino)ethanol (113 mg, 1.5 mmol) was
reacted with NaH (48 mg, 1.2 mmol) in 8 mL of dried
xylene and 11 (0.29 g, 1 mmol) dissolved in 15 mL of
xylene was added to the reaction mixture. After re¯uxing
overnight and elimination of the solvent, 15 mL of water
were added and 12a was isolated by extraction with
3£15 mL of dichloromethane. Yield: 50% (160 mg,
1
4-(2-(N-methylamino)ethoxy)-2,6-bis(2-methyl-(1,3-
dioxan-2-yl))pyridine, 9a, and 4-(2-(N-methylamino)
ethoxy)-2,6-diacetylpyridine, 10a. Following the pro-
cedure described above and starting from sodium hydride
(69 mg, 1.72 mmol in 10 mL of xylene), 2-(methylamino)-
ethanol (0.17 mL, 2.13 mmol) and 8 (0.45 g, 1.43 mmol in
25 mL of xylene), there was obtained a 1:12 mixture of the
starting material 8 and of 9a. The crude 9a was deprotected
and after work-up, 10a was obtained as a pale beige powder
49.3 mmol), light brown oil. H NMR (CDCl3): dˆ1.69
(s, 6 H, CH3CO2), 2.46 (s, 3 H, CH3N), 2.95 (t, Jˆ5.1 Hz,
2 H, CH2N), 3.89 (m, 4 H, CH2O), 4.02 (m, 4 H, CH2O),
4.09 (t, Jˆ5.1 Hz, 2 H), 6.97 (s, 2 H, Hpy); 13C NMR
(CDCl3): dˆ25.26, 37.07, 51.23, 65.78, 68.04, 105.79,
109.36, 162.95, 166.31; ES/MS (CH3CN/H2O 50/50):
m/zˆ325 (M1H)1. Anal calcd for C16H24N2O5: C,
59.24; H, 7.46; N, 8.64. Found: C, 59.05; H, 7.60; N,
8.82.
1
(0.27 g, 1.13 mmol, 69%), mp 138.1±140.38C; H NMR
(CDCl3): 2.37 (s, 3 H, CH3N), 2.61 (s, 6 H, CH3CvO),
2.89 (t, Jˆ5.1 Hz, 2 H, CH2N), 4.09 (t, Jˆ5.1 Hz, 2 H,
CH2O), 7.54 (s, 2 H, Hpy); 13C NMR (CDCl3): dˆ26.35,
37.01, 50.85, 68.79, 111.47, 155.22, 167.45, 199.92; ES/MS
(CH3CN/H2O 50/50): m/zˆ237 (M1H)1. Anal calcd for
C12H16N2O3: C, 61.00; H, 6.83; N, 11.86. Found: C,
60.73; H, 6.80; N, 11.69.
4-(2-(N-methylamino)ethylamino)-2,6-bis(2-methyl-(1,3-
dioxolan-2-yl))pyridine, 12f. Following the procedure
described above and starting from sodium hydride (48 mg,
1.2 mmol in 8 mL of xylene), N,N0-dimethyl-ethylenedia-
mine (0.11 g, 1.2 mmol) and 11 (0.29 g, 1.0 mmol in
15 mL of xylene), a 1:16 mixture of the starting material
and of 12f was isolated. The mixture was taken up in 10 mL
of ethyl acetate, the insoluble material was discarded and
the solvent was evaporated under vacuum. Yield: 70%
(0.24 g, 0.7 mmol); brownish oil. 1H NMR (CDCl3):
dˆ1.77 (s, 6H, CH3CO2), 2.51 (s, 3H, CH3N), 2.85 (t,
Jˆ7.3 Hz, 2H, CH2N), 3.08 (s, 3H, CH3Npy), 3.62 (t,
Jˆ7.3 Hz, 2H, CH2Npy), 3.95 (m, 4H, CH2O), 4.11 (m,
4H, CH2O), 6.81 (s, 2H, Hpy); 13C NMR (CDCl3):
dˆ25.60, 37.19, 38.82, 49.68, 52.08, 65.37, 101.64,
109.55, 152.98, 161.45; ES/MS (CH3CN/H2O 50/50):
m/zˆ339 (M1H)1. Anal calcd for C17H27N3O4: C,
60.51; H, 8.07; N, 12.45. Found: C, 60.55; H, 7.96; N,
12.52.
4-(2-Aminoethoxy)-2,6-bis(2-methyl-(1,3-dioxan-2-yl))-
pyridine, 9b, and 4-(2-aminoethoxy)-2,6- diacetylpyri-
dine, 10b. Following the procedure described above and
starting from sodium hydride (145 mg, 3.62 mmol in
10 mL of xylene), 2-aminoethanol (0.28 mL, 4.6 mmol)
and 8 (0.95 g, 3.03 mmol in 25 mL of xylene), a 1:9 mixture
of the starting material and of 9b was isolated. The crude
9b was deprotected and after work-up, 10b was obtained
as a straw-yellow powder that was used immediately for
the synthesis of lanthanide complexes. Yield: 81%
1
(0.55 g, 2.45 mmol), mp 87.1±89.38C. H NMR (CDCl3):
dˆ2.69 (s, 6 H, CH3CvO), 3.07 (t, Jˆ5.2 Hz, 2 H,
CH2N), 4.03 (t, Jˆ5.2 Hz, 2 H, CH2O), 7.63 (s, 2 H,
Hpy); 13C NMR (CDCl3): dˆ26.43, 41.80, 71.82, 111.62,
156.72, 167.23, 199.32; ES/MS (CH3CN/H2O 50/50):
m/zˆ223 (M1H)1.
General procedure for the protection of the amino group
of 4-substituted 2,6-diacetyl pyridines
A solution of the appropriate 4-substituted 2,6-diacetylpyri-
dine (1 mmol) and di-tert-butyl dicarbonate (0.24 g,
1.1 mmol) in methanol (10 mL) was stirred overnight at
room temperature. The reaction mixture was evaporated
and the remaining solid was dissolved in 10 mL of water.
The aqueous solution was extracted with dichloromethane
(3£10 mL). The organic phases were collected and dried
over MgSO4. The solvent was eliminated and the remaining
oil was dried under vacuum.
4-(N-hydroxyethyl-N-methylamino)-2,6-bis(2-methyl-
(1,3-dioxan-2-yl))pyridine, 9c, and 4-(N-hydroxyethyl-N-
methylamino)-2,6-diacetylpyridine, 10c. The synthesis of
10c was carried out following the procedure described
above using 2-(methylamino)ethanol (0.34 g, 4.45 mmol),
NaH (0.39 g, 9.8 mmol) suspended in 10 mL of xylene
and 8 (1.4 g, 4.46 mmol) in 30 mL of xylene. An approxi-
mately 1:1 mixture of 8 and 9c was obtained after re¯uxing
overnight. Deprotection of crude 9c to obtain 10c was
performed with 15 mL of 2 M HCl at room temperature
during 40 h. A pale yellow solid was isolated. Yield: 45%
4-(2-(N-(t-butoxycarbonyl)-N-methylamino)ethoxy)-2,6-
diacetylpyridine, 10d. Pale yellow vitreous solid; yield
1
1
(2 mmol, 0.47 g), mp 99.3±100.28C. H NMR (CDCl3):
97% (0.33 g, 0.97 mmol). H NMR (CDCl3): dˆ1.39 (s, 9
dˆ2.65 (s, 6 H, CH3CvO), 3.08 (s, 3 H, CH3N), 3.58 (t,
Jˆ4.8 Hz, 2 H, CH2N), 3.80 (t, Jˆ4.8 Hz, 2 H, CH2O), 7.6
(s, 2 H, Hpy); 13C NMR (CDCl3): dˆ26.43, 39.32, 54.35,
60.43, 107.55, 154.11, 155.99, 201.74; ES/MS (CH3CN/
H2O 50/50): m/zˆ237 (M1H)1. Anal calcd for
C12H16N2O3: C, 61.00; H, 6.83; N, 11.86. Found: C,
60.82; H, 6.94; N, 12.12.
H, CH3t-Bu), 2.69 (s, 6 H, CH3CvO), 2.91 (s, 3 H, CH3N),
3.58 (t, Jˆ5.5 Hz, 2 H, CH2N), 4.19 (broad t, 2 H, CH2O),
7.62 (s, 2 H, Hpy); 13C NMR (CDCl3): dˆ26.35, 29.16,
36.23, 48.74, 69.10, 80.67, 111.54, 155.48, 167.37,
199.97; ES/MS (CH3CN/H2O 50/50): m/zˆ337 (M1H)1.
Anal calcd for C17H24N2O5: C, 60.70; H, 7.19; N, 8.33.
Found: C, 60.53; H, 7.17; N, 8.16.

2050
A. Dumont et al. / Tetrahedron 56 (2000) 2043±2052
4-(2-(N-(t-butoxycarbonyl)-amino)ethoxy)-2,6-diacetyl-
pyridine, 10e. Pale yellow vitreous solid; yield 98%
(0.32 g, 0.98 mmol).1H NMR (CDCl3): dˆ1.39 (s, 9 H,
CH3t-Bu), 2.68 (s, 6 H, CH3CvO), 3.56 (m, 2 H, CH2N),
4.04 (t, Jˆ5.1 Hz, 2 H, CH2O), 5.14 (broad, 1H, NH), 7.61
(s, 2 H, Hpy); 13C NMR (CDCl3): dˆ26.39, 29.22, 39.42,
68.73, 80.03, 111.56, 155.41, 167.12, 199.95; ES/MS
(CH3CN/H2O 50/50): m/zˆ323 (M1H)1. Anal calcd for
C16H22N2O5: C, 59.61; H, 6.88; N, 8.69. Found: C, 59.72;
H, 6.70; N, 8.54.
(M2CH3COO)1, 359 (M22CH3COO)11/2; FAB/MS
(NOBA): m/zˆ990 (M1NOBA1H)1, 884, 824.
Europium complex: brown vitreous solid, yield: 98%
1
(0.35 g, 0.41 mmol). H NMR (CD3OD): dˆ22.13 (s, 8
H, CH2NvC), 2.50 (s, 6 H, CH3N), 3.02 (broad t, 4 H,
CH2N), 3.11 (s, 12 H, CH3CvN), 3.76 (s, 4 H, Hpy), 3.88
(broad t, 4 H, CH2O), 8.40 (broad s, 9 H, CH3COO); 13C
NMR (CD3OD): dˆ220.91 (CH3CvN), 0.5 (very broad,
CH3COO), 33.90 (CH3N), 48.66 (CH2NvC), 52.31 (CH2N),
65.52 (CH2O), 85.36 (b-py), 129.64, 158.39, 174.82; ES/
MS (CH3CN/H2O 50/50): m/zˆ789 (M2CH3COO)1, 365
(M22CH3COO)11/2; FAB/MS (NOBA): m/zˆ1002
(M1NOBA1H)1, 789 (M2CH3COO)1, 896, 731.
General procedure for the synthesis of lanthanide
complexes
The appropriate substituted 2,6-diacetylpyridine 4 or 10c±e
(1 mmol) and a lanthanide acetate (0.55 mmol) were
dissolved in absolute methanol (25 mL). A solution of
distilled 1,2-diaminoethane (60 mg, 1.07 mmol) was
added dropwise and the reaction mixture was re¯uxed for
20 h. The resulting yellow solution was brought to dryness
in a rotavapor and the remaining pink solid was dissolved in
dichloromethane (3 mL). The slightly cloudy solution was
clari®ed by ®ltration on glasswool and ethyl ether (about
100 mL) was added dropwise under stirring. The solution
was ®ltered through sintered glass with an ethyl ether wash
and the collected solid was dried under vacuum. The lantha-
nide complexes featuring amine functions protected with
Boc groups (1 mmol) were placed in a reaction ¯ask
equipped with a septum and thoroughly ¯ushed with
argon. The solid was dissolved in 60 mL of dichloro-
methane previously dried over CaH2 and 0.86 mL
(6 mmol) of iodotrimethylsilane were added dropwise
with a syringe. A precipitate formed immediately. After
stirring during 45 min, methanol (10 mL) was added. The
solvents were evaporated in a rotavapor and the remaining
solid was stirred with 10 mL of dichloromethane during
15 min. The precipitate was collected by ®ltration and
washed with a few mL of dichloromethane. Elemental
analyses, ES/MS and NMR spectra indicated that the
complexes were obtained as iodide salts. The corresponding
acetate salts were obtained by an ion-exchange procedure. A
14 mL glass column was ®lled with a DOWEX 1£2 200
resin (14 mL) in the acetate form. The resin was thoroughly
washed with methanol and a solution of the metal complex
(in 2 mL methanol) was passed onto the column. Elution
with methanol (40 mL) and evaporation of the solvent
afforded a solid material that did not form a precipitate
upon the addition of AgNO3.
Lanthanide 10,21-bis-(2-aminoethoxy)-2,7,13,18-tetra-
methyl-3,6,14,17,23,24-hexaazatricyclo[17.3.1.18,12]-
tetracosa-1(22),2,6,8,10,12(24),13,17,19(23),20-decaene
triacetate, 14b. Lanthanum complex: brown solid, yield:
1
97% (0.33 g, 0.40 mmol); mp 128.3±130.28C. H NMR
(CD3OD): dˆ1.86 (s, 9 H, CH3COO), 2.65 (s, 12 H,
CH3CvN), 3.48 (t, Jˆ4.9 Hz, 4 H, CH2N), 4.09 (s, 8 H,
CH2NvC), 4.53 (t, Jˆ4.9 Hz, 4 H, CH2O), 7.84 (s, 4 H,
Hpy); 13C NMR (CD3OD): dˆ16.78 (CH3CvN), 24.21
(CH3COO), 40.22 (CH2N), 54.21 (CH2NvC), 67.94
(CH2O), 114.34 (b-py), 158.72 (a-py), 170.03 (CvN
imine), 172.20 (g-py), 183.05 (CvO acetate). ES/MS
(CH3CN/H2O 50/50): m/zˆ749 (M2CH3COO)1, 345
(M22CH3COO)11/2. FAB/MS (NOBA): m/zˆ962
(M1NOBA1H)1, 749 (M2CH3COO)1, 856, 796, 689.
Lanthanide 10,21-bis-(N-hydroxyethyl-N-methylamino)-
2,7,13,18-tetramethyl-3,6,14,17,23,24-hexaazatricyclo-
[17.3.1.18,12]tetracosa-1(22),2,6,8,10,12(24),13,17,19(23),
20-decaene triacetate, 14c. Lanthanum complex: off white
solid, yield: 81% (0.34 g, 0.41 mmol); mp 237±2408C
1
(decomp.). H NMR (CDCl3): dˆ1.61 (s, 9 H, CH3COO),
2.40 (s, 12 H, CH3CvN), 3.07 (s, 6 H, CH3N), 3.62 (t,
Jˆ4.7 Hz, 4 H, CH2N), 3.70 (t, Jˆ4.7 Hz, 4 H, CH2O),
3.89 (s, 8 H, CH2NvC), 7.09 (s, 4 H, Hpy); 13C NMR
(CDCl3): dˆ15.94 (CH3CvN), 24.14 (CH3COO), 38.03
(CH3N), 52.31 (CH2N), 54.11 (CH2NvC), 58.27 (CH2O),
107.69 (b-py), 155.16 (a-py), 156.65 (g-py), 169.72 (CvN
imine), 183.36 (CvO acetate); ES/MS (CH3CN/H2O 50/
50): m/zˆ777 (M2CH3COO)1, 359 (M2 2CH3COO)11/2;
FAB/MS (NOBA): m/zˆ990 (M1NOBA1H)1, 777
(M2CH3COO)1.
Europium complex: straw yellow solid, yield: 96% (0.41 g,
0.48 mmol); mp 372±3808C (decomp). H NMR (D2O):
1
Lanthanide 10,21-bis-(2-(N-methylamino)ethoxy)-2,7,13,
18-tetramethyl-3,6,14,17,23,24-hexaazatricyclo[17.3.1.18,12]-
tetracosa-1(22),2,6,8,10,12(24),13,17,19(23),20-decaene tri-
acetate, 14a. Lanthanum complex: brown solid, yield: 98%
(0.36 g, 0.44 mmol); mp 143.3±145.98C. 1H NMR
(CD3OD): dˆ1.87 (s, 9 H, CH3COO), 2.65 (s, 12 H,
CH3CvN), 2.81 (s, 6 H, CH3N), 3.53 (t, Jˆ4.9 Hz, 4 H,
CH2N), 4.09 (s, 8 H, CH2NvC), 4.67 (t, Jˆ4.9 Hz, 4 H,
CH2O), 7.84 (s, 4 H, Hpy); 13C NMR (CD3OD): dˆ16.72
(CH3CvN), 23.94 (CH3COO), 34.59 (CH3N), 39.01
(CH2N), 54.18 (CH2NvC), 67.13 (CH2O), 114.32 (b-py),
158.74 (a-py), 169.92 (CvN imine), 172.16 (g-py), 182.63
(CH3COO); ES/MS (CH3CN/H2O 50/50): m/zˆ777
dˆ25.78 (s, 8 H, CH2NvC), 20.29 (s, 12 H, CH3CvN),
1.94 (s, 6 H, CH3N), 2.39 (broad t, 4 H, CH2N), 2.94 (broad
s, 4 H, CH2O), 3.20 (s, 4 H, Hpy), 8.9 (broad s, 9 H,
CH3COO); 13C NMR (D2O): dˆ221.37 (CH3CvN), 3
(broad, CH3COO), 37.57 (CH3N), 41.77 (CH2NvC),
52.96 (CH2N), 60.95 (CH2O), 74.97 (b-py), 104.15,
118.76, 148.76, 159.40; ES/MS (CH3CN/H2O 50/50):
m/zˆ789 (M2CH3COO)1, 365 (M22CH3COO)11/2;
FAB/MS (NOBA): m/zˆ1002 (M1NOBA1H)1.
Lanthanide 10,21-bis-(2-N-(t-butoxycarbonyl)-N-methyl-
amino)ethoxy)-2,7,13,18-tetramethyl-3,6,14,17,23,24-
hexaazatricyclo[17.3.1.18,12]tetracosa-1(22),2,6,8,10,

A. Dumont et al. / Tetrahedron 56 (2000) 2043±2052
2051
12(24),13,17,19(23),20-decaene triacetate, 14d. Lantha-
num complex: pale pink solid, yield: 90% (0.47 g,
0.45 mmol); mp 108.2±1128C (decomp.). 1H NMR
(CDCl3): dˆ1.43 (s, 18 H, CH3t-Bu), 1.67 (s, 9 H,
CH3COO), 2.52 (s, 12 H, CH3CvN), 2.95 (s, 6 H, CH3N),
3.56 (broad t, 4 H, CH2N), 4.02 (s, 8 H, CH2NvC), 4.38
(broad t, 4 H, CH2O), 7.58 (broad s, 4 H, Hpy); 13C NMR
(CDCl3): dˆ17.22 (CH3CvN), 25.02 (CH3COO), 28.99
(CH3t-Bu), 38.14 (CH3N), 48.46 (CH2N), 53.43
(CH2NvC), 68.22 (CH2O), 80.38 (Ct-Bu), 113.14 (b-py),
156.65 (NCvO carbamate), 157.52 (a-py), 169.45 (CvN
imine), 170.03 (g-py), 183.11 (CvO acetate). ES/MS
(CH3CN/H2O 50/50): m/zˆ977 (M2CH3COO)1, 459
(M22CH3COO)11/2. FAB/MS (NOBA): m/zˆ1190
(M1NOBA1H)1.
Praseodymium complex: beige solid, yield: 83% (0.31 g,
0.42 mmol); mp 248±2528C. 1H NMR (CD3OD):
dˆ22.14 (s, 6 H, CH3N), 2.10 (broad s, 9 H, CH3COO),
4.16 (s, 12 H, CH3CvN), 5.95 (s, 8 H, CH2NvC), 16.26 (s,
4 H, Hpy). 13C NMR (CD3OD): dˆ24.82, 33.52, 35.78,
37.99, 106.03, 133.49, 170.66, 186.18, 194.02 all broad;
ES/MS (CH3CN/H2O 50/50): m/zˆ691 (M2CH3COO)1,
316 (M22CH3COO)11/2; FAB/MS (NOBA): m/zˆ905
(M1NOBA1H)1, 691 (M2CH3COO)1.
Europium complex: beige solid, yield: 84% (0.32 g,
0.42 mmol); mp 137±139.28C. 1H NMR (CD3OD):
dˆ23.48 (s, 8 H, CH2NvC), 0.52 (s, 4 H, Hpy), 1.15 (s,
12 H, CH3CvN), 1.84 (s, 6 H, CH3N), 9 (broad s, 9 H,
CH3COO); 13C NMR (CD3OD): dˆ225.93 (CH3CvN),
25 (broad, CH3COO), 41.35 (CH3N), 43.98 (CH2NvC),
75.71 (b-py), 121.04, 150.84, 160.40; ES/MS (CH3CN/
Europium complex: pale pink solid, yield: 85% (0.45 g,
0.43 mmol); mp 121.6±124.28C (decomp). 1H NMR
(CDCl3): dˆ1.15 (broad s, 9 H, CH3COO), 1.40 (broad s,
30 H, CH3t-Bu and CH3CvN), 2.83 (s, 6 H, CH3N), 3.42
(broad t, 4 H, CH2N), 4.28 (broad t, 4 H, CH2O), 4.98 (s, 8
H, CH2NvC), 5.91 (s, 4 H, Hpy); 13C NMR (CDCl3):
dˆ217.60 (CH3CvN), 20.2 (broad, CH3COO), 28.15
(CH3Ct-Bu), 35.65 (CH3N), 46.99 (CH2NvC), 57.68
(CH2N), 66.34 (CH2O), 78.80 (Ct-Bu), 75.71 (b-py),
134.63, 155.12, 162.47, 174.74; ES/MS (CH3CN/H2O 50/
50): m/zˆ989 (M2CH3COO)1, 465 (M22CH3COO)11/2.
FAB/MS (NOBA): m/zˆ1203 (M1NOBA1H)1, 989
(M2CH3COO)1.
H2O
50/50):
m/zˆ701
(M2CH3COO)1,
321
(M22CH3COO)11/2; FAB/MS (NOBA): m/zˆ914
(M1NOBA1H)1, 701 (M2CH3COO)1.
Ytterbium complex: beige solid, yield: 78% (0.30 g, 0.39
mmol); mp 260±2658C (decomp). 1H NMR (CD3OD):
dˆ22.73 (s, 4 H, Hpy), 20.76 (s, 8 H, CH2NvC), 1.30
(s, 12 H, CH3CvN), 9.5 (broad s, 6 H, CH3N), 24.76 (s, 9 H,
CH3COO); 13C NMR (CD3OD): dˆ10.15, 25.90, 79.81,
88.75, 99.23, 145.11, 147.48, all broad; ES/MS (CH3CN/
H2O
50/50):
m/zˆ724
(M2CH3COO)1,
333
(M22CH3COO)11/2; FAB/MS (NOBA): m/zˆ937
(M1NOBA1H)1, 724 (M2CH3COO)1.
Lanthanide 10,21-bis-(2-(N-(t-butoxycarbonyl)-amino)-
ethoxy)-2,7,13,18-tetramethyl-3,6,14,17,23,24-hexaaza-
tricyclo[17.3.1.18,12]tetracosa-1(22),2,6,8,10,12(24),13,17,
19(23),20-decaene triacetate, 14e. Lanthanum complex:
rosy solid, yield: 85%, (0.43 g, 0.43 mmol); mp 126.6±
Acknowledgements
We gratefully acknowledge the ®nancial support of the
Fonds National de la Recherche Scienti®que; V. J. is
Â
Chercheur Quali®e at this institution. We are all grateful
for support by the Institut Interuniversitaire des Sciences
Nucleaires, the Fonds pour la Formation a la Recherche
dans l'Industrie et dans l'Agriculture and the European
Cooperation in the Field of Scienti®c and Technical
Research COST D8.
1
128.98C (decomp.). H NMR (CDCl3): dˆ1.39 (s, 18 H,
CH3t-Bu), 1.64 (s, 9 H, CH3COO), 2.53 (s, 12 H,
CH3CvN), 3.53 (m, 4 H, CH2N), 4.00 (s, 8 H,
CH2NvC), 4.40 (t, Jˆ5.8 Hz, 4 H, CH2O), 6.19 (broad, 2
H, NH), 7.62 (s, 4 H, Hpy); 13C NMR (CDCl3): dˆ16.43
(CH3CvN), 24.30 (CH3COO), 29.19 (CH3Ct-Bu), 39.98
(CH2N), 53.55 (CH2NvC), 68.91 (CH2O), 80.46 (Ct-Bu),
113.60 (b-py), 156.64 (NCvO carbamate), 157.63 (a-py),
169.54 (CvN imine), 170.20 (g-py), 183.06 (CvO acetate).
ES/MS (CH3CN/H2O 50/50): m/zˆ949 (M2CH3COO)1,
445 (M22CH3COO)11/2. FAB/MS (NOBA): m/zˆ1162
(M1NOBA1H)1, 996.
Â
Á
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