Full control of the regiospecific N-functionalization of C-functionalized cyclam bisaminal derivatives and application to the synthesis of their TETA, TE2A, and CB-TE2A analogues

Article abstract of DOI:10.1021/jo4028566

We describe an easy synthesis of original C-functionalized cyclam derivatives based on the efficient bisaminal template method. In the perspective of developing bifunctional chelating agents (BCAs), this new synthetic strategy offers the possibility of introducing various coupling functions on one carbon atom in the β-N position of the macrocycle, leaving the four nitrogen atoms available for the introduction of pendant coordinating arms. The methodology is based on a keystone C-functionalized oxo-cyclam bisaminal intermediate that is obtained by cyclization of a preorganized tetraamine using various methyl acrylate analogues. These compounds constitute valuable precursors for selective preparation of mono- and di-N-protected C-functionalized cyclams and C-functionalized cyclams, cross-bridged cyclams, and oxo-cyclam derivatives. This approach was successfully adapted to the synthesis of three BCAs with great interest especially for biomedical applications: TETA, TE2A, and CB-TE2A. The structures of different intermediates and Cu(II) complexes of C-functionalized cyclam derivatives were confirmed using single-crystal X-ray diffraction, while reactivity of the key intermediates was rationalized by the analysis of the electrostatic potentials calculated at the TPSSh/6-311G(d,p) level.

Full text of DOI:10.1021/jo4028566

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Full Control of the Regiospecific N‑Functionalization of
C‑Functionalized Cyclam Bisaminal Derivatives and Application to
the Synthesis of their TETA, TE2A, and CB-TE2A Analogues
Nathalie Camus,† Zakaria Halime,† Nathalie Le Bris,† Helene Bernard,† Carlos Platas-Iglesias,‡
́
̀
and Raphael Tripier*,†
̈
†Universite
́
de Brest, UMR-CNRS 6521/SFR148 ScInBioS, UFR Sciences et Techniques, 6 Avenue Victor le Gorgeu, C.S. 93837,
29238 Brest, France
‡Departamento de Química Fundamental, Universidade da Coruna, Campus da Zapateira, Rua da Fraga 10, 15008 A Coruna, Spain
́
̃
̃
S
* Supporting Information
ABSTRACT: We describe an easy synthesis of original C-functionalized
cyclam derivatives based on the efficient bisaminal template method. In
the perspective of developing bifunctional chelating agents (BCAs), this
new synthetic strategy offers the possibility of introducing various
coupling functions on one carbon atom in the β-N position of the
macrocycle, leaving the four nitrogen atoms available for the introduction
of pendant coordinating arms. The methodology is based on a keystone
C-functionalized oxo-cyclam bisaminal intermediate that is obtained by
cyclization of a preorganized tetraamine using various methyl acrylate
analogues. These compounds constitute valuable precursors for selective
preparation of mono- and di-N-protected C-functionalized cyclams and
C-functionalized cyclams, cross-bridged cyclams, and oxo-cyclam
derivatives. This approach was successfully adapted to the synthesis of
three BCAs with great interest especially for biomedical applications: TETA, TE2A, and CB-TE2A. The structures of different
intermediates and Cu(II) complexes of C-functionalized cyclam derivatives were confirmed using single-crystal X-ray diffraction,
while reactivity of the key intermediates was rationalized by the analysis of the electrostatic potentials calculated at the TPSSh/6-
311G(d,p) level.
Chart 1
INTRODUCTION
■
In the past few decades, significant progress has been achieved
in the field of nuclear medicine to find stable chelates for
radioactive metal ions, particularly 68Ga, 64Cu, 99mTc, and
67Cu.1−5 The use of these radioisotopes for positron emission
tomography (PET), single photon emission computed
tomography (SPECT), and radio immunotherapy (RIT)
requires the development of specific ligands able to form
complexes of radioactive metal ions with high thermodynamic,
kinetic, and electrochemical stability to avoid their trans-
chelation in competitive biological media.1
Tetraazamacrocycles such as cyclam (Chart 1) are renowned
as efficient chelating agents for numerous metal ions.2 Owing to
the presence of secondary amine functions, these macrocycles
can be N-functionalized3 with various coordinating groups,
which allows the preparation of a wide range of ligands suitable
for many applications such as molecular recognition, catalysis,
purification of liquids, and the development of metal-based
imaging and therapeutic agents in medicine.4 In particular, N-
functionalized cyclam derivatives such as TETA, TE2A, and
CB-TE2A were chosen as Cu(II) chelators for radiolabeling
applications (Chart 1).5 These compounds were preferred to
the well-known commercially available DOTA (1,4,7,10-
tetraazacyclododecane-1,4,7,10-tetraacetic acid) because of
their favorable coordinating properties: TETA or TE2A form
Cu(II) complexes with very high thermodynamic stability6
while CB-TE2A7 provides complexes with exceptional inert-
Received: December 23, 2013
Published: February 19, 2014
© 2014 American Chemical Society
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ness, which prevents their dissociation following either an acid-
catalyzed pathway or a reduction of Cu(II) to Cu(I).8 Among
the other cyclam derivatives, oxo-cyclams containing one amide
function in the cyclam backbone (Chart 1), first used as
monoprotected macrocycles, have also been the subjects of
numerous studies on 99mTc complexation for SPECT
applications.9
However, many applications require a bifunctional chelating
agent (BCA) bearing an additional specific group on the
macrocyclic structure able to hold the ligand fixed on a solid
support10 (silica gel, resins, electrodes, nanoparticles...) or on
specific biomolecular vectors11 (antibodies, haptens, peptides,
proteins...) for PET, SPECT, or RIT applications. Unlike
cyclam or TE2A where the available secondary amines can be
used to introduce a new coupling function, ligands such as
TETA and CB-TE2A are incompatible for such applications.
Different strategies were described in the literature to overcome
this limitation: (a) the replacement of one of coordinating arms
with coupling function;12 (b) the modification of a coordinating
group for instance by replacing a carboxylate function by an
amide;13 and (c) the introduction of a pendant arm bearing
both the chelating group and the coupling function (Chart 2).14
type of condensation requires long reaction times and often
gives low yields.16 Another original way is the annelation
reaction between an α,β-unsaturated ester and a linear
tetraamine, with the pendant arm being provided either by
the cyclizing reagent or by the polyamine.17 The idea of a
template effect induced by rigidifying a linear tetraamine by
condensation with a dicarbonyl compound followed by the
cyclization of the resulting bisaminal with a biselectrophilic
reagent18 emerged 20 years ago as a powerful synthetic tool for
the synthesis of tetraazacycloalkanes and their selective N-
functionalization.19 Surprisingly, this approach has been
scarcely employed for the preparation of C-functionalized
macrocycles. To our knowledge, only two close examples have
recently been simultaneously reported.20,21 In these studies, the
bisaminal bridge can be easily removed after the cyclization to
give rise to cyclams bearing C-appended ester, acid,
hydroxymethyl, or 4-nitrobenzyl groups with good yields.
However, the limited availability of such cyclizing reagents is
probably one of the reasons for the lack of applications of this
strategy for the preparation of BCAs. Thus, the development of
direct and efficient synthetic pathways for the preparation of
bifunctional cyclam-based ligands constitutes a challenge of
great importance in the field of azamacrocyclic chemistry.
In this paper, we report the synthesis of new bifunctional
chelating agents, analogues of the cyclam-based macrocycles
shown in Chart 1, as well as various regioselectively mono- and
diprotected cyclams. Our method consists in the cyclization of
the bisaminal of the linear tetraamine 1,4,8,11-tetraazaundecane
with functionalized-α,β-unsaturated esters through the reaction
of the secondary amines of the bisaminal via both an aza-
Michael addition and a nucleophilic addition/elimination while
generating an appended arm on the carbon skeleton.22 This
simple reaction leads to a new class of C-functionalized oxo-
cyclam bisaminals, the keystone of our methodology. The
bisaminal chemistry can subsequently be applied to these
intermediates providing access to oxo-, “naked-”, or mono-N-
benzylated C-functionalized cyclam derivatives that constitute
valuable precursors for the synthesis of macrocycles of major
interest. X-ray diffraction studies were used to confirm the
structure and the stereochemistry of each intermediate. In
addition, DFT calculations were used to rationalize the
reactivity of these intermediates. Finally, we also report X-ray
structures of several Cu(II) complexes synthesized to
investigate the influence of the coupling function on the
complex structure. The overall methodology is presented in
four parts: (i) synthesis of C-functionalized oxo-cyclam
bisaminal derivatives; (ii) regiospecific mono- and di-N-
protections of C-functionalized cyclam derivatives and exten-
sion to the synthesis of C-functionalized oxo-, “naked-”, and
cross bridged-cyclams; (iii) synthesis of C-functionalized
TETA, TE2A, and CB-TE2A derivatives; and (iv) preliminary
Cu(II) complexation studies.
Chart 2. Different Types of Cyclam-Based BCAs (Example
of CB-TE2A)
The major drawbacks of approaches a and b are that both the
removal of a coordinating arm and the introduction of an amide
function, to replace a carboxylate group, are expected to
decrease the binding affinity of the ligand toward a metallic ion.
Strategy C, requires the previous preparation of the bifunctional
arm in parallel with the synthesis of the macrocycle, which leads
to overall poor yields. An alternative strategy is to introduce the
coupling function on a carbon atom of the carbon skeleton
such as in model compound d (Chart 2). An important
advantage of this approach is that the additional anchoring
group can be directly introduced during the cyclization step,
thereby reducing the number of synthetic steps compared to
traditional synthesis of these types of macrocycles.
One of the best known methods for the synthesis of such
tetraazamacrocycles (d) is the condensation of N-tosyl
derivatives of linear tetraamines with a C-functionalized bis-
electrophile such as a ditosylate.15 Nevertheless, this method
necessitates in the last deprotection step a strong acidic
medium leading to low yields. Alternatively, C-functionalized
cyclams can also be obtained by the condensation of a linear
tetraamine with C-functionalized malonic esters. However, this
RESULTS AND DISCUSSION
■
Synthesis of C-Functionalized Oxo-cyclam Bisaminal
Derivatives. Our strategy consists in the cyclization of the
preorganized tetraamine 1, in its cis-bisaminal intermediate
form 3, with derivatives of methyl acrylate in order to achieve
C-functionalization on the macrocycle skeleton. Cyclizing
reagents 4−6 (Chart 3) are, respectively, the precursors of a
methyl acetate, a 4-nitrobenzyl, or a hydroxyethyl group in α
position of the carbonyl group of oxo-macrocycles 7−9
(Scheme 1). Compounds 4 and 6 are commercially available,
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and C32) are present in the asymmetric unit. Compounds 7
and 8 also crystallize as racemic mixtures in which the two
enantiomers are centrosymmetrically related. Density func-
tional theory (DFT) calculations performed at the TPSSh/6-
311G(d,p) level on 9 indicated that the cis/syn-isomer is more
stable than the cis/anti one by 23.3 kJ·mol−1. These results
suggest that the cyclization step proceeds under thermody-
namic control. One can note that reagents 4 and 5 necessitate
longer reaction times than 6 (Table 1). This difference can be
explained by the superior reactivity of 6 probably due to its
cyclic nature blocked in synperiplanar conformation, which
favors to the formation of the macrocycle. Moreover, the
reaction yields are significantly higher with reagents 5 and 6
than with 4. This result may be attributed to the progressive
precipitation of 8 and 9 in the reaction medium, which
displaces the equilibrium toward the formation of the
macrocycle.
Regiospecific Mono- and Di-N-protections of C-
Functionalized Cyclam Derivatives and Extension to
the Synthesis of C-Functionalized Oxo-, “Naked-”, and
Cross-Bridged Cyclams. Regiospecific N-alkylation reactions
of cyclam derivatives are a synthetic challenge, which prompted
us to study the reactivity of C-functionalized oxo-macrocycle
bisaminals toward electrophilic reagents. We focused our efforts
on the derivative containing the hydroxyethyl group 9 due to its
relatively fast synthesis and its inertness toward various
solvents, electrophiles, or deprotecting reagents used for the
N-functionalization of the macrocycle. In order to determine
the influence of the amide group on the reactivity of 9, the C-
functionalized cyclam bisaminal analogue 10 was also
synthesized using NaBH4 according to a previously described
procedure (Scheme 2).24 Compounds 9 and 10 were reacted
with benzyl bromide, a reagent of interest owing to its high
reactivity and the easy removal of benzyl groups by Pd-
catalyzed hydrogenolysis. The stoichiometric reaction of the
electrophile on the oxo-macrocycle 9 in dry dichloromethane
led quantitatively to the mono-N-benzylated derivative 11 as a
white precipitate. Even when the reaction is performed in a
solvent where 11 is completely soluble, such as acetonitrile, or
in the presence of an excess of electrophile, no dialkylated
compound was observed. These results make the new
compound 9 a key intermediate for the regiospecific mono-
N-functionalization of such C-functionalized cyclams. In
contrast, the reaction of stoichiometric benzyl bromide with
10 gave, as expected, a mixture of two mono-N-benzylated
regioisomers 12 and 12′ in an approximate 1:1 ratio
(determined by NMR). Thus, compound 10 presents the
Chart 3. Cyclizing Reagents 4−6
while 5 was synthesized according to previously described
procedures.23
The synthesis of bisaminal 3 in its cis-configuration was
performed using glyoxal 2 in methanol at 0 °C to minimize the
formation of the undesirable trans-isomer because, to our
knowledge, there is no known method for the deprotection for
the trans-bisaminal bridge of azamacrocycles.19d The cyclization
step involving reagents 4−6 was initially carried out in
methanol as a conventional solvent for Michael-type reactions.
13C NMR spectra of the crude reaction mixtures revealed the
presence of two cis-diastereoisomers which differ by the relative
position (syn or anti) of the chain R with respect to the
hydrogen atom of the closer aminal carbon. However, small
amounts of trans-isomers (about 20%) were also formed by
isomerization of the bisaminal bridge during the cyclization
step. All our attempts to isolate one of the cis-isomers were
unsuccessful. Moreover, several byproducts resulting from the
reaction between cyclizing reagents and methanol were
observed. Further investigations showed that this undesired
reaction occurs only under a basic catalysis such as that of the
cyclization reaction medium. For all these reasons, the
cyclization step of bisaminal 3 by reagents 4−6 was carried
out in a less basic medium such as acetonitrile (Scheme 1).
Under these reaction conditions, only one of the cis-
diastereoisomers (as a racemic mixture) was obtained
exclusively with trace amounts of trans-isomers (<5%).
However, 13C NMR monitoring of the cyclization reaction
revealed the formation of the other cis-isomer in the early stages
of the reaction, which then disappeared. This can be explained
by the reversible formation of this isomer through a retro-
Michael reaction, which finally led to the formation of the most
stable isomer. Compounds 8 and 9 progressively precipitated
from the corresponding reaction mixtures and were isolated in
62% and 65% yield, respectively, while compound 7 was
isolated in 30% yield after recrystallization from diethyl ether.
Single crystals suitable for X-ray diffraction analysis were
obtained for the three compounds. The X-ray structures of
these compounds revealed the relative syn-position of the R
groups with respect to the bisaminal bridge (Figure 1). In the
case of compound 9, the two cis/syn enantiomers with
configurations RRS (C2, C11, and C12) and SSR (C22, C31,
Scheme 1
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Figure 1. Views of the crystal structures of 7−9. The ORTEP plots are at the 30% probability level.
Table 1. Isolated Compounds for the Cyclization of 3 with 4−6 in CH3CN
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a
water molecules are involved in hydrogen-bonding interactions
with the hydroxyl group and the third one with N2 and the
bromide anion (Figure 2).
Scheme 2
Theoretical studies were conducted in order to rationalize
the reactivity of the oxo-macrocycle 9 with electrophilic
reagents. Full geometry optimizations of 9 using DFT
calculations (TPSSh functional) show a molecular geometry
very similar to the corresponding X-ray structure described
above. Subsequent molecular orbital calculations indicate that
the HOMO of 9 presents very important contributions of the
N2, N3, and N4 lone pairs, while the LUMO is mainly localized
on the amide group. The lone pairs of N2 and N4 are pointing
to the convex side of the molecule, while the lone pair of N3
points to the concave side. Consequently, N2 and N4 are
expected to exhibit a more pronounced nucleophilic character
(Figure 3). Molecular electrostatic potential (MEP)25 calcu-
a
Reagents and conditions: (i) NaBH4, H2O, rt, 18 h, 90%; (ii)
PhCH2Br (4 equiv), CH2Cl2, rt, 18 h, 98%; (iii) PhCH2Br (1 equiv),
CH2Cl2, rt, 18 h, 90%.
same reactivity as the “naked” cyclam-glyoxal with two reactive
nitrogen atom lone pairs situated in trans-positions. This result
shows that the presence of the hydroxyethyl substituent in 10
does not affect its reactivity toward N-alkylation reactions
(Scheme 2).
The structure of 11 was established by 2D NMR experiments
1
1
(see HMBC H−15N, HMQC/HMBC H−13C, and COSY
1
and TOCSY H−1H in the Supporting Information). These
correlation experiments clearly confirmed the presence of the
benzyl group on N4. The most significant structural
information was gained from the HMBC H−13C spectrum,
1
which exhibits a correlation between one of the diastereotopic
hydrogen atoms on the carbon atom on β position with respect
to the nitrogen of the amide group and the carbon atom on the
benzylic position. In addition, slow evaporation of an aqueous
solution of the ammonium salt gave single crystals of the
bisaminal compound suitable for X-ray diffraction analysis
(Figure 2). The crystal data confirm that N-benzylation
occurred on N4. In addition, N-alkylation does not affect the
configuration of the molecule, which retains its cis/syn-
stereochemistry with the hydroxyethyl group in an equatorial
position. Compound 11 crystallizes as a trihydrate, where two
Figure 3. (Top) Calculated isosurface (0.03 au) of the HOMO and
LUMO obtained from TPSSh/6-311G(d,p) calculations for 9.
(Bottom) Computed TPSSh/6-311G(d,p) electrostatic potential
(hartree) of 9 on the molecular surface defined by the 0.001
electrons·bohr−3 contour of the electronic density.
lations represent a well-established tool for investigating
chemical reactivity, intermolecular interactions, and a range of
other chemical phenomena.26 Figure 3 shows the electrostatic
potential on the molecular surfaces of compound 9 at the
density functional TPSSh/6-311G(d,p) level, defined by the
0.001 electrons·bohr−3 contour of the electron density
following the suggestion of Bader.27 As expected, the most
negative electrostatic potential on the molecular surface of this
system is located at the oxygen atoms of the hydroxyl and the
carbonyl groups. In addition, a region with substantial negative
electrostatic potential is observed for N2, and particularly for
N4, on the convex side of the molecule. Furthermore, the
contribution of the N4 lone pair to the HOMO (41.6%
according to Mulliken population analysis) is clearly higher
than that of N2 (5.1%) and N3 (15.9%). These results point to
a higher reactivity of N4 toward nucleophilic substitution
compared to N2 and particularly N3 (Figure 3).
Figure 2. View of the crystal structure of 11·3H2O. The ORTEP plot
is at the 30% probability level.
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The bisaminal bridge of monobenzylated compound 11 was
easily removed using hydrazine monohydrate in ethanol to give
monobenzyl oxo-cyclam derivative 13 with 70% yield (Scheme
3). Single crystals of 13 as a hydrobromide salt were obtained
explained previously, oxo-cyclams can be attractive chelators for
metal radioisotopes such as 99mTc9 or transition-metal ions,2
which also make them interesting BCAs for different
applications.
The results obtained with the stoichiometric reaction of
benzyl bromide with bisaminal derivative 10 (Scheme 2)
prompted us to explore the di-N-functionalization of this
compound using an excess of electrophile. For this purpose, we
used 10 equiv of electrophile and chose dry acetonitrile as a
solvent. Under such conditions, the mono-N-benzylated
intermediates 12 and 12′ are completely soluble and continue
to react with the electrophile to form the expected trans-di-N-
alkylated salt 16, which is obtained as a white precipitate with
86% yield (Scheme 4). Single crystals of 16·2H2O were
obtained from a saturated aqueous solution of the compound.
The X-ray diffraction data confirm the trans-dialkylation of the
macrocycle (Figure 5).
a
Scheme 3
The total deprotection of the bisaminal bridge of compound
16 was performed using hydrazine monohydrate to give the di-
N-benzylcyclam derivative 17 with 85% yield. Compound 17
can be considered a precursor of trans-difunctionalized cyclam-
based ligands (see below). The benzyl groups of 17 were then
removed by Pd-catalyzed hydrogenolysis to give the C-
functionalized cyclam (cyclam-EtOH) 18 with 75% yield. On
the other hand, the partial cleavage of the bisaminal bridge of
16 was achieved with NaBH4 in ethanol to give the cross-
bridged cyclam analogue. The 13C NMR spectrum of the crude
reaction product showed two sets of signals with similar
chemical shifts in an approximate 9:1 ratio. The major
compound was recrystallized in acetonitrile with 85% yield.
The elemental analysis showed that 19 was isolated in its
nonprotonated form. Most likely the minor compound, soluble
in acetonitrile, is a protonated species of 19 as often reported in
the literature for cross-bridged tetraazamacrocycles, which are
known to behave as proton sponges.28 An elemental analysis
performed on the crude reaction mixture of 19 revealed the
presence of small amounts of bromide anion (about 4%), which
is consistent with the hypothesis of the presence of a minor
monoprotonated species of the cross-bridged cyclam analogue.
Compound 19 was then debenzylated by hydrogenolysis to
give the corresponding reinforced macrocycle CB-cyclam-
EtOH 20 as a free base with 88% yield.
a
Reagents and conditions: (i) NH2NH2·H2O, EtOH, reflux, 4 h, 70%;
(ii) BH3·THF (4 equiv), THF, reflux 1.5 d; 72%; (iii) H2, Pd/C,
EtOH, rt, 4 d, 85%.
from the crude reaction mixture. The X-ray structure shows
that the macrocycle is protonated on N3, which is involved in a
hydrogen-bond interaction with the bromide anion (Figure 4).
Synthesis of C-Functionalized TETA-EtOH, TE2A-EtOH,
and CB-TE2A-EtOH. As described in the previous section,
cyclam derivatives 17, 18, and 20 constitute key intermediates
for the synthesis of a wide range of C-functionalized BCAs.
Thus, we decided to N-functionalize these compounds with
acetate functions in order to obtain C-functionalized TETA,
TE2A, and CB-TE2A analogues as efficient Cu(II) chelators.
The alkylation of the secondary amino functions of these
macrocycles by tert-butyl bromoacetate led to TE2AtBu-EtOH
21b (via the removal of N-benzyl protecting groups of 21a by
Pd-catalyzed hydrogenolysis), TETAtBu-EtOH 22, and CB-
TE2AtBu-EtOH 23 with very good yields (Scheme 5). Because
of its remarkably basic character and its proton sponge
behavior, the cross-bridged derivative 23 was exclusively
Figure 4. View of the crystal structure of 13·HBr. The ORTEP plot is
at the 30% probability level.
Compound 13 can be considered a cis-diprotected macrocycle
because of the presence of both the amide function on N1 and
the benzyl group on N4. Interestingly, these protections can be
removed independently. Indeed, the reduction of the amide
group of 13 was achieved using BH3·THF to give the mono-N-
benzylated cyclam derivative 14 with 72% yield, while Pd-
catalyzed hydrogenolysis of 13 led to oxo-cyclam-EtOH 15
with 85% yield (“EtOH” is mentioned as suffix to characterize
the nature of the additional chain). Because of their different
protected positions and protecting groups, the new C-
functionalized macrocycles 13−15 represent useful precursors
for various regiospecific N-functionalizations. Additionally, as
1
isolated as its monohydrobromide salt. The H NMR analysis
of 23 confirms the presence of the hydrogen atom inserted into
the cleft of the ligand with a characteristic downfield-shifted
broad resonance at 10.2 ppm.14b,28
Finally, the deprotection of the tert-butyl ester groups by
treatment with trifluoroacetic acid in dichloromethane at room
temperature gave quantitatively the new ligands TE2A-EtOH
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a
Scheme 4
a
Reagents and conditions: (i) PhCH2Br (10 equiv), CH3CN, rt, 14 d, 86%; (ii) NH2NH2·H2O, reflux, 4 h, 85%; (iii) H2, Pd/C, EtOH, rt, 4 d, 75%;
(iv) NaBH4 (40 equiv), EtOH, reflux, 18 h, 85%; (v) H2, Pd/C, EtOH, rt, 4 d, 88%.
complexes with precursors 17−19 were obtained. Views of the
structures of these complexes are shown in Figure 6, while
bond distances of the metal coordination environments are
given in Table 2. The crystal structures confirm that the
hydroxyethyl group of the ligands does not participate in the
coordination of the metal ion.
Two different structures of Cu(II) complexes of 17 have
been determined: 17·CuBr(ClO4) and 17·Cu(ClO4)2. In 17·
CuBr(ClO4), the Cu(II) ion is directly bound to the four
nitrogen atoms of the macrocycle and a bromide anion in a
square pyramidal coordination. The basal plane of the pyramid
is defined by the four nitrogen atoms of the ligand, with the
bromide anion occupying the apical position. The overall
structure of the complex resembles that of [Cu(Me4cyclam)-
Br]Br.29 In 17·Cu(ClO4)2, the Cu(II) ion shows a Jahn−Teller
Figure 5. View of the crystal structure of 16·2H2O. The ORTEP plot
is at the 30% probability level.
distorted octahedral environment with tetragonal elongation,
where the equatorial plane of the octahedron is defined by the
four nitrogen atoms of the macrocycle and the axial positions
are occupied by oxygen atoms of the perchlorate groups. The
24, TETA-EtOH 25, and CB-TE2A-EtOH 26 as trifluoroace-
tate salts. Attempts to perform the hydrolysis of the ester
five-membered chelate rings also adopt the same conformation
in both complexes [(λλ)],30 with the six-membered chelate
functions using hydrochloric acid solutions under reflux
resulted in the formation of lactone derivatives due to the
rings adopting chair conformations.
reaction of the hydroxyl group and one of the carboxylic
The metal coordination environment in 18·Cu(ClO4)2 is
groups. No trace of these lactones were observed in the
very similar to that observed for 17·Cu(ClO4)2. The six-
relatively mild reaction conditions of the hydrolysis using
membered chelate rings adopt also chair conformations, while
trifluoroacetic acid.
the five-membered chelate rings present different helicities
Cu(II) Complexes of C-Functionalized Cyclam Ligands.
[(λδ)]. Tetragonally elongated octahedral coordination envi-
In order to evaluate the ability of the newly synthesized C-
ronments have been previously observed for Cu(II) complexes
functionalized cyclam ligands to coordinate transition metal
with cyclam-based ligands in the presence of weakly
ions and to verify that the C-functionalization does not affect
the overall complexation behavior of the ligands, we
coordination anions such as perchlorate.31
Upon metal coordination, cyclam-based complexes may
adopt five possible configurations depending on the spatial
alignment of the NH protons, RSRS, RSRR, SSRR, RSSR, and
RRRR, designed trans-I to trans-V, respectively.32 The cyclam
unit in 17·CuBr(ClO4) and 17·Cu(ClO4)2 adopts a trans-I
configuration, which is usually favorable over the trans-III
configuration in five-coordinated Cu(II) complexes of ligands
investigated the structure of the corresponding Cu(II)
complexes. This metal ion was chosen because of the potential
application of its radioisotopes (64Cu or 67Cu) in PET imaging
or radio immunotherapy. These new ligands form stable Cu(II)
complexes, but all our attempts to obtain single-crystals of the
Cu(II) complexes of the “acetate” derivatives 24−26 were
unsuccessful so far. However, the structures of the Cu(II)
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a
Scheme 5
a
Reagents and conditions: (i) t-BuCO2CH2Br (2 equiv), CH3CN, 80 °C, 2.5 d, 75%; (ii) H2, Pd/C, EtOH, rt, 4 d, 86%; (iii) t-BuCO2CH2Br (4
equiv), CH3CN, 80 °C, 2 d, 84%; (iv) t-BuCO2CH2Br (1.8 equiv), CH3CN, rt, 18 h, 75%; (v) TFA, CH2Cl2, rt, quantitative yields.
containing cyclam units.33 However, a trans-III conformation is
observed in the case of 18·Cu(ClO4)2.
The N-functionalization with acetate groups of the C-
functionalized macrocycle containing a hydroxyethyl unit led to
very attractive bifunctional analogues of TETA, TE2A, and CB-
TE2A. The same synthetic route could obviously be transposed
to the two other versions of C-functionalized cyclams, thereby
giving access to a large panel of compounds with a great
importance in the field of nuclear medicine.
In addition to our ongoing coordination studies involving
TE2A-EtOH, TETA-EtOH, and CB-TE2A-EtOH, we are also
exploring different synthetic strategies in order to obtain more
suitable anchoring functions for a future coupling to
biomolecules such as antibodies or small peptides. These
anchoring functions can be obtained for instance by activating
the ester group or by transforming the hydroxyethyl or 4-
nitrobenzyl groups into amine functions. Our current efforts are
also focused on the generalization of our methodology to other
starting polyamines to provide access to BCAs versions of other
azamacrocycles.
Finally, in the complex of the dibenzyl cross-bridged ligand
19·CuBr(ClO4) the Cu(II) ion is five-coordinated in a square-
pyramidal coordination environment, with N3 occupying the
apical position, due to an agostic interaction between the
Cu(II) ion and a ortho-hydrogen of one of the benzyl pendant
arms that is blocking the sixth potential coordination site
(Cu(1)···H(26) = 2.56 Å, Figure 6).34
CONCLUSION
■
We have shown that the bisaminal approach can be an efficient
tool for the development of a new synthetic route for the
preparation of a wide variety of C-functionalized cyclam
derivatives under mild reaction conditions and with limited
protection/deprotection steps. This method offers the
possibility of introducing various types of functions (hydrox-
yethyl, 4-nitrobenzyl, or methyl acetate substituents) on the
carbon atom in β-N position of the carbon skeleton. The C-
functionalized oxo-compounds obtained as direct products of
the cyclization step are keystone intermediates for various
regiospecific N-alkylations due to their different protected
positions and their different protecting groups introduced in
different stages of this new synthetic route. These key-
intermediates are also precursors of cyclam and cross-bridged
cyclam BCAs from which two examples bearing a hydroxyethyl
function, cyclam-EtOH and CB-cyclam-EtOH, were isolated.
EXPERIMENTAL SECTION
■
Materials and Methods. Bisaminal 335 and cyclizing reagent 523
were synthesized as previously described. 2D NMR 1H−1H
homonuclear, 1H−13C and 1H−15N heteronuclear correlations, and
homonuclear decoupling experiments were used for assignment of the
1H and 13C signals. The δ scales are relative to TMS (1H, 13C) and
CH3NO2 (15N). The signals are indicated as follows: chemical shift,
intensity, multiplicity (s, singlet; br s, broad singlet; d, doublet; t,
triplet; m, multiplet; q, quartet), coupling constants J in hertz (Hz),
assignment: Hα, Cα and Hβ, Cβ correspond to CH or CH2 located in
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Figure 6. Views of the crystal structures of Cu(II) complexes with ligands 17−19. Uncoordinated anions and hydrogen atoms are omitted for
simplicity. The ORTEP plots are at the 30% probability level.
the α or β position, respectively, of the considered nitrogen atom; Am,
Ar, and Ph are the abbreviations used for aminal, aromatic, and phenyl,
respectively). All analytical spectra and data are given in the
Supporting Information.
Cyclization Step: Synthesis of C-functionalized Oxo-cyclam
Bisaminal Derivatives. Methyl 1-Oxo-10b,10c-cis-3a,5a,8a,10a-
tetraazaperhydropyren-2-ylacetate (7). A solution of dimethyl
itaconate 4 (626 mg, 3.96 mmol) in CH3CN (5 mL) was added
dropwise to a solution of compound 3 (703 mg, 3.84 mmol) in
CH3CN (30 mL). The reaction mixture was heated at 40 °C for 8 d,
and then the solvent was evaporated under reduced pressure. The
crude reaction product was recrystallized in Et2O to give 7 (355 mg,
of compound 3 (2.24 g, 12.29 mmol) in CH3CN (100 mL). The
reaction mixture was stirred at room temperature for 7 d, and then the
white precipitate was isolated by filtration. The solid was washed with
CH3CN (2 × 15 mL) and then with Et2O (2 × 15 mL) and finally
dried under vacuum. Compound 8 was obtained as a white powder
(2.86 g, 62%). Mp: 186−188 °C. IR: ν
̃
= 1631 cm−1 (CO, strong,
sharp). 1H NMR (400 MHz, CDCl3, 25 °C, TMS): δ = 8.11 (d, J = 8.8
Hz, 2H, CH-Ar), 7.35 (d, J = 8.8 Hz, 2H, CH-Ar), 4.45 (d, J = 12.0
Hz, 1H), 4.26 (d, J = 3.2 Hz, 1H, N-CH-N), 3.51 (dd, J = 14.0, 4.0 Hz,
1H), 3.41 (td, J = 8.0, 3.2 Hz, 1H), 3.14−3.09 (m, 2H), 2.96−2.85 (m,
6H), 2.78 (td, J = 8.0, 3.2 Hz, 1H), 2.72−2.64 (m, 2H), 2.39−2.34 (m,
2H), 2.21−2.14 (m, 3H), 1.25−1.05 ppm (m, 1H). 13C Jmod NMR
(100 MHz, CDCl3, 25 °C, TMS): δ = 173.3 (CO), [150.6, 149.5]
(CH-Ar), [132.72, 126.59] (CH), [78.88, 73.76] (N-CH-N), 58.74
(CH2-Ph), [56.80, 56.05, 55.89, 47.31, 46.83, 43.45] (CH2-α-N), 39.63
(CH-β-N), 38.01 (CH2-α-N), 22.47 ppm (CH2-β-N). MS (MALDI-
TOF, matrix: dithranol): m/z 372.17 [M + H]+. Anal. Calcd for
C19H25N5O3·0.5H2O: C, 59.98; H, 6.89; N, 18.41. Found: C, 59.98; H,
6.72; N, 18.19.
30%) as white crystals. Mp: 150−152 °C. IR: ν
̃
= 1733 (CO, strong,
sharp), 1630 cm−1 (CO, strong, sharp). 1H NMR (500 MHz,
CDCl3, 25 °C, TMS): δ = 4.32−4.26 (m, 1H), 4.25 (d, J = 3.0 Hz, 1H,
N-CH-N), 3.57 (s, 3H, CH3), 3.32 (td, J = 12.0, 3.0 Hz, 1H), 3.13 (td,
J = 12.0, 2.5 Hz, 1H), 3.08 (d, J = 3.0 Hz, 1H, N-CH-N), 3.06−3.00
(m, 2H), 2.98−2.82 (m, 4H), 2.73−2.68 (m, 1H), 2.67 (d, J = 5.0 Hz,
1H), 2.62 (dt, J = 11.5, 2.0 Hz, 1H), 2.44 (dt, J = 10.5, 3.0 Hz, 1H),
2.37 (d, J = 6.5 Hz, 1H), 2.35−2.28 (m, 1H), 2.18 (td, J = 11.5, 3.0 Hz,
1H), 2.14−2.00 (m, 2H), 1.19−1.13 ppm (m, 1H). 13C Jmod NMR
(125 MHz, CDCl3, 25 °C, TMS): δ = 172.3 (CO-amide), 170.6 (CO-
ester), [75.9, 70.8] (N-CH-N), [55.7, 53.8, 53.1, 52.8, 44.3, 43.8, 40.4]
(CH2-α-N, CH2-α-OH), 51.5 (COOCH3), 33.0 (CH2-β-OH), 32.3
(CH-β-N), 19.4 ppm (CH2-β-N). MS (MALDI-TOF, matrix:
dithranol): m/z 309.14 [M + H]+. Anal. Calcd for C15H24N4O3·
0.2H2O: C, 57.75; H, 7.88; N, 17.96. Found: C, 57.76; H, 7.82; N,
18.19.
2-(2-Hydroxyethyl)-10b,10c-cis-3a,5a,8a,10a-tetraazaperhropy-
ren-1-one (9). A solution of α-methylene-γ-butyrolactone 6 (450 μL,
5.12 mmol) in CH3CN (5 mL) was added dropwise to a solution of
compound 3 (890 mg, 4.88 mmol) in CH3CN (30 mL). The reaction
mixture was heated at 40 °C for 4 d, and then the white precipitate was
isolated by filtration. The solid was washed with CH3CN (2 × 5 mL)
and then with Et2O (2 × 5 mL) and finally dried under vacuum. This
process was repeated with the filtrate twice more to recover more
material. The white powder of 9 was dried under vacuum (890 mg,
65%). Mp: 176−178 °C. IR: ν
̃
= 1613 cm−1 (CO, strong, sharp). 1H
2-(4-Nitrobenzyl)-10b,10c-cis-3a,5a,8a,10a-tetraazaperhydropy-
ren-1-one (8). A solution of methyl 2-(4-nitrobenzyl) acrylate 5 (2.89
g, 12.29 mmol) in CH3CN (15 mL) was added dropwise to a solution
NMR (500 MHz, CDCl3, 25 °C, TMS) δ = 4.62 (br s, 1H, OH), 4.43
(d, J = 10.0 Hz, 1H), 4.30 (d, J = 3.0 Hz, 1H, N-CH-N), 3.76−3.72
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then with Et2O (2 × 5 mL) and finally dried under vacuum to give 11
Table 2. Selected Bond Distances (Å) and Bond angles (deg)
for the Metal Coordination Environment in Cu(II)
Complexes
as a white powder (1.50 g, 98%). IR: ν
̃
= 1639 cm−1 (CO, strong,
1
sharp). H NMR (500 MHz, D2O, 25 °C, TMS): δ = 7.65−7.55 (m,
5H, CH-Ar), 5.65 (d, J = 2.0 Hz, 1H, N-CH-N), 5.11 (d, J = 13.5 Hz,
1H, N-CH2-Ph), 4.79 (d, J = 13.5 Hz, 1H, N-CH2-Ph), 4.60−4.55 (m,
1H), 4.40−4.30 (m, 1H), 4.01 (d, J = 2.0 Hz, 1H, N-CH-N),3.85−
3.60 (m, 4H), 3.45−3.30 (m, 3H), 3.30−3.20 (m, 2H), 3.15−3.05 (m,
3H), 2.80−2.70 (m, 1H), 2.70−2.60 (m, 1H), 2.55−2.45 (m, 1H),
2.25−2.15 (m, 2H), 1.85−1.80 (m, 1H), 1.75−1.65 ppm (m, 1H). 13C
Jmod NMR (125 MHz, D2O, 25 °C, TMS): δ = 177.6 (CO), [135.9,
134.0, 132.2] (CH-Ar), 128.0 (C-Ar), [83.2, 67.8] (N-CH-N), [64.7,
62.7, 61.9, 55.8, 55.3, 54.6, 50.0, 44.7, 38.3] (CH2-α-N, CH2-α-OH),
35.5 (CH-β-N), 33.9 (CH2-β-OH), 20.9 ppm (CH2-β-N). MS
(MALDI-TOF, matrix: HCCA): m/z 371.16 [M − Br−]+. Anal.
Calcd for C21H31BrN4O2·1.5H2O: C, 52.72; H, 7.16; N, 11.71. Found:
C, 53.01; H, 6.94; N, 11.60.
17·
18·
Cu(ClO4)2
19·
CuBr(ClO4)
CuBr(ClO4) 17·Cu(ClO4)2
Cu(1)-N(1)
Cu(1)-N(2)
Cu(1)-N(3)
Cu(1)-N(4)
Cu(1)−Br
2.133(11)
1.997(11)
2.114(11)
1.981(12)
2.791(3)
91.4(4)
2.098(10)
1.973(9)
2.055(9)
1.996(9)
2.007(3)
2.013(3)
1.995(3)
2.020(3)
2.132(6)
2.088(6)
2.189(7)
2.056(6)
2.4802(13)
94.6(2)
N(1)−Cu(1)-
N(2)
90.4(6)
170.3(5)
86.6(4)
93.6(7)
171.1(7)
90.6(6)
92.73(11)
178.02(11)
86.43(11)
86.14(11)
177.20(11)
94.78(11)
N(1)−Cu(1)-
N(3)
155.6(4)
87.1(4)
86.9(5)
172.8(5)
91.6(5)
101.2(3)
83.7(3)
85.5(2)
N(1)−Cu(1)-
N(4)
Compounds 12 and 12′. Benzyl bromide (170 μL, 1.31 mmol)
was added dropwise to a solution of compound 10 (350 mg, 1.31
mmol) in distilled CH2Cl2 (3.0 mL). The solution was stirred at room
temperature for 18 h and then evaporated under reduced pressure.
The white solid resulting was dissolved in CH3CN (3 mL). A small
amount of precipitate was formed and eliminated by filtration. The
filtrate was concentrated under vacuum to give the mixture of 12 and
N(2)−Cu(1)-
N(3)
85.7(2)
N(2)−Cu(1)-
N(4)
179.6(3)
94.8(3)
N(3)−Cu(1)-
N(4)
N(1)−
Cu(1)−
Br(1)
170.52(18)
1
12′ as a white powder (510 mg, 90%). H NMR (300 MHz, D2O, 25
°C, TMS): δ = 7.70−7.40 (m, 10H, CH-Ar), 5.20−5.00 (m, 2H),
4.90−4.65 (m, 2H), 4.45−4.25 (m, 2H), 4.25−4.10 (m, 2H), 3.80−
3.40 (m, 10H), 3.40−2.90 (m, 18H), 2.85−2.60 (m, 2H), 2.60−2.00
(m, 12H), 1.85−1.70 (m, 1H), 1.60−1.35 ppm (m, 5H). 13C Jmod
NMR (75 MHz, D2O, 25 °C, TMS): δ = [136.2 ( × 2), 134.0 ( × 2),
132.3 ( × 2)] (CH-Ar), [128.54, 128.54] (C-Ar), [84.8, 84.5, 72.4,
72.2] (N-CH-N), [66.7, 65.5, 65.4, 62.7, 62.4, 61.7, 61.2, 60.5, 59.8,
56.8, 56.2, 56.1, 54.8, 54.2, 52.1, 51.3, 49.5, 49.4, 45.7, 44.8] (CH2-α-
N, CH2-α-OH), [36.1, 35.1] (CH2-β-OH), [28.8, 27.3] (CH-β-N),
[21.3, 20.9] ppm (CH2-β-N). HRMS (ESI): m/z calcd for
C21H33N4O+ [M − Br−]+ 357.2649, found 357.2650.
N(2)−
Cu(1)−
Br(1)
91.4(3)
103.2(3)
95.8(3)
90.91(18)
104.40(19)
88.91(18)
N(3)−
Cu(1)−
Br(1)
N(4)−
Cu(1)−
Br(1)
(m, 1H), 3.62−3.58 (m, 1H), 3.40 (td, J = 12.0, 3.5 Hz, 1H), 3.18 (d, J
= 3,0 Hz, 1H, N-CH-N), 3.16−3.04 (m, 2H), 3.01−2.88 (m, 4H),
2.82−2.76 (m, 2H), 2.69 (dt, J = 11.0, 2.5 Hz, 1H), 2.48 (dt, J = 11.0,
2.5 Hz, 1H), 2.44−2.37 (m, 1H), 2.25 (td, J = 11.0, 2.5 Hz, 1H),
2.21−2.10 (m, 2H), 1.95−1.88 (m, 1H), 1.45−1.38 (m, 1H), 1.28−
1.20 ppm (m, 1H). 13C Jmod NMR (125 MHz, CDCl3, 25 °C, TMS):
δ = 172.5 (CO), [75.7, 70.6] (N-CH-N), [61.0, 55.6, 54.7, 52.9, 52.7,
44.1, 43.7, 40.2] (CH2-α-N, CH2-α-OH), 34.4 (CH-β-N), 31.8 (CH2-
β-OH), 19.3 ppm (CH2-β-N). MS (MALDI-TOF, matrix: dithranol):
m/z 281.10 [M + H]+. Anal. Calcd for C14H24N4O2·0.4H2O: C, 58.47;
H, 8.69; N, 19.48. Found: C, 58.64; H, 8.49; N, 19.39.
Synthesis of Mono-N-protected Cyclam Derivatives. 2-
(10b,10c-cis-3a,5a,8a,10a-Tetraazaperhydropyren-2-yl)ethanol
(10). Sodium borohydride (4.05 g, 107.1 mmol) was added to a
solution of compound 9 (3.00 g, 10.71 mmol) in H2O (30 mL) at
room temperature. The solution was stirred for 18 h and then
saturated with NaOH pellets. The product was extracted with CH2Cl2
(5 × 50 mL). The combined organic fractions were dried over MgSO4,
filtrated, and evaporated under reduced pressure to give 10 as a
colorless oil (2.80 g, 90%). 1H NMR (500 MHz, CDCl3, 25 °C,
TMS): δ = 3.60 (br s, 1H, OH), 3.45 (t, J = 7.0 Hz, 2H, CH2OH),
3.40−3.25 (m, 2H), 2.94 (d, J = 2.5 Hz, 1H, N-CH-N), 2.84 (d, J = 2.5
Hz, 1H, N-CH-N), 2.80−2.70 (m, 5H), 2.60−2.50 (m, 2H), 2.45−
2.35 (m, 1H), 2.30−2.15 (m, 3H), 2.15−2.00 (m, 3H), 2.00−1.90 (m,
1H), 1.65−1.50 (m, 1H), 1.17 (q, J = 6.5 Hz, 2H), 1.10−1.00 ppm (m,
1H). 13C Jmod NMR (125 MHz, CDCl3, 25 °C, TMS): δ = [76.6,
76.5] (N-CH-N), [61.9, 59.4, 58.4, 55.7, 54.0, 53.9, 52.2, 45.3, 44.4]
(CH2-α-N, CH2-α-OH), 34.6 (CH2-β-OH), 25.4 (CH-β-N), 19.3 ppm
(CH2-β-N). HRMS (ESI): m/z calcd for C14H27N4O+ [M + H]+
267.2179, found 267.2185.
1-Benzyl-6-(2-hydroxyethyl)-1,4,8,11-tetraazacyclotetradecan-5-
one (13). Hydrazine monohydrate (4.0 mL, 64% in water, 82.38
mmol) was added dropwise to a solution of compound 11 (4.33 g,
9.59 mmol) in EtOH (50 mL). The reaction mixture was heated at
reflux for 4 h, and then the solution was concentrated in vacuo. HCl
(10 mL, 3 M) was added to the residue, a first extraction with CHCl3
(5 × 25 mL) was performed to eliminate organic impurities, and then
the pH of the aqueous layer was adjusted to 14 by the addition of
NaOH pellets. The product was extracted with CHCl3 (5 × 25 mL).
The combined organic fractions were dried over MgSO4, filtrated, and
removed under reduced pressure to give 13 as a yellow oil (2.35 g,
70%). IR: ν
̃
= 1637 cm−1 (CO, strong, sharp). 1H NMR (500 MHz,
CDCl3, 25 °C, TMS): δ = 8.62 (br s, 1H, CO-NH), 7.40−7.20 (m,
5H, CH-Ar), 3.77 (d, J = 13.0 Hz, 1H, N-CH2-Ph), 3.75−3.60 (m,
3H), 3.31 (d, J = 13.0 Hz, 1H, N-CH2-Ph), 3.25−3.15 (m, 1H), 3.00−
2.90 (m, 1H), 2.90−2.85 (m, 2H), 2.80−2.65 (m, 3H), 2.65−2.55 (m,
4H), 2.55−2.50 (m, 1H), 2.50−2.40 (m, 1H), 2.40−2.30 (m, 1H),
1.95−1.85 (m, 1H), 1.85−1.75 (m, 1H), 1.75−1.65 (m, 1H), 1.65−
1.55 (m, 1H), 1.18 (br s, 2H, NH). 13C Jmod NMR (75 MHz, CDCl3,
25 °C, TMS): δ = 175.7 (CO), 137.9 (C-Ar), [129.6, 128.1, 127.1]
(CH-Ar), [59.8, 57.6, 54.2, 53.0, 50.6, 50.2, 49.1, 45.8] (CH2-α-N,
CH2-α-OH), 42.8 (CH-β-N), [35.5, 32.9] (CH2-α-N, CH2-β-OH),
23.8 ppm (CH2-β-N). HRMS (ESI): m/z calcd for C19H33N4O2+ [M +
H]+ 349.2598, found 349.2599. Anal. Calcd for C19H32N4O2·0.09HCl·
0.7H2O: C, 62.63; H, 9.26; N, 15.38, Cl 0.88. Found: C, 62.67; H,
8.90; N, 15.54, Cl 0.82.
2-(1-Benzyl-1,4,8,11-tetraazacyclotetradecan-6-yl)ethanol (14).
A solution of BH3·THF (17.0 mL, 1.0 M, 17.00 mmol) was added
dropwise to a solution of compound 13 (1.49 g, 4.28 mmol) in
distilled THF (30 mL) under a nitrogen atmosphere. The solution was
stirred at room temperature for 1 h and then heated at reflux for 1.5 d.
After cooling to room temperature, water (20 mL) was added to the
reaction mixture, then the solvent was evaporated under reduced
pressure. HCl (30 mL, 3 M) was added to the residue and the solution
was refluxed for 1 h. After cooling down to room temperature a first
8a-Benzyl-2-(2-hydroxyethyl)-10b,10c-cis-3a,5a,8a,10a-tetraaza-
perhydropyren-1-one Bromide Salt (11). Benzyl bromide (1.62 mL,
13.56 mmol) was added dropwise to a solution of compound 9 (950
mg, 3.39 mmol) in distilled CH2Cl2 (8.0 mL). The solution was stirred
at room temperature for 4 d, and then the precipitate was isolated by
filtration. The solid was washed with cold CH2Cl2 (2 × 5 mL) and
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extraction with CHCl3 (5 × 50 mL) was performed to eliminate
organic impurities, then the pH of the aqueous layer was adjusted to
14 by the addition of NaOH pellets. The product was extracted with
CHCl3 (5 × 50 mL). The combined organic fractions were dried over
MgSO4, filtered and the solvent concentrated under reduced pressure
6H), 2.40−2.35 (m, 2H), 2.30−2.15 (m, 2H), 2.10−2.15 (m, 1H),
1.95−1.80 (m, 1H), 1.70−1.60 (m, 1H), 1.50−1.45 (m, 1H), 1.45−
1.35 ppm (m, 1H). 13C Jmod NMR (75 MHz, CDCl3, 25 °C, TMS): δ
= [137.3, 137.2] (C-Ar), [129.3 ( × 2), 129.2 ( × 2), 126.9 ( × 2)]
(CH-Ar), [58.9, 58.1, 57.5, 55.7, 53.9, 52.8, 52.2, 51.7, 49.6, 47.5, 46.7]
(CH2-α-N, CH2-α-OH), 36.2 (CH2-β-OH), 33.7 (CH-β-N), 26.0 ppm
(CH2-β-N). HRMS (ESI): m/z calcd for C26H41N4O+ [M + H]+
425.3275, found 425.3276.
1
to give 14 as a colorless oil (1.03 g, 72%). H NMR (500 MHz,
CDCl3, 25 °C, TMS): δ = 7.30−7.10 (m, 5H, CH-Ar), 3.55−3.50 (m,
1H), 3.50−3.35 (m, 4H), 2.85−2.75 (m, 1H), 2.75−2.56 (m, 6H),
2.53 (d, J = 13.5 Hz, 1H), 2.53−2.35 (m, 6H), 2.35−2.25 (m, 2H),
1.85−1.75 (m, 2H), 1.75−1.65 (m, 1H), 1.50−1.35 ppm (m, 2H). 13C
Jmod NMR (125 MHz, CDCl3, 25 °C, TMS): δ = 138.3 (C-Ar),
[129.0, 127.9, 126.8] (CH-Ar), [59.0, 57.5, 53.5, 52.9, 52.4, 52.3, 48.3,
48.2, 47.5, 46.5] (CH2-α-N, CH2-α- OH), 35.5 (CH-β-N), 35.1 (CH2-
β-OH), 26.0 ppm (CH2-β-N). MS (MALDI-TOF, matrix: dithranol):
m/z 335.20 [M + H]+. Anal. Calcd for C19H34N4O·0.4HCl·0.5H2O: C,
63.73; H, 9.96; N, 15.65. Found: C, 64.06; H, 9.58; N, 15.28.
Cyclam-EtOH: 2-(1,4,8,11-Tetraazacyclotetradecan-6-yl)ethanol
(18). Compound 17 (1.00 g, 2.36 mmol) was dissolved in EtOH
absolute ethanol (30 mL). 10% Pd/C-activated (300 mg) was added,
the reaction mixture was stirred under a hydrogen atmosphere at room
temperature for 4 d, the reaction mixture was filtered through Celite,
and the solvent was evaporated under reduced pressure. The residue
was dissolved in distilled H2O (15 mL), and the organic impurities
were extracted with Et2O (3 × 20 mL). The aqueous layer was
concentrated under vacuum. The addition of CH3CN (10 mL) to the
resulting yellow oil led to the formation of a precipitate which was
filtered and dried under vacuum to give compound 18 as a white
powder (433 mg, 75%). Mp: 129−131 °C. 1H NMR (400 MHz,
CDCl3, 25 °C, TMS): δ = 3.50−3.30 (m, 2H), 2.70−2.40 (m, 14H),
2.40−2.20 (m, 2H), 1.80−1.55 (m, 1H), 1.55−1.40 (m, 2H), 1.40−
1.30 ppm (m, 2H). 13C Jmod NMR (100 MHz, CDCl3, 25 °C, TMS):
δ = [59.0, 53.6, 50.0, 48.64, 48.61] (CH2-α-N, CH2-α-OH), 36.0 (CH-
β-N), 35.2 (CH2-β-OH), 29.0 ppm (CH2-β-N). MS (MALDI-TOF,
matrix: dithranol): m/z 245.17 [M + H]+. Anal. Calcd for C12H28N4O:
C, 58.98; H, 11.55; N, 22.93. Found: C, 58.68; H, 11.64; N, 23.10.
2-(4,11-Dibenzyl-1,4,8,11-tetraazabicyclo[6.6.2]hexadec-6-yl)-
ethanol (19). Sodium borohydride (998 mg, 66.0 mmol) was slowly
added to a solution of compound 18 (1.00 g, 1.65 mmol) in 95%
EtOH (50 mL). The mixture was refluxed for 18 h, then the solvent
was evaporated under reduced pressure. A precipitate was formed after
addition of CH2Cl2 (50 mL) and was eliminated by filtration. The
filtrate was concentrated under vacuum. This process was repeated
twice to recover more material. The major product was recrystallized
in CH3CN. Compound 19 was obtained as a white powder (744 mg,
85%). 1H NMR (300 MHz, CDCl3, 25 °C, TMS): δ = 7.50−7.00 (m,
10H, CH-Ar), 4.80−4.70 (m, 1H), 4.05−3.85 (m, 1H), 3.85−3.50 (m,
5H), 3.45−3.30 (m, 1H), 3.30−2.80 (m, 5H), 2.70−2.35 (m, 8H),
2.35−2.00 (m, 4H), 1.75−1.40 (m, 3H), 1.40−1.15 ppm (m, 1H). 13C
Jmod NMR (75 MHz, CDCl3, 25 °C, TMS): δ = [140.6, 137.9] (C-
Ar), [129.4, 128.9, 128.4, 128.1, 127.2, 126.6] (CH-Ar), [64.4, 62.5,
61.4, 59.9, 59.2, 57.7, 56.6, 54.5, 53.5, 52.8, 51.9, 50.1, 43.6] (CH2-α-
N, CH2-α-OH), 39.0 (CH2-β-OH), 35.9 (CH-β-N), 25.2 ppm (CH2-
β-N). HRMS (ESI): m/z calcd for C28H44N4O2+ [M + 2H]2+
226.1752, found 226.1757, error = −2.2 ppm. Anal. Calcd for
C28H42N4O.1·1H2O: C, 71.48; H, 9.47; N, 11.91. Found: C, 71.70; H,
9.16; N, 11.84.
Oxo-cyclam-EtOH: 6-(2-Hydroxyethyl)-1,4,8,11-tetraazacyclote-
tradecan-5-one (15). Compound 13 (1.00 g, 2.87 mmol) was
dissolved in EtOH absolute ethanol (30 mL). 10% Pd/C-activated
(300 mg) was added, and the reaction mixture was stirred under a
hydrogen atmosphere at room temperature for 4 d. The mixture was
then filtered through Celite and the solvent was evaporated under
reduced pressure. The resulting yellow oil was dissolved in water (5
mL) and the organic impurities were extracted with Et2O (3 × 10
mL). The aqueous layer was evaporated under reduced pressure to
give compound 15 as a yellow oil (630 mg, 85%). IR: ν
̃
= 1648 cm−1
(CO, strong, sharp). 1H NMR (300 MHz, D2O, 25 °C, TMS): δ =
3.85−3.70 (m, 1H), 3.70−3.40 (m, 2H), 3.10−2.90 (m, 1H), 2.90−
2.30 (m, 14H), 1.90−1.35 ppm (m, 4H). 13C Jmod NMR (75 MHz,
D2O, 25 °C, TMS): δ = 180.4 (CO), [62.2, 53.0, 50.4, 49.4, 49.3, 48.7
( × 2), 40.9] (CH2-α-N, CH2-α-OH), 46.0 (CH-β-N), 35.2 (CH2-β-
OH), 29.5 ppm (CH2-β-N). HRMS (ESI): m/z calcd for
+
C12H27N4O2 [M + H]+ 259.2129, found 259.2133.
Synthesis of Di-N-protected Cyclam Derivatives and Their
Deprotected Analogues. 2-(3a,8a-Dibenzyl-10b,10c-cis-
3a,5a,8a,10a-tetraazaperhydropyren-2-yl)ethanol Dibromide Salt
(16). A solution of benzyl bromide (6.20 mL, 51.80 mmol) in distilled
CH3CN (20 mL) was added dropwise to a solution of compound 10
(1.38 g, 5.18 mmol) in distilled CH3CN (25 mL). The solution was
stirred at room temperature for 14 d, and then the precipitate was
isolated by filtration. The solid was washed with CH3CN (2 × 10 mL)
and then with Et2O (2 × 10 mL) and finally dried under vacuum to
1
give 16 as a white powder (2.70 g, 86%). H NMR (500 MHz, D2O,
25 °C, TMS): δ = 7.70−7.55 (m, 10H, CH-Ar), 5.34 (d, J = 13.0 Hz,
1H, N-CH2-Ph), 5.30 (d, J = 13.0 Hz, 1H, NCH2-Ph), 5.14 (d, J = 12.5
Hz, 2H, N-CH-N), 4.90−4.70 (m, 2H, N-CH2-Ph), 4.55−4.40 (m,
2H), 3.85−3.75 (m, 2H), 3.75−3.55 (m, 4H), 3.55−3.40 (m, 5H),
3.40−3.20 (m, 4H), 2.95−2.80 (m, 1H), 2.65−2.45 (m, 2H), 2.40−
2.25 (m, 1H), 2.00−1.90 (m, 1H), 1.65−1.45 ppm (m, 2H). 13C Jmod
NMR (75 MHz, D2O, 25 °C, TMS): δ = [136.1 ( × 2), 134.3 ( × 2),
132.4 ( × 2)] (CH-Ar), [127.56, 127.51] (C-Ar), [79.8, 79.5] (N-CH-
N), [67.3, 65.3, 65.2, 63.4, 61.2, 59.7, 54.1, 49.74, 49.68, 49.6, 48.9]
(CH2-α-N, CH2α-OH), 35.0 (CH2-β-OH), 28.6 (CH-β-N), 20.9 ppm
(CH2-β-N). HRMS (ESI): m/z calcd for C28H40N4O2+ [M − 2Br−]2+
224.1596, found 224.1603. Anal. Calcd for C28H40Br2N4O·H2O: C,
53.68; H, 6.76; N, 8.94. Found: C, 53.57; H, 6.81; N, 9.01.
CB-cyclam-EtOH: 2-(1,4,8,11-Tetraazabicyclo[6.6.2]hexadec-6-
yl)ethanol (20). Compound 19 (2.70 g, 5.99 mmol) was dissolved
in EtOH absolute ethanol (100 mL). 10 % Pd/C-activated (810 mg)
was added, the reaction mixture was stirred under a hydrogen
atmosphere at room temperature for 4 d, the mixture was then filtered
through Celite, and the solvent was evaporated under reduced
pressure. The resulting oil was dissolved in distilled H2O (20 mL), and
the organic impurities were extracted with Et2O (3 × 30 mL). The
aqueous layer was concentrated under vacuum to give compound 20
2-(1,8-Dibenzyl-1,4,8,11-tetraazacyclotetradecan-6-yl)ethanol
(17). Compound 16 (1.25 g, 2.06 mmol) was dissolved in hydrazine
monohydrate (6.0 mL, 64% in water, 123.58 mmol), and the reaction
mixture was heated at reflux for 4 h. The solution was cooled to 0 °C
with an ice bath, which led to product precipitation, and then the
excess of hydrazine was eliminated by filtration. The precipitate was
dissolved in a solution of NaOH (3M, 15 mL), and the product was
extracted with CH2Cl2 (3 × 30 mL). The organic fractions were dried
over MgSO4, filtrated, and evaporated under reduced pressure to give
1
as a yellow oil (1.45 g, 88%). H NMR (300 MHz, CDCl3, 25 °C,
TMS): δ = 4.20−3.50 (br s, 1H), 3.28 (t, J = 6,0 Hz, 2H), 2.85−2.70
(m, 1H), 2.70−2.25 (m, 15H), 2.25−2.00 (m, 6H), 1.90−1.70 (m,
1H), 1.15−0.90 ppm (m, 3H). 13C Jmod NMR (75 MHz, CDCl3, 25
°C, TMS): δ = [66.3, 59.2, 58.6, 58.5, 57.5, 54.8, 51.1, 50.4, 49.2,
44.00, 44.04] (CH2-α-N, CH2-α-OH), 34.8 (CH2-β-OH), 26.9 (CH-β-
N), 22.0 ppm (CH2-β-N). HRMS (ESI): m/z calcd for C14H32N4O2+
[M + 2H]2+ 136.1283, found 136.1284.
Synthesis of C-Functionalized TETA-EtOH, TE2A-EtOH, and
CB-TE2A-EtOH. 2-(1,8-Dibenzyl-4,11-(2-tert-butoxy-2-oxoethyl)-
1,4,8,11-tetraazacyclotetradecan-6-yl)ethanol (21a). A solution of
tert-butyl bromoacetate (390 μL, 2.68 mmol) in distilled CH3CN (5
mL) was added dropwise to a suspension of compound 17 (570 mg,
1
17 (740 g, 85%) as a yellow oil. H NMR (500 MHz, CDCl3, 25 °C,
TMS): δ = 7.30−7.10 (m, 10H, CH-Ar), 3.89 (d, J = 14.0 Hz, 1H, N-
CH2-Ph), 3.69 (d, J = 13.5 Hz, 1H, N-CH2-Ph), 3.60−3.45 (m, 3H),
3.51 (d, J = 14.0 Hz, 1H, N-CH2-Ph), 3.33 (d, J = 13.5 Hz, 1H, N-
CH2-Ph), 2.92−2.65 (m, 7H), 2.65−2.55 (m, 1H), 2.55−2.40 (m,
1895
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1.34 mmol) and K2CO3 (1.48 g, 10.72 mmol) in distilled CH3CN (20
mL). The reaction mixture was stirred at 80 °C for 2.5 d. After being
cooled to room temperature, the solution was filtrated and the filtrate
was evaporated under reduced pressure. The resulting yellow oil was
dissolved in CHCl3 (10 mL). The organic fraction was washed with a
solution of NaOH (3M, 3 × 25 mL), dried over MgSO4, filtrated, and
1.33 ppm (s, 9H, CH3). 13C Jmod NMR (75 MHz, CDCl3, 25 °C,
TMS): δ = [170.4, 169.9] (CO), [81.9, 81.2] (C(CH3)3), [65.5, 62.0,
57.8, 57.5, 56.4, 56.0, 55.8, 54.9, 54.7, 50.7, 49.9, 49.2, 48.3] (CH2-α-
N, CH2-α-OH), 33.2 (CH2-β-OH), 28.0 (CH-β-N), 27.9 (CH3, × 2),
25.7 ppm (CH2-β-N). HRMS (ESI): m/z calcd for C26H51N4O5+ [M +
H]+ 499.3854, found 499.3857.
1
evaporated to give compound 21a as a yellow oil (660 mg, 75%). H
TE2A-EtOH: 6-Hydroxyethyl-1,4,8,11-tetraazacyclotetradecane-
1,8-diacetic Acid, Ditrifluoroacetic Acid (24). Compound 21 (350
mg, 0.74 mmol) was dissolved in a mixture of anhydrous CH2Cl2/TFA
1:1 (10 mL). The solution was stirred at room temperature for 18 h
then the solvent was evaporated under reduced pressure at room
temperature to give a yellow oil which was lyophilized. Compound 24
NMR (300 MHz, CDCl3, 25 °C, TMS): δ = 7.40−7.10 (m, 10H, CH-
Ar), 3.70−3.30 (m, 6H), 3.15−3.00 (m, 4H), 2.90−2.75 (m, 1H),
2.75−2.45 (m, 10H), 2.45−2.30 (m, 2H), 2.30−2.10 (m, 2H), 1.90−
1.75 (m, 1H), 1.70−1.45 (m, 3H), 1.45−1.10 (m, 3H), 1.35 ppm (s,
18H, CH3). 13C Jmod NMR (75 MHz, CDCl3, 25 °C, TMS): δ =
[170.4, 170.2] (CO), [139.0, 138.0] (C-Ar), [129.2, 128.6, 128.0,
127.8, 127.0, 126.5] (CH-Ar), [80.4, 80.3] (C(CH3)3), [61.1, 60.6,
60.5, 59.7, 59.0, 57.2, 56.5, 51.5, 51.0, 50.9, 50.6, 48.8] (CH2-α-N,
CH2-α-OH), 37.6 (CH2-β-OH), 35.4 (CH-β-N), [27.90, 27.86]
(CH3), 24.7 ppm (CH2-β-N). HRMS (ESI): m/z calcd for
1
was obtained as an off-white powder (430 mg, quantitative yield). H
NMR (300 MHz, D2O, 25 °C, TMS): δ = 3.8−3.45 (m, 4H), 3.45−
3.20 (m, 3H), 3.20−2.85 (m, 8H), 2.85−2.30 (m, 8H), 2.20−2.00 (m,
1H), 2.00−1.60 (m, 2H), 1.45−1.20 ppm (m, 2H). 13C Jmod NMR
(75 MHz, D2O, 70 °C, TMS): δ = [179.1, 178.9] (CO), 165.3 (q, 2JCF
1
+
C38H61N4O5 [M + H]+ 653.4636, found 653.4639.
= 35.3 Hz, CF3CO2H), 119.7 (q, JCF = 262.5 Hz, CF3CO2H), [65.8,
62.1, 59.8, 58.0, 57.7, 57.0 ( × 2), 52.6 ( × 2), 48.5, 48.3] (CH2-α-N,
CH2-α-OH), 35.8 (CH2-β-OH), 33.6 (CH-β-N), 25.8 ppm (CH2-β-
N). 19F NMR (282 MHz, 25 °C, CD3OD, 1-fluoro-2-nitrobenzene
secondary reference set at −121.56 ppm): δ = −77.78 ppm (the
integration of this peak with respect to the reference FC6H4NO2 used
in this experiment is consistent with the formulation C16H32N4.2TFA).
HRMS (ESI): m/z calcd for C16H33N4O5+ [M + H]+ 361.2445, found
361.2445.
TE2AtBu-EtOH: 2-(1,8-Di(2-tert-butoxy-2-oxoethyl)-1,4,8,11-tet-
raazacyclotetradecan-6-yl)ethanol (21b). Compound 21a (660
mg, 1.00 mmol) was dissolved in EtOH absolute ethanol (30 mL).
10% Pd/C-activated (200 mg) was added, the reaction mixture was
stirred under a hydrogen atmosphere at room temperature for 4 d, the
mixture was filtrated through Celite, and the solvent was evaporated
under reduced pressure. The resulting yellow oil was dissolved in
distilled H2O (8 mL), and then the organic impurities were extracted
with Et2O (3 × 15 mL). The aqueous layer was evaporated to give 21b
TETA-EtOH: 6-Hydroxyethyl-1,4,8,11-tetraazacyclotetradecane-
1,4,8,11-tetraacetic Acid, Tetratrifluoroacetic Acid (25). Compound
22 (300 mg, 0.43 mmol) was dissolved in a mixture of anhydrous
CH2Cl2/TFA 1:1 (12 mL). The solution was stirred at room
temperature for 36 h, and then the solvent was evaporated under
reduced pressure at room temperature to give a brown oil which was
lyophilized. Compound 25 was obtained as an off-white solid (400 mg,
1
as a pale solid (410 mg, 86%). H NMR (300 MHz, D2O, 25 °C,
TMS): δ = 3.80−3.50 (m, 4H), 3.50−2.50 (m, 17H), 2.50−2.15 (m,
1H), 2.15−1.70 (m, 2H), 1.70−1.30 (m, 3H), 1.55 ppm (s, 18H,
CH3). 13C Jmod NMR (75 MHz, CDCl3, 25 °C, TMS): δ = [170.3,
170.2] (CO), [80.51, 80.48] (C(CH3)3), [59.2, 55.7, 54.6, 54.2, 53.4,
52.55, 52.52, 49.2, 47.5, 46.6] (CH2-α-N, CH2-α-OH), 36.0 (CH2-β-
OH), 34.0 (CH-β-N), 28.0 (CH3 × 2), 26.2 ppm (CH2-β-N). HRMS
1
quantitative yield). H NMR (300 MHz, D2O, 25 °C, TMS): δ =
+
(ESI): m/z calcd for C24H49N4O5 [M + H]+ 473.3696, found
4.20−3.75 (m, 2H), 3.75−3.50 (m, 6H), 3.50−2.50 (m, 18H), 2.25−
2.10 (m, 1H), 2,10−1,85 (m, 1H), 1,85−1,60 (m, 1H), 1,50−1,30
ppm (m, 2H). 13C Jmod NMR (125 MHz, D2O, 50 °C, TMS): δ =
473.3697.
TETAtBu-EtOH: 2-(1,4,8,11-Tetra(2-tert-butoxy-2-oxoethyl)-
1,4,8,11-tetraazacyclotetradecan-6-yl)ethanol (22). A solution of
tert-butyl bromoacetate (3.48 mL, 23.88 mmol) in distilled CH3CN
(10 mL) was added dropwise to a suspension of compound 18 (1.46 g,
5.97 mmol) and K2CO3 (6.60 g, 47.76 mmol) in distilled CH3CN (50
mL) heated to 80 °C. The suspension was stirred for 2 d, at the same
temperature, cooled to room temperature, and filtered. After the
removal of the solvent under vacuum, the residue was dissolved in
CHCl3 (20 mL). The organic fraction was washed with a solution of
NaOH (3M, 5 × 35 mL), dried over MgSO4, filtrated, and evaporated
under reduced pressure to give 22 as a yellow oil (3.50 g, 84%). If
necessary, the compound can be purified by aluminum oxide
chromatography (CHCl3/MeOH, 100:0−94:6). 1H NMR (300
MHz, CDCl3, 25 °C, TMS): δ = 3.70−3.60 (m, 2H), 3.40−3.10
(m, 8H), 2.90−2.50 (m, 13H), 2.40−2.10 (m, 3H), 1.90−1.70 (m,
1H), 1.70−1.35 (m, 5H), 1.45 (s, 18H, CH3), 1.44 ppm (s, 18H,
CH3). 13C Jmod NMR (125 MHz, CDCl3, 25 °C, TMS): δ = [170.7,
170.3] (CO), [81.0, 80.6] (C(CH3)3), [61.1, 60.3, 57.6, 56.7, 51.7,
51.0, 50.9] (CH2-α-N, CH2-α-OH), 37.6 (CH2-β-OH), 36.0 (CH-β-
N), 28.1 ( × 12) (C(CH3)3), 25.4 ppm (CH2-β-N). HRMS (ESI): m/
2
[172.2, 171.5] (CO), 162.5 (q, JCF = 36.3 Hz, CF3CO2H), 116.5 (q,
1JCF = 288.6 Hz, CF3CO2H), [62.1, 59.1, 55.6 ( × 2), 55.5, 51.4, 50.8]
(CH2-α-N, CH2-α-OH), 33.1 (CH2-β-OH), 29.5 (CH-β-N), 20.8 ppm
(CH2-β-N). 19F NMR (282 MHz, 25 °C, CD3OD, 1-fluoro-2-
nitrobenzene secondary reference set at −121.44 ppm): δ = −77.71
ppm (the integration of this peak with respect to the reference
FC6H4NO2 used in this experiment is consistent with the formulation
C20H36N4O9·4TFA). HRMS (ESI): m/z calcd for C20H37N4O9+ [M +
H]+ 477.2555, found 477.2560.
CB-TE2A-EtOH: 6-Hydroxyethyl-1,4,8,11-tetraazabicyclo[6.6.2]-
hexadecane-1,8-diacetic Acid, Tetratrifluoroacetic Acid (26). Com-
pound 23 (430 mg, 0.74 mmol) was dissolved in a mixture of
anhydrous CH2Cl2/TFA 1:1 (12 mL). The solution was stirred at
room temperature for 2 d, and then the solvent was evaporated under
reduced pressure at room temperature to give a brown oil which was
lyophilized. Compound 26 was obtained as an off-white solid (610 mg,
1
quantitative yield). H NMR (300 MHz, D2O, 25 °C, TMS): δ =
4.10−3.70 (m, 2H), 3.70−2.70 (m, 25H), 2.60−2.40 (m, 1H), 2.40−
2.15 (m, 1H), 1.80−1.60 (m, 1H), 1.50−1.30 ppm (m, 2H). 13C Jmod
NMR (75 MHz, D2O, 25 °C, TMS): δ = [175.1, 174.9] (CO), [67.0,
65.3, 62.1, 61.3, 60.8, 58.0 ( × 2), 56.0, 55.9, 51.4, 50.8, 50.5, 50.1]
(CH2-α-N, CH2-α-OH), 34.8 (CH2-β-OH), 29.3 (CH-β-N), 22.3 ppm
(CH2-β-N). 19F NMR (282 MHz, 25 °C, CD3OD, 1-fluoro-2-
nitrobenzene secondary reference set at −121.52 ppm): δ = −77.55
ppm (the integration of this peak with respect to the reference
FC6H4NO2 used in this experiment is consistent with the formulation
C18H34N4O5·4TFA). HRMS (ESI): m/z calcd for C18H35N4O5+ [M +
H]+ 387.2602, found 387.2603.
Synthesis of Cu(II) Complexes of C-Functionalized Cyclam Based
Ligands. In each case, a slight excess of Cu(ClO4)2·6H2O (0.18
mmol) was added to a solution of the ligand (0.15 mmol) in 10 mL of
water, and if necessary, the pH of the solution was adjusted to ∼7 with
an aqueous solution of KOH . The mixture was steered at 90 °C for 24
+
z calcd for C36H69N4O9 [M + H]+ 701.5059, found 701.5059.
CB-TE2AtBu-EtOH, HBr: 2-(1,8-Bis(2-tert-butoxy-2-oxoethyl)-
1,4,8,11-tetraazabicyclo[6.6.2]hexadec-6-yl)ethanol Hydrobromide
(23). A solution of tert-butyl bromoacetate (375 μL, 2.32 mmol) in
distilled CH3CN (2 mL) was added dropwise to a suspension of
compound 20 (350 mg, 1.29 mmol) and K2CO3 (712 mg, 5.16 mmol)
in distilled CH3CN (13 mL). The reaction mixture was stirred at room
temperature for 18 h, the reaction mixture was filtrated, and the filtrate
was concentrated under reduced pressure. The resulting yellow oil was
purified by flash chromatography on aluminum oxide (CHCl3/MeOH,
98:2−85:15) to give 23 as a monohydrobromide salt (750 mg, 75%).
1H NMR (300 MHz, CDCl3, 25 °C, TMS): δ = 10.40−10.20 ppm (br
s, 1H), 4.70−4.20 (br s, 1H), 3.90−3.45 (m, 5H), 3.40−2.90 (m,
10H), 2.90−2.20 (m, 12H), 1.80−1.20 (m, 4H), 1.34 (s, 9H, CH3),
1896
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Table 3. X-ray Crystal Data Collection and Refinement Details of Organic Compounds
7
8
9
11
13
16
formula
MW
C15H24N4O3
308.38
orthorhombic
Pbcn
C19H25N4O3
371.44
C28H48N8O4
560.74
orthorhombic
Pna21
C19H33BrN4O2
429.40
C21H37BrN4O5
505.46
monoclinic
Cc
C28H44Br2N4O3
644.49
crystal system
space group
T (K)
monoclinic
P21/c
monoclinic
P21/c
monoclinic
P21
170(2)
13.0852(13)
11.4562(12)
20.7283(19)
90
170(2)
13.4633(18)
13.1738(15)
10.3885(14)
90
170(2)
8.0687(5)
16.6793(10)
20.4007(11)
90
170(2)
7.0723(2)
9.7167(3)
30.2173(12)
90
170(2)
19.9358(19)
8.2953(6)
14.5790(14)
90
170(2)
8.5713(6)
16.2981(9)
10.6625(8)
90
a (Å)
b (Å)
c (Å)
α (deg)
β (deg)
γ (deg)
v (Å3)
90
94.933(11)
90
90
97.090(4)
90
106.925(11)
90
104.408(8)
90
90
90
3107.3(5)
1328
1835.7(4)
792
2745.5(3)
1216
2060.64(12)
904
2306.6(4)
1064
1442.70(17)
668
F(000)
Z
8
4
4
4
4
2
λ (Å) (Mo Kα)
0.71073
1.318
0.71073
1.344
0.71073
1.357
0.71073
1.384
0.71073
1.456
0.71073
1.484
Dcalc (g cm−3
)
μ (mm−1
)
0.094
0.094
0.093
2.015
1.822
2.845
θ range (deg)
Rint
3.07−26.36
0.1175
22375
3.41−26.37
0.1411
2.80−26.36
0.0350
20000
2.90−30.50
0.0422
3.73−26.36
0.0542
8530
3.50−26.36
0.0381
reflns collect
unique reflns
GOF on F2
13921
20240
11129
3173
3744
5583
6226
3295
4781
0.841
0.923
1.072
0.858
0.909
0.905
a
R1
0.049
0.0650
0.0556
0.1441
0.0330
0.0394
0.0711
0.0355
b
wR2 (all data)
largest diff peak and hole (e Å−3
0.0849
0.1086
0.0630
0.0616
)
b
0.156 and −0.144 0.163 and −0.191 0.466 and −0.343 0.690 and −0.536 0.522 and −0.292 0.689 and −0.317
a
4
R1 = ∑||F0| − |Fc||/ ∑|F0|. wR2 = {∑[w(||F0|2 − |Fc|2)2]/∑[w(F0 )]}1/2
.
Table 4. X-ray Crystal Data Collection and Refinement Details of the Cu(II) Complexes
17·CuBr(ClO4)
17·Cu(ClO4)2
18·Cu(ClO4)2
19·CuBr(ClO4)
formula
MW
C52H78Br2Cl2Cu2N8O11
1349.02
C26H38Cl2CuN4O9
685.04
C12H28Cl2CuN4O9
506.82
C28H42BrClCuN4O5
693.56
crystal system
space group
T (K)
triclinic
triclinic
monoclinic
P21/c
monoclinic
P21/c
P1
̅
170(2)
P1
̅
170(2)
170(2)
170(2)
a (Å)
13.3503(14)
14.8457(14)
15.8604(14)
92.710(7)
94.643(8)
110.551(9)
2924.1(5)
1392
8.9495(16)
13.606(2)
25.842(5)
77.317(15)
82.748(14)
89.651(14)
3044.6(9)
1428
8.6196(8)
30.658(2)
8.3348(9)
90
13.0582(9)
10.9400(7)
20.2904(13)
90
b (Å)
c (Å)
α (deg)
β (deg)
γ (deg)
v (Å3)
118.123(13)
90
91.285(6)
90
1942.5(3)
1052
2897.9(3)
1436
F(000)
Z
2
4
4
4
λ, Å (Mo Kα)
0.71073
1.532
0.71073
1.494
0.71073
1.733
0.71073
1.590
Dcalc (g cm−3
)
μ (mm−1
)
2.249
0.950
1.454
2.270
θ range (deg)
Rint
2.91−20.92
0.0909
3.16−25.35
0.1624
3.44−28.28
0.0490
3.54−26.37
0.1425
reflns collect
unique reflns
GOF on F2
13515
21667
17132
21830
6109
11071
4822
5925
0.882
0.853
1.053
1.008
a
R1
0.0853
0.0886
0.0468
0.0802
b
wR2 (all data)
largest diff peak and hole (e Å−3
R1 = ∑||F0| − |Fc||/ ∑|F0|. wR2 = {∑[w(||F0|2 − |Fc|2)2]/∑[w(F0 )]}1/2
0.2480
0.2101
0.1068
0.1445
)
0.982 and −0.992
0.671 and −0.512
0.570 and −0.399
0.550 and −0.583
a
b
4
.
h, solid impurities were filtered off, and the solution was concentrated.
The crystals of the Cu(II) complexes used for X-ray study were
obtained by slow evaporation of the solvent (water) at room
temperature.
1897
dx.doi.org/10.1021/jo4028566 | J. Org. Chem. 2014, 79, 1885−1899

The Journal of Organic Chemistry
Featured Article
Computational Methods. All calculations were performed employ-
ing DFT within the hybrid meta-generalized gradient approximation
(hybrid meta-GGA), with the TPSSh exchange-correlation func-
tional,36 and the Gaussian 09 package (Revision A.02).37 Full
geometry optimizations of 9 were performed in vacuo by using the
standard 6-311G(d,p) basis set. No symmetry constraints have been
imposed during the optimizations. The default values for the
integration grid (“fine”) and the SCF energy convergence criteria
(10−8) were used. The stationary points found on the potential energy
surfaces as a result of the geometry optimizations have been tested to
represent energy minima rather than saddle points via frequency
analysis. Relative free energies of the cis/syn and cis/anti isomers of 9
include nonpotential energy contributions (zero point energies and
thermal terms) obtained from frequency analysis. The electrostatic
potential V(r) that the electrons and nuclei create at any point r in the
surrounding space was calculated at the MPWLYP/6-311G** level
according to eq 1
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ZA
|RA − r|
ρ(r′) dr′
|r′ − r|
V(r) =
−
∑
∫
(1)
A
where Z is the charge on nucleus A, located at RA, and ρ(r) is the
electron density of the molecule.
X-ray Diffraction Measurements. Single-crystal X-ray diffraction
data were collected with graphite-monochromatized Mo Kα radiation
(λ = 0.71073). Crystal data and structure refinement details are given
in Tables 3 and 4. Unit cell determination and data reduction,
including interframe scaling, Lorentz, polarization, empirical absorp-
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attached programs of Crysalis software (Oxford Diffraction).38
Structures were solved by direct methods and refined by full matrix
least-squares method on F2 with the SHELXL39 suite of programs. The
hydrogen atoms were identified at the last step and refined under
geometrical restraints and isotropic U-constraints.40 CCDC 977486−
977496 contain the supplementary crystallographic data for this paper.
These data can be obtained free of charge from the Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/
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ASSOCIATED CONTENT
■
S
* Supporting Information
1H, 13C NMR, MS, HRMS, and IR spectra and microanalysis.
X-ray data for 7−9, 11, 13, 16, 17·CuBr(ClO4), 17·Cu(ClO4)2,
18·Cu(ClO4)2, and 19·.CuBr(ClO4) (CIF) and optimized
Cartesian coordinates of 9 obtained with DFT calculations.
This material is available free of charge via the Internet at
http://pubs.acs.org.
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■
Corresponding Author
*E-mail: raphael.tripier@univ-brest.fr.
(13) Sprague, J. E.; Peng, Y.; Fiamengo, A. L.; Woodin, K. S.;
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
R.T. acknowledges the Reg
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