Synthesis of Orthogonal N-Protected C-Functional Side-Bridged Cyclams to Give Access to Unsymmetrical Constrained BCAs

Article abstract of DOI:10.1002/ejoc.201901013

Considering the current importance of unsymmetrical mono- and di-N-functionalized ethylene side-bridged (sb) cyclams and the need to have their C-appended derivatives bearing an additional function dedicated to a conjugation to an external moiety as a targeting biomolecule, we have developed a general procedure to obtain orthogonally N-protected sb-cyclams with a benzyl or a Boc group. Despite the lack of symmetry of the compounds, this methodology allows the specific protection of one or the other remaining secondary amine function.

Full text of DOI:10.1002/ejoc.201901013

A Journal of
Accepted Article
Title: Synthesis of Orthogonal N-Protected C-functional Side-Bridged
Cyclams to give access to unsymmetrical constrained BCAs
Authors: Thomas Le Bihan, Nathalie Le Bris, Hélène Bernard, Carlos
Platas-Iglesias, and Raphael Tripier
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201901013
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10.1002/ejoc.201901013
European Journal of Organic Chemistry
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Synthesis of Orthogonal N-Protected C-functional Side-Bridged
Cyclams to give access to unsymmetrical constrained BCAs
Thomas Le Bihan,[a] Nathalie Le Bris,[a]* Hélène Bernard,[a] Carlos Platas-Iglesias,[b] Raphaël Tripier[a]*
Abstract: Considering the current importance of unsymmetrical
mono- and di-N-functionalized ethylene side-bridged (sb) cyclams
and the need to have their C-appended derivatives bearing an
additional function dedicated to a conjugation to an external
moiety as a targeting biomolecule, we have developed a general
procedure to obtain orthogonally N-protected sb-cyclams with a
benzyl or a Boc group. Despite the lack of symmetry of the
compounds, this methodology allows the specific protection of
one or the other remaining secondary amine function.
cb-cyclams di-N-functionalized respectively with acetic acid,
methylphosphonic acid or mixed acetic/methylphosphonic arms
have proved to form stable and inert 64Cu radiopharmaceuticals
for application in nuclear medicine as both PET (positron emission
tomography) imaging and radioimmunotherapy agents (Figure 1).
The synthetic technology to prepare bifunctionalized analogues
(BCA: bifunctional chelating agents) of these cb-ligands is now
available. This term BCA refers to the capability of the chelators
to be both coordinated to a metallic cation and conjugated to a
second moiety, such as a biovector, to allow their use for 64Cu
immuno-PET applications for instance.[12],[13],[14] An additional
anchoring function is introduced via a carbon atom of the ring
skeleton to keep intact, as far as possible, the overall properties
of the chelator. This was made possible mainly thanks to the
powerful and versatile bisaminal chemistry.[15],[16],[17],[18]
Introduction
Over these past decades, saturated tetraazamacrocycles, such
as cyclam (1,4,8,11-tetraazacyclotetradecane) have proved their
efficiency for cationic metal chelation.[1] The deserved reputation
of these ligands is due to their high binding capabilities with
several cationic substrates in terms of fast complexation kinetics,
thermodynamic stability and inertness toward dissociation. Thus,
in their naked form, these macrocycles have a high affinity for
transition metals and, thanks to the regiocontrolled
N-functionalizations (mono-, di-, tri- or full) the cyclic scaffold can
be adjusted to other metals with higher coordination numbers
such as easy metals or lanthanides. Furthermore, the subtle N-
alkylation of these macrocycles consisting in a simple ethylene
bridge linking two adjacent (side-bridged: sb) or opposite (cross-
bridged: cb) nitrogen atoms can also confer to metallic chelates
an improved inertness even in the most drastic media, including
hot and concentrated hydrochloric acid.[2] Indeed, cyclam has
proved to be tunable for several metals even on its constrained
sb or cb forms, leading to the most inert chelates with transition
metals such as Cu(II), Cu(I), Ni(II) and also with the lanthanide
ions.[2],[3],[4],[5],[6] Such stability properties make these ligands well
prized for numerous applications, where cations must be chelated
Unfortunately, no equivalent route to C-functionalized
sb-derivatives has yet been reported, as other types of BCAs
based on sb-cyclams, justifying that they currently are less used.
Furthermore, sb-constrained chelators bearing on their remaining
unbridged nitrogen atoms only one, or two different chelating
functions, may also provide very efficient chelators, since ligands
such as sb-te1a,[19] sb-te1py[20] (with
te1BnNO2
a picolyl arm), sb-
[21]
and sb-te1a1p[22] have proved their potential for
radiopharmaceutical applications (Figure 1).
to ensure
a safe use whatever the medium: catalysis,
electrochemistry, purification and especially medical applications,
where their inertness in biological media is of crucial importance.
For instance cb-te2a,[7],[8],[9] cb-te2p[10] and cb-te1a1p,[11] three
Figure 1. Structures of some reinforced cyclam derivatives.
In view of the importance of sb-cyclams and their mono- or
unsymmetrical di-N-functionalized derivatives, we decided to take
up the challenge to give access to their BCA analogues. This task
is not easy since, once obtained the C-functionalized sb-cyclam,
the previously described statistic N-alkylation method, although
very attractive, cannot be adapted.[22],[23] Indeed, because of the
presence of the anchoring C-function rendering the molecule
unsymmetrical, the direct mono-N-functionalization obviously
gives the two regioisomers. Therefore, the macrocycle must be
specifically N-protected on one of the remaining secondary amine
functions to obtain the targeted constrained BCA.
[a] Dr. T. Le Bihan, Dr. N. Le Bris, Dr. H. Bernard, Pr. R. Tripier, Univ-
Brest, UMR CNRS-UBO 6521 CEMCA, 6 avenue Victor le Gorgeu,
29200, Brest, France.
E-mail : nathalie.lebris@univ-brest.fr
E-mail: raphael.tripier@univ-brest.fr
http://www.umr6521.cnrs.fr/
[b] Pr C. Platas-Iglesias,
Departamento de Química, Facultade de Ciencias & Centro de
Investigaciones Científicas Avanzadas
Universidade da Coruña,
15071 A Coruña, Spain
Supporting information for this article is given via a link at the end of
the document.
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10.1002/ejoc.201901013
European Journal of Organic Chemistry
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We present here the easy synthesis of a series of
regiospecific mono-N-protected sb-cyclams, precursors of the
targeted constrained compounds. The ligands are C-
functionalized with hydroxyethyl and p-nitrobenzyl groups, which
constitute precursors of valuable coupling functions (respectively
mesylate or amine and aniline or isothiocyanate). In order to
extend the study to a larger range of macrocycle derivatives, the
synthesis was also carried out on “simple” sb-cyclams (without
C-appended function). Finally, Boc groups, which are orthogonal
to benzyl ones, were introduced to offer a wider panel of
regioprotected sb-cyclam derivatives.
2b’ is in line with the slightly lower Mulliken charge of the carbon
atom of the carbonyl group 3b (+0.16) with respect to 2b’ (+0.18);
ii) route B: expected reduction of the amide function giving the
reduced hemiaminal 2b”, followed by the cleavage of N4-Caminal
bond to give sb-cyclam derivative 4b containing the favoured
6-membered piperazine ring (Scheme 2). As a result, NaBH4 is
not appropriate for
a
one-pot synthesis of “non-oxo”
sb-compounds 4a-c.
OH
OH
O
O
N3 N4
N
N
N4
OH
Results and Discussion
N2 N1 Ph
Route A
N1 Ph
O
2b
The methodology uses key-intermediate bisaminals 1a-c
(1a: R=H, 1b: R=(CH2)2OH, 1c: R=p-BnNO2) obtained by an easy
and general two-step synthesis starting from the linear tetraamine
N,N’-bis(2-aminoethyl)-1,3-propanediamine.[14] We proved that
these bisaminals have a dual astonishing reactivity: on the one
hand, their amide function can be reduced by NaBH4; on the
second hand, they lead univocally to bisaminal ammonium salts
2 via the regiospecific mono-alkylation on N1 by reaction with
benzyl bromide. Such salts are known to be involved in a tailored
reduction step with NaBH4 that induces the partial cleavage of the
bisaminal bridge leading to sb-cyclams bearing a benzyl group
according to the typical Kolinski procedure.[18] Thus, we assumed
that the one-pot reduction of the amide function and the sb
formation was possible.
Monoammonium salts 2a-c were synthesized following our
previous methodology.[14,24] Then, as described by Kolinski,[18] we
used NaBH4 in refluxing water to achieve the reduction of the
bisaminal bridge of 2a-c hoping to get the sb-reinforced synthons.
However, in our case, the reduction of 2a-c led to a mixture of
“oxo” and “non-oxo” sb-derivatives, respectively compounds 3a-c
and 4a-c (Scheme 1).
N3 N4
3b (major)
OH
OH
N2 N1 Ph
OH
2b’
O
N3 N4
N
N
N4
Route B
N3 N4
N2 N1 Ph
N2 N1 Ph
N1 Ph
4b (minor)
2b’’
Scheme 2. Proposed routes for the reduction of bisaminal salt 2b with NaBH4.
The expected sb-compounds 4a-c, although in minor
amount, could be separated from their amide analogues 3a-c by
crystallization. The reinforced sb-structure was thus confirmed by
X-ray diffraction of single crystals of 4b and 4c formed by slow
evaporation of a solution of the mixture in water. The structures
revealed that the compounds crystallized in their deprotonated
form in which the piperazine rings adopt chair conformations. The
conformation of the macrocycle is conditioned by intramolecular
hydrogen bond involving the secondary amine functions and one
of the nitrogen atoms of the piperazine ring (Figure 2): N4···N3,
2.823(2) (4b) and 2.824(3) Å (4c); N4-H···N3, 2.110(17) (4b) and
2.121(18) Å (4c); N4-H···N3, 135.8(17)° (4b) and 133.3(15)º (4c).
R
R
R
R
O
O
O
H
H
Ph
N3
N
N4
N1
Br
N
N
HN4
N1 Ph
N
N
N4
N1
N
N
HN4
N1 Ph
NaBH4
, Br
Ph
+
2 H
H
1a-c
2a (90%)
2b (98%)
2c (97%)
4a-c (minor)
"non-oxo"
3a-c (major)
"oxo"
Scheme 1. Synthesis of bisaminal salts 2a-c from bisaminals 1a-c and
subsequent reduction with NaBH4.
A DFT study was carried out to provide a reasonable
explanation for the formation of both “oxo” and “non-oxo”
derivatives upon reaction of 2a-c with NaBH4. The structure of 2b
+
obtained with DFT presents a rather long N1 -Caminal bond (1.544
Å), when compared with the N4-C (1.479 Å), N3-C (1.434 Å) and
N2-C (1.441 Å) bonds. Furthermore, calculations of the
electrostatic potential on the molecular surface of 2b shows that
the region with the most positive electrostatic potential resides on
+
the N1 -Caminal bond (Figure S 36, Supporting Information). Thus,
it is reasonable to assume that the reduction with NaBH4 results
in the rapid formation of hemiaminal 2b’, still bearing the “oxo”
function. This intermediate can then evolve following two distinct
pathways: i) route A: breaking of N4-Caminal bond leading to “oxo”
sb-compound 3b whose amide function can no longer be reduced
by NaBH4. The lower reactivity of 3b with respect to intermediate
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10.1002/ejoc.201901013
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It has to be noted that the C-appended functions are not
necessarily inert towards the reducing agent and can be
transformed during the reaction. In order to point out these
eventual transformations, the compounds are noted with a
superscript to facilitate the comprehension. So, in the case of
compound 2c, the p-nitrobenzyl arm was converted to an aniline
function leading to 4cNH
2
.
Scheme 4. Full reduction of 2a-c with BH3·THF leading to sb-cyclams 4a-c.
To our knowledge, this synthesis gives rise to the two first
examples of C-functionalized sb-cyclams 4b and 4c. Furthermore,
compounds 4a-c have to be considered as N1-protected
reinforced cyclam derivatives that could lead, after the alkylation
of N4 and the further removal of the benzyl group, to mono-N4-
alkylated sb-analogues. Nevertheless, the reactivity of these
compounds towards alkylation should be carefully considered as
previously demonstrated by Kotek on a similar sb-cyclam
derivative.[21] Indeed, in the case of compound 4b, taken as a
C-functionalized example, the tertiary nitrogen atom N2 of the
piperazine ring was alkylated preferentially with benzyl chloride
over the secondary amine N4 to give as the major product the
quaternary ammonium A (Scheme 5).
Figure 2. View of the crystal structure of 4b (top) and 4c (bottom). The thermal
ellipsoids are plotted at the 50% probability level. Water molecules are omitted
for simplicity.
OH
OH
To confirm our mechanistic pathway, we then hypothesized
that a milder reducing agent would promote the formation of “oxo”
sb-compounds 3a-c (route A). We then used NaBH3CN, which is
known to selectively reduce iminiums in the presence of carbonyl
functions such as amides.[25] The reduction carried out in refluxing
water led, as expected, exclusively to “oxo” sb-cyclam derivatives
3a-c with good yields; no trace of “non-oxo” sb-analogues 4a-c
was detected under these conditions (Scheme 3).
Ph
Cl
N3 HN4
N3 HN4
, Cl
THF
N2 N1 Ph
Ph
N2 N1 Ph
A
4b
Scheme 5. Alkylation of 4b with benzyl chloride leading to A.
To rationalize this unexpected reactivity, we calculated the
electrostatic potential on the molecular surface of 4b, defined by
the 0.001 electrons·bohr-3 contour of the electron density
(Figure 3). The results show that the regions with the most
negative electrostatic potential of the molecule are located on the
oxygen atom of the hydroxyl group and on the two nitrogen atoms
N4 and N2. However, the region with negative electrostatic
potential on N2 is more exposed on the molecular surface, since
the lone pair of N2 is pointing to the outer part of the molecule due
to the chair conformation of the piperazine ring. Conversely, the
lone pair of N4 is more buried in the macrocyclic cavity, and thus
less prone to nucleophilic substitution.
Scheme 3. Mild reduction of 2a-c with NaBH3CN leading to “oxo” sb-cyclams
3a-c.
On the contrary, the exclusive formation of “non-oxo”
sb-derivatives 4a-c (route B) requires a reducing agent able to
perform the total reduction of the amide function of 2a-c. For that
purpose, BH3·THF was employed as a powerful reducing reagent
of amide functions. The reaction was carried out in refluxing THF,
followed by an acidic hydrolysis of amino-borane bonds and a
subsequent basic extraction. The expected sb-cyclam derivatives
4a-c were obtained with good yields (Scheme 4).
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Figure 3. Molecular structure of 4b and electrostatic potential (hartree)
calculated at the TPSSh/Def2-TZVP level on the molecular surface defined by
a 0.001 electrons·bohr-3 contour of the electron density.
Figure 5. View of the crystal structure of diammonium salt A. Water molecules
and anions are omitted for simplicity.
A second factor that may be related to the observed
reactivity is the high basicity of this type of ligands, which exist
partially in their protonated form in solution. Indeed, single crystals
of 4b·HCl, suitable for X-ray diffraction, were obtained by slow
evaporation of a solution of CH2Cl2 (Figure 4). The additional
proton, located on the secondary amine function N4, is involved in
a hydrogen bond between N4 and N3. This deactivates these
atoms for further alkylation with an alkyl halide, resulting in the
alkylation of one of the tertiary amine of the six-membered cycle.
To solve the problem encountered for the functionalization
of 4a-c at N4, alternative conditions should be considered such as
a Mannich-type reaction to introduce a single methylphosphonic
acid arm on the secondary amine of sb-compounds, as described
by Kotek[21] and Brechbiel.[23] In order to have access to a
precursor of mono-N1-alkylated sb-analogues, we sought to
functionalize N4 with an orthogonal protection to the benzyl group
present on N1. Thus, we chose the Boc-protection, which has the
undeniable advantage of allowing the full control of the
regiospecificity of the N-functionalization of the unsymmetrical
macrocycle. Additionally, the hydroxyethyl group as well as the
aniline function, which are likely to interact with any reactant are
then also protected. As expected, the sequence led to the N4-Boc-
protected cyclams 5a-c. N2 was not reactive under these
experimental conditions but, as anticipated, the C-appended
functions of 4b-c were respectively transformed into (CH2)2OBoc
and p-BnNHBoc groups. It has to be noted that for compounds 4a
and 4cNH the reaction was carried out in refluxing THF without the
2
use of any base. These conditions allowed the Boc-protection,
which was not the case under the classical conditions as used for
the protection of 4b, namely in CH2Cl2 at room temperature in the
presence of Et3N (Scheme 6).
R
R
Boc
Boc
Figure 4. View of the crystal structure of 4b·HCl. Counterions and water
molecules and anions are omitted for simplicity. The thermal ellipsoids are
plotted at the 50% probability level.
Boc2O
H2/Pd-C
N3 N4
N2 N1
N3 N4
N2 HN1
4
Ph
Single crystals of A obtained by slow evaporation of a
solution in water were suitable for X-ray diffraction. The structure
highlights the formation of a dicationic form with a supplementary
proton located on N4 and a quaternarized nitrogen atom N2
(Figure 5).
5a (21%)
6a (95%)
5bOBoc (67%)
5cNHBoc (53%)
6bOBoc (95%)
6cNHBoc (95%)
Scheme 6. Synthesis of Boc-protected sb-cyclams 6a-c from benzyl-protected
sb-cyclams 4a-c.
In a last step, compounds 5a-c were debenzylated by
Pd-catalyzed hydrogenolysis to generate Boc-protected
sb-cyclams 6a-c with quantitative yields (Scheme 6). As long as
no alkyl halide is used, these compounds can now be specifically
alkylated on N1 nitrogen atom according to previously cited
methodologies[21],[22] to lead to mono-N1-functionalized
C-appended sb-cyclams after the removal of the Boc-protection.
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10.1002/ejoc.201901013
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was heated at 40 °C during 3 days. After cooling to room temperature, the
precipitate was filtrated and washed with THF (2 x 5 mL) and Et2O (2 x 5
mL). The precipitate was dried under vacuum to yield 2a as a white solid
Conclusions
In conclusion, we have highlighted a new and efficient
general procedure leading to the first regiospecific mono-N-
protected sb-cyclams and their C-functionalized analogues.
In these last cases, we have succeeded in specifically protecting
one or the other of the two remaining secondary nitrogen atoms
and, finally, the methodology led easily to the C-functionalized sb-
cyclams. Such syntheses and compounds have never been
reported so far (Figure 6).
1
(4.65 g, 90%). H NMR (300 MHz, D2O, 25 °C, TMS):  7.70 – 7.50 (m,
5H), 5.60 (s, 1H), 5.11 (d, J = 15.0 Hz, 1H), 4.60 (d, J = 15.0 Hz, 1H), 4.45
– 4.25 (m, 1H), 4.03 (s, 1H), 3.94 – 3.75 (m, 1H), 3.47 – 3.25 (m, 1H), 3.53
– 2.87 (m, 9H), 2.78 – 2.58 (m, 2H), 2.58 – 2.38 (m, 2H), 2.31 – 2.10 (m,
1H), 1.93 – 1.75 (m, 1H). 13C NMR Jmod (75 MHz, CDCl3, 25 °C, TMS): 
175.5 (CO), [136.0 (x2), 134.1, 132.3 (x2)] (CHAr), 128.1 (CAr), [83.4, 68.0]
(N-CH-N), [64.8, 62.8, 55.4, 54.9, 50.5, 40.1, 44.1, 38.1, 29.3] (CH2 α-N,
CH2 β-N), 21.0 (CH2 β-N+). ESI-HRMS (positive) m/z calcd. for
C19H27N4O+ [M]+ 327.2179, found 327.2178.
Compound 3a. Sodium cyanoborohydride (1.25 g, 19.8 mmol) was added
to a solution of compound 2a (1.01 g, 2.48 mmol) in H2O (20 mL). The
mixture was refluxed overnight. MeOH was evaporated under reduced
pressure. A saturated solution of NaOH was added to the residue and the
compound was extracted with CH2Cl2 (4 x 30 mL). The organic layer was
dried over MgSO4, filtrated and evaporated under reduced pressure to give
compound 3a as a white powder (0.65 g, 67%). RMN 1H (300 MHz, CDCl3,
25 °C, TMS):  7.35 – 7.05 (m, 6H), 3.70 – 3.45 (m, 2H), 3.45 – 3.22 (m,
Boc
N
N
HN
N
N
N
N
Ph
HN
6a
4a
NH2
NHBoc
OH
OBoc
2H), 3.17 – 2.60 (m, 10H), 2.47 – 2.15 (m, 8H), 1.75 – 1.45 (m, 2H). 13
C
NMR Jmod (75 MHz, DMSO-d6, 25 °C):  172.3 (CO), 137.7 (CAr), [129.5
(x2), 128.1 (x2), 127.0] (CHAr), [56.0, 52.0, 51.4, 50.4, 48.2 (x2), 44.3, 40.8
(x2), 35.4, 31.4 (CH2 β-N), 20.1 (CH2 β-N).
Boc
N
Boc
N
N
HN
N
HN
N
N
N
N
N
N
Ph
N
Ph
N
HN
HN
Compound 3b. Sodium cyanoborohydride (4.17 g, 66.5 mmol) was added
to a solution of compound 2b (2.87 g, 7.65 mmol) in H2O (50 mL). The
reaction mixture was refluxed for 4 hours. After cooling down to room
temperature the solution was saturated with NaOH pellets and the product
was extracted with CH2Cl2 (6 × 40 mL). The organic fraction was dried over
MgSO4, filtrated and evaporated under reduced pressure to give 3b as a
6bOBoc
6cNHBoc
4cNH
2
4b
Figure 6. Protected (benzyl or Boc) sb-cyclams described in this paper.
The first series (R = H) may be very useful as starting materials
to give the mono- or di-N-functionalized unsymmetrical
sb-cyclams,[19],[20],[21],[22] while the second series (R ≠ H) gives the
only current access to their C-appended analogues, so-prized for
crucial applications in nuclear medicine. Even though the strategy
excludes using alkyl halides for further N-functionalization (to
avoid the formation of suralkylated ammonium salt derived from
A), the range of possibilities is wide. These compounds and their
use, now our new targets, are currently under process.
1
white powder (1.78 g, 72%). RMN H (300 MHz, CDCl3, 25 °C, TMS): 
7.30 – 7.20 (m, 5H), 4.50 (m, 1H), 4.16 (m, 1H), 3.76 (m, 1H), 3.66 – 3.51
(m, 4H), 3.39 – 3.34 (m, 2H), 3.29 – 3.11 (m, 2H), 3.03 (m, 3H), 2.92 –
2.80 (m, 4H), 2.74 – 2.70 (m, 1H), 2.61 – 2.39 (m, 5H), 2.28 (m, 1H), 2.08
(m, 1H), 1.88 (m, 1H), 1.85 – 1.57 (m, 2H) 13C NMR Jmod (75 MHz, CDCl3,
25 °C, TMS):  175.8 (CO), 137.7 (CAr), [129.3 (x2), 128.3 (x2), 127.2]
(CHAr), [60.0, 59.3, 56.8, 52.5, 51.4, 50.6, 48.5, 47.7, 46.1, 42.8, 36.4] (CH2
α-N, CH2 α-OH), 38.6 (CH β-N), 33.9 (CH2 β-OH), 22.4 (CH2 β-N). ESI-
HRMS m/z calcd for C21H35N4O2+ [M+H]+ 375.2754, found 375.2756.
Compound 3c. Sodium cyanoborohydride (2.78 g, 44.2 mmol) was added
to a solution of compound 2c (2.00 g, 3.69 mmol) in methanol (50 mL).
The mixture was refluxed overnight. Methanol was evaporated under
reduced pressure. A saturated solution of NaOH was added to the residue
and the compound was extracted with CH2Cl2 (4 x 30 mL). The organic
layer was dried over MgSO4, filtrated and evaporated under reduced
pressure to give compound 3c as a white powder (1.50 g, 87%). 1H NMR
(500 MHz, CDCl3, 25 °C, TMS):  8.06 (d, J = 8.4 Hz, 2H), 7.31 – 7.15 (m,
7H), 3.64 – 3.52 (m, 2H), 3.49 (d, J = 14.0 Hz, 1H), 3.23 (m, 2H), 3.10 –
2.85 (m, 7H), 2.80 – 2.60 (m, 5H), 2.60 – 2.44 (m, 3H), 2.45 – 2.30 (m, 2H),
2.30 – 2.20 (m, 2H), 1.70 (m, 1H), 1.53 (m, 1H). 13C NMR Jmod (125 MHz,
CDCl3, 25 °C, TMS):  173.5 (CO), [147.5, 146.5, 138.1] (CAr), [129.7 (x2),
128.9 (x2), 128.3 (x2), 127.2, 123.5 (x2)] (CHAr), [58.9, 57.4, 53.2, 51.3,
50.4, 49.1, 48.2, 46.4, 36.6, 36.4] (CH2 α-N), 43.6 (CH β-N), 43.1 (CH2 α-
PhNO2), 22.8 (CH2 β-N).
Experimental Section
Experimental section, analytical data and all compounds characterization
are given in Supporting Information. Reagents were purchased from
ACROS Organics, TCI and from ALDRICH Chemical Co. Compounds
1a,[26] 1b,[14] 1c,[14] 2b,[14] and 2c[24] were synthesized as previously
described.
Materials and Methods
NMR spectra were recorded at the “Services communs” of the University
of Brest. 1H and 13C NMR spectra were recorded with Bruker Avance 500
(500 MHz), Bruker Avance 400 (400 MHz), or Bruker AMX-3 300 (300
MHz) spectrometers. 2D NMR 1H-1H homonuclear, 1H-13C and 1H-15N
heteronuclear correlations and homonuclear decoupling experiment
permitted as much as possible the assignation of the H and 13C signals.
1
The  scales are relative to TMS (1H, 13C). 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), assignation: H, C and H, C correspond to CH or CH2 located
respectively in alpha or beta position of considered nitrogen atom. (Am, Ar
and Ph are the abbreviations used for aminal, aromatic and phenyl
respectively).
Compound 4a. A solution of BH3-THF (2.95 mL, 1.0 M, 3.0 mmol) was
slowly added on compound 2a (100 mg, 0.25 mmol) under a nitrogen
atmosphere. The solution was refluxed for 2 days. After cooling to room
temperature MeOH (15 mL) was added to the reaction mixture and then
the solvent was evaporated under reduced pressure. HCl (20 mL, 3M) was
added to the residue and the solution was refluxed for 1h. After cooling to
room temperature, organic impurities were extracted with CH2Cl2 (3 x 30
mL). Then the aqueous layer was saturated with NaOH pellets to adjust
the pH at 14. Compound 4a was extracted with CH2Cl2 (5 x 30 mL). The
organic fraction was dried over MgSO4, filtrated and evaporated under
Compound 2a. Benzyl bromide (17.4 g, 100 mmol) was added to a
solution of compound 1a (3.00 g, 12.7 mmol) in THF (20 mL). The mixture
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201901013
European Journal of Organic Chemistry
FULL PAPER
reduced pressure to give 4a as a colorless oil (70 mg, 84%). 1H NMR (300
MHz, CDCl3, 25 °C, TMS):  7.34-7.10 (m, 5H), 3.58 (s, 2H), 3.27 (m, 2H),
3.20-3.05 (m, 2H), 2.79 (m, 3H), 2.72 (m, 4H), 2.60 (m, 4H), 2.48 (m, 4H),
2.27 (m, 2H), 1.96 (m, 2H), 1.70 (m, 2H). 13C NMR Jmod (75 MHz, CDCl3,
25 °C, TMS):  137.6 (CAr), [129.3 (x2), 128.5 (x2), 127.7] (CHAr), [58.0,
56.6, 56.0, 55.9, 54.3, 53.1, 50.9, 49.7, 48.8 (x2), 46.7] (CH2 α-N), [23.0,
22.6] (CH2 β-N).
eliminate impurities. Compound 5bOBoc was obtained as a yellowish oil
(150 mg, 67 %). 1H NMR (300 MHz, CDCl3, 25 °C, TMS):  7.35 – 2.20 (m,
5H), 4.15 – 4.10 (m, 1H), 3.75 – 3.40 (m, 5H), 3.15 - 2.05 (m, 20H), 1.90
– 1.75 (m, 2H), 1.55 – 1.20 (m, 19H). 13C NMR Jmod (75 MHz, CDCl3,
25 °C, TMS):  [156.5, 153.3] (CO), 138.6 (CAr), [129.7 (x2), 128.0 (x2),
126.9] (CHAr), [81.6, 79.6] (Cquat t-Bu), [64.8, 61.3, 59.8, 53.8, 52.9, 51.0,
49.1, 45.5, 43.3] (CH2 α-N, CH2 α-OH), , 37.1 (CH2 β-OH), 33.5 (CH β-N),
[28.1, 27.6] (CH3 t-Bu).
Compound 4b. A solution of BH3.THF (14 mL, 1.0 M, 14.0 mmol) was
added dropwise on compound 2b (500 mg, 1.33 mmol) under a nitrogen
atmosphere. The solution was refluxed for 1.5 days. After cooling to room
temperature, water (15 mL) was added to the mixture. Then solvents were
evaporated under reduced pressure. HCl (20 mL, 3 M) was added to the
residue and the solution was refluxed for 1 hour. After cooling down to
room temperature organic impurities were extracted with CH2Cl2 (3 x 40
mL). Then the solution was saturated with NaOH pellets to adjust the pH
at 14. Compound 4b was extracted with CH2Cl2 (5 x 40 mL). The organic
fractions were dried over MgSO4, filtrated and evaporated under reduced
pressure to give 4b as a colorless oil (420 mg, 87%). 1H NMR (500 MHz,
CDCl3, 25 °C, TMS):  7.37-7.26 (m, 5H), 3.86 (m, 1H), 3.75-3.65 (m, 3H),
3.42 (m, 2H) 3.24-3.19 (m, 2H), 3.00-2.93 (m, 3H) 2.83 (m, 2H), 2.72-2.58
(m, 5H), 2.52-2.37 (m, 4H), 2.35-2.32 (m, 1H), 1.88 (m, 5H), 1.64 (m, 1H),
1.47-1.43 (m, 1H), 1.25-1.19 (m, 1H). 13C NMR Jmod (125 MHz, CDCl3,
25 °C, TMS):  137.4 (CAr), [129.4 (x2), 128.7 (x2), 127.8] (CHAr), [62.7,
59.2 (x2), 58.2, 55.4, 55.2, 54.2, 52.8, 49.4, 49.0, 48.7, 47.2] (CH2 α-N,
CH2 α-OH), 32.9 (CH2 β-OH), 30.3 (CH β-N), 22.9 (CH2 β-N). ESI-HRMS
m/z calcd for C21H36N4O+ [M+H]+ 361.2962, found 361.2963.
Compound 5cNHBoc. Di-tert-butyl dicarbonate (1.68 mg, 7.71 mmol) was
added to a solution of compound 4c (500 mg, 1.19 mmol) in dry THF
(20 mL). The solution was refluxed and the reaction followed by HPLC-MS.
Once the reaction was completed (after about 3 hours), the solvent was
evaporated under reduced pressure. The residue was purified by
chromatography on neutral aluminum oxide (CHCl3/MeOH 100:0 to 90:10)
to afford compound 5cNHBoc as a colorless oil (510 mg, 51%). 1H NMR (500
MHz, CD3CN, 70 °C):  7.48 (s, 1H), 7.40 - 7.15 (m, 6H, CHAr), 7.07 (m,
2H), 3.65 - 3.45 (m, 3H), 3.45 - 3.30 (m, 1H), 3.30 - 3.10 (m, 2H), 3.10 -
2.70 (m, 8H), 2.70 - 2.40 (m, 7H), 2.35 - 2.30 (m, 2H), 2.25 - 2.20 (m,
2H),1.96 (br s, 1H), 1.72 (br s, 2H) 1.50 - 1.10 (m, 18H). 13C NMR Jmod
(125 MHz, CD3CN, 70 °C):  [157.1, 154.3] (CO Boc), [141.2, 138.2, 136.5]
(CAr), [130.6 (x2), 130.4 (x2)] (CHAr Ph),129.2 (x2) (CHAr PhNHBoc),127.9
(CHAr Ph),119.9 (x2) (CHAr PhNHBoc), [80.6, 79.7] (Cquat t-Bu), [60.7, 58.6,
56.2, 54.6 54.4, 54.2, 51.7, 51.1, 48.9, 47.6, 47.1] (CH2 -N), 40.3 (CH β-
N), 38.3 (CH2-PhNHBoc), 28.8 (x6) (CH3 Boc), 26.1 (CH2 β-N). ESI-HRMS
(positive) m/z calcd. for [C36H56N5O4]+ [M+H]+ 622.4326; found 622.4327.
Compound 6a. Compound 5a (180 mg, 0.43 mmol) was dissolved in
absolute EtOH (15 mL), 10% Pd/C-activated (80 mg) was added to the
solution in an autoclave. The reaction mixture was stirred under a
hydrogen atmosphere for 7 days at room temperature. The reaction was
followed by HPLC-MS. Once complete, the mixture was filtrated through
Celite and the solvent was evaporated under reduced pressure to give
compound 6a as a yellow oil (135 mg, 95%).1H NMR (300 MHz, CDCl3,
25 °C, TMS):  3.47 – 3.15 (m, 4H), 3.15 - 3.02 (m, 2H), 3.02 – 2.88 (m,
1H), 2.88 – 2.77 (m, 2H), 2,75 – 2.60 (m, 4H), 2.60 – 2.50 (m, 2H), 2.50 –
2.30 (m, 4H), 2.22 – 2.02 (m, 2H), 1.79 – 1.50 (m, 4H) 1.36 (s, 9H).
13C NMR Jmod (75 MHz, CDCl3, 25 °C, TMS):  79.7 (Cquat Boc), 56.4,
52.2, 51.1, 49.5, 48.7, 48.1 (x3), 47.6 (x3)] (CH2 α-N), 28.4 (CH3), 26.0,
24.7 (CH2 -N).
Compound 4cNH2. A solution of BH3.THF (25.2 mL, 1.0 M, 25.0 mmol) was
slowly added on compound 2c (1.17 g, 2.51 mmol) under a nitrogen
atmosphere. The solution was refluxed for 2 days. After cooling to room
temperature, MeOH (15 mL) was added to the reaction mixture and then
solvents were evaporated under reduced pressure. HCl (20 mL, 3 M) was
added to the residue and the solution was refluxed for 1h. After cooling to
room temperature, an extraction with CH2Cl2 (3 x 30 mL) was performed
to eliminate organic impurities. Then the aqueous layer was saturated with
NaOH pellets to adjust the pH at 14. The compound was extracted with
CH2Cl2 (5 x 30 mL). The organics fractions were dried over MgSO4,
filtrated and evaporated under reduced pressure to give compound 4cNH2
as a yellowish powder (0.910 g, 85%). 1H NMR (500 MHz, CDCl3, 25 °C,
TMS):  7.34 - 7.14 (m, 5H), 6.95 - 6.80 (m, 2H), 6.60 - 6.50 (m, 2H), 3.80
- 3.40 (m, 4H), 3.30 - 3.10 (m, 3H), 2.92 - 2.85 (m, 1H), 2.80 - 2.15 (m,
19H), 2.10 - 1.98 (m, 1H), 1.88 (m, 1H), 1.50 (m, 1H). 13C NMR Jmod (125
MHz, CDCl3, 25 °C, TMS):  [144.6, 137.4, 129.0] (CAr), [129.6 (x2), 129.5
(x2), 128.1(x2), 127.1, 115.1 (x2)] (CHAr), [62.5, 56.9, 55.7, 55.5, 54.1, 53.5,
53.5, 49.2, 48.4, 48.1, 47.4] (CH2-α-N), 37.5 (CH2-BnNH2), 36.0 (CH-β-N),
23.1 (CH2-β-N). ESI-HRMS (positive) m/z calcd. for [C26H40N5]+ [M+H]+
422.3278; found 422.3277.
.
Compound 6bOBoc Compound 5bOBoc (150 mg, 0.27 mmol) was
dissolved in absolute EtOH (15 mL) and 10% Pd/C-activated (80 mg) was
added to the solution. The mixture was placed in an autoclave and stirred
at room temperature under 20 bars of hydrogen for 7 days. The mixture
was filtrated through Celite and the solvent was evaporated under reduced
pressure to give compound 6bOBoc as a yellow oil (126 mg, 95%). 1H NMR
(300 MHz, CDCl3, 25 °C):  4.26-3.96 (m, 2H), 3.92 - 2.97 (m, 16H), 2.97
- 2.80 (m, 3H), 2.80 - 2.55 (m, 3H), 2.55 - 2.30 (m, 2H), 2.31 - 2.17 (m, 1H)
1.99 - 1.77 (m, 1H), 1.71 - 1.23 (m, 18H). 13C NMR Jmod (75 MHz, CDCl3,
25 °C, TMS):  [157.5, 156.5] (CO), [82.0, 81.5] (Cquat t-Bu), [64.8, 59.5,
56.2, 55.3, 50.6, 48.1, 47.7, 46.0] (CH2-α-N, CH2-α-OH), 30.7 (CH2-β-OH),
33.0 (CH-β-N), [28.4, 27.7] (CH3 t-Bu), 22.2 (CH2 -N).
Compound 5a. Di-tert-butyl dicarbonate (885 mg, 4.06 mmol) was added
to a solution of 4a (642 mg, 2.03 mmol) in dry THF (15 mL). The solution
was refluxed for 3 hours. Then the solvent was evaporated under reduced
pressure. The residue was purified by chromatography with neutral
aluminum oxide (CHCl3/MeOH 100:0 to 90:10) to afford compound 5a as
a colourless oil (180 mg, 21%). 1H NMR (300 MHz, CDCl3, 25 °C, TMS): 
7.36 - 7.15 (m, 5H), 3.79 (m, 1H), 3.52 (s, 2H), 3.37 - 3.26 (m, 4H), 3.06 –
2.84 (m, 5H), 2.75 (m, 2H), 2,65 – 2.35 (m, 8H), 1.68 (m, 4H), 1.39 (m, 9H).
13C NMR Jmod (125 MHz, CDCl3, 25 °C, TMS):  155.8 (CO), 139.3 (CAr),
[128.8 (x2), 128.1 (x2), 126.8] (CHAr), 79.0 (Cquat Boc) 60.0 (CH2 α-Ph),
[53.0 (x2), 52.6 (x2), 52.4, 47.5, 46.9, 46.3 (x2), 45.4] (CH2 α-N), 28.4 (x3)
(CH3 t-Bu), [26.2, 25.0] (CH2 -N). ESI-HRMS (positive) m/z calcd. for
[C24H41N4O2]+ [M+H]+ 417.3223; found 417.3224.
Compound 6cNHBoc. Compound 5cNHBoc (510 mg, 0.82 mmol) was
dissolved in EtOH (20 mL) and 10% Pd/C-activated (280 mg) was added
to the solution. The mixture was stirred under a hydrogen atmosphere at
room temperature for 5 days and followed by HPLC-MS. Once the reaction
was completed, the mixture was filtrated through Celite and the solvent
was evaporated under reduced pressure to give the compound 6cNHBoc as
yellowish oil (401 mg, 95%). 1H NMR (300 MHz, CD3CN, 70 °C):  7.35 (d,
J = 9 Hz, 2H), 7.21 (d, J = 9 Hz, 2H), 3.53 (s, 2H), 3.44 – 3.17 (m, 4H),
3.10 – 2.90 (m, 4H), 2.90 – 2.28 (m, 5H), 2.58 – 2.25 (m, 6H), 2.20 – 1.96
(s, 3H), 1.84 (m, 2H), 1.49 (s, 9H), 1.44 (s, 9H). 13C NMR Jmod (75 MHz,
CD3CN, 70 °C):  [158.3, 154.6] (CO), [138.9, 135.4] (CAr), [130.9 (x2),
120.3 (x2)] (CHAr), [81.5, 80.8] (Cquat t-Bu), [59.7, 56.7, 54.3 (x3), 51.6 (x2),
49.4 (x3), 47.9] (CH2--N), 38.6 (CH2-PhNHBoc), 37.9 (CH β-N), 29.1
Compound 5bOBoc. Di-tert-butyl dicarbonate (181 mg, 0.80 mmol) was
added to a solution of 4b (144 mg, 0.40 mmol) in CH2Cl2 (7 mL) and Et3N
(61 μL, 0.80 mmol). The solution was stirred at room temperature for
2 hours and then the solvent was evaporated under reduced pressure. The
residue was dissolved in CH2Cl2 (5 mL) and washed with water (1 mL) to
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10.1002/ejoc.201901013
European Journal of Organic Chemistry
FULL PAPER
(CH3 Boc), 23.5 (CH2 β-N). ESI-HRMS (positive) m/z calcd. for
[C29H50N5O4]+ [M+H]+ 532.3857; found 532.3857.
www.ccdc.cam.ac.uk/data_request/cif. X-ray crystal structures were
visualized with the OLEX2 program.[29]
Compound A. Benzyl chloride (276 mg, 2.18 mmol) was added to a
solution of 4b (782 mg, 2.18 mmol) in THF (10 mL). The solution was
stirred at room temperature for 18 hours. The precipitate was filtered and
washed with THF. Compound A was obtained as a white powder (700 mg,
61%). 1H NMR (300 MHz, D2O, 25 °C, TMS):  7.67 – 7.18 (m, 10H), 4.63
– 4.38 (m, 2H), 4.09 – 3.90 (m, 1H), 3.78 – 3.20 (m, 10H), 3.16 – 2.65 (m,
12H), 2.62 – 2.48 (m, 1H), 2.34 – 2.20 (m, 1H), 2.15 – 1.87 (m, 2H), 1.63
– 1.42 (m, 2H). 13C NMR Jmod (75 MHz, CDCl3, 25 °C, TMS):  139.1 (CAr),
[136.1 (x2), 133.9, 133.2 (x2), 132.2 (x2), 131.8 (x2), 131.1] (CHAr), 129.3
(CAr), [67.9, 66.1, 64.2, 61.7, 59.6, 57.4, 57.1, 56.4, 55.6, 54.0, 50.7, 48.8,
47.0, 35.6] (CH2 α-N), 32.3 (CH -N), 24.2 (CH2 -N).
DFT calculations. All DFT calculations were carried out with the Gaussian
09 program package[30] within the hybrid meta-GGA aproximation to
density functional theory with the TPSSh exchange-correlation
functional[31] and the Def2-TZVP[32] basis set. Analytical frequency
calculations were used to confirm the nature of the stationary points
obtained from geometry optimizations as true energy minima. An ultrafine
integration grid (integral=ultrafine) was used in all calculations.
Electrostatic potentials were calculated at the TPSSh/Def2-TZVP level and
mapped on the molecular surfaces defined by 0.001 electrons·bohr-3
contours of the electron density, as suggested by Bader [33]
Single crystal X-ray diffraction measurements. Single-crystal X-ray
diffraction data were collected at 170 K on an X-CALIBUR-2 CCD 4-circle
diffractometer (Oxford Diffraction) with graphite monochromatized MoKα
radiation (λ = 0.71073). Crystal data and structure refinement details are
given in Table 1. Unit-cell determination and data reduction, including
interframe scaling, Lorentz, polarization, empirical absorption, and
detector sensitivity corrections, were carried out using attached programs
of Crysalis software (Oxford Diffraction).[27] Structures were solved by
direct methods and refined by the full matrix least-squares method on F2
with the SHELXL[28] suite of programs. The hydrogen atoms were identified
at the last step and refined under geometrical restraints and isotropic U-
constraints. CCDC numbers CCDC numbers 1923020 (4b), 1923019 (4c),
1937279 (4b·HCl), 1937444 (A) contain the supplementary
crystallographic data for this paper. These data can be obtained free of
charge from the Cambridge Crystallographic Data Centre via
Acknowledgments
R.T. and N.L.B. acknowledge the Ministꢀre de l’Enseignement
Supꢁrieur et de la Recherche, the Centre National de la
Recherche Scientifique and the “Service Commun” of NMR
facilities of the University of Brest. R.T., N.L.B. and T.L.B. thank
the “Ligue Contre le Cancer” for the three years fellowship. C. P.-
I. thanks Centro de Supercomputación de Galicia (CESGA) for
providing the computer facilities.
Table 1. Crystal data and structure refinement details for 4b, 4c, 4b·HCl and A.
4c
4b.HCl
A
Identification code
4b
C26H41N5O4
487.64
297(2)
C21H41ClN4O3
433.03
170(2)
C28H50Cl2N4O4
577.62
170(2)
Empirical formula
Formula weight
Temperature / K
C21H40N4O3
396.57
297(2)
0.71073
Triclinic
̅
P1
0.71073
Monoclinic
P21/n
8.9213(5)
18.4395(13)
14.5484(8)
90.00
90.894(5)
90.00
2393.0(3)
4
0.71073
Triclinic
̅
P1
0.71073
Triclinic
̅
P1
Wavelength , Å (MoK)
Crystal system
Space group
a/Å
b/Å
c/Å
/deg
/deg
9.9100(6)
13.8912(7)
18.5111(11)
70.819(5)
76.684(5)
84.396(5)
2341.4(2)
4
9.5999(11)
12.3752(16)
13.4556(16)
62.645(13)
78.991(10)
87.123(10)
1392.4(3)
2
9.443(2)
10.316(2)
16.290(4)
88.897(17)
74.71(2)
80.210(18)
1507.9(6)
2
/deg
v/Å3
Z
Dcalc/g cm-3
/mm-1
F(0,0,0)
1.125
0.076
872
1.163
0.079
528
1.202
0.187
944
1.272
0.254
624
3
0.19 x 0.17 x 0.11
0.20 x 0.10 x 0.01
0.40 x 0.30 x 0.15
0.25 x 0.20 x 0.10
Crystal size / mm
3.51 to 26.37
-11≤h≤11,
-12≤k≤15,
-16≤l≤16
3.597 to 23.80
-11≤h≤11,
-23≤k≤22,
-18≤l≤16
2.90 to 20.44
-8≤h≤8,
-9≤k≤9,
-14≤l<14
0.286
3.11 to 26.37
-11≤h≤12,
-16≤k≤17,
-23≤l≤23
 range/deg
Index ranges
0.0574
0.1067
R(int)
0.0427
10102
5605
4883
3082
6749
1875
Reflections collected
Unique reflns
18194
9549
99.8%
0.9797 and 0.6233
1.025
62.5%
0.9987 and 0.9665
0.903
Completeness to  = 25.242°
Max. and min. transmission
GOF on F2
99.6%
0.9888 and 0.9704
0.855
98.5%
0.9921 and 0.9804
0.869
5605 /14 /340
4883 / 11 / 283
R1 = 0.0610
wR2 = 0.1224
R1 = 0.1185
wR2 = 0.1525
0.399 and -0.290
1875 / 65 / 304
R1 = 0.0831
wR2 = 0.1433
R1 = 0.2432
wR2 = 0.1884
0.298 and -0.216
Data / restraints / parameters
Final R indices [I>2sigma(I)] a
9549 / 23 / 541
R1 = 0.052
wR2 = 0.0909
R1 = 0.149
wR2 = 0.1126
0.252 and -0.187
R1 = 0.0557
wR2 = 0.0860
R1 = 0.1952
wR2 = 0.1190
00157 and -0.135
4
R indices (all data)b
Largest diff. peak and hole / e.Å-3
a R1 = F0-Fc/ F0. b wR2 = [w(F02-Fc2)2]/[ w(F0 )]1/2
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201901013
European Journal of Organic Chemistry
FULL PAPER
Rheingold, J. Am. Chem. Soc. 2000, 122, 10561–10572.
Keywords: cyclam
•
side-bridged
•
constrained
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10.1002/ejoc.201901013
European Journal of Organic Chemistry
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We have developed
a
general
Constrained tetraazamacrocycles
procedure to obtain orthogonally
N-protected side-bridged cyclams
with a benzyl or a Boc group. Such
methodology is especially possible
on C-functionalized macrocycles.
Despite the lack of symmetry of these
compounds, this strategy allows the
specific protection of one or the other
remaining secondary amine function.
C- and N-functionalization
T. Le Bihan, N. Le Bris*, H. Bernard,
C. Platas-Iglesias, R. Tripier*
Page No. – Page No.
Synthesis of Orthogonal N-Protected
C-functional Side-Bridged Cyclams
to give access to unsymmetrical
constrained BCAs
C-functionalized side-bridged cyclams
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