Selectively functionalized constrained polyazamacrocycles: Building blocks for multifunctional chelating agents

Article abstract of DOI:10.1002/ejoc.201201337

A new class of cross-bridged and side-bridged 1,4,7,10- tetraazacyclotridecanes (homocyclens) bearing an aminomethyl pendant arm on the carbon skeleton has been prepared. The regioselectivity of the quaternization of the bis-aminal intermediates is discus

Full text of DOI:10.1002/ejoc.201201337

FULL PAPER
DOI: 10.1002/ejoc.201201337
Selectively Functionalized Constrained Polyazamacrocycles: Building Blocks
for Multifunctional Chelating Agents
Pauline Désogère,[a] Claire Bernhard,[a] Christine Goze,[a] Marie-José Penouilh,[a]
Yoann Rousselin,[a] and Franck Denat*[a]
Keywords: Ligand design / Chelates / Macrocyclic ligands / Cage compounds / Amines / Copper
A new class of cross-bridged and side-bridged 1,4,7,10-tetra- mediates is discussed on the basis of X-ray diffraction and
azacyclotridecanes (homocyclens) bearing an aminomethyl
pendant arm on the carbon skeleton has been prepared. The
regioselectivity of the quaternization of the bis-aminal inter-
NMR experiments. These new polyazamacrocycles are valu-
able precursors of bifunctional chelating agents for applica-
tions in nuclear medicine.
volves harsh conditions that are incompatible with fragile
biomolecules such as antibodies.[2] To overcome this prob-
lem, the synthesis of new constrained ligands based on
homocyclen was developed (Figure 1) and it has been
shown that the metalation can be performed at room tem-
perature, which is convenient for biomolecule labeling.[5]
Introduction
Bioconjugated radiopharmaceuticals are currently under
intense investigation for their potential applications in tar-
get-directed molecular imaging such as single photon emis-
sion computed tomography (SPECT) and positron emission
tomography (PET), and cancer radioimmunotherapy. These
bioconjugates represent efficient tools for target-specific de-
livery of radionuclides to cancer tissues.[1] Metal radio-
nuclides have gained considerable interest for diagnostic
and therapeutic applications. The most reliable and most
frequently used method for linking the metal ion (111In,
67/68Ga, 64Cu, 89Zr) to the biomolecule is to use a bifunc-
tional chelating agent (BFCA), which forms a stable com-
plex and enables covalent attachment to the biological mo-
lecule. In particular, 64Cu is an attractive radionuclide for Figure 1. General structures of compounds L1 and L2.
PET imaging due to the favorable characteristics of the iso-
tope [t1/2 = 12.7 h, β+ = 0.655 MeV (17.8%)] and its avail-
These promising properties have led to the synthesis of
ability with high specific activity.[2] Increased use of 64Cu new BFCAs based on constrained homocyclens, which can
for PET imaging, as well as 67Cu for radiotherapy, has cre- be accomplished using well-established methods of selective
atedaneedforfinelydesignedligandssuchasmacrocyclicpoly- N- and C-functionalization.[6] The C-functionalization ap-
amines that present excellent complexation properties. proach enables attachment of the targeting biomolecule to
BFCAs containing topologically constrained azamacro- a carbon atom of the macrocyclic BFCA. Thus, all nitrogen
cycles such as side-bridged (SB) and cross-bridged (CB) cy- atoms remain available for further introduction of coordi-
clams have recently been developed.[3] Their pendant-armed nating pendant arms. This approach also avoids the
derivatives have been especially useful in endowing copper multistep synthesis of a sophisticated pendant arm bearing
complexes with remarkable kinetic inertness and high both a chelating group and a grafting functionality. Our
thermodynamic stability.[4] Moreover, the resulting Cu com- group has recently developed a strategy for the preparation
plexes seem to be resistant to CuII reduction in vivo. How- of C-functionalized homocyclens that is based on the use
ever, in most cases, the radiolabeling of such ligands in- of a bis-aminal moiety acting both as a template and as a
protecting group.[6c] Therefore, we decided to use this con-
[a] Institut de Chimie Moléculaire de l’Université de Bourgogne,
UMR CNRS 6302, Université de Bourgogne,
9, Av. Alain Savary, 21078 Dijon, France
Fax: +33-3-80396117
venient method for the preparation of new C-functionalized
side-bridged and cross-bridged homocyclens. We report
here a powerful route for the synthesis of new macrocyclic
tetraamines L1 and L2 bearing an additional aminomethyl
group on the carbon skeleton in both side-bridged and
cross-bridged homocyclen series (Figure 1).
E-mail: franck.denat@u-bourgogne.fr
Homepage: www.icmub.fr
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201201337.
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Functionalized Constrained Polyazamacrocycles
The selectivity of the cyclization of the bisaminal inter-
mediates with biselectrophilic reagents and the selective
quaternization of the protected macrocycles are discussed
on the basis of X-ray structure determinations, NMR mea-
surements and molecular modeling calculations.
Results and Discussion
The bis-aminal route has been widely used in the last
decade to prepare macrocyclic tetraamines, in particular
constrained macrocycles.[7] This method provides macro-
cycles in good yield without requiring high dilution condi-
tions or metal cation templates.
The bis-aminal compound was synthesized by rigidifica-
tion of the starting linear tetraamine with glyoxal
(Scheme 1).[7a–7c] The condensation of chloroacetaldehyde
with the resulting bis-aminal in the presence of benzotri-
azole and potassium carbonate in acetonitrile gave the cor-
responding cyclic adducts, which were not isolated. The
benzotriazole was then displaced by sodium cyanide. Sev-
eral stereoisomers can be expected due to the presence of
many chiral centers, i.e., the nitrogen and carbon atoms of
the aminal bridge, as well as the carbon atom bearing the
nitrile group. Interestingly, we obtained a mixture of only
two diastereoisomers 1 and 1Ј, which could be separated by
recrystallization in cyclohexane. However, only dia-
stereoisomer 1 was obtained with sufficient purity to be
used in further reactions. The orientation of the nitrile
group and of aminal hydrogen atoms in 1 was determined
from the X-ray structures obtained after quaternization re-
action of 1 (see below).
Scheme 2. Reagents and conditions: (a) BnBr (1 equiv.), toluene,
room temp., 24 h; (b) BnBr (10 equiv.), CH3CN, 1% H2O, room
temp., 10 d; (c) NaBH4 (15 equiv.), EtOH, 0 °C, 12 h.
precipitate formed during the reaction, showing that 2 is
the sole product of the reaction (see the Supporting Infor-
mation).
Figure 2. ORTEP[9] view of 2. Thermal ellipsoids are drawn at 50%
probability. Solvent molecules are not shown for clarity.[10]
The regioselective quaternization reaction on N1 can be
highlighted by comparison of the thermodynamic stability
of the four potential regioisomers. Thus, DFT calculations
were performed by varying the position and the orientation
Scheme 1. Reagents and conditions: (a) EtOH, 0 °C, 2 h; (b) chloro-
acetaldehyde, benzotriazole, K2CO3, CH3CN, 0 °C, 2 h; NaCN,
room temp., 12 h.
The addition of one equivalent of benzyl bromide to 1 of the benzyl group. The results revealed that the most ther-
was performed in toluene to precipitate the mono-N-alkyl- modynamically stable products arose from N1 and N3
ated cationic compounds (Scheme 2).[7e–7g]
quaternization (see the Supporting Information).
The monoquaternization of 1 can lead to the formation
The difference of values between N1 and N3 quaterni-
of four potential regioisomers obtained upon alkylation of zation is not significant and at this stage and the thermo-
N1, N2, N3 or N4. The reaction led to the formation of 2, dynamic aspect cannot explain the selective formation of 2.
which was isolated by filtration after 24 h in 85% yield; the To gain further insight into the regioselectivity, we studied
remaining 15% corresponded to starting material. The mo- the kinetic aspects of the reaction, by evaluating the accessi-
lecule could be recrystallized from acetonitrile and its struc- bility of the lone pair on the N1 and N3 nitrogen atoms of
ture was elucidated by X-ray diffraction (Figure 2). The the starting compound 1 by molecular modeling calcula-
crystal structure indicated that 2 results from N1 quaterni- tions. The values of C–N1–C angles and of the distance
zation and that the nitrile group and the aminal hydrogen between N1 and the mean plane formed by the three carbon
atoms point in the same direction. Moreover, the NMR atoms C1, C2 and C3 are reported in Table 1. N1 is in-
spectrum of the crystals is superimposable with that of the volved in both a five- and a six-membered rings and pres-
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F. Denat et al.
FULL PAPER
ents a classical trigonal pyramidal geometry (AX3E accord- scopic analysis (see Figure S15 to S20 in the Supporting
1
ing to VSEPR theory). The data reveal that N3, which is Information). The H NMR spectrum exhibits signals that
engaged in two six-membered rings, is closer to the are characteristic of the presence of terminal ethylenic pro-
(C4C5C6) plane. Taken together, these data show a higher tons (δ = 4.57 and 4.71 ppm), and the 13C NMR spectrum
accessibility of the lone pair on N1 than on N3 and confirm indicates the presence of a nitrile group (δ = 116.1 ppm)
that compound 2 is the kinetic product.
and confirms the presence of a double bond with a terminal
CH2 group (δ = 99.2 ppm). Moreover, analysis of the IR
spectrum revealed an absorption band at 2230 cm–1, which
is typical of the nitrile group. Another band is present at
1582 cm–1, which is characteristic of a conjugated carbon–
carbon double bond. The formation of the acrylonitrile
moiety could be explained by the removal of the acidic pro-
ton α to the nitrile by the hydride acting as a base, followed
by the formation of the carbon–carbon double bond and
cleavage of the carbon–nitrogen bond (Scheme 3).
Table 1. Angles [°] and distances [Å] in 1 obtained from molecular
modeling calculations.
Angles or distance
Angles or distance
C1–N1–C2
C1–N1–C3
C2–N1–C3
(C1C2C3) to N1
112.62
111.91
102.24
0.500
C4–N3–C5
C4–N3–C6
C5–N3–C6
(C4C5C6) to N3
113.76
113.87
109.98
0.409
Scheme 3. Proposed mechanism for the formation of 4.
Unfortunately, the addition of a large excess of NaBH4
to 3 did not yield the expected cross-bridged homocyclen 5,
We then investigated the di-quaternization reaction of 1
by adding a large excess of benzyl bromide (10 equiv.) to 1
in an acetonitrile/water mixture.[7f] Under these conditions,
3 was isolated in 76% yield after ten days at room tempera-
ture (Scheme 2).
The crystal structure of 3 is shown in Figure 3 and re-
veals that quaternization occurred on both N1 and N3. The
trans selectivity of the di-quaternization reaction of aminal
derivatives has been previously reported.[7e–8]
Figure 3. ORTEP[9] view of 3. Thermal ellipsoids are drawn at 50%
probability. Water molecules are not shown for clarity.[10]
Treatment of 2 with a large excess of NaBH4 in ethanol
did not result in double reductive ring expansion, but led
almost quantitatively to the formation of an unexpected
compound containing an acrylonitrile moiety (4;
Scheme 4. Reagents and conditions: (a) LiAH4 (1.1 equiv.), THF,
room temp., 12 h; (b) Boc2O (1 equiv.), CH2Cl2, room temp., 12 h;
(c) BnBr (1 equiv.), toluene, room temp., 5 d; (d) BnBr (10 equiv.),
Scheme 2). The structure of 4 was determined by spectro- CH3CN, 1% H2O, room temp., 7 d.
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Functionalized Constrained Polyazamacrocycles
but instead led to the formation of a mixture of products
that we were not able to separate or identify. To overcome
these issues, we decided to reduce the nitrile group prior to
quaternization reactions. The nitrile group was easily re-
duced to the primary amine using LiAlH4 to give 6 in 80%
yield (Scheme 4). The primary amine was then protected by
a Boc group, leading to 7 in 84% yield. Monoalkylation of
the latter was performed in toluene by reaction with one
equivalent of benzyl bromide. The resulting precipitate was
isolated in 94% yield and appeared to be composed of a
mixture of two regioisomers 8 and 8Ј, in a 65:35 ratio on
the basis of 1H NMR spectroscopic analysis (see Figure S27
in the Supporting Information). The regioisomer 8 could
be recrystallized from acetonitrile and its structure was es-
tablished by X-ray diffraction analysis (Figure 4).
The structure revealed that the major product resulted
from N1-alkylation, as in the case of 1. However, in this
case, the action of the electrophilic group on bis-aminal 7
was not 100% regioselective and led to a mixture of N1-
and N3-quaternized compounds 8 and 8Ј (Scheme 4). This
Figure 4. ORTEP[9] view of 8. Thermal ellipsoids are drawn at 50%
probability. Solvent molecules are not shown for clarity.[10]
Addition of a large excess of benzyl bromide to 7 in an
can be explained by the presence of the bulky Boc group, acetonitrile/water mixture gave access to the diquaternized
which reduces the accessibility of the lone pair on N1. bis-aminal 9 in 85% after seven days at room temperature.
Scheme 5. Reagents and conditions: (a) NaBH4 (10 equiv.), EtOH, room temp., 12 h; (b) HCl (3 m), room temp., 1 h; (c) H2 (1 equiv.),
Pd/C (0.04 equiv.), CH3COOH, H2O, room temp., 12 h; (d) H2 (1 equiv.), Pd/C (0.04 equiv.), CH3COOH, H2O, room temp., 12 h; (e)
HCl (3 m), room temp., 1 h; (f) NaBH4 (5 equiv.), EtOH, room temp., 12 h; (g) HCl (3 m), room temp., 1 h; (h) H2 (2 equiv.), Pd/C
(0.04 equiv.), CH3COOH, H2O, room temp. 12 h; (i) H2 (2 equiv.), Pd/C (0.04 equiv.), CH3COOH, H2O, room temp., 12 h; (j) HCl (3 m),
room temp., 1 h.
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The addition of NaBH4 to 8 and 9 in ethanol at room
temperature led, respectively, to the expected protected side-
bridged 10 and cross-bridged homocyclens 14 in 83 and
79% yield (Scheme 5). Selective deprotection reactions were
performed in both side-bridged and cross-bridged series.
The Boc protecting group was cleaved under acidic condi-
tions to give 11 and 15 in good yield, whereas benzyl groups
were deprotected through catalytic hydrogenation to form
12 and 16. Such selective deprotection reactions allow the
nitrogen atoms to be discriminated and enable the selective
introduction of various functional groups on the molecule.
The preparation of partially functionalized macrocycles is
of great interest because such derivatives are valuable bi-
functional chelating agents precursors. To obtain BFCAs,
the macrocyclic unit must comprise both a grafting func-
tion, which allows covalent binding to the targeting vector,
and coordinating sites such as carboxylate, phosphonate or
phosphinate groups.
Experimental Section
General: All analyses were performed at the “Plateforme d’Ana-
lyses Chimiques et de Synthèse Moléculaire de l’Université de
Bourgogne”. Infrared spectra were recorded with 1% sample mixed
1
with potassium bromide. H and 13C NMR spectra were recorded
at room temperature, 250 K or 220 K with 300, 500 or 600 spec-
trometers using perdeuterated solvents as internal standard.
COSY{1H-1H}, HMQC{1H-13C} experiments were recorded at
600 MHz (220, 250 and 300 K in CDCl3). Mass spectra were ob-
tained in the MALDI/TOF reflectron mode using dithranol as a
matrix or by ESI with an Orbitrap spectrometer. HRMS was per-
formed by ESI with an Orbitrap as analyzer.
Computational Methods: Structures 1 and potential isomers of 2
were computed by using hybrid density functional theory (B3LYP)
and the 6-31G** basic set, as implemented in Jaguar 5.5, release
16.5. All gas-phase minima were characterized by frequency analy-
sis.
Chemical and Reagents: All chemicals and solvents were used with-
out further purification.
Compounds 12, 15 and 16 are particularly promising
building blocks for the synthesis of new BFCAs. In com-
pounds 12 and 16, a Boc group protects the pendant pri-
mary amine so that coordinating pendant arms can be se-
Compounds 1 and 1Ј: A solution of 40% glyoxal in water (169.5 g,
1.17 mol) in ethanol (0.7 L) was added to a solution of N,N-bis-
(aminoethyl)propane-1,3-diamine (187.2 g, 1.17 mol) in ethanol
lectively introduced on the secondary amines of the cycle. (2 L) at 0 °C. After stirring at this temperature for 2 h, the solvent
was evaporated and the colorless oil was dissolved in ethanol
(300 mL) and acetonitrile (3.8 L). Benzotriazole (139.3 g, 1.17 mol)
and potassium carbonate (161.7 g, 1.17 mol) were added, then a
solution of 50% chloroacetaldehyde in water (183.7 g, 1.17 mol)
was slowly added at 0 °C and the resulting mixture was stirred for
2 h. Sodium cyanide (49.0 g, 1.17 mol) was then added and the
mixture was stirred overnight at room temperature. The solution
was filtered through Celite and the solid was washed with acetoni-
trile (500 mL). The filtrate was evaporated and the resulting solid
was taken in dichloromethane (1 L). After filtration, the organic
phase was washed with 3 m NaOH (2 ϫ 600 mL), dried with
MgSO4 and the solvent was evaporated. The residual brown solid
was purified by aluminum oxide chromatography (CH2Cl2) to give
a mixture of 1 and 1Ј as a white powder (114.5 g, 42%), m.p. 71–
73 °C. MS (ESI): m/z (1 and 1Ј ) = 234.17 [M + H]+. HRMS (ESI):
m/z calcd. for C12H19N5 + H 234.1713; found 234.1718. Dia-
stereoisomer 1 was recrystallized from cyclohexane. 1H NMR
(600 MHz, D2O, 300 K): δ = 1.20–1.25 (m, 1 H), 2.08–3.52 (m, 17
H), 3.95–3.97 (m, 1 H) ppm. 13C{1H} NMR (150 MHz, CDCl3,
250 K): δ = 19.8 (CH2β), 44.9, 46.2, 49.0, 49.5, 52.0, 52.8, 54.8
(CH2), 57.5 (CH), 75.2, 75.4 (NCN), 117.3 (CN) ppm. Elemental
In the case of 15, the primary amine can be selectively func-
tionalized to introduce a grafting function prior to debenz-
ylation and introduction of pendant coordinating arms. Af-
ter cleavage of the remaining protecting group, ami-
nomethyl side-bridged 13 and cross-bridged 17 homocy-
clens were isolated in more than 80% yield. These C-
aminomethyl reinforced macrocycles represent a new class
of ligands that may exhibit original chelating properties
towards metal cations.
Conclusions
The method reported herein represents a very powerful
route towards selectively functionalized reinforced homocy-
clens and, indirectly, toward new BFCAs based on these
macrocycles. The use of a bis-aminal bridge is the key point
of this method and presents two main advantages. It en-
ables the cyclization reaction by rigidification of the linear analysis calcd. for C12H19N5 C 61.77, H 8.21, N 30.02; found
C 61.80, H 8.31, N 29.64.
tetraamine through an “organic template effect” and gives
access to reinforced macrocycles after reductive ring expan-
sion.
Compound 2: Benzyl bromide (146 mg, 0.85 mmol) was added to a
solution of 1 (200 mg, 0.85 mmol) in acetonitrile (3 mL). After
24 h, the resulting precipitate was filtered, washed with CH3CN
Moreover, the method is highly regioselective. If two dia-
stereoisomers are formed during the reaction, they can be (30 mL) and recrystallized from methanol to give 2 as a white pow-
der (290 mg, 85%), m.p. 190–191 °C (dec.). 1H NMR (600 MHz,
easily separated by recrystallization. These new amino-
methyl constrained macrocycles are valuable precursors of
D2O, 300 K): δ = 1.53–1.55 (m, 1 H, CaH2), 2.18–2.26 (m, 1 H,
CaH2), 2.60–2.65 (m, 1 H, CiH2), 2.69–2.73 (m, 1 H, CcH2), 2.75–
new bifunctional chelating agents for labeling biomolecules.
2.81 (m, 1 H, CdH2), 2.90–2.95 (m, 1 H, ChH2), 3.08–3.16 (m, 4 H,
Indeed, the two secondary amine groups of the ring can
ChH2, CiH2, CbH2, CbH2), 3.29–3.32 (m, 1 H, CdH2), 3.49–3.54 (m,
be further functionalized with pendant coordinating arms.
1 H, CcH2), 3.65–3.70 (m, 1 H, CgH2), 3.72–3.78 (m, 1 H, CgH2),
Concerning the primary amine, it is available for the intro-
duction of a grafting function towards biomolecule cou-
pling. The functionalization of these homocyclens and the
study of their coordination properties are being investigated
in our group.
4.00–4.08 (m, 2 H, CkH, CfH2), 4.25–4.26 (m, 1 H, CjH), 4.48 (dd,
3
2
3
2J = 13.4, J = 3.3 Hz, 1 H, CfH2), 4.90 (dd, J = 8.3, J = 3.3 Hz,
1 H, CeH), 4.98 (d, 2J = 13.4 Hz, 1 H, CmH2), 5.02 (d, 2J = 13.4 Hz,
1 H, CmH2), 7.59–7.68 (m, 5 H) ppm. 13C{1H} NMR (150 MHz,
D2O, 300 K): δ = 18.6 (CaH2), 42.2 (CcH2), 46.3 (CdH2), 46.9
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Functionalized Constrained Polyazamacrocycles
(ChH2), 50.1 (CeH), 51.4 (CbH2), 53.4 (CiH2), 57.6 (CgH2), 61.6 temperature. After evaporation of the solvent, the residual oil was
(CmH2), 62.8 (CfH2), 70.6 (CjH), 78.8 (CkH), 114.0 (ClN), 126.0 purified by aluminum oxide chromatography (CH2Cl2) to give 7 as
1
(CHar), 129.9 (ϫ2) (CHar), 131.5 (Car), 132.7 (ϫ2) (CHar) ppm. MS a yellow oil (105.2 g, 80%). H NMR (500 MHz, CDCl3, 300 K):
(ESI): m/z = 324.22 [M – Br]+. HRMS (ESI): m/z calcd. for
C19H26N5 324.2182; found 324.2179. Elemental analysis calcd. for
C19H26BrN5 C 56.44, H 6.48, N 17.32; found C 56.12, H 6.43, N
17.16.
δ = 1.18–1.24 (m, 1 H, CH2β), 1.40 (s, 9 H, CH3), 1.62–1.72 (m, 1
H), 1.98–2.28 (m, 4 H), 2.36–2.42 (m, 1 H), 2.50–2.57 (m, 1 H),
3
2.58–2.62 (m, 1 H), 2.77–2.84 (m, 1 H), 2.80 (d, J = 2.5 Hz, 1 H,
N-CH-N), 2.86–3.01 (m, 5 H), 3.02–3.09 (m, 1 H), 3.10–3.20 (m, 1
3
H), 3.27 (d, J = 2.5 Hz, 1 H, N-CH-N), 3.33–3.43 (m, 2 H), 5.00
Compound 3: Benzyl bromide (4.4 g, 25.7 mmol) was added to a
solution of 1 (600 mg, 2.57 mmol) in acetonitrile (9 mL). The solu-
tion was stirred at room temperature for 10 d. The precipitate that
was formed during the reaction was filtered, washed with CH3CN
(30 mL) and recrystallized from water to give 3 as a white solid
(br. s, 1 H, NHC=O) ppm. 13C{1H} NMR (125 MHz, CDCl3,
300 K): δ = 20.3 (CH2β), 28.6 (ϫ3) (CH3), 43.9, 45.9, 50.4, 51.3,
52.5, 53.4, 54.7, 55.3 (CH2), 64.4 (CH), 76.3, 76.4 (NCN), 79.3 (C),
156.2 (C=O) ppm. MS (ESI): m/z = 338.25 [M + H]+, 360.23 [M
+ Na]+. HRMS (ESI): m/z calcd. for C17H31N5O2 + H 338.2551;
found 338.2553.
1
(1.12 g, 76%), m.p. 120–121 °C (dec.). H NMR (300 MHz, D2O,
300 K): δ = 1.80–1.95 (m, 1 H), 2.18–2.34 (m, 1 H), 2.66–2.83 (m,
1 H), 3.10–3.30 (m, 2 H), 3.34–3.57 (m, 4 H), 3.66–3.96 (m, 4 H),
4.08–4.20 (m, 1 H), 4.53–4.67 (m, 2 H), 4.72–4.73 (m, 1 H), 4.89–
5.03 (m, 2 H), 5.05–5.24 (m, 3 H), 5.41–5.44 (m, 1 H), 7.52–7.69
(m, 10 H) ppm. 13C{1H} NMR (75 MHz, D2O, 300 K): δ = 21.0
(CH2β), 42.8, 49.0, 49.7 (CH2), 50.5 (CH), 53.2, 55.0, 63.4, 63.7,
63.8, 65.1 (CH2), 77.5, 80.6 (NCN), 116.8 (CN), 127.1, 127.8 (Car),
132.1 (ϫ2), 132.4 (ϫ2) (CHar), 134.0, 134.2 (Car), 134.8 (ϫ2), 135.8
(ϫ2) (CHar) ppm. MS (ESI): m/z = 414.12 [M – 2Br – H]+, 496.19
[M Br]+. HRMS (ESI): m/z calcd. for C26H33N5-H 414.2652; found
414.2650. Elemental analysis calcd. for C26H33Br2N5·3H2O·
3CH3OH C 49.61, H 6.25, N 11.13; found C 49.37, H 6.42, N
11.08.
Compounds 8 and 8Ј: Benzyl bromide (30.8 g, 0.18 mol) was added
to a solution of 7 (62.1 g, 0.18 mol) in toluene (615 mL), and the
solution was stirred at room temperature for 5 d. The precipitate
that was formed during the reaction was filtered, washed with tolu-
ene (300 mL) and diethyl ether (300 mL) to give a mixture of 8 and
8Ј as a white solid (86.0 g, 94%). MS (ESI): m/z = 428.32 [M –
Br]+. HRMS (ESI): m/z calcd. for C24H38N5O2 428.3020; found
428.3013. The regioisomers 8 and 8Ј can be separated by recrystalli-
zation in acetonitrile.
Compound 8: M.p. 146–148 °C (dec.). 1H NMR (300 MHz, D2O,
300 K): δ = 1.49 (s, 9 H, CH3), 1.52–1.56 (m, 1 H, CH2β), 2.18–
2.32 (m, 1 H), 2.58–2.68 (m, 2 H), 2.86–2.97 (m, 2 H), 3.05–3.87
2
(m, 13 H), 4.11–4.12 (m, 1 H), 4.19 (s, 1 H), 4.72 (d, J = 13.2 Hz,
Compound 4: NaBH4 (280 mg, 7.42 mmol) was added to a suspen-
sion of 2 (200 mg, 0.495 mmol) in a mixture of ethanol/water
(5 mL, 95:5) and the solution was stirred at 0 °C overnight. The
solvent was evaporated to give a white solid, CH2Cl2 (10 mL) was
added and the insoluble salts were removed by filtration. The sol-
vent was evaporated to give 4 as a white powder (152 mg, 95%),
m.p. 85–86 °C (dec.). 1H NMR (600 MHz, CDCl3, 220 K): δ = 1.21
(m, 1 H, CH2β), 2.06–2.30 (m, 5 H), 2.61–2.67 (m, 2 H), 2.74–2.80
(m, 2 H), 2.86–2.98 (m, 2 H), 3.18–3.19 (m, 1 H, N-CH-N), 3.20–
3.33 (m, 2 H), 3.61–3.71 (m, 1 H), 3.84–3.86 (m, 1 H, N-CH-N),
4.05 (m, 1 H), 4.57 (d, 2J = 2.1 Hz, 1 H, C=CH2), 4.71 (d, 2J =
2.1 Hz, 1 H, C=CH2), 7.14–7.33 (m, 5 H) ppm. 13C{1H} NMR
(150 MHz, CDCl3, 220 K): δ = 19.3 (CH2β), 40.9, 44.5, 50.7, 51.8,
52.2, 56.4, 56.8 (CH2), 74.1, 75.9 (NCN), 99.2 (C=CH2), 116.1
(CN), 127.1 (C=CH2), 127.2 (CHar), 128.5 (ϫ2) (CHar), 129.5 (ϫ2)
(CHar), 137.5 (Car) ppm. MS (ESI): m/z = 324.22 [M + H]+. HRMS
(ESI): m/z calcd. for C19H25N5 + H 324.2182; found 324.2177. IR:
2
1 H, CH2Ph), 5.04 (d, J = 13.2 Hz, 1 H, CH2Ph), 7.60–7.62 (m, 5
H, CHar) ppm. 13C{1H} NMR (75 MHz, D2O, 300 K): δ = 18.6
(CH2β), 27.7 (ϫ3) (CH3), 39.1, 42.9, 43.8, 46.5, 51.3, 53.3, 53.9
(CH2), 54.6 (CH), 61.1, 63.2 (CH2), 70.8, 79.6 (NCN), 81.6 (C),
126.3 (Car), 129.6 (ϫ2), 131.2, 132.5 (ϫ2) (CHar), 158.1
(C=O) ppm.
1
Compound 8Ј: M.p. 151–153 °C (dec.). H NMR (300 MHz, D2O,
300 K): δ = 1.49 (s, 9 H, CH3), 1.84–1.90 (m, 1 H, CH2β), 2.13–
2.30 (m, 2 H), 2.38–2.47 (m, 1 H), 2.50–2.60 (m, 1 H), 2.81–2.85
(m, 1 H), 2.92–3.47 (m, 10 H), 3.58–3.72 (m, 2 H), 4.10–4.14 (m,
2
2
3 H), 4.76 (d, J = 13.3 Hz, 1 H, CH2Ph), 5.11 (d, J = 13.3 Hz, 1
H, CH2Ph), 7.59–7.68 (m, 5 H, CHar) ppm. 13C{1H} NMR
(150 MHz, D2O, 300 K): δ = 18.4 (CH2β), 27.2 (ϫ3) (CH3), 42.4,
43.0, 47.7, 49.6, 50.6, 52.0, 52.1, 59.4, 62.7 (CH2), 63.2 (CH), 68.7
(NCN), 80.8 (C), 81.4 (NCN), 125.1 (Car), 128.9 (ϫ2), 130.7, 132.9
(ϫ2) (CHar), 157.8 (C=O) ppm.
ν = 1582 (C=C), 2230 (CN) cm–1.
˜
Compound 9: Benzyl bromide (34.6 g, 0.20 mol) was added to a
solution of 8 (6.8 g, 20.3 mmol) in acetonitrile (200 mL) and water
(10 mL), and the solution was stirred at room temperature for 7 d.
The precipitate formed during the reaction was filtered, washed
with acetonitrile (150 mL) and diethyl ether (150 mL) to give 9 as
a white solid (4.98 g, 95%), m.p. 123–124 °C. 1H NMR (300 MHz,
D2O, 300 K): δ = 1.32 (s, 9 H, CH3), 1.83–1.90 (m, 1 H, CH2β),
2.21–2.26 (m, 1 H, CH2β), 2.68–2.77 (m, 1 H), 3.10–4.00 (m, 16
H), 4.26–4.35 (m, 1 H), 4.57–4.60 (m, 1 H), 4.76–4.84 (m, 2 H),
4.93–5.04 (m, 2 H), 7.53–7.63 (m, 10 H, CHar) ppm. 13C{1H} NMR
(125 MHz, D2O, 300 K): δ = 18.6 (CH2β), 27.6 (ϫ3) (CH3), 39.1,
39.8, 46.1, 47.5, 50.7, 51.7 (CH2), 55.7 (CH), 60.5, 60.6, 62.2, 62.8
(CH2), 75.1, 78.5 (NCN), 81.7 (C), 124.8, 125.7 (Car), 129.5 (ϫ2),
129.8 (ϫ2), 131.4, 131.6, 132.4 (ϫ2), 133.3 (ϫ2) (CHar), 157.9
(C=O) ppm. MS (ESI): m/z = 259.68 [M – 2Br]2+. HRMS (ESI):
m/z calcd. for C31H45N5O2 [M – 2Br]2+ 259.6781; found 259.6772.
Compound 6: A solution of 1 (90.2 g, 0.39 mmol) in anhydrous
THF (300 mL) was slowly added to a suspension of LiAlH4 (15.3 g,
0.43 mol) in THF (1 L) under nitrogen at –78 °C. The resulting
mixture was stirred overnight, then water was carefully added at
–78 °C to neutralize the excess of LiAlH4. After evaporation of the
solvent, CHCl3 (2 ϫ 500 mL) was added and insoluble impurities
were eliminated by filtration. Pure 6 was obtained as a colorless oil
1
(74.1 g, 80%). H NMR (300 MHz, CDCl3, 300 K): δ = 1.01–1.27
(m, 3 H), 1.49–1.57 (m, 1 H), 1.94–2.17 (m, 4 H), 2.22–2.55 (m, 5
H), 2.63–2.68 (m, 6 H), 2.89–2.98 (m, 1 H), 3.15–3.19 (m, 1 H),
3.22–3.32 (m, 2 H) ppm. 13C{1H} NMR (75 MHz, CDCl3, 300 K):
δ = 20.2 (CH2β), 45.8, 46.0, 50.4, 51.5, 52.4, 53.3, 55.2 (ϫ2) (CH2),
67.6 (CH), 75.8, 76.4 (NCN) ppm. MS (MALDI-TOF): m/z =
235.19 [M – 2H]+. HRMS (ESI): m/z calcd. for C12H23N5 + Na
260.1846; found 260.1834.
Compound 7: A solution of Boc2O (84.4 g, 0.39 mol) in CH2Cl2
(3 L) was slowly added to a solution of 6 (91.8 g, 0.39 mol) in
CH2Cl2 (0.9 L), and the solution was stirred overnight at room
Compound 10: NaBH4 (8.75 g,0.23 mol) was added to a solution of
8 (11.76 g, 23.12 mmol) in ethanol (300 mL), and the solution was
stirred at room temperature overnight. The solvent was evaporated
Eur. J. Org. Chem. 2013, 1538–1545
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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1543

F. Denat et al.
FULL PAPER
to give a white solid, then CH2Cl2 (500 mL) was added and the
insoluble salts were removed by filtration. After evaporation of the
solvent, the residue was washed with 3 m NaOH (10 mL) and ex-
tracted with chloroform (2 ϫ 200 mL). The organic phase was
dried with MgSO4, the solvent was then evaporated, and the re-
sulting oil was purified by aluminum oxide chromatography
(CH2Cl2/MeOH, 85:15) to give 10 as a colorless oil (8.09 g, 81%).
1H NMR (300 MHz, CDCl3, 300 K): δ = 1.43 (m, 9 H, CH3), 1.61–
with chloroform (2 ϫ 50 mL), the organic phase was dried with
MgSO4 and the solvent was evaporated to give 13 as a yellow oil
(1.76 g, 88%).
Route B: Compound 12 (2.0 g, 6.0 mmol) was dissolved in 37%
HCl (10 mL) and the mixture was stirred for 30 min at room tem-
perature. Acetone (50 mL) was added and a precipitate was formed
immediately. The precipitate was filtered, washed with acetone
(20 mL) and diethyl ether (20 mL), and dried under vacuum to give
13 (+ 5 HCl) as a white solid. The solid was dissolved in 16 m
NaOH until pH 14. After extraction with chloroform
(3 ϫ 100 mL), the organic phase was dried with MgSO4 and the
solvent was evaporated. Compound 13 was obtained as a colorless
2
1.75 (m, 2 H, CH2β), 2.32–3.08 (m, 21 H), 3.49 (d, J = 13.8 Hz,
1 H, CH2Ph), 3.55–3.65 (m, 1 H), 3.80 (d, 2J = 13.8 Hz, 1 H,
CH2Ph), 4.98 (s, 1 H, NHC=O), 7.21–7.33 (m, 5 H, CHar) ppm.
13C{1H} NMR (75 MHz, CDCl3, 300 K): δ = 26.0 (CH2β), 28.6
(ϫ3) (CH3), 40.7, 41.2, 48.6, 49.8, 49.9, 50.7, 51.3, 54.8, 55.4, 56.3,
58.8 (CH2), 59.1 (CH), 79.3 (C), 127.4, 128.4 (ϫ2), 129.8 (ϫ2)
(CHar), 136.3 (Car), 156.1 (C=O) ppm. MS (ESI): m/z = 432.35 [M
+ H]+, 454.32 [M + Na]+. HRMS (ESI): m/z calcd. for C24H41N5O2
+ H 432.3333; found 432.3315.
1
oil (1.45 g, 82%). H NMR (300 MHz, CDCl3, 300 K): δ = 1.57–
1.67 (m, 2 H), 2.11–2.19 (m, 2 H), 2.39–2.97 (m, 21 H), 3.09–3.14
(m, 1 H), 3.30–3.35 (m, 1 H) ppm. 13C{1H} NMR (125 MHz,
CDCl3, 300 K): δ = 25.3 (CH2β), 38.8, 44.0, 45.9, 47.7, 49.5, 49.6,
51.0, 51.1, 51.6, 53.9 (CH2), 67.6 (CH) ppm. MS (ESI): m/z =
242.23 [M + H]+. HRMS (ESI): m/z calcd. for C12H27N5 + H
242.2339; found 242.2344.
Compound 11: Compound 10 (8.09 g, 18.7 mmol) was dissolved in
a 37% HCl (30 mL) and the mixture was stirred for 30 min at room
temperature. Acetone (250 mL) was added and a precipitate was
formed immediately. The precipitate was filtered, washed with ace-
tone (50 mL) and diethyl ether (50 mL), and dried under vacuum
to give 11 (+ 5 HCl) as a white solid. The solid was dissolved in a
16 m NaOH until pH 14. After extraction with chloroform
(2 ϫ 150 mL), the organic phase was dried with MgSO4 and the
solvent was evaporated. Pure 11 was obtained as a colorless oil
Compound 14: NaBH4 (2.32 g, 61.2 mmol) was added to a solution
of 9 (8.32 g, 12.2 mmol) in ethanol (120 mL) and the solution was
stirred at room temperature overnight. The solvent was evaporated
to give a white solid, CH2Cl2 was added (300 mL) and the insoluble
salts were removed by filtration. After evaporation of the solvent,
the residue was washed with 3 m NaOH (20 mL), extracted with
chloroform (2 ϫ 100 mL) and dried with MgSO4. After evapora-
tion of the solvent, the residual oil was purified by aluminum oxide
chromatography (CH2Cl2/MeOH, 90:10) to give 14 as a yellow oil
1
(5.41 g, 87%). H NMR (500 MHz, CDCl3, 300 K): δ = 1.67–1.78
2
(m, 2 H, CH2β), 2.38–3.05 (m, 23 H), 3.52 (d, J = 13.6 Hz, 1 H,
2
CH2Ph), 3.60–3.65 (m, 1 H), 3.86 (d, J = 13.6 Hz, 1 H, CH2Ph),
1
(6.36 g, 79%). H NMR (300 MHz, CDCl3, 300 K): δ = 1.39 (s, 9
7.25–7.34 (m, 5 H, CHar) ppm. 13C{1H} NMR (125 MHz, CDCl3,
300 K): δ = 26.5 (CH2β), 41.3, 42.4, 48.5, 49.8, 50.5, 50.7, 51.8,
55.4, 55.7, 56.5, 58.4 (CH2), 62.1 (CH), 127.2 (CHar), 128.2 (ϫ2)
(CHar), 129.6 (ϫ2) (CHar), 138.4 (Car) ppm. MS (ESI): m/z =
332.28 [M + H]+. HRMS (ESI): m/z calcd. for C19H33N5 + H
332.2809; found 332.2809.
H, CH3), 1.47–1.57 (m, 1 H, CH2β), 1.87–2.02 (m, 2 H), 2.20–2.32
(m, 2 H), 2.47–2.76 (m, 5 H), 2.87–3.35 (m, 13 H), 3.78–4.04 [m, 4
H, (CH2Ph)], 5.27–5.34 (m, 1 H, NHC=O), 7.18–7.25 (m, 10 H,
CHar), 11.15 (br. s, 1 H, N+H) ppm. 13C{1H} NMR (150 MHz,
CDCl3, 300 K): δ = 21.8 (CH2β), 28.7 (ϫ3) (CH3), 40.4, 43.0, 48.6,
49.7, 49.8, 50.9, 54.0, 55.4, 55.5, 56.3, 58.2, 60.0 (CH2), 64.4 (CH),
79.6 (C), 127.9, 128.2, 128.7 (ϫ4), 129.9 (ϫ2), 130.4 (ϫ2) (CHar),
134.6, 136.4 (Car), 156.5 (C=O) ppm. MS (ESI): m/z = 522.38 [M
+ H]+. HRMS (ESI): m/z calcd. for C31H47N5O2 + H 522.3803;
found 522.3802.
Compound 12: Compound 10 (5.55 g, 12.9 mmol) was dissolved in
a mixture of acetic acid (43 mL) and water (4 mL), and 10% Pd/C
(550 mg, 0.5 mmol) was added under H2. After consumption of
hydrogen, the mixture was filtered to remove palladium. After
evaporation of the solvent, the residue was dissolved in acetone
(100 mL), 3 m HCl (5 mL) was added and the resulting precipitate
was filtered after 1 h, washed with acetone (20 mL) and dried under
vacuum to give a white powder. The resulting precipitate was then
dissolved in 3 m NaOH until pH 12. After extraction with chloro-
form (2 ϫ 50 mL), the organic phase was dried with MgSO4 and
the solvent was evaporated to give 12 as a yellow oil (2.52 g, 57%).
1H NMR (300 MHz, CDCl3, 300 K): δ = 1.41 (s, 9 H, CH3), 1.60–
1.68 (m, 2 H, CH2β), 2.14–2.26 (m, 2 H), 2.42–3.35 (m, 21 H), 4.81
(s, 1 H, NHC=O) ppm. 13C{1H} NMR (125 MHz, CDCl3, 300 K):
δ = 25.3 (CH2β), 28.5 (ϫ3) (CH3), 39.0, 41.9, 46.2, 47.9, 49.7 (ϫ2),
50.7, 51.0, 51.1, 54.1 (CH2), 63.8 (CH), 79.1 (C), 157.8 (C=O) ppm.
MS (ESI): m/z = 342.29 [M + H]+. HRMS (ESI): m/z calcd. for
C17H35N5O2 + H 342.2864; found 342.2864.
Compound 15: Compound 14 (2 g, 3.83 mmol) was dissolved in
37% HCl (10 mL) and the mixture was stirred for 30 min at room
temperature. Acetone (150 mL) was added and a precipitate was
formed immediately. The precipitate was filtered, washed with ace-
tone, diethyl ether, and dried under vacuum. The white solid was
dissolved in 16 m NaOH until pH 14. After extraction with chloro-
form (2 ϫ 100 mL), the organic phase was dried with MgSO4 and
the solvent was evaporated to give 15 as a colorless oil (1.49 g,
92%). 1H NMR (500 MHz, CDCl3, 300 K): δ = 1.19–1.33 (m, 2 H,
CH2β), 1.58–1.85 (m, 6 H), 2.06–2.14 (m, 1 H), 2.38–2.44 (m, 1 H),
2.47–2.55 (m, 1 H), 2.61–2.74 (m, 3 H), 2.80–2.89 (m, 4 H), 2.92–
2.98 (m, 1 H), 3.05–3.10 (m, 1 H), 3.14–3.22 (m, 2 H), 3.26–3.62
(m, 2 H), 3.77 (d, 2J = 13.8 Hz, 1 H, CH2Ph), 3.89 (d, 2J = 13.8 Hz,
1 H,CH2Ph), 3.91 (d, 2J = 13.8 Hz, 1 H, CH2Ph), 3.96 (d, 2J =
13.8 Hz, 1 H, CH2Ph), 7.23–7.36 (m, 10 H, CHar), 10.99 (br. s, 1
H, N+H) ppm. 13C{1H} NMR (125 MHz, CDCl3, 300 K): δ = 21.9
(CH2β), 41.7, 43.1, 48.6, 50.0, 50.4, 50.8, 53.9, 55.7, 56.3, 56.5,
58.4, 60.4 (CH2), 68.1 (CH), 128.0, 128.2, 128.8 (ϫ4), 129.8 (ϫ2),
130.2 (ϫ2) (CHar), 134.8, 136.5 (Car) ppm. MS (ESI): m/z = 422.32
[M + H]+. HRMS (ESI): m/z calcd. for C26H39N5 + H 422.3278;
found 422.3271.
Compound 13. Route A: Compound 11 (2.83 g, 8.3 mmol) was dis-
solved in a mixture of acetic acid (30 mL) and water (3 mL), and
10% Pd/C (350 mg, 0.3 mmol) was added under H2. After con-
sumption of hydrogen, the mixture was filtered to remove palla-
dium. After evaporation of the solvent, the residue was dissolved
in acetone (75 mL), 37% HCl (3 mL) was added and the resulting
precipitate was filtered after 1 h, washed with acetone (20 mL) and
dried under vacuum to give a white powder. The resulting precipi-
tate was then dissolved in 16 m NaOH until pH 14. After extraction
Compound 16: Compound 14 (2 g, 3.83 mmol) was dissolved in a
mixture of acetic acid (13 mL) and water (1 mL), and 10% Pd/C
1544
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© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 1538–1545

Functionalized Constrained Polyazamacrocycles
(163 mg, 0.15 mmol, 0.04 equiv.) was added under H2. After con-
sumption of hydrogen, the mixture was filtered to remove palla-
dium. After evaporation of the solvent, the residue was dissolved
in acetone (50 mL), 3 m HCl (7 mL) was added and the resulting
precipitate was filtered after 1 h, washed with acetone (100 mL)
and dried under vacuum to give a white powder. The resulting pre-
cipitate was then dissolved in 3 m NaOH until pH 12. After extrac-
tion with chloroform (2 ϫ 100 mL), the organic phase was dried
with MgSO4 and the solvent was evaporated to give 16 as a yellow
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oil (1.15 g, 88%). H NMR (500 MHz, CDCl3, 330 K): δ = 1.21–
841.
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(m, 2 H), 2.08–2.16 (m, 1 H), 2.32–2.39 (m, 1 H), 2.43–2.49 (m, 1
H), 2.57–3.37 (m, 17 H), 4.56 (s, 1 H, NHC=O) ppm. 13C{1H}
NMR (150 MHz, CDCl3, 300 K): δ = 22.3 (CH2β), 28.7 (ϫ3)
(CH3), 29.9, 41.1, 44.1, 44.2, 45.4, 45.5, 46.7, 50.7, 53.0, 55.6, 64.4
(CH), 79.7 (C), 156.0 (C=O) ppm. MS (ESI): m/z = 342.29 [M +
H]+. HRMS (ESI): m/z calcd. for C17H35N5O2 + H 342.2864; found
342.2860.
Compound 17. Route A: Compound 15 (1.0 g, 3.06 mmol) was dis-
solved in a mixture of acetic acid (1 mL) and water (10 mL), and
10% Pd/C (130 mg, 0.12 mmol, 0.04 equiv.) was added under H2.
After consumption of hydrogen, the mixture was filtered to remove
palladium. After evaporation of the solvent, the residue was dis-
solved in acetone (80 mL), 37% HCl (5 mL) was added and the
resulting precipitate was filtered after 1 h, washed with acetone
(20 mL) and dried under vacuum to give a white powder. The re-
sulting precipitate was then dissolved in 16 m NaOH until pH 14.
After extraction with chloroform (2 ϫ 60 mL), the organic phase
was dried with MgSO4 and the solvent was evaporated to give 17
as a yellow oil (0.90 g, 82%).
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Route B: Compound 16 (1.0 g, 2.37 mmol) was dissolved in 37%
HCl (10 mL) and the mixture was stirred for 30 min at room tem-
perature. Acetone (100 mL) was added and a precipitate was
formed immediately. The precipitate was filtered, washed with ace-
tone, diethyl ether, and dried under vacuum to give 17 (+ 5 HCl)
as a white solid. The solid was dissolved in a solution of 16 m
NaOH until pH 14. After extraction with chloroform
(2 ϫ 100 mL), the organic phase was dried with MgSO4 and the
solvent was evaporated to give 17 as a colorless oil (0.46 g, 80%).
1H NMR (300 MHz, D2O, 300 K): δ = 1.74–1.79 (m, 1 H), 2.24–
2.50 (m, 2 H), 2.69–3.74 (m, 20 H) ppm. 13C{1H} NMR (150 MHz,
D2O, 300 K): δ = 18.9 (CH2β), 37.8, 43.1, 43.2, 45.7, 46.5, 47.3,
48.9, 51.7, 52.6, 55.2 (CH2), 60.4 (CH) ppm. MS (ESI): m/z =
242.23 [M + H]+. HRMS (ESI): m/z calcd. for C12H27N5 + H
242.2339; found 242.2333.
Supporting Information (see footnote on the first page of this arti-
cle): NMR spectra of all products, X-ray structures of compounds
2, 3 and 8, DFT calculations.
[8] T. J. Hubin, J. M. McCormick, N. W. Alcock, H. J. Clase, D. H.
Busch, Inorg. Chem. 1999, 38, 4435–4446.
Acknowledgments
[9] L. J. Farrugia, J. Appl. Crystallogr. 1997, 30, 565.
[10] CCDC-902370 (for 2), -902371 (for 3) and -902372 (for 8) con-
tain 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/cif.
Support was provided by the Centre National de la Recherche Sci-
entifique (CNRS), the University of Burgundy and the Conseil
Régional de Bourgogne through the 3MIM Project. P. D. and C. B.
thank the French Ministry of Research for PhD grants. Marc Pir-
rotta, Fanny Chaux and Marcel Soustelle are acknowledged for
technical support.
Received: October 9, 2012
Published Online: January 25, 2013
Eur. J. Org. Chem. 2013, 1538–1545
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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