Exo-diastereoisomer of 10-aryl-1,4,7-triazabicyclo[5.2.1]decane as intermediary in specific derivatisation of triazacyclononane

Article abstract of DOI:10.1016/j.tet.2012.04.057

Reaction of triazacyclononane (tacn) and aromatic aldehydes leads to aminal adducts, which exhibit only the exo configuration. In these aminal compounds, secondary amine function possesses a higher reactivity towards electrophilic reactants than the two nitrogen atoms linked to aminal carbon, giving rise to the specific derivatisation of tacn by different functionalised groups. Study of this behaviour also permits the access to a ditopic tacn-cyclam bicyclic polyamine.

Full text of DOI:10.1016/j.tet.2012.04.057

Tetrahedron 68 (2012) 5637e5643
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exo-Diastereoisomer of 10-aryl-1,4,7-triazabicyclo[5.2.1]decane as intermediary in
specific derivatisation of triazacyclononane
*
ꢀ
ꢀ
€
Melissa Roger, Veronique Patinec , Martine Bourgeois, Raphael Tripier, Smail Triki, Henri Handel
ꢀ
ꢀ
Laboratoire de Chimie, Electrochimie Moleculaires et Chimie Analytique, Universite de Bretagne Occidentale, UMR C NRS 6521, 6 Avenue Le Gorgeu, 29200 Brest, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Reaction of triazacyclononane (tacn) and aromatic aldehydes leads to aminal adducts, which exhibit only
the exo configuration. In these aminal compounds, secondary amine function possesses a higher re-
activity towards electrophilic reactants than the two nitrogen atoms linked to aminal carbon, giving rise
to the specific derivatisation of tacn by different functionalised groups. Study of this behaviour also
permits the access to a ditopic tacnecyclam bicyclic polyamine.
Received 17 February 2012
Received in revised form 6 April 2012
Accepted 13 April 2012
Available online 27 April 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Triazacyclonane
Aminal protecting group
Specific derivatisation
Ditopic ligand cyclam derivative
1. Introduction
Statistic N-functionalisation also constitutes a synthetic strategy
by reacting tacn and alkylating agent in a 1:1 or 1:2 ratio, but
The various applications of triazacyclononane (tacn) and de-
rivatives generally imply their remarkable coordinating proper-
ties.1 Protein orientation at interfaces,2 metalloenzyme biosite
models,3 diagnostical or therapeutical metal carriers,4 magnet
molecule clusters,5 sensors6. constitute examples of domains in
which the potentialities of these small azamacrocycles are in-
volved. Combination of tacn potentialities with different abilities of
other chelators could extend the applications fields. A possible
approach consists in synthesising polytopic ligands containing
different workable characteristic sites. Such an association exists in
ditopic cyclic-cyclic or cyclic-linear bispolyamines that have been
investigated for biological or medicinal applications.4,7
In the previous different examples, the use of modified tacn,
bearing one, two or three arms with- or without- coordinating
atoms is usually required. The introduction on the triazamacrocycle
of identical or different substituents necessitates to discriminate
the amine functions of the macrocycle. The classical method con-
sists in the introduction of the functional group before the cycli-
sation step leading to N-alkylated derivatives at the end of the
synthetic process, which has, obviously, to be reconsidered when
a new product is needed.8 Recently, this way was used to synthesise
tacn-containing cationic lipids with good buffering capacity, which
is an important behaviour for non-viral gene delivery reagents.9
generally requires purification steps to separate non-reacted tacn
and mono- or/and poly-substituted derivatives.10 Reaction of tacn
with BOC-ON in a 1:2 ratio has given rise to the diprotected 1,4-
diBOCetacn synthesis, which permitted for instance to obtain fur-
ther Cu(II) complexes of tacn derivatives with alkyl- or xylyl-linked
guanidinium groups studied as models compounds for cleaving the
phosphonate ester backbone of DNA.11 Protection of one or two
nitrogen atoms of tacn has also been employed by tosylation,12
carbamation13 or pH controlled sulfomethylation,14 including fur-
ther purification and/or deprotection steps. Finally, a method based
on an intermediate orthoamide has also been described and per-
mits to graft independently one, two or three substituents on the
tacn macrocycle by playing with the orthoamide hydrolysis.15
Dipicolyl-tacn derivative studied in low spinehigh spin iron mo-
lecular switching,16 N-aminoalkyl-tacn derivatives suitable for
functionalisation of carboxy terminated supports as self-assembled
monolayers SAM17 are examples of compounds issued from the
orthoamide protection method.
These different routes are complementary methods and it is still
important to develop such ways for grafting arms to cyclic poly-
amines in order to make it possible in various conditions offering
more choice in the nature of substituents.
Reaction of tacn with anhydrous paraformaldehyde and dia-
lkyloxyphosphine to give trimethylenephosphinate ester derivative
was studied by D. Parker et al.18 It was found to give a bicyclic
aminal monophosphinate ester as a secondary product together
with the expected trimethylenephosphinate ester. Acidic hydrolysis
* Corresponding author. Tel.: þ33 298 017 127; fax: þ33 298 017 001; e-mail
address: veronique.patinec@univ-brest.fr (V. Patinec).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.04.057

5638
M. Roger et al. / Tetrahedron 68 (2012) 5637e5643
eliminated the aminal group and yielded the phosphinic acid
substituent of tacn (Scheme 1). This result suggests a potential
protecting role of the aminal group for two secondary amine
functions, leaving the third one accessible to reactants. We there-
fore investigated the synthesis and characterisation of different
aminal derivatives of tacn to evaluate further the opportunity to
specifically substitute tacn and to apply the method to tacn-based
ditopic ligands synthesis.
Hindrance caused by the presence of substituent on aldehyde
should not allow such an easy dimer formation. With the aim of
obtaining a single aminal derivative without any trace of dimer-
isation, reactions of tacn with different substituted aldehydes were
investigated in the experimental conditions previously described
with paraformaldehyde (1 equiv of aldehyde, ethanol, molecular
sieve). Several aromatic aldehydes like benzaldehyde, 4-
fluorobenzaldehyde and 2-, 3- and 4-pyridinecarboxaldehyde
gave rise to monomeric aminal formation. Nevertheless, hindered
aldehyde as anthracenecarboxaldehyde never permitted total
aminal formation whatever the experimental conditions. The
products 3e7 were isolated with good to very good yields (Table 1).
For compounds 3e7, 1H NMR spectra exhibit a single peak for
the aminal hydrogen showing the presence of only one of the two
possible diastereoisomers between the endo and exo forms. 2D
NMR sequences permitted to attribute the exo configuration, es-
pecially the NOESY sequence. Indeed, NOESY spectra of compounds
3 and 6 exhibited correlation between the hydrogen aminal
CH3
O
OEt
O
EtO
H3C
H3C
N
O
EtO
N
P
P
P
H
H
N
N
N
CH3P(OEt)2
(CH2O)n
+
N
N
N
H
N
O
P
OEt
(d
¼5.66 ppm for 3 and 5.67 ppm for 6) and the diastereotopic
proton of the large bridge in the molecule (
¼3.32 ppm for 3 and
3.33 ppm for 6) and a second correlation between an aromatic
hydrogen ( ¼7.62 ppm and 8.57 ppm for 6)
¼7.50 ppm for 3 and
and one of the diastereotopic hydrogen of a CH2 of the small in-
HCl
H3C
d
d
d
O
H3C
NH
NH
P
ternal cycle (
d
¼3.07 ppm for 3 and 2.89 ppm for 6) (Fig. 2).
N
HO
Scheme 1. Sequence described by D. Parker et al.18
Table 1
Synthesis of aminal derivatives
H
R
N
N
NH
HN
2. Results and discussion
O
NH
R
EtOH, 4h, RT,
molecular sieve
NH
2.1. Aminal formation and characterisation
Our study was initialised by using paraformaldehyde showed by
D. Parker et al.18 The reaction took place in absolute ethanol at room
temperature with molecular sieve for trapping liberated water. The
white solid obtained after filtration and evaporation of the solvent
was characterised as a mixture of the good aminal derivative 1
together with initial tacn and an other species in small amount
containing two different kinds of aminal functions. According to 1H
NMR experiments, which exhibited an AB signal and a singlet one
integrating, respectively, for 2:1 in the aminal protons area, this by-
product was assumed to be a dimer 2 based on two units of 1 linked
by a CH2 aminal bridge (Fig. 1). Our different attempts by modifying
the reaction conditions (concentration, solvent) did not permit to
prevent the formation of this by-product.
Aqueous formaldehyde was then tested to replace para-
formaldehyde. Formaldehyde was already used to synthesise cyclic
aminal of cyclam (1,4,8,11-tetraazacyclotetradecane) in tetraaza-
macrocyclic analogues chemistry.19 Aqueous formaldehyde (37%)
(1 equiv) as carbonylated reactant was added to tacn in water at
room temperature for 12 h. The reaction product contained es-
sentially the attended aminal derivative 1,4,7-triazabicyclo[5.2.1]
decane 1 and traces of the same precedent dimer. If an excess of
paraformaldehyde or aqueous formaldehyde (1.5 equiv) was in-
troduced in the reaction, the dimer appeared to be the main
product showing the easiness of this bridge formation.
R
Compound
Yield (%)
90
3
4
5
80
88
F3C
N
6
7
77
84
N
N
H
δ =7.62
δ = 5.66
H
N
δ = 5.67
H
δ = 3.32
δ = 3.33
δ = 7.50
H
H
H
H
N
N
N
N
N
N
H
H
H
H
d = 8.57
H
H
H
H
HN
N
N
N
N
HN
HN
δ = 3.07
H
H
H
H
δ = 2.89
H
H
N
N
2
1
6
3
Fig. 1. Structure of aminal derivatives obtained with aqueous formaldehyde or
Fig. 2. NOESY correlations observed for exo configuration of aminal derivatives 3 and 6.
paraformaldehyde.

M. Roger et al. / Tetrahedron 68 (2012) 5637e5643
5639
2.2. Reactivity study
In this case, reaction with allyl bromide resulted in the unique mono-
N-alkylation of tacn (compound 12) with an excellent yield, when
benzyl bromide gave a lower yield than precedently (compound 11)
suggesting that the secondary amine function reactivity was also
weakened. Other mono-N-functionalisations were successfully per-
formed with 3 or 4 (Table 2) in good yields with aliphatic or aromatic
substituents like ethyl 13, 2-picolyl 16 or medium yields with decyl
15, 4-picolyl 14 and bipyridinyl 17. The aminal function of this last
compound 17 was hydrolysed directly by the acidic silica gel during
the purification step by column chromatography giving the mono-N-
bipyridinyl-tacn with 32% yield. Deprotection step of other com-
pounds was performed by hydrolysis in acidic conditions under
stirring in a solution of hydrochloride acid 1 M at room temperature
for 3 h. The final mono-N-substituted compounds were obtained in
quantitative yield in their hydrochloride form after evaporation and
washing with organic solvent. Obtention of product in their free base
form could be easily performed by using an anion-exchange resin or
by solubilisation of the chloride salt in water made basic (pH>12)
followed by a simple extraction with an organic solvent like
dichloromethane.
With the aim of verifying the efficiency of the protecting role of
aminal bridge, electrophilic reagents were used to investigate their
reactivity towards secondary amine and aminal functions. Different
kinds of reactants were studied to better appreciate the protecting
group capacity of the aminal function: activated reactants (benzyl
and allyl bromides), non activated ones with hydrophobic chains
(ethyl and decyl iodides) and electrophilic agents with coordinating
groups (picolyl chlorides). Halogenoalkanes (1 equiv) were added
to a solution of aminal derivatives in distilled acetonitrile with
potassium carbonate and reaction mixture was kept under stirring
at mild temperature (25e50 ꢀC).
Reactivity of aminal 1 was first studied, even in the presence
of traces of the dimeric by-product 2, which was assumed to be
kinetically less reactive towards electrophilic agent in the re-
action conditions because all nitrogen atoms were engaged in
aminal function. When benzyl bromide (1 equiv) was introduced
into an acetonitrile solution of aminal 1, one or several by-
products together with the mono-N-alkylated derivative
were obtained. After purification attempts by chromatography
on silica, neutral or basic alumina, the results were not re-
producible making difficult the characterisation of the secondary
products.
2.3. Application to ditopic polyamine synthesis
Multitopic polyamines, and especially ditopic ones (cyclic/cyclic
or cyclic/linear), display a growing development due to the possible
simultaneous characteristical interesting behaviours of both com-
plexing sites. Synthesis of ligands that allow complexation of two
metallic centres with identical or different nature in various co-
ordination modes and geometries are thus omnipresent challenges.
Indeed, such ditopic ligands can open access to bimodal sensors
with diagnostic/therapeutic/magnetic. co-properties.
The addition of benzyl bromide to compound 3 successfully pro-
duced a mono alkylated product 9 with a very good yield (Table 2).
Surprisingly, reactionwith allyl bromide gave rise to mono- and di-N-
alkylation (respectively, 10 and 100) of tacn, implying that one of the
nitrogen atoms of the aminal function was involved in the reaction.
Compound 4 was studied in the same conditions in order to evaluate
the effect of the electron-withdrawing CF3 group on such a reactivity.
Table 2
Reaction of 3 and 4 with alkylating agents and hydrolysis step
N
R1
N
N
R1-X
HCl 1M
3h, RT
NH
, 3 HCl
N
R1
N
R
R
NH
K2CO3
CH3CN
N
NH
19-24
3-4
9-18
Compound
R1eX
Product
Yield
(%)
Product
Yield
(%)
3
3
4
4
3
C6H5CH2Br
CH2]CHeCH2Br
C6H5CH2Br
CH2]CHeCH2Br
CH3CH2I
9
99
19
20
19
20
21
100
100
100
100
100
10þ100
(90)a
72
11
12
13
98
95
3
3
4
14
15
16
38
47
73
22
23
24
100
100
100
N
CH2Cl
C
10H21I
CH2Cl
N
32b
CH2Br
4
17
d
25
N
N
N O N
P
3
18
97
26
70
N
N
Cl
N
a
Mixture of mono- and di-allylation.
After acidic hydrolysis on silica gel column chromatography.
b

5640
M. Roger et al. / Tetrahedron 68 (2012) 5637e5643
Several symmetric and dissymmetric bismacrocyclic poly-
3. Conclusion
amines are known like bistetraazacycloalkanes (cyclam-cyclam,
cyclam-cyclen)20 and bistriazacyclononane.21 However, dissym-
metric bismacrocycles containing two different sizes, for instance
tacnecyclam, are more scarce. In this context, a combination be-
tween tacn and a cyclic tetraamine like cyclam could offer the
opportunity to complex two different metallic cations depending
on the nature of the coordinating arms present, respectively, on
each polyazamacrocycle.
Our group recently described the synthesis of ditopic poly-
ammonium anion receptors made up of a cyclam and a linear
polyamine.7 It needed to protect both the tetraazamacrocycle and
the linear polyamine by adapted ways. The cyclam was used in its
phosphoryl form, which kept a single amine function free.22 The
nature of the electrophilic reactant is a phosphorylcyclam with a 2-
methyl-6-(chloromethyl)pyridine arm bound to the amine function
(compound 8 in Scheme 2). This electrophilic agent was obtained
by reaction of cyclamphosphoryl with 2,6-bis(chloromethyl)pyri-
dine in acetonitrile and was mixed with protected linear polyamine
in solution to give the corresponding ditopic derivative.7
A simple and easy-to-make method for mono-N-substitution of
tacn has been described by using mild and rapid conditions of
aminal formation with substituted aromatic aldehydes. This aminal
function, which only presented the exo configuration played
a protecting role when reaction with halogenoalkanes was ach-
ieved. Hydrolysis with hydrochloric acid easily resulted in various
tacn derivatives bearing one grafted arm. This study offers an ad-
ditional tool to those that are usually employed for making original
triazamacrocyclic chelators.
The method showed its suitability to a larger application and
was extended to a dissymmetric bismacrocycle tacnecyclam syn-
thesis. This tacnecyclam compound opens the route to other
ditopic products of the bismacrocyclic family by using adequate
protection/deprotection steps. This aspect is under investigation
with the aim of studying the coordination properties of new tacn-
tetraazamacrocycle compounds.
4. Experimental section
4.1. General
The concept could be extended to the cyclic triamine tacn in
place of the linear polyamine. Aminal derivative 10-phenyl-1,4,7-
triazabicyclo[5.2.1]decane 3 has been introduced in this reaction
process with compound 8.
1,4,7-Triazacyclononane and cyclam were purchased from
CheMatech, Dijon, France. Other reagents were purchased from
ACROS Organics or Aldrich Chemical Co. Elemental analyses were
performed at the Service de Microanalyse (CNRS, 91198 Gif sur
Yvette (C, H, N) and 69360 Solaize (Cl), France), NMR and mass
spectrometry were investigated at the ‘Services Communs’ of the
University of Brest. Mass spectrometry analyses were performed
on an Autoflex MALDI TOF III LRF200 CID. 1H, 15N, 19F, 31P, 13C NMR
spectra were recorded with Advance 500 Bruker (500 MHz), Ad-
vance 400 Bruker (400 MHz) or AMX-3 300 Bruker (300 MHz)
spectrometers. 2D NMR 1He1H homonuclear, 1He13C and 1He15N
heteronuclear correlations and homonuclear decoupling experi-
ments permitted as much as possible the assignation of the 1H
The reaction of bismacrocyclic tacnecyclam synthesis took place
in similar conditions than those used for mono-N-alkylation of
tacn. The acetonitrile solution of 8 and 3 was stirred at 50 ꢀC for 4
days with potassium carbonate. A silica gel column chromatogra-
phy using CHCl3/MeOH (98:2) gave the dissymmetric diprotected
bismacrocycle 18 with a good yield. Double multiplicity of some
peaks appeared on 13C NMR spectra. This phenomenon has been
attributed to the presence of diastereotopic stereoisomers for 18
induced by the asymmetric nitrogen atoms of the rigid internal
aminal cycle and the stereogenic phosphorus atom in the pyr-
idinylcyclamphosphoryl group. This particularity disappeared after
deprotection, which took place in HCl 3 M for 12 h at room tem-
perature. These relatively mild conditions were efficient for elimi-
nating both aminal and phosphoryl cores and hydrochloride
deprotected derivative 26 was obtained in a good yield (Scheme 2).
This product was purified by using anion-exchange resin, which
allowed to obtain ditopic ligand 26 as a free base without any
phosphate traces.
and 13C signals. The
d
scales are relative to TMS (1H, 13C), CH3NO2
19F). The signals are indicated as
(
15N), H3PO4 31P) and CFCl3
(
(
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: Ha, Ca and Hb, Cb
correspond to CH or CH2 located in, respectively,
a or b position of
N; ar, pic, py were used, respectively, for aromatic, picolyl and
pyridine).
Phosphorylcyclam,22
2,6-bis(chloromethyl)pyridine23
and
24
25
5-(bromomethyl)-50-methyl-2,20-bipyridine24 were synthesized as
previously described.
23
4
22
H
N
H
5
3
N
21
N
N
N O N
P
6
7
N O N
P
4.2. General procedure for aminal synthesis
2
19
20
1
Cl
N
NH
18
11
N
N
To a solution of 1,4,7-triazacyclononane (2 mmol) in distilled
ethanol (50 mL) containing molecular sieve was added 1 equiv of
aldehyde. The reaction mixture was stirred at room temperature.
The solution was filtered and the filtrate was evaporated under
reduced pressure to yield the aminal adduct.
N
N
16
N
17
N
CH3CN, K2CO3,
50°C, 4 days
12
9
8
10
13
15
14
18
8
HCl 3M, 12h
4.2.1. 1,4,7-triazabicyclo[5.2.1]decane (1). Reaction with para-
formaldehyde (60 mg, 2 mmol) for 4 h. White solid (267 mg, 95%).
NMR (CDCl3) 1H (300 MHz) 2.65e2.84 (8H, m, Ha), 2.90e3.02 (5H,
m, HaþNH), 4.04 (d, 1H, J 9, Haminal), 4.22 (d, 1H, J 9, Haminal); 13C
(75 MHz) 48.6, 48.8, 57.4 (Ca), 76.8 (Caminal).
HN
NH
NH HN
NH
N
N
N
4.2.2. Bis(1,4,7-triazabicyclo[5.2.1]decan-4-yl)methane (2). To a so-
lution of 1,4,7-triazacyclononane (1.02 mmol) dissolved in dis-
tilled acetonitrile (20 mL) containing molecular sieve was added
dropwise an acetonitrile solution (15 mL) of 1.5 equiv of
, n HCl
26
Scheme 2. Bismacrocyclic tacnecyclam derivative synthesis.

M. Roger et al. / Tetrahedron 68 (2012) 5637e5643
5641
paraformaldehyde. The reaction mixture was stirred at room
temperature during 24 h. Evaporation of CH3CN under reduced
pressure yielded the dimeric adduct as the major product. NMR
(CDCl3) 1H (300 MHz) 2.66e2.79 (12H, m, Ha), 2.91e3.08 (12H, m,
Ha), 3.24 (2H, s, Haminal), 4.02 (2H, d, J 8, Haminal), 4.11 (2H, d, J 8,
Haminal); 13C (75 MHz) 48.7, 52.0, 55.2 (4C, Ca), 76.1 (2C, Caminal),
80.8 (Caminal).
(CbNH), 88.9 (Caminal), 122.3 (CHar); 145.3 (CHarN), 152.7 (Car);
MALDI-TOF 219.1 [Mþ1]þ.
4.3. General procedure for alkylation of aminal-protected
tacn
Aminal-protected tacn (3 or 4) was dissolved in freshly distilled
acetonitrile (25 mL) and halogenoalkane (1 equiv) and potassium
carbonate (2.5 equiv) were added. The reaction mixture was stirred
at room temperature. The solution was filtered and the filtrate was
evaporated under reduced pressure to yield a brown oil.
4.2.3. 10-Phenyl-1,4,7-triazabicyclo[5.2.1]decane (3). Reaction with
benzaldehyde (192 mL, 1.93 mmol) for 4 h. White solid (370 mg,
90%). NMR (CDCl3) 1H (300 MHz) 2.89e2.93 (4H, m, Ha), 2.99e3.03
(2H, m, Ha), 3.07e3.17 (4H, m, Ha), 3.32e3.39 (2H, m, Ha), 5.66 (1H,
s, Haminal), 7.18 (1H, t, J 7, Har), 7.29 (2H, t, J 7, Har), 7.50 (2H, d, J 7,
Har); 13C (75 MHz) 49.3 (CaN), 49.6 (CaNH), 58.8 (CaN), 88.3 (Caminal),
126.6, 126.7 128.2 (CHar), 145.8 (Car); 15N (50 MHz) ꢁ355 (NH),
ꢁ331 (N); MALDI-TOF 216.1 [M]þ 217.1 [Mþ1]þ. Anal. Calcd for
C13H19N3$0.1C2H5OH: C, 71.44; H, 8.90; N, 18.94. Found: C, 71.13; H,
8.88; N, 19.06.
4.3.1. 4-Benzyl-10-phenyl-1,4,7-triazabicyclo[5.2.1]decane
(9). Reaction with 3 (370 mg, 1.70 mmol) and benzyl bromide
(203 m
L, 1.70 mmol) for 4 h. Yield 99% (529 mg). NMR (CDCl3) 1H
(300 MHz) 2.48e3.34 (12H, m, Ha), 3.81 (2H, s, CH2Ph), 5.72 (1H, s,
Haminal), 7.18e7.64 (10H, m, Har); 13C (75 MHz) 49.6 (CaNaminal), 52.3
(CaN), 56.7 (CbN), 62.8 (CH2Ph), 87.7 (Caminal) 126.7, 127.2, 128.2,
128.6, 128.8, 130.0 (CHar), 140.5 (CarCH2N), 145.7 (CarCaminal);
MALDI-TOF 308.2 [Mþ1]þ.
4.2.4. 10-(4-(Trifluoromethyl)phenyl)-1,4,7-triazabicyclo[5.2.1]dec-
ane (4). Reaction with
a,a,a-trifluorotolualdehyde (270 mL,
1.97 mmol) for 4 h. The residue was purified by silica gel chroma-
tography (CHCl3/Et3N 9:1 then CHCl3/MeOH/Et3N 9:0.5:0.5) to
yield an oily white solid (450 mg, 80%). NMR (CDCl3) 1H (500 MHz)
2.91e2.97 (6H, m, Ha), 3.08e3.12 (2H, m, Ha), 3.15e3.19 (2H, m, Ha),
3.31e3.37 (2H, m, Ha), 5.70 (1H, s, Haminal), 7.53 (2H, d, J 8, Har), 7.61
(2H, d, J 8, Har); 13C (125 MHz) 49.0 (CaNH), 49.3, 58.7 (Ca), 87.5
(Caminal), 124.8 (CF3, 1J 272), 125.1 (CHar, 3J 4), 127.1 (CHar), 129.0
(Car, 2J 32), 149.7 (Car); 15N (50 MHz) ꢁ356.8 (NH), ꢁ332.2 (N); 19F
(282 MHz) ꢁ62.77; MALDI-TOF m/z 286.1 [Mþ1]þ. Anal. Calcd for
C14H17F3N3$0.2H2O: C, 58.40; H, 6.09; N, 14.60. Found: C, 58.80; H,
6.22; N, 14.23.
4.3.2. 4-Benzyl-10-(4-(trifluoromethyl)phenyl)-1,4,7-triazabicyclo
[5.2.1]decane (11). Reaction with 4 (254 mg, 0.89 mmol) and benzyl
bromide (106 mL, 0.89 mmol) for 4 h. Yield 72% (240 mg). NMR
(CDCl3) 1H (300 MHz) 2.58e3.25 (12H, m, Ha), 3.73 (2H, s, CH2Ph),
5.66 (1H, s, Haminal), 7.16e7.30 (5H, m, Har), 7.47 (2H, d, J 8, Har), 7.58
(2H, d, J 8, CHareCCF3); 13C (75 MHz) 49.4 (CaNaminal), 55.2 (CaN),
56.6 (CbN), 62.9 (CH2Ph), 87.1 (Caminal), 124.7 (CF3, 1J 250), 125.0
(CHar, 3J 3), 127.2 (CeCF3, 2J 4), 127.3 (CHar), 128.5, 128.8 (CHar), 140.4
(CareCH2), 149.5 (CarCaminal).
4.3.3. 4-Allyl-10-(4-(trifluoromethyl)phenyl)-1,4,7-triazabicyclo
[5.2.1]decane (12). Reaction with 4 (235 mg, 0.82 mmol) and allyl
4.2.5. 10-(Pyridin-2-yl)-1,4,7-triazabicyclo[5.2.1]decane
bromide (70 mL, 0.82 mmol) for 4 h. Yield 98% (262 mg). NMR
(5). Reaction with 2-pyridinecarboxaldehyde (210
mL, 2.20 mmol)
(CDCl3) 1H (300 MHz) 2.62e3.38 (14H, m, HaþCH2allyl), 5.09 (1H, d, J
11, CH]CH2), 5.14 (1H, d, J 18, CH]CH2), 5.67 (1H, s, Haminal),
5.77e5.95 (1H, m, CH]CH2), 7.52 (2H, d, J 8, Har), 7.63 (2H, d, J 8,
CHareCCF3); 13C (75 MHz) 49.4 (CaNaminal), 55.0 (CaN), 56.8 (CbN),
61.9 (CH2CH]CH2), 87.0 (Caminal), 117.0 (CH]CH2), 124.7 (CF3, 1J
272), 124.8 (CHareCCF3, 3J 4), 127.1 (CHar), 128.8 (CeCF3, 2J 32), 136.7
(CH]CH2), 149.6 (CareCaminal).
for 5 h. The residue was purified by silica gel chromatography
(CHCl3/Et3N 9:1 then CHCl3/MeOH/Et3N 9:0.5:0.5) to yield an oily
solid (425 mg, 88%). NMR (CDCl3) 1H (500 MHz) 2.72e2.76 (4H, m,
HaNH), 2.89e2.93 (2H, m, HbNH), 2.96e3.06 (4H, m, HaN), 3.18e3.25
(2H, m, HbNH), 5.61 (1H, s, Haminal), 6.91 (1H, dd, J 5, 7, Har), 7.29
(1H, d, J 8, Har), 7.42 (1H, dd, J 7, 8, Har), 7.42 (1H, d, J 5, Har); 13C
(126 MHz) 48.7 (CaNH), 48.9 (CaN), 58.0 (CbNH), 89.2 (Caminal), 119.6
(CHar), 121.0 (CHar), 135.8 (CHar), 149.0 (CHar), 163.7 (Car); 15N
(50 MHz) ꢁ357.1 (NH), ꢁ332.0 (N), ꢁ76.8 (Npy); MALDI-TOF m/z
219.1 [Mþ1]þ.
4.3.4. 4-Ethyl-10-(4-(trifluoromethyl)phenyl)-1,4,7-triazabicyclo
[5.2.1]decane (13). Reaction with
4
(263 mg, 0.92 mmol) and
iodoethane (74
m
L, 0.92 mmol) for 64 h. Yield 95% (265 mg). NMR
(CDCl3) 1H (300 MHz) 1.02 (3H, t, J 7, CH3), 2.57e2.34 (14H, m,
HaþCH2CH3), 5.73 (1H, s, Haminal), 7.51 (2H, d, J 8, Har), 7.62 (2H, d, J
8, CHareCCF3); 13C (126 MHz) 13.4 (CH3), 49.4 (CaNaminal), 54.9 (CaN),
56.9 (CbN), 52.6 (CH2CH3), 86.9 (Caminal), 124.7 (CF3, 1J 273), 124.8
(CareCCF3, 3J 4), 127.1 (CHar), 128.7 (CeCF3, 2J 32), 149.7(CareCaminal).
4.2.6. 10-(Pyridin-3-yl)-1,4,7-triazabicyclo[5.2.1]decane
(6). Reaction with 3-pyridinecarboxaldehyde (213 mL, 2.30 mmol)
for 4 h. The residue was purified by silica gel chromatography
(CHCl3/Et3N 9:1 to CHCl3/MeOH/Et3N 9:0.5:0.5) to yield a brown
solid (258 mg, 77%). NMR (CDCl3) 1H (500 MHz) 2.85e2.91 (6H, m,
4HaNHþ2HaN), 3.05e3.08 (2H, m, HbNH), 3.12e3.13 (2H, m, HaN),
3.30e3.36 (2H, m, HbNH), 5.55 (1H, s, Haminal), 7.01 (1H, dd, J 4, 7,
4.3.5. 4-(4-Picolyl)-10-phenyl-1,4,7-triazabicyclo[5.2.1]decane
(14). Reaction with 3 (220 mg, 1.02 mmol) and 4-picolylchloride
(100 mg, 0.79 mmol) for 140 h. The residue was purified by silica
gel chromatography (CHCl3/Et3N 9:1 then CHCl3/MeOH/Et3N
9:0.5:0.5) to yield a brown oil (64 mg, 38%). NMR (CDCl3) 1H
(300 MHz) 2.59e3.36 (12H, m, Ha), 3.82 (2H, s, CH2pic), 5.63 (1H, s,
Haminal), 7.18e7.33 (7H, m, C6H5þCHpic), 7.52 (2H, d, J 8, CHpic); 13C
(75 MHz) 49.4 (CaNeCaminal), 55.5(CaN), 56.4 (CbN), 61.4 (CH2pic), 87.8
(Caminal), 123.6 (CHpic), 126.7, 126.9, 128.2 (CHar), 145.3 (CareCaminal),
149.7 (Cpic), 150.1 (N]CHpic).
Har), 7.26 (1H, d, J 4, Har), 7.62 (1H, d, J 7, Har), 8.57 (1H, s, Har); 13
C
(126 MHz) 49.1 (CaNH), 49.4 (CaN), 58.3 (CbNH), 84.7 (Caminal), 122.1
(CHar), 134.2 (CHar), 140.4 (Car), 147.9 (CHar), 148.5 (CHar); MALDI-
TOF m/z 218.1 [M]þ.
4.2.7. 10-(Pyridin-4-yl)-1,4,7-triazabicyclo[5.2.1]decane
(7). Reaction with 4-pyridinecarboxaldehyde (196 mL, 2.21 mmol)
for 4 h. The residue was purified by silica gel chromatography
(CHCl3/Et3N 9:1 then CHCl3/MeOH/Et3N 9:0.5:0.5) to yield a brown
solid (385 mg, 84%). NMR (CDCl3) 1H (500 MHz) 2.84e2.98 (6H, m,
4HaNHþ2HaN), 3.04e3.07 (2H, m, HbNH), 3.11e3.17 (2H, m, HaN),
3.26e3.32 (2H, m, HbNH), 5.61 (1H, s, Haminal), 7.38 (2H, d, J 5, CHar),
8.46 (2H, d, J 5, CHarN); 13C (126 MHz) 49.2 (CaNH), 49.5 (CaN), 58.5
4.3.6. 4-Decyl-10-phenyl-1,4,7-triazabicyclo[5.2.1]decane
(15). Reaction of
(150 L, 0.70 mmol) for 4 days. After filtration and evaporation,
the residue was purified by silica gel chromatography neutralised
3 (200 mg, 0.70 mmol) with 1-iododecane
m

5642
M. Roger et al. / Tetrahedron 68 (2012) 5637e5643
with Et3N (CHCl3/hexane 1:1 then CHCl3) to yield a brown oil
(119 mg, 47%). NMR (CDCl3) 1H (300 MHz) 0.89 (3H, m, CH3), 1.28
(16H, m, C10H21), 2.58e3.21 (12H, m, Ha), 3.33e3.37 (2H, m,
N-CH2decyl), 5.65 (1H, s, Haminal), 7.18 (1H, t, J 7, Har), 7.29 (2H, t, J 7,
Har), 7.50 (2H, d, J 7, Har); 13C (75 MHz) 14.0 (CH3), 22.6 (CH2CH3),
27.2, 28.5, 29.2, 29.6 (Cdecyl), 31.9 (CH2CH2CH3), 49.2 (CaNeCaminal),
55.2 (CaN), 56.5 (CbN), 58.3 (CH2decyl), 87.3 (Caminal), 126.3, 127.8
(C6H5), 145.4 (CareCaminal).
CH]CH2), 5.32 (1H, d, J 6, CH]CH2, H2]C), 5.87 (1H, m, CH]CH2);
13C (75 MHz) 44.1, 44.4, 49.9 (Ca), 61.0 (CH2eCH]), 125.0 (CH2]),
133.5 (]CH); MALDI-TOF m/z 169.3 [M]þ for compound 20 as a free
base.
4.4.3. 1-Ethyl-1,4,7-triazacyclononane-1,4,7-trihydrochloride
(21). NMR (D2O) 1H (300 MHz) 3.21 (3H, t, J 7, CH3), 3.19 (2H, q, J 7,
CH2eCH3), 3.55 (4H, br s, Ha), 3.57 (4H, br s, Ha), 3.68 (4H, br s, Ha);
13C (75 MHz) 12.1 (CH3), 43.3, 43.9, 49.7 (Ca), 54.7 (Caminal); MALDI-
TOF m/z 157.9 [M]þas a free base.
4.3.7. 4-(2-Picolyl)-10-(4-(trifluoromethyl)phenyl)-1,4,7-
triazabicyclo[5.2.1]decane (16). Reaction of 4 (500 mg, 1.75 mmol)
with 4-picolylchloride (214 mg, 1.65 mmol) and sodium iodide
(247 mg, 1.65 mmol) for 165 h. After filtration and evaporation,
purification of the residue by silica gel chromatography (CHCl3/
Et3N 9:1 then CHCl3/MeOH/Et3N 9:0.5:0.5) to yield a brown oil
(443 mg, 73%). NMR (CDCl3) 1H (300 MHz) 2.70e2.75 (2H, m,
HaNeCaminal), 2.88e2.94 (4H, m, HaN), 3.04e3.14 (4H, m,
2HaNþ2HaNeCaminal), 3.31e3.36 (2H, m, HaN), 3.97 (2H, s, CH2pic),
5.65 (1H, s, Haminal), 7.13 (1H, dd, J 5, 6, Hpic), 7.43 (1H, d, J 8, Hpic),
7.52 (2H, d, J 8, CHeCCF3), 7.64 (3H, m, 2Harþ1Hpic), 8.52 (1H, d, J 5,
Hpic); 13C (75 MHz) 49.4 (CaNeCaminal), 55.2 (CaN), 56.2 (CbN), 63.7
(CH2pic), 87.2 (Caminal), 122.2, 122.8 (CHpic), 124.9 (CH]CCF3, 3J 4),
124.9 (CF3, 1J 279), 127.2 (CH]CeCaminal), 128.9 (CeCF3, 2J 30), 136.6
(CH]CHeN), 149.4 (]CHeN), 149.6 (]CeCaminal), 160.5 (C]N).
4.4.4. 1-(4-Picolyl)-1,4,7-triazacyclononane-1,4,7-trihydrochloride
(22). NMR (D2O) 1H (300 MHz) 3.16 (4H, t, J 6, Ha), 3.41 (4H, t, J 6,
Ha), 3.73 (4H, br s, Ha), 4.26 (2H, s, CH2pic), 8.09 (2H, d, J 6, CeCHar),
8.79 (2H, d, J 6, CHareN); 13C (75 MHz) 45.3, 46.7, 50.7 (Ca), 59.9
(Caminal), 130.6 (CHar]CeN), 143.9 (CHareN), 160.4 (C); MALDI-TOF
m/z 221.0 [Mþ1]þ as a free base.
4.4.5. 1-Decyl-1,4,7-triazacyclononane-1,4,7-trihydrochloride
(23). NMR (D2O) 1H (300 MHz) 0.79 (3H, t, J 7.5, CH3), 1.21 (14H, m,
Hdecyl), 1.56 (2H, m, Hbdecyl), 2.88 (2H, m, Hdecyl), 3.19 (4H, m, Ha),
3.38 (4H, m, Ha), 3.54 (4H, m, Ha); 13C (75 MHz) 16.6 (CH3), 25.3,
26.8, 29.7, 32.0 (2C), 32.2, 32.3 (Cdecyl), 34.6 (Cbdecyl), 44.3, 45.2, 50.4
(Ca), 54.5 (Cadecyl).
4.3.8. 2-(6-((1,4,7-Triazabicyclo[5.2.1]decane)methyl)pyridinyl)-
methylcyclamphosphoryl (18). Reaction of 3 (250 mg, 1.15 mmol)
and 2-(6-(chloromethyl)-pyridynyl)methylcyclamphosphoryl (8)
(440 mg, 1.15 mmol) at 50 ꢀC for 4 days. The solution was evapo-
rated under reduced pressure to yield a yellow oil (640 mg, 97%),
which was introduced into the next step without further purifica-
tion. When necessary, purification by silica gel column chroma-
tography neutralized with Et3N was possible by eluting with CHCl3,
then CHCl3/MeOH 98:2. NMR (CDCl3) 1H (400 MHz) 1.51e1.44
(2H, m, H9), 1.68e1.78 (2H, m, H4), 2.28e2.32 (2H, m, H1), 2.38e2.41
(2H, m, H2), 3.87 (18H, m, Ha), 3.23e3.33 (4H, m, H3þH5), 3.45e3.84
(4H, m, H11þHa), 3.87 (2H, s, H17), 5.57 (1H, s, H21), 7.09 (1H, m, H25),
7.20 (3H, m, H24þH15), 7.41 (2H, m, H23), 7.62 (1H, m, H14), 7.77
(1H, m, H13); 13C (125 MHz) 21.7 (C4), 26.2 (C9), 40.6 (C10), 41.6, 41.9
4.4.6. 1-(2-Picolyl)-1,4,7-triazacyclononane-1,4,7-trihydrochloride
(24). NMR (D2O) 1H (400 MHz) 1.13 (4H, t, J 5, Ha), 3.41 (4H, t, J 5,
Ha), 3.71 (4H, br s, HaNH), 4.32 (2H, s, CH2pic), 8.03 (1H, dd, J 6, 8,
CHar]CHareN), 8.11 (1H, d, J 8, CHar]C), 8.60 (1H, t, J 8, CHar]
CHar), 8.77 (1H, d, J 6, CHar]N); 13C (100 MHz) 45.3, 46.7, 50.9 (Ca),
58.1 (CH2pic), 129. 4 (CHar]CHareN), 131.1 (CHar]CHar), 144.8
(CHar]CHareCHar), 150.2 (CHar]N), 153.1 (C).
4.4.7. 1-((50-Methyl-2,20-bipyridin-5-yl)methyl)-1,4,7-
triazacyclononane (25). Compound 3 (216 mg, 1.00 mmol) and 5-
(bromomethyl)-50-methyl-2,20-bipyridine24 (262 mg, 1.00 mmol)
were dissolved in distilled acetonitrile and potassium carbonate
was added. The reaction mixture was stirred for 1 day at 50 ꢀC. After
cooling, the solution was filtered and the solvent evaporated. The
residue (corresponding to 4-((50-methyl-2,20-bipyridin-5-yl)
methyl)-10-phenyl-1,4,7-triazabicyclo[5.2.1]decane 17) was puri-
fied by silica gel chromatography (CHCl3 then CHCl3/MeOH 98:2) to
yield directly deprotected compound 25 as a white-off powder
(100 mg, 32%). NMR (CDCl3) 1H (400 MHz) 2.35 (3H, s, CH3), 2.66
(4H, m, Ha), 2.78 (4H, m, Ha), 3.02 (4H, m, Ha), 3.4 (2H, s, Haminal),
7.58 (1H, d, J 8, CHar]CHareC), 7.76 (1H, d, J 8, CHar]CHareN), 8.22
(1H, d, J 8, CHar]CeN), 8.28 (1H, d, J 8, CHar]CeC), 8.46 (1H, s, Har),
8.57 (1H, s, Har); 13C (75 MHz) 18.2 (CH3), 45.7, 52.2, 55.4 (Ctacn),
58.3 (CH2bipy), 120.4 (2C) (CHar]CeN), 133.2 (2C) (CqeN), 137.3
(2C), 137.5(2C) (CHar]CeN), 149.5 (2CHareN), 153.2, 155.2
(2CeCH]N); MALDI-TOF m/z: 312.1 [Mþ1]þ.
(Cacyclam), 44.1 (Ca
,
2J 11), 45.3 (Ca
,
2J 16), 48.7, 48.9
cyclam
cyclam
(CaNeCaminal), 51.5, 52.5, 52.6, 53.1 (Cacyclam), 54.5, 54.6 (CaNtacn),
55.6, 55.7 (CaNtacn), 58.2 (Cacyclam), 60.1 (NcyclameCH2py), 62.8
(NtacneCH2pyr), 87.2, 87.7 (Caminal), 120.2 (C15), 121.3 (C13), 126.0
(C25), 126.1 (C23), 127.5 (C24), 137.0 (C14), 145.1 (C22), 158.9 (C16),
159.2 (C12); 31P (161.9 MHz) 25.9; MALDI-TOF m/z 565.3 [Mþ1]þ.
4.4. General procedure for aminal hydrolysis
Compounds 9e16 and 18 were dissolved in 25 mL of hydro-
chloric acid 1 M and stirred for 3 h at room temperature. The so-
lution was evaporated under reduced pressure. The residue was
washed by chloroform to yield hydrochloride compounds as white-
off solids. Anion-exchange resin DOWEX gave the alkylated tri-
azacyclononane as a free base.
4.4.8. Ditopic tacn-cyclam (26). A solution of 18 (750 mg,
1.15 mmol) in hydrochloric acid 6 M (30 mL) was stirred at room
temperature during 14 h. The solution was evaporated under re-
duce pressure. Work-up of the residue by anion-exchange resin
Dowex yielded 26 as a free base. The very hygroscopic product was
conserved as a hydrochloride salt.
4.4.1. 1-Benzyl-1,4,7-triazacyclononane-1,4,7-trihydrochloride
(19). NMR (D2O) 1H (300 MHz) 3.01 (4H, t, J 5, Ha), 3.18 (4H, t, J 5,
Ha), 3.57 (4H, s, HaNH), 3.88 (2H, s, CH2Ph); 7.38 (5H, m, C6H5); 13C
(75 MHz) 44.9, 46.1, 50.3 (Ca), 61.9 (CH2Ph), 133.3, 131.7, 133.1
(CHar), 138.1 (Car); MALDI-TOF m/z 220.2 [Mþ1]þ for compound 19
as a free base. Anal. Calcd for C13H24Cl3N3$3HCl$2.5H2O: C, 41.73; H,
7.82; N, 11.23; Cl, 28.42. Found: C, 41.37; H, 7.46; N, 11.27; Cl, 28.18.
C23H44N8 $8HCl (26$8HCl) NMR (D2O) 1H (400 MHz) 1.86
(2H, m, H4), 2.14 (2H, m, H9), 2.78 (2H, m, Ha), 2.84 (2H, m, Ha), 2.96
(2H, m, Ha), 3.10 (4H, m, Ha), 3.23 (8H, m, Ha), 3.29 (2H, m, Ha),
3.35(4H, m, Ha), 3.87 (2H, s, H11), 4.07 (2H, s, H17), 7.36 (1H, d, J 8,
H
15), 7.52 (1H, d, J 8, H13), 7.93 (1H, dd, J 8, 8, H14); 13C (100 MHz)
4.4.2. 1-Allyl-1,4,7-triazacyclononane-1,4,7-trihydrochloride
(20). NMR (D2O) 1H (300 MHz) 3.07 (4H, t, J 6, HaN), 3.31 (4H, t, J 6,
HaN), 3.38 (2H, m, CH2eCH]), 3.57 (4H, s, HaNH), 5.29 (1H, d, J 10,
22.2 (C9), 25.0 (C4), 42.7 (Catacn), 42.8 (Cacyclam), 44.2 (Catacn), 44.4
(Cacyclam), 45.0 (C8), 46.5 (Cacyclam), 46.7 (Cacyclam), 48.6 (Catacn), 49.7
(Cacyclam), 49.8 (Cacyclam), 51.5 (Cacyclam), 52.9 (Cacyclam), 57.5 (C11),

M. Roger et al. / Tetrahedron 68 (2012) 5637e5643
5643
60.5 (C17), 123.8, 124.1 (C15, C13), 139.2 (C14), 156.4, 157.2 (C16, C12).
Anal. Calcd for C23H44Cl3N8$8HCl$5H2O C, 33.92; H, 7.67; N, 13.76;
Cl, 34.83. Found: C, 33.66; H, 7.72; N, 13.62; Cl, 34.89.
5. Parker, R. J.; Spiccia, L.; Berry, K. J.; Fallon, G. D.; Moubaraki, B.; Murray, K. S.
Chem. Commun. 2001, 333e334; Sokol, J. J.; Lee, A. G.; Long, J. R. J. Am. Chem. Soc.
2002, 7656e7657.
6. Tetilla, M. A.; Aragoni, M. C.; Arca, M.; Caltagirone, C.; Bazzicalupi, C.; Bencini,
A.; Garau, A.; Isaia, F.; Laguba, A.; Lippolis, V.; Meli, V. Chem. Commun. 2011,
3805e3807.
7. Pouessel, J.; Bazzicalupi, C.; Bencini, A.; Bernard, H.; Giorgi, C.; Handel, H.;
Matera, I.; Le Bris, N.; Tripier, R.; Valtancoli, B. Chem. Asian J. 2011, 6, 1582e1594.
8. Chong, H.; Brechbiel, M. W. Synth. Commun. 2003, 33, 1147e1154.
9. Zhang, Q. F.; Yang, W. H.; Yi, W. J.; Zhang, J.; Ren, J.; Luo, T. Y.; Zhu, W.; Yu, X. Q.
C23H44N8 (26) NMR (CDCl3) 1H (400 MHz) 1.79 (2H, m, H4), 1.88
(2H, m, H9), 2.64 (2H, m, H1), 2.75 (4H, m, H18), 2.78e2.86 (16, m,
HacyclamþHatacn), 2.98 (4H, s, H20), 3.84 (2H, s, H11), 3.88 (2H, s, H17),
4.86 (5H, s, NH), 7.13 (1H, d, J 8, H15), 7.33 (1H, d, J 8, H13), 7.64
(1H, dd, J 8, 8, H14); 13C (100 MHz) 25.0 (C9), 26.5 (C4), 43.3 (C20),
45.4 (C19), 46.6 (Ca), 46.7 (Ca), 47.9 (C8), 48.2 (Ca), 49.0 (Ca), 50.2 (Ca),
51.7 (C18), 52.8 (C10), 53.0 (C1), 58.7 (C11), 61.1 (C17), 121.3 (C15), 121.9
(C13), 137.2 (C14), 158.1 (C16), 158.4 (C12); MALDI-TOF m/z 433.38
[M]þ, 434.39 [Mþ1]þ.
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Acknowledgements
This research was supported by the Centre National de la
ꢀ
Recherche Scientifique. We gratefully acknowledge the Region
€
A. J.; Fallis, I. A.; Gould, R. O.; Parsons, S.; Ross, S. A.; Schroder, M. J. Chem. Soc.,
ꢀ ꢀ
ꢁ
Bretagne (MR) and the Conseil General du Finistere (MB) for grants
support. The authors thank the ‘Services Communs’ of the Univer-
sity of Brest for NMR facilities.
Chem. Commun. 1994, 2467e2469; Warden, A.; Graham, B.; Hearn, M. T. W.;
Spiccia, L. Org. Lett. 2001, 3, 2855e2858; Battle, A. R.; Spiccia, L. Tetrahedron 2005,
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Supplementary data
ꢀ
17. Sobiesciak, T. D.; Zielenkiewicz, P. J. Org. Chem. 2010, 75, 2069e2072.
NMR spectra (1H, 13C) of most of compounds and 2D NMR of
compounds 3 and 6 are provided. Supplementary data associated
with this article can be found in the online version, at doi:10.1016/
j.tet.2012.04.057.
18. Broan, C. J.; Cole, E.; Jankowski, K. J.; Parker, D.; Pulukkody, K.; Boyce, B. A.;
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