Selective mono-N-alkylation of triethylenetetraamine. A new versatile route to polylinear aza-ligands

Article abstract of DOI:10.1016/j.tetlet.2009.03.088

A new route to triethylenetetraamine selective mono-N-alkylation on secondary nitrogen atom using simultaneously bisaminal and diamide protections is presented and applied to the synthesis of poly-linear aza-ligands.

Full text of DOI:10.1016/j.tetlet.2009.03.088

Tetrahedron Letters 50 (2009) 2521–2524
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Selective mono-N-alkylation of triethylenetetraamine. A new versatile route to
polylinear aza-ligands
*
Anne-Sophie Delépine, Raphaël Tripier , Hélène Bernard, Nathalie Le Bris, Henri Handel
UMR CNRS 6521, Chimie, Electrochimie Moléculaires et Analytique, Université de Bretagne Occidentale, 6 avenue Victor 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:
A new route to triethylenetetraamine selective mono-N-alkylation on secondary nitrogen atom using
simultaneously bisaminal and diamide protections is presented and applied to the synthesis of poly-lin-
ear aza-ligands.
Received 4 February 2009
Revised 5 March 2009
Accepted 10 March 2009
Available online 17 March 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Macrocyclic saturated polyamines constitute versatile ligands
whose coordination properties are now well documented.1 They
are the center of interest of numerous research groups in the fields
of organic, inorganic, applied chemistry2 or medical applications.3
The relatively rigid architecture of azamacrocyclic ligands imposes
a coordination geometry on the metal ion and forms metal com-
plexes with high thermodynamic stability and kinetic inertness.
In contrast, linear ligands are more flexible and are then able to
encapsulate the ion in a way that achieves an optimal match be-
tween the requirements of both anionic and cationic species, at
the price of somewhat lower thermodynamical stability and higher
kinetic lability than those of cyclic homologs.1 As reported for tet-
raazacycloalkanes, the selective N-alkylation of linear tetraamines
allows a large pannel of applications as biomolecule or solid sup-
port coupling. Another idea aims in the formation of polytopic li-
gands. In general, tetraamines properties are obviously
maintained in their dimeric or trimeric analogs, which present
moreover several coordination centers.4,5
The known routes for the efficient selective N-alkylation of lin-
ear polyamines often consist in tedious multistep processes;6 for
instance, very few examples of selective mono-N-alkylation of
the primary amine of triethylenetetraamine 1 have been de-
scribed.7 The bisaminal tool, initially used as template agent of lin-
ear tetraamines for tetraazacycloalkanes synthesis,8 was
afterwards successfully employed as temporary protecting agent
for the mono-N-alkylation of cyclic tetraamine9 and of terminal
amine functions of linear tetraamines.10 Moreover, the bisaminal
tool is not suitable to the selective mono-N-alkylation of tetraam-
ines by one of the secondary amine functions, which remains tricky
to perform.
function (gem-cis, gem-trans, vic-cis, and vic-trans, see in Supple-
mentary data).8 The vic-trans derivative isolated in a 75% yield
proved to be the most suitable for condensation of the diester
agent (70% yield, Scheme 1). The intermediate 3 obtained as its
vic-cis isomer in a very good yield was previously used for cyclen
synthesis.11 Moreover, it presents similarities with the so-called
‘autoprotected’ macrocycles possessing unreactive amide func-
tions in their ring which proved to be interesting intermediates
for the selective alkylation of tetraazacycloalkanes.12 We found in-
deed that 3 combines advantageously the two kinds of protections
(bisaminal and autoprotection) previously cited and enables to
control the selective mono-N-alkylation of the azamacrocycle.
As established from its computer-generated model that fits well
to the observed ORTEP structure11 (Fig. 1), the synthesized bisami-
nal diamide 3 presents at the same time two non-reactive amide
functions (N1, N2) and a bent cis-configuration, which induce a dis-
crimination between the two remaining nitrogen atoms. As a mat-
ter of fact, the N4 atom possesses its lone pairs directed toward the
convex side of the molecular structure while the lone pair of N3 is
located on the concave side of the bisaminal. Consequently N4
atom exhibits a much more marked nucleophilic character as al-
ready mentioned for cyclenglyoxal.9 AM1 molecular orbital calcu-
lations on 3 are in favor of this analysis: N3 lone pair is involved in
the aminal bridge bonds while the N4 lone pair stays localized on
the nitrogen atom. Since N1,N2 were locked by the amide func-
tions, only N4 remains ready for further alkylation (Fig. 1, top).
Then, the formation of the monoammonium salt is univocal: the
N4
N1
N2
H
H
ii)
NH NH2
NH NH2
1
N
N
NH
NH
N
N
N
O
O
i)
It was previously shown that the reaction of triethylenetetra-
amine 1 with glyoxal affords a mixture of bisaminal derivatives
depending on the relative position/configuration of the bisaminal
N
H
H
N3
2
3
vic-trans
vic-cis
* Corresponding author. Tel.: +33 2 98017001; fax: +33 2 98017927.
E-mail address: raphael.tripier@univ-brest.fr (R. Tripier).
Scheme 1. Synthesis of 3: (i) glyoxal, (ii) diethyloxalate.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.03.088

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A.-S. Delépine et al. / Tetrahedron Letters 50 (2009) 2521–2524
Figure 1. AM1 molecular orbital calculations and computer-generated model of 3 vic-cis derivative.
reaction of one equivalent of an electrophile with 3 leads to the
corresponding mono-alkylated derivative without any special pre-
cautions. The use of an excess of electrophile leads to the same
result.
crystals for X-ray diffraction studies. The obtained structure
(Fig. 2) unambiguously shows the vic-cis-configuration of the bisa-
minal derivative and the alkylation on the exo-side of the tetra-
amine skeleton.
In a typical experiment (Scheme 2), the synthesis starts with the
preparation of the ammonium salts 4a–b using benzyl bromide (or
1-bromomethyl-4-nitrobenzene) as the electrophile. The reaction
is performed at room temperature in chloroform and the protected
adduct (monoammonium salt) precipitates as soon as it is formed
(70% yields). Crystallization of 4a from water afforded suitable
It is noteworthy that the alkylation also takes place with one of
the minor isomers of 3, the gem-cis derivative, isolated as pre-
sented in the literature.13 AM1 molecular orbital calculations on
the gem-cis isomer of 3 indicate that here again the N3 lone pair
is involved in the aminal bridge bonds while the N4 lone pair stays
localized on the nitrogen atom (Fig. 3). The selective alkylation per-
HN
NH2
N
H
N
N
NH2NH2, H2O
NH2
HCl
N
HN
O
N
O
N
N
H
O
O
N
4.HCl
R
Br
R
R
R
Br
10a, R = H
4a, R = H,
7a, R = H
4b, R = NO2
7b, R = NO2
10b, R = NO2
NH2
NH
8.HCl
NH2NH2, H2O
N
H
NH
N
H
HN
N
N
N
O
HCl
X
H
N
X
X
N
N
N
NH2
N
N
3
N
N
H
N
H
NH2
N
O
N
N
H2N
O
O
O
O
8a, X = CH
8b, X = N
11a, X = CH
11b, X = N
5a, X = CH
5b, X = N
O
O
O
I
I
2I
X
NH2
NH
O
O
N
N
H
NH
O
N
NH2
HN
N
N
N
N
NH2NH2, H2O
12.HCl
HCl
O
O
H2N
N
N
N
N
HN
N
N
H
N
H
N
N
N
O
I
O
NH
N
H
N
NH
O
HN
O
N
O
N
O
H2N
NH2
H2N
NH
N
6
9
12
3I
I
I
Scheme 2. From cyclic to linear polyamines; overview of the synthetic ways.

A.-S. Delépine et al. / Tetrahedron Letters 50 (2009) 2521–2524
2523
Figure 4. X-ray structures of 4b0, ORTEP view, 50% probability ellipsoids.
Figure 2. X-ray structures of 4a, ORTEP view, 50% probability ellipsoids.
configurations. The diammonium salt is constituted by a mixture
of racemic and meso diastereoisomers, possessing, respectively, a
C2 axis and a plane of symmetry, while the triammonium salt is
composed of a mixture of two racemic diastereoisomers: the first
one containing no element of symmetry and the second one pos-
sessing a C3 axis as the unique symmetry element. Thus, this situ-
ation results in complex NMR 13C/1H spectra for 5ab and 6, due to
the coexistence of multiple configurations. The presence of the dif-
ferently linked isomers has no impact on the end products ob-
tained in good yields (8a: 73%, 8b: 71%, 9: 71%).
The preparation of monomeric compounds 10a–b is very easy-
to-run and shows the suitability of our method to functionalize
selectively one of the secondary amines of triethylenetetraamine
1 (neither high dilution conditions nor chromatography workup
or fastidious deprotection step were needed). Bipodal 11ab and tri-
podal 12 polyamines constitute interesting ligands for further
coordination investigations with cationic or anionic guests based,
respectively, on their high number of functionalizable amines4 or
their protonation5 potentials. According to the nature of both tet-
raamine and linker, they also can prefigure the building blocks of
new generation of podands.
In conclusion, taking simultaneously advantage of two well-
known protecting strategies of tetraazacycloalkanes we report
here a very efficient route to the triethylenetetraamine selective
mono-N-alkylation in high yields and no restricting reaction condi-
tions (neither high dilution conditions nor chromatography work-
up or fastidious deprotection step were needed). The scope of this
method now remains to be extended to other tetraamines and
quaternizing agents. This strategy was applied to the synthesis of
two new kinds of podal ligands with very attractive potentialities
in coordination or applied chemistry. Investigations are now in
formed under the same conditions leads to 4b0 in similar yield. X-
ray diffraction studies made on crystals obtained by water evapo-
ration and structure of 4b0 (Fig. 4) clearly highlight the nature of
this ammonium salt.
The deprotection of 4a, 4b–b0 ammonium salts was performed
in hydrazine monohydrate as previously described,9 leading to
the free diamide ligands in good yield (7a–b: 78%). One can note
the particular inertness of the amide functions in respect to the
hydrazinolyzis workup.
At this point, the reduction of the amide functions could be con-
sidered to obtain mono-alkylated cyclen and derivatives, but we
found that the synthetic pathway presented here implies no real
advantage compared with the existing route, based on cyclengly-
oxal as the intermediate.9 However, after removing the amide
functions the reaction leads selectively to N-functionalized trieth-
ylenetetraamine: the hydrolysis of the diamides was achieved in
acidic medium (HCl 8 N, 80 °C) to give linear polyamines 10a–b,
in quantitative yields (X-ray structure in Fig. 5).
The reaction conditions were extended in order to obtain di-
meric and trimeric derivatives, playing on the type of alkylating
agents (bis- or tris-electrophile) and the stoichiometry of the re-
agents (electrophile/compound 3 1:2 or 1:3, respectively) to yield
dimeric derivatives using 1,3-bis(iodomethyl)benzene or 2,6-bis-
bromomethyl-pyridine and a trimeric derivative using the 1,3,5-
tris(iodomethyl)benzene.
It is noteworthy that the alkylation of 3, and consequently the
formation of the monoammonium salt, lead to racemic diastereoi-
somers. Therefore, the formation of the diammonium or triammo-
nium salts 5ab–6, consists in the formation of several possible
Figure 3. AM1 molecular orbital calculations on 3 gem-cis derivative.
Figure 5. X-ray structure of 10a, ORTEP view, 50% probability ellipsoids.

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A.-S. Delépine et al. / Tetrahedron Letters 50 (2009) 2521–2524
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Acknowledgments
This research work was supported by the Ministère de l0Educa-
tion Nationale et de la Recherche and by the Centre National de la
Recherche Scientifique. We also thank the CHEMATECH Society
(Dijon, France) for the starting triethylenetetraamine.
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Supplementary data
Compound 2 isomers, experimental procedure, 1H, 13C NMR
data, X-ray analytical data. CCDC references numbers: 4a CCDC
653285, 4b0 CCDC 653286, 10a CCDC 653287. Supplementary data
associated with this article can be found, in the online version, at
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