Cyclohexanedione bisaminals as intermediates for cyclen, homocyclen, and cyclam synthesis

Article abstract of DOI:10.1080/00397910600910633

A new easy-to-run route to cyclen, homocyclen, and cyclam is proposed, based on the cyclization with dibromo- or ditosyloxy-derivatives of bisaminal intermediates obtained by condensation of the appropriate linear tetraamine with cyclohexanedione. In the cyclization step, the use of cesium carbonate instead of potassium carbonate as proton trapper caused a remarkable increase of yields. Copyright Taylor & Francis Group, LLC.

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Cyclohexanedione Bisaminals as
Intermediates for Cyclen, Homocyclen, and
Cyclam Synthesis
Anton Prokhorov a , Nathalie Le Bris a , Hélène Bernard a , Géraldine
Claudon a & Henri Handel a
a Department of Chemistry, University of Brest, Brest, France
Version of record first published: 24 Nov 2006.
To cite this article: Anton Prokhorov, Nathalie Le Bris, Hélène Bernard, Géraldine Claudon & Henri Handel
(2006): Cyclohexanedione Bisaminals as Intermediates for Cyclen, Homocyclen, and Cyclam Synthesis,
Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
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Synthetic Communicationsw, 36: 3271–3282, 2006
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910600910633
Cyclohexanedione Bisaminals as
Intermediates for Cyclen, Homocyclen, and
Cyclam Synthesis
´ `
Anton Prokhorov, Nathalie Le Bris, Helene Bernard,
´
Geraldine Claudon, and Henri Handel
Department of Chemistry, University of Brest,
Brest, France
Abstract: A new easy-to-run route to cyclen, homocyclen, and cyclam is proposed,
based on the cyclization with dibromo- or ditosyloxy-derivatives of bisaminal inter-
mediates obtained by condensation of the appropriate linear tetraamine with cyclohex-
anedione. In the cyclization step, the use of cesium carbonate instead of potassium
carbonate as proton trapper caused a remarkable increase of yields.
Keywords: Bisaminal, cyclam, cyclen, cyclohexanedione, cyclization, homocyclen
INTRODUCTION
Macrocyclic tetraamines are interesting because of their remarkable complex-
ing properties and find applications in many areas. Their derivatives are
widely developed as extractants, as cation and anion sensors, and particularly
as magnetic resonance imaging (MRI) contrast agents.[1,2] Thus, easy-to-run
routes for the basic tetraazamacrocycles cyclen, cyclam, and analogues are
still of substantial interest. The well-known and most usual method for
different macrocyclic tetraamines synthesis is the Richman and Atkins con-
densation of N-tosyl derivatives of linear amines with a biselectrophile,
namely a ditosylate.[3] However, this general method is not without certain
Received in Poland April 4, 2006
Address correspondence to Henri Handel, Department of Chemistry, UMR CNRS
6521, University of Brest, 6 Avenue Victor Le Gorgeu, CS 93837, 29238 Brest, France.
E-mail: henri.handel@univ-brest.fr
3271

3272
A. Prokhorov et al.
disadvantages: the last deprotection step necessitates a strong acidic medium
and, above all, it is not “atom economic.”
The idea of a “template effect” induced by the rigidification of a linear
tetraamine obtained by condensation with a dicarbonyl compound and
followed by cyclization of the resulted bisaminal with a biselectrophile is rela-
tively recent.[4] We previously reported a successful procedure for the
synthesis of tetraazamacrocycles as cyclen, homocyclen, and cyclam via
cyclization of bisaminal derivatives obtained by condensation of an appropri-
ate linear tetraamine with butanedione.[5] Other bisaminal intermediates
issued from condensation of tetraamines with glyoxal,[6] pyruvic
aldehyde,[7] or phenylglyoxal[8] were reported in the literature; however, to
our knowledge, it seems that the use of these compounds as precursors of tetra-
azamacrocycles is sometimes more difficult for the following causes. First,
macrocyclic bisaminals issued from glyoxal are very stable;[9] they resist
acidic hydrolysis and necessitate more complicated deprotection reactions
involving hydroxylamine, oxidation agent, or hydrazine hydrate to release
the macrocycle.[4,6] Second, in some cases, linear tetraamine bisaminals are
not stable and, during the cyclization reaction or deprotection step, lead to
some complications: formation of amidinium salts or conversion to lactam
and even to amino acid.[8] Moreover, the formation of linear tetraamine bisam-
inals often gives rise to a mixture of stereoisomers because of several possibi-
lities for condensation.[10] That could yield multiple stereoisomers according
to the vic- or gem-insertion of the dicarbonyl reagent and cis- or trans-
configuration of the resulting bisaminal bridge (Scheme 1). In the case of
asymmetrical dicarbonyl compounds, the situation could be still more com-
plicated. Furthermore, it is not certain that all these isomers present the
same reactivity toward a biselectrophile derivative to give a macrocyclic
intermediate.
The formation of a bisaminal with a cyclic dicarbonyl compound should
allow us to avoid a complex mixture of isomers and to make the bisaminal
structure more rigid. As a matter of fact, bisaminals 1a, 2a, and 3a obtained
from condensation of triethylenetetraamine 1, N,N0-bis(2-aminoethyl)-1,3-
propanediamine 2, and N,N0-bis(3-aminopropyl)-1,2-ethylene-diamine 3
with cyclohexan-1,2-dione were, to our knowledge, never involved in cycliza-
tion processes.[11] So, it appeared interesting to study the possibility of their
Scheme 1. Theorical bisaminals of linear tetraamines.

Cyclohexanedione Bisaminals
3273
utilization to obtain cyclen, homocyclen, and cyclam through their subsequent
condensation with biselectrophiles and deprotection. In this article, we report
synthesis, properties, and particularities of cyclohexanedione bisaminals.
RESULTS AND DISCUSSION
As previously observed, the condensation of linear tetraamines 1, 2, and 3 with
cyclohexanedione in ethanol led to only a single condensation product, the
most stable isomer containing the maximum of six-membered fused rings:
the gem-cis isomer for bisaminals 1a and 2a and the vic-cis in the case of
bisaminal 3a (Scheme 2).[11] The resulting bisaminals, obtained in 80–90%
yield, were characterized by 13C NMR spectroscopy, and as expected for cis-
configurations, exchange phenomena were observed for the three bisaminals.
X-ray analysis performed for compound 1a showed asymmetrical
geometry of this bisaminal in a crystal state, which corresponds to the most
favorable thermodynamic form with all six-membered cycles in chair confor-
mation. The ORTEP view with principal bond lengths is given in Fig. 1.
The macrocyclization of linear tetraamine bisaminals 1a, 2a, and 3a with a
dielectrophilic substrate such as dichloro-, dibromo-, diiodo-, and ditosyloxy-
ethane or propane was performed under standard conditions for such
reactions (i.e., potassium carbonate as proton trapper in acetonitrile at mild
temperature) (Scheme 2). Cyclization of bisaminals 1a and 2a with dibromo-
and ditosyloxy- derivatives led to cyclen, homocyclen, and cyclam bisaminals
4a, 5a, and 6a, respectively, in 20–50% yield. The reaction generated a
significant quantity of oligomer products. In the case of reactions with
Scheme 2. General route to cyclen, homocyclen, and cyclam via cyclohexanedione
bisaminals.

3274
A. Prokhorov et al.
˚
Figure 1. ORTEP view of 1a. Selected bonds length, (A): C(1)–C(2) 1.552(2),
N(1)–C(2) 1.4748(19), N(2)–C(2) 1.457(2), C(1)–N(3) 1.4773(18), and C(1)–N(4)
1.4772(19).
dichloro- derivatives, no products were obtained, and the starting bisaminal was
recovered: obviously, dichloroethane and dichloropropane are not reactive
enough. On the contrary, diiodo-reagents are too reactive, and only oligomer
products were formed in a short space of time, even under very mild conditions
(208C), except in the case of 2a with diiodopropane, where cyclization occurs in
63% yield. The experimental conditions and results are given in Table 1. For
bisaminal 3a, no cyclization was observed in any case. The starting bisaminal
was entirely recovered, and no trace of substitution products was observed.
On the one hand, the configuration of the two nitrogen atoms is certainly not
favorable for a nucleophilic substitution, which should lead either to cyclocon-
densation or to oligomerization, and on the other hand, because the starting
biselectrophile was not recovered, certainly an elimination reaction occurred.
These very moderate yields of macrocyclic bisaminals 4a–6a prompted
us to look for more favorable conditions for the reaction. Changing of
solvent, time, or temperature had no great influence on the yields. We also
tried to use an alternative base. Replacement of potassium carbonate by tri-
ethylamine or diisopropylethylamine also kept yields at the same level.
However, the use of cesium carbonate instead of potassium carbonate
caused a remarkable increase of yields. Reaction of bisaminals 1a and 2a
with dibromoethane or dibromopropane in the presence of a double excess
of cesium carbonate in acetonitrile led to the formation of cyclic tetraamine

Cyclohexanedione Bisaminals
3275
Table 1. Experimental conditions of the cyclization step
Reagent
Starting
Yield (%)b
bisaminal
n
X
T (8C)
Time
Product
K2CO3
Cs2CO3
1a
1a
1a
1a
1a
1a
2a
2a
2a
2a
2a
2a
0
0
0
1
1
1
0
0
0
1
1
1
Br
I
40
20
40
40
20
40
40
20
40
40
20
40
5 days
18 h
4a
a
31
—
20
21
—
20
23
—
51
47
63
30
90
—
50
80
—
56
85
—
55
91
75
60
—
OTs
Br
I
4 days
3 days
18 h
4a
5a
a
—
OTs
Br
I
2 days
3 days
5 h
5a
5a
a
—
OTs
Br
I
4 days
3 days
18 h
5a
6a
6a
6a
OTs
2 days
aOnly oligomer products.
bYields after recrystallization.
bisaminals 4a–6a in about 80–90% yield. It appears that the nature of the
cation in the intramolecular nucleophilic substitution process is of crucial
importance. Such phenomenon, described in literature as the “cesium
effect,”[12] has been known for a long time and consists in a strong
promotion of cyclization reaction versus competitive oligomerization
process. The influence of the cesium cation was observed for various ring-
closure reactions as formation of macrocyclic lactones, crown-ethers, and
others. An initial interpretation of the phenomenon considered that a fast intra-
molecular reaction would take place on the surface of the large, polarizable
cesium ion.[13] It could be assumed that this effect is mainly due to the
close carbonate–cesium ion pair. After the first nucleophilic substitution
reaction, the second step of the cyclization implies the double activation of
the remaining electrophilic moiety and simultaneously of the nucleophilic
one. On the one hand, the cesium ion acts as a Lewis catalyst toward the
leaving group while, on the other hand, the carbonate ion activates the nucleo-
philicity of the neighboring nitrogen atom through hydrogen bonding. The
process takes place in the favorable shape of a six-membered ring. The best
results were obtained with bromine as leaving group (Scheme 3).
This situation, a base ion paired with a metal ion engaged in a cyclic tran-
sition state is very similar to the classical one invoked rationalized syn elim-
ination in the E2 reaction of neutral substances.[14] The higher solubility of
cesium salts in aprotic solvent undoubtedly constitutes the other determining
factor.[12]
Bisaminals 4a–6a were characterized by 13C NMR spectroscopy, and
temperature-dependent changes were observed as well. For example, the

3276
A. Prokhorov et al.
Scheme 3. Illustration of the “cesium effect.”
spectrum of the compound 4a recorded at 203 K (Fig. 2; spectrum a) consists
of seven signals: one corresponds to the two aminal carbons, four are assigned
to the eight a-carbon atoms, and two correspond to the bisaminal bridge cycle
carbons. This observation is consistent with conformationally labile enantio-
meric forms with axial symmetry. At 253 K, a coalescence phenomenon is
observed (spectrum b), and at room temperature, fast exchange between the
two enantiomeric forms occurs (spectrum c). Then, the spectrum consists of
five signals; only two of them are assigned to the eight a-carbon atoms: it cor-
responds to the mean spectrum in which carbon atoms exchange two by two
their situation (Scheme 4). The same observations are done between 298 K
and 343 K for bisaminal 5a and between 363 K and 403 K for bisaminal 6a.
Figure 2. 13C NMR spectra of bisaminal 4a in toluene-d8.

Cyclohexanedione Bisaminals
3277
Scheme 4. Equilibrium between two enantiomeric forms of bisaminal 4a.
X-ray analysis for 4a was performed and represents in solid state one of
the possible conformers characterized by chair conformation for all six-
membered rings as well (Fig. 3).
Bisaminal 6a was also prepared by direct reaction of cyclohexanedione
with the corresponding macrocycle; it corresponds also to the most stable
isomer containing the maximum of six-membered fused rings and therefore
is identical to the one obtained by cyclization. Concerning compounds 4a
and 5a, cyclohexanedione did not react with cyclen and homocyclen, conse-
quently, cyclization appeared to be the only way to obtain these bisaminals.
Bisaminals 4a–6a were easily deprotected to form tetraazamacrocycles.
Contrary to bisaminals of glyoxal derivatives, which require hard conditions
for the deprotection (treating by hydrazine hydrate at high temperature),
cyclohexanedione ones lose bisaminal bridges in 1 M hydrochloric acid
solution, at 608C, during a few hours. Resulting tetraamine hydrochlorides
˚
Figure 3. ORTEP of 4a. Selected bonds length, (A): C(1)–C(2) 1.518, N(1)–C(2)
1.454, N(2)–C(2) 1.472, C(1)–N(3) 1.462, and C(1)–N(4) 1.474.

3278
A. Prokhorov et al.
gave their free form after 3 h in refluxing acetonitrile in the presence of
potassium carbonate or, alternatively, using a strong anionic exchange resin
(Amberlystw A-26). Moreover, relatively expensive cyclohexanedione could
be successfully recovered after deprotection and used again.
In conclusion, compared to previous methods proposed for the synthesis
of cyclen, homocyclen, and cyclam based on the bisaminal chemistry, the
association of cyclohexanedione and cesium carbonate undoubtedly constitu-
tes an improvement: starting from the linear tetraamine, after three protection–
cyclization–deprotection steps, the desired macrocycles are obtained in 75–
80% yields. Removal and recovery of the protective group is cleanly and
quantitatively carried out under mild acidic conditions. This procedure
could certainly be successfully applied to synthesize more complicated struc-
tures containing a functionalized pendant arm brought by the biselectrophilic
moiety. Further work concerning this aspect is currently in progress.
EXPERIMENTAL
General
All reagents were of commercial quality, and solvents were dried according to
standard procedures. NMR spectra were acquired on a Bruker AC 300 spec-
trometer (1H: 300 MHz, 13C: 74.47 MHz). The chemical shifts are in d
values relative to the internal standard TMS. IR spectra were recorded on a
Perkin Elmer Spectrum One FT-IR spectrometer. Mass spectra were
measured using a ZabSpec TOF Micromass spectrometer. Elemental
analyses were carried out by the Service de Microanalyse, CNRS, 91198
Gif sur Yvette, France.
General Procedure for the Synthesis of Linear Tetraamine
Bisaminals 1a–3a
These three bisaminals were previously described;[11] here, their synthesis was
performed as following: a solution of cyclohexanedione (560 mg, 5 mmol) in
ethanol (30 mL) was added dropwise to a solution of the tetraamine (730 mg,
5 mmol for tetraamine 1; 800 mg, 5 mmol for tetraamine 2; or 870 mg,
5 mmol for tetraamine 3) in ethanol (30 mL) at 08C with intensive stirring,
and the mixture was kept at the same temperature for 3 h. The solvent was
removed under reduced pressure, and the residue was treated by diethyl
ether (50 mL). A small quantity of insoluble polymer product was filtered
off, and the solvent was removed to yield the corresponding bisaminal. The
bisaminal can be used as such in the next step or better, recrystallized in
hexane.
Bisaminal 1a: White solid, mp 1108C, yield 90%.

Cyclohexanedione Bisaminals
3279
Bisaminal 2a: White solid, mp 1248C, yield 90%.
Bisaminal 3a: White solid, mp 1338C, yield 80%.
General Procedure for the Synthesis of Cyclic Tetraamine
Bisaminals 4a–6a
The biselectrophile compound (1.1 mmol) was added to an acetonitrile
(10 mL) mixture of the corresponding linear tetraamine bisaminal (1 mmol)
and potassium or cesium carbonate (4 mmol). The resulting mixture was
stirred at the temperature and for the time indicated in Table 1. Then, the
solid was filtered off, and the solvent was removed under reduced pressure.
Resulting white powder was recrystallized from hexane. Yields and conditions
are indicated in Table 1.
Data
Bisaminal 4a. White solid, mp 768C. 1H NMR (300 MHz, CDCl3): d ¼ 1.53–
1.57 (m, 4H, CH2CH2Caminal), 1.65 (m, 4H, CH2CH2Caminal), 2.81–2.94
(m, 16H, CH2N). 13C NMR (75.47 MHz, CDCl3): d ¼ 22.3 (CH2CH2Caminal),
22.6 (CH2CH2Caminal), 47.5, 48.4 (CH2N), 77.4 (Caminal). IR (KBr):
n(cm21) ¼ 2950, 2919, 2896, 2803, 2854, 1214, 1180, 1125, 1041, 961.
¯
Anal. calcd. for C14H24N4: C, 67.70; H, 9.74; N, 22.56; found: C, 67.98; H,
10.02; N, 22.26.
Bisaminal 5a. White solid, mp 978C. 1H NMR (300 MHz, CDCl3):
d ¼ 1.07–1.17 (m, 1H, CH2CH2N), 1.40–1.55 (m, 4H, CH2CH2Caminal),
2.20–3.35 (m, 1H, CH2CH2N þ 4H, CH2CH2Caminal þ 15H, CH2N), 3.70–
3.85 (m, 1H, CH2N). 13C NMR (75.47 MHz, CDCl3): d ¼ 17.9, 18.3, 19.5,
21.3, 22.4 (CH2CH2N þ CH2CH2Caminal), 43.9, 44.3, 45.7, 45.8, 46.8, 48.8,
50.3, 51.3 (CH2N), 72.5, 78.9 (Caminal). IR (KBr): n(cm21) ¼ 2939, 2889,
¯
2857, 2810, 1256, 1211, 1190, 1142, 1046, 1001, 946, 878. Anal. calcd.
for C15H26N4: C, 68.66; H, 9.99; N, 21.35; found: C, 68.79; H, 9.74; N,
21.25. HRMS (ESI): calcd. for C15H27N4: 263.2236 [M þ H]þ; found:
263.2235.
Bisaminal 6a. White solid, mp 1458C. 1H NMR (300 MHz, CDCl3):
d ¼ 1.11–1.15 (m, 2H, CH2CH2N), 1.44–1.50 (m, 4H, CH2CH2Caminal),
2.16–2.25 (m, 4H, CH2CH2Caminal), 2.30–2.59 (m, 2H, CH2CH2N þ 8H,
CH2N), 2.72–2.78 (m, 4H, CH2N), 3.25–3.32 (m, 2H, CH2N), 3.89–3.95
(m, 2H, CH2N). 13C NMR (75.47 MHz, CDCl3): d ¼ 16.9, 17.7, 21.5
(CH2CH2N þ CH2CH2Caminal), 45.0, 45.6, 48.2, 49.5 (CH2N), 72.8
(Caminal). IR (KBr): n(cm21) ¼ 2943, 2883, 2809, 2777, 2752, 1355, 1345,
¯
1305, 1195, 1158, 1026, 943, 880. Anal. calcd. for C16H28N4: C, 69.52; H,

3280
A. Prokhorov et al.
10.21; N, 20.27; found: C, 69.27; H, 10.17; N, 20.02. HRMS (ESI): calcd. for
C16H29N4: 277.2392 [M þ H]þ; found: 277.2395.
General Procedure for the Deprotection of Bisaminals
The cyclic tetraamine bisaminal (1 mmol) was dissolved in 20 mL of 1 M
hydrochloric acid, and the solution was stirred at 608C for 6 h. Then, the
solution was extracted by 3 ꢀ 20 mL of chloroform. Evaporation of chloro-
form solution yields pure cyclohexanedione. The water phase was evaporated
as well to yield a brown solid, which was treated by ethanol (20 mL), and the
mixture was stirred at room temperature for 1 h. Then, the resulting solid was
filtered off and suspended in 20 mL of acetonitrile with potassium carbonate
(4 mmol). The mixture was stirred overnight under reflux. Then the solid
was filtered off, and the solvent was removed to yield quantitatively the
corresponding macrocycle. Physical and spectroscopic properties correspond
to literature data.
Data
Cyclen (4). White solid, mp 1108C. 1H NMR (400.13 MHz, CDCl3): d ¼ 2.02
(br.s, 4H, NH), 2.59 (s, 16H, CH2N). 13C NMR (75.47 MHz, CDCl3):
d ¼ 45.1.
1
Homocyclen (5). White solid, mp 1438C. H NMR (400.13 MHz, CDCl3):
d ¼ 2.14 (m, 2H, CH2CH2N), 3.12 (m, 4H, CH2N), 3.28 (m, 8H, CH2N),
3.37 (m, 4H, CH2N), 3.55 (br.s, 4H, NH). 13C NMR (75.47 MHz, CDCl3):
d ¼ 27.5 (CH2CH2N), 45.9, 46.1, 47.4, 48.4 (CH2N).
Cyclam (6). White solid, mp 1878C. 1H NMR (400.13 MHz, CDCl3):
d ¼ 1.72 (m, 4H, CH2CH2N), 2.55 (br.s, 4H, NH), 2.67 (s, 8H, CH2N), 2.75
(m, 8H, CH2N). 13C NMR (75.47 MHz, CDCl3): d ¼ 28.4 (CH2CH2N),
48.5, 50.0 (CH2N).
Crystal structure determination of 1a. C12H22N4, M ¼ 222.34,
˚
a ¼ 11.7087(9), b ¼ 8.0299(5), c ¼ 12.4228(9) A, a ¼ 90.008, b ¼ 99.418,
3
g ¼ 90.008, V ¼ 1152.28(14) A , m ¼ 0.080 cm21, Z ¼ 4, monoclinic,
˚
˚
space group P21/c, l ¼ 0.71073 A, T ¼ 293 K, 2352 reflections collected,
1885 independent (Rint ¼ 0.0468), 151 refined parameters, R ¼ 0.0545,
wR2 ¼ 0.1208.
Crystal structure determination of 4a. C14H24N4, M ¼ 248.37,
˚
a ¼ 24.228(8), b ¼ 8.1728(19), c ¼ 14.381(4) A, a ¼ 90.008, b ¼
3
112.80(4)8, g ¼ 90.008, V ¼ 2625.0(13) A , m ¼ 0.078 cm21
,
Z ¼ 8,
˚

Cyclohexanedione Bisaminals
3281
˚
monoclinic, space group C2/c, l ¼ 0.71073 A, T ¼ 295 K, 3863 reflections
collected, 1560 independent (Rint ¼ 0.088), 163 refined parameters,
R ¼ 0.0488, wR2 ¼ 0.0975.
CCDC 291336 (1a) and CCDC 291337 (4a) contain the supplementary
crystallographic data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, by e-mailing data_request@ccdc.
cam.ac.uk, or by contacting the Cambridge Crystallographic Data Centre, 12,
Union Road, Cambridge CB2 1EZ, UK; fax: þ44 1223 336033.
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