Phenylglyoxal for polyamines modification and cyclam synthesis

Article abstract of DOI:10.1016/S0040-4020(03)00656-2

The bis-aminals obtained by tetraamine and phenylglyoxal condensation display various behaviours such as equilibrium between different configurations, rearrangements that lead to lactam derivatives, or amine deprotection. Our investigations about them were focused on three different linear amines, and then extended to polyazacycloalkanes cyclen and cyclam. Cyclam was also synthesised with the bis-aminals issued from condensation of linear polyamines with phenylglyoxal. The lactam derivatives described here were moreover, employed for the mono-N-functionalisation of tetraamines by phenyl-acetic acid group.

Full text of DOI:10.1016/S0040-4020(03)00656-2

Tetrahedron 59 (2003) 4573–4579
Phenylglyoxal for polyamines modification and cyclam synthesis
*
¨
Raphael Tripier, Franc¸oise Chuburu, Michel Le Baccon and Henri Handel
´ ´
Chimie, Electrochimie Moleculaire et Analytique, Universite de Bretagne Occidentale, UMR CNRS 6521, B.P. 809, 6 avenue Le Gorgeu,
29285 Brest Cedex, France
Received 3 March 2003; revised 14 April 2003; accepted 18 April 2003
Abstract—The bis-aminals obtained by tetraamine and phenylglyoxal condensation display various behaviours such as equilibrium between
different configurations, rearrangements that lead to lactam derivatives, or amine deprotection. Our investigations about them were focused
on three different linear amines, and then extended to polyazacycloalkanes cyclen and cyclam. Cyclam was also synthesised with the bis-
aminals issued from condensation of linear polyamines with phenylglyoxal. The lactam derivatives described here were moreover, employed
for the mono-N-functionalisation of tetraamines by phenyl-acetic acid group. q 2003 Elsevier Science Ltd. All rights reserved.
1. Introduction
Here, we demonstrate that, by comparison with other
a-dicarbonyl derivatives, phenylglyoxal can induce all
these behaviours. Thus, this compound constitutes a good
model for gaining insight into these reaction mechanisms.
From a synthetic point of view, we provide evidence of the
usefulness of phenylglyoxal as protection in the synthesis of
cyclam and describe an easy route to linear and cyclic
mono-N-alkylated polyamines.
Over the last years, the complexation chemistry of cyclen
(1,4,7,10-tetraazacyclododecane), cyclam (1,4,8,11-tetra-
azacyclotetradecane) and especially of their functionalised
derivatives has been extensively studied. This ensues
mainly from their strong ligating ability towards a wide
range of cations including lanthanide ions.1,2 Cyclen and
cyclam have taken up a dominant position in biomedical
applications and research as evidenced by the common use
of their complexes as contrast agents in magnetic resonance
imaging, luminescent probes or in radioimmunotherapy.3,4
2. Results and discussion
Bis-aminals are easily obtained by condensation of an
a-dicarbonyl reagent on a linear or cyclic tetraamine. In
theory, this condensation reaction results in multiple
stereoisomers according to the vic/gem insertion of the
dicarbonyl reagent and cis/trans configuration of the
resulting bis-aminal bridge. In practice, few stereoisomers
are obtained; in addition, we previously showed that their
configuration is governed by kinetic and thermodynamic
factors.14 The formation of a first six-membered diiminium
cycle is the driving force of the reaction. Furthermore,
compared to the ketone function, the aldehyde moiety reacts
faster with a secondary amine function, whereas the latter
shows a higher affinity for primary amine. The formation of
two different six-membered diiminium intermediates, i.e.
central and lateral, explains the reaction process as follows:
two secondary amines are involved in the former, whereas, a
secondary and a primary amines are both implicated in the
latter. For linear polyamines 1–3, depending on the
nature (central vs lateral) of the intermediate diiminium
and further to nucleophilic amine attacks, its evolution leads
to cis and/or trans bis-aminals as follows:14 with the lateral
diiminium, the corresponding bis-aminals, indeed, exhibits
a gem cis configuration. With the central one, the
corresponding bis-aminal are generally obtained as a
From a synthetic point of view, cyclisation and mono-N-
functionalisation are challenging steps in the chemistry of
linear or cyclic polyamines; among the recently proposed
solutions, bis-aminals have proved their efficiency as tools
in polyazacycloalkanes syntheses or modifications.5–8 They
are easily prepared by condensation of an a-dicarbonyl
derivative with the suitable linear or cyclic tetraamine. The
control of the ensuing N-alkylation steps is decisive in the
preparation of functionalised macrocycles. However, the
subsequent reaction of an electrophile with such protected
tetraamines often leads to unexpected adducts, and different
behaviours have been reported. As a matter of fact,
depending on the nature of the involved reactants, even
the simple protonation of the bis-aminal results in amine
deprotection, equilibrium between different configurations
of the bis-aminals, or gives rise to more complicated
rearrangements leading to lactam derivatives.9–13
Keywords: tetraazacycloalkanes; amines; cyclam; cyclen; bis-aminals;
amides.
*
Corresponding author. Tel.: þ33-2-98-01-61-38; fax: þ33-2-98-01-70-
01; e-mail: henri.handel@univ-brest.fr
0040–4020/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)00656-2

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mixture of cis and trans isomers and their proportion is
governed by the kinetics of successive nucleophilic attacks
provide that no isomerisation process modifies their
respective abundance.
The products obtained here by condensation of phenyl-
glyoxal hydrate with linear or cyclic tetraamines were in
good agreement with the previously established model
(Scheme 1).
Reactions proceeded as described in Scheme 1 with very
good yields. For 1a–5a bis-aminals, the vic/gem configur-
ation was identified from 13C NMR data, and the
recognition of cis/trans isomers was deduced from the
temperature-dependent spectra since, the cis bis-aminal
junction presents a fluxional behaviour whereas, the trans
one remains rigid. The location of the benzyl group on the
bis-aminal bridge for 1a and 2a was elucidated with the help
of HMQC, HMBC and COSY NMR sequences when
required. With amines 1–2, only the isomers 1a-cis–2a-cis
were obtained. On the other hand, the use of amine 3
resulted in a mixture of 3a-cis and 3a-trans isomers.
Figure 1. AM1 geometry and energy of formation for 3a-cis,
E¼242.94 kJ mol21
.
Figs. 1 and 2). As the cis isomer was stable in anhydrous
ethanol and isomerised further to water addition, this
process was certainly catalysed by water from phenyl-
glyoxal hydrate. The 13C NMR spectrum of 3a-trans was
remarkable since, at room temperature, it displayed six
carbon signals for the phenyl group, which is consistent with
a slowed rotation; at higher temperature the rotation was
fast, four signals were, therefore, observed on NMR spectra.
Molecular modelling of 3a-cis and 3a-trans compounds
(Figs. 1 and 2) showed that the bis-aminal bridge
substituents were respectively, in axial–equatorial (3a-cis)
and equatorial–equatorial (3a-trans) positions with a
In the case of the cyclic tetraamines 4–5, the key feature of
the reaction was again the formation of a first six-membered
diiminium ring. Consequently, the corresponding tetra-
cyclic bis-aminals 4a–5a issued from its evolution
exhibited a systematic cis configuration of the bis-aminal
bridge. One should note that, when cyclam was involved in
the reaction, 5b was always formed at trace level even
though the reaction was performed at 08C (see below).
As regards to the mixture of compounds 3a, the first bis-
aminal formed was the 3a-cis isomer, which rapidly evolved
to the more stable isomer 3a-trans (D¼24.45 kJ mol21
,
Scheme 1. Synthesis of tri- and tetra-cyclic bis-aminals 1a–5a formation mechanism.

R. Tripier et al. / Tetrahedron 59 (2003) 4573–4579
4575
All these processes have a factor in common: water.
Concerning the reaction mechanisms depicted on Scheme 3,
the protonation of the benzylic secondary amine function
followed with C–N bond cleavage constitutes the first
common step of all subsequent evolutions; the amine
function is, indeed, released further to the formation of the
imidium intermediate. Scheme 3 evidences the three ways
this cation can evolve: (i) way 1 shows that the repetition of
this opening–locking sequence corresponds to an equili-
bration reaction which leads to the thermodynamically more
stable bis-aminal; (ii) in way 2, the migration of a hydrogen
atom leads to an amidinium species whose hydrolysis
generates the lactam adduct; (iii) way 3 takes place in acidic
medium where the fast opening of the first C–N aminal
bond followed by the cleavage of the second one produces
the bis-amidinium intermediate whose further hydrolysis
regenerates the tetraamine as a polyammonium salt together
with phenylglyoxal.
Figure 2. AM1 geometry and energy of formation for 3a-trans,
E¼218.49 kJ mol21
.
From a synthetic point of view, the treatment of lactams
1b–3b or bicyclic lactams 4b–5b in refluxing trifluoro-
acetic acid/water solution overnight gave the expected
corresponding amino-acid salts, which were easily con-
verted into their chlorohydrate salts, 1c–3c and 4c–5c,
respectively (Scheme 2). This reaction provides one with an
easy-to-use route to phenyl-acetic acids derivatives of linear
or cyclic polyamines; moreover, this new and interesting
example of mono-N-alkylation makes this type of alkylation
far less tedious than by using the classical methods.15
phenyl group in equatorial position. These geometries
evidenced severe intramolecular strains likely responsible
for the benzyl group slowed rotation.
Under more rigorous conditions (Scheme 2) such as boiling
water for instance, 1a–5a gave the corresponding lactams
derivatives 1b–3b and 4b–5b in good yields. An
intermediate amidinium ion is undoubtedly involved in
the bis-aminal hydrolysis: it was identified by mass
spectrometry and NMR investigation with evidence for
2a-cis bis-aminal. Phenylglyoxal condensation with linear
or cyclic tetraamines in boiling water gave directly the
lactam, which showed as being the end-product of the
hydrolysis process.
In addition, because of its easy removal, the bis-aminal
bridge is advantageously used as template in the synthesis of
cyclen or cyclam structures. Unfortunately, all attempts to
obtain cyclen from 1a-cis failed; cyclam–phenylglyoxal
was, however, prepared in good yields by reaction of 2a-cis
with the corresponding biselectrophile, here dibromopro-
pane (Scheme 4). Surprisingly, a 50/50 mixture of the two
isomers 5a-cis and 5a-trans of the cyclam phenylglyoxal
was obtained. Both the stability of 2a-cis isomer in the
Finally, the acidic hydrolysis (HCl 6 M) of linear and cyclic
tetramines–phenylglyoxal adducts 1a–5a regenerated the
starting polyamine 1–5 in good yields (Scheme 2).
Scheme 2. From bis-aminals to lactam derivatives. Mono-phenyl acetic acid alkylation and bis-aminals deprotection.

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R. Tripier et al. / Tetrahedron 59 (2003) 4573–4579
Scheme 3. General scheme of the three processes.
Scheme 4. Cyclam synthesis by cyclisation of bis-aminal 2a-cis.
medium before biselectrophile addition and the lack of
equilibrium for the end-products indicate that the isomer-
isation process takes place during the early step of
cyclisation. In this process, the biselectrophile acts as the
proton: the opening of the first formed ammonium ion gives
again an iminium ion along with a free secondary amine
function; consequently, an isomerisation likely occurs
before the cyclisation. When the cyclisation reaction was
performed at room temperature with diiodopropane, a single
product was isolated and characterised as the 5a-cis bis-
aminal, which highlights the important role of reaction
temperature in the isomerisation process. Isomers 5a-cis
and/or 5a-trans were very easily hydrolysed in acidic
medium, and cyclam was recovered in good yield. Starting
from the tetramine 2, this three-step procedure constitutes a
new, easy-to-run and attractive synthesis of cyclam.
3. Conclusion
In contrast to other dicarbonyl compounds like glyoxal,
phenylglyoxal allows a large range of behaviours for the
ensuing bis-aminals. A first electrophilic attack is at the
origin of cis/trans configuration rearrangements, lactam
derivative formations or polyamine deprotections. In
addition, the study reported here opens an alternative

R. Tripier et al. / Tetrahedron 59 (2003) 4573–4579
4577
route to mono-functionalised polyamines from linear or
cyclic tetraamine and constitutes an attractive pathway to
cyclam.16–19
54.1, 55.2, 74.8, 83.6, 126.6, 126.9, 127.5, 128.5, 130.3,
141.5. ESI-MS (MeOH): m/z 273.4, [MþH]þ. Anal. calcd
for C16H24N4: C, 70.55; H, 8.88; N, 20.57%; found: C,
70.71; H, 8.78; N, 20.63%.
4.3. General procedure for tetracyclic bis-aminals 4a-cis
and 5a-cis synthesis from the convenient
tetraazamacrocycle
4. Experimental
4.1. General information
Polyamine triethylenetetraamine 1 (222), N,N00-bis-(2-ami-
A solution of phenylglyoxal monohydrate (2 mmol) in
absolute ethanol (10 mL) was slowly added to a solution of
the convenient tetraazamacrocycle (2 mmol) in absolute
ethanol (10 mL) at room temperature and under vigorous
stirring. After one-week stirring for cyclen 4, 4 h for cyclam
5, solvent was evaporated to give the desired compound.
When required, the unreacted macrocycle was precipitated
with diethyl ether (yield for 4a-cis: 60%, 5a-cis: 95%).
noethyl)-1,3-propanediamine 2 (232) and N,N -bis-(3-ami-
nopropyl)ethylenediamine
3
(323),
1,4,7,10-
tetraazacyclotetradecane 4 (cyclen) and 1,4,8,11-tetraaza-
cyclotetradecane 5 (cyclam) were used as starting
compounds.
Molecular modelling was performed with the Spartan20
software on a Silicon Graphics station. Trial structures of
the compounds 3a-cis and 3a-trans, were generated and a
conformational search was made to find the global
minimum of each surface. Semi-empirical calculations
was then accomplished, geometries were fully optimised
and minima characterised by the number of negative
eigenvalues (none) of the Hessian matrix.
4.3.1. Compound 4a-cis. The title compound was obtained
as a yellow oil. 13C NMR (CDCl3, 100 MHz, 320 K): d
(ppm) 44.2, 46.1, 49.1, 51.2, 78.4, 79.4, 127.1, 127.8, 128.5,
128.7, 137.3, 145.5. ESI-MS (MeOH): m/z 271.4, [MþH]þ.
Anal. calcd for C16H22N4: C, 71.08; H, 8.20; N, 20.72%;
found: C, 70.92; H, 8.31; N, 20.74%.
4.3.2. Compound 5a-cis. The title compound was obtained
as a yellow solid. 13C NMR (CDCl3, 100 MHz, 320 K): d
(ppm) 18.3, 18.4, 47.3, 48.5, 49.7, 51.2, 74.2, 83.5, 125.1,
126.2, 127.3, 129.3, 138.6, 144.6. ESI-MS (MeOH): m/z
299.5, [MþH]þ.
4.2. General procedure for the tricyclic bis-aminals 1a–
3a synthesis
A solution of phenylglyoxal monohydrate (2 mmol) in
absolute ethanol (10 mL) was slowly added to a solution of
the convenient linear amine (2 mmol) in absolute ethanol
(10 mL) at room temperature under vigorous stirring. After
5 h, solvent was evaporated to give quantitatively the
desired compound.
4.4. General procedure for tetracyclic bis-aminals 5a-cis
and/or 5a-trans synthesis from tricyclic bis-aminal 2a-cis
A solution of 1,3-dibromopropane (2 mmol) in freshly
distilled acetonitrile (25 mL) was added dropwise to a
refluxing mixture of 2a-cis (2 mmol), freshly distilled
acetonitrile (50 mL) and dried K2CO3 (20 mmol) under
vigorous stirring. After 2 days, the solution was filtered and
the solvent evaporated to give a brown oil, which was added
to toluene (10 mL) to precipitate polymers. Toluene phase
was separated, then evaporated to give a mixture of 5a-cis
and 5a-trans in 48% yield.
4.2.1. Compound 1a-cis. The title compound was quanti-
tatively obtained as a yellow oil. 13C NMR (CDCl3,
100 MHz, 245 K): d (ppm) 41.3, 48.8, 48.9, 49.0, 68.8,
78.5, 125.9, 127.1, 127.9, 143.9. ESI-MS (MeOH): m/z
183.3, [MþH]þ. Anal. calcd for C9H18N4: C, 59.31; H,
9.95; N, 30.74%; found: C, 59.34; H, 9.90; N, 30.85%.
4.2.2. Compound 2a-cis. The title compound was quanti-
tatively synthesised as a yellow oil. 13C NMR (CDCl3,
100 MHz, 218 K): d (ppm) 19.0, 39.5, 42.1, 44.2, 52.6, 54.7,
56.3, 68.5, 78.5, 125.5, 127.1, 128.2, 143.6. ESI-MS
(MeOH): m/z 259.4, [MþH]þ. Anal. calcd for C15H22N4:
C, 69.73; H, 8.58; N, 21.69%; found: C, 69.88; H, 8.49; N,
21.76%.
When the same synthesis procedure was performed with
diiodopropane (2 mmol) at room temperature and for 3 days,
5a-cis was obtained as the unique compound (yield: 50%).
4.4.1. Compound 5a-cis. 13C NMR see before. Anal. calcd
for C18H26N4: C, 72.44; H, 8.78; N, 18.77%; found: C,
72.49; H, 8.71; N, 18.81%.
4.2.3. Compound 2a Amidinium ion derivative. 13C NMR
(CDCl3, 100 MHz, 218 K): d (ppm) 36.8, 48.2, 49.3, 72.4,
126.9, 129.1, 138.7, 162.4. ESI-MS (MeOH): m/z 257.3,
[M]þ.
4.4.2. Compound 5a-trans. 13C NMR (CDCl3, 100 MHz):
d (ppm) 19.7, 22.2, 43.0, 45.1, 49.7, 56.2, 66.4, 80.96, 121.4,
127.7, 128.1, 128.9, 129.4, 130.2. ESI-MS (MeOH): m/z
299.5, [MþH]þ.
4.2.4. Compound 3a-cis. 13C NMR (CDCl3, 100 MHz,
298 K): d (ppm) 24.9, 29.9, 39.9, 43.4, 44.0, 46.3, 52.4,
53.6, 81.7, 87.5, 126.6, 126.9, 127.5, 128.5, 130.3, 140.5.
ESI-MS (MeOH): m/z 273.4, [MþH]þ.
4.5. General procedure for lactams 1b–3b synthesis
from the convenient linear amine
A solution of phenylglyoxal monohydrate (2 mmol) in
distilled water (10 mL) was slowly added to a solution of the
convenient linear amine (2 mmol) in distilled water (10 mL)
4.2.5. Compound 3a-trans. The title compound was
quantitatively obtained as a yellow oil. 13C NMR (CDCl3,
100 MHz, 298 K): d (ppm) 17.7, 26.4, 40.0, 44.5, 45.0, 47.4,

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R. Tripier et al. / Tetrahedron 59 (2003) 4573–4579
at room temperature under vigorous stirring. After 2 h, water
was evaporated to give quantitatively the desired compounds.
(6 M, 10 mL) solution was refluxed overnight under
vigorous stirring. After solvent evaporation, a brown solid
was obtained and added to an aqueous hydrochloride
solution (6 M, 10 mL) and refluxed during 2 h. Then, the
solvent was evaporated to give quantitatively the desired
compound.
4.6. General procedure for lactams 1b–3b synthesis
from bis-aminals 1a–3a
A solution of the convenient tricyclic bis-aminal in boiling
water was vigorously stirred. After 2 days, solvent was
evaporated to give the desired compound.
4.7.1. Compound 1c. The title compound is obtained as a
brown powder. 13C NMR (D2O, 100 MHz): d (ppm) 38.2,
41.8, 56.5, 57.0, 57.4, 58.6, 63.0, 129.8, 132.1, 132.3, 134.2,
169.2. Anal. calcd for C14H28N4O2Cl4, 2H2O: C, 36.38; H,
6.98; N, 12.12%; found: C, 36.00; H, 7.09; N, 12.33%. IR
4.6.1. Compound 1b. The title compound was quantita-
tively synthesised as a yellow oil. 13C NMR (CDCl3,
100 MHz): d (ppm) 41.6, 41.7, 47.2, 47.6, 49.2, 51.5, 64.4,
128.2, 128.9, 129.6, 140.6, 169.7. ESI-MS (MeOH): m/z
263.2, [MþH]þ. Anal. calcd for C14H22N4O: C, 64.09; H,
8.45; N, 21.36%; found: C, 64.29; H, 8.27; N, 21.48%. IR
(KBr): nCO¼1710 cm21
.
4.7.2. Compound 2c. The title compound was obtained as a
brown powder. 13C NMR (D2O, 100 MHz): d (ppm) 26.2,
38.4, 41.5, 46.5, 47.15, 47.6, 48.5, 62.6, 132.5, 132.6, 133.5,
134.1, 168.4. Anal. calcd for C15H30N4O2Cl4, 3H2O: C,
35.17; H, 7.48; N, 10.94%; found: C, 34.98; H, 7.59; N,
(CH2Cl2): nCO¼1690 cm21
.
4.6.2. Compound 2b. The title compound was quantita-
tively obtained as a yellow oil. 13C NMR (CDCl3,
100 MHz): d (ppm) 26.6, 40.9, 41.0, 44.2, 45.8, 47.5,
51.9, 63.5, 127.9, 128.6, 128.7, 140.5, 169.0. ESI-MS
(MeOH): m/z 277.4, [MþH]þ. Anal. calcd for C15H24N4O:
C, 65.19; H, 8.75; N, 20.27%; found: C, 65.32; H, 8.61; N,
11.11%. IR (KBr): nCO¼1710 cm21
.
4.7.3. Compound 3c. The title compound was obtained as a
brown powder. 13C NMR (CDCl3, 100 MHz): d (ppm) 24.0,
26.6, 38.7, 39.4, 45.05£2, 47.0, 53.8, 71.8, 131.7, 132.3,
132.7, 136.1, 167.0. Anal. calcd for C16H32N4O2Cl4, 4H2O:
C, 36.51; H, 7.66; N, 10.64%; found: C, 36.32; H, 7.49; N,
20.46%. IR (CH2Cl2): nCO¼1690 cm21
.
4.6.3. Compound 3b. The title compound was quantita-
tively obtained as a yellow oil. 13C NMR (CDCl3,
100 MHz): d (ppm) 29.3, 29.6, 37.9, 39.0, 43.0, 45.3,
45.9, 50.9, 70.7, 126.7, 127.4, 128.1, 139.0, 167.5. ESI-MS
(MeOH): m/z 291.3, [MþH]þ. Anal. calcd for C16H26N4O:
C, 66.17; H, 9.02; N, 19.29%; found: C, 66.46; H, 9.32; N,
10.44%. IR (KBr): nCO¼1710 cm21
.
4.7.4. Compound 4c. The title compound was obtained as a
yellow powder. 13C NMR (D2O, 100 MHz): d (ppm) 37.5,
43.7, 47.5, 55.6, 60.8, 130.1, 131.6, 132.4, 136.1, 168.8.
Anal. calcd for C16H30N4O2Cl4, 2H2O: C, 39.36; H, 7.02; N,
11.47%; found: C, 39.07; H, 7.04; N, 11.33%. IR (KBr):
19.19%. IR (CH2Cl2): nCO¼1690 cm21
.
nCO¼1710 cm21
.
4.6.4. Lactam 4b synthesis. A solution of phenylglyoxal
monohydrate (2 mmol) in DMF/H2O (9/1, 10 mL) was
slowly added to a solution of cyclen (2 mmol) in refluxing
DMF/H2O (9/1, 10 mL) under vigorous stirring. After one
night, solvents were evaporated, 20 mL of distilled water
were added to the brown residue, then the mixture was
washed with dichloromethane (5£30 mL). The aqueous
phases were combined and evaporated to give the desired
compound (yield: 60%) 4b in yellow oil form. 13C NMR
(CDCl3, 100 MHz): d (ppm) 43.4, 44.3, 46.0, 46.2, 46.4,
47.9, 48.5, 49.8, 50.6, 127.2, 128.6, 129.6, 137.1, 172.5.
ESI-MS (MeOH): m/z 289.4, [MþH]þ. Anal. calcd for
C16H24N4O: C, 66.64; H, 8.39; N, 19.43%; found: C, 66.71;
4.7.5. Compound 5c. The title compound was obtained as a
yellow powder. 13C NMR (D2O, 100 MHz): d (ppm) 21.9,
25.2, 43.6, 43.8, 44.1, 44.3, 44.4, 46.2, 46.7, 53.9, 67.3,
132.7, 133.1, 134.1, 139.2, 166.8. Anal. calcd for
C18H34N4O2Cl4, 2H2O: C, 40.46; H, 7.55; N, 10.49%;
found: C, 40.69; H, 7.68; N, 10.20%. IR (KBr):
nCO¼1710 cm21
.
4.8. General procedure for 1a–5a hydrolysis
Bis-aminals derivatives (2 mmol) were placed in an aqueous
solution of hydrochloric acid (10 mL, 6 M) at 708C for 2 h
under vigorous stirring. After solvent evaporation, NaOH
(4N) was added to the product obtained as a brown powder
and the solution was extracted with CH2Cl2 (3£30 mL). The
organic phases were dried with MgSO4, filtered and
evaporated to give the desired compound (which was
purified by crystallisation in CH3CN for azamacrocycles)
(Yields obtained starting from: 1a-cis: 80%, 2a-cis: 84%,
3a-cis: 90%, 5a-cis, 70%, 5a-cis/trans: 72%).
H, 8.21; N, 19.58%. IR (CH2Cl2): nCO¼1690 cm21
.
4.6.5. Lactam 5b synthesis. Same procedure as the one
followed for 5a-cis from cyclam with a 2-days reflux, or
1-night reflux, in H2O (yield: 100%). 5b was produced as a
yellow solid. 13C NMR (CDCl3, 100 MHz): d (ppm) 24.6,
25.5, 35.4, 38.4, 46.4, 47.7, 48.7£2, 49.4, 50.4, 52.65, 67.9,
126.3, 126.7, 128.7, 133.1, 167.5. ESI-MS (MeOH): m/z
317.3, [MþH]þ. Anal. calcd for C18H28N4O: C, 68.32; H,
8.92; N, 17.71%; found: C, 68.59; H, 9.18; N, 17.49%. IR
(KBr): nCO¼1690 cm21
.
Acknowledgements
4.7. General procedure for mono-phenyl-acetic acid
derivatives 1c–5c synthesis
We thank Dr H. Bernard, Dr N. Le Bris and Dr M. P.
Friocourt for their precious fruitful help and N. Kervarec for
NMR 2D investigations.
A solution of lactam (2 mmol) 1b–5b in aqueous TFA

R. Tripier et al. / Tetrahedron 59 (2003) 4573–4579
4579
´
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