Regioselective synthesis of N-functionalized 12-membered azapyridinomacrocycles bearing trialkylcarboxylic acid side chains

Article abstract of DOI:10.1016/S0040-4020(01)00328-3

Selective protection of primary amine moieties of diethylenetriamine by 2-nitrophenylsulfonyl chloride followed by alkylation of the central N atom generates functionalized disulfonamide building blocks. When reacted with 2,6-bis(bromomethyl)pyridine following the Richman-Atkins methodology, such compounds yield the corresponding pyridine-containing azamacrocycles. Smooth removal of the N-sulfonyl groups provides versatile azamacrocyclic intermediates with transannular secondary amine functions. Subsequent N-alkylation regioselectively leads to tri N-functionalized 12-membered azapyridinomacrocycles bearing a sequence of N-acetate and N-propionate side chains.

Full text of DOI:10.1016/S0040-4020(01)00328-3

TETRAHEDRON
Pergamon
Tetrahedron 57 (2001) 4713±4718
Regioselective synthesis of N-functionalized 12-membered
azapyridinomacrocycles bearing trialkylcarboxylic
acid side chains
a
Jean-Michel Siaugue, Fabienne Segat-Dioury, Isabelle Sylvestre, Alain Favre-Reguillon,
a
a
b
Â
Jacques Foos,a Charles Madicc and Alain Guyb,p
a
  Â
Laboratoire des Sciences Nucleaires, Conservatoire National des Arts et Metiers, 2, rue Conte, 75003 Paris, France
b
Â
Laboratoire de Chimie Organique, ESA CNRS 7084, Conservatoire National des Arts et Metiers, 292, rue St Martin,
75141 Paris Cedex 3, France
c
Ã
CEA, Direction du Cycle du Combustible, Bat. 450 CEA/Saclay, 91191 Gif-sur-Yvette, France
Received 30 November 2000; revised 12 March 2001; accepted 19 March 2001
AbstractÐSelective protection of primary amine moieties of diethylenetriamine by 2-nitrophenylsulfonyl chloride followed by alkylation
of the central N atom generates functionalized disulfonamide building blocks. When reacted with 2,6-bis(bromomethyl)pyridine following
the Richman±Atkins methodology, such compounds yield the corresponding pyridine-containing azamacrocycles. Smooth removal of the
N-sulfonyl groups provides versatile azamacrocyclic intermediates with transannular secondary amine functions. Subsequent N-alkylation
regioselectively leads to tri N-functionalized 12-membered azapyridinomacrocycles bearing a sequence of N-acetate and N-propionate side
chains. q 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
luminescence4,6 thus extending the potential use of rare-
earth complexes in biomedical imaging.
Recent interest in polyazamacrocyclic chelates of para-
magnetic and radioactive metal ions largely results from
their biomedical applications, such as Magnetic Resonance
Imaging (MRI) contrast agents1 and diagnostic agents2 as
well as therapeutic radiopharmaceuticals.3
The regioselective N-functionalization of polyazamacro-
cycles is a synthetic challenge of interest as it may allow
a ®ne tuning of their complexation properties by adjusting
the nature of the coordinating subunits. Various approaches
have been used for the desymmetrization of azamacro-
cycles.7 Direct mono N-functionalization of unprotected
polyazamacrocycles has been performed using a large
excess of macrocycle relative to the electrophile reagent8
or by using strictly controlled conditions.9 These methods
suffer from time-consuming puri®cation steps and are
precluded for unreadily available macrocyclic compounds.
Monosubstitution was also achieved by alkylation of an
organometallic complex derivative10 or by previous regio-
selective protection.11 However, these approaches have
limited applicability as highly dependent on the nature
of both the macrocyclic compound and the alkylating
reagent.
A large number of 12- and 14-membered tetraazamacro-
cycles have been studied1b and it appears that the selectivity
of the complexation (i.e. the relative stability of the
corresponding complexes) of such ligands towards various
metal ions could be tuned by adjusting the ring size, the
number and nature of coordinating subunits. Pyridine-
containing azamacrocyclic ligands bearing three amines
and three acidic side chains offer a chromophoric subunit
as well as seven potential donor sites of various degrees of
hardness able to coordinate a lanthanide ion in its ®rst
coordination sphere.4 Potential applications of this type of
ligand exploit the high stability of their complexes together
with their ability to shield the encapsulated ion from inter-
actions with the neighbouring environment.5 Moreover,
recent spectroscopic investigations involving such ligands
were reported to allow UV-light induced Tb31 and Eu31
An alternative synthetic route to regioselective
N-functionalized azamacrocycles involves the differentia-
tion of the amines of the polyamine skeleton at the early
stage of the synthesis which requires the preparation of
appropriately functionalized linear polyamine precursors.
The synthesis of N-protected polyamines containing inde-
pendently removable N-protecting groups has recently
Keywords: aza compounds; macrocycles; protecting groups.
Corresponding author Tel: 133 1 4027 2013; Fax 133 1 4271 0534;
e-mail: guy@cnam.fr
p
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(01)00328-3

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J.-M. Siaugue et al. / Tetrahedron 57 (2001) 4713±4718
Scheme 1.
attracted a great deal of interest12 since such compounds are
valuable precursors for the synthesis of natural products.
Multistep syntheses of regioselectively N-protected poly-
amines have been described;13,14 however such syntheses
are somewhat long.
could be of interest for the construction of new orthogonally
protected polyamine building blocks. Indeed, we have
previously shown that differentiation of primary and
secondary amine moieties of polyamines could be achieved
with the use of 2-nitrophenylsulfonyl chloride.15 So, by
controlling the quantity of 2-nitrophenylsulfonyl chloride
introduced (2 equivalents), the primary amine moieties of
diethylenetriamine 1 have been selectively protected
to produce the N-diprotected amine 4 in 79% yield
(Scheme 2).
We report here an approach involving a highly chemo-
selective protection and activation of primary amine of
diethylenetriamine. Subsequent alkylation of the central
amine moiety affords a versatile tri N-functionalized
derivative that reacts with 2,6-bis(bromomethyl)pyridine
in a macrocyclization process. A selective deprotection
gives rise to a versatile pyridine-containing azamacrocycle
with transannular secondary amine functions which can be
further N-alkylated to yield 12-membered azamacrocyclic
compounds with the desired sequence of N-acetate and
N-propionate side chains.
The central amine function of compound 4 was then func-
tionalized following conventional methods (Scheme 2). The
Boc derivative 5 was obtained in 87% yield by reaction of
the corresponding anhydride in the presence of triethyl-
amine. Such a compound is of interest for the preparation
of monofunctionalized cyclens7,16 or pyridine-containing
azamacrocycles.4,5,17
The preparation of diethylenetriamine derivatives bearing
N-alkylcarboxylate side chains was realized either by
reaction of compound 4 with tert-butyl bromoacetate
leading to the acetate product 6 in 82% yield or with tert-
butyl acrylate leading quantitatively to the homologous
propionate derivative 7. Compounds 6 and 7 could serve
to investigate the in¯uence of the length of the side chains
on the metal ion coordination of azapyridinomacrocyclic
ligands.18
2. Results and discussion
We have recently reported that the reaction of 3 equivalents
of 2-nitrophenylsulfonyl chloride with diethylenetriamine 1
in heterogeneous NaHCO3/THF system led to the formation
of the tris(2-nitrophenylsulfonyl)-protected compound 2
(Scheme 1).4 Treatment of 2 with 2,6-bis(bromomethyl)-
pyridine in the presence of Na2CO3 gave the N-protected
azamacrocycle. Removal of the three N-sulfonyl groups
followed by alkylation with chloroacetic acid afforded
ligand 3 with identical side chains in good yield.
The macrocyclization step results from the Richman±
Atkins protocol16 (reaction of the functionalized 2-nitro-
phenylsulfonamide, i.e. 2, 5, 6 or 7, with 2,6-bis(bromo-
methyl)pyridine in the presence of anhydrous Na2CO3)4
For the synthesis of ligands with different side chains, we
anticipated that the use of 2-nitrophenylsulfonyl chloride
Scheme 2. (a) 2 eq. ClSO2(2-NO2Ph), NaHCO3, THF, 79%; (b) Boc2O, THF, TEA, 87%; (c) tert-butyl bromoacetate, THF, Et3N, 82%; (d) tert-butyl acrylate,
MeOH, 98%.

J.-M. Siaugue et al. / Tetrahedron 57 (2001) 4713±4718
4715
Scheme 3. (a) 2,6- bis(bromomethyl)pyridine, Na2CO3, DMF, 1008C; (b) PhSH, Na2CO3, DMF, r.t.
which produces the corresponding expected macrocycles
8±11 (Scheme 3) in medium to good yields. However, it
should be noted that the macrocyclization yield decreases
when the steric hindrance at the central N-atom decreases.
This result gives further support to the idea that steric and
conformational factors resulting from the presence of bulky
tosyl or nosyl groups play a key role in determining the
ef®ciency of Richman±Atkins cyclizations.16,19 Indeed,
central N-nosylated compound 2 should adopt the required
conformation for cyclization more readily than the less
bulky substrates 5±7 and, therefore, would cyclize more
readily (Thorpe±Ingold effect).20
The desired 12-membered azapyridinomacrocycles bearing
trialkylcarboxylic acid side chains 3, 16, 18 and 20 could be
prepared from the parent amines 12, 14 or 15 (Schemes 1, 4
and 5). Alkylation of compound 12 has been studied under
various conditions.22 The macrocycles 3 and 16 with
identical side chains were obtained under forcing conditions
(excess of alkylating reagent, pH 10 at 808C for 2 days). In
the case of the parent macrocyclic amines with the central
N-atom already substituted 14±15, milder conditions were
used. Compound 17 was obtained in 43% yield by treating
the amine 14 with an excess of tert-butyl acrylate. The tert-
butyl ester derivative was then cleaved with dry hydrogen
chloride leading to 18 in 56% yield.
The nosyl groups of macrocyclic compounds 8±11 could be
cleaved by aromatic nucleophilic substitution with thio-
glycolic acid in the presence of LiOH in DMF at room
temperature.21 However, puri®cation of the water soluble
amine 12 is complicated by the fact that both the excess
of thioglycolic acid and the thioether by-product are water
soluble. So, replacing the thioglycolic acid reagent by thio-
phenol gives rise to a lipophilic thioether by-product that
facilitates the puri®cation step. The nosylated macrocycles
8±11 were all treated under these conditions and gave
compounds 12±15 bearing secondary amine functions in
good to excellent yields (Scheme 3). It should be noted
that the regioselectively mono N-functionalized compounds
13±15 with transannular secondary amine functions could
be intermediates of choice for the synthesis of various
bismacrocycles or cryptands.7,14
Further alkylation of the propionate derivative 15 proved to
be more problematic as, under classical conditions of
reaction and treatment, the intermediate 19 could not be
isolated (Scheme 5). We found that a one-pot alkylation/
deprotection procedure leads to the desired macrocyclic
compound 20 in 59% yield. It should be noted that NMR
and SM analyses revealed the presence of a small proportion
of compound 3 in the crude mixture (20/3: 80/20). The
formation of such a by-product can be rationalized by a
retro-Michael process occurring at the N-propionate subunit
of 15 and the resulting secondary amine is alkylated in the
presence of the excess of tert-butyl bromoacetate to give
compound 3 as a by-product. Furthermore, such a retro
reaction can explain the poor stability of 19 that precludes
its isolation.
Scheme 4. (a) acrylic acid, NaOH/H2O (pHˆ10), 54%; (b) tert-butyl acrylate, MeOH, 43%; (c) HCl-Et2O sat., 56%.

4716
J.-M. Siaugue et al. / Tetrahedron 57 (2001) 4713±4718
Scheme 5. (a) tert-butyl bromoacetate, TEA, THF then (b) HCl-Et2O sat., 59%.
3. Conclusion
mixture was concentrated under vacuum and the resulting
aqueous layer was extracted with dichloromethane. The
organic layer was dried over sodium sulfate, concentrated
under vacuum and gave a crude oil that was puri®ed by
chromatography on silica gel (ethyl acetate/heptane: 5/5 to
7/3) to afford compound 5 as a yellow oil; 9.90g (87%). 1H
NMR (CDCl3) d: 1.45 (s, 9H), 3.30 (m, 4H), 3.40 (m, 4H),
5.60 (m, 1H), 5.80 (m, 1H), 7.80±8.20 (m, 8H). 13C NMR
(CDCl3) d: 28.2, 42.4, 81.1, 125.2, 130.8, 132.8, 133.2,
133.6, 147.9, 155.7. HRMS (FAB): found m/z 596.1096
([M1Na]1); calcd for C21H27N5O10S2Na 596.1097.
In this paper, we have shown that the selective protection/
activation of primary amines of diethylenetriamine 1 with
2-nitrophenylsulfonyl chloride provides a straightforward
route to versatile intermediates for the synthesis of
functionalized azamacrocycles. This protocol enabled us
to prepare two monosubstituted macrocyclic amines, 14
and 15, for the synthesis of symmetrical macrocycles 18
and 20 with the desired sequence of N-acetate and N-propio-
nate side chains. The four 12-membered aza-
pyridinomacrocycles prepared will allow an extension to
the study aimed at optimizing the complexation selectivity
of this class of compounds towards metallic cations.
4.1.3. 4-((tert-Butoxycarbonyl)methyl)-1,7-bis(2-nitro-
phenylsulfonyl)-1,4,7-triazaheptane (6). To a solution of
4 (0.94 g, 2 mmol) and triethylamine (1.24g, 12 mmol) in
25 mL of tetrahydrofuran was added tert-butyl bromo-
acetate (1.68 mL, 6 mmol). The reaction mixture was
re¯uxed overnight and then allowed to cool to room
temperature. 50 mL of a saturated aqueous solution of
ammonium chloride was added. The crude mixture was
concentrated under vacuum and the aqueous layer was
extracted with dichloromethane. The organic layer was
dried over sodium sulfate, and the solvent was evaporated
to afford an oil. After a chromatography on silica gel (ethyl
acetate/heptane: 5/5 to 8/2) the desired compound 6 was
4. Experimental
4.1. General
All reactions were carried out under an argon atmosphere.
Reactions were monitored by TLC or HPLC. H and 13C
NMR spectra were recorded on a Brucker AM400. Mass
1
Â
spectrometry was obtained from Ecole Normale Superieure
(24 rue Lhomond, 75231 Paris Cedex 05). Spectral data for
compounds 2, 8, 12 and 3 have been previously
published.15,22
1
obtained as a yellow oil; 0.97g (82%). H NMR (CDCl3)
d: 1.39 (s, 9H), 2.75 (t, 4H, Jˆ5.8 Hz), 3.05 (m, 4H), 3.10
(s, 2H), 5.96 (m, 2H), 7.70±8.05 (m, 8H). 13C NMR (CDCl3)
d: 27.9, 41.6, 54.2, 55.6, 81.8, 125.2, 130.6, 132.6, 133.1,
133.6, 147.9, 170.6. HRMS (FAB): found 588.1446
([M1H]1); calcd for C22H30N5O10S2: 588.1434.
4.1.1. 1,7-Bis(2-nitrophenylsulfonyl)-1,4,7-triazaheptane
(4). A solution of 2-nitrophenylsulfonyl chloride (2.21 g,
10 mmol) in 100 mL of tetrahydrofuran was added dropwise
to a stirred suspension of 1 (0.50 g, 5 mmol) and dried
NaHCO3 (1.68 g, 20 mmol) in 50 mL of tetrahydrofuran at
08C. The resulting mixture was allowed to warm to room
temperature and stirred for further 12h, ®ltered and concen-
trated under vacuum. The crude product was puri®ed by
chromatography on silica gel (CH2Cl2/MeOH: 100/0 to
4.1.4. 4-(2-(tert-Butoxycarbonyl)ethyl)-1,7-bis(2-nitro-
phenylsulfonyl)-1,4,7-triazaheptane (7). Compound 4
(16.50 g, 35 mmol) was dissolved in a mixture of tert-
butyl acrylate (13.46 g, 105 mmol) and methanol (20 mL).
The reaction mixture was re¯uxed overnight and then
concentrated under vacuum. The crude product was puri®ed
by chromatography on silica gel (ethyl acetate/heptane: 5/5
1
95/5) and yielded 4 as a white solid; 2.6 g, (79%). H
NMR (DMSO-d6) d: 2.48 (t, 4H, Jˆ6.3 Hz), 2.88 (t, 4H,
Jˆ6.3 Hz), 7.84±7.99 (m, 8H). 13C NMR (DMSO-d6) d:
42.5, 47.7, 124.2, 129.3, 132.4, 132.5, 133.8, 147.5.
HRMS (FAB): found m/z 474.0759 ([M1H]1); calcd for
C16H20N5O8S2 474.0753.
1
to 8/2) yielding 7 as a yellow oil; 20.7 g (98%). H NMR
(CDCl3) d: 1.43 (s, 9H), 2.32 (t, 2H, Jˆ6.5 Hz), 2.56 (t, 4H,
Jˆ5.8 Hz), 3.10 (m, 4H), 3.15 (t, 2H, Jˆ6.5 Hz), 5.84 (m,
2H), 7.70±8.10 (m, 8H). 13C NMR (CDCl3) d: 27.9, 32.9,
41.2, 48.7, 53.6, 81.1, 125.2, 130.7, 132.5, 133.2, 133.4,
148.0, 171.8. HRMS (FAB): found 602.1559 ([M1H]1);
calcd for C23H31N5O10S2: 602.1591.
4.1.2. 4-(tert-Butoxycarbonyl)-1,7-bis(2-nitrophenylsul-
fonyl)-1,4,7-triazaheptane (5). To a solution of 4 (9.43 g,
20 mmol) and triethylamine (5.46g, 54 mmol) in 100 mL of
tetrahydrofuran at 08C was added di-tert-butyl dicarbonate
(6.54 g, 30 mmol). The reaction mixture was stirred at room
temperature for 24 h. 150 mL of a saturated aqueous
solution of ammonium chloride was added. The crude
4.1.5. General procedure for the macrocyclization: reac-
tion of 2,6-bis(bromomethyl)pyridine with bis(2-nitro-
phenylsulfonamide) compounds 5-7. In
procedure, a solution of 2,6-bis(bromomethyl)pyridine
a
typical

J.-M. Siaugue et al. / Tetrahedron 57 (2001) 4713±4718
4717
(2.38 g, 9 mmol) in anhydrous N,N-dimethylformamide
(125 mL) was added dropwise to a stirred suspension of
the disulfonamide building block (9 mmol) and Na2CO3
(3.81 g, 36 mmol) in anhydrous N,N-dimethylformamide
(125 mL) at 1008C. The reaction mixture was heated over-
night and then concentrated under vacuum. The residue was
taken up in dichloromethane. The organic phase was
washed with an aqueous solution of sodium hydroxide
(0.1M) then dried over sodium sulfate and concentrated.
(d, 2H, Jˆ7.6 Hz), 7.5 (dd, 1H, Jˆ7.6 Hz). 13C NMR
(CDCl3) d: 28.3, 48.5, 50.5, 51.8, 78.8, 120.0, 136.3,
157.2, 157.9. HRMS (FAB): found m/z 307.2130
([M1H]1); calcd for C16H27N4O2 307.2134.
4.1.11. tert-Butyl 3,6,9,15-tetraazabicyclo[9.3.1]penta-
decane-1(15),11,13-triene-6-acetate (14). Compound 14
was obtained after chromatography on neutral alumina
(CH2Cl2/MeOH: 99/1) as a colourless oil; 0.21 g (67%).
1H NMR (CDCl3) d: 1.42 (s, 9H), 2.54 (m, 4H), 2.64 (m,
4H), 3.39 (s, 2H), 3.98 (s, 4H), 4.39 (m, 2H), 7.00 (d, 2H,
Jˆ7.6 Hz), 7.54 (dd, 1H, Jˆ7.6 Hz). 13C NMR (CDCl3) d:
28.2, 47.7, 52.9, 56.3, 59.4, 81.3, 120.2, 136.8, 157.7, 171.3.
HRMS (FAB): found m/z 321.2301 ([M1H]1); calcd for
C17H29N4O2 321.2291.
4.1.6. tert-Butyl 3,9-bis(2-nitrophenylsulfonyl)-3,6,9,15-
tetraazabicyclo[9.3.1]pentadecane-1(15),11,13-triene-6-
carbamate (9). Compound 9 was obtained after recrystal-
1
lization in acetone as a white solid; 4.1 g (67%). H NMR
(DMSO-d6) d: 1.38 (s, 9H), 3.53 (m, 8H), 4.60 (s, 4H), 7.35
(m, 2H), 7.80±8.10 (m, 9H). 13C NMR (DMSO-d6) d: 27.8,
44.5, 45.3, 49.6, 49.8, 55.0, 78.6, 122.3, 124.4, 129.2, 130.9,
132.5, 134.4, 138.2, 147.7, 154.4, 155.6. HRMS (FAB):
found 677.1696 ([M1H]1); calcd for C28H33N6O10S2
677.1700.
4.1.12. tert-Butyl 3,6,9,15-tetraazabicyclo[9.3.1]penta-
decane-1(15),11,13-triene-6-propanoate (15). Compound
15 was obtained after chromatography on neutral alumina
(CH2Cl21/MeOH: 100/0 to 98/2) as a colourless oil; 0.28 g
(85%). H NMR (CDCl3) d: 1.38 (s, 9H), 2.52 (t, 2H,
Jˆ6.2 Hz), 2.60 (m, 4H), 2.70 (m, 4H), 2.92 (t, 2H,
Jˆ6.2 Hz), 4.15 (s, 4H), 5.85 (m, 2H), 7.10 (d, 2H,
Jˆ7.7 Hz), 7.66 (dd, 1H, Jˆ7.7 Hz). 13C NMR (CDCl3)
d: 27.9, 33.7, 47.2, 51.2, 53.2, 55.7, 80.9, 120.7, 137.6,
154.8, 172.7. HRMS (FAB): found m/z 334.2371
([M1H]1); calcd for C18H30N4O2 334.2369.
4.1.7. tert-Butyl 3,9-bis(2-nitrophenylsulfonyl)-3,6,9,15-
tetraazabicyclo[9.3.1]pentadecane-1(15),11,13-triene-6-
acetate (10). Compound 10 was obtained after chromato-
graphy on silica gel (ethyl acetate/heptane: 5/5 to 8/2) as a
white solid; 3.60 g (58%). 1H NMR (CDCl3) d: 1.39 (s, 9H),
2.55 (t, 4H, Jˆ7.6 Hz), 3.17 (s, 2H), 3.30 (t, 4H, Jˆ7.6 Hz),
4.56 (s, 4H), 7.42 (d, 2H, Jˆ7.7 Hz), 7.82±8.06 (m, 9H). 13C
NMR (CDCl3) d: 28.1, 44.8, 51.1, 54.2, 57.4, 81.1, 124.1,
124.2, 130.7, 131.8, 132.6, 133.7, 139.0, 148.1, 154.5, 1709.
HRMS (FAB): found 691.1824 ([M1H]1); calcd for
C29H35N6O10S2 691.1856.
4.1.13. 3,6,9,15-Tetraazabicyclo[9.3.1]pentadecane-1(15),
11,13-triene-3,6,9-tripropanoic acid (16). Compound 12
(1.26 g, 4 mmol) was dissolved in water (16 mL). Acrylic
acid (4.32 g, 60 mmol) was added and the pH of the solution
was adjusted to 10 with an aqueous solution of NaOH (3N).
The reaction mixture was heated at 808C for 48 h, then
concentrated, and the residue was pre-puri®ed by chromato-
graphy on an ion-exchange resin (Dowex 1£8, formate
form) eluting with formic acid (0.02N). The resulting
product was further puri®ed by gel-®ltration (Sephadex
G-10 eluting with water) and compound 16 was obtained
as a white solid; 0.92g, 54%. 1H NMR (D2O/NaOD) d: 2.31
(m, 4H), 2.43 (t, 2H, Jˆ6.7 Hz), 2.50 (t, 4H, Jˆ7.9 Hz),
2.61 (m, 6H), 2.97 (t, 4H, Jˆ7.9 Hz), 3.85 (s, 4H), 7.43
(d, 2H, Jˆ7.7 Hz), 7.95 (dd, 1H, Jˆ7.7 Hz).13C NMR
(NaOD) d: 37.6, 37.7, 49.4, 49.5, 53.3, 56.4, 61.4, 126.8,
141.7, 158.2, 183.6. HRMS (FAB): found m/z 423.2238
([M1H]1); calcd for C20H31N4O6 423.2244.
4.1.8. tert-Butyl 3,9-bis(2-nitrophenylsulfonyl)-3,6,9,15-
tetraazabicyclo[9.3.1]pentadecane-1(15),11,13-triene-6-
propanoate (11). Compound 11 was obtained after chroma-
tography on silica gel (ethyl acetate/heptane: 5/5 to 5/0) as a
yellow oil; 3.23 g (51%). 1H NMR (CDCl3) d: 1.39 (s, 9H),
2.22 (t, 2H, Jˆ7.1 Hz), 2.45 (t, 4H, Jˆ7.7 Hz), 2.64 (t, 2H,
Jˆ7.1 Hz), 3.25 (t, 4H, Jˆ7.7 Hz), 4.57 (s, 4H), 7.45 (d, 2H,
Jˆ7.7 Hz), 7.68±8.05 (m, 9H). 13C NMR (CDCl3) d: 28.1,
35.2, 44.4, 50.2, 50.7, 54.3, 80.1, 124.1, 124.3, 130.8, 131.8,
132.6, 133.7, 139.1, 148.2, 154.6, 171.5. HRMS (FAB):
found m/z 705.2014 ([M1H]1); calcd for C30H37N6O10S2
705.2013.
4.1.9. General procedure for the cleavage of the nosylate
group of dinosylated macrocycles 9±11. In a typical
procedure, anhydrous sodium carbonate (0.85 g, 8 mmol)
was added to a solution of dinosylated macrocycle
(1 mmol) and thiophenol (0.27 g, 2.5 mmol) in N,N-
dimethylformamide (20 mL). The reaction mixture was stir-
red at room temperature overnight and then concentrated
under vacuum. The residue was taken up in dichloro-
methane and the organic phase was washed with water
then dried over sodium sulfate and concentrated.
4.1.14. Di-tert-butyl 6-[(tert-butoxycarbonyl)methyl]-
3,6,9,15-tetraazabicyclo[9.3.1]pentadecane-1(15),11,13-
triene-3,9-dipropanoate (17). Compound 14 (2.66 g,
8.29 mmol) was dissolved in tert-butyl acrylate (12.5 g,
99.5 mmol) and methanol (5 mL). The reaction mixture
was re¯uxed for 48 h and then cooled to room temperature.
The crude mixture was concentrated under vacuum and
the residue was puri®ed by chromatography on neutral
alumina (ethyl acetate) yielding 17 as a yellow oil; 2.05 g
1
(43%). H NMR (CDCl3) d: 1.42 (s, 27H), 2.45 (m, 8H),
4.1.10. tert-Butyl 3,6,9,15-tetraazabicyclo[9.3.1]pentade-
cane-1(15),11,13-triene-6-carbamate (13). Compound 13
was obtained after chromatography on silica gel (MeOH/
NH3 aq 32%: 100/0 to 95/5) as a colourless oil; 0.28 g
(91%). H NMR (CDCl3) d: 1.47 (s, 9H), 2.59 (t, 4H,
Jˆ5.3 Hz), 2.95 (m, 2H), 3.50 (m, 4H), 3.92 (s, 4H), 6.91
2.55 (t, 4H, Jˆ7.3 Hz), 2.94 (t, 4H, Jˆ7.3 Hz), 3.10 (s, 2H),
3.79 (s, 4H), 7.16 (d, 2H, Jˆ7.6 Hz), 7.65 (dd, 1H,
Jˆ7.6 Hz). 13C NMR (CDCl3) d: 28.1, 34.4, 49.3, 49.8,
53.1, 58.0, 60.5, 80.3, 122.7, 137.2, 157.4, 171.9. HRMS
(FAB): found m/z 577.3984 ([M1H]1); calcd for
C31H53N4O6 577.3965.
1

4718
J.-M. Siaugue et al. / Tetrahedron 57 (2001) 4713±4718
3. Guo, Z.; Sadler, P. J. Angew. Chem. Int. Ed 1999, 38, 1512±
1531.
Â
4. Siaugue, J.-M.; Segat-Dioury, F.; Favre-Reguillon, A.; Madic,
4.1.15. 6-(Carboxymethyl)-3,6,9,15-tetraazabicyclo[9.3.1]-
pentadecane-1(15),11,13-triene-3,9-dipropanoic acid (18).
Compound 17 (2.05 g, 3.55 mmol) was dissolved in 25 mL
of anhydrous diethylether. The reaction mixture was then
cooled to 08C and 100 mL of a saturated solution of HCl in
diethylether was added. The reaction mixture was stirred
overnight. The white precipitate obtained was ®ltered and
then pre-puri®ed on an ion-exchange resin (Dowex 1X8,
formate form) eluting with formic acid (0.02N). The residue
was puri®ed by gel ®ltration (Sephadex G-10 eluting with
C.; Foos, J.; Guy, A. Tetrahedron Lett. 2000, 41, 7443±7446.
5. Sabbatini, N.; Guardigli, M.; Lehn, J.-M. Coord. Chem. Rev.
1993, 123, 201±228.
6. Bornhop, D. J.; Hubbard, D. S.; Houlne, M. P.; Adair, C.;
Kiefer, G. E.; Pence, B. C.; Morgan, D. L. Anal. Chem.
1999, 71, 2607±2615.
Á
7. Denat, F.; Brandes, S.; Guilard, R. Synlett 2000, 5, 561±574.
1
8. Studer, M.; Kaden, T. A. Helv. Chim. Acta 1986, 69, 2081±
2086.
water) yielding 18 as a white solid; 0.81 g, 56%. H NMR
(D2O) d: 2.84 (m, 2H), 3.03 (t, 4H, Jˆ6.9 Hz), 3.18 (m, 2H),
3.51 (m, 2H), 3.59 (m, 2H), 3.68 (s, 2H), 3.79 (m, 4H), 4.80
(s, 2H), 4.95 (s, 2H), 7.53 (d, 2H, Jˆ7.8 Hz), 8.04 (dd, 1H,
Jˆ7.8 Hz).13C NMR (D2O) d: 31.1, 52.6, 54.5, 56.6, 57.4,
60.3, 124.7, 142.9, 151.4, 176.7, 177.4. HRMS (FAB):
found m/z 409.2108 ([M1H]1); calcd for C19H29N4O6
409.2087.
9. (a) Desreux, J. F.; Dumont, A.; Jacques, V.; Qixiu, P.
Tetrahedron Lett. 1994, 35, 3707±3710. (b) Kim, W. D.;
Hencir, D. C.; Kiefer, G. E.; Sherry, A. D. Inorg. Chem.
Á
1995, 34, 2225±2232. (c) Brandes, S.; Gros, C.; Denat, F.;
Pullumbi, P.; Guilard, R. Bull. Soc. Chem. Fr. 1996, 133,
65±73.
Â
10. (a) Yaouanc, J. J.; Le Bris, N.; Le Gall, G.; Clement, J. C.;
Handel, H.; Des Abbayes, H. J. Chem. Soc., Chem. Commun.
1991, 206±207. (b) Parker, D.; Pulukoddy, K.; Norman, T. J.;
Harrison, A.; Royle, L.; Walker, C. J. Chem. Soc., Chem.
Commun. 1992, 1441±1443.
4.1.16. 3,9-Bis(carboxymethyl)-3,6,9,15-tetraazabicyclo-
[9.3.1]pentadecane-1(15),11,13-triene-6-propanoic acid
(20). Compound 15 (0.62 g, 1.85 mmol) was dissolved in
60 mL of anhydrous tetrahydrofuran. Triethylamine
(0.9 mL, 7.00 mmol) and tert-butyl bromoacetate (1.5 mL,
10.2 mmol) were then added. The reaction mixture was
heated at 708C during 3 h and then concentrated under
vacuum. The residue was taken up in dichloromethane
(90 mL), washed with water (30 mL). The organic phase
was dried over sodium sulfate, concentrated under vacuum
and dissolved in 30 mL of diethylether. 150 mL of a
saturated solution of HCl in diethylether was added and
the reaction mixture was stirred overnight. The white
precipitate was ®ltered and then pre-puri®ed by gel ®ltration
(Sephadex G-10 eluting with water). The residue was
further puri®ed by chromatography on an ion-exchange
resin (Dowex 1X8, formate form) eluting with formic acid
(0.02N) to provide compound 20 as a white solid; 0.43 g
11. Boldrini, V.; Giovenzana, G. B.; Pagliarin, R.; Palmisano, G.;
Sisti, M. Tetrahedron Lett. 2000, 41, 6527±6530.
12. Theodoridis, G. Tetrahedron 2000, 56, 2339±2358.
13. Wang, T.; An, H.; Vickers, T. A.; Bharadwaj, R.; Cook, P. D.
Tetrahedron 1998, 54, 7955±7976.
14. Barros, M. T.; SinÄeriz, F. Tetrahedron 2000, 56, 4759±4764.
Â
15. Favre-Reguillon, A.; Segat-Dioury, F.; Nait-Bouda, L.;
Cosma, C.; Siaugue, J.-M.; Foos, J.; Guy, A. Synlett 2000,
6, 868±870.
16. Richman, J. E.; Atkins, T. J. J. Am. Chem. Soc. 1974, 96,
2268±2270.
17. Burgete, M. I.; Escuder, B.; Luis, S. V.; Miravet, J. F.; Querol,
M. Tetrahedron Lett. 1998, 39, 3799±3802.
18. (a) Lecomte, C.; Dahaoui-Gindrey, V.; Chollet, H.; Gros, C.;
Mishra, A. K.; Barbette, F.; Pullumbi, P.; Guilard, R. Inorg.
Chem. 1997, 36, 3827±3838. (b) Jang, Y. H.; Blanco, M.;
Dasgupta, S.; Keire, D. A.; Shively, J. E.; Goddard, W. A.
J. Am. Chem. Soc., 1999, 121, 6142±6151.
1
(59%). H NMR (D2O) d: 2.95 (t, 2H, Jˆ6.7 Hz), 3.20
(broad m, 4H), 3.38 (broad m, 4H), 3.57 (t, 2H,
Jˆ6.7 Hz), 3.99 (s, 4H), 4.60 (s, 4H), 7.78 (d, 2H,
Jˆ7.9 Hz), 8.38 (dd, 1H, Jˆ7.9 Hz).13C NMR (D2O) d:
30.5, 51.9, 53.6, 54.7, 59.1, 60.5, 126.5, 148.2, 154.2,
176.5, 177.0. HRMS (FAB): found m/z 395.1921
([M1H]1); calcd for C18H27N4O6 395.1931.
19. (a) Bradshaw, J. S.; Krakowiak, K. E.; Izatt, R. M. In Common
Methods for the Formation of Polyaza Macrocyclic Rings,
Aza-Crown Macrocyles, Taylor, E. C., Ed.; The Chemistry
of Heterocyclic Compounds, John Wiley: New York, 1993;
Vol. 51, pp 123±171. (b) Altava, B.; Burguete, M. I.; Escuder,
B.; Luis, S. V. Tetrahedron 1997, 53, 2629±2640.
20. Jung, M. E.; Gervay J. Am. Chem. Soc. 1991, 113, 224±232.
21. Fukuyama, T.; Jow, C.-K.; Cheung, M. Tetrahedron Lett.
1995, 36, 6373±6374.
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