Preparation of hexaaza and heptaaza macrocycles functionalized with a single aminoalkyl pendant arm

Article abstract of DOI:10.1039/b210663a

A practical and reproducible route for the preparation of 1,4,7,10,13,16,19-heptaazacyclohenicosane (1), 1,4,7,10,13,16-hexaazacyclooctadecane (2), and 1,4,7,10,13,17-hexaazacycloicosane (3) bearing a single N-(2-amino-ethyl) pendant arm has been develope

Full text of DOI:10.1039/b210663a

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Preparation of hexaaza and heptaaza macrocycles functionalized
with a single aminoalkyl pendant arm†
Zhibo Zhang, Satu Mikkola and Harri Lönnberg*
Department of Chemistry, University of Turku, FIN-20014, Turku, Finland
Received 30th October 2002, Accepted 17th January 2003
First published as an Advance Article on the web 11th February 2003
A practical and reproducible route for the preparation of 1,4,7,10,13,16,19-heptaazacyclohenicosane (1),
1,4,7,10,13,16-hexaazacyclooctadecane (2), and 1,4,7,10,13,17-hexaazacycloicosane (3) bearing a single N-(2-amino-
ethyl) pendant arm has been developed. Richman–Atkins cyclization in the presence of caesium carbonate was
applied to construct the macrocycle from 3-benzoyl-N 1,N 5-ditosyl-3-azapentane-1,5-diamine and the appropriate
fully N-tosylated N α,N ω-bis(2-mesyloxyethyl) tri- or tetra-amine. The benzoyl group was selectively removed with
potassium tert-butoxide, and the exposed nitrogen atom was reacted with N-tosylaziridine. The tosyl protections were
removed with hydrogen bromide in acetic acid, and the product was converted to a free base with the aid of a strong
anion exchange resin (OHϪ form).
Introduction
Results and discussion
Macrocyclic polyamines, the so-called azacrowns, have received
increasing interest as artificial receptors and carriers of bio-
logically important phosphoesters,1 receptors of nucleic acid
bases,2–5 catalysts of phosphoryl transfer reactions,6–9 and
carriers of metal ions in simple chemical enzyme models.10–16
Many of these applications are dependent on covalent conju-
gation of the azacrown to a biomolecule that increases the
overall lipophilicity of the conjugate17 or provides it with a
desired bioaffinity.18,19 For efficient conjugation, the azacrown
has to be derivatized with a pendant arm that bears the desired
functionality. The ring nitrogen atoms obviously are potential
sites for the attachment of such tethers, but the presence of
several similar nitrogen atoms implies a synthetic challenge.
Even relatively large azacrowns may be derivatized with a single
pendant arm by using the azacrown in excess, as evidenced by
the preparation of a monofunctionalized pentaaza macrocycle,
1,4,7,10,13-pentaazacyclopentadecane-1-(α-1,4-toluic acid),20
but this approach wastes the precious azacrown and leads to
tedious purification. More efficient synthetic methods that
make use of orthogonal protecting groups on various nitrogen
atoms upon the assembly of the azacrown from smaller frag-
ments are undoubtedly needed to obtain reasonable yields.
Considerable progress has recently been made in the field of
N-functionalization of tri-21–28 and tetra-azacycloalkanes.29–31
In contrast, the data on derivatization of hexa- and hepta-aza
cycloalkanes are scarce.32 In fact, among the fully saturated
azacrowns, only a mixed dioxa hexaaza cycloalkane, 1,13-
dioxa-4,7,10,16,19,22-hexaazacyclotetracosane, has been been
monofunctionalized with 2-aminoethyl, 2-hydroxyethyl and
2-mercaptoethyl tethers at N7.33 We now report on the syn-
thesis of N-(2-aminoethylated) derivatives of three large fully
saturated azacrowns, viz., 1,4,7,10,13,16,19-heptaazacyclo-
henicosane (1), 1,4,7,10,13,16-hexaazacyclooctadecane (2), and
1,4,7,10,13,17-hexaazacycloicosane (3). These compounds are
expected to find applications as constituents of cleaving agents
targeted towards polyphosphate bridges, such as the tri-
phosphate bridge present in the 5Ј-cap structure of mRNA,34
since large azacrowns have been shown to bind firmly pyro-
phosphate anion35 and its organic derivatives.36
The pathway utilized to obtain N-(2-aminoethylated) aza-
crowns 1–3 is outlined in Scheme 1. Accordingly, the parent
azacrowns having one of the ring nitrogen atoms benzoylated
and all the rest tosylated were obtained by a slightly modified
Richman–Atkins cyclization37 between 3-benzoyl-N 1,N 5-dito-
syl-3-azapentane-1,5-diamine (8) and the appropriate fully N-
tosylated N α,N ω-bis(2-mesyloxyethyl) polyamine (11a–c), as
reported previously for smaller azacrowns.38 The mono-
functionalization was then achieved by removal of the benzoyl
protection and treatment with N-tosylaziridine (6).33 Finally,
the tosyl protections were removed by repeated treatment with
hydrogen bromide in acetic acid, and the products were con-
verted to free bases by passing them through a strong anion
exchange resin in the hydroxide ion form.
The building blocks employed in the cyclization were pre-
pared as follows. N 1,N 5-Ditosyl-3-azapentane-1,5-diamine (7)
was obtained in an almost quantitative yield by reacting N-(2-
aminoethyl)-p-toluenesulfonamide (4) with N-tosylaziridine
(6), as described previously.38 Benzoylation of the unprotected
secondary nitrogen atom then gave the desired orthogonally
protected triamine (8). The fully tosylated acyclic tri- and tetra-
amines (9a–c) were obtained in a 70% yield by tosylation of
the corresponding unprotected amines. Previously the same
compounds had been prepared by a stepwise elongation of
N,NЈ-ditosylethane-1,2-diamine with N-(2-bromoethyl)-p-
toluenesulfonamide,39 but this approach led in our hands to a
more complicated product mixture. Repeated chromatographic
purification was needed, and the yield of the properly purified
material ranged from 30 to 40%, making the reaction unsuitable
for an early step reaction of a multi-step synthesis. By direct
tosylation, the fully protected amines could easily be syn-
thesized on a multi-gram scale. The N α,N ω-bis(2-mesyloxy-
ethyl) building blocks (11a–c) were then obtained in a nearly
quantitative yield by the reaction of the fully tosylated amines
with ethylene carbonate and subsequent mesylation of the
resulting diols (10a–c).40
The Richman–Atkins type coupling of the ditosylated amine
(8) with the dimesylated diol (11a–c) was carried out under the
conditions described previously for the preparation of closely
related fully tosylated macrocyclic polyamines.41 Reasonably
high yields were, however, obtained only when caesium carbon-
ate was used as a base instead of potassium carbonate which
was employed in the previously reported work. On using the
latter base, the yield remained below 30% and was not repro-
† Electronic supplementary information (ESI) available: preparative
details for compounds which have been reported previously. See http://
www.rsc.org/suppdata/ob/b2/b210663a/
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 8 5 4 – 8 5 8
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 3
854

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Scheme 1 a) TsCl–pyridine, Ϫ13 ЊC, 2 h, 75%; b) TsCl–pyridine, Ϫ40 ЊC, 1 h, Ϫ10 ЊC, 1 h, 0 ЊC, 12 h, 85%; c) KOH–benzene, 0.5 h, 95%; d) MeCN,
reflux, 4 h, 75%; e) BzCl–toluene, 12 h, 90%; f) 1. ethylene carbonate–KOH, 160–170 ЊC, 4 h, 2. MeOH, reflux, 70–80%; g) MsCl–Et3N–CH2Cl2, Ϫ15
to Ϫ20 ЊC, 0.5 h, 98%; h) Cs2CO3–DMF, 7 d, 60–70%; i) Me3COK–THF, 2 h, reflux, 70–90%; j) 6–MeCN–toluene, reflux, 3 d, 98%; k) HBr–AcOH,
PhOH, 80 ЊC, 7 d, 60–75%.
ducible. Cyclization to 12a, in particular, almost entirely failed;
the yield was about 5%. Potassium carbonate, as well as sodium
methoxide, resulted in formation of several side products,
among which the elimination product 12d predominated. In
striking contrast, the fully protected heptaaza (12a) and hexa-
aza (12b,c) macrocycles were reproducibly obtained in a 60%
and 70% yield, respectively, on using caesium carbonate as the
base and keeping the concentration of the starting material
below the effective molarity.42 In this manner the cyclization
could be carried out on a multi-gram scale.
advantageous to subject the crude reaction mixture of the
Richman–Atkins coupling reaction as such to the debenzoyl-
ation, since the chromatographic purification of the depro-
tected macrocycle is easier than that of the fully protected
azacrowns.
The N-benzoyl protection was readily removed with potas-
sium tert-butoxide to yield 13a–c.43 In fact, it proved to be
The monofunctionalized azacrowns were obtained in an
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 8 5 4 – 8 5 8
855

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almost quantitative yield by reacting the debenzoylated macro-
cycles (13a–c) with 1.2 equiv. of N-tosylaziridine in a mixture of
toluene and MeCN at 65–70 ЊC for about one week. The tosyl
groups were then removed with 37% hydrogen bromide in acetic
acid in the presence of a large excess of phenol.44,45 The depro-
tected products were hence obtained as hydrobromide salts.
Unfortunately, the deprotection was not fully quantitative,
though the situation improved at an elevated temperature.
Evidently owing to limited solubility of partially deprotected
starting material, even a prolonged treatment was not usually
sufficient to remove all the tosyl groups, but traces of azacrowns
bearing one or two tosyl groups could be detected by mass
spectroscopy. Among the compounds studied, 14c proved to be
easiest to deprotect, and the fully deprotected compound could
be nicely precipitated with cold diethyl ether. 14a and 14b were
more difficult to deblock entirely, and to get rid of mono- and
ditosylated impurities, the deprotection was repeated. Precipi-
tation with cold diethyl ether gave the fully deprotected material
as a fine-grained powder. The fully deprotected products were
finally converted to free bases (1–3) by passing them through a
Dowex 1 × 8 resin in the hydroxide ion form.
details for the preparation and characterization of these com-
pounds are given as Electronic Supplementary Information.†
3,7,11-Tritosyl-3,7,11-triazatridecane-1,13-diol (10c)
A mixture of 9c (1.78 g, 3.00 mmol), ethylene carbonate (0.58 g,
6.7 mmol) and powdered potassium hydroxide (5.1 mg,
0.091 mmol) was stirred at 160–170 ЊC for 4 h, allowed to cool
to 90 ЊC, and a large excess of MeOH (50 cm3) was rapidly
added. The white solid precipitate was separated by filtration
and purified by silica gel chromatography to obtain 10c in an
1
80% (1.64 g) yield. H NMR (CDCl3): 7.61 (d, J 8.0 Hz, 6H,
H2 and 6 of Ts), 7.24 (d, J 8.0 Hz, H3 and 5 of Ts), 3.70 (q,
J 5.3 Hz, 4H, CH2OH), 3.07–3.12 (m, 12H, CH2–N), 2.93 (t,
J 5.4 Hz, 2H, OH ), 2.34 (s, 9H, CH3), 1.86–1.93 (m, 4H,
CH2CH2CH2). 13C NMR (CDCl3): 143.6, 143.4, 135.7, 135.3,
129.8, 129.7, 127.2, 127.1, 61.5, 52.0, 48.4, 47.2, 28.9, 21.5. νmax
(KBr)/cmϪ1 3329, 1238, 1157. HRMS: required for C31H43-
N3O8S3 682.2291(M ϩ Hϩ), found 682.2259.
1,13-Dimesyloxy-3,7,11-tritosyl-3,7,11-triazatridecane (11c)
In conclusion, an efficient and reproducible method for the
preparation of large symmetric and asymmetric azacrowns that
allows attachment of a pendant arm at a single nitrogen atom
has been described. By optimizing both the synthesis of the
tosylated acyclic precursors and the actual Richman–Atkins
coupling/cyclization a protocol has been developed that enables
multi-gram yields for individual laboratory scale syntheses.
The most essential factors are the use of caesium carbonate as
a base in the coupling/cyclization and proper control of the
concentrations employed.
A mixture of compound 10c (2.73 g, 4.00 mmol) and triethyl-
amine (1.7 cm3) in dry dichloromethane was cooled to Ϫ15 to
Ϫ20 ЊC, and methanesulfonyl chloride (0.653 cm3) was added
over 10 min. The mixture was transferred onto an ice bath, and
the solution was stirred for 30 min. Crushed ice (100 cm3)
and 10% aq. hydrogen chloride (50 cm3) were added, and the
mixture was thoroughly shaken. The organic layer was washed
with water, dried over MgSO4, and evaporated to dryness to
obtain a white solid. Purification by silica gel chromatography
1
(CH2Cl2 : MeOH 200 : 1) gave 11c in a 98% (3.28 g) yield. H
NMR (CDCl3): 7.60 (d, J 8.0 Hz, 6H, H2 and 6 of Ts), 7.26
(d, J 8.0 Hz, 6H, H3 and 5 of Ts), 4.31 (t, J 5.8 Hz, 4H, CH2-
OMs), 3.33 (t, J 5.8 Hz, 4H, NCH2CH2OMs), 3.11 (t, J 7.3 Hz,
4H, C4-H2 and C10-H2), 3.06 (t, J 7.3 Hz, 4H, C6-H2 and C8-
H2), 2.97 (s, 6H, OMs), 2.35 (s, 9H, CH3 of Ts), 1.83–1.93
(quin., J 7.4 Hz, 4H, C5-H2 and C9-H2). 13C NMR (CDCl3):
143.9, 143.6, 135.6, 135.1, 130.0, 129.9, 127.2, 127.1, 68.3, 48.2,
47.0, 37.3, 28.7, 21.5 (2C: Ms and Ts). HRMS: m/z required for
C33H47N3O12S5 838.1842 (M ϩ Hϩ), found 838.1830.
Experimental section
General
Dichloromethane, acetonitrile and dimethylformamide were
distilled from CaH2 and triethylamine from KOH, and sub-
sequently stored over 4 Å molecular sieves. Pyridine was dried
with BaO, followed by distillation from CaH2. Tetrahydrofuran,
benzene and toluene were distilled from Na–benzophenone
under N2 atmosphere. The air- and moisture-sensitive reactions
were carried out under N2 using oven-dried glassware and a
standard syringe/septum technique. All the other reagents
(Aldrich, Lab Scan) were used as supplied unless otherwise
stated.
1-Benzoyl-4,7,10,13,16,19-hexatosyl-1,4,7,10,13,16,19-hepta-
azacyclohenicosane (12a)
A mixture of compounds 8 (2.26 g, 4.39 mmol) and 11a (5.30 g,
5.27 mmol) in 250 cm3 DMF was stirred in the presence of
anhydrous caesium carbonate (14.30 g, 43.89 mmol) at ambient
temperature for 7 d. The reaction mixture was filtered through
Celite, and the solvent was removed under reduced pressure.
The residue was chromatographed on a silica column (CH2Cl2 :
MeOH 93 : 7) to afford 12a as a colorless amorphous powder in
1
The H NMR and 13C NMR spectra were recorded on a
JEOL JNM-GX 400 or Bruker 200 NMR spectrometer using
Me4Si as an internal reference. The IR spectra were recorded as
KBr pellets on a Unicam SP 1100 spectrophotometer. The
ESI-mass spectra were obtained with a Perkin Elmer Sciex API
365 triple quadrupole MS spectrometer. The HRMS spectra
and the FABϩ spectra were recorded with a ZabSpecETOF
instrument. The melting points reported are uncorrected.
Many of the compounds prepared to be used as inter-
mediates of the synthesis of the desired monofunctionalized
azacrowns (1–3) have been previously reported. They include
N-(2-aminoethyl)-p-toluenesulfonamide (4),46–48 N-(2-tosyloxy-
1
a 70% (4.09 g) yield. Mp 149.9–150.2 ЊC. H NMR (CDCl3):
7.20–7.80 (m, 29H, Bz and Ts), 3.25–3.75 (m, 28H, CH2), 2.43
(s, 9H, CH3), 2.42 (s, 3H, CH3), 2.40 (s, 3H, CH3), 2.37 (s, 3H,
CH3). 13C NMR (CDCl3): 173.1, 143.7, 135.8, 134.9, 134.2,
129.9, 129.6, 128.6, 127.5, 127.3, 126.9, 51.2, 50.9, 49.9, 49.7,
49.4, 49.1, 47.8, 44.9, 21.5. νmax (KBr)/cmϪ1 1632, 1599, 1341,
1159. HRMS: m/z required for C63H75N7O13S6 1330.3825 (M ϩ
Hϩ), found 1330.3831.
ethyl)-p-toluenesufonamide
(5),38,45,49,50
N-tosylaziridine
(6),38,45,51 N 1,N 5-ditosyl-3-azapentane-1,5-diamine (7),38 3-ben-
zoyl-N 1,N 5-ditosyl-3-azapentane-1,5-diamine (8),38 N 1,3,6,N 8-
tetratosyl-3,6-diazaoctane-1,8-diamine (9a),51–53 N 1,3,N 5-trito-
syl-3-azapentane-1,5-diamine (9b),53–55 N 1,4,N 7-tritosyl-4-aza-
heptane-1,7-diamine (9c),56 3,6,9,12-tetratosyl-3,6,9,12-tetraa-
zatetradecane-1,14-diol (10a),57,58 3,6,9-tritosyl-3,6,9-triazaun-
decane-1,11-diol (10b),40,55,58 1,14-dimesyloxy-3,6,9,12-tetrato-
syl-3,6,9,12-tetraazatetradecane (11a)58 and 1,11-dimesyloxy-
3,6,9-tritosyl-3,6,9-triazaundecane (11b).39,58 N 1,3,N 5-Tritosyl-
N 1,N 5-divinyl-3-azapentane-1,5-diamine (12d), observed as a
side product, is also a known compound.58,59 The experimental
1-Benzoyl-4,7,10,13,16-pentatosyl-1,4,7,10,13,16-hexaazacyclo-
octadecane (12b)
The reaction of 8 with 11b, when conducted as described above
for 12a, afforded 12b as a colorless amorphous powder in a
1
70% yield. H NMR (CDCl3): 7.10–7.69 (m, 25H, Bz and Ts),
3.05–3.55 (m, 24H, CH2), 2.37 (s, 9H, CH3), 2.35 (s, 3H,
CH3), 2.33 (s, 3H, CH3). 13C NMR: 172.7, 144.1, 143.9,
143.8, 135.6, 135.3, 135.1, 135.0, 134.5, 129.9, 129.8, 129.7,
128.6, 127.4, 127.2, 126.7, 50.9, 50.7, 50.4, 50.3, 49.7, 49.4, 49.3,
49.2, 48.5, 47.6, 44.9, 21.5. νmax (KBr)/cmϪ1 1632, 1599, 1341,
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 8 5 4 – 8 5 8
856

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1159. HRMS: m/z required for C54H64N6O11S5 1133.3315 (M ϩ
νmax (KBr)/cmϪ1 3437, 1633, 1338, 1159. HRMS: m/z required
Hϩ), found: 1133.3176.
for C49H64N6O10S5 1057.3366 (M ϩ Hϩ), found: 1057.3373.
1-(N-Tosyl-2-aminoethyl)-4,7,10,13,16,19-hexatosyl-1,4,7,10,13,
16,19-heptaazacyclohenicosane (14a)
7-Benzoyl-1,4,10,13,17-pentatosyl-1,4,7,10,13,17-hexaazacyclo-
icosane (12c)
Equal amounts of debenzoylated macrocycle 13a and N-tosyl-
aziridine (6) were heated in a mixture of toluene and MeCN
under N2 at 70 ЊC for several days. The solvent was removed
under reduced pressure and the residue was chromatographed
on a silica gel column (acetone : CH2Cl2 1 : 4) to give 14a as a
white solid in a 98% yield. 1H NMR (CDCl3): 7.65–7.74
(m, 14H, H2 and 6 of Ts), 7.18–7.32 (m, 14H, H3 and 5 of Ts),
5.48 (t, J 5.6 Hz, 1H, NHTs), 3.24–3.30 (m, 20H, TsNCH2-
CH2NTs), 3.10 (m, 4H, TsNCH2CH2N1), 2.93 (m, 2H, TsNH-
CH2CH2N1), 2.63 (m, 6H, CH2N1), 2.40 (s, 6H, CH3), 2.39
(s, 6H, CH3), 2.38 (s, 6H, CH3), 2.34 (s, 3H, CH3). 13C NMR
(CDCl3): 143.8, 143.6, 143.4, 143.0, 136.6, 135.4, 134.7, 134.4,
129.8, 129.7, 129.6, 129.5, 127.3, 127.1, 126.8, 53.7, 53.4, 52.8,
50.0, 49.9, 49.6, 49.4, 48.5, 47.9, 40.6, 30.7, 21.3. HRMS:
m/z required for C65H82N8O14S7 1423.3896 (M ϩ Hϩ), found
1423.3810.
The reaction of 8 with 11c, when conducted as described above
for 12a, afforded 12c as a colorless amorphous powder in a
70% yield. H NMR(CDCl3): 7.15–7.70 (m, 25H, Bz and Ts),
1
3.5–3.7 (m, 4H, BzNCH2), 2.96–3.33 (m, 20H, TsNCH2),
2.35 (s, 9H, CH3), 2.32 (s, 6H, CH3), 1.98 (m, 2H, N-CH2CH2-
CH2N), 1.85 (m, 2H, N-CH2CH2CH2N). 13C NMR (CDCl3):
172.9, 143.8, 143.7, 143.6, 143.5, 135.6, 135.4, 135.1, 134.7,
134.6, 134.3, 129.8, 128.6, 127.3, 127.1, 126.9, 51.0, 50.7,
49.6, 48.8, 48.4, 48.3 48.2, 48.1, 47.8, 47.4, 45.0, 29.4, 28.8,
21.5. νmax (KBr)/cmϪ1 1632, 1599, 1341, 1159. HRMS: m/z
required for C56H68N6O11S5 1161.3628 (M ϩ Hϩ), found:
1161.3637.
1,4,7,10,13,16-Hexatosyl-1,4,7,10,13,16,19-heptaazacyclo-
henicosane (13a)
To a solution of macrocycle 12a (2.86 g, 2.16 mmol) in 50 cm3
THF, water (77.6 mg, 4.31 mmol) and potassium tert-butoxide
(1.60 g, 14.22 mmol) were added under nitrogen. The mixture
was refluxed and the progress of the debenzoylation of 12a was
followed by TLC. After completion of the reaction, ice was
added to the cooled solution, resulting in separation of two
phases. The aqueous layer was extracted thoroughly with
CH2Cl2. The combined organic layers were dried and evapor-
ated under reduced pressure to obtain an orange solid that was
chromatographed on a silica gel column (CH2Cl2 containing 1
to 3% MeOH) to obtain 13a as a white solid in a 90% yield. 1H
NMR (CDCl3): 7.73 (d, J 8.4 Hz, 4H, H2 and 6 of Ts), 7.67 (d,
J 8.3 Hz, 4H, H2 and 6 of Ts), 7.61 (d, J 8.4 Hz, 4H, H2 and 6
of Ts), 7.25–7.32 (m, 12H, H3 and 5 of Ts), 3.17–3.51 (m, 24H,
TsNCH2), 2.78–2.81 (m, 4H, HNCH2), 2.47 (s, 3H, CH2), 2.43
(s, 3H, CH2), 2.40 (s, 3H, CH2). 13C NMR (CDCl3): 143.8,
143.7, 143.5, 135.9, 135.5, 135.0, 129.9, 129.8, 127.5, 127.4,
127.2, 50.9, 50.7, 50.3, 49.1, 48.8, 48.6, 48.4, 21.5. νmax (KBr)/
cmϪ1 3439, 1327, 1156 cmϪ1. HRMS: m/z required for
C56H71N7O12S6 1226.3563 (M ϩ Hϩ), found: 1226.3563.
1-(N-Tosyl-2-aminoethyl)-4,7,10,13,16-pentatosyl-1,4,7,10,13,
16-hexaazacyclooctadecane (14b)
Compound 14b was obtained by reacting 13b with an equal
amount of 6, as described for 14a. 1H NMR (CDCl3): 7.58–7.69
(m, 12H, H2 and 6 of Ts), 7.19–7.28 (m, 12H, H3 and 5 of Ts),
5.20 (t, J 5.8 Hz, 1H, NHTs), 3.17–3.24 (m, 16H, TsNCH2-
CH2NTs), 3.01–3.07 (m, 4H, TsNCH2CH2N1), 2.81–2.88 (m,
2H, TsNHCH2CH2N1), 2.55–2.59 (m, 4H, C2H2 and C18H2),
2.50–2.53 (m, 2H, TsNHCH2CH2N1), 2.39 (s, 6H, CH3), 2.36
(s, 6H, CH3), 2.34 (s, 3H, CH3), 2.31 (s, 3H, CH3). 13C NMR
(CDCl3): 144.1, 144.0, 143.8, 143.3, 136.8, 135.6, 134.9, 134.5,
130.0, 129.9, 129.7, 127.5, 127.4, 127.3, 127.1, 53.8, 53.5,
50.5, 49.9, 49.1, 48.3, 40.8, 21.6. HRMS: m/z required for
C56H71N7O12S6 1226.3563 (M ϩ Hϩ), found 1226.3414.
7-(N-Tosyl-2-aminoethyl)-1,4,10,13,17-pentatosyl-1,4,7,10,13,
17-hexaazacycloicosane (14c)
Compound 14c was obtained by reacting 13c with an equal
amount of 6, as described for 14a. 1H NMR (CDCl3): 7.59–7.86
(m, 12H, H2 and 6 of Ts), 7.19–7.33 (m, 12H, H3 and 5 of Ts),
5.37 (t, J 5.8 Hz, 1H, NHTs), 2.81–3.32 (m, 22H, CH2NTs),
2.70–2.74 (m, 4H, C2H2 and C20H2), 2.62–2.65 (m, 2H, TsN-
HCH2CH2N1), 2.41 (s, 6H, CH3), 2.40 (s, 6H, CH3), 2.39 (s,
3H, CH3), 2.35 (s, 3H, CH3), 1.92–1.95 (m, 4H, TsNCH2CH2-
CH2NTs). 13C NMR: 143.7, 143.6, 143.2, 136.8, 135.4, 135.3,
134.9, 134.8, 129.9, 129.7, 127.4, 127.3, 127.2, 127.1, 54.1, 53.8,
53.6, 49.8, 49.4, 48.6, 48.5, 47.8, 40.9, 29.7, 21.5. HRMS:
m/z required for C58H75N7O12S6 1254.3876 (M ϩ Hϩ), found:
1254.3875.
1,4,7,10,13-Pentatosyl-1,4,7,10,13,16-hexaazacyclooctadecane
(13b)
Debenzoylation of 12b by the method described above for 13a
1
gave 13b in a 90% yield. H NMR (CDCl3): 7.65 (d, J 8.3 Hz,
4H, H2 and 6 of Ts), 7.62 (d, J 8.3 Hz, 4H, H2 and 6 of Ts),
7.60 (d, J 8.3 Hz, 2H, H2 and 6 of Ts), 7.22–7.27 (m, 10H, H3
and 5 of Ts), 3.20–3.36 (m, 16H, TsNCH2CH2NTs), 3.08 (t, J
5.6 Hz, 4H, TsNCH2CH2NH), 2.65 (t, J 5.6 Hz, 4H, TsNCH2-
CH2NH), 2.35 (s, 15H, CH3). 13C NMR (CDCl3): 144.0, 143.8,
143.6, 135.5, 135.0, 134.2, 129.9, 129.8, 127.5, 127.3, 50.6, 50.5,
50.0, 49.4, 21.5. HRMS: m/z required for C47H60N6O10S5
1029.3053 (M ϩ Hϩ), found: 1029.3054. νmax (KBr)/cmϪ1 3437,
1633, 1338.
1-(2-Aminoethyl)-1,4,7,10,13,16,19-heptaazacyclohenicosane (1)
The functionalized macrocycle 14a (0.28 mmol; 400 mg) and
excess of phenol (4.25 mmol; 400 mg) were dissolved in acetic
acid containing 37% hydrogen bromide. The mixture was kept
at 80 ЊC for 7 days. The solvent was evaporated under reduced
pressure, the residue was dissolved in distilled water and washed
with CH2Cl2, and finally with diethyl ether. The water phase
was evaporated to dryness to obtain 1 as a yellow solid. This
was dissolved in water, and passed through a Dowex 1 × 8
1,4,10,13,17-Pentatosyl-1,4,7,10,13,17-hexaazacycloicosane
(13c)
Debenzoylation of 12c by the method described above for 13a
1
gave 13c in a 90% yield. H NMR (CDCl3): 7.63 (d, J 8.3 Hz,
4H, H2 and 6 of Ts), 7.60 (d, J 8.3 Hz, 4H, H2 and 6 of Ts),
7.55 (d, J 8.3 Hz, 2H, H2 and 6 of Ts), 7.22–7.28 (m, 10H, H3
and 5 of Ts), 3.21–3.27 (m, 8H, TsNCH2CH2NTs), 3.07–3.10
(m, 8H, TsNCH2CH2CH2NTs), 2.95–3.01 (t, J 6.2 Hz, 4H,
TsNCH2CH2NH), 2.77–2.80 (t, J 6.2 Hz, 4H, TsCH2CH2NH),
2.34 (s, 6H, CH3), 2.32 (s, 9H, CH3), 1.81–1.91 (m, 4H,
TsNCH2CH2CH2NTs). 13C NMR: 143.6, 135.0, 134.9, 129.8,
127.5, 127.3, 127.2, 50.6, 49.9, 49.5, 48.5, 48.1, 47.8, 29.3, 21.5.
1
(OHϪ) resin to convert the product to a free base. H NMR
(D2O): 3.26–3.59 (m, 20H, HNCH2CH2NH), 3.05 (m, 2H,
CH2NH2), 2.80 (m, 6H, CH2N1), 2.52 (m, 4H, C3H2 and
C20H2). 13C NMR (D2O): 50.8, 47.0, 44.6, 44.4, 43.9, 43.8,
43.7, 37.0, 35.7. HRMS: m/z required for C16H40N8 345.3454
(M ϩ Hϩ), found 345.3456.
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 8 5 4 – 8 5 8
857

View Article Online
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1-(2-Aminoethyl)-1,4,7,10,13,16-hexaazacyclooctadecane (2)
Compound 14b was deblocked as described above for 1 to
obtain compound 2. 1H NMR (D2O): 3.45–3.61 (m, 16H, HN-
CH2CH2NH), 3.22 (m, 4H, C2H2 and C18H2), 3.02 (m, 2H,
CH2NH2), 2.73 (m, 4H, C3H2 and C17H3), 2.67 (m, 2H, N1-
CH2CH2N2). 13C NMR (D2O): 51.1, 49.5, 47.2, 45.6, 45.1, 45.0,
44,9, 36.2. HRMS: m/z required for C14H35N7 302.3032 (M ϩ
Hϩ), found 302.3033.
7-(2-Aminoethyl)-1,4,7,10,13,17-hexaazacycloicosane (3)
Compound 14c was deblocked as described above for 1 to
obtain compound 2. 1H NMR (D2O): 3.08–3.40 (m, 20H,
CH2NH), 2.97 (m, 2H, CH2NH2), 2.64–2.70 (m, 6H, CH2N1),
1.99 (m, 4H, HNCH2CH2CH2NH). 13C NMR (D2O): 52.8,
52.4, 48.9, 47.5, 47.0, 46.1, 46.0, 38.8, 24.2. HRMS: m/z
required for C16H39N7 330.3345 (M ϩ Hϩ), found 330.3347.
36 A. Domenech, E. Garcia-Espana, J. A. Ramirez, B. Celda,
M. C. Martinez, D. Monleon, R. Tejero, A. Bencini and A. Bianchi,
J. Chem. Soc., Perkin Trans. 2, 1999, 23–32.
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O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 8 5 4 – 8 5 8
858