New macrocyclic ligands. XV.* Isomeric, benzylated and xylyl-linked macrocyclic ligands derived from selectively protected N3O2-donor rings

Article abstract of DOI:10.1071/CH02164

Direct alkylation of the N₃O₂-macrocycle 1,12,15-triaza-3,4 : 9,10-dibenzo-5,8-dioxacycloheptadecane (1) with benzyl bromide in the presence of sodium hydrogen carbonate (in the respective molar ratios 1.0 : 2.0 : 1.3) led to a mixture of the mono-, bis-, and tris-N-benzylated derivatives (2)-(6) which were separated using their differential solubilities in warm acetone, fractional crystallization, coupled with column chromatography on silica gel. The X-ray structure of the symmetrical dibenzylated product (4) (as its HNO₃ salt) is described. In a parallel study, N-protection of (1) using 1.7 molar equivalents of di-tert-butyl dicarbonate (Boc)₂O yielded a mixture from which the symmetrical and unsymmetrical di-protected isomers (8) and (9) were separated by chromatography. Reaction of the symmetrically protected derivative (8) with benzyl chloride in the presence of excess sodium carbonate, followed by removal of the Boc groups, provided an alternative route to the corresponding (symmetrical) mono-N-benzylated macrocycle (2). A similar strategy, involving the use of α,α′-dibromo-p-xylene as a dialkylating agent, was employed to bridge a pair of N-diprotected macrocycles of type (8) or (9) to yield isomeric linked products (12) and (14), respectively. Deprotection of the resulting bis-macrocyclic products gave the 'central' and 'side' linked ligands (13) and (15), respectively.

Full text of DOI:10.1071/CH02164

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Aust. J. Chem. 2002, 55, 773–778
New Macrocyclic Ligands. XV.* Isomeric, Benzylated and
Xylyl-Linked Macrocyclic Ligands Derived from
Selectively Protected N3O2-Donor Rings
Kyoung Ju Park,A,B Jin-Ho Kim,A,C George V. Meehan,D Tomoko Nishimura,A,E
Leonard F. Lindoy,A,F Shim Sung Lee,A,B,F Ki-Min ParkB and Il YoonB
A Centre for Heavy Metals Research, School of Chemistry F11, University of Sydney, N.S.W. 2006, Australia.
B Department of Chemistry and Institute of Natural Sciences, Gyeongsang National University,
Chinju 660-701, South Korea.
C Department of Chemistry, Kangwon National University, Chuncheon 200-701, South Korea.
D School of Pharmacy and Molecular Sciences, James Cook University, Townsville, Qld. 4811, Australia.
E Department of Chemistry, Osaka City University, Osaka 558-8585, Japan.
F Authors to whom correspondence should be addressed (e-mail: lindoy@chem.usyd.edu.au and
sslee@nongae.gsnu.ac.kr).
Direct alkylation of the N3O2-macrocycle 1,12,15-triaza-3,4 : 9,10-dibenzo-5,8-dioxacycloheptadecane (1) with
benzyl bromide in the presence of sodium hydrogen carbonate (in the respective molar ratios 1.0 : 2.0 : 1.3) led to a
mixture of the mono-, bis-, and tris-N-benzylated derivatives (2)–(6) which were separated using their differential
solubilities in warm acetone, fractional crystallization, coupled with column chromatography on silica gel. The
X-ray structure of the symmetrical dibenzylated product (4) (as its HNO3 salt) is described. In a parallel study,
N-protection of (1) using 1.7 molar equivalents of di-tert-butyl dicarbonate (Boc)2O yielded a mixture from which
the symmetrical and unsymmetrical di-protected isomers (8) and (9) were separated by chromatography. Reaction
of the symmetrically protected derivative (8) with benzyl chloride in the presence of excess sodium carbonate,
followed by removal of the Boc groups, provided an alternative route to the corresponding (symmetrical)
mono-N-benzylated macrocycle (2). A similar strategy, involving the use of α,α´-dibromo-p-xylene as a
dialkylating agent, was employed to bridge a pair of N-diprotected macrocycles of type (8) or (9) to yield isomeric
linked products (12) and (14), respectively. Deprotection of the resulting bis-macrocyclic products gave the ‘central’
and ‘side’ linked ligands (13) and (15), respectively.
C
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02146
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Manuscript received: 19 August 2002.
Final version: 18 September 2002.
Introduction
as models for the electron transport behaviour found in
particular metal-containing biochemical systems. An
additional attraction of the incorporation of macrocyclic
rings is that their cyclic nature imposes an element of
preorganization for metal ion binding, usually resulting in
enhanced kinetic and thermodynamic stabilities of the
products.[5]
Recently, tert-butyloxycarbonyl (Boc) has been used for
the selective protection of secondary amines in macrocycles
that include both all-nitrogen donor systems [such as
1,4,8,11-tetraazacyclotetradecane (cyclam)][6,7] as well as
mixed donor systems.[8] Using a related strategy, we now
report the synthesis of the single ring, selectively benzylated
macrocycle (2) and the related bis-ring (isomeric) N,N-linked
macrocycles (13) and (15) in which the position of the p-xylyl
linkage between the macrocyclic units is varied.
In previous studies we have been interested in the effect of
N-benzylation of mixed-donor macrocyclic ligands on the
latters’ metal ion recognition behaviour.[1] In particular, it
has been demonstrated that it is sometimes possible to
‘detune’ the affinity of a given macrocyclic species of the
above type towards a number of divalent transition and
post-transition ions by N-benzylation while the affinity for
silver(I) remains much less affected. As a consequence,
enhanced discrimination for silver occurs.[2]
In recent years a considerable number of linked
polyamine bis-macrocyclic ligands capable of complexing
two metal ions in close proximity have been reported.[3,4]
There is continuing interest in such systems since they tend
to yield metal complexes exhibiting unusual electronic,
catalytic, and/or redox properties that, for example, may act
* Part XIV, Aust. J. Chem. 2002, 55, 597.
© CSIRO 2002
10.1071/CH02164
0004-9425/02/120773

774
K. J. Park et al.
Results and Discussion
The latter is a common strategy applied previously for the
synthesis of a range of linked two-ring systems that includes
linked cyclam derivatives.[3,4] In the present study, we also
used this approach and carried out the condensation of
α,α´-dibromo-p-xylene with two equivalents of the
selectively diprotected precursors (8) and (9) followed by
deprotection to yield (13) or (15), respectively (see Schemes
1 and 2).
The reaction of di-tert-butyl dicarbonate (Boc2O) with
the parent O2N3-macrocycle (1) was carried out in one step
(Scheme 1). A (Boc)2O/macrocycle molar ratio of 1.7 was
found to be optimum for maximizing the yields of the
desired di-Boc protected species precursors (8) and (9).
However, this ratio also resulted in the formation of some
tri-protected derivative (7) as well as, in lesser yields, the
mono-protected species (10) and (11). Some unreacted
starting material (1), also remained. Separation of the
desired di-Boc protected precursors (8) and (9), was
achieved by column chromatography on silica gel using
gradient elution (20% ethyl acetate/hexane to 100% ethyl
acetate). The latter procedure was found to be superior for
the present systems compared with the methanol/dichloro-
methane mixture employed previously for related
separations involving all-nitrogen heteroatom systems.[7]
In an initial experiment, direct alkylation of (1) using two
molar equivalents of benzyl bromide in acetonitrile in the
presence of 1.3 molar equivalents excess of sodium
hydrogen carbonate yielded a mixture of the N-benzylated
derivatives (2)–(6) as their HBr salts (Diagram 1). This
mixture of partially and fully benzylated derivatives was
successfully separated using a combination of solubility
difference, recrystallization, and conventional column
chromatography on silica gel. Thus solubility differences in
warm acetone allowed separation of the original mixture into
two parts – a less soluble solid component, largely a mixture
of (4) and (6) [with some (3)], and a more soluble
component, largely a mixture of (3) and (5) [with some (2)].
Fractional crystallization of the solid from methanol yielded
a mixture of (4) and (6). From this mixture (4) was isolated
following chromatography (5 : 95, methanol/dichloro-
methane as eluent) on silica gel. The acetone solution
containing the soluble fraction was taken to dryness and the
residue was chromatographed (10 : 90, methanol/dichloro-
methane as eluent) to afford (3). After (3) was isolated, crude
(5) was obtained from the initial portion of the eluent by
removal of the solvent; it was purified by chromatography on
silica gel (using 60 : 40, ethyl acetate/hexane as eluent). All
products isolated as their HBr salts were neutralized with
aqueous NaOH followed by normal workup procedures. On
HBr removal, the chemical shifts of the methylene protons
closest to the nitrogen heteroatoms typically shifted upfield
by ca. 0.2–0.4 ppm.
Under the synthetic conditions employed, only a trace of
the mono-substituted derivative (2) was formed. Due to this
extremely low yield, and subsequent difficulties with
chromatographic separation, (2) was synthesized using an
alternative procedure that employed the corresponding
di-Boc precursor. All new derivatives were characterized
from their 1H and 13C NMR and HRMS data. In all cases the
results were in accordance with the structures assigned. An
X-ray analysis (see later) of the symmetrical dibenzylated
derivative (4) (as its HNO3 salt) provided confirmation of its
structure (Fig. 1).
Two alternative general routes to the synthesis of p-xylyl
linked polyamine macrocyclic species such as (13) and (15)
appeared feasible. The first involved the incorporation of the
p-xylyl linking group in a difunctional precursor prior to
carrying out a (bis-) macrocyclization reaction. The second
involved the linking via an α,α´-dihalo-p-xylene of two
appropriately protected macrocyclic precursors, each
incorporating a single unprotected amine site. Deprotection
of the amine groups would then result in the required bis-ring
system.
Fig. 1. X-Ray structure of the nitric acid salt of the N-dibenzylated
O2N3 macrocycle, (4).HNO3.
O
O
O
O
i
H
N
N R2
R1
N
NH
HN
N
R3
(1) R1 = R2 = R3 = H
O
O
(2) R1 = R2 = H, R3 = Bz
(3) R1 = R3 = H, R2 = Bz
(4) R1 = R2 = Bz, R3 = H
(5) R1 = R3 = Bz, R2 = H
(6) R1 = R2 = R3 = Bz
(1)
(7) R1 = R2 = R3 = Boc
(8) R1 = R2 = Boc, R3 = H
(9) R1 = R3 = Boc, R2 = H
(10) R1 = R2 = H, R3 = Boc
(11) R1 = Boc, R2 = R3 = H
N
R2
R1
N
N
R3
Scheme 1. Boc = tert-butyloxycarbonyl. Reagents and conditions:
(i) Boc2O, dichloromethane.
Diagram 1

Isomeric, Benzylated and Xylyl-Linked Macrocyclic Ligands
775
followed by removal of the Boc groups, provided the
alternative route to the mono-N-benzylated macrocycle (2)
mentioned previously. The Boc-protecting groups were
readily removed by treating the protected species with
trifluoroacetic acid.
O
O
N
R
R
N
N
O
O
Having successfully obtained the di-protected species (8)
and (9), we proceeded to the synthesis of the xylyl-linked
dimers (Scheme 2). Exclusive mono-N-alkylation of the
available secondary amines on two molecules of (8) or (9)
with α,α´-dibromo-p-xylene in acetonitrile in the presence
of sodium carbonate gave the dimeric intermediates (12) and
(14), in reasonable yields. These two compounds were
isolated and purified by recrystallization from ethyl
i, ii
H
N
N
Boc
Boc
N
N
N
R
R
N
(8)
1
acetate/hexane. Their H and 13C NMR spectra exhibited
O
O
characteristic singlets at 3.48 (12), 3.76 (14) ppm and 59.6
(12), 58.7 (14) ppm, respectively, arising from the xylyl
methylene groups. The Boc groups of (12) and (14) were
readily removed by treatment with trifluoroacetic acid, the
desired linked-macrocycle products (13) and (15),
respectively, being isolated and recrystallized from acetone
in almost quantitative yield.
(12) R = Boc
(13) R = H
O
O
Finally, it may be noted that the alternative approach to
the preparation of (13), via the [1 + 2] bicyclization of
1,4-bis(bis(2-aminoethyl)aminomethyl)benzene[9] with two
equivalents of the appropriate dialdehyde[10] followed by
reduction of the corresponding tetraimine derivative, was
also accomplished during the present study. However, in our
hands this procedure was less efficient than that described
above, resulting in a lower yield and requiring a more
time-consuming workup procedure.
N
R
N
N
R
O
O
i, ii
NH
Boc
N
N
R
Boc
N
N
R
N
(9)
O
O
X-Ray Structure of (4).HNO3
The molecular structure of the salt is shown in Figure 1
together with the atomic labelling. Selected bond dimensions
defining the macrocycle skeleton are given in Table 1. These
structural features may be compared with those of the
tribenzylated derivative (6), which has been described
previously.[1]
(14) R = Boc
(15) R = H
Scheme 2. Boc = tert-butyloxycarbonyl. Reagents and conditions:
(i) α,α´-dibromo-p-xylene, Na2CO3, acetonitrile; (ii) trifluoroacetic
acid.
The 1H and 13C NMR spectra of (8) and (9) clearly show
the success of the (isomeric) di-protecting manipulations and
subsequent workup procedures. The 1H spectra of the
purified products are readily assignable, despite the presence
of somewhat broad resonances caused by a combination of
the slow rotation of the ‘amide rotamers’ and the restricted
(and hence slower) ring flexing engendered by the presence
of the bulky protecting groups. The 1H NMR spectrum of (8)
resembles that of (1), except for the chemical shift of the
benzylic methylene resonance (see below), while the
spectrum of (9) exhibits the expected increase in signal
complexity arising from its asymmetrical nature. On Boc
protection, the proton resonance of the benzylic methylene
shifts from 3.80 ppm in (1) to 4.64 ppm in (8). The tert-butyl
components of the Boc-protecting groups show a strong
singlet resonance at 1.43 ppm for symmetric (8), while
asymmetric (9) exhibits two singlets at 1.48 and 1.39 ppm.
Reaction of the symmetrically protected derivative (8)
with benzyl chloride in the presence of sodium carbonate,
Table 1. Selected bond lengths (Å) and angles (deg) for
(4).HNO3
Bond
Length
Bond
Angle
O(1)–C(34)
O(2)–C(3)
N(1)–C(19)
N(2)–C(17)
N(3)–C(20)
C(1)–C(2)
1.3701(18)
1.3729(18)
1.4884(19)
1.4622(18)
1.4593(19)
1.484(2)
1.498(2)
1.510(2)
1.395(2)
1.4328(17)
1.4312(18)
1.494(2)
1.4715(18)
1.4626(19)
1.400(2)
C(34)–O(1)–C(1)
C(19)–N(1)–C(18)
C(20)–N(3)–C(28)
O(2)–C(2)–C(1)
C(3)–C(8)–C(9)
N(2)–C(17)–C(18)
N(1)–C(19)–C(20)
N(3)–C(28)–C(29)
O(1)–C(34)–C(29)
C(3)–O(2)–C(2)
C(17)–N(2)–C(9)
O(1)–C(1)–C(2)
O(2)–C(3)–C(8)
N(2)–C(9)–C(8)
N(1)–C(18)–C(17)
N(3)–C(20)–C(19)
117.68(11)
114.13(12)
113.53(12)
109.90(13)
121.09(13)
112.51(12)
110.35(12)
115.12(12)
115.95(12)
116.37(11)
108.48(11)
109.10(13)
115.98(12)
116.62(12)
112.47(12)
111.01(13)
C(8)–C(9)
C(19)–C(20)
C(29)–C(34)
O(1)–C(1)
O(2)–C(2)
N(1)–C(18)
N(2)–C(9)
N(3)–C(21)
C(3)–C(8)
C(17)–C(18)
C(28)–C(29)
1.507(2)
1.504(2)
C(34)–C(29)–C(28) 122.18(13)

776
K. J. Park et al.
A crystal of (4).HNO3 was obtained for X-ray analysis. A sample of
(4) was dissolved in warm methanol (2 cm3) to which dilute nitric acid
(1 cm3) was added; colourless crystals separated on allowing the
solution to stand.
The molecular structure displays no unusual features, but
it does confirm the structure assignment based on the other
physical measurements. The central amine group is involved
in H-bonding to one oxygen atom (O3) of the nitrate group
(N1–H1F, 0.95; N1···O3, 2.786; H1F···O3, 1.89 Å), and
electrostatic interactions with the other four heteroatoms of
the macrocyclic ring are indicated. The latter is evidenced by
the equidistant positioning of proton H2F relative to those
four atoms (N1–H2F, 1.36; H2F···O1, 2.56; H2F···O2, 2.57;
H2F···N2, 2.54, H2F···N3, 2.49 Å). These intramolecular
interactions cause an obvious increase in puckering of the
macrocycle compared with the tribenzylated structure (6).[1]
Like the structure of (6), the absence of pseudo-symmetry in
the molecule and the shortened C–C bond between the ether
oxygens (1.484(2) Å) are again noted.
1-Benzyl-1,12,15-triaza-3,4 : 9,10-dibenzo-5,8-dioxacyclo-
heptadecane (3)
The solvent was removed from the original acetone-soluble component
and the residue, primarily a HBr salt mixture of (3) and (5), was
separated on silica gel by eluting with 10% methanol/dichloromethane.
The major product was the HBr salt of (3) (0.72 g), m.p. 198–200 ºC.
δ
H (CDCl3; 200 MHz) 2.65, m, 6H, HNCH2CH2NHCH2CH2NCH2Ar;
2.83, m, 2H, HNCH2CH2NH; 3.58, s, 2H, NCH2Ar; 3.60, s, 2H,
ArCH2NCH2Ar; 3.85, s, 2H, ArCH2NH; 4.34, d, 2H, OCH2CH2O;
4.38, d, 2H, OCH2CH2O; 6.93–7.29, m, 13H, ArH. The free form of (3)
was obtained as a colourless glassy solid (0.22 g, 3%) in a similar
manner to that described above, m.p. 90–91 ºC (Found: M + H+,
431.2565. C27H34N3O2 requires 431.2573). δH (CDCl3; 500 MHz) 2.60,
m, 6H, HNCH2CH2NHCH2CH2–NCH2Ar; 2.75, m, 2H,
HNCH2CH2NH; 3.56, s, 2H, NCH2Ar; 3.58, s, 2H, ArCH2N CH2Ar;
3.81, s, 2H, ArCH2NH; 4.32, d, 2H, OCH2CH2O; 4.38, d, 2H,
OCH2CH2O; 6.90–7.31, m, 13H, ArH. δC (CDCl3; 125 MHz) 46.6,
48.7, 48.8, 51.0, 51.8, 55.6, 59.5, 66.6, 67.1, 110.8, 111.5, 120.4, 120.9,
126.6, 127.1, 128.0, 128.5, 128.7, 128.8, 131.0, 132.5, 139.6, 157.2,
157.6.
Experimental Section
General
Where available, all reagents were analytical grade. The parent
N3O2-donor
macrocycle,
1,12,15-triaza-3,4 : 9,10-dibenzo-5,8-
dioxacycloheptadecane (1) was synthesized as described previously.[10]
1H and 13C NMR spectra were recorded on a Bruker AC-200 NMR
spectrometer with tetramethylsilane (TMS) as internal standard.
High-resolution mass spectra were obtained on a Bruker BioApex 47e
ICR mass spectrometer while low-resolution spectra (ESIMS) were
obtained on a Finnigan Mat LCQ spectrometer (using dimethyl
sulfoxide/methanol solutions).
1,15-Dibenzyl-1,12,15-triaza-3,4 : 9,10-dibenzo-5,8-dioxacyclo-
heptadecane (5)
After the HBr salt of (3) was obtained using the chromatographic
procedure described above, the initial fraction of the eluent [before the
appearance of (3)] was taken to dryness to yield crude (5) as its HBr
salt. This product was purified by chromatography on silica gel (eluting
with 60% ethyl acetate/hexane). Yield 0.66 g, m.p. 114–115 ºC. δH
(CDCl3; 200 MHz) 2.43, t, 2H, NCH2CH2NCH2Ar; 2.53, t, 2H,
NCH2CH2NCH2Ar; 2.66, m, 4H, HNCH2CH2N; 3.24, s, 2H,
CH2CH2NCH2Ar; 3.33, s, 2H, ArCH2NCH2Ar; 3.81, s, 2H,
ArCH2NCH2Ar; 3.86, s, 2H, ArCH2NHCH2CH2N; 4.41, m, 4H,
OCH2CH2O; 6.85–7.33, m, 18H, ArH. δC (CDCl3; 50 MHz) 45.7, 48.8,
51.0, 51.8, 53.2, 57.7, 58.9, 66.4, 66.7, 111.0, 120.8, 126.6, 126.9,
127.7, 128.0, 128.2, 128.7, 129.3, 130.3, 131.5, 138.4, 139.5, 156.5,
156.8. The free form of (5) was obtained as a colourless glassy solid
(0.32 g, 4%) in a similar manner to that described above, m.p. 62–64 ºC
(Found: M + H+, 521.3036. C34H40N3O2 requires M + H+, 521.3042). δH
(CDCl3; 500 MHz) 2.41, t, 2H, NCH2CH2NCH2Ar; 2.52, t, 2H,
NCH2CH2NCH2Ar; 2.66, m, 4H, HNCH2CH2N; 3.25, s, 2H,
CH2CH2NCH2Ar; 3.35, s, 2H, ArCH2NCH2Ar; 3.80, s, 2H,
ArCH2NCH2Ar; 3.85, s, 2H, ArCH2NHCH2CH2N; 4.41, m, 4H,
OCH2CH2O; 6.87–7.29, m, 18H, ArH. δC (CDCl3; 500 MHz) 48.1,
51.5, 52.7, 53.5, 54.7, 55.9, 59.2, 60.9, 68.4, 68.5, 112.7, 112.8, 122.4,
122.6, 128.4, 128.5, 129.1, 129.8, 129.9, 130.2, 130.3, 130.5, 130.8,
131.0, 131.2, 131.5, 132.7, 141.1, 141.9, 158.4, 158.7.
Direct Benzylation of (1) and Separation of (3)–(6)
To a stirred solution of (1) (5.71 g, 16.73 mmol) and sodium hydrogen
carbonate (1.89 g, 22.47 mmol) in acetonitrile (500 cm3) two mole
equivalents of benzyl bromide (5.72 g, 33.46 mmol) in acetonitrile (100
cm3) was added over 40 min. The mixture was then stirred at room
temperature for 17 h. The solvent was removed under reduced pressure
and acetone (50 cm3) was added to the residue with stirring. The
resulting mixture was filtered to separate the acetone-soluble and
insoluble components. The solution was later shown to contain a
mixture of (3) (major) and (5) (minor) together with a trace amount of
(2). The insoluble component proved to be a mixture of (3) (small
amount), (4), and (6) (by means of combined thin-layer
chromatography (TLC) and NMR analysis). The separation of these
mixtures is described below.
1,12-Dibenzyl-1,12,15-triaza-3,4 : 9,10-dibenzo-5,8-dioxacyclo-
heptadecane (4)
The acetone-insoluble component was recrystallized from methanol to
give a mixture of (4) and (6) as their colourless crystalline HBr salts.
This mixture was separated by flash chromatography on silica gel,
eluting with 5% methanol/dichloromethane. The HBr salt of (4) was
collected and isolated (1.19 g), m.p. 235–236 °C. δH (CDCl3; 500 MHz)
2.78, m, 8H, NCH2CH2NH; 3.50, s, 4H, NCH2Ar; 3.68, s, 4H,
ArCH2NCH2Ar; 4.56, s, 4H, OCH2CH2O; 6.95–7.45, m, 18H, ArH. δc
(CDCl3; 500 MHz) 45.2, 48.5, 55.5, 59.4, 67.5, 112.2, 121.1, 125.45,
127.4, 128.4, 129.1, 129.7, 132.7, 137.9, 157.2. In order to obtain (4) in
free form, the salt was redissolved in dichloromethane and the solution
was shaken three times with aqueous 2 M NaOH. The dichloromethane
phase was then washed three times with distilled water and dried over
anhydrous sodium sulfate. After removal of the solvent, the residue was
dried under high vacuum to yield (4) as a colourless glassy solid (0.40
g, 5%), m.p. 135–136 ºC (Found: M + H+, 521.3049. C34H40N3O2
requires 521.3042). δH (CDCl3; 500 MHz) 2.51, m, 8H, NCH2CH2NH;
3.52, s, 4H, NCH2Ar; 3.62, s, 4H, ArCH2NCH2Ar; 4.41, s, 4H,
OCH2CH2O; 6.88–7.33, m, 18H, ArH. δC (CDCl3; 125 MHz) 46.3,
53.0, 55.1, 59.6, 67.2, 111.3, 120.3, 126.5, 127.2, 127.9, 128.6, 128.9,
132.7, 140.0, 157.8.
1,12,15-Tribenzyl-1,12,15-triaza-3,4 : 9,10-dibenzo-5,8-dioxacyclo-
heptadecane (6)
Product (6) was obtained by the direct benzylation method described
previously.[1]
1,12-Bis(tert-butoxycarbonyl)-1,12,15-triaza-3,4 : 9,10-dibenzo-
5,8-dioxacycloheptadecane (8)
To a stirred solution of (1) (5.00 g, 14.64 mmol) in dichloromethane
(500 cm3) was added 1.7 equiv. of di-tert-butyl dicarbonate (5.43 g,
24.89 mmol) in dichloromethane (150 cm3) over 1.5 h and the mixture
stirred at room temperature for a further 2 h. The solvent was then
removed under reduced pressure. Chromatography on silica gel using
20% ethyl acetate/hexane then 100% ethyl acetate as the eluent led to
the isolation of (8) (3.00 g, 45%) as a white powder (Found: C, 66.4; H,
7.7; N, 7.5%. Calc. for C30H43N3O6: C, 66.5; H, 8.0; N, 7.8%. Found:
M + H+, 542.3213. C30H43N3O6 requires 542.3224). δH (CDCl3; 200

Isomeric, Benzylated and Xylyl-Linked Macrocyclic Ligands
777
MHz) 1.42, s, 18H, (CH3)3; 2.81, s, 4H, Boc–NCH2CH2NH; 3.28, s,
4H, Boc–NCH2CH2NH; 4.32, s, 4H, OCH2CH2O; 4.64, s, 4H,
ArCH2N; 6.80–7.35, m, 8H, ArH. δC (CDCl3; 50 MHz) 28.4, 46.4,
48.7, 66.6, 79.7, 110.9, 121.1, 126.7, 127.2, 127.9, 156.2.
Linked Derivative (13)
To (12) (2.49 g, 2.10 mmol) in dichloromethane (30 cm3) was added
trifluoroacetic acid (30.0 g) with vigorous stirring at room temperature.
Stirring was continued for 2 h. The solution was then taken to dryness
on a rotary evaporator, methanol was added, and the solution again
taken to dryness. This procedure was repeated a further two times to
ensure evaporation of any remaining trifluoroacetic acid. Aqueous
sodium carbonate (15%, 50 cm3) was added to the residue, which was
then extracted three times with dichloromethane. The combined
organic phases were dried over anhydrous sodium sulfate and
evaporated to dryness. The crude product was recrystallized from
acetone to yield (13) as a colourless solid (1.33 g, 81%) (Found: C,
73.0; H, 7.8; N, 10.7%. C48H60N6O4 requires C, 73.4; H, 7.7; N, 10.7%.
Found: M + H+, 785.4721. C48H61N6O4 requires 785.4748). δH (CDCl3;
200 MHz) 2.44, m, 8H, NHCH2CH2N–xylyl; 2.58, br, 12H,
15-Benzyl-1,12,15-triaza-3,4 : 9,10-dibenzo-5,8-dioxacyclo-
heptadecane (2)
Benzyl chloride (353 mg, 2.79 mmol) in acetonitrile (50 cm3) was added
dropwise to a refluxing suspension of (8) (1.00 g, 1.86 mmol) and
sodium carbonate (0.48 g, 4.50 mmol) in acetonitrile (100 cm3). The
reaction mixture was maintained under reflux for an additional 24 h with
rapid stirring and was then cooled to room temperature and filtered. The
filtrate was evaporated and the residue was partitioned between water
and dichloromethane. The aqueous phase was separated and extracted
with two further portions of dichloromethane. The combined organic
phases were dried over anhydrous sodium sulfate and the solution then
evaporated. Chromatography of the residue on silica gel using 50% ethyl
acetate/hexane as the eluent led to the isolation of the intermediate
diprotected product as a white microcrystalline solid (1.05 g, 90%); MS
(ES) m/z, 632.4 (M + H+). This product (1.00 g, 1.58 mmol) was stirred
at room temperature for 2 h with excess trifluoroacetic acid (12.0 g). The
solution was then taken to dryness on a rotary evaporator, methanol was
added and the solution again taken to dryness. This procedure was
repeated a further two times to ensure full evaporation of any remaining
trifluoroacetic acid. Aqueous sodium carbonate (50 cm3 of a 15%
solution) was added to the residue and the resulting mixture extracted
three times with dichloromethane. The combined organic phases were
dried with anhydrous sodium sulfate, filtered, then the solvent was
removed under reduced pressure to yield (2) as an orange viscous oil
(642 mg, 93%) (Found: M + H+, 431.2575. C27H33N3O2 requires
431.2573). δH (CDCl3; 300 MHz) 2.53, s, 4H, NHCH2CH2NCH2Ar;
2.62, s, 4H, NHCH2CH2NCH2Ar; 3.21, 4H, ArCH2N(CH2)2); 3.47, s,
2H, NH; 3.75, s, 4H, ArCH2NH; 4.42, s, 4H, OCH2CH2O; 6.89–7.26,
m, 13H, ArH. δC (CDCl3; 50 MHz) 46.3, 50.2, 53.8, 57.9, 67.4, 111.9,
121.7, 127.3, 128.6, 129.1, 129.6, 131.8, 138.6, 157.5.
NHCH2CH2N–xylyl; 3.16, s, 4H, NCH ArCH2N; 3.72, s, 8H,
2
ArCH2NH; 4.41, s, 8H, OCH2CH2O; 6.86–7.22, m, 20H, ArH. δC
(CDCl3; 50 MHz) 45.3, 48.3, 51.6, 58.6, 67.8, 113.1, 121.6, 124.7,
129.4, 129.9, 131.9, 136.9, 157.3.
Linked Derivative (14)
A solution of α,α´-dibromo-p-xylene (0.66 g, 1.76 mmol) in 20%
tetrahydrofuran/acetonitrile (80 cm3) was added dropwise to a refluxing
suspension of (9) (3.20 g, 5.54 mmol) and sodium carbonate (0.66 g,
6.25 mmol) in acetonitrile (280 cm3). The reaction mixture was
maintained under reflux for an additional 24 h with rapid stirring and it
was then cooled to room temperature and filtered. After the solvent was
removed by rotary evaporation, the yellow solid that remained was
dissolved in ethyl acetate (15 cm3). Excess hexane was added to the
solution to yield a sticky yellow precipitate. The clear solution above
the precipitate was decanted and discarded. The precipitate was
recrystallized from ethyl acetate/hexane to yield (14) as a colourless
solid (2.46 g, 83%) (Found: C, 69.3; H, 8.1; N, 6.9%. C68H92N6O12
requires C, 68.9; H, 7,8; N, 7.09%. Found: M + H+, 1185.6787.
C68H93N6O12 requires 1185.6845). δH (CDCl3; 200 MHz) 1.30–1.55,
m, 36H, (CH3)3; 2.76, br, 4H, Boc–NCH2CH2N–xylyl; 3.38, br, 12H,
Boc–NCH2CH2N(Boc)CH2; 3.76, br, 8H, ArCH2N(xylyl)CH2; 4.45,
br, 8H, OCH2CH2O; 4.58, br, 4H, ArCH2N–Boc; 6.97–7.39, m, 20H,
ArH. δC (CDCl3; 50 MHz) 28.4, 43.6, 44.8, 45.4, 51.1, 51.5, 58.7, 67.0,
79.0, 79.2, 79.6, 111.1, 111.3, 120.8, 121.3, 126.9, 127.9, 128.4, 129.0,
129.3, 130.9, 138.3, 155.2, 155.6, 156.0, 156.3, 156.6.
1,15-Bis(tert-butoxycarbonyl)-1,12,15-triaza-3,4 : 9,10-dibenzo-
5,8-dioxacycloheptadecane (9)
After (8) was separated, successive gradient elution of the column (from
20% ethyl acetate/hexane to 100% ethyl acetate) yielded (9) (1.74 g,
26%) as a viscous pink oil (Found: M + H+, 542.3228. C30H43N3O6
requires 542.3224). δH (CDCl3; 200 MHz) 1.42, s, 9H,
ArCH2NCOOC(CH3)3; 1.48, br, 9H, NHCH2CH2NCOOC(CH3)3; 2.78,
m, 2H, NHCH2CH2; 3.30, m, 6H, Boc–NCH2CH2N(–Boc)CH2; 3.87,
s, 2H, ArCH2NH; 4.37, m, 4H, OCH2CH2O; 4.57, d, 2H,
ArCH2N–Boc; 6.88–7.30, m, 8H, ArH. δC (CDCl3; 50 MHz) 28.4, 43.5,
44.8, 46.6, 47.0, 47.6, 48.3, 66.8, 67.2, 79.6, 79.7, 111.2, 112.0, 121.2,
121.6, 126.6, 128.2, 128.4, 129.0, 130.4, 151.1, 155.6, 156.1, 156.6.
Linked Derivative (15)
Precursor (14) (2.12 g, 1.79 mmol) was stirred at room temperature for
2 h with excess trifluoroacetic acid (20.0 g). The solution was then
taken to dryness on a rotary evaporator, methanol was added and the
solution was again taken to dryness. This procedure was repeated a
further two times to ensure evaporation of any remaining trifluoroacetic
acid. Aqueous sodium carbonate (50 cm3 of a 15% solution) was added
to the residue and the resulting mixture extracted with dichloromethane
three times. The combined organic phases were dried with anhydrous
sodium sulfate and then taken to dryness. The residue that remained
was recrystallized from acetone to yield (15) as a colourless solid (1.02
g, 73%) (Found: C, 73.6; H, 7.6; N, 10.7%. C48H60N6O4 requires C,
73.4; H, 7.7; N, 10.7%. Found: M + H+, 785.5). δH (CDCl3; 200 MHz)
2.33–2.72, m, 20H, HNCH2CH2NHCH2CH2N–xylyl; 3.45, s, 4H,
CH2ArCH2; 3.55, br, 4H, ArCH2NH; 3.78, br, 4H, ArCH2N–xylyl;
4.28, br, 8H, OCH2CH2O; 6.87–7.36, m, 20H, ArH. δC (CDCl3; 50
MHz) 46.6, 48.8, 51.0, 51.6, 55.3, 59.0, 66.6, 67.0, 110.8, 111.5, 120.5,
120.9, 127.3, 128.6, 131.0, 132.2, 137.8, 157.5, 157.7.
Linked Derivative (12)
A
solution of α,α´-dibromo-p-xylene (0.32 g, 1.21 mmol) in
acetonitrile and tetrahydrofuran (1 : 1, 40 cm3) was added dropwise to a
refluxing suspension of (8) (1.46 g, 2.70 mmol) and sodium carbonate
(0.32 g, 3.00 mmol) in acetonitrile (150 cm3). The reaction mixture was
maintained at reflux for an additional 24 h with rapid stirring, allowed
to cool to room temperature, then filtered. The filtrate was evaporated
and the residue was partitioned between water and dichloromethane.
The aqueous phase was separated and extracted with two further
portions of dichloromethane. The combined organic phases were dried
with anhydrous sodium sulfate and the solution then evaporated to
dryness. The residue was recrystallized from 40% ethyl acetate/hexane
to yield (12) (0.85 g, 59%) (Found: C, 69.2; H, 8.0; N, 7.1%.
C68H92N6O12 requires C, 68.9; H, 7.8; N, 7.1%. Found: M + H+,
1185.6870. C68H93N6O12 requires M + H+, 1185.6845). δH (CDCl3; 200
MHz) 1.31, s, 36H, (CH3)3; 2.68–2.35, s, 8H, Boc–NCH2CH2N–xylyl;
3.42–3.10, s, 8H, Boc–NCH2CH2N–xylyl; 3.48, s, 4H, NCH2ArCH2N;
4.36, s, 8H, OCH2CH2O; 4.53, s, 8H, ArCH2N; 6.78–7.32, m, 20H,
ArH. δC (CDCl3; 50 MHz) 29.0, 45.7, 52.8, 59.6, 67.2, 67.3, 80.1,
111.5, 121.8, 127.8, 128.7, 129.0, 129.7, 138.5, 156.7, 156.9.
Structure Determination
Crystal data for (4).HNO3. C34H40N4O5, M 584.70, monoclinic, space
group P21/n (non-std., no.14), a 14.9322(10), b 12.2162(8), c
17.4693(11) Å, β 105.9970(10)º, V 3063.3(3) Å3, Z 4, Dc 1.268 Mg/m3,
colourless plates, λ(Mo Kα) 0.71073 Å, µ(Mo Kα) 0.086 mm–1, F(000)
1248.

778
K. J. Park et al.
Data Collection, Structure Solution and Refinement
References
A crystal of dimensions 0.2 × 0.4 × 0.45 mm3 was attached to a thin
glass fibre and mounted on a Bruker SMART CCD 3-circle diffractom-
eter employing graphite monochromated Mo Kα radiation generated
from a sealed tube. Cell dimensions were obtained from a least squares
refinement for selected reflections. Data were collected at 298(2) K us-
ing ω scans for 19658 reflections in the theta range 2.06 to 28.39°
(97.3% completeness). These were reduced to 7477 independent reflec-
tions (Rmerge 0.0276) in the index ranges –19 ≤ h ≤ 16, –16 ≤ k ≤ 14,
–21 ≤ l ≤ 22, which were used for structure solution and refinement un-
corrected for absorption effects.[11] The structure was solved by direct
methods and refined on ||F||2 by full-matrix least-squares methods using
SHELXTL software.[12] After preliminary refinement, H atoms (H1F
and H2F) on the central amine group (N1) were located in a differ-
ence-Fourier synthesis. Anisotropic thermal parameters were employed
for all non-hydrogen atoms, while a riding atom model was used for all
non-amine hydrogen atoms placed in idealized positions. In final re-
finement cycles 396 parameters were varied with 0 restraints, which in-
cluded positional and isotropic thermal parameters for H1F and H2F.
Final refinement converged to R1(F) 0.071, wR2(F2) 0.131 for all data
and R1(F) 0.046, wR2(F2) 0.117 for data with I >2σ(I). A final differ-
ence-Fourier synthesis showed no electron densities outside the range
–0.26 to 0.46 e Å3. A full set of data defining the crystal structure has
been deposited with the Cambridge Crystallographic Data Centre
(CCDC 186157).
[1] J. Kim, Y. Lee, S. S. Lee, L. F. Lindoy, T. Strixner, Aust. J. Chem.
1999, 52, 1055.
[2] (a) L. F. Lindoy, Pure Appl. Chem. 1997, 69, 2179; (b) T. W.
Hambley, L. F. Lindoy, J. R. Reimers, P. Turner, G. Wei, A. N.
Widmer-Cooper, J. Chem. Soc., Dalton Trans. 2001, 614; (c)
Effendy, R. R. Fenton, L. F. Lindoy, B. W. Skelton, J. R. Price, T.
Strixner, G. Wei, A. H. White, J. Inclusion Phenom. Macrocyclic
Chem. 2001, 41, 185.
[3] A. McAuley, S. Subramanian, Coord. Chem. Rev. 2000, 200, 75.
[4] (a) L. F. Lindoy, Adv. Inorg. Chem. 1998, 45, 75; (b) J. D.
Chartres, L. F. Lindoy, G. V. Meehan, Coord. Chem. Rev. 2001,
216, 249.
[5] L. F. Lindoy, The Chemistry of Macrocyclic Ligand Complexes
1989 (Cambridge University Press: Cambridge).
[6] See for example: B. Boitrel, B. Andrioletti, M. Lachkar, R.
Guilard, Tetrahedron Lett. 1995, 36, 4995.
[7] S. Brandes, C. Gros, F. Denat, P. Pullumbi, R. Guilard, Bull. Soc.
Chim. Fr. 1996, 133, 65.
[8] See for example: (a) A. M. Groth, L. F. Lindoy, G. V. Meehan, J.
Chem. Soc., Perkin Trans. 1 1996, 1553; (b) J. D. Chartres, A. M.
Groth, L. F. Lindoy, M. P. Lowe, G. V. Meehan, J. Chem. Soc.,
Perkin Trans. 1 2000, 3444.
[9] C. Y. Ng, R. J. Motekaitis, A. E. Martell, Inorg. Chem. 1979, 18,
2982.
[10] K. R. Adam, L. F. Lindoy, H. C. Lip, J. H. Rea, J. Chem. Soc.,
Dalton Trans. 1981, 74.
Acknowledgments
[11] SMART & SAINT Software Reference Manuals, Version 4.0, 1996
(Siemens Analytical Instruments: Madison).
[12] SHELXTL Reference Manual, Version 5.03, 1996 (Siemens
Analytical Instruments: Madison).
SSL thanks the LG Yonam Foundation (Korea), JHK the
Ministry of Education of the Republic of Korea
(BSRI-97-3440) and LFL and GVM the Australian Research
Council for support. We thank Professor H. Tsukube,
Department of Chemistry, Osaka City University, for his
interest.