New macrocyclic ligands. XIII single-ring and tri-linked macrocyclic systems derived from selectively protected cyclam

Article abstract of DOI:10.1071/CH01070

The synthesis of the four single-ring cyclam derivatives together with the related tri-linked ring derivatives and tetrabenzylated derivative was reported. In the synthesis, differential Boc-protected cyclam derivatives were used as key intermediates. Benzylated and tri-linked cyclam products were found to rely heavily on high-resolution mass spectrometry (HRMS) and all compounds yielded satisfactory HRMS data.

Full text of DOI:10.1071/CH01070

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Aust. J. Chem. 2001, 54, 291–297
New Macrocyclic Ligands. XIII*
Single-Ring and Tri-Linked Macrocyclic Systems
Derived from Selectively Protected Cyclam
Ying DongA and Leonard F. LindoyA,B
A Centre for Heavy Metals Research, School of Chemistry F11,
University of Sydney, N.S.W. 2006, Australia.
B Author to whom correspondence should be addressed
(e-mail: l.lindoy@chem.usyd.edu.au).
The selective use of the tert-butoxycarbonyl protecting group has enabled efficient syntheses of the tri-linked
cyclam derivatives (6)–(8). Using a related protecting group strategy, a series of related single-ring, N-benzylated
cyclam derivatives (1)–(4) has also been prepared.
Manuscript received: 15 June 2001.
Final version: 21 August 2001.
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Introduction
Results and Discussion
There has been continuing interest in the synthesis of larger
supramolecular and supermolecular entities incorporating
multi-metal ion binding sites.[1] Arising from their tendency
to yield both kinetically and thermodynamically stable metal
complexes,[2] macrocyclic rings have frequently been
employed as structural components in such systems. One
category of this type involves larger structures composed of
covalently linked macrocyclic ligand species incorporating
nitrogen heteroatoms in their donor sets.[3] While there are
now many examples in which two macrocyclic rings of the
above type have been linked, systems involving three (or
more) linked rings are much less common.[4–9] As a
continuation of our previous studies in the area,[8,10–12] we
now report the use of protecting group chemistry to prepare
the four single-ring cyclam derivatives given by (1)–(4),
together with the related tri-linked ring derivatives (6)–(8).
The previously reported[13] tetrabenzylated derivative (5)
was also synthesised directly from cyclam as part of the
present study.
Synthesis of Benzylated Cyclam Derivatives
In the present study, differentially Boc-protected cyclam
derivatives have been used as key intermediates in the
synthesis of (1)–(4) and (6)–(8).[18] In particular, the tris(N-
Boc)cyclam species (9)[19] has been employed for many of
the syntheses. In an initial study (9) was reacted with benzyl
bromide in refluxing acetonitrile over caesium carbonate to
yield the mono-N-benzylated derivative (10). Deprotection
of (10) to give (1) was then achieved in near quantitative
yield by hydrolysis by using 3 M HCl–MeOH as shown in
Scheme 1. Alternative syntheses of (1) have been reported
previously.[20–24]
It needs to be noted that the interaction of (5) with
particular transition and post-transition metal ions has been
carried out by a number of groups,[14–16] and that the rich
transition metal coordination chemistry of the parent cyclam
macrocycle has been well documented over many years.[2]
Cyclam, with its 14-membered ring, tends to form more
kinetically and thermodynamically stable complexes than
the corresponding N4-donor rings incorporating other ring
sizes. Further, coordination to 1,4,8,11-tetraazacyclotetra-
decane (cyclam) has been shown to promote access to a
number of less common metal oxidation states, including
nickel(III), copper(III) and both silver(II) and silver(III).[17]
Scheme 1. Boc = tert-butoxycarbonyl. Reagents and conditions: (i)
Cs2CO3, dry CH3CN, reflux; (ii) 3 M HCl–MeOH.
*Part XII, Aust. J. Chem. 2001, 54, 59.
© CSIRO 2001
10.1071/CH01070
0004-9425/01/050291

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Y. Dong and L. F. Lindoy
Scheme 2. Boc = tert-butoxycarbonyl; dmfdma = dimethylfor-
mamidedimethylacetal. Reagents and conditions: (i) CH3CN, reflux;
(ii) (Boc)2O, EtOH, H2O; (iii) conc. NaOH aqueous solution, EtOH;
(iv) PhCH2Br, Cs2CO3, dry CH3CN; (v) 3 M HCl–MeOH.
product was then acylated with two equivalents of (Boc)2O
followed by treatment with conc. NaOH in order to destroy
the amidine intermediate (12). Benzylation of this product
followed by deprotection of (14) with HCl–MeOH yielded
the required cis-dibenzylated product (2).
Tris-N-benzylated cyclam (4) was also obtained starting
from tris-N-Boc protected cyclam (9). The latter was initially
converted into (15), which contained both Boc and Troc
protecting groups. Selective removal of the Boc groups with
acid then yielded (16). Tris-N-benzylation under basic
conditions followed by deprotection of the Troc group
resulted in the desired derivative (4) (Scheme 3).
Linked Systems
The attachment of three cyclam molecules to a phloroglu-
cinol (1,3,5-trihydroxybenzene) core was achieved as shown
in Scheme 4.
The 1,3,5-tribenzyl-linked compound (7) was obtained in
a related manner, which involved the direct acylation of three
molecules of (9) with trimesoyl chloride (benzene-1,3,5-
tricarbonyl trichloride) as shown in Scheme 5. A brief report
of the synthesis of this compound by a different procedure
has appeared,[6] with the reported 1H nuclear magnetic
resonance (NMR) and mass spectrometry (MS) data being
similar to that obtained in the present study.
The synthesis of (8) was achieved using a procedure that
started from the 1,8-bis(N-Boc)cyclam derivative (23) (see
Scheme 6).
Characterization of the above benzylated and tri-linked
cyclam products relied heavily on high-resolution mass
spectrometry (HRMS) [electron ionization (EI) and fast-
1,5-Bis-N-benzylated cyclam was obtained using a
closely related procedure (Scheme 2) to that reported
previously[25] for the preparation of the corresponding bis(2-
hydroxyethyl) derivative. The addition of one equivalent of
dimethylformamidedimethylacetyl (dmfdma) to cyclam in a
minimum amount of hot chloroform yielded the formamidi-
nium salt (11), which was obtained as a hygroscopic red-
brown glass after removal of the reaction solvent. This

New Macrocyclic Ligands. XIII
293
Scheme 3. Boc = tert-butoxycarbonyl; Troc = 2,2,2-trichloro-
ethoxycarbonyl. Reagents and conditions: (i) Et3N, dry CH2Cl2;
(ii) 3 M HCl–MeOH; (iii) PhCH2Br, Cs2CO3, dry CH3CN, reflux;
(iv) Zn, HOAc.
atom bombardment (FAB)] since most of these compounds
were either glasses or viscous oils which tenaciously retained
the last traces of solvent. All compounds yielded satisfactory
HRMS data. In all cases, the 1H and 13C NMR spectra were
consistent with the proposed structures, although in some
cases considerable spectral overlap arising from the
inherently similar chemical environment of the ring
methylene groups of the constituent macrocycles was in
evidence. Interpretation of the spectra of particular acylated
intermediates tended to be complicated by signal broadening
and/or splitting, which was apparently largely caused by slow
interconversion of the amide rotamers. However, this
situation was generally improved in the final products
following deprotection and amide reduction.
Scheme 4. Boc = tert-butoxycarbonyl. Reagents and conditions:
(i) C6H3(OH)3, Cs2CO3, dimethylformamide; (ii) 3 M HCl–MeOH;
.
iii) BH3 Me2S then MeOH/H2O/conc. HCl (20 : 10 : 10).
Where available, all chemicals were analytical-grade. Dry
acetonitrile was prepared by shaking AR-grade acetonitrile with Linde
4-Å molecular sieves, stirring with CaH2 until no further hydrogen was
evolved, and then fractionally distilling over CaH2. 1,4,8,11-
Tetraazacyclotetradecane (cyclam) was prepared using the procedure
detailed by Barefield and Wagner.[26] 1,4,8-Tris(tert-butoxycarbonyl)-
1,4,8,11-tetraazacyclotetradecane (9) was synthesized by following a
literature procedure,[19] as was 1,8-bisbenzyl-1,4,8,11-tetraazacyclo-
tetradecane (3),[27] compound (11),[25] 1,4,8,11-tetrabenzyl-1,4,8,11-
tetraazacyclotetradecane (5),[28–29] 1,4,8-tris(tert-butoxycarbonyl)-11-
chloroacetyltetraazacyclotetradecane (18)[12] and 1,8-bis(tert-butoxy-
carbonyl)-1,4,8,11-tetraazacyclotetradecane (23).[30]
Concluding Remarks
Synthesis
A comparative investigation of aspects of the metal binding
of the present single-ring and tri-linked derivatized
macrocycles is at present underway and the results of this
study will be reported in due course.
1-Benzyl-4,8,11-tris(tert-butoxycarbonyl)-1,4,8,11-tetraazacyclo-
tetradecane (10)
Benzyl bromide (0.342 g, 2.0 mmol) and caesium carbonate (0.977 g,
3.0 mmol) were added to a stirred solution of 1,4,8-tris(tert-butoxy-
carbonyl)-1,4,8,11-tetraazacyclotetradecane (1.000 g, 2.0 mmol) in dry
acetonitrile (30 mL). The resultant mixture was refluxed overnight,
filtered through Filter-Aid Celite 521 and washed with hot chloroform
(30 mL). The filtrate was taken to dryness on a rotary evaporator to give
a colourless viscous oil which was purified by column chromatography
on silica gel (with CH2Cl2/MeOH/saturated NH3 aqueous solution,
150 : 1 : 0.5 as eluent) to give (10) as a colourless oil (1.06 g, 90%)
(Found (EI): M+, 590.4025. C32H54N4O6 requires 590.4043). 1H NMR
Experimental
General
NMR spectra were recorded on Bruker AC-200 and Bruker DPX-400
spectrometers. δH values are relative to Me4Si; δC values are relative to
CDCl3 at 77.1 ppm, and J values are given in Hertz (Hz). HRMS spectra
were obtained on a Kratos M25RFA spectrometer and low-resolution
MS [electrospray (ES)] on a Finnigan LCQ-8 spectrometer.

294
Y. Dong and L. F. Lindoy
1-Benzyl-1,4,8,11-tetraazacyclotetradecane (1)
The above protected compound (10) (0.800 g, 1.36 mmol) was
dissolved in 3 M HCl–MeOH (30 mL) and stirred overnight at room
temperature. The white precipitate that formed was filtered off and
washed with cold MeOH. It was then dissolved in 10% aqueous NaOH
(40 mL) and CH2Cl2 (40 mL) was added. The resultant mixture was
stirred at room temperature for 0.5 h and the two layers were separated.
The aqueous phase was then extracted with CH2Cl2 (3×40 mL). The
combined organic extracts were dried (anhydrous Na2SO4) and the
solvent was removed to dryness on a rotary evaporator. Compound (1)
was obtained as a colourless viscous oil (0.36 g, 92%) (Found (EI): M+,
290.2474. Calc. for C17H30N4: 290.2470). 1H NMR (CDCl3) δ 1.67,
quintet, J 5.3 Hz, 2H, NCH2CH2CH2N; 1.85, quintet, J 5.5 Hz, 2H,
PhCH2NCH2CH2CH2N; 2.49–2.85, m, 16H, NCH2; 3.57, s, 2H,
PhCH2; 7.22–7.36, m, 5H, ArH. 13C NMR (CDCl3) δ 26.2, 28.5, 47.4,
47.9, 49.0, 49.2, 49.4, 50.7, 53.4, 54.5, 57.9, 126.9, 128.1, 129.3,138.8.
Compound (12)
To a solution of (11) (0.500 g, 2.02 mmol) in water (10 mL) that had
been previously cooled to near-freezing was added (Boc)2O (0.89 g,
4.08 mmol) in ethanol (10 mL). The reaction vessel was stoppered, the
mixture allowed to rise to ambient temperature, and was then stirred for
8 h. The solution was then evaporated on a rotary evaporator to yield
(12) as a red-brown viscous oil (0.81 g, 90%), which was used without
further purification (Found (EI): [M–Cl]+, 411.2967. C21H39N4O4
requires 411.2971). 1H NMR (D2O) δ 1.47, s, 18H, But; 1.70, quintet, J
6.2 Hz, 2H, BocNCH2CH2CH2; 2.20, quintet, J 6.0 Hz, 2H, CH+NCH2-
CH2CH2N; 3.22, t, J 6.2 Hz, 4H, BocNCH2CH2CH2NBoc; 3.43–3.56,
m, 8H, NCH2; 3.68, t, J 6.0 Hz, 4H, CH+NCH2CH2NBoc; 8.18, s, 1H,
CH ortho. 13C NMR (D2O) δ 21.0, 27.5, 30.2, 48.0, 51.1, 52.5, 56.5,
84.7, 154.9, 160.0.
Scheme 5. Boc = tert-butoxycarbonyl. Reagents and conditions:
(i) C6H3(COCl)3, Et3N, tetrahydrofuran; (ii) 3 M HCl–MeOH; (iii)
.
BH3 Me2S then MeOH/H2O/conc. HCl (20 : 10 : 10).
Compound (13)
Compound (12) (0.85 g, 1.9 mmol) was dissolved in ethanol (10 mL)
and the solution cooled to 0°C whereupon conc. NaOH solution
(10 mL) was added. The mixture was stirred at reflux for 10 h and then
cooled. The ethanol was removed on a rotary evaporator and the
remaining aqueous phase was extracted with chloroform (8×10 mL).
The combined extracts were dried (anhydrous Na2SO4), filtered and
evaporated to dryness. The resulting brown viscous oil was purified by
column chromatography on silica gel (with 1% MeOH/CH2Cl2 as
eluent) giving the title compound (13) as a pale-yellow sticky oil
(0.61 g, 80%) (Found (EI): M+, 400.3051. C20H40N4O4 requires
400.3050). 1H NMR (CDCl3) δ 1.45, s, 18H, But; 1.68, quintet, J
5.4 Hz, 2H, NCH2CH2CH2N; 1.95, quintet, J 5.6 Hz, 2H, BocNCH2-
CH2CH2; 2.68–2.76, m, 8H, NCH2; 3.22–3.32, m, 8H, BocNCH2. 13
NMR (CDCl3) δ 28.4, 29.5, 47.7, 48.9, 49.8, 79.2, 155.9.
C
Compound (14)
Benzyl bromide (0.45 g, 2.6 mmol) and caesium carbonate (1.92 g,
5.9 mmol) were added to a stirred solution of (13) (0.52 g, 1.3 mmol)
in dry acetonitrile (40 mL). The resultant mixture was refluxed
overnight, filtered through Filter-Aid Celite 521, and washed
thoroughly with hot chloroform (100 mL). The filtrate was taken to
dryness on a rotary evaporator to give the crude product as an oil which
was purified by column chromatography on silica gel (with CH2Cl2/
MeOH, 100 : 1 as eluent) to give (14) as a viscous colourless oil (0.72 g,
95%) (Found (EI): M+, 580.3976. C34H52N4O4 requires 580.3989). 1H
NMR (CDCl3) δ 1.38, s, 18H, But; 1.58, quintet, J 6.2 Hz, 2H,
PhCH2NCH2CH2CH2; 1.96, quintet, J 7.0 Hz, 2H, BocNCH2CH2CH2;
Scheme 6. Boc = tert-butoxycarbonyl. Reagents and conditions:
(i) Et3N, dichloromethane; (ii) Compound (9), Cs2CO3, KI, CH3CN;
.
(iii) 3M HCl–MeOH; (iv) BH3 Me2S, then MeOH/H2O/conc. HCl
(20 : 10 : 10).
2.38, m, 4H, PhCH2NCH2CH2CH2N; 2.59, t,
J 6.2 Hz, 4H,
PhCH2NCH2; 3.29–3.36, m, 8H, BocNCH2; 7.19–7.26, m, 5H, ArH.
13C NMR (CDCl3) δ 28.4, 46.5, 51.3, 52.8, 59.5, 79.3, 126.8, 128.1,
128.9, 139.5, 155.7.
(CDCl3) δ 1.39, s, 9H, But; 1.44, s, 9H, But; 1.47, s, 9H, But; 1.68,
quintet, J 6.5 Hz, 2H, PhCH2NCH2CH2CH2NBoc; 1.88, quintet, J 6.8
Hz, 2H, BocNCH2CH2CH2NBoc; 2.39, t, J 6.5 Hz, 2H, PhCH2NCH2-
CH2CH2NBoc; 2.61, t, J 5.7 Hz, 2H, PhCH2NCH2CH2NBoc; 3.23–
1,5-Bisbenzyl-1,4,8,11-tetraazacyclotetradecane (2)
3.34, m, 12H, NCH2; 3.52, s, 2H, PhCH2; 7.18–7.33, m, 5H, ArH. 13
C
The product from the above preparation (14) (0.58 g, 1.0 mmol) was
stirred in a solution of 3 M HCl–MeOH (20 mL) overnight at room
temperature. The white precipitate was filtered off and washed with cold
NMR (CDCl3) δ 28.6, 46.0, 47.4, 51.5, 53.2, 59.5, 79.5, 79.7, 127.0,
128.2, 129.2, 138.8, 155.6.

New Macrocyclic Ligands. XIII
295
MeOH.Itwasthendissolvedin10% aqueousNaOH(15mL)andCH2Cl2
(30 mL) was added. The resultant mixture was stirred at room
temperature for 0.5 h and the two layers were separated. The aqueous
phasewas then extractedwithCH2Cl2 (3×30 mL).The combinedorganic
extracts were dried (anhydrous Na2SO4) and the solvent was removed on
a rotary evaporator. The title compound (2) was obtained as a colourless
viscous oil (0.35 g, 92%) (Found (EI): M+, 380.2935. C24H36N4 requires
380.2940). 1H NMR (CDCl3) δ 1.63–1.83, m, 4H, NCH2CH2CH2N;
2.40–2.56, m, 8H, NCH2; 2.65–2.79, m, 8H, PhCH2NCH2; 3.49, s, 4H,
PhCH2; 7.17–7.29, m, 10H, ArH. 13C NMR (CDCl3) δ 26.7, 28.1, 47.6,
48.8, 50.7, 53.7, 59.2, 126.9, 128.2, 129.0, 139.6.
stirred at room temperature for 2 h, filtered through Celite and washed
with glacial acetic acid, which was then removed under reduced
pressure. The residue was partitioned between 10% aqueous NaOH
(20 mL) and CH2Cl2 (30 mL) at 0°C. The aqueous layer was then
extracted with CH2Cl2 (2×30 mL) and the combined organic layers were
dried (anhydrous Na2SO4) then evaporated under reduced pressure to
give (4) as a colourless viscous oil (0.33 g, 70%) (Found (EI): M+,
470.3415. C31H42N4 requires 470.3409). 1H NMR (CDCl3) δ 1.68–
1.80, m, 4H, NCH2CH2CH2; 2.39–2.79, m, 16H, NCH2; 3.41, s, 2H,
PhCH2; 3.56, s, 2H, PhCH2; 3.61, s, 2H, PhCH2; 7.16–7.34, m, 15H,
ArH. 13C NMR (CDCl3) δ 25.4, 25.9, 47.0, 48.0, 49.5, 51.8, 52.3, 53.1,
58.3, 59.1, 126.7, 128.0, 129.1, 129.3, 138.6, 139.6.
1,4,8-Tris(tert-butoxycarbonyl)-11-(2,2,2-trichloroethoxycarbonyl)-
1,4,8,11-tetraazacyclotetradecane (15)
1,3,5-Tris[(4,8,11-tert-butoxycarbonyl)carbonylmethoxy]benzene (19)
1,4,8-Tris(tert-butoxycarbonyl)cyclam (9) (0.91 g, 1.82 mmol) was
dissolved in dry CH2Cl2 (40 mL). Triethylamine (0.23 g, 2.27 mmol)
and then 2,2,2-trichloroethyl chlorofomate (0.39 g, 1.84 mmol) were
added by syringe. The reaction mixture was stirred at room temperature
for 6 h. The organic layer was then washed with water (2×20 mL),
separated, dried (anhydrous Na2SO4) and evaporated on a rotary
evaporator. Purification of this material was achieved by column
chromatography on silica gel (with CH2Cl2/MeOH/saturated NH3
aqueous solution, 25 : 1 : 0.5 as eluent) to yield the title compound (15)
as a colourless viscous oil (1.17 g, 95%) (Found (EI): M+, 674.2592.
C28H49N4O8Cl3 requires 674.2615). 1H NMR (CDCl3) δ 1.46, s, 27H,
But; 1.75, m, 4H, NCH2CH2; 3.30–3.51, m, 16H, NCH2; 4.74, s, 2H,
Cl3CCH2OCO. 13C NMR (CDCl3) δ 28.5, 46.4, 47.1, 48.2, 75.2, 79.8,
80.0, 80.1, 95.5, 154.4, 155.6, 155.9.
This compound was prepared by an analogous procedure[10] to that
described previously and was purified by column chromatography on
silica gel (with CH2Cl2/MeOH/saturated NH3 aqueous solution,
50 : 1 : 0.5 as eluent) to give (19) as a white powder (75%) (Found: C,
59.6; H, 8.6; N, 9.3%. Calc. for C87H150N12O24: C, 59.8; H, 8.7; N,
9.6%). 1H NMR (CDCl3) δ 1.46, br s, 81H, But; 1.81, m, 12H,
NCH2CH2CH2; 3.38, br m, 48H, NCH2CH2CH2; 4.62, s, 6H,
OCH2CON; 6.21, s, 3H, core ArH. 13C NMR (CDCl3) δ 27.7, 28.5,
29.0, 45.0, 46.6, 47.1, 47.7, 47.9, 48.5, 49.8, 67.0, 67.4, 80.0, 80.5,
95.3, 155.7, 156.2, 159.9, 167.4. Pronounced broadening of signals in
the 1H and 13C NMR spectra of this compound was observed.
1,3,5-Tris[(4,8,11-tetraazacyclotetradec-1-yl)carbonylmethoxy]ben-
zene (20)
Protected triamide (19) (1.75 g, 1.0 mmol) was stirred in a solution of
3 M HCl–MeOH (35 mL) at room temperature overnight. The white
powder was filtered off and washed with cold MeOH then basified with
10% aqueous NaOH (50 mL). The basic solution was extracted with
chloroform (5×50 mL) and the combined organic extracts were dried
(anhydrous Na2SO4) and then the solvent was removed on a rotary
evaporator. The crude product was dissolved in absolute EtOH (10 mL)
and 47% HBr in acetic acid (5 mL) was added at 0°C. The mixture was
stirred for 0.5 h and the off-white powder that formed was filtered off
and washed thoroughly with cold absolute EtOH, dried, and then
redissolved in 10% aqueous NaOH (40 mL). This basic solution was
extracted with chloroform (5×50 mL) and the combined extracts were
dried (anhydrous Na2SO4) and the solvent was removed under reduced
pressure. The title compound (20) was isolated as a colourless viscous
oil (0.72 g, 85%) (Found (FAB): [M+H]+, 847.6236. C42H78N12O6
requires [M+H]+, 847.6245). 1H NMR (CDCl3) δ 1.72, m, 12H,
NCH2CH2CH2; 2.63–2.90, m, 36H, NCH2; 3.48, t, J 6.5 Hz, 6H,
CH2CONCH2CH2CH2N; 3.61, t, J 6.9 Hz, 6H, CH2CONCH2; 4.65, s,
6H, OCH2CON; 6.22, s, 3H, ArH. 13C NMR (CDCl3) δ 28.5, 29.1, 29.3,
29.6, 45.2, 47.2, 47.9, 48.6, 49.1, 50.6, 66.7, 67.0, 95.0, 159.8, 167.2,
167.4.
1-(2,2,2-Trichloroethoxycarbonyl)-1,4,8,11-tetraazacyclotetradecane
(16)
Compound (15) (1.01 g, 1.5 mmol) was dissolved in 3 M HCl–MeOH
(40 mL) and the solution was stirred overnight at room temperature. The
white precipitate was filtered off and washed with cold MeOH. It was
then dissolved in 10% aqueous NaOH (30 mL) and CH2Cl2 (60 mL) was
added. The resultant mixture was stirred at room temperature for 0.5 h
and the two layers were separated. The aqueous phase was then extracted
with CH2Cl2 (3×30 mL). The combined organic extracts were dried
(anhydrous Na2SO4) and the solvent was removed on a rotary
evaporator. The title compound (16) was obtained as a colourless
viscous oil (0.5 g, 89%) (Found (EI): M+, 374.1037. C13H25N4O2Cl3
requires 374.1043). 1H NMR (CDCl3)
δ 1.63–1.82, m, 4H,
NCH2CH2CH2; 2.63–2.79, m, 10H, NCH2; 2.86–2.91, t, J 5.5 Hz, 2H,
TrocNCH2CH2; 3.44, t, J 5.5 Hz, 2H, TrocNCH2CH2 N; 3.54, t, J 7.1
Hz, 2H, TrocNCH2CH2CH2N; 4.74, s, 2H, Cl3CCH2OCO. 13C NMR
(CDCl3) δ 29.5, 45.1, 47.0, 47.3, 48.1, 48.5, 49.7, 75.0, 95.8, 154.7.
1-(2,2,2-Trichloroethoxycarbonyl)-4,8,11-trisbenzyltetraazacyclo-
tetradecane (17)
Benzyl bromide (0.63 g, 3.69 mmol) and caesium carbonate (4.09 g,
12.56 mmol) were added to a stirred solution of (16) (0.46 g, 1.23
mmol) in dry acetonitrile (30 mL). The resultant mixture was refluxed
for 2 h and then stirred at room temperature overnight, filtered through
Filter-Aid Celite 521, and washed thoroughly with hot chloroform. The
filtrate was taken to dryness on a rotary evaporator to give a pale-yellow
viscous oil which was purified by column chromatography on silica gel
(with CH2Cl2/MeOH/saturated NH3 aqueous solution, 200 : 1 : 0.35, as
eluent) to give (17) as a white powder (0.40 g, 50%) (Found: C, 63.1;
H, 6.6; N, 8.6%; (FAB) [M+H]+, 645.2538. C34H43N4O2Cl3 requires C,
63.2; H, 6.7; N, 8.7%; [M+H]+, 645.2530). 1H NMR (CDCl3) δ 1.71–
1.77, m, 4H, NCH2CH2CH2; 2.37–2.58, m, 12H, NCH2; 3.37–3.45, m,
4H, TrocNCH2; 3.45, s, 2H, PhCH2; 3.50, s, 2H, PhCH2; 3.54, s, 2H,
PhCH2; 4.51, s, 1H, Cl3CCH2OCO; 4.58, s, 1H, Cl3CCH2OCO; 7.18–
7.27, m, 15H, ArH. 13C NMR (CDCl3) δ 25.1, 25.5, 26.3, 45.4, 46.1,
47.0, 51.3, 51.7, 52.6, 52.9, 59.9, 74.9, 95.7, 126.9, 128.2, 128.8, 129.2,
139.6, 154.1.
1,3,5-Tris[2-(4,8,11-tetraazacyclotetradec-1-yl)ethoxy]benzene (6)
This product was obtained by an analogous procedure[10] to that
described previously and was purified by a similar method to that used
for (20). Compound (6) was obtained as a colourless oil (90%) (Found
(FAB): [M+H]+, 805.6877. Calc. for C42H84N12O3: [M+H]+, 805.6868).
1H NMR (CDCl3) δ 1.66–1.85, m, 12H, NCH2CH2CH2; 2.45–2.81,
overlapping m, 48H, NCH2CH2CH2; 2.90, t, J 5.6 Hz, 6H, OCH2-
CH2N; 4.03, t, J 5.6 Hz, 6H, OCH2CH2N; 6.07, s, 3H, ArH. 13C NMR
(CDCl3) δ 26.4, 28.6, 47.7, 47.9, 48.9, 49.4, 50.8, 51.4, 53.7, 55.6, 65.6,
93.9, 160.7.
1,3,5-Tris[(4,8,11-tert-butoxycarbonyl-4,8,11-tetraazacyclotetradec-
1-yl)carbonyl]benzene (21)
This compound was prepared by the method described previously.[10] It
was purified by column chromatography on silica gel (with CH2Cl2/
MeOH/saturated NH3 aqueous solution, 50 :1 : 0.5 as eluent) to give
(21) as a white powder (90%) (Found: C, 60.7; H, 8.8; N, 9.6%. Calc.
1,4,8-Trisbenzyl-1,4,8,11-tetraazacyclotetradecane (4)
1
for C84H144N12O21: C, 60.9; H, 8.8; N, 10.1%). H NMR (CDCl3) δ
Activated Zn dust (3.27 g, 50 mmol) was added to a solution of (17)
(0.65 g, 1.0 mmol) in glacial acetic acid (10 mL). The suspension was
1.46, s, 81H, But; 1.79, m, 12H, NCH2CH2CH2; 3.18–3.60, overlapping
m, 48H, NCH2CH2CH2; 7.52, s, 3H, ArH. 13C NMR (CDCl3) δ 27.2,

296
Y. Dong and L. F. Lindoy
28.5, ca. 44–50 (broad overlapping signals), 80.0, 125.9, 137.3, 155.5,
155.9, 169.9. Pronounced broadening of signals in the 1H and 13C NMR
spectra of this compound was observed.
(CDCl3) δ 1.68, m, 6H, NCH2CH2CH2; 1.85, m, 6H, NCH2CH2CH2;
2.53–2.81, overlapping m, 40H, NCH2; 3.42–3.70, overlapping m, 8H,
CONCH2; 3.59, s, 4H, ArCH2N; 7.33–7.41, m, 8H, ArH. 13C NMR
(CDCl3) δ 26.2, 28.6, 46.3, 47.3, 48.0, 48.9, 49.2, 49.3, 50.7, 53.4, 54.9,
57.6, 126.4, 129.0, 135.6, 140.2, 172.2. Pronounced broadening of
signals in the 1H NMR spectrum of this compound was observed.
1,3,5-Tris[(4,8,11-tetraazacyclotetradec-1-yl)carbonyl]benzene (22)
This compound was prepared and purified (89%) by a similar method
to that employed for the synthesis of (20) (Found (FAB): [M+H]+,
757.5909. C39H72N12O3 requires [M+H]+, 757.5929). 1H NMR
(CDCl3) δ 1.64, m, 12H, NCH2CH2CH2; 2.60–2.81, overlapping m,
36H, NCH2; 3.44–3.63, overlapping m, 12H, CH2NCO; 7.41, s, 3H,
ArH. 13C NMR (CDCl3) δ 29.4, 45.4, 47.7, 48.1, 48.8, 49.4, 49.6, 50.7,
125.5, 137.7, 170.3. Pronounced broadening of signals in the 1H NMR
spectrum of this compound was observed.
Compound (8)
This compound was prepared and purified (91%) by a similar
procedure to that used for (6) (Found (FAB): [M+H]+, 805.6999.
1
C46H84N12 requires [M+H]+, 805.7020). H NMR (CDCl3) δ 1.66, m,
6H, NCH2CH2CH2; 1.82, m, 6H, NCH2CH2CH2; 2.49–2.74, m, 48H,
NCH2; 3.55, s, 4H, ArCH2N; 3.70, s, 4H, ArCH2N; 7.20–7.29, m, 8H,
ArH. 13C NMR (CDCl3) δ 25.8, 26.2, 28.6, 47.4, 47.6, 47.9, 48.9, 49.3,
50.0, 50.6, 51.5, 53.0, 53.2, 53.9, 54.5, 57.4, 129.0, 129.3, 135.7, 137.4.
The product was further characterized as its hydrobromide salt which
was obtained by dropwise addition of conc. HBr to an absolute EtOH
solution of the above product. This crude salt was purified by
recrystallization from H2O/EtOH to yield fine colourless crystals
(Found: C, 30.8; H, 5.8; N, 8.9. C46H96N12Br12·3H2O.0.5HAc requires
C, 30.4; H, 5.6; N, 9.0%). 1H NMR (D2O) δ 2.21, br m, 12H,
NCH2CH2CH2; 3.42, br m, 32H, NCH2; 3.63, br m, 16H, ArCH2NCH2;
4.46, br s, 8H, ArCH2N; 7.67, m, 8H, ArH. 13C NMR (D2O) δ 17.6,
19.5, 21.4, 21.8, 22.0, 40.7, 44.2, 44.8, 47.7, 50.6, 57.1, 60.1, 60.7,
134.1, 134.5.
1,3,5-Tris[(4,8,11-tetraazacyclotetradec-1-yl)methyl]benzene (7)
The title compound was prepared and purified (90%) by a similar
method to that used for (6) (Found (FAB): [M+H]+, 715.6552. Calc. for
C39H78N12: [M+H]+, 715.6551). 1H NMR (CDCl3) δ 1.69, quintet, J 6.0
Hz, 6H, NCH2CH2CH2; 1.85, quintet, J 5.8 Hz, 6H, NCH2CH2CH2;
2.42–2.83, overlapping m, 48H, NCH2; 7.13, s, 3H, ArH. 13C NMR
(CDCl3) δ 26.3, 28.8, 29.6, 47.4, 48.0, 48.9, 49.1, 49.5, 50.7, 50.9, 52.6,
1
54.5, 57.8, 129.4, 137.9. Pronounced broadening of signals in the H
NMR spectrum of this compound was observed.
[1,8-bis(tert-butoxycarbonyl)-4,11-bis(chloromethyl)benzoyl]-
1,4,8,11-tetraazacyclotetradecane (24)
Acknowledgments
1,8-Bis(tert-butoxycarbonyl)-1,4,8,11-tetraazacyclotetradecane (23)
(1.2 g, 3.0 mmol) was dissolved in dry CH2Cl2 (50 mL). Triethylamine
(0.79 g, 7.8 mmol) and then 4-(chloromethyl)benzoyl chloride (1.25 g,
6.6 mmol) were added by syringe. The reaction mixture was stirred at
room temperature for 12 h and the organic layer was then washed with
water (2×30 mL), dried (anhydrous Na2SO4), and the solvent was
removed on a rotary evaporator. Purification of this compound was
achieved by column chromatography on silica gel (with CH2Cl2/
MeOH/saturated NH3 aqueous solution, 100 : 1 : 0.5, as eluent) to give
(24) as a white powder (1.91 g, 90%) (Found: C, 61.2; H, 7.0; N, 7.8.
C36H50N4O6Cl2 requires C, 61.3; H, 7.1; N, 7.9%). 1H NMR (CDCl3) δ
1.26, br s, 9H, But; 1.46, br s, 9H, But; 1.90, m, 4H, NCH2CH2CH2;
3.26–3.63, overlapping m, 16H, NCH2; 4.58, s, 4H, ArCH2Cl; 7.41, m,
8H, ArH. 13C NMR (CDCl3) δ 27.4, 28.4, ca. 44–50 (broad overlapping
signals), 80.3, 126.8, 128.7, 136.5, 138.7, 155.4, 156.0, 171.4.
We thank the Australian Research Council and the
Australian Institute for Nuclear Science and Engineering for
support.
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C46H80N12O2·1.5CH2Cl2 requires C, 59.4; H, 8.7; N, 17.5%). 1H NMR

New Macrocyclic Ligands. XIII
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