Mono- and bis-alkylation of glyoxal-bridged tetraazamacrocycles using mechanochemistry

Article abstract of DOI:10.1021/acs.joc.5b02464

Glyoxal-bridged bisaminal tetraazamacrocyclic derivatives of 1,4,7,10-tetraazacyclododecane (cyclen) and 1,4,8,11-tetraazacyclotetradecane (cyclam) can be N-functionalized to incorporate coordinating groups or for conjugation to biomolecules. Herein, we p

Full text of DOI:10.1021/acs.joc.5b02464

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Article
Mono- and bis-alkylation of glyoxal-bridged
tetraazamacrocycles using mechanochemistry
Bassim H Abdulwahaab, Benjamin P. Burke, Juozas Domarkas,
Jon David Silversides, Timothy J Prior, and Stephen J. Archibald
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b02464 • Publication Date (Web): 15 Dec 2015
Downloaded from http://pubs.acs.org on December 15, 2015
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The Journal of Organic Chemistry
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Mono- and bis-alkylation of glyoxal-bridged tetraazamacrocycles
using mechanochemistry
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Bassim H. Abdulwahaab†, Benjamin P. Burke†,‡, Juozas Domarkas†,‡, Jon D. Silversides†,
Timothy J. Prior† and Stephen J. Archibald†,‡*
†Department of Chemistry, University of Hull, Cottingham Road, Hull, HU6 7RX, United Kingdom.
‡Positron Emission Tomography Research Centre, University of Hull, Cottingham Road, Hull HU6 7RX, United Kingdom.
Keywords: Mechanochemistry, chelator, macrocycle, cyclam, cyclen, CB-TE2A, copper-64
ABSTRACT: Glyoxalꢀbridged bisaminal tetraazamacrocyclic derivatives of 1,4,7,10ꢀ
tetraazacyclododecane (cyclen) and 1,4,8,11ꢀtetraazacyclotetradecane (cyclam) can be Nꢀfunctionalized
to incorporate coordinating groups or for conjugation to biomolecules. Herein, we present an improved
Nꢀfunctionalization methodology using mechanochemistry which reduces reaction times in comparison
with conventional synthetic routes. A range of six alkyl halides were reacted with cyclen and cyclam
bisaminal derivatives in various ratios to form monoꢀ and bisꢀfunctionalized quaternary ammonium
salts. Crossꢀbridged cyclam, a key intermediate for CBꢀTE2A, a commonly used chelator in positron
emission tomography medical imaging with 64Cu, has been synthesized using nonꢀconventional synthetꢀ
ic methodologies (grinding and microwave heating) with intermediates characterized by 2DꢀNMR and
single crystal XRD. The overall synthesis time of CBꢀTE2A from cyclam could be shortened to 5 days
from the 35 days required for the conventional synthesis.
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1. Introduction
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Mechanochemistry is the application of mechanical actions, such as grinding, milling, rubbing or
shearing, in order to induce a chemical transformation.1ꢀ3 It is based on the principle that, once an intiꢀ
mate mixture of chemicals is subjected to mechanical stress, frictional energy is sufficient to overcome
energy barriers and induce chemical transformations. Mechanochemical synthesis can be carried out eiꢀ
ther manually, using a mortar and a pestle, or by employing specialized grinding/milling machines.4 The
former is the cheapest and the simplest method to set up but lacks the required reproducibility, making
the outcome of the reaction dependent not only on the energetics of the chemical process, but also the
physical characteristics of the manipulating chemist.1,2 The use of automated ball milling apparatus
overcomes this problem, giving a possibility to standardize reaction conditions by controlling parameꢀ
ters, such as reaction time and energy transferred.4,5 Two different types of ball mills are commonly
available in organic synthesis laboratory: vibration or mixer ball mills (MBMs) and planetary ball mills
(PBMs)..A planetary ball mill was used in this work. 6,7
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Scheme 1 - General schematic for mono- and bis-N-alkylation of tetraazamacrocycles.
In recent years, the capacity of mechanochemistry to generate complex molecules has attracted the atꢀ
tention of a broad audience from different research areas across organic and inorganic chemistry, includꢀ
ing catalyst design and the preparation of pharmaceutical materials.8,9 The main advantages of mechaꢀ
nochemistry over more conventional laboratory techniques, such as the heating of solutions, are reaction
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time, reduced solvent use and efficiency of activation energy input.10ꢀ12 Furthermore, simple milling
protocols have been improved further by developing new methods, such as liquid or/and ion assisted
grinding (LAG or ILAG),10,13 or the more recently developed polymerꢀassisted grinding (POLAG).14
Mechanochemistry has been applied for solventꢀfree peptide synthesis,15 preparation of monoꢀ and bisꢀ
(thio)ureas,5 and optimization of multiple CꢀC bond forming reactions, such as Suzuki–Miyaura, Heck,
and Sonogashira couplings, aldol reactions, cycloadditions, and heterocycle synthesis.16ꢀ18 Here we preꢀ
sent a novel application of mechanochemistry in Nꢀalkylation of glyoxal bridged bisaminal derivatives
of cyclam (1,4,8,11ꢀtetraazacyclotetradecane) and cyclen (1,4,7,10ꢀtetraazacyclododecane) – macrocyꢀ
clic polyamines with high affinity for various metal ions.
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The affinity of tetraaza macrocycles for a given metal depends on ring size, macrocycle backbone
flexibility, and the nature and number of coordinating atoms.19 Thus, different macrocyclic polyamine
derivatives have been produced, exhibiting increased affinity and concurrent complex stability towards
certain metal cations (transition metals or lanthanides).20 Tetraazamacrocyclic complexes have found
use in a range of applications, dependent on the chelated metal ion. The majority of applications relate
to medical imaging agents, such as MRI contrast agents containing gadolinium(III),21,22 optical agents
containing europium(III) and terbium(III) or nearꢀIR emitting lanthanides,23ꢀ25 along with nuclear mediꢀ
cine probes incorporating galliumꢀ68,26,27 technetiumꢀ99m28,29 and copperꢀ6430,31. Tetraazamacrocyclic
complexes with various metals have also been used as protein binding agents,32,33 antiꢀmalarial
drugs34,35 and as catalysts.9,36
Cyclam (1,4,8,11ꢀtetraazacyclotetradecane) is one of the most used macrocyclic polyamines because it
can form stable complexes with 1st row transition metal cations. Usually, metal selectivity is achieved
by variation of the nature of pendant arms attached to the ring nitrogen atoms. The majority of cyclam
chelator focus has been with acetate functionalized derivatives such as TETA, TE2A, and CBꢀTE2A.31,32
There is interest in the controlled synthesis of monoꢀ or bisꢀ substituted derivatives which may have opꢀ
timized chelation properties for particular metal ions.33 Selective stepꢀwise functionalization to form
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unsymmetrical chelators is relevant to advanced chelator design.37,38 The increased reactivity of bisꢀ
aminal cyclen leads to challenges in the synthesis of unsymmetrical chelators, the development of a
method selectively functionalize would allow access to a range of novel chelators beyond the ubiquitous
four arm derivative DOTA.39,35
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Increase of backbone rigidity of cyclam and cyclen can be achieved by including an internal bridge
between adjacent (sideꢀbridge) or nonꢀadjacent (crossꢀbridge) nitrogen atoms and plays an important
role in developing configurationally restricted chelators which can form metal complexes of increased
stability.36 The key intermediate in both cases is a glyoxal bridged bisaminal azamacrocycle which is
alkylated at one or two of the aminal nitrogen atoms to include side arms carrying a functionality to imꢀ
prove coordination properties, such as stability, or for conjugation to a biomolecule or solid phase supꢀ
port.
2. Results and discussion
2.1. Alkylation of glyoxal cyclam and cyclen
Conventional solution chemistry can provide access to mono Nꢀalkylated glyoxalꢀbridged macrocyꢀ
cles, however, this transformation requires a large excess of alkyl bromide and, dependent on reactivity
of alkyl bromide, may take several days.40,41 The reaction is usually stopped at the monoꢀalkylation
stage by selection of an appropriate type and amount of solvent to create reaction conditions where the
precipitation of a monoꢀsubstituted product occurs.42 Bis Nꢀalkylation, under conventional conditions, is
more challenging due to the reduced reactivity of the second exoꢀnitrogen and may require up to three
weeks to reach completion.42,43
An initial test reaction was carried out by grinding glyoxal bridged bisaminal cyclam with a stoichioꢀ
metric amount of 4ꢀcyanobenzyl bromide in the presence of a small amount of acetonitrile (90 ꢀL) for a
relatively short period of time (30 min.) to give a mono Nꢀsubstituted macrocycle 1 in a quantitative
yield (see Table 1). This discovery encouraged us to investigate this method of alkylation of cyclam usꢀ
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ing various alkyl bromides, see Scheme 1, and to extend this methodology to alkylation of 12 membered
ring macrocycle analogue, cyclen.
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Table 1. Alkylation of glyoxal cyclam by grinding for 30 min in presence of a stoichiometric amount of alkyl bromide
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Alkylation
BrꢀR
Product
yield a, %
97 ± 2b
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85
89 ± 1b
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a
Alkylation yield is based on a macrocycle and is calculated by dividing the mass of product(s) obtained by the theoretical mass for a
given mixture of mono-armed and doubled-armed products. b An average of three independent experiments.
Various bromides ꢀ 4ꢀtolyl, benzyl, 4ꢀcyanobenzyl, 4ꢀnitrobenzyl, 3,5ꢀdibromobenzyl bromides and tꢀ
butyl bromoacetate – were trialled. The choice of the alkyl bromide was guided by the potential to inꢀ
vestigate the impact of the electronic properties of the substituents and also consideration of target molꢀ
ecules for future application. Of particular interest are the following: (i) 4ꢀcyano and 4ꢀnitrobenzyl subꢀ
stituents which can be reduced to benzylamine or aniline derivatives and the primary amine group used
for a bioconjugation reaction to a protein or peptide, as a bifunctional chelator.23,32 (ii) Bis Nꢀsubstituted
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nonꢀfunctionalized benzyl and tolyl derivatives are key intermediates in crossꢀbridge cyclen / cyclam
synthesis.35,44 (iii) Nꢀtertꢀbutyl acetate derivatives can be easily deprotected to reveal carboxylates
which can either act as supplementary metal chelating groups or be used for bioconjugation
reactions.43,45 The reactivity of benzyl bromides is governed by the nature of phenyl ring substituents
which influence the electron density on benzyl carbon. Highly reactive aryl bromides carrying electron
donating groups would be preferred for synthesis of bisꢀalkylated products, whereas less reactive elecꢀ
tron poor bromides might be applied in the exclusive preparation of mono substituted derivatives.
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Table 2. Alkylation of glyoxal cyclam by grinding for 3 hours in presence of a 4-fold excess of alkyl bromide
Alkylation
BrꢀR
Product
yield a, %
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95 ± 1b
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Alkylation yield is based on a macrocycle and is calculated by dividing the mass of product(s) obtained by the theoretical mass for a
given mixture of mono-armed and doubled-armed products. b An average of three independent experiments. c In 2:1 mixture with 16.
Glyoxalꢀbridged bisaminal cyclam and cyclen were synthesized following standard literature methodꢀ
ology.46 Mechanochemical alkylation of glyoxalꢀbridged cyclam and cyclen has been carried out using a
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planetary ball mill (PBM) apparatus under LAG conditions (90 ꢀL acetonitrile) at a 0.1 g scale of
azamacrocycle. One arm substitution was targeted by using a stoichiometric amount of alkyl bromide
and 30 mins grinding time, whilst the two arm bisꢀsubstitution reaction was attempted by employing a
fourꢀfold excess of alkyl bromide and a 3 h grinding time, see Tables 1 and 2.
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Table 3. Alkylation of glyoxal cyclam via conventional solution chemistry
Macrocycle
/
Alkylation
yield, %
BrꢀR
Product alkyl bromide raꢀ
tio
Time
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1 : 2.5
1 : 4
2 days
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16 days
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1 : 3
1 : 4
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1 : 16
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1 : 1
16 hours
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1 : 4
16 hours
21 days
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70
18
1 : 15
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These conditions were selected after multiple trials in which reaction time, ratio of reagents and numꢀ
ber of grinding balls were varied (data not shown). In order to confirm the reproducibility and extent of
applicability of mechanochemical Nꢀalkylation of azamacrocycles, reactions with 4ꢀcyanobenzyl and 4ꢀ
tolyl bromide were repeated in triplicate. In order to separate alkylated species from unreacted azamacꢀ
rocycle and/or excess of alkyl bromide, at the end of reaction, pasteꢀlike mixtures were washed multiple
times with diethyl ether and tetrahydrofuran. The isolated powders were dried under vacuum, weighed
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and analyzed by H NMR to determine their composition. In case of the mixtures obtained from tolyl
substitution reactions, analytically pure samples of monoꢀ (3) and bis Nꢀsubstituted products (15) could
be obtained by rewashing the dried mixtures with a minimum amount of chloroform in which monoꢀ
substituted products were highly soluble whereas bisꢀsubstituted products were almost insoluble.
Grinding of the bisꢀaminal cyclam with a stoichiometric amount of 4ꢀcyanobenzyl, 4ꢀnitrobenzyl, 4ꢀ
tolyl, benzyl, 3,5ꢀdibromobenzyl bromide or tꢀbutyl bromoacetate for 30 mins produced only monoꢀNꢀ
substituted derivatives 1-6 with isolated yields of 98%, 85%, 90%, 81%, 64% and 34% respectively (see
Scheme 1, n = 1, Table 1). The reaction of 4ꢀtolyl benzyl bromide to form 5 was carried out with a 1:1
molar ratio for 3 hours showing no significant (< 5%) increase in yield.
An attempt was made to probe the conditions required to either (a) increase the yields of the monoꢀ
substituted products or (b) drive the reactions to form the bisꢀsubstituted compounds. Increasing the
amount of alkyl bromide to 4 equivalents and the grinding time up to 3 h did not improve the near quanꢀ
titative 98% yield for monoꢀ4ꢀcyanobenzyl substitution (1), but increased the yield of tꢀbutyl bromoaceꢀ
tate monoꢀsubstituted product (6) to 50% and drove the 4ꢀnitrobenzyl and 3,5ꢀdibromobenzyl bromide
monoꢀsubstitution reactions almost to completion (98% (2) and 92% (5) respectively, see Table 2). Theꢀ
se alkyl halides did not react further to form bisꢀalkylated macrocycles upon increase of reaction time
and/or molar ratio. The use of benzyl bromide under these conditions led to a 2:1 mixture of monoꢀ (4)
and bisꢀ (16) Nꢀsubstituted compounds, but when 4ꢀtolyl bromide was used, exclusively bisꢀNꢀ
substituted derivative (15) was obtained in an almost quantitative 95% yield (see Table 2). It should be
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noted that, broadly, reactivity of different benzyl/alkyl bromides in mechanochemical syntheses mirꢀ
rored that observed for conventional in solution reactions (see Table 3), i.e. even when used in excess,
electron poor 4ꢀcyano, 4ꢀnitro and 3,5ꢀdibromobenzyl bromides gave exclusively monoꢀsubstituted
products (see Table 1 and 2) when the use of excess of 4ꢀtolyl bromide yielded a pure bisꢀNꢀsubstituted
product (see Table 2).
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Table 4. Alkylation of glyoxal cyclen by grinding for 30 min in presence of a stoichiometric amount of alkyl bromide
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8
Alkylation
BrꢀR
Product
yield a, %
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given mixture of mono-armed and doubled-armed products. b An average of three independent experiments. c In 10:1 mixture with 20. d In
5:1 mixture with 21. e In 17:1 mixture with 22. f In 2:1 mixture with 24.
The same methodology was subsequently applied to the synthesis of cyclen derivatives, however, a
clean production of either monoꢀ or bisꢀNꢀsubstituted products was rarely obtained, confirming the inꢀ
creased reactivity of glyoxalꢀbridged bisaminal cyclen to alkylation (see Scheme 1, n = 0 and Table 4
and 5). Clean mono Nꢀsubstituted products were only obtained by using a short grinding time (30 min.)
and stoichiometric amounts of deactivated 4ꢀcyanobenzyl and 3,5ꢀdibromo benzyl bromides (87% (7)
and 60% (11) respectively (see Table 4). Pure bisꢀNꢀsubstituted products were only isolated for reactive
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4ꢀtolyl and tꢀbutyl acetyl bromides using a 4ꢀfold excess of alkyl bromide and 3 h grinding (94% (21)
and 86% (24) respectively, see Table 5). For these reasons, apart from the benefits of shortening reaction
times, advantages of mechanochemical syntheses over the conventional approach are less marked. It
should be noted, however, that conventional in solution syntheses suffer from some of the same limitaꢀ
tions and pure compounds could be obtained only using electron poor 4ꢀnitro and 3,5ꢀdibromo benzyl
bromides (7 and 11 respectively, see Table 6).
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Table 5. Alkylation of glyoxal cyclen by grinding for 3 hours in presence of a 4-fold excess of alkyl bromide
Alkylation
BrꢀR
Product
yield a, %
86 ± 1b
19c
20d
21
96
94 ± 1b
98
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23f
24
92
86
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Alkylation yield is based on a macrocycle and is calculated by dividing the mass of product(s) obtained by the theoretical mass for a
given mixture of mono-armed and doubled-armed products. b An average of three independent experiments. c In 1:8 mixture with 7. d In 3:1
mixture with 8, e In 1:1 mixture with 10. f In 4:1 mixture with 11.
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A comparison between the reactivity of bisaminal cyclam and cyclen towards Nꢀalkylation under LAG
conditions reveals that, as expected, the cyclen derivative is more reactive than the cyclam derivative,
due to the rigidified nature of the macrocycle influencing the orientation of the exo nitrogen atoms. As
mentioned, for cyclen derivatives, pure monoꢀsubstituted products were only available from deactivated
4ꢀcyanobenzyl and 3,5ꢀdibromobenzyl bromides reactions (7 and 11 respectively). However, this inꢀ
creased reactivity allowed preparation of pure bisꢀsubstituted bisaminal cyclen using electronically neuꢀ
tral tꢀbutyl bromoacetate (24), which was not possible in the case of the cyclam equivalent.
Table 6. Alkylation of glyoxal cyclen via conventional solution chemistry.a
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Alkylation
BrꢀR
Product
yield b, %
7d
8
72
88± 1c
9e
77
10f
72
11
84 ± 1c
60
12g
b
a All reactions carried out for 24 hours. Alkylation yield is based on a macrocycle and is calculated by dividing the mass of product(s)
obtained by the theoretical mass for a given mixture of mono-armed and doubled-armed products. c An average of two independent exper-
iments. d In 5:1 mixture with 19. e In 6:1 mixture with 21. f In 8:1 mixture with 22. g In 4: 1 mixture with 24.
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2.2. Efficient synthesis of CB-cyclam
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Due to the increased kinetic stability of their metal complexes, crossꢀbridged cyclam derivatives are
preferred candidates for radiometal chelation in biomedical applications, especially in the use of copꢀ
per(II) radioisotopes such as copperꢀ64.47 Two general methods are used to symmetrically Nꢀ
functionalize the crossꢀbridged cyclam azamacrocycle. The first procedure involves the addition of the
selected pendent arms onto the tetracyclic bisaminal directly at the start of the synthesis followed by reꢀ
ductive ring cleavage to give the desired crossꢀbridged species. This strategy, however, is limited to the
specific cases when a sufficiently reactive side arm precursor is available due to the lower reactivity of
the second aminal nitrogen atom in cyclam.40,48 The second strategy relies on the initial preparation of
an unsubstituted crossꢀbridged cyclam (by using a highly reactive side arm which is removed after the
crossꢀbridge formation by catalytic hydrogenation) which is then functionalized with the desired penꢀ
dent arm(s). Thus, the second approach is much more versatile and is generally preferred.40
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CBꢀTE2A (Scheme 2) is a widely used copper(II) chelator consisting of a crossꢀbridged cyclam Nꢀ
substituted by two methylcarboxylic acid pendent arms.40,49 It has been specifically developed to form
stable in vivo complexes with copper(II) for 64Cu PET imaging and offers significant stability adꢀ
vantages over unbridged analogues.50,51 CBꢀTE2A is generally prepared following the method originally
proposed by Weisman and coꢀworkers.40 First, unsubstituted crossꢀbridged cyclam is prepared by reducꢀ
tion and hydrolysis of a bisꢀbenzyl aminal intermediate which is then reacted with ethyl bromoacetate
yielding the bisꢀsubstituted crossꢀbridged species. Finally, the ethyl ester protecting groups are subjected
to acid hydrolysis, revealing the carboxymethyl arms of CBꢀTE2A which improve the metal ion coordiꢀ
nation by offering additional donor atoms to give highly stable complexes.
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Scheme 2 - Synthesis of CB-cyclam (26) for efficient synthesis of CB-TE2A.
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The synthesis of CBꢀTE2A by conventional methods is a time consuming six step process taking 35
days with an average 45% yield (calculated from cyclam). The most time consuming steps are glyoxalꢀ
bridged cyclam alkylation (16 days for benzyl bromide) and reductive ring opening in presence of a
large excess of NaBH4 (50 eq., 14 days).40 We believed that by using the alkylation method described in
this work we could dramatically reduce the overall time spent in preparation of CBꢀcyclam, a key inꢀ
termediate in CBꢀTE2A synthesis. As the bisꢀNꢀbenzyl substitution is only required to direct the openꢀ
ing of the bridged system towards CBꢀcyclam, in our synthesis we replaced benzyl bromide by more
reactive tolyl bromide (see Scheme 2). Mechanochemical alkylation requires only 4ꢀfold excess of tolyl
bromide and is complete in 3 hours (15, Scheme 1, Table 2) giving a 95% yield which is a significant
increase in efficiency when compared with the 16 day reaction using benzyl bromide following convenꢀ
tional methodology.
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As 15 is a novel key intermediate, further analysis was carried out in order to fully characterise its
structure. Full assignment of the NMR was carried out using 2DꢀNMR (1HꢀDQFꢀCOSY) and compared
with spectra of analogous reported compounds and the monoꢀsubstituted derivative (3) (full details are
reported in the ESI). In order to determine the structure of 15 in the solid state, single crystals of 15 and
21, suitable for singleꢀcrystal Xꢀray structure determination, were obtained within 2ꢀ7 days from vapour
diffusion of diethyl ether into a methanolic solution at room temperature. The Xꢀray crystal structures
confirm the identity of 15 and 21 (see ESI) and show that the cis geometry has been adopted around the
bisaminal bridge, as expected from the synthetic method used. The two ‘exo’ nitrogen atoms, where the
lone pairs points out of the central cavity, have been alkylated to form quaternized derivatives. The full
details of the structural data of 15 and the two crystalline forms of compound 21 are presented in the
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supplementary data. A useful comparison of the relative strains on the alkylated bisaminal macrocycles
can be obtained by examining the bond angles around the benzyl substituted nitrogens. The 14ꢀ
membered cyclam ring (15) has bond angles in the range 107.5ꢀ112.6° around the quaternized ring niꢀ
trogen and the equivalent positions in the 12ꢀmembered cyclen derivative (form II of 21) show more
flexibility with a wider range of angles from 101.5ꢀ 113.3°. This matches with the reactivity observed in
the formation of these products
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After reducing alkylation time from 16 days to 3 hours we looked for ways to increase the efficiency
of reductive ring cleavage leading to formation of the crossꢀbridged derivative. We found that using onꢀ
ly ten molar equivalents of sodium borohydride and heating the reaction by microwave irradiation we
could reduce the reaction time from 14 days to 30 minutes and form 25 in an 83% yield. Given that the
intermediate 25 carries tolyl rather than the traditional benzyl arms, we also confirmed effectiveness of
catalytic hydrogenation and obtained expected CBꢀcyclam (26) in an 80% yield. Therefore, the demonꢀ
strated optimization of the first two steps employing nonꢀconventional synthesis methods could shorten
preparation of CBꢀTE2A to less than one week, which would represent a fiveꢀfold acceleration in comꢀ
parison to the conventional five week synthesis time (see Scheme 2).
3. Conclusion
The rapid synthesis of different glyoxalꢀbridged cyclen and cyclam derivatives has been achieved usꢀ
ing mechanochemical activation under liquid assisted grinding (LAG) conditions. To the best of our
knowledge, this is the first report of preparation of monoꢀ and/or bisꢀNꢀsubstituted glyoxalꢀbridged
tetraazamacrocyclic derivatives which, after a further transformation, could give access to a variety of
interesting bifunctional chelators. Using a stoichiometric ratio of reagents, monoꢀNꢀalkylated products
were obtained with short reaction times and in moderate to high yields. The amount of bisꢀNꢀalkylated
products in the final reaction mixtures can be increased by selecting electronically activated alkyl broꢀ
mides, increasing the reagent ratio and prolonging the grinding time. The syntheses were easy to exeꢀ
cute and often approached quantitative yields. Furthermore, the ability to stop the reaction at the mono
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alkylation stage is very important and permits application of this technique to the design of more sophisꢀ
ticated molecules. In the field of functionalized azamacrocycle preparation, these findings present grindꢀ
ing methodology as an attractive alternative to more conventional solutionꢀbased synthetic methods. As
a proof of principle, mechanochemical activation together with a rapid microwave synthetic step has
been used for preparation of crossꢀbridged cyclam, a key intermediate in the synthesis of CBꢀTE2A.
The novel synthetic route showed a significant increase in efficiency resulting in a fiveꢀfold reduction in
the synthesis time.
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4. Experimental
4.1. Materials and methods
The starting glyoxalꢀbridged bisaminal cyclam and cyclen were prepared following published protoꢀ
cols.52 Solvents used were of reagent grade. Grinding experiments were carried out in a Retsch PM100
(Retsch (U.K.) Limited) planetary ball mill using a 12 mL stainless steel grinding jar and a single 10
mm diameter stainless steel ball at 400 RPM. Dry acetonitrile was used as a liquid phase throughout all
Liquid Assisted Grinding (LAG) experiments. All reactions were run at room temperature (r.t.) unless
otherwise stated. Microwave assisted reduction was carried out in 35 mL reactor using CEM Discovery
(CEM Microwave Technology Ltd) apparatus with temperature measured via external infrared sensor.
Bulk solvent was removed by evaporation under reduced pressure and trace solvent was removed using
13
a Schlenk line. 1HꢀNMR and 13CꢀNMR were obtained at 400 MHz for 1H spectra and 100 MHz for C
spectra, and were referenced against standard internal TMS or residual non deuterated solvent signal.
Splitting patterns are designated as s (singlet), d (doublet), t (triplet), m (multiplet) and dt (double triꢀ
plet). When a mixture of products is present, a ratio of characteristic aminal protons in 1HꢀNMR is used
to determine ratios and calculate yields. DoubleꢀQuantum Filtered Correlation Spectroscopy (1HꢀDQFꢀ
COSY) was carried out on 3 and 15. High and low resolution mass spectra were recorded using an elecꢀ
trospray ionꢀtrap LCꢀMS in positive mode. Single crystal Xꢀray diffraction data were collected using an
imaging plate diffractometer operating with Mo radiation. Routine data collection and processing proꢀ
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cedures were adopted. CCDC 1417374ꢀ1417376 contain the supplementary crystallographic data for
this paper. These data can be obtained free of charge via
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http://www.ccdc.cam.ac.uk/conts/retrieving.html (or from the Cambridge Crystallographic Data Centre,
12, Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033).
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4.2. Synthesis
General procedure for mono- and bis-N-alkylation of glyoxal-bridged tetraazamacrocycles via grind-
ing
A mixture of alkylbromide and glyoxalꢀbridged cyclam or cyclen in 1:1 molar ratio was ground in the
presence of dry acetonitrile (90 µl) for 30 min (for one arm) and in 1:4 molar ratio for 3 h (for two
arms). The crude products were scraped off the walls of the grinding jar and were washed multiple times
with diethyl ether and tetrahydrofuran (THF) to remove unꢀreacted starting materials and give expected
monoꢀ or bisꢀNꢀsubstituted products (pure or in mixtures) in powdery form.
General procedure for mono- and bis-N-alkylation of glyoxal-bridged cyclam or cyclen via a conven-
tional in solution method
A selected alkylbromide and glyoxalꢀbridged cyclam or cyclen in 1:4 molar ratio was stirring for the
tabulated time in dry acetonitrile (25 mL). The precipitated products were isolated by filtration and
washed multiple times with diethyl ether and tetrahydrofuran (THF) to remove unꢀreacted starting mateꢀ
rials.
10a-(4-cyanobenzyl)dodecahydro-1H-3a,5a,8a,10a-tetraazapyren-10a-ium bromide (1), first reported
by Silversides et al.37: From cisꢀ3a,5a,8a,10aꢀtetraazaperhydropyrene (100 mg, 0.45 mmol, 1 eq.) and 4ꢀ
(bromomethyl)benzonitrile (88.2 mg, 0.45 mmol, 1 eq.). White solid (184 mg, 98%). From cisꢀ
3a,5a,8a,10aꢀtetraazaperhydropyrene (100 mg, 0.45 mmol, 1 eq.) and 4ꢀ(bromomethyl)benzonitrile
(352.8 mg, 1.8 mmol, 4 eq.). White solid (184 mg, 98%). 1H NMR (400 MHz, D2O, δ): 1.40 (d, J = 13.5
Hz, 1H), 1.73 (d, J = 13.5 Hz, 1H), 2.05ꢀ2.32 (m, 3H), 2.38ꢀ2.49 (m, 2H), 2.57 (td, J = 3.1 Hz, J = 12.4
Hz, 1H), 2.90ꢀ4.13 (m, 7H), 3.15ꢀ3.34 (m, 2H), 3.39ꢀ3.63 (m, 2H), 3.92 (s, 1H), 4.19 (td, J = 3.6 Hz, J =
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13.1 Hz, 1H), 4.29 (d, J = 1.6 Hz, 1H), 4.75 (d, J = 13.1 Hz, 1H), 5.18 (d, J = 13.1 Hz, 1H), 7.66 (d, J =
8.4 Hz, 2H), 7.87 (d, J = 8.4 Hz, 2H).
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10a-(4-nitrobenzyl)dodecahydro-1H-3a,5a,8a,10a-tetraazapyren-10a-ium bromide (2), first reported
by Plutnar et al.53: From cisꢀ3a,5a,8a,10aꢀtetraazaperhydropyrene (100 mg, 0.45 mmol, 1 eq.) and 4ꢀ
(bromomethyl)nitrobenzene (97 mg, 0.45 mmol, 1 eq.). White solid (168 mg, 85%). From cisꢀ
3a,5a,8a,10aꢀtetraazaperhydropyrene (100 mg, 0.45 mmol, 1 eq.) and 4ꢀ(bromomethyl)nitrobenzene
(389 mg, 1.8 mmol, 4 eq.). White solid (212 mg, 98%). 1H NMR (400 MHz, D2O, δ): 1.45 (d, J = 14.9
Hz, 1H), 1.77 (d, J = 14.9 Hz, 1H), 2.08ꢀ2.36 (m, 3H), 2.43ꢀ2.52 (m, 2H), 2.63 (td, J = 3.5 Hz, J = 13.0
Hz, 1H), 2.95ꢀ3.18 (m, 7H), 3.19ꢀ3.38 (m, 2H), 3.44ꢀ3.64 (m, 2H), 3.71 (d, J = 2.0 Hz, 1H), 4.15ꢀ4.27
(m, 1H), 4.34 (d, J = 2.0 Hz, 1H), 4.83 (d, J = 13.3 Hz, 1H), 5.26 (d, J = 13.3 Hz, 1H), 7.76 (d, J = 8.8
Hz, 2H), 8.35 (d, J = 8.8 Hz, 2H).
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10a-(4-methylbenzyl)dodecahydro-1H-3a,5a,8a,10a-tetraazapyren-10a-ium bromide (3): From cisꢀ
3a,5a,8a,10aꢀtetraazaperhydropyrene (100 mg, 0.45 mmol, 1 eq.) and 1ꢀ(bromomethyl) 4ꢀ
methylbenzene (83 mg, 0.45 mmol, 1 eq.). The crude solid was purified by washing with chloroform to
1
yield a soluble product which was dried in vacuo to yield a white solid (166 mg, 90%). H NMR (400
MHz, D2O, δ): 1.43 (d, J = 14.1 Hz, NꢀβꢀCH2, 1H), 1.75 (d, J = 14.1 Hz, NꢀβꢀCH2, 1H), 2.02ꢀ2.29 (m,
NꢀαꢀCH2, 3H), 2.36 (s, Ar CH3, 3H), 2.38ꢀ2.48 (m, NꢀβꢀCH2, 2H), 2.60 (td, J = 3.7 Hz, J = 12.7 Hz, Nꢀ
αꢀCH2, 1H), 2.92ꢀ3.13 (m, NꢀαꢀCH2, 7H), 3.14ꢀ3.36 (m, NꢀαꢀCH2,2H), 3.40ꢀ3.56 (m, NꢀαꢀCH2, 2H),
3.62 (d, J = 1.8 Hz, CH, 1H ), 4.14 (td, J = 4.1 Hz, J = 13.4 Hz, NꢀαꢀCH2, 1H), 4.33 (d, J = 1.8 Hz,
CH, 1H), 4.73 (d, J = 13.5 Hz, Ar CH2, 1H), 4.96 (d, J = 13.5 Hz, Ar CH2, 1H), 7.35 (d, J = 8.4 Hz, Ar
H, 2H), 7.39 (d, J = 8.4 Hz, Ar H, 2H). 13C{1H}NMR (100 MHz, D2O, δ): 18.0 (CH2), 18.4 (CH2), 20.4
(CH3), 42.0 (CH2), 46.6 (CH2), 48.6 (CH2), 51.3 (CH2), 52.0 (CH2), 53.3 (CH2), 54.0 (CH2), 59.7 (CH2),
62.5 (CH2), 69.6 (CH), 81.7 (CH), 122.5 (C), 129.9 (CH), 133.2 (CH), 141.9 (CH). HRMS: calc. for
C20H31N4: 327.2543, found: 327.2548. Elemental analysis calc. for C20H31BrN4.2H2O: C, 54.17; H,
7.96; N, 12.64%; found: C, 54.16; H, 8.22; N, 12.82. m.p. 144ꢀ145oC.
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10a-benzyldodecahydro-1H-3a,5a,8a,10a-tetraazapyren-10a-ium bromide (4), first reported by Silꢀ
versides et al.37: From cisꢀ3a,5a,8a,10aꢀtetraazaperhydropyrene (100 mg, 0.45 mmol, 1 eq.) and benzyl
bromide (77 mg, 0.45 mmol, 1 eq.). White solid (143 mg, 81%). From cisꢀ3a,5a,8a,10aꢀ
tetraazaperhydropyrene (100 mg, 0.45 mmol, 1 eq.) and benzyl bromide (308 mg, 1.8 mmol, 4 eq.).
White solid, obtained in 2:1 mixture with 16 (175 mg, 99%). 1H NMR (400 MHz, D2O, δ): 1.39 (d, J =
14.5 Hz, 1H), 1.70 (d, J = 14.5 Hz, 1H) 2.02ꢀ2.26 (m, 3H), 2.33ꢀ2.48 (m, 2H), 2.56 (td, J = 4.0 Hz, J =
13.5 Hz, 1H), 2.86ꢀ3.11 (m, 7H), 3.13ꢀ3.33 (m, 2H), 3.37ꢀ3.56 (m, 2H), 3.59 (d, J = 1.5 Hz, 1H), 4.06ꢀ
4.18 (m, 1H), 4.30 (d, J = 1.5 Hz, 1H), 4.72 (d, J = 13.5 Hz, 1H), 4.99 (d, J = 13.5 Hz, 1H), 7.43ꢀ7.58
(m, 5H).
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10a-(3,5-dibromobenzyl)dodecahydro-1H-3a,5a,8a,10a-tetraazapyren-10a-ium bromide (5): From
cisꢀ3a,5a,8a,10aꢀtetraazaperhydropyrene (100 mg, 0.45 mmol, 1 eq.) and 1,3ꢀdibromoꢀ5ꢀ
(bromomethyl)benzene (127 mg, 0.45 mmol, 1 eq.). White solid (159 mg, 64%). From cisꢀ3a,5a,8a,10aꢀ
tetraazaperhydropyrene (100 mg, 0.45 mmol, 1 eq.) and 1,3ꢀdibromoꢀ5ꢀ(bromomethyl)benzene (508
1
mg, 1.8 mmol, 4 eq.). White solid (229 mg, 92%). H NMR (400 MHz, D2O, δ): 1.39 (d, J = 14.4 Hz,
1H), 1.73 (d, J = 14.4 Hz, 1H) 2.02ꢀ2.32 (m, 3H), 2.36ꢀ2.49 (m, 2H), 2.55 (td, J = 3.0 Hz, J = 13.0 Hz,
1H), 2.85ꢀ3.21 (m, 8H), 3.31 (d, J = 11.5 Hz, 1H), 3.36ꢀ3.55 (m, 2H), 3.63 (d, J = 1.1 Hz, 1H), 4.08ꢀ
4.22 (m, 1H), 4.24 (d, J = 1.1 Hz, 1H), 4.64 (d, J = 13.4 Hz, 1H), 5.03 (d, J = 13.4 Hz, 1H), 7.64 (d, J
13
= 1.0 Hz, 2H), 7.91ꢀ7.99 (m, 1H). C{1H}NMR (100 MHz, D2O, δ): 18.0, 18.4, 41.9, 46.5, 48.6, 51.3,
51.9, 53.3, 53.9, 60.2, 69.6, 82.5, 123.2, 129.3, 134.7, 136.6. HRMS: calc. for C19H27N4Br2: 471.0581,
found 471.0577. Elemental analysis calc. for C19H27Br3N4: C, 41.40; H, 4.94; N, 10.17%; found: C,
41.79; H, 5.12; N, 10.01. m.p. 178ꢀ179οC.
10a-(2-(tert-butoxy)-2-oxoethyl)dodecahydro-1H-3a,5a,8a,10a-tetraazapyren-10a-ium bromide (6),
first reported by Silversides et al.54: From cisꢀ3a,5a,8a,10aꢀtetraazaperhydropyrene (100 mg, 0.45 mmol,
1 eq.) and tꢀbutyl bromoacetate (88 mg, 0.45 mmol, 1 eq.). White solid (60 mg, 32%). From cisꢀ
3a,5a,8a,10aꢀtetraazaperhydropyrene (100 mg, 0.515 mmol, 1 eq.) and tꢀbutyl bromoacetate (351 mg,
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1
1.8 mmol, 4 eq.). White solid (94 mg, 50%). H NMR (400 MHz, D2O, δ): 1.42 (d, J = 13.0 Hz, 1H),
1.56 (s, 9H) 1.90 (d, J = 13.0 Hz, 1H), 2.12ꢀ2.29 (m, 1H), 2.30ꢀ2.62 (m, 5H), 2.83ꢀ3.21 (m, 7H), 3.49 (t,
J = 11.2 Hz, 1H), 3.64 (d, J = 12.7 Hz, 1H), 3.81 (t, J = 11.2 Hz, 1H), 3.91ꢀ4.10 (m, 3H), 4.30ꢀ4.49 (m,
2H), 4.67 (d, J = 15.6 Hz, 1H).
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8a-(4-cyanobenzyl)decahydro-1H-2a,4a,6a,8a-tetraazacyclopenta[fg]acenaphthylen-8a-ium bromide
(7): From cisꢀ13ꢀ1,4,7,10ꢀ tetraazatetracyclo[5.5.1.04,14010,13]tetradecane (100 mg, 0.515 mmol, 1 eq.)
and 4ꢀcyanobenzylbromide (101 mg, 0.515 mmol, 1 eq.). White solid (178 mg, 89%). From cisꢀ13ꢀ
1,4,7,10ꢀ tetraazatetracyclo[5.5.1.04,14010,13]tetradecane (100 mg, 0.515 mmol, 1 eq.) and 4ꢀ
cyanobenzylbromide (404 mg, 2.06 mmol, 4 eq.) White solid (135 mg, 72%). 1H NMR (400 MHz, D2O,
δ): 2.45ꢀ2.62 (m, 2H), 2.73ꢀ2.98 (br m, 4H), 3.05ꢀ3.35 (br m, 5H), 3.43ꢀ3.65 (m, 4H), 3.77 (d, J = 1.8
Hz, 1H), 4.06 (d, J = 1.8 Hz, 1H), 4.13ꢀ4.29 (m, 1H), 4.74 (d, J = 13.5 Hz, 1H), 4.99 (d, J = 13.5 Hz,
13
1H), 7.76 (d, J = 8.2 Hz, 2H), 7.91 (d, J = 8.2 Hz, 2H) C{1H}ꢀNMR (100 MHz, D2O, δ): 43.7, 47.5,
47.6, 48.2, 48.2, 51.3, 57.1, 60.6, 61.5, 71.6, 83.1, 113.8, 118.6, 132.0, 133.1, 133.5. HRMS: calc. for
+
C18H24N5 : 310.2026; found: 310.2022. Elemental analysis calc. for C18H24BrN5: C, 55.39; H, 6.20; N,
17.94%; found: C, 55.18; H, 6.04; N, 17.73. m.p. 200–202 °C.
8aꢀ(4ꢀnitrobenzyl)decahydroꢀ1Hꢀ2a,4a,6a,8aꢀtetraazacyclopenta[fg]acenaphthylenꢀ8aꢀium
bromide
cisꢀ13ꢀ1,4,7,10ꢀ
(8),
first
reported
by
Rohovec
et
al.42:
From
tetraazatetracyclo[5.5.1.04,14010,13]tetradecane (100 mg, 0.515 mmol, 1 eq.) and 4ꢀnitrobenzylbromide
(111 mg, 0.515 mmol, 1 eq.). White solid, obtained in 10:1 mixture with 20 (138 mg, 65%). From cisꢀ
13ꢀ1,4,7,10ꢀtetraazatetracyclo[5.5.1.04,14010,13] tetradecane (100 mg, 0.515 mmol, 1 eq.) and 4ꢀ
nitrobenzylbromide (445 mg, 2.06 mmol, 4 eq.). White solid (175 mg, 89%). 1H NMR (400 MHz, D2O,
δ): 2.33ꢀ2.46 (m, 2H), 2.59ꢀ2.73 (br m, 3H), 2.74ꢀ2.84 (m, 1H), 2.94ꢀ4.03 (m, 1H), 3.10ꢀ3.22 (m, 3H),
3.28ꢀ3.39 (m, 1H), 3.40ꢀ3.59 (m, 4H), 3.65 (d, J = 2.3 Hz, 1H), 3.94 (d, J = 2.3 Hz, 2H), 4.03ꢀ4.13 (m,
1H), 4.88 (d, J = 13.5 Hz, 1H), 7.67 (d, J = 8.5 Hz, 2H), 8.2 (d, J = 8.5 Hz, 2H).
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8a-(4-methylbenzyl)decahydro-1H-2a,4a,6a,8a-tetraazacyclopenta[fg]acenaphthylen-8a-ium bromide
(9): From cisꢀ13ꢀ1,4,7,10ꢀtetraazatetracyclo[5.5.1.04,14010,13]tetradecane (100 mg, 0.515 mmol, 1 eq.)
and 4ꢀmethylbenzylbromide (95 mg, 0.515 mmol, 1 eq.). White solid, obtained in 5:1 mixture with 21
(153 mg, 78%). From cisꢀ13ꢀ1,4,7,10ꢀtetraazatetracyclo[5.5.1.04,14010,13]tetradecane (100 mg,
0.515 mmol, 1 eq.) and 4ꢀmethylbenzylbromide (380 mg, 2.06 mmol, 4 eq.). White solid, obtained in
6:1 mixture with 21 (152 mg, 77%).
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8a-benzyldecahydro-1H-2a,4a,6a,8a-tetraazacyclopenta[fg]acenaphthylen-8a-ium bromide (10):
From cisꢀ13ꢀ1,4,7,10ꢀtetraazatetracyclo[5.5.1.04,14010,13]tetradecane (100 mg, 0.515 mmol, 1 eq.) and
benzylbromide (88 mg, 0.515 mmol, 1 eq.). White solid, obtained in 17:1 mixture with 22 (149 mg,
79%). From cisꢀ13ꢀ1,4,7,10ꢀ tetraazatetracyclo[5.5.1.04,14010,13]tetradecane (100 mg, 0.515 mmol, 1 eq.)
and benzylbromide (352 mg, 2.06 mmol, 4 eq.). White solid, obtained in 8:1 mixture with 22 (128 mg,
72%).
8a-(3,5-dibromobenzyl)decahydro-1H-2a,4a,6a,8a-tetraazacyclopenta[fg]acenaphthylen-8a-ium
bromide (11): From cisꢀ13ꢀ1,4,7,10ꢀtetraazatetracyclo[5.5.1.04,14010,13]tetradecane (100 mg, 0.515 mmol,
1 eq.) and 1,3ꢀdibromoꢀ5ꢀ(bromomethyl)benzene (145 mg, 0.515 mmol, 1 eq.). White solid (162 mg,
60%). From cisꢀ13ꢀ1,4,7,10ꢀtetraazatetracyclo[5.5.1.04,14010,13]tetradecane (100 mg, 0.515 mmol, 1 eq.)
1
and 1,3ꢀdibromoꢀ5ꢀ(bromomethyl)benzene (580 mg, 2.06 mmol, 4 eq.). White solid (210 mg, 85%). H
NMR (400 MHz, D2O, δ): 2.42ꢀ2.56 (br m, 2H), 2.70ꢀ2.86 (m, 3H), 2.84ꢀ2.98 (br m, 1H), 3.00ꢀ3.18 (m,
2H), 3.20ꢀ3.34 (m, 3H), 3.40ꢀ3.51 (m, 1H), 3.51ꢀ3.64 (m, 3H), 3.71 (d, J = 2.5 Hz, 1H), 4.00 (d, J = 2.5
Hz, 1H), 4.08ꢀ4.20 (m, 1H), 4.63 (d, J = 13.4 Hz, 1H), 4.82 (d, J = 13.4 Hz, 1H), 7.71 (d, J = 1.6 Hz,
2H), 7.96 (t, J = 1.6 Hz, 1H); 13C{1H}ꢀNMR (100 MHz, D2O, δ): 43.7, 47.4, 47.6, 48.2, 48.2, 51.2,
+
57.1, 59.9, 61.4, 71.6, 83.0, 123.4, 130.4, 134.0, 136.6. HRMS: calc. for C17H23Br2N4 : 441.0284,
found: 441.0277. Elemental analysis calc. for C17H23Br3N4: C, 39.03; H, 4.43; N, 10.71; found: C,
39.01; H, 4.35; N, 10.66. m.p. dec. at 187 °C.
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8a-(2-(tert-butoxy)-2-oxoethyl)dodecahydro-2a,4a,6a,8a-tetraazacyclopenta[fg]acenaphthylene-8a-
ium bromide (12): From cisꢀ13ꢀ1,4,7,10ꢀtetraazatetracyclo[5.5.1.04,14010,13]ꢀtetradecane (100 mg,
0.515 mmol, 1 eq.) and tꢀbutyl bromoacetate (101 mg, 0.515 mmol, 1 eq.). White solid, obtained in 2:1
mixture with 24 (127 mg, 68%). From cisꢀ13ꢀ1,4,7,10ꢀtetraazatetracyclo[5.5.1.04,14010,13]tetradecane
(100 mg, 0.515 mmol, 1 eq.) and 4ꢀmethylbenzylbromide (380 mg, 2.06 mmol, 4 eq.). White solid, obꢀ
tained in 4:1 mixture with 24 (113 mg, 60%).
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5a,10a-bis-(4-methylbenzyl)tetradecahydro-3a,5a,8a,10a-tetraazapyrene-5a,10a-diium bromide (15),
first reported by Silversides et al.43: From cisꢀ3a,5a,8a,10aꢀtetraazaperhydropyrene (100 mg, 0.45 mmol,
1 eq.) and 4ꢀmethylbenzylbromide (333 mg, 1.8 mmol, 4 eq.). The crude solid was purified by washing
with chloroform to yield a white insoluble solid (253 mg, 95%). 1H NMR (400 MHz, D2O, δ): 1.87 (d, J
= 15.4 Hz, NꢀβꢀCH2, 2H), 2.14ꢀ2.32 (m, NꢀαꢀCH2, 2H), 2.37(s, Ar CH3, 6H), 2.81 (td, J = 3.5 Hz, J =
12.5 Hz, NꢀβꢀCH2, 2H,), 3.18 (d, J = 13.0 Hz, NꢀαꢀCH2, 4H), 3.34ꢀ3.59 (m, NꢀαꢀCH2, 2H), 3.63ꢀ3.77
(m, NꢀαꢀCH2, 4H), 3.72 (td, J = 4.0 Hz, J = 12.6 Hz, NꢀαꢀCH2, 2H), 4.34 (td, J = 5.5 Hz, J = 13.0 Hz, Nꢀ
αꢀCH2, 2H), 4.70 (d, J = 13.0 Hz, Ar CH2, 1H), 5.08 (s, CH, 2H), 5.22 (d, J = 13.0 Hz, Ar CH2, 2H),
7.37 (d, J = 7.8 Hz, Ar H, 4H), 7.46 (d, J = 7.8 Hz, Ar H, 4H).
3a,8a-dibenzyltetradecahydro-3a,5a,8a,10a-tetraazapyrene-3a,8a-diium bromide (16), first reported
by Weisman et al.40: From cisꢀ3a,5a,8a,10aꢀtetraazaperhydropyrene (100 mg, 0.45 mmol, 1 eq.) and
benzyl bromide (308 mg, 1.8 mmol, 4 eq.). White solid, obtained in a 1:2 mixture with 4. (127 mg,
50%)
4a,8a-bis-(4-cyanobenzyl)dodecahydro-2a,4a,6a,8a-tetraazacyclopenta[fg]acenaphthylene-4a,8a-
diium bromide (19): From cisꢀ13ꢀ1,4,7,10ꢀtetraazatetracyclo[5.5.1.04,14010,13]tetradecane (100 mg, 0.515
mmol, 1 eq.) and 4ꢀcyanobenzylbromide (404 mg, 2.06 mmol, 4 eq.). White solid, obtained in 1:8 mixꢀ
ture with 7 (262 mg, 87%).
4a,8a-bis-(4-nitrobenzyl)dodecahydro-2a,4a,6a,8a-tetraazacyclopenta[fg]acenaphthylene-4a,8a-
diium bromide (20): From cisꢀ13ꢀ1,4,7,10ꢀtetraazatetracyclo[5.5.1.04,14010,13]tetradecane (100 mg,
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0.515 mmol, 1 eq.) and 4ꢀnitrobenzylbromide (445 mg, 2.06 mmol, 4 eq.). White solid, obtained in 3:1
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mixture with 8 (310 mg, 96%).
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8
4a,8a-bis-(4- methylbenzyl)dodecahydro-2a,4a,6a,8a-tetraazacyclopenta[fg]acenaphthylene-4a,8a-
diium bromide (21): From cisꢀ13ꢀ1,4,7,10ꢀtetraazatetracyclo[5.5.1.04,14010,13]tetradecane (100 mg,
0.515 mmol, 1 eq.) and 4ꢀmethylbenzylbromide (381 mg, 2.06 mmol, 4 eq.). White solid (253 mg,
94%). 1H NMR (400 MHz, D2O, δ): 2.36 (s, 6H), 3.03ꢀ3.12 (br m, 2H), 3.37 (d, J = 7.0 Hz, 4H), 3.50ꢀ
3.66 (br m, 6H), 3.76ꢀ3.88 (m, 2H), 4.19ꢀ4.30 (m, 2H), 4.71 (d, J = 13.3 Hz, 2H), 4.88 (d, J = 13.3 Hz,
2H), 7.36 (d, J = 7.7 Hz, 4H), 7.45 (d, J = 7.7 Hz, 4H); 13C NMR (100 MHz, D2O, δ): 20.4, 42.8, 46.1,
54.8, 60.8, 60.9, 77.4, 123.1, 130.3, 132.2, 142.2. HRMS: calc. for C26H36N42+: 202.1465, found:
202.1473. Elemental analysis calc. for C26H36Br2N4.2H2O: C, 52.01; H, 6.71; N, 9.33; found: C, 51.98;
H, 6.65; N, 9.09. m.p. 182–185 °C.
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4a,8a-bis-benzyldodecahydro-2a,4a,6a,8a-tetraazacyclopenta[fg]acenaphthylene-4a,8a-diium
bro-
mide (22): From cisꢀ13ꢀ1,4,7,10ꢀtetraazatetracyclo[5.5.1.04,14010,13]tetradecane (100 mg, 0.515 mmol, 1
eq.) and benzylbromide (352 mg, 2.06 mmol, 4 eq.). White solid, obtained in 1:1 mixture with 10 (270
mg, 98%).
4a,8a-bis-(3,5-dibromobenzyl)dodecahydro-2a,4a,6a,8a-tetraazacyclopenta[fg]acenaphthylene-
4a,8a-diium bromide (23): From cisꢀ13ꢀ1,4,7,10ꢀtetraazatetracyclo[5.5.1.04,14010,13]tetradecane (100 mg,
0.515 mmol, 1 eq.) and 1,3ꢀdibromoꢀ5ꢀ(bromomethyl)benzene (677 mg, 2.06 mmol, 4 eq.). White solid,
obtained in 4:1 mixture with 11 (404 mg, 92%).
4a,8a-bis(2-(tert-butoxy)-2-oxoethyl)dodecahydro-2a,4a,6a,8a-
tetraazacyclopenta[fg]acenaphthylene-4a,8a-diium bromide (24), first reported by Oukhatar et al.55:
From cisꢀ13ꢀ1,4,7,10ꢀtetraazatetracyclo[5.5.1.04,14010,13]tetradecane (100 mg, 0.515 mmol, 1 eq.) and tꢀ
butyl bromoacetate (402 mg, 2.06 mmol, 4 eq.). White solid (260 mg, 86%). 1H NMR (400 MHz, D2O,
δ): 1.47 (s, 18H), 2.92ꢀ3.03 (m, 2H), 3.03 ꢀ3.16 (m, 2H), 3.36 (d, J = 13.9 Hz, 2H), 3.53ꢀ3.64 (m, 2H),
4.00ꢀ4.13 (m, 6H,), 4.17 ꢀ4.27 (m, 2H), 4.41 (d, J = 16.7 Hz, 2H), 4.51 (s, 2H), 4.64 (d, J = 16.7 Hz,
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2H). 13C NMR (100 MHz, D2O, δ): 27.1, 42.9, 47.0, 56.9, 57.2, 64.0, 79.1, 87.4, 163.3. HRMS: calc. for
C22H40N4O4 Br+: 503.2227, found: 503.2228. Elemental analysis calc. for C22H40Br2N4.O4.4H2O: C,
40.25; H, 7.37; N, 8.53; found: C, 40.77; H, 7.29; N, 8.75. m.p. 125ꢀ127 °C.
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4,11-bis(4-methylbenzyl)-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane (25), first reported by Silversides
et al.43: To a stirred solution of 5a,10aꢀbisꢀ(4ꢀmethylbenzyl)tetradecahydroꢀ3a,5a,8a,10aꢀtetraazapyreneꢀ
5a,10aꢀdiium bromide (15) (100 mg, 0.168 mmol) in ethanol (10 mL) was added slowly sodium boroꢀ
hydride (317 mg, 8.3 mmol) and the mixture was stirred for 30 min at r.t. before heated using microꢀ
wave irradiation at 100οC for 30 min. After cooling to r.t., water (10 mL) was added to decompose exꢀ
cess NaBH4 and solvents were removed under vacuum. Water (30 mL) was added to the residue, the soꢀ
lution was made basic by addition of excess of solid KOH (pH 14), and extracted with dichloromethane
(4 x 30 mL). Combined organic extracts were dried and solvent was removed to yield a white solid (139
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mg, 83%). H NMR (400 MHz, CDCl3, δ): 1.33ꢀ1.43 (m, 2H), 1.52ꢀ1.63 (m, 2H), 2.30 (s, 6H), 2.35ꢀ
2.37 (m, 8H), 2.46ꢀ2.51 (m, 3H) 2.8ꢀ2.9 (m, 2H), 3.15 (d, J = 13.5 Hz, 2H), 3.21 (d, J = 8.6 Hz, 2H),
3.74 (d, J = 13.5 Hz, 2H), 3.89ꢀ4.00 (m, 2H), 7.12 (d, J = 8.0 Hz, 4H), 7.23 (d, J = 8.0 Hz, 4H).
1,4,8,11-tetra azabicyclo [6.6.2]hexadecane (26), first reported by Weisman et al.41: A solution of 25
(200 mg, 0.46 mmol) in glacial acetic acid (20 mL) was added to a stirred suspension of 10% palladium
on carbon (25 mg) in glacial acetic acid (2 mL) and the reactor was flushed with nitrogen and hydrogen
before filling with hydrogen. The mixture was stirred at r.t. under 1 bar of hydrogen for 24 h. Then, the
reactor was flushed with nitrogen and the reaction mixture was filtered through a pad of Hyflo filtration
aid and washed with glacial acetic acid (3 x 15 mL). Solvents were removed under vacuum and the resiꢀ
due dried to yield a yellow oil (83 mg, 80%). 1H NMR (400 MHz, C6D6, δ): 1.11ꢀ1.23 (m, 2H), 1.40ꢀ
1.54 (m, 2H), 2.00ꢀ2.08 (m, 2H), 2.09ꢀ2.19 (m, 12H), 2.22 ꢀ2.30 (m, 2H), 2.40ꢀ2.56 (m, 6H), 2.72ꢀ2.86
(m, 4H), 2.13ꢀ2.26 (m, 2H), 3.55 (br s, 2H).
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Corresponding Author
*Email: S.J.Archibald@Hull.ac.uk. Tel +44 (0)1482 465488
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ACKNOWLEDGMENT
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The authors would like to thank Carol Kennedy for carrying out CHN analyses. We gratefully
acknowledge Yorkshire Cancer Research (Grant: HEND376) and the Daisy Appeal Charity (Grant: DAꢀ
hul0211) for funding and the University of Hull for support of the PET Research Centre. We thank Dr
Assem Allam for his generous donation and ongoing support to the PET Research Centre at the Univerꢀ
sity of Hull. The authors also wish to thank the EPSRC National Mass Spectrometry Service at
Swansea.
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ASSOCIATED CONTENT
Supporting Information: NMR spectra and crystallographic data. This material is available free of
charge via the internet at http://pubs.acs.org.
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