Linear and macrocyclic ligands containing alternating pyridine and imidazolidin-2-one units

Article abstract of DOI:10.1039/a707131k

Linear oligomers of alternating 2,6-disubstituted pyridine (P) and N,N′-disubstituted imidazolidine-2-one (I) units have been made rapidly and in high yield with up to nine repeating units, terminating in either pyridine or imidazolidin-2-one units, or one of each. Synthetic methods include: (1) the sodium hydride-mediated condensation of N-(tert-butyl)imidazolidin-2-one with 2,6-difluoropyridine (F-P-F) or with higher analogues such as F-PIP-F, to give IPI, IPIPI and IPIPIPI. (The tert-butyl protection is readily and quantitatively removed with acid.) (2) The caesium fluoride catalysed interaction of N,N′-[dimethyl(1,1,3-trimethylpropyl)]-protected IPI with Bu^t-IP-F sequentially leads firstly to IPIPIPI which by the same method reacts with F-P-F to give F-PIPIPIPIP-F. (3) F-P-F also reacts with 1,2-ethylenediamine (E) sequentially to give F-PEP-F, EPEPE and F-PEPEPEP-F while similar reactions starting from F-PIP-F give EPIPE and F-PEPIPEP-F in sequence. Alternative routes examined include: (1) the interaction of F-P-F with imidazole to give 2,6-bis(imidazol-1-yl)pyridine and salts therefrom followed by (unsuccessful) oxidation. (2) The reaction of 2,6-diaminopyridine with 2-chloroethyl isocyanate followed by cyclisation to give IPI. (3) The interaction of 2,6-diaminopyridine with oxalate esters (O) to give OPO or H₂N-POP-NH₂, the latter of which was reduced to H₂N-PEP-NH₂. Cyclisation of the linear assemblies was not successful. However macrocyclic systems were made by linking two IPI units with two ethoxyethyl or with two ethoxyethoxyethyl units. Also two F-PIP-F units were similarly reacted to give polyether-linked macrocycles. Mono- and bis-prop-2-ynylated IPI derivatives were made but could not be cyclised. Attempts to cyclise ethylenediamine and oxamide based systems were also unsuccessful. The linear and macrocyclic ligands showed calcium selectivity in a study of their metal complexing abilities.

Full text of DOI:10.1039/a707131k

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Linear and macrocyclic ligands containing alternating pyridine and
imidazolidin-2-one units1
Otto Meth-Cohn* and Zegui Yan
Chemistry Department, Sunderland University, Sunderland, UK SR1 3SD
Linear oligomers of alternating 2,6-disubstituted pyridine (P) and N,NЈ-disubstituted imidazolidine-2-one
(I) units have been made rapidly and in high yield with up to nine repeating units, terminating in either
pyridine or imidazolidin-2-one units, or one of each. Synthetic methods include: (1) the sodium hydride-
mediated condensation of N-(tert-butyl)imidazolidin-2-one with 2,6-difluoropyridine (F-P-F) or with
higher analogues such as F-PIP-F, to give IPI, IPIPI and IPIPIPI. (The tert-butyl protection is readily and
quantitatively removed with acid.) (2) The caesium fluoride catalysed interaction of N,NЈ-[dimethyl-
(1,1,3-trimethylpropyl)]-protected IPI with But-IP-F sequentially leads firstly to IPIPIPI which by the
same method reacts with F-P-F to give F-PIPIPIPIP-F. (3) F-P-F also reacts with 1,2-ethylenediamine (E)
sequentially to give F-PEP-F, EPEPE and F-PEPEPEP-F while similar reactions starting from F-PIP-F
give EPIPE and F-PEPIPEP-F in sequence. Alternative routes examined include: (1) the interaction of
F-P-F with imidazole to give 2,6-bis(imidazol-1-yl)pyridine and salts therefrom followed by (unsuccessful)
oxidation. (2) The reaction of 2,6-diaminopyridine with 2-chloroethyl isocyanate followed by cyclisation
to give IPI. (3) The interaction of 2,6-diaminopyridine with oxalate esters (O) to give OPO or H2N-POP-
NH2, the latter of which was reduced to H2N-PEP-NH2.
Cyclisation of the linear assemblies was not successful. However macrocyclic systems were made
by linking two IPI units with two ethoxyethyl or with two ethoxyethoxyethyl units. Also two F-PIP-F
units were similarly reacted to give polyether-linked macrocycles. Mono- and bis-prop-2-ynylated IPI
derivatives were made but could not be cyclised. Attempts to cyclise ethylenediamine and oxamide based
systems were also unsuccessful. The linear and macrocyclic ligands showed calcium selectivity in a study
of their metal complexing abilities.
be effective calcium ligands. Kumars and co-workers6 and
Introduction
Parifer and co-workers7 have made imidazolidin-2-one based
macrocyclic systems with ether bridges, which show selective
binding, while Still and co-workers8 have incorporated
imidazolidin-2-one units into complex ligands, some of which
were homochiral and behave as hosts for imidazole and amino
acid amides. Nolte and co-workers9 have utilised bicyclic
imidazolidin-2-one units in the design of complex ligands
capable of binding alkali metal picrates.
Some years ago we published the first examples of synthetic
‘crown ureides’, that is systems in which a macrocycle contains
urea carbonyl functions as ligand units such as 1 and 2.2 The
compounds 1 and 2 proved to be particularly effective, and in
(CH2)n
N
N
N
N
We considered that the use of alternating 2,6-dihalopyridines
with imidazolidin-2-one units would allow a rapid, more simple
assembly of novel ligands for group II metal ions as well as
generating interesting systems containing two types of alternat-
ing ligand atoms. To this end we first explored the synthesis of
alternating pyridine–imidazolidin-2-one oligomers, secondly
we investigated methods for their macrocyclisation and finally
examined the ligand properties of the macrocycles.
Consideration of ring geometries suggest that a macrocycle 3
containing four units each of 2,6-disubstituted pyridine and
N,NЈ-disubstituted imidazolidin-2-one would be almost planar
and unstrained and preorganised for complexation (the sum of
the external angles would be ~415Њ) (Scheme 1). With this target
in mind, we first examined potential routes to such a system and
in particular to appropriate linear precursors.
O
O
(CH2)n
1
O
O
O
O
N
N
N
N
O
O
2
In order to simplify the nomenclature of such linear alternat-
ing systems we herein refer to the 2,6-disubstituted pyridine
system as ‘P’ and the N,NЈ-disubstituted imidazolidin-2-one
unit as ‘I’, and append terminal groups other than hydrogen.
We envisaged two alternative pyridine building blocks, namely
2,6-diamino- and 2,6-dihalo-pyridines. We did not consider the
de novo synthesis of a pyridine ring as deserving attention
as a short approach to our targets. N,NЈ-Disubstituted
imidazolidin-2-ones could be derived from the heterocycle itself
or a protected derivative, from a close analogue such as imid-
azole followed by functional manipulation, or from a urea or
some cases, very selective for calcium ions, giving stable crystal-
line complexes. Later, Cram and co-workers3 developed a num-
ber of designed crown ureides usually containing three ureides
alternating with aryl units, their synthesis requiring many steps,
but the ligand properties of which were of considerable interest.
Weber et al.4 and Shi and Thummel5 have reported an altern-
ative approach to compounds 1 and 2 and their analogues, and
other acyclic analogues have also been examined and shown to
* E-Mail: otto.meth-cohn@sunderland.ac.uk
J. Chem. Soc., Perkin Trans. 1, 1998
423

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N
N
NaH in THF
RT
+
HN
N
N
N
N
N
N
N
N
O
N
F
F
N
N
N
N
O
6
7 85%
(But-IP-F)
N
O
O
O
O
N
F
O
O
N
61.17°
N
5b
excess I
I
NaH in THF
42.74°
NaH in THF
NaH in THF
RT
N
∆
∆
N
N
N
N
N
3
N
N
N
N
N
Scheme 1
O
N
N
O
N
N
O
an ethylenediamine unit. The above nomenclature system also
utilises ‘E’ to imply an N,NЈ-disubstituted 1,2-diaminoethane
unit and ‘O’ to indicate an N,NЈ-disubstituted oxamide unit.
Each of these approaches have been explored, some having
merit depending upon the target intermediate, and will be dis-
cussed below in order based upon the starting 2,6-disubstituted
pyridine.
O
O
R
N
N
53% (But-IPI)
(But-IPI-But)
R
R
8a R = H
8b R = But,
9a R = But
9b R = H
81% (But-IPIPI-But)
(IPIPI)
99%
9c R = DMTS 88% (DMTS-IPIPI-DMTS)
Synthesis of linear assemblies based on halopyridines
N
N
N
N
1. Halopyridines and imidazolidin-2-ones. Since imidazolidin-
2-one is non-nucleophilic we first investigated the reaction of
cheap 2,6-dichloropyridine with imidazolidin-2-one in the
presence of sodium hydride in either THF or DMF. At
temperatures from ambient (no action) to 150 ЊC no effec-
tive pathway to simple products was found, polymers being
produced under forcing conditions. Thus after 5 days in reflux-
ing THF the mono- and di-substituted products 4a and 5a were
N
O
O
H
H
10 (IPI)
Scheme 2
N
N
N
N
N
F
N
NaH in THF
F-P-F, ∆
N
N
N
O
O
HN
N
N
N
HN
NH
N
N
N
O
O
N
O
O
10
X
X
X
F
4a X = Cl
b X = F
5a X = Cl
b X = F
11 57%
MH in THF
M = Na, 0%
M = K, 31%
7, ∆
isolated in 3 and 5%, respectively. The much more reactive 2,6-
difluoropyridine gave N,NЈ-bis(6-fluoropyridin-2-yl)imidazol-
idin-2-one 5b (F-PIP-F) in 83% yield after 20 h in refluxing
THF, so long as an excess of the pyridine was utilised.
N
N
N
We therefore next explored the use of protected imidazol-
idin-2-ones. 1-tert-Butylimidazolidin-2-one 6 is easily made on
a large scale by the sulfuric acid catalysed tert-butylation
of imidazolidin-2-one.10 Other workers have found that N,NЈ-
bis(trimethylsilyl)imidazolidin-2-one readily forms a polymer
with 2,6-difluoropyridine11 in the presence of caesium fluoride.
We examined both of these potentially useful approaches.
Reaction of the latter imidazolidin-2-one with 2,6-difluoro-
pyridine in DMF at 120 ЊC again gave F-PIP-F 5 in 79% yield.
However the tert-butylated imidazolidin-2-one proved a versa-
tile and key reagent, being crystalline and, unlike its parent,
very soluble, easily reacted and easily deprotected. Some typical
applications are shown in Scheme 2. The rapid assemblies of
But-IP-F 7, But-IPI 8a, But-IPI-But 8b and But-IPIPI-But 9a
were performed in high yields by interaction of 1-tert-butyl-
imidazolidin-2-one 6 with sodium hydride in THF and
subsequently a fluoropyridine. Deprotection of the latter two
systems proceeds in almost quantitative yield with refluxing
mineral acid to give IPI 10 and IPIPI 9b. Treatment of IPI 10
with an excess of 2,6-difluoropyridine and with NaH in THF
under reflux gives F-PIPIP-F 11 in 57% yield (Scheme 3).
However, the increasing insolubility and unreactivity of these
compounds as chain length increases made further progress
using this protocol less attractive for the higher members of
the series. Thus while the sodium hydride mediated reaction
N
N
N
N
N
N
O
O
O
O
N
N
12
7
NaH, DMF
100 °C
30%
N
N
N
NaH
N
N
7
+
O
O
THF, ∆
66%
F
N
F
N
F
Scheme 3
was no longer effective, we were able to make the heptamer,
But-IPIPIPI-But 12 in moderate yields by using the more
424
J. Chem. Soc., Perkin Trans. 1, 1998

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reactive KH instead of NaH in the coupling reaction or
alternatively by reacting two moles of mono-protected IPI
with 2,6-difluoropyridine (31%) (Scheme 3). Fortunately an
adaption of the above N-protected imidazolidin-2-one meth-
odology proved to be an excellent method for the higher
oligomers.
monosubstituted derivative, disubstitution being very difficult
to achieve.19 In practice, however, chloro- and bromo-pyridines
resulted in polymer formation, while 2,6-difluoropyridine
reacted with an excess of E in refluxing THF to give F-PE 16
in 62% yield. When two moles of 2,6-difluoropyridine were
reacted with one of E in the presence of triethylamine, F-PEP-F
17 was formed in 89% yield. This product was readily trans-
formed into EPEPE 18 with an excess of ethylenediamine,
which, without purification was further reacted with 2,6-
difluoropyridine to give the heptamer, F-PEPEPEP-F 19 in an
overall yield of 81% (Scheme 5). It is noteworthy that
oligomers terminating in E units tend to be viscous oils, not
easily purified except by chromatography, while those bearing
F-P termini are crystalline solids.
N-Silyl derivatives of amides are considerably less stable than
their O-silylated counterparts. However, the (1,1,3-trimethyl-
propyl)dimethylsilyl derivatives (herein referred to as DMTS
reagents) are excellent derivatives, capable of isolation, crystal-
lisation and chromatography.12 They were easily made by, for
example, reaction of IPI 10 with DMTS chloride and triethyl-
amine in 79% yield. This product 13, reacted readily with But-
IP-F 7 and a catalytic amount of caesium fluoride in DMF at
120 ЊC to give But-IPIPIPI-But 12 in 88% yield, which was
again quantitatively deprotected to give IPIPIPI 14. In a similar
manner, even the nonamer, F-PIPIPIPIP-F 15 was readily made
from silylated IPIPIPI 14 and an excess of 2,6-difluoropyridine
in 79% yield (Scheme 4). Indeed, given the need, this meth-
odology should allow higher members of such a series to be
readily assembled.
We also have made mixed systems containing ethylenedi-
amine and imidazolidin-2-one units in order to obtain crystal-
line products for optimal isolation and purification purposes.
Thus F-PIP-F 5 reacts successively with ethylenediamine, giv-
ing EPIPE 20 (in 92% yield) and then 2,6-difluoropyridine to
produce F-PEPIPEP-F 21 in 85% yield, both products being
crystalline solids (Scheme 6).
2. Halopyridines and ethanediamines. Because of the insolu-
bility of the oligomeric pyridine–imidazolidin-2-ones we envis-
aged that our ultimate goal may be better realised by linking
pyridines with 1,2-ethylenediamine units and only form the
imidazolidin-2-ones at a late stage. This approach would have
the added virtue of utilising a highly nucleophilic reagent allow-
ing easier synthetic manipulation, as well as yielding products
with greater flexibility for macrocyclisation. The ultimate
carbonylation of the oligomeric ethylenediamines to give
imidazolidin-2-ones is well documented in principle, using
phosgene,13 diethyl carbonate,14 urea,15 selenium catalysed
carbonylation with carbon monoxide16 and other methods by
way of thiocarbonyl groups.17
3. Halopyridines and imidazoles. One other route briefly
explored as a means to build linear assemblies relied upon the
considerable nucleophilicity of imidazole and its potential for
conversion into an imidazol-2-one. 2,6-Dichloropyridine has
been reported to react with neat imidazole at 190 ЊC to give
2,6-bis(imidazol-1-yl)pyridine 22 in 28% yield.20 Using 2,6-
difluoropyridine, we obtained the same product at 120 ЊC
in 80% yield, which gave the corresponding bis-benzyl imid-
azolium salt 23 on warming with benzyl chloride. Surprisingly,
unlike observations in the earlier reported reactions, irrespect-
ive of the ratio of the 2,6-difluoropyridine and imidazole, pre-
dominately the bis-substitution product 22 was isolated. The
pure monobenzyl salt 24 was formed in 83% yield if the reac-
tion was performed in ethyl acetate solution. However, attempts
to oxidise the salt 23 to give the corresponding imidazol-2-ones,
were not successful using alkaline hydrogen peroxide, sodium
perborate, sulfur and base, or sodium hydride and cupric chlor-
ide with oxygen.21 Similar failure was observed from metal-
Since the amine was nucleophilically reactive, the cheaper
chloro- and bromo-pyridines could possibly be utilised. Thus
2-bromopyridine reacts with ethylenediamine (‘E’ in our ter-
minology) to give PE in 60% yield18 while N,N-diisopropyl-
ethylenediamine reacts with 2,6-dichloropyridine to give the
N
N
N
N
N
N
N
N
N
N
N
O
O
O
O
N
7
O
O
Si
Si
DMF, 120 °C
CsF (cat)
N
N
13
N
N
12 88%
20% HCl
∆
N
N
N
N
N
N
N
N
O
O
O
N
N
N
N
N
N
O
O
F-P-F
DMF, 120 °C
N
N
O
O
N
CsF (cat)
O
N
N
N
N
N
F
F
NR
RN
a R = H 99%
b R = DMTS 85%
14
15 79%
Scheme 4
J. Chem. Soc., Perkin Trans. 1, 1998
425

View Article Online
rapid and efficient, giving the product in 78% yield. On the
E, THF
∆
other hand, in acetonitrile, a salt was formed, which we pre-
sume is the triazepinopyridine 29. The bis(chloroethylureido)-
pyridine 25 readily cyclised with sodium hydride to give IPI
10 in 78% yield (Scheme 7). It is worth noting that the 3- and 5-
N
H
N
F
F
N
F
H2N
16 62%
E, THF
NEt3, ∆
F
F
N
N
N
H
MeCN, H2O
E, Na2CO3
∆
H
imidazole
N
H
N
H
N
N
∆
N
N
HN
NH
F
N
N
N
F
17 89%
NH2
H2N
N
N
18
22 80%
F-P-F
Ph2CH2Cl
EtOAc
∆
Ph2CH2Cl
MeCN, H2O
Na2CO3
∆
∆
N
N
N
N
N
N
N
N
H
H
N
N
+
N
N
+
+
N
N
Ph
Ph
Ph
Cl–
2Cl–
HN
NH
24 83%
23 73%
Scheme 7
NH
HN
H’s of the pyridine ring of IPI 10 are non-equivalent, due we
believe, to considerable bond fixation of the two imidazolidino-
nyl units in opposite but coplanar geometries (Scheme 8).
Alkylation of the diaminopyridine with, for example, 1,2-
dibromoethane is fraught with potential problems of non-
chemoselectivity, mixture formation, polymerisation and for-
mation of elimination products. The literature reports that
2-aminopyridine reacts at 160–200 ЊC with diethyl oxalate to
give N,NЈ-di(2-pyridyl)oxamide24 while 2,6-diaminopyridine at
150 ЊC surprisingly is reported to give a 1,8-naphthyridine. On
the contrary, we found that the former reaction proceeded well
at ambient temperature and the latter gave the desired N,NЈ-
bis(6-aminopyridin-2-yl)oxamide 26 (referred to as H2N-POP-
NH2 in our nomenclature) in 37% yield. Reduction of this
product with borane in THF gave the corresponding N,NЈ-
bis(6-aminopyridin-2-yl)ethane-1,2-diamine 27 in high yield.
Furthermore, the use of an excess of dimethyl or diethyl oxalate
gave the bis(oxamido)pyridines 28a and 28b. No further chem-
istry was conducted with this series of precursors as a result
of their limited synthetic success compared to that of other
methods.
N
N
F
F
19 81%
Scheme 5
N
N
N
N
E
∆
N
N
N
N
O
O
HN
NH
F
F
H2N
NH2
5
20 92%
F-P-F
MeCN, H2O
Na2CO3
∆
N
N
N
N
O
HN
HN
Cyclisations of the linear assemblies
NH
NH
Attempted synthesis of the macrocycle 3. In principle, the
macrocycle 3 can be assembled from appropriate 7 ϩ 1, 6 ϩ 2,
5 ϩ 3 and 4 ϩ 4 units as well as by cyclisation of an 8 unit
assembly. Of the various potential precursors, symmetry
aspects would favour a 4 ϩ 4 reaction, though this precursor is
not easily assembled; precursors terminating in similar units
(i.e. totalling an odd number of units—7 ϩ 1 or 5 ϩ 3) are both
simpler to make and to interact. We therefore examined this
protocol in detail. Of the various modes of linkage examined
for the linear assemblies, the interaction of an N-[dimethyl-
(1,1,3-trimethylpropyl)silylated] (DMTS) imidazolidinone with
a 2-fluoropyridine under caesium fluoride catalysis proved
most effective for the higher oligomers. We therefore studied
the interaction of DMTS-IPIPIPI-DMTS 14 with 2,6-
difluoropyridine (7 ϩ 1) and DMTS-IPIPI-DMTS 9c with
F-PIP-F 5b (5 ϩ 3) both under high dilution conditions and
with caesium fluoride catalysis (the caesium ion could also act
as a template cation). The two reagents were added slowly
dropwise in DMF solution to caesium fluoride in DMF at
N
N
F
F
21 85%
Scheme 6
lation of the bis-imidazole 22 with butyllithium followed by
treatment with tert-butyl hydroperoxide.22
Synthesis of linear assemblies based on aminopyridines
The alternative, and much cheaper starting material for this
work was 2,6-diaminopyridine which was readily converted
into useful precursors to the desired oligomers. Reaction with
commercially available 2-chloroethyl isocyanate to give 2,6-bis-
[3-(2-chloroethyl)ureido]pyridine 25 in 30% yield has been
reported.23 We found that in THF solution, the reaction was
426
J. Chem. Soc., Perkin Trans. 1, 1998

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O
Cl
Cl
H
H
N
N
N
N
N
N
NH
HN
N
O
O
N
Cl
O
NCO
THF
H
H
25 78%
10 78%
BH3•SMe2
NaOMe
(CO2R)2
H2N
Cl
N
H2N
H2N
N
NH2
N
H2N
N
NH2
N
NHCOCONH
NHCH2CH2NH
26 37%
27 86%
NCO
MeCN
NaOR excess
(CO2R)2
Cl–
NH
Cl
N
N
+
RO2COCHN
N
NHCOCO2R
O
N
O
NH
29
28a R = Me 71%
28b R = Et 66%
Scheme 8
120 ЊC. Solubility considerations required the dropping funnel
to be maintained at 110–120 ЊC in the case of the 7 ϩ 1 reac-
tion. The major product apart from polymer was the nonameric
system F-PIPIPIPIP-F 15. Use of the better solvent, N-
methylpyrrolidone, allowed the solution of reagents to be
added at ambient temperature by way of a syringe pump. How-
ever, only polymer was obtained, as was also the case when the
reaction temperature was raised to 160 ЊC with addition over
two days. Similar problems were encountered with the more
soluble reagents, DMTS-IPIPI-DMTS 9c and F-PIP-F 5b. We
studied the energy difference between the ground state con-
formation (apparently helical; conformational NMR effects in
such compounds have already been briefly addressed earlier) of
F-PIP-F 5b and IPIPI 9b and that required for macrocyclisa-
tion, comparing the results with those for PPPPP. (It is already
well established that the macrocycle, ‘sexipyridine’ cannot be
made by cyclisation of linear precursors but requires an indirect
approach.25) Chem-X data suggests that F-PIP-F 5b and IPIPI
9b have energy differences of 7.8 and 15.0 kcal molϪ1, respect-
ively, compared to 12.7 kcal molϪ1 for that of PPPPP. Clearly,
the longer the precursor, the greater the energy difference and
since the two-step reaction from F-PIP-F 5b and IPIPI 9b
involves F-PIPIPIPI as the immediate potential precursor to
the formation of 1, the chance of such a cyclisation succeeding
is vanishingly small in the absence of a templating effect. We
have not found any effective templating metal ions that influ-
ence this process. We therefore decided to investigate the linkage
of our precursors via either alkynic units, well known in the
chemistry of annulenes, or polyether systems, or to build up
the imidazolidinone unit from ethylenediamine units after
macrocyclisation.
N
N
N
N
N
O
O
n
N
N
N
Cl
O
Cl
O
O
NaH, DMF
90 °C
N
H
N
H
O
O
n
n
10 IPI
Cl
Cl
30 n = 1 73%
31 n = 2 70%
IPI
NaH, DMF
100 °C
direct method
N
N
N
N
N
O
O
O
O
N
n
n
O
O
N
N
N
N
32 indirect 20%
direct 14%
33 indirect 36%
direct 22%
Polyether-linked macrocycles
IPI 10 was readily transformed into N,NЈ-substituted deriv-
atives containing either -(CH2)2O(CH2)2Cl [-EOE-Cl] 30 or
-(CH2)2[O(CH2)2]2Cl [-EOEOE-Cl] 31 functions in over 70%
yield by reaction with an excess of the appropriate dichloro-
alkyl ether and base. These compounds reacted well with
equimolar IPI 10 and sodium hydride in hot DMF under high
dilution to give the corresponding macrocycles (c-IPI-EOE-
IPI-EOE- 32 and c-IPI-EOEOE-IPI-EOEOE- 33, respectively)
in 20 and 36% yield, respectively (Scheme 9). The direct inter-
action of the dichloroalkyl ether with IPI 10 under the same
conditions gave the macrocycles in lower yields (14 and 22%,
respectively). Interestingly, the ether-linked system 33 in
Scheme 9
[2H6]DMSO solution suggests NMR evidence for a helical dis-
position of the imidazolidinone units since the pyridine β-
protons are non-equivalent.
The analogous series of macrocycles in which two PIP 10
units are linked by polyether groups were also easily assembled
utilising the interaction of di- and tri-ethylene glycol with
F-PIP-F 5b and K2CO3 in refluxing xylene either directly or
in a stepwise manner (Scheme 10). In this way c-PIP-OEOEO-
PIP-OEOEO- 35 (35% by the indirect route by way of 34)
J. Chem. Soc., Perkin Trans. 1, 1998
427

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N
N
N
N
N
N
N
N
N
N
O
Cl
N
N
N
N
O
O
O
O
O
O
O
H
NaH, DMF, 0 °C
O
diethylene glycol
8a But-IPI
39 88%
K2CO3, xylene, ∆
But-IPI
HO
Cu(OAc)2 ∆
pyridine, CH2Cl2
OH
34 74%
F-PIP-F
N
N
N
F
NaH, THF, ∆
N
O
But-IPI
F
N
N
40 87%
N
N
5 F-PIP-F
O
Scheme 12
O
O
O
problem, which is much greater with the deprotected analogues,
caused us to drop this stepwise approach. Furthermore,
attempted dimerisation of the diprop-2-ynylated IPI 37 with
copper acetate again gave solely polymeric material.
O
O
n
n
triethylene glycol
K2CO3, xylene, ∆
O
O
N
Ethylenediamine-linked macrocycles
N
F-PE 16, F-PEP-F 17, EPEPE 18, EPIPE 20, F-PEPEPEP-F 19
and F-PEPIPEP-F 21 were all made readily. Several different
approaches to macrocycles from these precursors were exam-
ined. Thus F-PE 16 was heated in DMF with KF or solid
K2CO3 at 130 ЊC without effect (we have already commented on
the greatly reduced reactivity of the 2-fluoro substituent when
a 6-amino group is also present). We therefore examined the
interaction of F-PIP-F 5b with EPIPE 20 under similar
conditions—again without any sign of reaction! Even in N-
methylpyrrolidone at 170 ЊC with the same catalysts no reaction
was observed. We therefore endeavoured to increase the activity
of the nucleophilic units by firstly adding KH to generate
potassium amide units. The potassium ions could well also
show some template benefit. Reaction at 170 ЊC led solely to
polymer. We next studied the interaction of F-PEP-F 17 with
imidazolidinone and with bis-DMTS-protected imidazolidin-
one. We noted in preliminary work that F-PEP-F 17 polymer-
ised on treatment with sodium hydride, so we were not sur-
prised that a similar result from interaction of F-PEP-F 17 and
imidazolidinone in the presence of NaH in DMF was observed.
Surprisingly, bis-DMTS-protected imidazolidinone remained
unchanged on heating with F-PEP-F 17 at 150 ЊC with CsF in
N-methylpyrrolidone, again attesting to the non-reactivity of
aminofluoropyridines. Similar non-reactivity was noted from
the interaction of F-PEP-F 17 and DMTS-IPI-DMTS 13. In
order to remove the deactivating effect of the amino units on
the aryl fluoride we reacted the N,NЈ-acetyl, -trifluoroacetyl
and toluene-4-sulfonyl derivatives of ethylenediamine with 2,6-
difluoropyridine in DMF at 100 ЊC as a model for the higher
analogues. Again the reaction was unsuccessful and this
approach was abandoned.
N
N
35 n = 1 35%
36 n = 2 11%
Scheme 10
and c-PIP-OEOEOEO-PIP-OEOEOEO- 36 [11% by the
direct approach; an intractable gluey intermediate (cf. 34)
resulted from the interaction of F-PIP-F 5 and triethylene
glycol].
Alkyne-linked macrocycles
Recent studies by Lehn and co-workers26 and others27 have
made the prospect of macrocyclisation by dimerisation of
N-prop-2-ynylated IPI 37 an attractive proposition. The
diprop-2-ynylated IPI 37 was readily synthesised by base-
catalysed prop-2-ynylation of IPI 10 in 86% yield (Scheme 11).
10 IPI
NaH, DMF, 20 °C
NaH,
DMF 0 °C
Cl
Cl
N
N
N
N
N
N
N
N
N
N
O
O
O
O
•
•
38 12%
37 86%
Cu(OAc)2
pyridine
CH2Cl2, ∆
Macrocyclisations based on aminopyridine precursors
H2N-POP-NH2 26 was treated with methyl oxalate and sodium
methylate under high dilution conditions. No reaction occurred
at ambient but a polymer formed under reflux conditions.
Similar problems were encountered when 2,6-bis(methox-
amido)pyridine was reacted with 2,6-diaminopyridine.
polymer
Scheme 11
When the reaction was conducted at 20 ЊC rather than 0 ЊC,
only a low yield of the isomeric allene 38 resulted. In a similar
manner the monoprotected IPI (But-IPI 8a) was prop-2-
ynylated to give the derivative 39 in 88% yield which could
be easily dimerised with copper acetate in 87% yield to give
the highly insoluble dimer 40 (Scheme 12). This insolubility
Complexation studies on the macrocyclic ligands 8, 9, 12 and 13
and their acyclic precursors
Reedijk et al.28 showed that imidazolidinone itself effectively
forms oxygen coordinated complexes with the divalent cations
of Mg, Mn, Co, Ni, Cu, Zn and Cd. Kiriakidou and Manessi-
428
J. Chem. Soc., Perkin Trans. 1, 1998

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Table 1 Dissolution test for some linear pyridine–imidazolidinone ligands compared to TDA-1a
Ligand
LiBr
NaBr
KBr
CsBr
MgBr2
CaBr2
SrBr2
BaI2
TDA-1
ϩϩ
ϩ
ϩ
ϩ
ϩ
ϩϩ
—
—
—
—
ϩϩ
—
—
—
—
ϩϩ
—
—
—
—
ϩϩ
ϩ
ϩ
ϩ
—
—
ϩϩ
ϩ
ϩ
ϩ
—
—
ϩϩ
ϩ
ϩ
ϩ
—
—
ϩϩ
ϩ
ϩ
ϩ
—
—
But-IP
But-IPI-But 8b
F-PIP-F 5b
But-IPIPI-But 9a
DMTS-IPIPIPI-DMTS 14b
ϩ
—
—
—
a ϩϩ indicates immediate change; ϩ indicates slow dissolution; — indicates no change.
Table 2 Extraction rates (%)a for some linear and cyclic pyridine–
Zoupa29 have shown that N,NЈ-bis(2-pyridyl)urea forms a 2:1
complex with nickel() nitrate. We have studied the complex-
ation of these compounds from several standpoints, namely
their ability to solubilise metal ions in organic solution,2b their
ability to extract ions, examined both by UV and NMR spec-
troscopic studies, and finally their ability to generate stable,
isolable complexes with metal ions. In each case we have com-
pared the macrocycle with related acyclic precursors that could
have similar ligand properties.
1. Solubilisation of metal ions in organic media. We have
reported elsewhere a simple ‘yes–no’ test for potential ligands2b
which involves the dissolution of a precipitated inorganic salt
(from a solution of a salt in methanol by dropwise addition of
toluene) by addition of the ligand. Although crude, this is a
rapid first indication of a potential ligand. In our current study,
this test requires ready solubilisation of the potential ligand in
methanol–toluene, which precludes the macrocyclic systems.
For comparison, we also examined TDA-1 [tris(3,6-dioxa-
heptyl)amine] and the results are collected in Table 1. TDA-1
is a general, but non-selective ligand, hence its use as a catalyst,
and is much more powerful than any of our acyclic ligands.
Interestingly, apart from lithium which complexes with all of
our systems, only the shorter ligand units were effective, no
doubt due to the large preference for a helical rather than
ligand-effective conformation. Also complexation was only
observed with the divalent cations, suggesting our ligand
groups were ‘hard’.
imidazolidin-2-one ligandsb
Ligand
Mg2ϩ
Ca2ϩ
Sr2ϩ
Ba2ϩ
But-IPI-But 8b
But-IPIPI-But 9a
But-IPIPIPI-But 12
Compound 30
Compound 31
Compound 32
Compound 33
Compound 34
Compound 35
Compound 36
—
—
—
2.9
2.2
3.3
3.1
2.5
20.6
38
47.1
11.8
37
ppt
ppt
19.3
—
—
—
—
—
—
—
—
—
—
ppt
ppt
—
ppt
ppt
ppt
insoluble insoluble insoluble insoluble
2.5 ppt ppt
—
a This percentage is the ion to ligand ratio in the chloroform solution.
b — indicates no extraction and ‘ppt’ indicates that a precipitate
formed.
was isolated while the larger ligand 9 gave both a calcium and a
barium 1:1 complex, indicative of a larger cavity. Although the
complexes analysed well (with chloroform of crystallisation)
they were unstable to crystallisation, precluding X-ray crys-
tallography. Complexation was also indicated by significant
melting point changes (reasonably sharp melting points were
observed for the complexes) and lowering of solid state infra-
red carbonyl absorptions (e.g. from 1707 to 1678–1690 cmϪ1).
Insolubility precluded ambient NMR measurements but at
120 ЊC not surprisingly the free ligand and its complex were
identical in [2H6]DMSO solution.
2. Extraction of metal ions into organic solvents. We examined
the rate of extraction of metal and ammonium picrates into
chloroform, following the process by UV spectrophotometry,
as described by Cram and co-workers.30 The picrates studied
Experimental
ϩ
included the following cations: NH4 , Liϩ, Naϩ, Kϩ, Rbϩ, Csϩ,
General conditions
Mg2ϩ, Ca2ϩ, Sr2ϩ, Ba2ϩ and Ag2ϩ. No univalent cations showed
any sign of picrate extraction. Furthermore the macrocyclic
ligands tended to cause precipitation, possibly of the liganded
metal picrate complex. However, the acyclic ligands proved
effective for magnesium and calcium cations with a strong pref-
erence for calcium ion extraction, as we have noted elsewhere2b
for ureido ligands (Table 2). Increased rates of extraction were
noted for ligands with a greater number of ureido groups. While
the cyclic ligands 8 and 9 containing four ureido ligands were
the best complexes for magnesium, the cyclic systems proved
less selective, and the slow rate of precipitate formation may
have also indicated a slow rate of complexation.
3. NMR spectroscopic studies of complexation with alkylam-
monium salts. In order to check whether the cyclic ligands were
capable of complexing alkylammonium salts we examined both
the extraction of the salt from D2O by a CDCl3 solution of the
potential ligand, as used by Timko and Cram31 and the NMR
titration method of Nolte and co-workers32 whereby the change
in chemical shift of a CDCl3–[2H6]DMSO solution of the lig-
and and of the salt were changed on making up 1:1, 1:2 and
2:1 mixtures. Essentially no complexation was evident with the
cyclic ligands.
Melting points were determined on either an Electrothermal
capillary or a Reichert Hot-stage Microscope melting point
apparatus and are uncorrected. Infrared spectra were recorded
on a UNICAM Research Series 1 FT-IR spectrophotometer as
liquid films or KBr discs, and ultra-violet spectra on a UNI-
CAM UV-2 spectrophotometer. NMR spectra were taken on a
JEOL GSX 270 MHz FT NMR spectrophotometer. Chemical
shifts are quoted to higher frequency of SiMe4 as internal
standard and are given in ppm, with coupling constants in Hz.
Elemental analyses and accurate mass spectra were con-
ducted at Newcastle University on a Carlo Erba 1106 Elem-
ental Analyser and a Kratos MS80RF mass spectrometer,
respectively. Silica gel TLC was performed on E. Merck plas-
tic plates coated with 0.2 mm silica 60 F254. Flash chrom-
atography was performed with Janssen or Merck silica gel,
particle size 35–70 mm.
Commercial reagents were normally used without further
purification. For air sensitive reactions, solid reagents were
dried over phosphorus pentoxide in a dessicator under reduced
pressure for one day prior to use; liquid reagents were dried
and distilled according to standard methods.33 Tetrahydrofuran
(THF) was freshly distilled from sodium benzophenone ketyl.
N,N-Dimethylformamide (DMF) was dried by stirring over
P2O5 for 24 h, followed by distillation. The fraction boiling at
153–155 ЊC was collected and kept over 4 Å molecular sieves in
the dark. Toluene and xylene were distilled with the first 10%
being discarded and the remainder collected and stored over
4. Isolation of metal complexes. In line with the above find-
ings, the interaction of a chalcogen thiocyanate salt in acetone
was mixed with a chloroform solution of the ligands indicated
in Table 2. Only the IPI-based macrocycles gave precipitates.
Thus from the smaller macrocycle 8 only a 1:1 calcium complex
J. Chem. Soc., Perkin Trans. 1, 1998
429

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4 Å molecular sieves. Chloroform, methanol and ethanol were
distilled from calcium hydride and stored over 3 Å molecular
sieves. Other solvents were purified by standard procedures as
necessary. Light petroleum refers to the fraction of boiling
range 60–80 ЊC, and ether implies diethyl ether. Sodium hydride
or potassium hydride was dispensed in oil, and was washed
three times with dried hexane prior to use. Reactions requiring
anhydrous conditions were performed in oven-dried apparatus
under nitrogen. Reaction solutions were dried using magnesium
sulfate (MgSO4ؒ1H2O).
extracted with chloroform using a Soxhlet apparatus, and the
extract evaporated and purified by chromatography if neces-
sary. Only one reaction gave non-polymeric products, con-
ducted as follows. To a stirred mixture of sodium hydride
(1.06 g, 50% in oil, 22 mmol) in THF (100 cm3) was added
imidazolidin-2-one (8.60 g, 10 mmol). The mixture was heated
under reflux for 0.5 h when 2,6-dichloropyridine (1.48 g, 10
mmol) was added and reflux continued until the dichloropyrid-
ine was minimal (~5 days). The solvent was removed and water
(~100 cm3) added and the solution neutralised with 2  hydro-
chloric acid. The precipitate was filtered and extracted with
chloroform in a Soxhlet apparatus and the evaporated extract
subjected to flash chromatography with dichloromethane–ethyl
acetate as eluent. Two products, 2-chloro-6-(2-oxoimidazolidin-
1-yl)pyridine 4a (0.06 g, 3%) and 2,6-bis(2-oxoimidazolidin-1-
yl)pyridinium chloride 10ؒHCl (0.10 g, 5%) were isolated.
1-tert-Butylimidazolidin-2-one 610
This is an adaption of the literature method.10 To a 500 cm3
three-necked flask equipped with a fast mechanical stirrer, a 200
cm3 dropping funnel and a thermometer and surrounded by an
ice-bath, was added sulfuric acid (98%, 75 cm3). Finely pow-
dered imidazolidin-2-one (60.0 g, 0.67 mol) was then added
slowly at such a rate that the temperature remained between 0–
15 ЊC, followed by the dropwise addition of tert-butyl alcohol
(125 cm3, 98.70 g, 1.33 mol) at 20–25 ЊC. After the addition was
complete, the mixture was stirred for 30 min, and then poured
with stirring into ~1.0 kg ice–water. The mixture was brought to
pH 6 by slow addition of a solution of 4  NaOH, while the
temperature was kept below 25 ЊC. The mixture was cooled to
15 ЊC (CAUTION: Na2SO4ؒ10H2O precipitates below this tem-
perature). The product, a colourless solid (17.0 g) was collected
by filtration. The filtrate was extracted with chloroform
(4 × 150 cm3) and the combined organic layers were dried and
evaporated under reduced pressure. The filtered product and
the extract were combined (62.0 g) and recrystallised from ethyl
acetate–light petroleum giving 1-tert-butylimidazolidin-2-one 6
as colourless plates (58.0 g, 61.5%), mp 138.5–139 ЊC (lit.,10 mp
135–136 ЊC).
2-Chloro-6-(2-oxoimidazolidin-1-yl)pyridine (IP-Cl) 4a.—
Mp 235–236 ЊC (Found: C, 48.9; H, 4.2; N, 21.0. C8H8N3ClO
requires C, 48.6; H, 4.1; N, 21.3%); νmax(KBr)/cmϪ1 3239 (NH),
1706 (C᎐O), 1591, 794 (Py); δ ([2H ]DMSO) 3.79 (2H, t, CH ),
᎐
H
6
2
3.95 (2H, t, CH2), 7.03 (1H, d, J 8.1, Py H ortho to Cl), 7.31 (1H,
br, NH), 7.72 (1H, t, J 8.1, Py-4-H), 8.14 (d, 1H, J 8.1, Py-5-H).
2,6-Bis(2-oxoimidazolidin-1-yl)pyridinium chloride (IPIؒHCl)
10ؒHCl.—Mp 183–184 ЊC (Found: C, 46.85; H, 5.1; N, 24.4.
C11H14N5ClO2 requires C, 46.6; H, 5.0; N, 24.7%); νmax(KBr)/
cmϪ1 3260 (NH), 1710 (C᎐O), 1579, 768 (Py); δ ([2H ]DMSO)
᎐
H
6
3.29 (6H, t, CH2), 3.73 (2H, t, CH2), 6.42 (1H, d, J 8.0, Py-3-H),
6.48 (1H, d, J 8.0, Py-5-H), 6.99 (1H, br, NH), 7.37 (1H, t, J 8.0,
Py-4-H), 7.45 (1H, br, NH), 8.21 (1H, br, PyNЈH).
2,6-Bis(3-tert-butyl-2-oxoimidazolidin-1-yl)pyridine But-IPI-But
8b
(1). To a stirred mixture of NaH (9.60 g, 50% in oil, 200
mmol) in THF (250 cm3) was added 1-tert-butylimidazolidin-
2-one 6 (25.56 g, 180 mmol) with gas evolution. Then 2,6-
difluoropyridine (9.20 g, 80 mol) was added and the mixture
was heated at reflux under N2 for 40 h. The mixture was then
concentrated to ~50 cm3 and ice–water (~200 g) was added. The
precipitate was filtered and recrystallised from ethyl acetate to
give But-IPI-But 8b as colourless plates (21.10 g, 73%), mp 248–
249 ЊC (sublimes above 240 ЊC) (Found: C, 63.5; H, 8.2; N, 19.4.
C19H29N5O2 requires C, 63.5; H, 8.1; N, 19.5%); νmax(KBr)/cmϪ1
1,3-Bis(trimethylsilyl)imidazolidin-2-one11
This is an adaption of the literature method.11 To a stirred mix-
ture of imidazolidin-2-one (3.30 g, 38 mmol) and hexamethyl-
disilazane (9.60 g, 50 mmol) was added 4 drops trimethylsilyl
chloride at ambient temperature. The mixture was heated to
110 ЊC for 6 h, and then cooled and distilled in vacuo on a
Kugelrohr apparatus. 1,3-Bis(trimethylsilyl)imidazolidin-2-one
was collected at 130 ЊC/0.01 mbar, which solidified as colourless
needles (7.40 g, 81%), mp 67–68 ЊC (lit.,11 mp 52–54 ЊC);
2974 (C–H, aliphatic), 1701 (C᎐O), 1583, 797 (Py); δ (CDCl )
᎐
νmax(KBr)/cmϪ1 2957 (C–H, aliphatic), 1655 (C᎐O); δ (CDCl )
H
3
᎐
1.35 (18H, s, But), 3.37 (4H, t, CH2), 3.81 (4H, t, CH2), 7.43
(1H, t, J 8.1, Py-4-H), 7.71 (2H, d, J 8.1, Py-3-H and Py-5-H).
(2). In a similar manner 2,6-bis(3-tert-butyl-2-oxoimidazol-
idin-1-yl)pyridine 8b could be obtained from 2,6-dichloropyr-
idine instead of 2,6-difluoropyridine in DMF (100 ЊC, 24 h)
in 52% yield together with 2-chloro-6-(3-tert-butyl-2-oxoimid-
azolidin-1-yl)pyridine (34%); δH(CDCl3) 1.42 (9H, s, But), 3.47
(2H, t, CH2), 3.91 (2H, t, CH2), 6.86 (1H, d, J 8.1, Py-3-H), 7.52
(1H, t, J 8.1, Py-4-H), 8.17 (1H, d, J 8.1, Py-5-H).
H
3
0.25 (18H, s, 6 × Me), 3.42 (4H, s, CH2).
1,3-Bis[dimethyl(1,1,3-trimethylpropyl)silyl]imidazolidin-2-one
To a stirred mixture of imidazolidin-2-one (2.20 g, 25 mmol)
and dimethyl(1,1,3-trimethylpropyl)silyl chloride (13.72 g, 75
mmol) in DMF (30 cm3) was added triethylamine (15.0 g,
150 mmol). The mixture was heated at 90 ЊC for 12 h. Most of
the solvent was removed under reduced pressure. The residue
was then distilled in vacuo on a Kugelrohr apparatus. Pure 1,3-
bis[dimethyl(1,1,3-trimethylpropyl)silyl]imidazolidin-2-one was
collected at 170 ЊC/0.1 mbar which solidified as colourless
crystals (6.90 g, 74%), mp 62–63 ЊC (Found: C, 61.5; H, 11.4;
N, 7.6. C19H42N2OSi2 requires C, 61.6; H, 11.4; N, 7.6%);
2,6-Bis(2-oxoimidazolidin-1-yl)pyridine 10 by hydrolysis of But-
IPI-But 8b
A mixture of But-IPI-But 8b (8.0 g, 22 mmol) in aqueous hydro-
chloric acid (20%, 80 cm3) was heated at reflux overnight. The
mixture was cooled and neutralised with 4  NaOH. The pre-
cipitate was filtered to give 2,6-bis(2-oxoimidazolidin-1-yl)-
pyridine 10 as colourless crystals from DMSO (5.40 g, 98%), mp
>320 ЊC (Found: C, 53.3; H, 5.4; N, 28.1. C11H13N5O2 requires
C, 53.4; H, 5.3; N, 28.3%); νmax(KBr)/cmϪ1 3257 (N–H), 1697
νmax(KBr)/cmϪ1 2959 (C–H, aliphatic), 1670 (C᎐O); δ (CDCl )
᎐
H
3
0.21 (12H, s, SiMe), 0.84 (12H, d, CHMe), 0.92 (12H, s, CMe),
1.52–1.67 (2H, m, CH), 3.38 (4H, s, CH2).
Synthesis of 2,6-bis(2-oxoimidazolidin-1-yl)pyridine (IPI) 10
The reaction of 2,6-dichloro- or 2,6-difluoro-pyridine with
imidazolidin-2-one. The reaction of 2,6-dichloropyridine (or
2,6-difluoropyridine) and imidazolidin-2-one with added
sodium hydride was performed under a variety of different
conditions (the use of DMF or THF as solvent, with temper-
atures from 60 to 150 ЊC and various molar ratios of reagents).
After completion of the reaction, the mixture was concen-
trated, poured into ice–water and neutralised with 2  hydro-
chloric acid. The resulting precipitate was filtered, the solid
(C᎐O), 1583, 790 (Py); δ ([2H ]DMSO, 120 ЊC) 3.50 (4H, t,
᎐
H
6
NHCH2), 4.11 (4H, t, CH2), 6.73 (2H, br, NH), 7.63 (1H, dd,
J 7.5 and 8.7, Py-4-H), 7.77 (1H, d, J 7.5, PyH), 7.78 (1H,
d, J 8.7, PyH).
1,3-Bis(6-fluoropyridin-2-yl)imidazolidin-2-one (F-PIP-F) 5b
(1). To a stirred mixture of NaH (5.28 g, 50% in oil, 110
mmol) in THF (80 cm3) was added imidazolidin-2-one (4.48 g,
430
J. Chem. Soc., Perkin Trans. 1, 1998

View Article Online
50 mmol) at ambient temperature. The mixture was heated at
reflux for 30 min and then 2,6-difluoropyridine (12.19 g, 110
mmol) was added. After 20 h, most of the solvent was removed
under reduced pressure and water (~500 cm3) was added to
precipitate a solid which was filtered and recrystallised from
ethyl acetate (effective for small amounts of product) or DMF
(better for large amounts of product) to give F-PIP-F 5b as
colourless plates (11.47 g, 83%), mp 267–268 ЊC (sublimes
above 200 ЊC, plates change slowly to needles) (Found: C, 56.4;
H, 3.6; N, 20.05. C13H10N4F2O requires C, 56.5; H, 5.65;
2-(2-Oxoimidazolidin-1-yl)-6-(3-tert-butyl-2-oxoimidazolidin-1-
yl)pyridine (But-IPI) 8a
But-IP-F 7 (6.50 g, 27 mmol) in DMF (80 cm3) was added
dropwise to a stirred solution of imidazolidin-2-one (5.80 g,
0.067 mol) and NaH (2.0 g, 60%, 50 mmol) in DMF (100 cm3)
at 100 ЊC over 1 h. After a further 8 h heating, the solvent was
removed under reduced pressure and water was added and the
precipitate filtered. Flash silica chromatography using ethyl
acetate–dichloromethane (from 10→30%) gave firstly But-
IPIPI-But 9a (2.90 g), and then But-IPI 8a which was recrystal-
lised from ethyl acetate as colourless crystals (4.80 g, 73%),
mp 267–268 ЊC (Found: C, 59.4; H, 6.8; N, 23.2. C15H21N5O2
requires C, 59.4; H, 7.0; N, 23.1%); νmax(KBr)/cmϪ1 3210 (N–
N, 20.28%); νmax(KBr)/cmϪ1 1714 (C᎐O), 1575, 797 (Py);
᎐
5
δH(CDCl3) 4.08 (4H, s, CH2), 6.52 (2H, dd, JHH 8.1, JHF 2.4,
Py-5-H), 7.68 (2H, q, J 8.1, Py-4-H), 8.10 (2H, dd, JHH 8.1,
5
4JHH 2.4, Py-3-H).
H), 2976 (C–H, aliphatic), 1701 (C᎐O), 1584, 804 (Py);
᎐
(2). F-PIP-F 5b was also obtained from 1,3-bis(trimethyl-
silyl)imidazolidin-2-one as follows. To a stirred mixture of 2,6-
difluoropyridine (4.60 g, 40 mmol) and 1,3-bis(trimethyl-
silyl)imidazolidin-2-one (2.40 g, 10 mmol) in DMF (50 cm3) at
110 ЊC was added a catalytic amount of caesium fluoride (~10
mg). After overnight heating at this temperature, the solvent
was removed under reduced pressure and water was added. Fil-
tration gave 1,3-bis(6-fluoropyridin-2-yl)imidazolidin-2-one 5b
(2.81 g, 79%).
δH(CDCl3) 1.43 (9H, s, But), 3.46 (2H, t, CH2), 3.52 (2H, t,
CH2), 3.89 (2H, t, CH2), 4.11 (2H, t, CH2), 5.13 (1H, br, NH),
7.56 (1H, t, J 8.1, Py-H), 7.77 (2H, d, J 8.1, Py-H), 7.83 (2H, d,
J 8.1, Py-H).
2,6-Bis[3-(6-fluoropyridin-2-yl)-2-oxoimidazolidin-1-yl]pyridine
(F-PIPIP-F) 11
To a stirred mixture of NaH (1.20 g, 50% in oil, 25 mmol) in
THF (80 cm3) was added IPI 10 (2.47 g, 10 mmol). The mixture
was heated at reflux for 1 h and then 2,6-difluoropyridine (2.79
g, 24 mmol) was added and heating under reflux continued.
After 40 h, the mixture was concentrated, water (~100 cm3) was
added and the precipitate was filtered and recrystallised from
DMF to give F-PIPIP-F 11 as colourless crystals (2.50 g,
57%), mp 318–319 ЊC (Found: C, 57.66; H, 3.92; N, 22.69.
C21H17N7F2O2 requires C, 57.67; H, 3.91; N, 22.41%);
νmax(KBr)/cmϪ1 1730, 1714 (C᎐O), 1586, 788 (Py); δ (TFA) 4.44
1-tert-Butyl-3-(6-fluoropyridin-2-yl)imidazolidin-2-one (But-IP-
F) 7
To a stirred mixture of NaH (2.64 g, 50% in oil, 55 mmol) in
THF (100 cm3) was added 1-tert-butylimidazolidin-2-one 6 (7.0
g, 50 mmol) with gas evolution. Then 2,6-difluoropyridine (6.80
g, 59 mmol) was added and the mixture was heated at reflux
under N2 for 20 h. The mixture was concentrated and water
(∼500 cm3) was added. The precipitate was filtered and
recrystallised from light petroleum to give But-IP-F 7 as colour-
less needles (10.80 g, 85%), mp 103–104 ЊC (Found: C, 60.65; H,
6.8; N, 17.65. C12H16N3FO requires C, 60.7; H, 6.80; N, 17.7%);
᎐
H
(4H, t, CH2), 4.51 (4H, t, CH2), 7.11 (2H, d, J 8.1, Py-H), 7.16
(2H, d, J 8.1, Py-5-H), 7.72 (2H, d, J 8.1, Py-3-H), 8.32 (2H, q,
J 8.1, Py-4-H), 8.49 (1H, t, J 8.1, Py-H).
νmax(KBr)/cmϪ1 2982 (C–H, aliphatic), 1692 (C᎐O), 1572, 801
2,6-Bis{3-[dimethyl(1,1,3-trimethylpropyl)silyl]-2-oxoimidazol-
idin-1-yl}pyridine (DMTS-IPI-DMTS) 13
᎐
(Py); δH(CDCl3) 1.43 (9H, s, But), 3.49 (2H, t, CH2), 3.89 (2H, t,
CH2), 6.45 (1H, dd, JHH 8.1, 5JHF 2.7, Py-5-H), 7.65 (1H, q, J 8.1,
Py-4-H), 8.11 (1H, dd, 5JHH 8.1, 3JHF 2.7, Py-3-H).
To a stirred mixture of IPI 10 (2.60 g, 10.5 mmol) and triethyl-
amine (5.0 g, 49.4 mmol) in DMF (50 cm3) was added dimethyl-
(1,1,3-trimethylpropyl)silyl chloride (5.36 g, 30.1 mmol) at
90 ЊC under nitrogen. The mixture was heated at 90 ЊC with
stirring for a further 16 h. The cooled solution was poured
into ice–water (~200 g) and the precipitate was collected
and recrystallised from ethyl acetate to give 2,6-bis{3-
[dimethyl(1,1,3-trimethylpropyl)silyl]-2-oxoimidazolidin-1-yl}-
pyridine 13 as colourless plates (4.40 g, 79%), mp 217–218 ЊC
(Found: C, 61.2; H, 9.5; N, 13.2. C27H49N5O2Si2 requires C,
61.0; H, 9.3; N, 13.2%); νmax(KBr)/cmϪ1 2959 (C–H, aliphatic),
1,3-Bis[6-(3-tert-butyl-2-oxoimidazolidin-1-yl)pyridin-2-yl]-
imidazolidin-2-one (But-IPIPI-But) 9a
(1). To a stirred mixture of NaH (3.20 g, 50% in oil, 66 mmol,
washed with hexane) in THF (150 cm3) was added 1-tert-
butylimidazolidin-2-one 6 (9.37 g, 66 mmol) at ambient tem-
perature with gas evolution. F-PIP-F 5b (8.28 g, 30 mmol) was
then added and the mixture heated at reflux for 48 h, most of
the solvent removed and water (~500 cm3) added. The precipi-
tate was filtered and recrystallised from toluene to give But-
IPIPI-But 9a as colourless crystals (12.60 g, 81%), mp 298–
299 ЊC (Found: C, 62.2; H, 7.1; N, 21.2. C27H36N8O3 requires C,
62.3; H, 7.0; N, 21.5%); νmax(KBr)/cmϪ1 2973 (C–H, aliphatic),
1690 (C᎐O), 1582, 801 (Py); δ (CDCl ) 0.29 (12H, s, SiMe),
᎐
H
3
0.82–0.85 (12H, d, CHMe), 0.92 (12H, s, CMe), 1.65 (2H, m,
CH), 3.43 (4H, t, CH2), 3.97 (4H, t, CH2), 7.46 (1H, t, J 8.1, Py-
4-H), 7.73 (2H, d, J 8.1, Py-3-H and Py-5-H).
1709 (C᎐O), 1584, 792 (Py); δ (CDCl ) 1.42 (18H, s, But), 3.45
᎐
H
3
(4H, t, CH2), 3.88 (4H, t, CH2), 4.02 (4H, s, CH2), 7.58 (2H, t, J
8.1, Py-H), 7.85 (2H, d, J 8.1, Py-H), 7.87 (2H, d, J 8.1, Py-H).
(2). Using similar conditions to those above, But-IPIPI-But
9a was also produced in 81% yield from the reaction of 2 mol of
compound 7 (But-IP-F) with 1 mol of imidazolidin-2-one.
2,6-Bis{3-[6-(3-tert-butyl-2-oxoimidazolidin-1-yl)pyridin-2-yl]-
2-oxoimidazolidin-1-yl}pyridine (But-IPIPIPI-But) 12
(1). To a stirred mixture of DMTS-IPI-DMTS 13 (4.26 g, 8
mmol) and But-IP-F 7 (4.18 g, 17.6 mmol) in DMF (100 cm3)
was added caesium fluoride (0.20 g, 1.3 mmol). The mixture
was heated at 110 ЊC for 48 h, cooled, and poured into water
(~500 cm3). The precipitate was filtered and recrystallised
from toluene to give But-IPIPIPI-But 12 as colourless crystals
(4.80 g, 88%), mp >320 ЊC (Found: C, 61.8; H, 6.1; N, 22.7.
C35H43N11O4 requires C, 61.7; H, 6.4; N, 22.6%); νmax(KBr)/
1,3-Bis[6-(2-oxoimidazolidin-1-yl)pyridin-2-yl]imidazolidin-2-
one (IPIPI) 9b
But-IPIPI-But 9a (4.10 g) in aqueous HCl (20%, 80 cm3) was
heated at reflux overnight. The mixture was cooled and neutral-
ised with 4  NaOH to give IPIPI 9b which was recrystallised
from aqueous TFA as a colourless solid (3.18 g, 99%), mp
320 ЊC (Found: C, 55.6; H, 4.9; N, 27.2. C19H20N8O3 requires C,
55.9; H, 4.9; N, 27.45%); νmax(KBr)/cmϪ1 3232 (N–H), 1697
cmϪ1 2969 (C–H, aliphatic), 1712 (C᎐O), 1585, 796 (Py);
᎐
δH(CDCl3) 1.44 (18H, s, But), 3.49 (4H, t, CH2), 3.94 (4H, t,
CH2), 4.14 (8H, s, CH2), 7.62 (2H, t, J 8.1, Py-γ-H), 7.69 (1H,
t, J 8.1, Py-γ-H), 7.88 (2H, d, J 8.1, Py-β-H), 7.92 (2H, d, J 8.1,
Py-β-H), 7.98 (2H, d, J 8.1, Py-β-H).
(C᎐O), 1586, 793 (C–H, Py); δ (TFA) 3.45 (4H, t, CH ), 3.78
᎐
H
2
(4H, t, CH2), 3.95 (4H, s, CH2), 6.48 (2H, d, J 8.1, Py-H), 6.51
(2H, d, J 8.1, Py-H), 7.90 (2H, t, J 8.1, Py-H).
(2). A mixture of IPI 10 (2.0 g, 8.1 mmol), But-IP-F 7 (4.20 g,
17.7 mmol) and NaH (0.80 g, 60%, 20 mmol) in THF (50 cm3)
J. Chem. Soc., Perkin Trans. 1, 1998
431

View Article Online
was heated at reflux for 24 h. TLC indicated no reaction.
Potassium hydride (2.30 g, 35%, 20 mmol) was then added. The
mixture was heated at reflux for a further two days, concen-
trated to 20 cm3 and poured into ice–water (~80 g). The precipi-
tate was filtered and separated through a silica flash chrom-
atography column with ethyl acetate–dichloromethane (v/v
15:85) as eluent. But-IPIPIPI-But 12 was obtained (1.70 g,
31%).
DMTS-IPIPIPI-DMTS 14b (85%), mp 285–288 ЊC (Found:
C, 60.6; H, 7.2; N, 18.3. C43H63N11O4Si2 requires C, 60.5; H, 7.4;
N, 18.0%); νmax(KBr)/cmϪ1 2960 (C–H, aliphatic), 1718, 1695
(C᎐O), 1583, 798 (Py); δ (CDCl ) 0.36 (12H, s, SiMe), 0.90
᎐
H
3
(12H, d, CHMe), 0.98 (12H, s, CMe), 1.71 (2H, m, CH), 3.51
(4H, t, CH2), 4.05 (4H, t, CH2), 4.05 (8H, s, CH2), 7.59 (2H, t,
J 8.1, Py-γ-H), 7.65 (1H, t, J 8.1, Py-γ-H), 7.84 (2H, d, J 8.1, Py-
β-H), 7.87 (2H, d, J 8.1, Py-β-H), 7.94 (2H, d, J 8.1, Py-β-H).
The reaction of But-IPI 8a with 2,6-difluoropyridine—synthesis
of But-IPIP-F
2,6-Bis(3-{6-[3-(6-fluoropyridin-2-yl)-2-oxoimidazolidin-1-yl]-
pyridin-2-yl}-2-oxoimidazolidin-1-yl)pyridine (F-PIPIPIPIP-F)
15
A mixture of But-IPI 8a (4.62 g, 15 mmol), 2.6-difluoropyridine
(0.88 g, 7.5 mmol) and sodium hydride (0.80 g, 60%, 20 mmol)
in THF (100 cm3) was heated at reflux for 40 h. Most of the
solvent was removed and ice–water (~80 g) was added. The
resulting solid was filtered and separated through silica flash
chromatography with ethyl acetate–dichloromethane (v/v
10:90→30:70) as eluent to give firstly But-IPIP-F (3.80 g,
66%), mp 178–179 ЊC (Found: C, 60.2; H, 6.0; N, 21.2.
C20H23N6FO2 requires C, 60.3; H, 5.8; N, 21.1%); νmax(KBr)/
To a stirred mixture of DMTS-IPIPIPI-DMTS 14b (0.48 g, 0.5
mmol) and 2,6-difluoropyridine (0.13 g, 1.1 mmol) in DMF (100
cm3) at 110–120 ЊC was added caesium fluoride (~10 mg). The
reaction mixture was heated at this temperature for a further 24
h, the solvent was removed under reduced pressure, and water
(~30 cm3) added and the precipitate filtered. Recrystallisation
from DMF gave F-PIPIPIPIP-F 15 as very fine colourless crys-
tals (0.58 g, 79%), mp >320 ЊC (Found: C, 58.4; H, 4.2; N, 24.0.
C37H31N13F2O4 requires C, 58.5; H, 4.1; N, 24.0%); νmax(KBr)/
cmϪ1 2978 (C–H, aliphatic), 1709 (C᎐O), 1585, 792 (Py);
᎐
δH(CDCl3) 1.44 (9H, s, But), 3.48 (2H, t, CH2), 3.91 (2H, t,
CH2), 4.10 (4H, m, CH2), 6.56 (1H, dd, JHH 8.1, JHF 2.7, Py-H,
α to F), 7.58–7.64 (t, 1H, J 8.1, Py-H), 7.73 (1H, q, J 8.1, Py-H
α to F), 7.83 (1H, d, J 8.1, Py-H), 7.92 (1H, d, J 8.1, Py-H), 8.20
(1H, dd, JHH 8.1, JHH 2.7, Py-H γ to F). This was followed by
But-IPIPIPI-But 12 (0.40 g, 7.8%) and starting material, But-IPI
(1.0 g).
cmϪ1 1720 (C᎐O), 1583, 798 (Py); δ (TFA) 3.86 (4H, t, CH ),
᎐
H
2
4.06 (4H, t, CH2), 4.35 (8H, s, CH2), 6.73 (2H, d, J 8.1, mid-Py-
H), 6.84 (2H, d, J 8.1, Py-H), 7.02 (2H, d, J 8.1, Py-H), 7.19
(2H, d,† J 8.1, Py-H), 7.42 (2H, d,† J 8.1, Py-H), 7.70 (2H,
2 × d,† J 8.1, Py-β-H), 8.22–8.39 (3H, m, mid-Py-γ-H); m/z (EI)
759.
N,NЈ-Bis(6-fluoropyridin-2-yl)ethane-1,2-diamine (F-PEP-F) 17
To a stirred mixture of 1,2-ethylenediamine (2.10 g, 35 mmol)
and triethylamine (10.10 g, 100 mmol) in THF (30 cm3) at 55 ЊC
was added 2,6-difluoropyridine (8.60 g, 75 mmol) and the mix-
ture heated at this temperature for a further 14 h. Solvent was
removed, water (~30 cm3) added and the resulting precipitate
filtered and washed with water to give N,NЈ-bis(6-fluoropyridin-
2-yl)ethane-1,2-diamine 17 which was recrystallised from tolu-
ene as colourless plates (7.78 g, 89%), mp 170–171 ЊC (Found:
C, 57.6; H, 4.8; N, 22.4. C12H12N4F2 requires C, 57.6; H, 4.8; N,
22.4%); νmax(KBr)/cmϪ1 3282 (N–H), 1586, 771 (Py); δH(CDCl3,
55 ЊC) 3.55 (4H, s, CH2), 4.50 (2H, br, NH), 6.12 (2H, dd, 5JHH
8.1, 4JHH 2.4, Py-3-H), 6.22 (2H, dd, 5JHH 8.1, 5JHF 2.4, Py-5-H),
7.42 (2H, q, J 8.1, Py-4-H).
The reaction of But-IPI 8a with But-IPIP-F to give But-IPIPIPI-
But 12
A mixture of But-IPIP-F (2.70 g, 7.0 mmol), But-IPI 8a (2.12 g,
7.0 mmol) and sodium hydride (0.80 g, 60%, 20 mmol) in DMF
(100 cm3) was heated at 100 ЊC overnight. Most of the solvent
was removed under reduced pressure and ice–water (~80 g) was
added. Filtration gave a solid which was separated through sil-
ica flash chromatography with ethyl acetate–dichloromethane
(v/v 10:90—30:70) as eluent to give But-IPIPIPI-But 12 (1.30 g,
30%).
2,6-Bis{3-[6-(2-oxoimidazolidin-1-yl)pyridin-2-yl]-2-oxoimid-
azolidin-1-yl}pyridine (IPIPIPI) 14a
A mixture of But-IPIPIPI-But 12 in aqueous HCl (20%, 80 cm3)
was heated at 80 ЊC overnight. The cooled solution was neutral-
ised with aqueous NaOH (4 ) to give IPIPIPI 14 as a colour-
less solid (99%), mp >350 ЊC; νmax(KBr)/cmϪ1 3297 (N–H), 1714
N-(6-Fluoropyridin-2-yl)ethane-1,2-diamine (F-PE) 16
2,6-Difluoropyridine (4.60 g, 0.04 mmol) and 1,2-ethylene-
diamine (7.0 g, 116 mmol) in THF (20 cm3) were stirred at 45 ЊC
overnight. The mixture was filtered and the filtrate was con-
centrated under reduced pressure. Aqueous sodium hydroxide
(2 , 30 cm3) was added and the mixture was extracted with
dichloromethane. The combined organic layer was dried with
magnesium sulfate, filtered, the solvent removed and the
residue separated by flash chromatography using ethyl acetate
and ethyl acetate–methanol (v/v, 1:1) as eluent. F-PEP-F
17 was obtained as colourless crystals (0.30 g, 6%), followed
by N-(6-fluoropyridin-2-yl)ethane-1,2-diamine 16 as a colour-
less viscous liquid (3.80 g, 62%), δH(CDCl3) 2.88 (2H, t,
NH2CH2), 2.90 (2H, br, NH2), 3.35 (2H, q, NHCH2), 5.80
(C᎐O), 1583, 798 (C–H, Py); δ (CDCl , 50 ЊC) 4.01 (4H, br,
᎐
H
3
CH2), 4.33 (4H, br, CH2), 4.53 (8H, br, CH2), 7.05 (4H, br, Py-
H), 7.32 (2H, br, Py-H), 8.45 (2H, br, Py-H), 8.54 (1H, br, Py-
H); m/z (EI) 569. This compound was not capable of ready
crystallisation and was thus used without further purification
and characterisation.
1,3-Bis(6-{3-[dimethyl(1,1,3-trimethylpropyl)silyl]-2-oxoimid-
azolidin-1-yl}pyridin-2-yl)imidazolidin-2-one (DMTS-IPIPI-
DMTS) 9c and 2,6-bis[3-(6-{3-[dimethyl(1,1,3-trimethylpropyl)-
silyl]-2-oxoimidazolidin-2-yl}pyridin-2-yl)-2-oxoimidazolidin-1-
yl]pyridine (DMTS-IPIPIPI-DMTS) 14b
DMTS-IPIPI-DMTS 9c and DMTS-IPIPIPI-DMTS 14b were
synthesised from IPIPI 9b and IPIPIPI 14a respectively, utilis-
ing the same method used for the synthesis of DMTS-IPI-
DMTS 13 and were recrystallised from ethyl acetate as colour-
less crystals.
5
4
(1H, br, NH), 6.07 (1H, dd, JHH 8.1, JHH 2.4, Py-3-H), 6.23
(1H, dd, 5JHH 8.1, 5JHF 2.4, Py-5-H), 7.40 (1H, q, J 8.1, Py-4-H);
m/z (EI) 155.
N,NЈ-Bis[6-(2-aminoethylamino)pyridin-2-yl]ethane-1,2-diamine
(EPEPE) 18 and N,NЈ-bis(6-{2-[(6-fluoropyridin-2-yl)amino]-
ethylamino}pyridin-2-yl)ethane-1,2-diamine (F-PEPEPEP-F)
19
DMTS-IPIPI-DMTS 9c (86%), mp 270–273 ЊC (Found: C,
60.9; H, 7.9; N, 16.4. C35H56N8O3Si2 requires C, 60.7; H, 8.1; N,
16.2%); νmax(KBr)/cmϪ1 2960 (C–H, aliphatic), 1710, 1687
To a stirred suspension of sodium carbonate (3.20 g, 30 mmol)
(C᎐O), 1583, 804 (Py); δ (CDCl ) 0.36 (12H, s, SiMe), 0.90
in 1,2-ethylenediamine (50 cm3) was added PEP (2.0 g, 8 mmol).
᎐
H
3
(12H, d, CHMe), 0.98 (s, 12H, CMe), 1.71 (2H, m, CH), 3.51
(4H, t, CH2), 4.05 (4H, t, CH2), 4.07 (4H, s, CH2), 7.57 (2H, t, J
8.1, Py-H), 7.87 (2H, d, J 8.1, Py-H), 7.88 (d, 2H, J 8.1, Py-H).
† No H–F coupling evident probably due to hydrolysis of fluorides in
TFA solution.
432
J. Chem. Soc., Perkin Trans. 1, 1998

View Article Online
The mixture was heated under reflux overnight, the solvent
removed under reduced pressure and the residue vacuum dried.
To the residue {which contained EPEPE 18 δH([2H6]DMSO)
2.74 (4H, t, NH2CH2), 3.08 (br, NH2), 3.21 (4H, q, NH2CH2-
CH2), 3.36 (4H, s, mid-CH2), 5.66 (4H, d, J 8.1, Py-β-H), 5.95
(2H, br, NH), 6.05 (2H, br, NH), 7.08 (2H, t, J 8.1, Py-γ-H)}
was added acetonitrile (50 cm3), water (10 cm3), 2,6-
difluoropyridine (3.0 g, 26 mmol) and extra sodium carbonate
(1.6 g). The mixture was heated at reflux again for 10 h. The
solvent was removed and water (~30 cm3) added, and the mix-
ture was extracted with dichloromethane (4 × 30 cm3). The
combined organic layer was dried with magnesium sulfate, the
solvent removed and the residue separated by flash chrom-
atography with ethyl acetate as eluent. F-PEPEPEP-F 19 was
obtained as a brown glue which later solidified as low-melting,
dark crispy prisms (2.60 g, 81%) (Found: C, 59.8; H, 6.0; N,
27.1. C26H30N10F2 requires C, 60.0; H, 5.8; N, 26.9%);
νmax(KBr)/cmϪ1 3330 (N–H), 1568, 775 (Py); δH(CDCl3) 3.39
2,6-Bis(imidazol-1-yl)pyridine 22
A mixture of 2,6-difluoropyridine (1.50 g, 13 mmol) and
imidazole (4.40 g, 65 mmol) was heated to 90 ЊC with stirring
for 5 h and then at 120 ЊC for a further 30 h. The mixture was
cooled and water was added (~100 cm3). The precipitate was
filtered and recrystallised from ethyl acetate to give 2,6-
bis(imidazol-1-yl)pyridine 22 as colourless crystals (2.20 g,
80%), mp 150.5–151.5 ЊC (lit.,20 mp 152 ЊC); νmax(KBr)/cmϪ1
1604 (Im), 1588, 792 (Py); δH([2H6]DMSO, 50 ЊC) 7.14 (2H,
t, J 1.1, ᎐NCHCH of imidazole), 7.73 (2H, d, J 8.1, Py-H),
᎐
8.08 (2H, t, J 1.4, ᎐NCHCH of imidazole), 8.17 (1H, t, J 8.1,
᎐
Py-H), 8.70 (2H, br s, imidazole ᎐NCHN); δ (CDCl ) 7.23
᎐
H
3
(2H, t, J 1.4, ᎐NCHCH of imidazole), 7.28 (2H, d, J 8.1, Py-H),
᎐
7.26 (2H, t, J 1.4, ᎐NCHCH of imidazole), 7.94–7.80 (1H,
᎐
t, J 8.1, Py-H), 8.38 (2H, br s, imidazole ᎐NCHN).
᎐
Oxidation of 2,6-bis(imidazol-1-yl)pyridine 22
To a stirred mixture of 2,6-bis(imidazol-1-yl)pyridine 22
(2.11 g, 10 mmol) in THF (50 cm3) at room temperature was
added n-butyllithium (in hexane, 21 mmol) slowly through
a syringe under nitrogen. The mixture became dark-brown
and was stirred for a further 2 h, and then cooled with an
ice-bath and tert-butyl peroxide (3.30 g, 22 mmol) in THF
(20 cm3) was added dropwise to the mixture through a
pressure equalised-dropping funnel over 45 min. The mixture
was then stirred overnight at room temperature. 2,2Ј-
Thiodiethanol (2.3 cm3) and water (80 cm3) were added
(CAUTION: before proceeding further, negative tests with KI-
starch test paper are essential to ensure no peroxide remains).
The mixture was extracted with ether (3 × 50 cm3). The com-
bined organic layer was dried with magnesium sulfate, filtered
and the solvent was removed. Starting material (0.77 g) was
obtained.
5
(12H, s, CH2), 5.03 (6H, br, NH), 5.64 (2H, d, JHH 8.1, Py-β-
H), 5.66 (2H, d, 5JHH 8.1, Py-β-H), 6.01 (2H, dd, 5JHH 8.1, 3JHF
5
5
2.4, Py-H γ to F), 6.07 (2H, dd, JHH 8.1, JHF 2.4, Py-H α to
F), 7.11 (2H, t, J 8.1, Py-H), 7.30 (2H, q, J 8.1, Py-H β to F);
m/z (EI) 520.
1,3-Bis[6-(2-aminoethylamino)pyridin-2-yl]imidazolidin-2-one
(EPIPE) 20
To a stirred solution of 1,2-ethylenediamine (15 cm3) was
added F-PIP-F 5b (2.80 g, 10 mmol), the mixture was heated to
100 ЊC for 4 h, when the solvent was removed under reduced
pressure. Aqueous sodium hydroxide (2 , 15 cm3) was added
and the mixture stirred for a few minutes then extracted with
chloroform (4 × 50 cm3). The combined organic layer was dried
with magnesium sulfate and the solvent removed to give 1,3-
bis[6-(2-aminoethylamino)pyridin-2-yl]imidazolidin-2-one 20 as
a colourless glassy solid which could not be recrystallised (3.30
g, 92%), mp 120–125 ЊC; νmax(KBr)/cmϪ1 3363 (N–H), 1706
2,6-Bis(3-benzylimidazol-3-ium-1-yl)pyridine dichloride 23
A mixture of 2,6-bis(imidazol-1-yl)pyridine 22 (6.33 g, 30
mmol) and benzyl chloride (38.0 g, 300 mmol) was heated to
100 ЊC for 1 h. The excess of benzyl chloride was removed
under reduced pressure, the mixture cooled to ambient tem-
perature and ethanol (80 cm3) was added. After heating to
reflux, ethyl acetate was slowly added until precipitation just
occurred and the mixture slowly cooled. 2,6-Bis(3-benzyl-
imidazol-3-ium-1-yl)pyridine dichloride 23 was collected as col-
ourless crystals (10.10 g, 73%), mp >320 ЊC (Found: C, 64.65;
H, 5.1; N, 15.2. C25H23N5Cl2 requires C, 64.8; H, 5.0; N,
15.1%); νmax(KBr)/cmϪ1 1611 (Im), 1535, 811 (Py), 712 (Ph);
δH([2H6]DMSO, 50 ЊC) 5.66 (4H, s, benzyl CH2), 7.44 (10H, m,
(C᎐O), 1597, 782 (Py); δ (CDCl ) 1.52 (4H, br, NH ), 2.95
᎐
H
3
2
(4H, t, J 5.7, NH2CH2), 3.37 (4H, q, J 5.8, NHCH2), 4.08 (4H,
s, CH2), 4.69 (2H, t, NH), 6.09 (2H, d, J 8.1, Py-H), 7.41 (2H, t,
J 8.1, Py-H), 7.57 (2H, d, J 8.1, Py-H); δH([2H6]DMSO) 2.71
(4H, t, J 6.2, NH2CH2), 3.18 (4H, t, J 6.0, NHCH2), 3.22 (4H,
NH2 and NHCH2), 4.0 (4H, s, CH2), 6.11 (d, 2H, J 8.1, Py-H),
4.69 (2H, br, NH), 732 (2H, d, J 8.1, Py-H), 7.34 (2H, t, J 8.1,
Py-H)
1,3-Bis(6-{2-[(6-fluoropyridin-2-yl)amino]ethylamino}pyridin-2-
yl)imidazolidin-2-one (F-PEPIPEP-F) 21
To a stirred mixture of sodium carbonate (0.53 g, 5 mmol) in
MeCN–H2O (5:1, 60 cm3) was added EPIPE 20 (0.36 g, 1
mmol). The mixture was heated at 80 ЊC overnight. The
acetonitrile was removed under reduced pressure and water
(~20 cm3) was added. The mixture was extracted with di-
chloromethane (4 × 20 cm3). The combined organic layer was
dried with magnesium sulfate and filtered. Removal of solvent
gave F-PEPIPEP-F 21 which was recrystallised from ethyl
acetate as colourless crystals (0.45 g, 85%), mp 139–140 ЊC
(Found: C, 59.4; H, 5.2; N, 25.7. C27H28N10F2O requires C,
59.3; H, 5.2; N, 25.6%); νmax(KBr)/cmϪ1 3305 (N–H), 1706
Ph), 8.14 (2H, t, J 2.0, ᎐NϩCHCH of imidazole), 8.29 (2H,
᎐
d, J 8.1, Py-H), 8.56 (1H, t, J 8.1, Py-H), 8.88 (2H, t, J 2.0,
᎐NϩCHCH of imidazole), 11.55 (2H, br s, imidazole NϩCHN);
᎐
δH(D2O, 80 ЊC) 6.16 (4H, s, benzyl CH2), 8.11 (10H, br, Ph),
8.32 (2H, d, J 2.2, ᎐NϩCHCH of imidazole), 8.56 (2H, d, J 8.1,
᎐
Py-H), 8.88 (2H, d, J 2.2, ᎐NϩCHCH of imidazole), 9.03 (1H, t,
᎐
J 8.1, Py-H).
Oxidation of 2,6-bis(3-benzylimidazol-3-ium-1-yl)pyridine
dichloride 23
(1). To a stirred mixture of 2,6-bis(3-benzylimidazol-3-ium-
1-yl)pyridine dichloride (1.30 g, 2.8 mmol) in water (30 cm3) at
50 ЊC was added sodium perborate tetrahydrate (1.35 g, 8.4
mmol). The mixture was stirred for a further 18 h. 2,2Ј-Thio-
diethanol (1.0 cm3) was added (CAUTION: before proceeding
further negative tests with KI-starch test paper are essential to
ensure no peroxide remains). The mixture was extracted with
chloroform (3 × 20 cm3). The combined organic layer was dried
with magnesium sulfate, filtered and the solvent removed. A
sticky purple inseparable mixture (0.58 g) was obtained. Fol-
lowing the same procedure as above, but using hydrogen per-
oxide as oxidant with 2.5 mol equiv. of sodium hydroxide, a
similar result was observed.
(C᎐O), 1565, 777 (Py); δ (CDCl ) 3.34 (4H, t, J 4.3, CH ),
᎐
H
3
2
3.55 (4H, t, J 4.3, CH2), 4.08 (4H, s, CH2), 4.69 (2H, br, NH),
5
5.15 (2H, br, NH), 6.08 (2H, d, JHH 8.1, Py-H), 6.12 (2H,
5
3
5
dd, JHH 8.1, JHF 2.4, Py-H γ to F), 6.18 (2H, dd, JHH 8.1,
5JHF 2.4, Py-H α to F), 7.40 (2H, t, JHH 8.1, Py-H), 7.43
(2H, q, J 8.1, Py-H β to F), 7.57 (2H, d, JHH 8.1, Py-H);
δH([2H6]DMSO) 3.37 (8H, br s, CH2), 3.98 (4H, s, CH2), 6.04
5
3
5
(2H, dd, JHH 8.1, JHF 2.4, Py-H γ to F), 6.13 (2H, d, JHH
8.1, Py-H), 6.30 (2H, dd, 5JHH 8.1, 5JHF 2.4, Py-H α to F), 6.59
(2H, br, NH), 7.02 (2H, br, NH), 7.26 (2H, d, 5JHH 8.1, Py-H),
5
7.33 (2H, t, JHH 8.1, Py-H), 7.44 (2H, q, J 8.1, Py-H β to F);
m/z (ESϩ, MHϩ) 547.
J. Chem. Soc., Perkin Trans. 1, 1998
433

View Article Online
(2). A mixture of 2,6-bis(3-benzylimidazol-3-ium-1-yl)pyrid-
ine dichloride salt (1.16 g, 2.5 mmol), sulfur (0.16 g, 5.0 mmol)
and potassium carbonate in methanol (50 cm3) was heated
at reflux for one day. TLC indicated that no reaction had
occurred.
q, NHCH2), 3.77 (4H, t, ClCH2), 7.29 (2H, d, J 8.1, Py-β-H),
7.58–7.64 (t, 1H, J 8.1, Py-γ-H), 7.93–7.98 (2H, t, CH2NH),
9.22 (2H, s, Py-NH).
To a stirred mixture of NaH (0.96 g, 50% in oil, 20 mmol)
in THF (50 cm3) was added 2,6-bis[3-(2-chloroethyl)ureido]-
pyridine 25 (2.15 g, 6.7 mmol). The mixture was heated under
reflux for 40 h, the solvent removed under reduced pressure and
water added. The precipitate was filtered to give IPI 10 (1.30 g,
78%).
6-(Imidazol-1-yl)-2-(3-benzylimidazol-3-ium-1-yl)pyridine
chloride 24
The reaction of 2,6-bis(imidazol-1-yl)pyridine 22 (0.90 g, 4.3
mmol) and benzyl chloride (1.10 g, 8.7 mmol) in ethyl acetate
(30 cm3) at reflux for 40 h gave 6-(imidazol-1-yl)-2-(3-
benzylimidazol-3-ium-1-yl)pyridine chloride 24 as colourless
crystals (1.20 g, 83%) from ethyl acetate, mp 242–243 ЊC
(Found: C, 64.0; H, 4.85; N, 20.9. C18H16N5Cl requires C, 64.1;
H, 4.8; N, 20.8%); νmax(KBr)/cmϪ1 1614 (Im), 1536, 816 (Py),
709 (benzene); δH([2H6]DMSO, 50 ЊC) 5.62 (2H, s, benzyl CH2),
N,NЈ-Bis(6-aminopyridin-2-yl)oxamide (H2N-POP-NH2) 26.
In a 150 cm3 thoroughly dried two-necked flask equipped with
reflux condenser with calcium chloride guard-tube, a magnetic
stirrer and ice-bath, was added methanol (50 cm3) and clean
sodium pieces (1.20 g, 50 mmol). When all the sodium had
dissolved, 2,6-diaminopyridine (6.60 g, 60 mmol) was added
which dissolved slowly while being raised to ambient temper-
ature. Diethyl oxalate (2.92 g, 20 mmol) in methanol (20 cm3)
was added dropwise to the mixture with stirring and the stirring
was continued for a further hour after the addition was com-
plete. Hydrochloric acid (36%, 5 cm3) was added dropwise to
the mixture, most of the methanol removed under reduced
pressure at 35 ЊC and cold water (~50 cm3) was added. The
precipitate was filtered and washed with water and a little
methanol to give N,NЈ-bis(6-aminopyridin-2-yl)oxamide 26
which was collected as a grey solid (2.0 g, 37%). Recrystallisa-
tion was unsuccessful, mp >320 ЊC (Found: C, 52.7; H, 4.5; N,
31.0. C11H12N6O2 requires C, 52.9; H, 4.4; N, 30.9%); νmax(KBr)/
7.18 (1H, t, J 1.1, ᎐NCHCH of imidazole), 7.41–7.59 (5H, m,
᎐
Ph), 8.02 (1H, d, J 8.1, Py-3-H), 8.03 (1H, d, J 8.1, Py-5-H),
8.09 (1H, t, J 1.8, ᎐NCHCH of imidazole), 8.22 (1H, t, J 1.5,
᎐
᎐NϩCHCH of imidazole), 8.37 (1H, t, J 8.1, Py-4-H), 8.75 (2H,
᎐
t, J 2.0, ᎐NϩCHCH of imidazole), 8.85 (1H, br s, imidazole
᎐
NCHN), 10.78 (1H, br s, imidazole NϩCHN).
2-Fluoro-6-(imidazol-1-yl)pyridine
A mixture of 2,6-difluoropyridine (23.10 g, 200 mmol) and
imidazole (1.36 g, 20 mmol) was heated to 100 ЊC and stirred
for 3 h. The excess of 2,6-difluoropyridine was removed under
reduced pressure, the residue cooled and water added (50 cm3).
The precipitate was filtered and then added to light petroleum
(50 cm3). The mixture was then heated to reflux and filtered.
The insoluble solid which was recrystallised from ethyl acetate
and found to be 2,6-bis(imidazol-1-yl)pyridine (0.78 g, 38%).
Removal of the solvent from the filtrate gave 2-fluoro-6-
(imidazol-1-yl)pyridine (0.66 g, 20%) as colourless needles from
light petroleum, mp 80–81 ЊC (Found: C, 58.9; H, 3.7; N, 25.6.
C8H6N3F requires C, 58.9; H, 3.71; N, 25.75); νmax(KBr)/cmϪ1
cmϪ1 3371, 3202 (N–H), 1694 (C᎐O), 1573, 791 (Py);
᎐
δH([2H6]DMSO) 6.08 (4H, br, NH2), 6.33 (2H, d, J 8.1, Py-5-H),
7.23 (2H, d, J 8.1, Py-3-H), 7.50 (2H, t, J 8.1, Py-4-H), 9.30
(2H, br, NH); m/z (ESϩ, MHϩ) 273.
N,NЈ-Bis(6-aminopyridin-2-yl)ethane-1,2-diamine
(H2N-
PEP-NH2) 27. To a 150 cm3 two-necked round bottomed flask
equipped with a pressure equalised-dropping funnel, a con-
denser and magnetic stirrer, was added THF (50 cm3) and N,N-
bis(6-aminopyridin-2-yl)oxamide 26 (0.27 g, 1 mmol), and the
mixture heated to reflux. Boraneؒdimethyl sulfide (0.44 cm3,
0.44 mmol) in THF (20 cm3) was added dropwise through a
syringe to the mixture over 10 min. After stirring for a further
3 h at reflux, the solvent was removed, hydrochloric acid (3 ,
10 cm3) was added and the mixture was stirred at ambient tem-
perature for 10 min, neutralised with sodium hydroxide (5 ),
and extracted with ether (3 × 20 cm3). The combined organic
layer was dried with magnesium sulfate, filtered and evapor-
ated. The title compound 27 was obtained as a dark, crispy solid
(0.21 g, 86%), νmax(KBr)/cmϪ1 3354, 3230 (N–H), 1567, 813
(Py); δH(CDCl3) 3.35 (4H, s, CH2), 4.21 (4H, br, NH2), 4.80 (2H,
br, NH), 5.69 (2H, d, J 8.1, Py-5-H), 5.72 (2H, d, J 8.1, Py-3-H),
7.11 (2H, t, J 8.1, Py-4-H); m/z (EIϩ) 244.
1603 (Im), 1580, 793 (Py); δH([2H6]DMSO, 50 ЊC) 7.13 (1H, dd,
3
3JHH 8.1, JHF 2.4, Py-3-H), 7.13 (1H, t, J 1.2, ᎐NCHCH of
᎐
imidazole), 7.75 (1H, dd, 3JHH 8.1, 5JHF 2.4, Py-5-H), 7.90 (1H,
t, J 1.6, ᎐NCHCH of imidazole), 8.17 (1H, q, J 8.1, Py-4-H),
᎐
8.48 (br s, 2H, N᎐CHN).
᎐
Preparations based on 2,6-diaminopyridine
N,NЈ-Bis(pyridin-2-yl)oxamide (F-POP-F). In a 50 cm3 thor-
oughly dried two-necked flask equipped with reflux condenser,
calcium chloride guard-tube, a magnetic stirrer and an ice-bath,
was added methanol (15 cm3) and clean sodium pieces (0.69 g,
30 mmol). When all the sodium had dissolved, 2-aminopyridine
(1.88 g, 20 mmol) was added and the clear solution slowly
raised to ambient temperature. Diethyl oxalate (1.46 g, 10
mmol) in methanol (10 cm3) was added slowly through a drop-
ping funnel to the mixture with stirring, which was continued
for 1 h after the addition was complete. Hydrochloric acid
(36%, 2 cm3) was added dropwise to the mixture, most of the
methanol removed under reduced pressure at 35 ЊC and cold
water (~30 cm3) added. The precipitate was filtered and washed
with water and then a little methanol. The solid was recrystal-
lised from ethanol to give N,N-bis(pyridin-2-yl)oxamide as
colourless crystals (0.96 g, 40%), mp 161–162 ЊC (lit.,34 mp
161–162 ЊC).
2,6-Bis(methoxamido)pyridine 28a. In a 500 cm3 thoroughly
dried two-necked flask equipped with reflux condenser with
calcium chloride guard-tube, a magnetic stirrer and an ice-bath,
was added methanol (150 cm3) and clean sodium pieces (4.60 g,
200 mmol). When all the sodium had dissolved, 2,6-diamino-
pyridine (11.0 g, 100 mmol) was added and to the clear solution
dimethyl oxalate (47.27 g, 400 mmol) in methanol (100 cm3) was
added dropwise. The mixture was slowly raised to ambient
temperature and stirred for a further 2 h, cooled with an ice-
bath and aqueous hydrochloric acid (20%) was slowly added to
neutralise the mixture. Most of the methanol was removed
under reduced pressure at 35 ЊC, cold water (~100 cm3) added
and the precipitate filtered, washed with water, and then
recrystallised from methanol to give 2,6-bis(methoxamido)-
pyridine 28a as colourless crystals (20.10 g, 71%), mp 208–
209 ЊC (Found: C, 46.9; H, 3.9; N, 15.0. C11H11N3O6 requires
C, 47.0; H, 3.9; N, 14.9%); νmax(KBr)/cmϪ1 3396, 3330 (N–H),
2,6-Bis[3-(2-chloroethyl)ureido]pyridine 25 and its cyclis-
ation to IPI 10. 2-Chloroethyl isocyanate (17.10 g, 160 mmol)
was added dropwise to a stirred solution of 2,6-diamino-
pyridine (7.80 g, 71 mmol) in THF (50 cm3) at 0–5 ЊC, and the
mixture was stirred at ambient temperature overnight. The
solvent was removed under reduced pressure. The resulting
solid was recrystallised from ethanol to give 2,6-bis[3-(2-
chloroethyl)ureido]pyridine 25 as white plates (17.50 g, 78%),
mp 169–170 ЊC (lit.,23 mp 171–174 ЊC); νmax(KBr)/cmϪ1 3214
1735, 1711 (C᎐O), 1591, 801 (Py); δ (CDCl ) 4.0 (6H, s, Me),
᎐
H
3
7.85 (1H, t, J 8.1, Py-H), 8.06 (2H, d, J 8.1, Py-H), 9.22 (2H, s,
NH).
2,6-Bis(ethoxamido)pyridine 28b. Using the same method as
(N–H), 1690 (C᎐O), 1572, 793 (Py); δ ([2H ]DMSO) 3.57 (4H,
᎐
H
6
434
J. Chem. Soc., Perkin Trans. 1, 1998

View Article Online
above but replacing methyl oxalate with ethyl oxalate gave 2,6-
bis(ethoxamido)pyridine 28b as colourless crystals (20.40 g,
66%), mp 176–177 ЊC (Found: C, 50.4; H, 4.95; N, 13.7.
C13H15N3O6 requires C, 50.5; H, 4.9; N, 13.6%); νmax(KBr)/cmϪ1
8.7, Py-4-H), 7.67 (2H, d, J 7.5, Py-3-H), 7.68 (2H, d, J 8.7, Py-
5-H); m/z (ES, MHϩ) 723.
The direct approach to this product 33 performed as above
using 1,2-bis(2-chloroethoxy)ethane and IPI 10 gave a yield of
22%.
3402, 3331 (N–H), 1723, 1705 (C᎐O), 1590, 803 (Py);
᎐
δH(CDCl3) 1.44 (6H, t, MeCH2), 4.45 (4H, q, MeCH2), 7.84
(1H, t, J 8.1, Py-4-H), 8.04 (2H, d, J 8.1, Py-3-H and Py-5-H),
9.26 (2H, s, NH).
1,3-Bis{6-[2-(2-hydroxyethoxy)ethoxy]pyridin-2-yl}imidazol-
idin-2-one 34 and its macrocyclisation to give 35
To a flask fitted with a Dean and Stark water separator was
added F-PIP-F 5b (1.25 g, 4.5 mmol), diethylene glycol (4.80 g,
45 mmol), potassium carbonate (5.0 g, 36 mmol) and xylene (80
cm3) and the mixture was heated under reflux for 6 h. The solv-
ent was removed and water and dichloromethane added and the
organic layer was evaporated to give the title product 34 as
colourless crystals from light petroleum and ethyl acetate
(1.50 g, 74%), mp 76–77 ЊC (Found: C, 56.4; H, 6.35; N, 12.4.
C21H28N4O7 requires C, 56.2; H, 6.3; N, 12.5%); νmax(KBr)/cmϪ1
Macrocyclisations of chloroethoxyethyl derivatives
2,6-Bis{3-[2-(2-chloroethoxy)ethyl]-2-oxoimidazolidin-1-yl}-
pyridine 30 and its macrocyclisation to give 32. To a stirred
mixture of sodium hydride (0.40 g, 60% in oil, 10 mmol) in dry
DMF (50 cm3) was added IPI 5 (0.96 g, 3.9 mmol). The mixture
was heated at 110 ЊC for 30 min and cooled to ambient temper-
ature. Chloroethyl ether (5.6 g, 39 mmol) was added and the
mixture heated at 90 ЊC with stirring for 14 h, the solvent
removed under reduced pressure and water added. The pre-
cipitate was filtered dried and flash chromatographed using
ethyl acetate to give the title compound 30 as colourless crystals
(1.30 g, 73%), mp 102–103 ЊC (Found: C, 49.5; H, 6.0; N, 15.2.
C19H27Cl2N5O4 requires C, 49.7; H, 5.9; N, 15.25%); νmax(KBr)/
3417 (OH), 1712 (C᎐O), 1592, 784; δ (CDCl ) 2.28 (2H, br,
᎐
H
3
OH), 3.67 (4H, m, OCH2CH2OH), 3.78 (4H, m, OCH2-
CH2OH), 3.86 (4H, t, J 4.9, OCH2CH2OPy), 4.13 (8H, s,
NCH2CH2N), 4.44 (4H, t, J 4.9, PyOCH2CH2O), 6.46 (2H, d,
J 7.8, Py-3-H), 7.59 (2H, t, J 7.8, Py-4-H), 7.85 (2H, d, J 7.8,
Py-5-H).
cmϪ1 1699 (C᎐O), 1583, 794; δ (CDCl ) 3.51 (4H, t, J 5.1,
᎐
H
3
ClCH2), 3.63 (4H, t, J 8.1, NCH2CH2N), 3.64 (4H, t, J 5.1,
OCH2), 3.71 (4H, t, J 5.1, OCH2), 3.74 (4H, t, J 5.1, OCH2),
4.02 (4H, t, J 8.1, NCH2CH2N), 7.58 (1H, t, J 8.1, Py-4-H), 7.81
(2H, d, J 8.1, Py-3,5-H); m/z (EI) 459.
To a flask fitted with a Soxhlet extractor was added sodium
hydride (0.20 g, 60% in oil, 5 mmol) and dry THF (150 cm3). F-
PIP-F 5b (0.28 g, 1 mmol) was placed in the extractor and the
mixture heated to reflux. Through a syringe pump was added
the above compound 34 (0.45 g, 1 mmol) in THF (30 cm3) over
10 h and the mixture refluxed for a further 16 h. Removal of the
solvent and addition of water precipitated a solid which was
subjected to Soxhlet extraction with dichloromethane for 5 h.
The extract was evaporated and the residue subjected to flash
chromatography on silica gel using ethyl acetate as eluent to
give the title compound 35 (0.12 g, 35%) as a colourless solid,
mp 280–283 ЊC (Found: C, 59.5; H, 5.4; N, 16.4. C34H36N8O8
To a stirred mixture of sodium hydride (0.40 g, 60% in oil, 10
mmol) in dry DMF (100 cm3) was added IPI 10 (0.62 g, 2.5
mmol). The mixture was heated at 100 ЊC for 30 min and the
chloroethoxyethyl ether 30 (1.15 g, 2.5 mmol) in DMF (30 cm3)
was added through a syringe pump over 10 h at the same tem-
perature with stirring. The mixture was heated at 100 ЊC with
stirring for a further 24 h, the solvent removed under reduced
pressure and water added. The precipitate was filtered, dried
and extracted in a Soxhlet apparatus with dichloromethane for
5 h and the extract flash chromatographed using methanol–
ethyl acetate (20:80) to give the title compound 32 as colour-
less crystals from ethyl acetate and chloroform (0.32 g, 20%),
mp >320 ЊC (Found: C, 56.6; H, 6.15; N, 22.3. C30H38N10O6
requires C, 59.6; H, 5.3; N, 16.4%); νmax(KBr)/cmϪ1 1717 (C᎐O),
᎐
1592, 790; δH(CDCl3, 50 ЊC) 3.80 (8H, t, J 5.4, PyOCH2CH2O),
4.01 (8H, s, NCH2CH2N), 4.40 (8H, t, J 5.4, PyOCH2CH2O),
6.27 (4H, d, J 8.1, Py-3-H), 7.44 (2H, t, J 8.1, Py-4-H), 7.71
(2H, d, J 8.1, Py-5-H); m/z (ES, MHϩ) 685.
requires C, 56.8; H, 6.0; N, 22.1%); νmax(KBr)/cmϪ1 1707 (C᎐O),
᎐
1584, 791; δH(CDCl3) 3.42–3.60 (24H, m, CH2), 3.66 (4H, t, J
8.1, NCH2CH2N), 7.56 (2H, t, J 8.1, Py-4-H), 7.84 (4H, d, J 8.1,
Py-3,5-H); m/z (ES, MHϩ) 635.
Using the above method, addition of an equimolar amount
of bis(2-chloroethyl) ether to IPI 10 in DMF by way of a syr-
inge pump gave the same macrocycle 32 in 14% yield.
Synthesis of the macrocycle 36
To a stirred mixture of F-PIP-F 5b (1.38 g, 5 mmol) and sodium
hydride (0.5 g, 60% in oil, 12.5 mmol) in DMF (30 cm3), trieth-
ylene glycol (0.75 g, 5 mmol) was added through a syringe
pump over 10 h. The mixture was stirred for a further 24 h, the
solvent removed under reduced pressure and water and di-
chloromethane added and the organic layer was dried (MgSO4)
and evaporated. Flash chromatography of the residue with
ethyl acetate as the eluent gave the title product 36 as colourless
crystals (10.21 g, 11%), mp 189–191 ЊC (Found: C, 58.9; H,
5.80; N, 14.6. C38H44N8O10 requires C, 59.1; H, 5.7; N, 14.5%);
2,6-Bis{3-{2-[2-(2-chloroethoxy)ethoxy]ethyl}-2-oxoimidazol-
idin-1-yl}pyridine 31 and its macrocyclisation to give 33. In an
exactly analogous manner but utilising IPI 10 (1.93 g, 2.5
mmol) and 1,2-bis(2-chloroethoxy)ethane (19.0 g, 100 mmol)
was obtained the title product 31 (3.0 g, 70%) as colourless
crystals from ethyl acetate, mp 65–66 ЊC (Found: C, 50.45;
H, 6.4; N, 12.7. C23H35Cl2N5O6 requires C, 50.4; H, 6.45; N,
νmax(KBr)/cmϪ1 1712 (C᎐O), 1592, 785; δ (CDCl ) 3.76 (8H, s,
᎐
H
3
CH2), 3.88 (8H, t, J 5.4, PyOCH2CH2O), 4.11 (8H, s, NCH2-
CH2N), 4.44 (8H, t, J 5.4, PyOCH2CH2O), 6.41 (4H, d, J 8.1,
Py-3-H), 7.54 (2H, t, J 8.1, Py-4-H), 7.81 (2H, d, J 8.1, Py-5-H);
m/z (ES, MHϩ) 773.
12.8%); νmax(KBr)/cmϪ1 1705 (C᎐O), 1584, 802; δ (CDCl ) 3.50
᎐
H
3
(4H, t, J 5.4, ClCH2), 3.63–3.77 (20H, m, CH2), 4.0 (4H, t, J 8.1,
NCH2CH2N), 7.57 (1H, t, J 8.1, Py-4-H), 7.81 (2H, d, J 8.1, Py-
3,5-H).
Similarly to the above macrocyclisation, from IPI and the
compound 31 treated in exactly the same manner was obtained
the title product 33 as the fine colourless crystals from ethyl acet-
ate and chloroform (36%), mp 275–276 ЊC (Found: C, 56.4;
H, 6.5; N, 19.5. C34H46N10O8 requires C, 56.6; H, 6.4; N, 19.4%);
2,6-Bis(3-propargyl-2-oxoimidazolidin-1-yl)pyridine 37
To a stirred mixture of sodium hydride (0.24 g, 60% in oil, 6
mmol) in DMF (15 cm3) was added IPI (0.312 g, 1.1 mmol).
The mixture was heated at 110 ЊC for 0.5 h and then cooled to
0 ЊC with an ice-bath. Propargyl chloride (0.33 cm3, 70% in
toluene, 33 mmol) was added slowly through a 1 cm3 syringe to
the mixture then the ice-bath was withdrawn and the mixture
stirred for a further 2 h, and poured into ice-water (~50 g). The
precipitate was filtered and recrystallised from ethyl acetate
to give 2,6-bis(3-propargyl-2-oxoimidazolidin-1-yl )pyridine 37
as white crystals (0.31 g, 86%), mp 232–234 ЊC (Found: C, 63.0;
H, 5.4; N, 21.8. C17H17N5O2 requires C, 63.15; H, 5.3; N,
νmax(KBr)/cmϪ1 1707 (C᎐O), 1584, 792; δ (CDCl ) 3.48–3.55
᎐
H
3
(16H, m, CH2), 3.63 (8H, t, J 8.1, OCH2CH2O), 3.66 (8H, t, J
5.1, NCH2CH2O), 3.83 (8H, t, J 8.1, NCH2CH2N), 7.59 (2H, t,
J 8.1, Py-4-H), 7.83 (4H, d, J 8.1, Py-3,5-H); δH([2H6]DMSO)
3.36 (8H, t, J 5.4, NCH2CH2O), 3.46 (8H, t, J 8.1, NCH2-
CH2O), 3.57 (8H, s, OCH2CH2O), 3.61 (8H, t, J 5.4, NCH2-
CH2O), 3.78 (8H, t, J 8.1, NCH2CH2N), 7.52 (2H, dd, J 7.5 and
J. Chem. Soc., Perkin Trans. 1, 1998
435

View Article Online
D. J. Cram, J. Am. Chem. Soc., 1984, 106, 4977; D. J. Cram,
21.7%); νmax(KBr)/cmϪ1 3296 (C᎐CH), 1714 (C᎐O), 1584, 802;
᎐
᎐
᎐
H. E. Katz and I. B. Dicker, J. Am. Chem. Soc., 1984, 106, 4987;
D. J. Cram, I. B. Dicker, M. Lauer, C. B. Knobler and K. N.
Trueblood, J. Am. Chem. Soc., 1984, 106, 7150; K. M. Doxsee,
M. Feigel, K. D. Stewart, J. M. Canary, C. B. Knobler and D. J.
Cram, J. Am. Chem. Soc., 1987, 109, 3098; J. Bryant, S. P. Ho,
C. B. Knobler and D. J. Cram, J. Am. Chem. Soc., 1990, 112, 5837.
4 E. Weber, M. Piel, H.-J. Buschmann and E. Cleve, Chem. Ber., 1992,
125, 2483.
5 Z. Shi and R. P. Thummel, Tetrahedron Lett., 1995, 36, 2741.
6 S. Kumar, R. Saini and H. Singh, Tetrahedron Lett., 1992, 33, 7937;
S. Kumar, R. Saini, N. S. Poonia and H. Singh, Ind. J. Chem., 1995,
34B, 81.
7 M. Rosser, D. Parifer, G. Ferguson, J. F. Gallagher, J. A. K. Howard
and D. S. Yufit, J. Chem. Soc., Chem. Commun., 1993, 1267.
8 J. D. Kilburn, A. R. MacKenzie and W. C. Still, J. Am. Chem. Soc.,
1988, 110, 1307; R. Liu, P. E. J. Sanderson and W. C. Still, J. Org.
Chem., 1990, 56, 5184.
9 J. W. H. Smeets, R. P. Sijbesma, L. van Dalen, A. L. Spek, W. J. J.
Smeets and R. J. M. Nolte, J. Org. Chem., 1989, 54, 3710; J. W. H.
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J. Org. Chem., 1991, 56, 3122.
10 H. Quast and U. Nahr, Chem Ber., 1984, 117, 2761.
11 H. R. Kricheldorf and O. Stober, Eur. Polym. J., 1992, 28, 1377.
12 H. Wetter and K. Oertle, Tetrahedron Lett., 1985, 26, 5515.
13 N. A. Puschin and R. V. Mitic, Liebigs Ann. Chem., 1937, 523, 300.
14 J. Tafel and L. Reindl, Chem. Ber., 1901, 34, 3286.
15 C. E. Schweitzer, J. Org. Chem., 1950, 15, 471; A. R. Butler and
I. Hussain, J. Chem. Soc., Perkin Trans. 1, 1981, 317.
16 T. Yoshida, N. Kambe, S. Murai and N. Sonoda, Tetrahedron Lett.,
1986, 27, 3037; Bull. Chem. Soc. Jpn., 1987, 60, 1793; K. Kondo,
S. Yokoyama, N. Miyoshi, S. Murai and N. Sonoda, Angew. Chem.,
Int. Ed. Engl., 1979, 18, 692.
17 S. G. Davis and A. A. Mortlock, Tetrahedron Lett., 1991, 32, 4791.
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Chem., 1987, 22, 91.
19 J. Bernstein, B. Stearns, E. Shaw and W. A. Lott, J. Am. Chem. Soc.,
1947, 69, 1151; P. Buhlmann and W. Simon, Tetrahedron,, 1993, 49,
7627.
δH(CDCl3) 2.25 (2H, t, J 2.4, CH), 3.54 (4H, t, J 8.1, Im
CH2), 4.03 (4H, t, J 8.1, Im CH2), 4.12 (4H, d, J 2.4, CH2), 7.59
(1H, t, J 8.1, Py-H), 7.84 (2H, d, J 8.1, Py-H).
Propargyl chloride should be added slowly at 0 ЊC. If it was
added in one portion at ambient temperature, the mixture
became black. The mixture was poured into ice-water and
the resulting black oil which was purified by silica chrom-
atography. Only bis(3-allenyl-2-oxoimidazolidin-1-yl )pyridine 38
was obtained (12%) as an oil, δH(CDCl3) 3.40 (4H, t, J 8.1, Im
CH ), 3.98 (4H, t, J 8.1, Im CH ), 5.38 (4H, d, J 6.2, ᎐CH ), 7.01
᎐
2
2
2
(2H, t, J 6.2, ᎐CH), 7.55 (1H, t, J 8.1, Py-H), 7.81 (2H, d, J 8.1,
᎐
Py-H).
2-(3-tert-Butyl-2-oxoimidazolidin-1-yl)-6-(3-propargyl-2-oxo-
imidazolidin-1-yl)pyridine (But-IPI-Pg) 39
The title compound was synthesised exactly as for the synthesis
of 37 utilising But-IPI 8a as starting material. Recrystallisation
from ethyl acetate gave title compound 39 as white needle crys-
tals (88%), mp 200–201 ЊC (Found: C, 63.35; H, 6.8; N, 20.6.
C18H23N5O2 requires C, 63.3; H, 6.8; N, 20.5%); νmax(KBr)/cmϪ1
t
᎐
3231 (C᎐CH), 2971 (Bu ), 1709, 1693 (C᎐O), 1582, 798;
᎐
᎐
δH(CDCl3) 1.43 (9H, s, But), 2.27 (2H, t, J 2.4, CH), 3.47 (4H, t,
J 8.1, Im CH2), 3.55 (4H, t, J 8.1, Im CH2), 3.90 (4H, t, J 8.1, Im
CH2), 4.04 (4H, d, J 2.4, CH2), 7.58 (1H, t, J 8.1, Py-H), 7.84
(2H, d, J 8.1, Py-H).
Coupling reaction of But-IPI-Pg 39, to give 40
But-IPI-Pg (0.80 g, 2.34 mmol) and copper() acetate mono-
hydrate (4.0 g, 20 mmol) were added to 25:5 (v/v) dichloro-
methane–pyridine (30 cm3) solution. The mixture was heated
at reflux overnight, cooled and dichloromethane (100 cm3)
added, and the solution was washed with aqueous ammonium
hydroxide solution (3 × 30 cm3, d 0.880) and then with distilled
water (3 × 30 cm3). The organic layer was dried with sodium
sulfate and filtered to obtain a cloudy solution. The solvent was
removed and the dimer 40 was obtained as a brown solid which
was insoluble in common solvents (0.69 g, 87%), mp 240–
20 T. Kauffman, J. Legler, E. Ludorff and H. Fischer, Angew. Chem.,
Int. Ed. Engl., 1972, 11, 846.
21 M. Begtrup, Bull. Soc. Chim. Belg., 1988, 97, 573.
22 B. H. Lipshutz, B. Huff and W. Hagen, Tetrahedron Lett., 1988, 29,
3411.
23 T. P. Johnston, G. S. McCaleb, P. S. Opliger and J. A. Montgomery,
J. Med. Chem., 1966, 9, 892.
24 V. Burckhardt, H. Sutter and W. Kundig, GP 829 894/1954 (Chem.
Abstr., 1958, 52, 11 127e).
243 ЊC; νmax(KBr)/cmϪ1 2969 (But), 1710, 1693 (C᎐O), 1581, 802
᎐
(Py); δH(TFA) 2.00 (18H, s, But), 4.37–4.67 (16H, m, Im CH2),
᎐
4.81 (4H, s, C᎐CCH ), 7.15 (1H, d, J 8.4, Py-H), 7.16 (2H, d,
᎐
2
J 8.4, Py-H), 8.70 (2H, t, J 8.4, Py-H); MS (EIϩ) Found: M,
680.3547. C36H44N10O4 requires M, 680.3547.
25 J. E. B. Ransohoff and H. A. Staab, Tetrahedron Lett., 1985, 26,
6179.
26 A. Lorente, M. Fernandez-Saiz, J.-M. Lehn and J.-P. Vigneron,
Tetrahedron Lett., 1995, 36, 8279.
27 M. E. Haeg, B. J. Whitlock and H. W. Whitlock, J. Am. Chem. Soc.,
1989, 111, 692.
28 J. Reedijk, T. M. Mulder and J. A. Smit, Inorg. Chim. Acta, 1975, 13,
219.
Acknowledgements
One of us (Z. Y.) thanks the University of Sunderland for a
studentship.
29 F. Kiriakidou and E. Manessi-Zoupa, Polyhedron, 1996, 15, 1031.
30 E. P. Kyba, R. C. Helgeson, K. Madan, G. W. Gokel, T. L.
Tarnowski, S. S. Moore and D. J. Cram, J. Am. Chem. Soc., 1977,
99, 2564.
31 J. M. Timko and D. J. Cram, J. Am. Chem. Soc., 1977, 99, 4207.
32 J. W. H. Smeets, L. van Dalen, V. E. M. Kaats-Richter and R. J. M.
Nolte, J. Org. Chem., 1990, 55, 454.
33 D. D. Perrin and W. L. F. Armarego, Purification of Organic
Compounds, 3rd edn., Pergamon Press, Oxford, 1988.
34 A. E. Chichibabin, Chem. Ber., 1924, 67, 1172.
References
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Paper 7/07131K
Received 2nd October 1997
Accepted 7th October 1997
436
J. Chem. Soc., Perkin Trans. 1, 1998