Novel cryptands containing thiourea units as a part of the macrocyclic framework

Article abstract of DOI:10.1039/b207902j

Alkylation of diaza-18-crown-6 by N-substituted phthalimides having a terminal halogen in the substituent, and subsequent product interaction with hydrazine hydrate and acid hydrolysis gave corresponding N,N′-disubstituted diaza-18-crown-6 compounds with terminal primary amino groups in the side chains. The reaction of these compounds with carbon disulfide or with appropriate bis[oligo(ethyleneoxy)]isothiocyanates afforded a series of novel cryptands with one or two thiourea units in one of the bridges.

Full text of DOI:10.1039/b207902j

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Novel cryptands containing thiourea units as a part of the
macrocyclic framework
Nikolay G. Lukyanenko,* Tatiana I. Kirichenko and Sergey V. Scherbakov
1
Department of Bioorganic Chemistry, A. V. Bogatsky Physico-Chemical Institute,
National Academy of Sciences of Ukraine, Lustdorfskaya doroga 86, 65080 Odessa, Ukraine.
E-mail: ngl@farlep.net.; Fax: ϩ38-0482-652-012
Received (in Cambridge, UK) 13th August 2002, Accepted 10th September 2002
First published as an Advance Article on the web 24th September 2002
Alkylation of diaza-18-crown-6 by N-substituted phthalimides having a terminal halogen in the substituent, and
subsequent product interaction with hydrazine hydrate and acid hydrolysis gave corresponding N,NЈ-disubstituted
diaza-18-crown-6 compounds with terminal primary amino groups in the side chains. The reaction of these
compounds with carbon disulfide or with appropriate bis[oligo(ethyleneoxy)]isothiocyanates afforded a series of
novel cryptands with one or two thiourea units in one of the bridges.
Earlier we described a series of crown ethers 1, 2 and
Introduction
cryptands 3 incorporating thiourea moieties in the macrocyclic
framework.8 In all cases, the complexation selectivity of these
compounds was unusual in comparison with ordinary crown
ethers and cryptands.8d,f In cryptands 3, one of the nitrogen
atoms of the thiourea units simultaneously serves as a bridge-
head. This decreases the basicity of this nitrogen and, as a
result, the binding behavior of the cryptands. We were intrigued
by cryptands containing thiourea units in one of the bridges at
some distance from the nitrogen bridgeheads. Herein, we report
an efficient and general approach to this type of cryptand.
The synthesis and chemistry of crown ethers and cryptands that
contain not only traditional ether oxygen and nitrogen atoms,
but also other heteroatoms and/or functional groups have
attracted considerable attention due to their unusual ability to
act as hosts to both neutral and ionic species.1 Such synthetic
receptors provide a controlled means for studying the funda-
mentals of non-covalent intermolecular forces in nature
and open new routes for the development of sensors, catalysts,
switches and other molecular devices.2 The binding power of a
host is governed by the cavity size, the shape, the rigidity and
the nature of the binding sites. Particularly important is the fact
that highly flexible hosts often make binding entropically
unfavorable. Therefore, structurally rigid cryptands have
become an important area of investigation.3
The powerful binding abilities of macrocyclic receptors
incorporating urea units are well documented.3,4 However,
cyclic receptors having thiourea groups as a part of the
macrocyclic framework have received little attention, despite
the fact that the binding ability and selectivity of such receptors
is likely to be improved because of the expected preorganization
of the binding sites.
The mesomeric π-character of the thiourea group restricts
the C–N bond rotation. This makes N,NЈ-substituted thioureas
rigid coplanar structures with the substituents in the sterically
preferred Z,Z-conformations. The high polarizability of the
thiourea group facilitates interactions with “soft” cations.5
Moreover, since the thiourea groups are relatively strong
hydrogen bond donors, they can exhibit anion-binding ability.
Therefore, these compounds can be considered as bifunctional
receptors in which the binding sites for anions and cations
are linked covalently enabling them to exhibit allosteric or
cooperative complexation where the binding affinity for anions
(cations) is modified because of the cation (anion) complex-
ation. Recently, such receptors have attracted much attention as
a new class of reagent with possible application for a membrane
transport, ion-selective electrodes and as catalysts.6
Results and discussion
The synthetic routes for preparing the starting phthalimides
7a,b and bis[oligo(ethyleneoxy)]isothiocyanates 9a–d are shown
in Scheme 1. Heating of the potassium phthalimide in a tenfold
excess of dichloride 5a or 5b at 130 ЊC for 20 h afforded the
In most cases, bifunctional receptors are acyclic com-
pounds; however, in our opinion, the best results can be
achieved by integration of the binding sites for cations and
anions in a combined macrocyclic system. However, to the best
of our knowledge, no cryptands and only a few examples of
crown ethers containing thiourea units in the macrocyclic
framework, have been reported,7 with the exception of our
communications.8
Scheme 1
DOI: 10.1039/b207902j
J. Chem. Soc., Perkin Trans. 1, 2002, 2347–2351
This journal is © The Royal Society of Chemistry 2002
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Scheme 2
chlorides 6a and 6b in yields of 91% and 89%, respectively.
The synthesis of the cryptands 13 and 14 was accomplished
Reaction of chlorides 6a,b with an excess of sodium iodide
in acetonitrile give iodides 7a and 7b in yields of 97% and
96%, respectively. Bis[oligo(ethyleneoxy)]isothiocyanates 9 were
prepared in good overall yields (65–85%) by the following
reaction sequence. The diamines 8 reacted with carbon disulfide
in the presence of triethylamine with formation of the corre-
sponding dithiocarbamate salts, which were acylated with ethyl
chloroformate in chloroform at 0 ЊC. Thermal decompos-
ition of the acylation products under reduced pressure and
subsequent distillation afforded the desired isothiocyanates 9.
The key precursors of the cryptands 13 and 14 are diaza-
crown ethers 12 bearing terminal primary amine groups in the
side chains (Scheme 2). Azacrown ethers with terminal amine
groups are usually prepared by the reaction of azacrown ethers
with derivatives of α-amino or α-halogen acids with the
subsequent reduction of formed amides, or by alkylation of
primary amines or secondary diamines with appropriate
ditosylates or dihalides with following ring closure.9 These
multistage and time consuming methods are not common and
afford desired products in only moderate yields. The alkylation
of diazacrown ethers with N-substituted phthalimides bearing
terminal halogen in the side chain, and deprotection of formed
diphthalimides seems most rational and a more common
pathway of deriving of the substituted azacrown ethers with
terminal amine groups in the side chain.
under high dilution conditions. The low concentration of
reactants was maintained by their simultaneous addition to the
reaction vessel by calibrated pumps. Azacrown ethers 12 react
with carbon disulfide in acetonitrile with the formation of
dithiocarbamate salts, the thermal decomposition of which
under reduced pressure at 120–130 ЊC afforded cryptands 13 in
37–66% yields. The reaction of 13 with diisothiocyanates 8 in
boiling dioxane gave the corresponding cryptands 14 in 48–69%
yields.
In summary, reaction of the azacrown ethers bearing ter-
minal amino groups in the side chains with carbon disulfide
or diisothiocyanates constitutes an efficient and common
approach to cryptands containing thiourea units in the macro-
cyclic framework. Such ligands may be employed as either
monofunctional receptors for cations or bifunctional receptors
for cations and anions. Now we are evaluating their com-
plexation properties. These will be reported elsewhere.
Experimental
N-(2-Bromoethyl)phthalimide 4, dichlorides 5, diamines 8 and
diaza-18-crown-6 10 were commercially available and used
without purification. All other reagents and solvents were used
as supplied unless otherwise stated. Mps were determined in
1
open capillaries and are uncorrected. H NMR spectra at 250
The reaction of diaza-18-crown-6 10 with N-(2-bromoethyl)-
phthalimide 4 in boiling acetonitrile in the presence of sodium
carbonate resulted in 11a in moderate yield (65%). The exe-
cution of the same reaction without solvent at 100 ЊC increased
the yield of 11a to 91%. In contrast to this, the alkylation of
diazacrown ether 10 by iodides 7a and 7b under similar con-
ditions did not yield satisfactory results, while the reaction
carried out in acetonitrile in the presence of lithium carbonate
with heating under reflux for 30 h gave the target products 11b
and 11c in yields of 65% and 48%, respectively. Increasing the
reaction time reduced the yield of main products, apparently
because of partial quaternization.
The reaction of diphthalimides 11a–c with hydrazine hydrate
in ethanol at reflux for 7 h, with subsequent hydrolysis with 6 M
HCl, gave the hydrochlorides of diamines 12a–c. Treatment of
these hydrochlorides with saturated aqueous lithium hydroxide
afforded the corresponding azacrown ethers 12a–c. Use of
sodium or potassium hydroxides led to the formation of com-
plexes of 12a–c with the chlorides of sodium or potassium.
MHz were recorded with a Bruker AM-250 spectrometer for
solutions in CDCl3 unless otherwise specified, with TMS as
internal standard. J values are given in Hz. EI mass spectra
were obtained on Varian MAT 112 and MX 1321 spectrometers
(70 eV). UV spectra were recorded on a Specord M-40 spectro-
photometer and are given in nm with log ε in parentheses. IR
spectra were measured on a Perkin Elmer 580B spectrometer.
2-[2-(2-Chloroethoxy)ethyl]isoindole-1,3-dione 6a
A mixture of dichloride 5a (152.20 g, 1.06 mol) and potassium
phthalimide (20.37g, 0.11 mol) was stirred at 130 ЊC for 20 h.
After concentration, in vacuo, the residue was treated with
benzene (700 cm3) and solid material was removed by filtration.
The filtrate was concentrated under reduced pressure and the
residue was extracted with pentane using a Soxhlet extractor for
50 h. The extract was evaporated to give compound 6a (25.39 g,
91%) as a white solid, mp 71–72 ЊC (Found: C, 56.78; H, 4.78;
N, 5.49; Mϩ, 253. C12H12ClNO3 requires C, 56.81; H, 4.77; N,
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5.52; M, 253.68); δH 3.60–3.68 (4 H, m, CH2O), 3.82 (2 H, t,
J 6.6, CH2Cl), 3.96 (2 H, t, J 5.8, CH2N), 7.55–7.72 (4 H,
m, Ph).
43.33; H, 5.85; N, 10.15; Mϩ, 276. C10H16N2O3S2 requires C,
43.46; H, 5.84; N, 10.14; M, 276.38); δH 3.47 (8 H, t, J 6.9,
CH2O), 3.75–3.90 (8 H, m, CH2N, CH2O).
2-{2-[2-(2-Chloroethoxy)ethoxy]ethyl}isoindole-1,3-dione 6b
1,18-Dithioxo-5,8,11,14-tetraoxa-2,17-diazaoctadecane 9d.
Pale yellow oil (65%), bp 205–208 ЊC/0.05 mmHg; (Found: C,
45.16; H, 6.30; N, 8.76; Mϩ, 320. C12H20N2O4S2 requires C,
44.98; H, 6.29; N, 8.74; M, 320.43); δH 3.47 (8 H, t, J 6.9,
CH2O), 3.57 (4 H, t, J 6.9, CH2O), 3.75–3.90 (8 H, m, CH2N,
CH2O).
Compound 6b was prepared analogously to 6a from 5b (187.06
g, 1.00 mol) and potassium phthalimide (18.52 g, 0.10 mol).
Colourless oil (26.50 g, 89%); (Found: C, 56.41; H, 5.45; N,
4.68; Mϩ, 297. C14H16ClNO4 requires C, 56.48; H, 5.42; N, 4.70;
M, 297.74); δH 3.47–3.64 (8 H, m, CH2O), 3.82–3.93 (4 H, m,
CH2Cl, CH2N), 7.55–7.70 (4 H, m, Ph).
7,16-(2-Phthalimidoethyl)-1,4,10,13-tetraoxa-7,16-diazacyclo-
octadecane 11a
2-[2-(2-Iodoethoxy)ethyl]isoindole-1,3-dione 7a
A mixture of diaza-18-crown-6 10 (2.62 g, 10 mmol), phthal-
imide 4 (12.70 g, 50 mmol) and powdered Na2CO3 (5.30 g,
50 mmol) was stirred at 100 ЊC for 10 h. To the hot solution
was added dropwise chloroform (30 cm3). After cooling, solid
material was removed by filtration and the solvent was evap-
orated under reduced pressure. The residue was dissolved in
benzene-1 M HCl (1:1, 100 cm3) at 40–60 ЊC. The organic layer
was separated and discarded. The aqueous layer was basified
with Na2CO3 to pH 9–10 and extracted with benzene (2 × 50
cm3). The combined extracts were dried (MgSO4) and evap-
orated under reduced pressure. The residue was purified by
recrystallization from heptane-benzene (1:1) to give diazacrown
ether 11a (5.29 g, 87%) as a white solid, mp 116–117 ЊC (Found:
C, 62.97; H, 6.63; N, 9.18; Mϩ, 608. C32H40N4O8 requires C,
63.14; H, 6.62; N, 9.20; M, 608.68); δH 2.69 (8 H, t, J 6.1,
CH2N), 2.93 (4 H, t, J 6.9, CH2N), 3.35 (8 H, t, J 6.1, CH2O),
3.53 (8 H, s, CH2O), 3.75 (8 H, t, J 6.9, CH2N), 7.65–7.80 (8 H,
m, Ph).
A mixture of chloride 6a (9.13 g, 36 mmol) and sodium iodide
(11.99 g, 80 mmol) in dry acetonitrile (50 cm3) was stirred with
heating under reflux for 10 h. After cooling, it was filtered and
concentrated to dryness under reduced pressure. The residue
was dissolved in chloroform (30 cm3), the solution was washed
with aqueous sodium thiosulfate (5%, 2 × 10 cm3) and dried
over CaCl2, and the solvent was evaporated off under reduced
pressure. The residue was purified by recrystallization from
hexane–benzene (10:3) to give the iodide 7a (12.05 g, 97%) as a
white solid, mp 84–86 ЊC (Found: C, 41.62; H, 3.49; N, 4.07;
Mϩ, 345. C12H12INO3 requires C, 41.76; H, 3.50; N, 4.06; M,
345.13); δH 3.22 (2 H, t, J 7.0, CH2I), 3.58 (2 H, t, J 5.8, CH2O),
3.76 (2 H, t, J 7.0, CH2O), 3.91 (2 H, t, J 5.8, CH2N) 7.54–7.71
(4 H, m, Ph).
2-{2-[2-(2-Iodoethoxy)ethoxy]ethyl}isoindole-1,3-dione 7b
Compound 7b was prepared analogously to 7a from 6b (8.93 g,
30 mmol) and sodium iodide (10.49 g, 70 mmol). After evapor-
ation of acetonitrile, the residue was extracted with boiling
hexane (100 cm3). The solvent was removed under reduced
pressure to give the iodide 7b (11.59 g, 96%) as pale yellow oil
(Found: C, 43.15; H, 4.15; N, 3.61; Mϩ, 386. C14H16INO4
requires C, 43.21; H, 4.14; N, 3.60; M, 386.19); δH 3.25 (2 H, t,
J 6.9, CH2I), 3.40–3.53 (4 H, m, CH2O), 3.61 (2 H, t, J 5.8,
CH2O), 3.74 (2 H, t, J 6.9, CH2O), 3.90 (2 H, t, J 5.8, CH2N)
7.56–7.73 (4 H, m, Ph).
7,16-Bis(5-phthalimido-3-oxapentyl)-1,4,10,13-tetraoxa-7,16-
diazacyclooctadecane 11b
A stirred mixture of diaza-18-crown-6 10 (1.05 g, 4 mmol),
phthalimide 7a (3.45 g, 10 mmol) and powdered Li2CO3 (3.32 g,
45 mmol) in dry acetonitrile (20 cm3) was heated under reflux
for 30 h. After cooling, the mixture was filtered and concen-
trated to dryness under reduced pressure. The residue was dis-
solved in benzene-1 M HCl (1:1, 40 cm3) at 50–60 ЊC. The
organic layer was separated and discarded. The aqueous layer
was basified with Na2CO3 to pH 9–10 and extracted with warm
benzene (50–60 ЊC, 2 × 20 cm3). The combined extracts were
dried (MgSO4) and evaporated under reduced pressure. The
residue was purified by recrystallization from heptane-benzene
(9:5) to give diazacrown ether 11b (1.78 g, 64%) as a white solid,
mp 96–97 ЊC (Found: C, 61.89; H, 6.95; N, 8.06; Mϩ, 696.
C36H48N4O10 requires C, 62.05; H, 6.94; N, 8.04; M, 696.79);
δH 2.48–2.64 (12 H, m, CH2N), 3.29–3.61 (24 H, m, CH2O), 3.85
(4 H, t, J 5.8, CH2N), 7.67–7.78 (8 H, m, Ph).
General procedure for the synthesis of isothiocyanates 9
To a solution of appropriate diamine 8 (0.5 mol) and triethyl-
amine (1.0 mol) in chloroform (750 cm3) was added carbon
disulfide (1.0 mol). The mixture was stirred for 2 h at room
temperature then cooled to 0 ЊC. Ethyl chloroformate (1.0 mol)
was added dropwise. The mixture was stirred at 0 ЊC for 0.5 h,
then at room temperature for 2 h, whereupon it was washed
with water (3 × 250 cm3), dried over Na2SO4 and evaporated.
The residue was heated at 110–130 ЊC under reduced pressure
(∼30 mmHg) until gas evolution ceased. The crude material was
purified by distillation in vacuo to give the desired isothio-
cyanates 9 as colourless or pale yellow oils.
7,16-Bis(8-phthalimido-3,6-dioxaoctyl)-1,4,10,13-tetraoxa-7,16-
diazacyclooctadecane 11c
This compound was prepared by the reaction of diaza-18-
crown-6 10 (1.05 g, 4 mmol) with phthalimide 7b (3.86 g, 10
mmol) as described for diazacrown ether 11b. After evaporation
of benzene diazacrown ether 11c (1.51 g, 48%) was obtained as
a pale yellow oil (Found: C, 61.12; H, 7.21; N, 7.12; Mϩ, 784.
C40H56N4O12 requires C, 61.21; H, 7.19; N, 7.14; M, 784.89);
δH 2.48–2.62 (12 H, m, CH2N), 3.35–3.61 (32 H, m, CH2O),
3.78 (4 H, t, J 5.8, CH2N), 7.63–7.78 (8 H, m, Ph).
1,9-Dithioxo-5-oxa-2,8-diazanonane 9a. Colourless oil (78%),
bp 150–154 ЊC/0.2 mmHg; (Found: C, 38.16; H, 4.30; N, 14.84;
Mϩ, 188. C6H8N2OS2 requires C, 38.28; H, 4.28; N, 14.88; M,
188.27); δH 3.73–3.79 (4 H, m, CH2N), 3.84–3.90 (4 H, m,
CH2O).
1,12-Dithioxo-5,8-dioxa-2,11-diazadodecane 9b. Colourless
oil (85%), bp 165–163 ЊC/0.08 mmHg; (Found: C, 41.26; H,
5.23; N, 12.08; Mϩ, 232. C8H12N2O2S2 requires C, 41.36; H,
5.21; N, 12.06; M, 232.32); δH 3.46 (4 H, s, CH2O), 3.75–3.90
(8 H, m, CH2N, CH2O).
General procedure for the synthesis of diazacrown ethers 12
Hydrazine hydrate (67 mmol) was added dropwise to a boiling
solution of compound 11 (33 mmol) in ethanol (100 cm3) with
intensive stirring. The mixture was heated under reflux for 7 h
whereupon it was acidified with 6 M HCl (22 cm3), filtered and
1,15-Dithioxo-5,8,11-trioxa-2,14-diazapentadecane
9c.
Colourless oil (80%), bp 177–180 ЊC/0.05 mmHg; (Found: C,
J. Chem. Soc., Perkin Trans. 1, 2002, 2347–2351
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evaporated under reduced pressure. Water (120 cm3) was added
to the residue and the precipitate was removed by filtration. The
filtrate was basified with saturated aqueous LiOH to pH 10–11
and extracted with chloroform using a liquid–liquid extractor
for 10 h. The chloroform was evaporated off in vacuo to give the
desired products 12.
4,7,15,18,24,27,32,35-Octaoxa-1,10,12,21-tetraazabicyclo-
[19.8.8]heptatriacontane-11-thione 13c
This compound was prepared by the reaction of diazacrown
ether 12c (2.0 g, 3.81 mmol) with carbon disulfide (0.29 g,
3.81 mmol) as described for cryptand 13a. The crude product
was purified by column chromatography on basic alumina
using chloroform–dioxane (1:3) as the eluent to give cryptand
13c (0.799 g, 37%) as a pale yellow oil (Found: C, 52.85; H,
8.91; N, 9.87; Mϩ, 566. C25H50N4O8S requires C, 52.98; H, 8.89;
N, 9.89; M, 566.75); νmax (KBr)/cmϪ1 3440, 3260, 3080, 1560,
1540 and 1110; λmax(MeOH)/nm 207 and 241 (log ε 4.16 and
4.11); δH 2.62 (4 H, t, J 5.0, NCH2), 2.70 (8 H, t, J 5.0, NCH2),
3.46–3.58 (36 H, m, NCH2, OCH2), 7.12 (2 H, br s, NH).
2-[16-(2-Aminoethyl)-1,4,10,13-tetraoxa-7,16-diazacyclo-
octadecan-7-yl]ethylamine 12a. Pale yellow oil (75%); (Found:
C, 55.01; H, 10.42; N, 16.12; Mϩ, 348. C16H36N4O4 requires C,
55.15; H, 10.41; N, 16.08; M, 348.48); δH 1.67 (4 H, br s, NH2),
2.49–2.67 (16 H, m, CH2N, CH2NH2), 3.37 (8 H, t, J 6.2,
CH2O), 3.53 (8 H, s, CH2O).
2-(2-{16-[2-(2-Aminoethoxy)ethyl]-1,4,10,13-tetraoxa-7,16-
diazacyclooctadecan-7-yl}ethoxy)ethylamine 12b. Pale yellow oil
(71%); (Found: C, 55.11; H, 10.19; N, 12.79; Mϩ, 436.
C20H44N4O6 requires C, 55.02; H, 10.16; N, 12.83; M, 436.59);
δH 1.78 (4 H, br s, NH2), 2.48 (8 H, t, J 6.2 CH2N), 2.60 (4 H, t,
J 5.8, CH2N), 2.74 (4 H, t, J 5.8, CH2NH2), 3.31 (8 H, t, J 6.2,
CH2O), 3.43–3.55 (16 H, m, CH2O).
9,20,23,28,31-Pentaoxa-1,4,6,12,14,17-hexaazabicyclo[15.8.8]-
tritriacontane-5,13-dithione 14a
Solutions of diazacrown ether 12a (2.50 g, 7.18 mmol) in dry
dioxane (500 cm3) and of diisothiocyanate 9a (1.35 g, 7.18
mmol) in dry dioxane (500 cm3) were added dropwise and
simultaneously over 5 h to dry dioxane (500 cm3) under reflux
using calibrated pumps. The mixture was refluxed and stirred
for a further 1 h and the solvent was evaporated off under
reduced pressure. The residue was purified by column chrom-
atography on basic alumina using chloroform as the eluent to
give the cryptand 14a (2.1 g, 55%) as a white solid, mp 139–140
ЊC (Found: C, 49.11; H, 8.24; N, 15.68; Mϩ, 536. C22H44N6O5S2
requires C, 49.23; H, 8.26; N, 15.66; M, 536.75); νmax(KBr)/cmϪ1
3240, 1555 and 1120; λmax(MeOH)/nm 206 (log ε 4.39); δH 2.44
(4 H, t, J 4.5, NCH2), 2.56 (8 H, t, J 5.2, NCH2), 3.30 (8 H, t,
J 5.2, OCH2), 3.37 (4 H, t, J 4.5, NCH2), 3.44–3.58 (16H, m,
OCH2, NCH2), 7.31 (4 H, br s, NH).
2-{2-[2-(16-{2-[2-(2-Aminoethoxy)ethoxy]ethyl}-1,4,10,13-
tetraoxa-7,16-diazacyclooctadecan-7-yl)ethoxy]ethoxy}ethyl-
amine 12c. Pale yellow oil (79%); (Found: C, 54.79; H, 9.97;
N, 10.71; Mϩ, 524. C24H52N4O8 requires C, 54.94; H, 9.99;
N, 10.68; M, 524.69); δH 1.95 (4 H, br s, NH2), 2.50 (8 H, t,
J 6.2 CH2N), 2.62 (4 H, t, J 5.8, CH2N), 2.77 (4 H, t, J 5.8,
CH2NH2), 3.29 (8 H, t, J 6.2, CH2O), 3.39–3.53 (24 H, m,
CH2O).
4,7,13,16-Tetraoxa-1,10,21,23-tetraazabicyclo[8.8.7]penta-
cosane-22-thione 13a
9,12,23,26,31,34-Hexaoxa-1,4,6,15,17,20-hexaazabicyclo-
[18.8.8]hexatriacontane-5,16-dithione 14b
Solutions of diazacrown ether 12a (1.0 g, 2.87 mmol) in dry
acetonitrile (250 cm3) and of carbon disulfide (0.22 g, 2.87
mmol) in dry acetonitrile (250 cm3) were added dropwise simul-
taneously over 2.5 h to dry acetonitrile (250 cm3) under reflux
using calibrated pumps. The mixture was refluxed and stirred
for a further 7.5 h and the solvent was evaporated off. The
residue was heated under reduced pressure (∼20 mmHg) at
120–130 ЊC until gas evolution ceased (∼0.5 h). The crude
product was purified by column chromatography on basic
alumina using chloroform–hexane (3:4) as the eluent. The main
fraction was evaporated and the residue was washed succes-
sively with water (10 cm3) and ethanol (2 × 10 cm3), and dried
in vacuo to give the cryptand 13a (0.61 g, 54%) as a white solid,
mp 198–199 ЊC (Found: C, 52.15; H, 8.79; N, 14.32; Mϩ, 390.
C17H34N4O4S requires C, 52.28; H, 8.77; N, 14.35; M, 390.54);
νmax(KBr)/cmϪ1 3450, 3295, 3240, 1565, 1540 and 1110;
λmax(MeOH)/nm 209 and 235 (log ε 4.26 and 4.25); δH 2.43 (4 H,
t, J 5.0, NCH2), 2.50 (8 H, t, J 4.5, NCH2), 3.32 (8 H, t, J 4.5,
OCH2), 3.50 (8 H, s, OCH2), 3.56 (4 H, q, J 5.0, NCH2), 6.98
(2 H, br s, NH).
This compound was prepared by the reaction of diazacrown
ether 12a (1.74 g, 5.0 mmol) with diisothiocyanate 9b (1.16 g,
5.0 mmol) as described for cryptand 14a. The crude product
was purified by column chromatography on basic alumina
using chloroform as the eluent to give cryptand 14b (2.03 g,
70%) as a white solid, mp 169–170 ЊC (Found: C, 49.75; H, 8.35;
N, 14.43; Mϩ, 580. C24H48N6O6S2 requires C, 49.63; H, 8.33; N,
14.47; M, 580.81); νmax(KBr)/cmϪ1 3450, 3240, 3070, 1560 and
1110; λmax(MeOH)/nm 207 (log ε 4.38); δH 2.48 (4 H, t, J 5.2,
NCH2), 2.65 (8 H, t, J 4.8, NCH2), 3.29 (8 H, t, J 4.8, OCH2),
3.37 (4 H, t, J 5.2, NCH2), 3.46–3.50 (8 H, m, OCH2, NCH2), 3.53
(8 H, s, OCH2), 3.65 (4 H, t, J 5.8, OCH2), 7.18 (4 H, br s, NH).
9,12,15,26,29,34,37-Heptaoxa-1,4,6,18,20,23-hexaazabicyclo-
[21.8.8]nonatriacontane-5,19-dithione 14c
This compound was prepared by the reaction of diazacrown
ether 12a (1.74 g, 5.0 mmol) with diisothiocyanate 9c (1.38 g,
5.0 mmol) as described for cryptand 14a. The crude product
was purified by column chromatography on basic alumina
using chloroform as the eluent to give cryptand 14c (1.91 g,
61%) as a white solid, mp 80–81 ЊC (Found: C, 49.86; H, 8.41;
N, 13.42; Mϩ, 624. C26H52N6O7S2 requires C, 49.98; H, 8.39;
N, 13.45; M, 624.86); νmax(KBr)/cmϪ1 3450, 3230, 3070, 1555
and 1115; λmax(MeOH)/nm 207 and 241 (log ε 4.39 and 4.38); δH
2.45 (4 H, t, J 5.2, NCH2), 2.68 (8 H, t, J 4.8, NCH2), 3.30–3.39
(12 H, m, NCH2, OCH2), 3.44–3.49 (12 H, m, NCH2, OCH2),
3.55 (8 H, s, OCH2), 3.67 (4 H, t, J 5.8, OCH2), 7.41 (4 H, br s,
NH).
4,12,18,21,26,29-Hexaoxa-1,7,9,15-tetraazabicyclo[13.8.8]-
hentriacontane-8-thione 13b
This compound was prepared by the reaction of diazacrown
ether 12b (2.0 g, 4.58 mmol) with carbon disulfide (0.35 g, 4.58
mmol) as described for cryptand 13a. The crude product was
purified by column chromatography on basic alumina using
chloroform–hexane (1:1) as the eluent to give cryptand 13b
(1.45 g, 66%) as a white solid, mp 74–75 ЊC (Found: C, 52.83; H,
8.82; N, 11.68; Mϩ, 478. C21H42N4O6S requires C, 52.70; H,
8.84; N, 11.71; M, 478.65); νmax (KBr)/cmϪ1 3450, 3260, 3080,
1555, 1540 and 1105; λmax(MeOH)/nm 207 and 241 (log ε 4.15
and 4.11); δH 2.57 (4 H, t, J 5.0, NCH2), 2.65 (8 H, t, J 4.5,
NCH2), 3.42 (16 H, t, J 4.5, OCH2), 3.52 (8 H, s, OCH2), 3.65
(4 H, q, J 5.0, NCH2), 7.43 (2 H, br s, NH).
9,12,15,18,29,32,37,40-Octaoxa-1,4,6,21,23,26-hexaaza-
bicyclo[24.8.8]dotetracontane-5,22-dithione 14d
This compound was prepared by the reaction of diazacrown
ether 12a (1.74 g, 5.0 mmol) with diisothiocyanate 9d (1.60 g,
2350
J. Chem. Soc., Perkin Trans. 1, 2002, 2347–2351

View Article Online
5.0 mmol) as described for cryptand 14a. The crude product
was purified by column chromatography on basic alumina
using chloroform–dioxane (1:1) as the eluent to give cryptand
14d (1.61 g, 48%) as a white solid, mp 68–69 ЊC (Found: C,
50.39; H, 8.42; N, 12.59; Mϩ, 668. C28H56N6O8S2 requires C,
50.28; H, 8.44; N, 12.56; M, 668.91); νmax(KBr)/cmϪ1 3450,
3300, 3070, 1555 and 1115; λmax(MeOH)/nm 208 and 242 (log ε
4.39 and 4.38); δH 2.44 (4 H, t, J 5.2, NCH2), 2.72 (8 H, t, J 4.8,
NCH2), 3.29–3.41 (12 H, m, NCH2, OCH2), 3.44–3.49 (16 H,
m, NCH2, OCH2), 3.54 (8 H, s, OCH2), 3.65 (4 H, t, J 5.8,
OCH2), 7.35 (4 H, br s, NH).
References
1 (a) B. Dietrich, P. Viout and J.-M. Lehn, Macrocyclic Chemistry:
Aspects of Organic and Inorganic Supramolecular Chemistry, VCH,
New York, 1993; (b) R. M. Izat, K. Pawlak and J. S. Bradshaw, Chem.
Rev, 1995, 95, 2529; (c) J. H. Hartley, T. D. James and C. J. Ward,
J. Chem. Soc., Perkin Trans. 1, 2000, 3155.
2 (a) H. Dugas, Bioorganic Chemistry: A Chemical Approach to Enzyme
Action, Springer-Verlag, New York, 1996; (b) P. Bühlmann, E. Pretsch
and E. Bakker, Chem. Rev, 1998, 98, 1593; (c) J.-M. Lehn,
Supramolecular Chemistry, VCH, New York, 1995; (d ) V. Balzani,
A. Credi, F. M. Raymo and J. F. Stoddart, Angew. Chem., Int. Ed,
2000, 39, 3348.
3 D. J. Cram, Angew. Chem., Int. Ed. Engl, 1986, 25, 1039.
4 For representative examples see: (a) A. V. Bogatskii, N. G.
Luk’yanenko, T. I. Kirichenko, V. V. Limich and L. P. Karpenko,
J. Org. Chem. USSR (Engl. Transl.), 1984, 20, 89; (b) Y. M. Jeon,
J. Kim, D. Whang and K. J. Kim, J. Am. Chem. Soc., 1996, 118, 9790;
(c) P. R. Dave, G. Doyle, T. Axenrod and H. Yazdekhasti, J. Org.
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J. K. Su, H.-C. Yeh, W.-Y. Lin and M. Leung, Org. Lett., 2001, 3, 3999.
5 (a) S. McKenzle, in Organic Compounds of Sulphur, Selenium and
Tellurium, ed. D. H. Reid, The Chemical Society, London, 1970,
vol. 1, chapter 5; (b) W. Walter, E. Schaumann and H. Rose,
Tetrahedron, 1972, 28, 3233; (c) P. Hanson and D. A. R. Williams,
J. Chem. Soc., Perkin Trans. 2, 1973, 2162.
6 (a) F. P. Schmidtchen and M. Berger, Chem. Rev., 1997, 97, 1609;
(b) B. Linton and A. D. Hamilton, Chem. Rev., 1997, 97, 1669;
(c) P. D. Beer, P. K. Hopkins and J. D. McKinney, J. Chem. Soc.,
Chem. Commun., 1999, 1253; (d ) S. Nishizawa, K. Shigemori and
N. Teramae, Chem. Lett., 1999, 1185.
4,12,20,26,29,34,37-Heptaoxa-1,7,9,15,17,23-hexaazabicyclo-
[21.8.8]nonatriacontane-8,16-dithione 14e
This compound was prepared by the reaction of diazacrown
ether 12b (2.50 g, 5.73 mmol) with diisothiocyanate 9a (1.08 g,
5.73 mmol) as described for cryptand 14a. The crude product
was purified by column chromatography on basic alumina
using chloroform–methanol (100:1) as the eluent to give
cryptand 14e (2.11 g, 59%) as a white solid, mp 72–73 ЊC
(Found: C, 50.11; H, 8.41; N, 13.48; Mϩ, 624. C26H52N6O7S2
requires C, 49.98; H, 8.39; N, 13.45; M, 624.86); νmax(KBr)/cmϪ1
3440, 3260, 3080, 1560 and 1110; λmax(MeOH)/nm 207 and 241
(log ε 4.40 and 4.41); δH 2.47–2.54 (12 H, m, NCH2), 3.20–3.32
(12 H, m, NCH2, OCH2), 3.43–3.48 (8 H, m, NCH2), 3.53–3.58
(16 H, m, OCH2), 7.10 (4 H, br s, NH).
7 (a) M. Rosser, D. Parker, G. Ferguson, J. F. Gallagher, J. A. K.
Howard and D. S. Yufit, J. Chem. Soc., Chem. Commun., 1993, 1267;
(b) J. M. G. Fernandes, J. L. J. Blanko, C. O. Mellet and J. Fuentes,
J. Chem. Soc., Chem. Commun., 1995, 57; (c) Y. Tobe, S. Sasaki,
M. Mizuno and K. Naemura, Chem. Lett., 1998, 835; (d ) S. Sasaki,
M. Mizuno, K. Naemura and Y. Tobe, J. Org. Chem., 2000, 65, 275.
8 (a) A. V. Bogatsky, N. G. Lukyanenko and T. I. Kirichenko,
Tetrahedron Lett., 1980, 21, 313; (b) A. V. Bogatskii, N. G.
Luk’yanenko, T. I. Kirichenko and S. V. Shcherbakov, J. Org. Chem.
USSR (Engl.Transl.), 1981, 17, 1133; (c) N. G. Luk’yanenko,
T. I. Kirichenko, V. V. Limich and A. V. Bogatsky, Chem. Heterocycl.
Compd. (Engl. Transl.), 1987, 23, 222; (d ) N. G. Luk’yanenko,
T. I. Kirichenko, S. V. Shcherbakov, N. Yu. Nazarova, L. P. Karpenko
and A. V. Bogatskii, J. Org. Chem. USSR (Engl. Transl.), 1986, 22,
1589; (e) N. G. Lukyanenko, A. V. Bogatsky, T. I. Kirichenko and
V. V. Limich, Synthesis, 1984, 136; ( f ) N. G. Lukyanenko, A. V.
Bogatsky, T. I. Kirichenko, S. V. Scherbakov and N. Yu. Nazarova,
Synthesis, 1984, 137.
4,12,15,23,29,32,37,40-Octaoxa-1,7,9,18,20,26-hexaazabicyclo-
[24.8.8]dotetracontane-8,19-dithione 14f
This compound was prepared by the reaction of diazacrown
ether 12b (2.18 g, 5.00 mmol) with diisothiocyanate 9b (1.16 g,
5.00 mmol) as described for cryptand 14a. The crude product
was purified by column chromatography on basic alumina
using chloroform–dioxane–isopropyl alcohol (5:5:1) as the
eluent to give cryptand 14f (1.71 g, 51%) as pale yellow oil
(Found: C, 50.15; H, 8.46; N, 12.59; Mϩ, 668. C28H56N6O8S2
requires C, 50.28; H, 8.44; N, 12.56; M, 668.91); νmax(KBr)/
cmϪ1 3450, 3250, 3065, 1560 and 1105; λmax(MeOH)/nm
207 and 241 (log ε 4.34 and 4.33); δH 2.47–2.54 (12 H, m,
NCH2), 3.23–3.29 (12 H, m, NCH2, OCH2), 3.44–3.49 (12 H,
m, NCH2, OCH2), 3.53–3.61 (16 H, m, OCH2), 7.47 (4 H, br s,
NH).
9 J. S. Bradshaw, K. E. Krakowiak and R. M. Izatt, Aza-Crown
Macrocycles, Wiley, New York, 1993, p. 245.
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