Synthesis and metal-ion binding properties of monoazathiacrown ethers

Article abstract of DOI:10.1021/jo015709i

Synthetic procedures for monoazathiacrown ethers were explored, and monoazatrithia-12-crown-4, monoazatetrathia-15-crown-5, and monoazapentathia-18-crown-6 were obtained in moderate yields by the reaction of bis(2-chloroethyl)amine with the appropriate dithiols in the presence of lithium hydroxide in THF. To evaluate metal-ion binding properties of the monoazathiacrown ethers by solvent extraction, lipophilic dodecyl and dodecanoyl groups were incorporated onto the monoazathiacrown ethers. The solvent extraction experiments suggested that monoazathiacrown ethers have Ag⁺ and Hg²⁺ selectivities and that the relative selectivity between Ag⁺ and Hg²⁺ depends on their nitrogen atom properties and numbers of sulfur atoms reflecting the respective affinities of nitrogen and sulfur atoms to Hg²⁺ and Ag⁺. An interesting ability to bind Mg²⁺ was observed in the case of N-dodecyl monoazatrithia-12-crown-4.

Full text of DOI:10.1021/jo015709i

7008
J . Org. Chem. 2001, 66, 7008-7012
Syn th esis a n d Meta l-Ion Bin d in g P r op er ties of Mon oa za th ia cr ow n
Eth er s
Mutsuo Tanaka,*,† Makoto Nakamura,§ Tomokazu Ikeda,‡ Kiyomi Ikeda,† Hisanori Ando,†
Yasuhiko Shibutani,‡ Setsuko Yajima,§ and Keiichi Kimura*,§
Special Division for Human Life Technology, National Institute of Advanced Industrial Science and
Technology, 1-8-31, Midorigaoka, Ikeda, Osaka 563-8577, J apan, Department of Chemistry, Faculty of
Engineering, Osaka Institute of Technology, 5-16-1, Ohmiya, Asahi-ku, Osaka 535-8585, J apan, and
Department of Applied Chemistry, Faculty of Systems Engineering, Wakayama University, 930,
Sakae-dani, Wakayama, Wakayama 640-8510, J apan
mutsuo-tanaka@aist.go.jp
Received April 25, 2001 (Revised Manuscript Received J uly 26, 2001)
Synthetic procedures for monoazathiacrown ethers were explored, and monoazatrithia-12-crown-
4, monoazatetrathia-15-crown-5, and monoazapentathia-18-crown-6 were obtained in moderate
yields by the reaction of bis(2-chloroethyl)amine with the appropriate dithiols in the presence of
lithium hydroxide in THF. To evaluate metal-ion binding properties of the monoazathiacrown ethers
by solvent extraction, lipophilic dodecyl and dodecanoyl groups were incorporated onto the
monoazathiacrown ethers. The solvent extraction experiments suggested that monoazathiacrown
ethers have Ag+ and Hg2+ selectivities and that the relative selectivity between Ag+ and Hg2+
depends on their nitrogen atom properties and numbers of sulfur atoms reflecting the respective
affinities of nitrogen and sulfur atoms to Hg2+ and Ag+. An interesting ability to bind Mg2+ was
observed in the case of N-dodecyl monoazatrithia-12-crown-4.
In tr od u ction
the purpose of their application as building blocks in
supramolecular systems.
Since crown ethers were first recognized to have
selective metal-ion binding properties by Pedersen,1
various crown ethers have been prepared and their
metal-ion binding properties have been studied exten-
sively. Of particular note are commercially available
monoaza- and hydroxymethyl-crown ethers used as build-
ing blocks to induce a metal-ion-selective function in
supramolecular systems.2 At the same time, various
thiacrown ethers have also been prepared3 and their
heavy-metal-ion binding properties are well-known.4
However, little use seems to have been made of thiacrown
ethers as building blocks in supramolecular systems
because there are few thiacrown ethers that have func-
tional groups to incorporate into a supramolecule.5 To the
best of our knowledge, general procedures for preparing
monoazathiacrown ethers, which could be quite useful
to incorporate into a supramolecule, have not been
reported yet. In this paper, therefore, we report the
synthesis of monoazathiacrown ethers and their metal-
ion binding properties evaluated by solvent extraction for
Resu lts a n d Discu ssion
P r ep a r a tion of Mon oa za tr ith ia -12-cr ow n -4. First,
we examined cyclization of diethanolamine derivatives
with 3-thiapentane-1,5-dithiol in the preparation of
monoazatrithia-12-crown-4 by three methods shown in
Schemes 1-3. In method 1 (Scheme 1), the reaction of
diethanolamine with p-toluenesulfonyl chloride in pyri-
(4) (a) Hu, K.; Bradshow, J . S.; Pastushok, V. N.; Krakowiak, K. E.;
Dalley, N. K.; Zhang, X. X.; Izatt, R. M. J . Org. Chem. 1998, 63, 4786.
(b) Kamata, S.; Higo, M.; Kamibeppu, T.; Tanaka, I. Chem. Lett. 1982,
287. (c) Oue, M.; Kimura, K.; Akama, K.; Tanaka, M.; Shono, T. Chem.
Lett. 1988, 409. (d) Rosen, W.; Busch, D. H. J . Am. Chem. Soc. 1969,
91, 4694. (e) Saito, K.; Masuda, Y.; Sekido, E. Anal. Chim. Acta 1983,
151, 447. (f) Brzozka, Z.; Cobben, P. L. H. M.; Reinhoudt, D. N.; Edeme,
J . J . H.; Buter, J .; Kellogg, R. M. Anal. Chim. Acta 1993, 273, 139. (g)
Kamata, S.; Yamasaki, K.; Higo, M.; Bhale, A.; Fukunaga, Y. Analyst
1988, 113, 45. (h) Lai, M.; Shih, J . Analyst 1986, 111, 891. (i) Oue, M.;
Akama, K.; Kimura, K.; Tanaka, M.; Shono, T. J . Chem. Soc., Perkin
Trans. 1 1989, 1675. (j) J ones, T. E.; Rorabacher, D. B.; Ochrymowycz,
L. A. J . Am. Chem. Soc. 1975, 97, 7485. (k) Dockal, E. R.; J ones, T. E.;
Sokol, W. F.; Engerer, R. J .; Rorabacher, D. B.; Ochrymowycz, L. A. J .
Am. Chem. Soc. 1976, 98, 4322. (l) Sakamoto, H.; Ishikawa, J .; Otomo,
M. Bull. Chem. Soc. J pn. 1995, 68, 2831. (m) Ishikawa, J .; Sakamoto,
H.; Mizuno, T.; Otomo, M. Bull. Chem. Soc. J pn. 1995, 68, 3071. (n)
Ishikawa, J .; Sakamoto, H.; Wada, H. J . Chem. Soc., Perkin Trans. 2
1999, 1273. (o) Craig, A. S.; Kataky, R.; Matthews, R. C.; Parker, D.;
Ferguson, G.; Lough, A.; Adams, H.; Bailey, N.; Schneider, H. J . Chem.
Soc., Perkin Trans. 2 1990, 1523. (p) Sakamoto, H.; Ishikawa, J .;
Mizuno, T.; Doi, K.; Otomo, M. Chem. Lett. 1993, 609. (q) Oue, M.;
Akama, K.; Kimura, K.; Tanaka, M.; Shono, T. J . Chem. Soc., Perkin
Trans. 1 1989, 1675. (r) Rosen, W.; Busch, D. H. J . Am. Chem. Soc.
1969, 91, 4694. (s) Ishikawa, J .; Sakamoto, H.; Wada, H. J . Chem.
Soc., Perkin Trans. 2 1999, 1273. (t) Rurack, K.; Kollmannsberger, M.;
Resch-Genger, U.; Daub, J . J . Am. Chem. Soc. 2000, 122, 968. (u) Bryce,
M. R.; Batsanov, A. S.; Finn, T.; Hansen, T. K.; Howard, J . A. K.;
Kamenjicki, M.; Lednev, I. K.; Asher, S. A. Chem. Commun. 2000, 295.
(v) Alberts, A. H.; Annunziata, R.; Lehn, J . J . Am. Chem. Soc. 1977,
99, 8502. (w) Alberts, A. H.; Lehn, J .; Parker, D. J . Chem. Soc., Dalton
Trans. 1985, 2311.
* Corresponding authors. E-mail for K. Kimura: kimura@sys.
wakayama-u.ac.jp.
†National Institute of Advanced Industrial Science and Technology.
‡ Osaka Institute of Technology.
§ Wakayama University.
(1) (1) Pedersen, C. J . J . Am. Chem. Soc. 1967, 89, 7017.
(2) Gokel, G. W. Advances in Supramolecular Chemistry; J AI Press,
Inc.: Stamford, CT, 1999; Vol. 5.
(3) (a) Bradshow, J . S.; Hui, J . Y.; Haymore, B. L.; Christensen, J .
J .; Izatt, R. M. J . Heterocycl. Chem. 1973, 10, 1. (b) Black, D. St. C.;
McLean, I. A. J . Chem. Soc., Chem. Commun. 1968, 1004. (c) Groth,
A. M.; Lindoy, L. F.; Meehan, G. V. J . Chem. Soc., Perkin Trans. 1
1996, 1553. (d) Hoover, L. R.; Pryor, T.; Weitgenant, J . A.; Williams,
P. E.; Storhoff, B. N.; Huffman, J . C. Phosphorus, Sulfur Silicon Relat.
Elem. 1997, 122, 155. (e) Chartres, J . D.; Groth, A. M.; Lindoy, L. F.;
Lowe, M. P.; Meehan, G. V. J . Chem. Soc., Perkin Trans. 1 2000, 3444.
10.1021/jo015709i CCC: $20.00 © 2001 American Chemical Society
Published on Web 09/18/2001

Monoazathiacrown Ethers
Sch em e 1. Meth od 1
J . Org. Chem., Vol. 66, No. 21, 2001 7009
Sch em e 4
Sch em e 5
Sch em e 2. Meth od 2
to those in method 1, but the yield was only 14%.
Subsequent removal of the N-protecting group was
accomplished with 35 wt % hydrochloric acid-acetic acid
in a 70% yield.6
Method 3 (Scheme 3) is a one-step preparation of
monoazatrithia-12-crown-4, namely, the cyclization reac-
tion of commercially available bis(2-chloroethyl)amine
with 3-thiapentan-1,5-dithiol. The reaction was carried
out under conditions similar to those in method 1, and
the yield was 39%.
On the basis of the high total yield and simplicity,
method 3 appears to be the most promising procedure.
In light of this, various combinations of solvent and bases
such as lithium, sodium in ethanol, lithium hydroxide,
sodium hydroxide, potassium hydroxide, sodium hydride
in THF, and cesium carbonate in DMF were examined
according to method 3. Lithium hydroxide in THF gave
the best yield at 39%. Cesium carbonate in DMF has been
reported to give excellent yields in thiacrown ether
preparation;7 however, no improvement was observed in
this study.
Sch em e 3. Meth od 3
dine gave N-tosyldiethanolamine ditosylate in an excel-
lent yield (>95%). Subsequent cyclization of N-tosyldi-
ethanolamine ditosylate with 3-thiapentan-1,5-dithiol in
THF in the presence of lithium hydroxide produced
N-tosylmonoazatrithia-12-crown-4 in a 25% yield. At-
tempts to remove the N-protecting tosyl group with
various reagents such as sulfuric acid at various concen-
trations (47 wt % hydrobromic acid-acetic acid and 35
wt % hydrochloric acid-ethanol) resulted in decomposi-
tion or no reaction. Finally, 35 wt % hydrochloric acid-
acetic acid gave monoazatrithia-12-crown-4, but the yield
was only 10%.
In method 2 (Scheme 2), the benzyloxycarbonyl group
was introduced to diethanolamine as the N-protecting
group. Selective reaction of benzyloxycarbonyl chloride
with the amino group of diethanolamine was attained in
acetone-water in the presence of sodium carbonate with
a 58% yield. Methanesulfonyl chloride was chosen to
react with N-benzyloxycarbonyldiethanolamine, as meth-
anesulfonyl chloride (>95%) gave a better yield than
p-toluenesulfonyl chloride (75%). Cyclization of N-ben-
zyloxcarbonyldiethanolamine dimesylate with 3-thiap-
entan-1,5-dithiol was carried out under conditions similar
P r ep a r a tion of Mon oa za th ia cr ow n Eth er s a n d
Th eir Der iva tives. To prepare monoazatetrathia-15-
crown-5 and monoazapentathia-18-crown-6, syntheses of
3,6-dithiaoctan-1,9-dithiol and 3,6,9-trithiaundecan-1,11-
dithiol were carried out according to reported procedures
(Scheme 4).8 The cleavage of thioether bonds9 resulted
in a low yield of 22% in the case of 3,6-dithiaoctan-1,9-
dithiol preparation, and 3,6,9-trithiaundecan-1,11-dithiol
was not formed by this method. Therefore, a modified
procedure for 3,6,9-trithiaundecan-1,11-dithiol prepara-
tion was examined as shown in Scheme 5, and the yields
were 53 and 51% for the first and second steps, respec-
tively.
Monoazatetrathia-15-crown-5 and monoazapentathia-
18-crown-6 were prepared according to method 3 with
34 and 26% yields, respectively, and two noncyclic
analogues were also prepared for comparison (Scheme
6). To evaluate the metal-ion binding properties of
monoazathiacrown ethers by solvent extraction, lipophilic
groups such as dodecyl and dodecanoyl groups were
introduced onto monoazathiacrown ethers by the reaction
of dodecyl halide and dodecanoyl halide in the presence
of bases. Similarly, noncyclic analogues were converted
(5) (a) Comba, P.; Fath, A.; Nuber, B.; Peters, A. J . Org. Chem. 1997,
62, 8459. (b) Neve, F.; Ghedini, M. Inorg. Chim. Acta 1994, 217, 1. (c)
Blake, A. J .; Bruce, D. W.; Fallis, I. A.; Parsons, S.; Scho¨der, M. J .
Chem. Soc., Chem. Commun. 1994, 2471. (d) Neve, F.; Ghedini, M.;
Munno, G. D.; Levelut, A. Chem. Mater. 1995, 7, 688. (e) Neve, F.;
Ghedini, M. J . Inclusion Phenom. 1993, 15, 259. (f) Baumann, T. F.;
Reynolds, J . G.; Fox, G. A. J . Chem. Soc., Chem. Commun. 1998, 1637.
(6) A common procedure using HCOOH-Pd/C was unsuccessful.
(7) Buter, J .; Kellogg, R. M. J . Org. Chem. 1981, 46, 4481.
(8) Wolf, R. E., J r.; Hartman, J . R.; Storey, J . M. E.; Foxman, B.
M.; Cooper, S. R. J . Am. Chem. Soc. 1987, 109, 4328.
(9) Ochrymowycz, L. A.; Mak, C.; Michna, J . D. J . Org. Chem. 1974,
39, 2079.

7010 J . Org. Chem., Vol. 66, No. 21, 2001
Tanaka et al.
relative Ag+ selectivities to Hg2+ were 34, 36, and 41%,
respectively, indicating that the relative Ag+ selectivity
is proportional to the number of sulfur atoms. This
tendency was observed with other hosts. When the
relatively low Hg2+ extractability of 6-10 bearing an
amide carbonyl group is considered, the Hg2+ selectivity
of 1-5 seems to be derived from an affinity of their amine
nitrogen atoms for Hg2+. On the other hand, the com-
parison between cyclic and noncyclic thiacrown ethers
did not show any meaningful difference.
Sch em e 6
In conclusion, the syntheses of monoazatrithia-12-
crown-4, monoazatetrathia-15-crown-5, and monoaza-
pentathia-18-crown-6 were attained by the reaction of
bis(2-chloroethyl)amine with the corresponding dithiols
in the presence of lithium hydroxide in THF in moderate
yields. Solvent extraction experiments suggested that
monoazathiacrown ethers have Ag+ and Hg2+ selectivities
and that relative selectivity between Ag+ and Hg2+
depends on their nitrogen atom properties and sulfur
atom numbers. An interesting ability to bind Mg2+ was
observed in the case of dodecyl monoazatrithia-12-crown-
4.
Sch em e 7
Exp er im en ta l Section
All chemicals were of available purity and used without
further purification. Prepared monoazathiacrown ethers, non-
cyclic analogues, and 1-5 tended to suffer from oxidation, but
6-10 were quite stable. We prepared 3,6-dithiaoctan-1,8-
dithiol according to ref 8.
Ca u tion ! Mustard gaslike materials such as 3-thiapentan-
1,5-dimesylate and bis(2-chloroethyl)amine hydrochloride (pur-
chased from Tokyo Kasei Kogyo) are blistering agents. Some
materials have the potential to become a blistering agent
during the preparation process.
to the corresponding dodecyl and dodecanoyl derivatives
(Scheme 7).
P r ep a r a tion of Mon oa za th ia cr ow n Der iva tives. 3-Th i-
a p en ta n -1,5-d im esyla te. 3-Thiapentan-1,5-diol (1.22 g, 10
mmol), pyridine (4.0 g, 50 mmol), and dichloromethane (50 mL)
were put into a three-necked flask at room temperature. A
dichloromethane solution (10 mL) of methanesulfonyl chloride
(3.44 g, 30 mmol) was added dropwise to the mixture, and the
reaction mixture was stirred for 2 h at room temperature. The
reaction mixture was poured into water, and the organic layer
was separated. The aqueous layer was extracted with chloro-
form once. After solvent evaporation, THF (30 mL) was poured
into the obtained crude product and the insoluble pyridinium
salt was filtrated. The crude product (53%) was obtained as a
colorless liquid by solvent evaporation and was used for the
subsequent preparation after drying.
3,6,9-Tr ith ia u n d eca n -1,11-d ith iol. Caution! This material
is a blistering agent! Under a nitrogen atmosphere, dithioet-
hyleneglycol (4.71 g, 50 mmol), powdered sodium hydroxide
(2.0 g, 50 mmol), and THF (50 mL) were put into a three-
necked flask, and the mixture was refluxed. A THF solution
(10 mL) of crude 3-thiapentan-1,5-dimesylate (2.78 g, 10 mmol)
was added dropwise, and the reaction mixture was then
refluxed for 12 h under a nitrogen atmosphere. The cooled
reaction mixture was poured into 5 wt % aqueous hydrochloric
acid, and the product was extracted with chloroform. The
resulting precipitate was filtrated. The colorless, solid product
(51%) was purified by recrystallization with chloroform.
3-Th iapen tan -1-th iol. Under a nitrogen atmosphere, dithio-
ethyleneglycol (65.8 g, 0.7 mol), powdered sodium hydroxide
(8.40 g, 210 mmol), and THF (700 mL) were put into a three-
necked flask, and the mixture was refluxed. A THF solution
(280 mL) of ethyl iodide (21.88 g, 140 mmol) was added
dropwise, and the reaction mixture was refluxed for 1 h under
Solven t Extr a ction . Solvent extraction experiments
were carried out using metal picrate salts in a chloroform-
water system at 30 °C, and the extracted metal-ion %
was determined from the decrease in the picrate concen-
tration in the aqueous phase by UV measurement. The
percentages of extracted metal ions are summarized in
Table 1. There was no significant metal-ion extraction
of alkali metal ions with any of the thiacrown ethers as
anticipated. For alkaline-earth metal ions, small amounts
of Ca2+ were extracted with 1-5. However, 6-10 ex-
tracted only small amounts of alkaline-earth metal ions,
even though the thiacrown ether concentration was 10-
fold that of 1-5. In the case of 6-10, the electron-
withdrawing carbonyl group suppressed the metal-ion
binding of the nitrogen atom of the crown ethers. An
interesting tendency was exhibited by 1: it extracted a
small amount of Mg2+, which is generally difficult to
extract from aqueous to organic phases. This result
implies that the monoazatrithia-12-crown-4 unit has
some binding ability for Mg2+. Among the heavy metal
ions studied, Ag+ and Hg2+ were extracted effectively by
the thiacrown ethers as expected,10 but significant dif-
ferences in selectivities were observed between groups
1-5 and 6-10. While dodecyl derivatives 1-5 showed
Hg2+ selectivities, the selectivities of dodecanoyl deriva-
tives 8 and 10 were for Ag+. The Ag+ selectivities relative
to Hg2+, the ratio of Ag+/(Ag+ + Hg2+) in the organic
phase, are also summarized in Table 1. Among 1-3, the
a
nitrogen atmosphere. The residue obtained by solvent
evaporation was poured into water, and the product was
extracted with chloroform twice. The colorless liquid product
(95%) was purified by vacuum distillation.
(10) (a) Sakamoto, H.; Ishikawa, J .; Nakao, S.; Wada, H. Chem.
Commun. 2000, 2395. (b) Rurack, K.; Resch-Genger, U.; Bricks, J . L.;
Spieles, M. Chem. Commun. 2000, 2103.

Monoazathiacrown Ethers
J . Org. Chem., Vol. 66, No. 21, 2001 7011
Ta ble 1. P er cen ta ge of Meta l Ion Extr a cted fr om Aqu eou s to Or ga n ic P h a sesa
host
Li+ Na+ K+ Rb+ Cs+ Mg2+ Ca2+ Sr2+ Ba2+ Ag+ Tl+ Pb2+ Hg2+ Zn2+ Cu2+ Ag+ selectivityb
1
2
3
4
5
6
7
8
9
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
7
0
0
0
0
0
0
0
0
0
8
8
9
7
5
0
3>
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
23
20
31
6
25
0
9
41
0
5
1>
7
2>
0
0
4>
0
7
4>
8
4>
4>
0
0
0
45
36
45
20
28
0
11
8
0
0
0
0
0
0
0
0
0
0
0
4>
3>
6
3>
0
0
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34
36
41
23
47
-
45
84
-
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21
10
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68
a
Host ) 1 × 10-4 mol dm-3 for 1-5 and 1 × 10-3 mol dm-3 for 6-10, and MPic and M(Pic)2 ) 5 × 10-5 mol dm-3; CHCl3(10 mL)/
H2O(10 mL); 30 °C. Ag+ selectivity represents the Ag+ selectivity relative to that for Hg2+, which is defined as the ratio of Ag+/(Ag+
+
b
Hg2+) in the organic phase.
N-Tosyldieth an olam in e Ditosylate. Diethanolamine (1.05
g, 10 mmol) and pyridine (20 mL) were put into a three-necked
flask at 0 °C. A pyridine solution (20 mL) of p-toluenesulfonyl
chloride (8.57 g, 45 mmol) was added dropwise, and the
reaction mixture was stirred at 0 °C for 2 h and then at room
temperature for 12 h. The reaction mixture was poured into
ice-water and neutralized by hydrochloric acid. The product
was extracted with chloroform twice. The obtained crude
brown liquid product (>95%) was used for the subsequent
preparation after drying.
mL) of 3-thiopentan-1,5-dithiol (1.54 g, 10 mmol) and crude
N-benzyloxycarbonyldiethanolamine dimesylate (3.95 g, 10
mmol) was added dropwise, and the reaction mixture was
refluxed for 24 h under a nitrogen atmosphere. The residue
obtained by solvent evaporation was poured into water, and
the product was extracted with chloroform and then purified
by gel permeation chromatography to give a colorless liquid
(14%). 1H NMR (CDCl3, 500 MHz): δ 2.7-2.9 (12H, m, SCH2),
3.5-3.6 (4H, m, NCH2), 5.13 (2H, s, CH2), 7.3-7.4 (5H, m,
ArH).
N-Tosylm on oa za tr ith ia -12-cr ow n -4. Under a nitrogen
atmosphere, lithium hydroxide (960 mg, 40 mmol) and dry
THF (300 mL) were put into a three-necked flask, and the
mixture was refluxed. A dry THF solution (20 mL) of 3-thio-
pentan-1,5-dithiol (1.54 g, 10 mmol) and crude N-tosyldietha-
nolamine ditosylate (5.67 g, 10 mmol) was added dropwise,
and the reaction mixture was refluxed for 24 h under a
nitrogen atmosphere. The residue obtained by solvent evapo-
ration was poured into water, and the product was extracted
with chloroform and then purified by gel permeation chroma-
tography to give a pale-yellow solid (25%). 1H NMR (CDCl3,
500 MHz): δ 2.43 (3H, s, CH3), 2.7-2.8 (12H, m, SCH2), 3.4-
3.5 (4H, m, NCH2), 7.32 (2H, d, J ) 8.5 Hz, ArH), 7.70 (2H, d,
J ) 8 Hz, ArH).
Mon oa za tr ith ia -12-cr ow n -4 (Meth od 2). Under a nitro-
gen atmosphere, N-benzyloxycarbonylmonoazatrithia-12-crown-4
(179 mg, 0.5 mmol), 35 wt % aqueous hydrochloric acid (20
mL), and acetic acid (10 mL) were put into a three-necked
flask, and the reaction mixture was stirred at 100 °C for 3 h.
The cooled reaction mixture was poured into 20 wt % aqueous
sodium hydroxide (100 mL), and the product was extracted
with chloroform three times. The product was purified by
recrystallization with n-hexane to give a colorless solid (70%).
Mon oa za tr ith ia -12-cr ow n -4 (Meth od 3). Under a nitro-
gen atmosphere, 3-thiopentan-1,5-dithiol (308 mg, 2 mmol),
bis(2-chloroethyl)amine hydrochloride (357 mg, 2 mmol), lithium
hydroxide (288 mg, 12 mmol), and dry THF (150 mL) were
put into a three-necked flask, and the reaction mixture was
refluxed for 24 h. Residue obtained by solvent evaporation was
poured into water, and the product was extracted with
chloroform twice. The product was purified by recrystallization
with hexane to give a colorless solid (39%).
Mon oa za tetr a th ia -15-cr ow n -5. The preparation proce-
dure was the same as that used for monoazatrithia-12-crown-
4, except 3,6-dithiooctan-1,8-dithiol (428 mg, 2 mmol) was used
instead of 3-thiopentan-1,5-dithiol to give a colorless solid
(34%). Mp: 60-62 °C. 1H NMR (CDCl3, 400 MHz): δ 1.68 (1H,
s, NH), 2.7-3.0 (20H, m, SCH2, NCH2).
Mon oa za p en ta th ia -18-cr ow n -6. The preparation proce-
dure was the same as that used for monoazatrithia-12-crown-
4, except 3,6,9-trithioundecan-1,11-dithiol (548 mg, 2 mmol)
was used instead of 3-thiopentan-1,5-dithiol to give a colorless
solid (26%). Mp: 53-56 °C. 1H NMR (CDCl3, 400 MHz): δ
2.7-3.0 (24H, m, SCH2, NCH2).
Mon oa za tr ith ia -12-cr ow n -4 (Meth od 1). Under a nitro-
gen atmosphere, N-tosylmonoazatrithia-12-crown-4 (189 mg,
0.5 mmol), 35 wt % aqueous hydrochloric acid (20 mL), and
acetic acid (10 mL) were put into a three-necked flask, and
the reaction mixture was stirred at 100 °C for 24 h. The cooled
reaction mixture was poured into 20 wt % aqueous sodium
hydroxide (100 mL), and the product was extracted with
chloroform three times. The product was purified by recrys-
tallization with hexane to give a colorless solid (10%). Mp: 80-
1
83 °C. H NMR (CDCl3, 400 MHz): δ 1.59 (1H, s, NH), 2.7-
3.0 (16H, m, SCH2, NCH2).
N-Ben zyloxyca r bon yld ieth a n ola m in e. Diethanolamine
(1.16 g, 11 mmol), sodium carbonate (2.65 g, 25 mmol), acetone
(25 mL), and water (25 mL) were put into a three-necked flask
at 0 °C. Benzyloxycarbonyl chloride (1.71 g, 10 mmol) was
added dropwise, and the reaction mixture was stirred at 0 °C
for 3 h. The reaction mixture was poured into water, and the
product was extracted with chloroform. The crude colorless
liquid product (58%) obtained by solvent evaporation was used
for the subsequent preparation after drying.
N-Ben zyloxycar bon yldieth an olam in e Dim esylate.Crude
N-benzyloxycarbonyldiethanolamine (478 mg, 2 mmol), pyri-
dine (474 mg, 6 mmol), and chloroform (50 mL) were put into
a three-necked flask at 0 °C. Methanesulfonyl chloride (687
mg, 6 mmol) was added dropwise, and the reaction mixture
was stirred at 0 °C for 1 h. The reaction mixture was poured
into water, and the product was extracted with chloroform.
The crude colorless liquid product (>95%) obtained by solvent
evaporation was used for the subsequent preparation after
drying.
3,9-Dith ia -6-m on oa za u n d eca n e. Under a nitrogen atmo-
sphere, sodium (4.60 g, 200 mmol) was dissolved in ethanol
(200 mL), and ethanethiol (7.44 g, 120 mmol) was added to
the solution. An ethanol solution (100 mL) of bis(2-chloroethyl)-
amine hydrochloride (7.14 g, 40 mmol) was added dropwise
with refluxing, and the reaction mixture was refluxed for 2 h
under a nitrogen atmosphere. The residue obtained by solvent
evaporation was poured into water, and the product was
extracted with chloroform twice. The product was purified by
1
vacuum distillation to give a colorless liquid (84%). H NMR
(CDCl3, 400 MHz): δ 1.27 (6H, t, J ) 7.2 Hz, CH3), 1.68 (1H,
s, NH), 2.55 (4H, q, J ) 7.3 Hz, SCH2CH3), 2.70 (4H, t, J )
6.4 Hz, SCH2), 2.83 (4H, t, J ) 6.6 Hz, NCH2).
3,6,12,15-Tetr a th ia -9-m on oa za h ep ta d eca n e. Under
a
N-Ben zyloxyca r bon ylm on oa za tr ith ia -12-cr ow n -4. Un-
der a nitrogen atmosphere, lithium hydroxide (960 mg, 40
mmol) and dry THF (300 mL) were put into a three-necked
flask, and the mixture was refluxed. A dry THF solution (20
nitrogen atmosphere, sodium (5.75 g, 250 mmol) was dissolved
in ethanol (250 mL), and 3-thiapentan-1-thiol (18.3 g, 150
mmol) was added to the solution. An ethanol solution (150 mL)
of bis(2-chloroethyl)amine hydrochloride (8.93 g, 50 mmol) was

7012 J . Org. Chem., Vol. 66, No. 21, 2001
Tanaka et al.
added dropwise with refluxing, and the reaction mixture was
refluxed for 4 h under a nitrogen atmosphere. The residue
obtained by solvent evaporation was poured into water, and
the product was extracted with chloroform twice. The crude
brown liquid product (71%) obtained by solvent evaporation
was used for the subsequent preparation after removing low-
boiling material under vacuum conditions at 100 °C. 1H NMR
(CDCl3, 400 MHz): δ 1.27 (6H, t, J ) 7.6 Hz, CH3), 1.69 (1H,
s, NH), 2.58 (4H, q, J ) 7.3 Hz, SCH2CH3), 2.7-2.8 (12H, m,
SCH2), 2.84 (4H, t, J ) 6.2 Hz, NCH2).
N-Dod ecylm on oa za tr ith ia -12-cr ow n -4 (1). Under a ni-
trogen atmosphere, monoazatrithia-12-crown-4 (446 mg, 2
mmol), bromododecane (747 mg, 3 mmol), sodium carbonate
(530 mg, 5 mmol), and acetonitrile (50 mL) were put into a
three-necked flask, and the reaction mixture was refluxed for
48 h. The cooled reaction mixture was poured into 5 wt %
aqueous sodium hydroxide, and the product was extracted with
chloroform. The product was purified by gel permeation
chromatography to give a 15% yield of 1 as a colorless solid.
Mp: 54-56 °C. 1H NMR (CDCl3, 500 MHz): δ 0.88 (3H, t, J )
7.0 Hz, CH3), 1.2-1.4 (18H, m, (CH2)9), 1.48 (2H, m, NCH2CH2),
2.46 (2H, m, NCH2CH2), 2.6-2.9 (16H, m, SCH2, NCH2). Anal.
Calcd for C20H41NS3: C, 61.38; H, 10.49; N, 3.58; S, 24.55.
Found: C, 61.15; H, 10.47; N, 3.54; S, 24.05. m/z: 391 (M+).
IR (neat, cm-1): 2915, 2845 (-CH2-).
Dodecanoyl chloride (657 mg, 3 mmol) was added dropwise,
and the reaction mixture was stirred for 6 h at room temper-
ature under a nitrogen atmosphere. The reaction mixture was
poured into water, and the product was extracted with
chloroform. The product was purified by gel permeation
chromatography to give 90% of 6 as a colorless solid. Mp: 85-
1
86 °C. H NMR (CDCl3, 500 MHz): δ 0.88 (3H, t, J ) 7.0 Hz,
CH3), 1.2-1.4 (16H, m, (CH2)8), 1.63 (2H, m, COCH2CH2), 2.31
(2H, t, J ) 8.0 Hz, COCH2), 2.7-2.9 (12H, m, SCH2), 3.5-3.6
(4H, m, NCH2). Anal. Calcd for C20H39NOS3: C, 59.26; H, 9.63;
N, 3.46; S, 23.70. Found: C, 59.23; H, 9.96; N, 3.43; S, 23.60.
m/z: 405 (M+). IR (neat, cm-1): 2920, 2845 (-CH2-); 1645
(CdO).
N-Dod eca n oylm on oa za tetr a th ia -15-cr ow n -5 (7). The
preparation procedure was the same as that used for 6, except
monoazatetrathia-15-crown-5 (566 mg, 2 mmol) was used
instead of monoazatrithia-12-crown-4 to give 90% of 7 as a
1
colorless solid. Mp: 71-73 °C. H NMR (CDCl3, 500 MHz): δ
0.88 (3H, t, J ) 8.0 Hz, CH3), 1.2-1.4 (16H, m, (CH2)8), 1.63
(2H, m, COCH2CH2), 2.30 (2H, t, J ) 7.5 Hz, COCH2), 2.7-
2.9 (16H, m, SCH2), 3.4-3.6 (4H, m, NCH2). Anal. Calcd for
C
22H43NOS4: C, 56.77; H, 9.25; N, 3.01; S, 27.53. Found: C,
56.59; H, 9.16; N, 2.97; S, 27.40. m/z: 465 (M+). IR (neat, cm-1):
2920, 2845 (-CH2-); 1635 (CdO).
N-Dod ecylm on oa za tetr a th ia -15-cr ow n -5 (2). The prepa-
ration procedure was the same as that used for 1, except
monoazatetrathia-15-crown-5 (566 mg, 2 mmol) was used
instead of monoazatrithia-12-crown-4 to give 74% of 2 as a
N-Dod eca n oylm on oa za p en ta th ia -18-cr ow n -6 (8). The
preparation procedure was the same as that used for 6, except
monoazapentathia-18-crown-6 (686 mg, 2 mmol) was used
instead of monoazatrithia-12-crown-4 to give 69% of 8 as a
1
colorless solid. Mp: 37-38 °C. H NMR (CDCl3, 500 MHz): δ
1
colorless solid. Mp: 49-50 °C. H NMR (CDCl3, 400 MHz): δ
0.88 (3H, t, J ) 7.0 Hz, CH3), 1.2-1.4 (18H, m, (CH2)9), 1.45
(2H, m, NCH2CH2), 2.50 (2H, t, J ) 7.5 Hz, NCH2CH2), 2.6-
2.9 (20H, m, SCH2, NCH2). Anal. Calcd for C22H45NS4: C,
58.54; H, 9.98; N, 3.10; S, 28.38. Found: C, 58.48; H, 9.98; N,
3.08; S, 28.22. m/z: 451 (M+). IR (neat, cm-1): 2920, 2845
(-CH2-).
0.85 (3H, t, J ) 7.2 Hz, CH3), 1.2-1.4 (16H, m, (CH2)8), 1.61
(2H, m, COCH2CH2), 2.34 (2H, t, J ) 7.6 Hz, COCH2), 2.6-
2.9 (20H, m, SCH2), 3.5-3.7 (4H, m, NCH2). Anal. Calcd for
C
24H47NOS5: C, 54.86; H, 8.95; N, 2.67; S, 30.48. Found: C,
55.00; H, 8.90; N, 2.62; S, 30.17. m/z: 525 (M+). IR (neat, cm-1):
2920, 2850 (-CH2-); 1640 (CdO).
N-Dodecylm on oazapen tath ia-18-cr own -6 (3). The prepa-
ration procedure was the same as that used for 1, except
monoazapentathia-18-crown-6 (686 mg, 2 mmol) and iodo-
dodecane (888 mg, 3 mmol) were used instead of monoaza-
trithia-12-crown-4 and bromododecane, respectively, to give
38% of 3 as a pale-yellow solid. Mp: 42-44 °C. 1H NMR (CDCl3,
400 MHz): δ 0.88 (3H, t, J ) 6.8 Hz, CH3), 1.2-1.4 (18H, m,
(CH2)9), 1.58 (2H, m, NCH2CH2), 2.6-2.9 (26H, m, NCH2CH2-
SCH2, NCH2). Anal. Calcd for C24H49NS5: C, 56.36; H, 9.59;
N, 2.74; S, 31.31. Found: C, 55.97; H, 9.42; N, 2.67; S, 31.33.
m/z: 511 (M+). IR (neat, cm-1): 2920, 2850 (-CH2-).
N-Dod eca n oyl-3,9-d ith ia -6-m on oa za u n d eca n e (9). The
preparation procedure was the same as that used for 6, except
3,9-dithia-6-monoazaundecane (386 mg, 2 mmol) was used
instead of monoazatrithia-12-crown-4 to give 93% of 9 as a
1
colorless liquid. H NMR (CDCl3, 500 MHz): δ 0.88 (3H, t, J
) 7.0 Hz, CH3), 1.2-1.4 (22H, m, SCH2CH3, (CH2)8), 1.6-1.7
(2H, m, COCH2CH2), 2.32 (2H, t, J ) 7.5 Hz, COCH2), 2.5-
2.6 (4H, m, SCH2CH3), 2.68 (4H, q, J ) 8.0 Hz, SCH2), 3.50
(4H, t, J ) 7.5 Hz, NCH2). Anal. Calcd for C20H41NOS2: C,
64.00; H, 10.93; N, 3.73; S, 17.07. Found: C, 63.81; H, 11.08;
N, 3.74; S, 17.04. m/z: 375 (M+). IR (neat, cm-1): 2940, 2845
(-CH2-); 1650 (CdO).
N-Dodecyl-3,9-dith ia-6-m on oazau n decan e (4). The prepa-
ration procedure was the same as that used for 1, except 3,9-
dithia-6-monoazaundecane (386 mg, 2 mmol) was used instead
of monoazatrithia-12-crown-4 to give 56% of 4 as a colorless
N-Dod eca n oyl-3,6,12,15-tetr a th ia -9-m on oa za h ep ta d e-
ca n e (10). The preparation procedure was the same as that
used for 6, except 3,6,12,15-tetrathia-9-monoazaheptadecane
(626 mg, 2 mmol) was used instead of monoazatrithia-12-
crown-4 to give 37% of 10 as a colorless liquid. 1H NMR (CDCl3,
500 MHz): δ 0.88 (3H, t, J ) 8.0 Hz, CH3), 1.2-1.4 (22H, m,
SCH2CH3, (CH2)8), 1.6-1.7 (2H, m, COCH2CH2), 2.32 (2H, t,
J ) 8.0 Hz, COCH2), 2.5-2.6 (4H, m, SCH2CH3), 2.7-2.8 (12H,
1
liquid. H NMR (CDCl3, 500 MHz): δ 0.88 (3H, t, J ) 7.0 Hz,
CH3), 1.2-1.4 (24H, m, SCH2CH3, (CH2)9), 1.54 (2H, m,
NCH2CH2), 2.58 (4H, q, J ) 7.3 Hz, SCH2CH3), 2.6-2.9 (10H,
m, SCH2, NCH2). Anal. Calcd for C20H43NS2: C, 66.48; H,
11.91; N, 3.88; S, 17.73. Found: C, 65.83; H, 11.85; N, 3.83; S,
17.43. m/z: 361 (M+). IR (neat, cm-1): 2920, 2850
(-CH2-).
N -Dod e cyl-3,6,12,15-t e t r a t h ia -9-m on oa za h e p t a d e -
ca n e (5). The preparation procedure was the same as that
used for 1, except 3,6,12,15-tetrathia-9-monoazaheptadecane
(626 mg, 2 mmol) and iodododecane (888 mg, 3 mmol) were
used instead of monoazatrithia-12-crown-4 and bromodode-
cane, respectively, to give 12% of 5 as a colorless liquid. 1H
NMR (CDCl3, 500 MHz): δ 0.88 (3H, t, J ) 7.5 Hz, CH3), 1.2-
1.4 (24H, m, SCH2CH3, (CH2)9), 1.43 (2H, m, NCH2CH2), 2.57
(4H, q, J ) 7.3 Hz, SCH2CH3), 2.6-2.8 (18H, m, SCH2, NCH2).
Anal. Calcd for C24H51NS4: C, 59.88; H, 10.60; N, 2.91; S,
26.61. Found: C, 60.14; H, 10.46; N, 2.81; S, 26.33. m/z: 481
(M+). IR (neat, cm-1): 2920, 2845 (-CH2-).
m, SCH2), 3.5-3.6 (4H, m, NCH2). Anal. Calcd for C24H49
-
NOS4: C, 58.18; H, 9.90; N, 2.83; S, 25.86. Found: C, 57.92;
H, 9.95; N, 2.86; S, 25.86. m/z: 495 (M+). IR (neat, cm-1): 2920,
2845 (-CH2-); 1650 (CdO).
Solven t Extr a ction . Equal volumes (10 mL) of a chloro-
form solution containing a thiacrown ether (1 × 10-4 mol dm-3
for dodecyl- and 1 × 10-3 mol dm-3 for dodecanoylthiacrown
ethers) and an aqueous solution of metal picrates (5 × 10-5
mol dm-3) were thoroughly shaken in a 50 mL flask at 30 °C.
The picrate concentration in the organic phase was determined
by following its absorbance decrease in the aqueous phase. In
control experiments, no distribution of thiacrown ether to the
aqueous phase was observed under these conditions.
N-Dod eca n oylm on oa za tr ith ia -12-cr ow n -4 (6). Under a
nitrogen atmosphere, monoazatrithia-12-crown-4 (446 mg, 2
mmol), triethylamine (303 mg, 3 mmol), and chloroform (50
mL) were put into a three-necked flask at room temperature.
J O015709I