Synthesis and properties of new macrocyclic compounds: Utilization of bond character of hypervalent sulfur in tetraazathiapentalene derivatives

Article abstract of DOI:10.1002/jhet.5570420621

2,3-Bis[(p-isothiocyanatomethylphenyl)methyl]-6,7-dihydro-5H-2a-thia(2a- S^IV)-2,3,4a,7a-tetraazacyclopent[cd]indene-1,4(2H,3H)-dithione (3), prepared by the reaction of 2,3-dimethyl-6,7-dihydro-5H-2a-thia(2a-S ^IV)-2,3,4a,7a-tetraazac

Full text of DOI:10.1002/jhet.5570420621

Sep-Oct 2005
1175
Synthesis and Properties of New Macrocyclic Compounds:
Utilization of Bond Character of Hypervalent Sulfur in
Tetraazathiapentalene Derivatives
Noboru Matsumura,* Ryuji Hirase, Shigeki Kamitani, Yasuyuki Okumura,
and Kazuhiko Mizuno*
Department of Applied Chemistry, Graduate School of Engineering, Osaka Prefecture university, Sakai,
Osaka 599-8531, Japan
Received June 30, 2004
IV
2,3-Bis[(p-isothiocyanatomethylphenyl)methyl]-6,7-dihydro-5H-2a-thia(2a-S )-2,3,4a,7a-tetraaza-
cyclopent[cd]indene-1,4(2H,3H)-dithione (3), prepared by the reaction of 2,3-dimethyl-6,7-dihydro-5H-2a-
IV
thia(2a-S )-2,3,4a,7a-tetraazacyclopent-[cd]indene-1,4(2H,3H)-dithione (1) with p-xylylene diisothio-
cyanate, reacted with N,N'-dialkyl substituted diamines to give macrocyclic compounds bearing hypervalent
sulfur by a ring closure reaction in good yields. These macrocyclic compounds were converted into ring-
expanded macrocyclic compounds with release of the hypervalent sulfur by treating with NaBH and
4
CF COOH.
3
J. Heterocyclic Chem., 42, 1175 (2005).
Introduction.
at the 6 position of 1 gave the ring-opened compound bear-
ing two thiourea groups with elimination of the C=S
IV
π-Hypervalent heterocyclic systems have attracted con-
siderable attention because of their unusual structure and
reactivity [1]. An example of such systems is compounds
containing a 10-S-3 sulfurane species, and their chemistry
has extensively been studied [2-3]. However, little is
reported about the utility of the bond character of the
hypervalent sulfur in these π-electron systems in organic
synthesis. Previously, we have reported an efficient
method for the synthesis of 10-S-3 tetraazathiapentalene
derivatives, 2,3-disubstituted 6,7-dihydro-5H-2a-thia(2a-
moiety [8]. On the basis of these results, we have recently
synthesized macrocyclic compounds that contain thiourea
groups in the ring and are soluble in organic solvents [8-9].
These macrocyclic compounds have been shown to be use-
ful as anion receptors [10]. We now report a new method
for preparing new macrocycles having a π-hypervalent
sulfur in the ring and the subsequent conversion of these
macrocycles to new compounds that bear various func-
tional groups such as thiourea moiety, amino group, ether
chain, and carbonyl groups in the ring via various ring-
opening reactions [11].
IV
S )-2,3,4a,7a-tetraazacyclopent[cd]-indene-1,4(2H,3H)-
dithiones, and have found that they undergo unique reac-
tions that depend on the nature of the hypervalent sulfur
[4]. For example, the reaction of the tetraazathiapentalene
derivative 1 with an excess of isothiocyanates and iso-
cyanates gave substituted tetraazathiapentalene derivatives
bearing thiocarbonyl and carbonyl groups in the com-
Result and Discussion.
Synthesis of Tetraazathiapentalene Derivative 3.
p-Xylylene diisothiocyanate [12-13] was added to a
stirred solution of 1, which was prepared by a one-pot
reaction using lithium cyclic thioureide/phenacyl chlo-
ride/methyl isothiocyanate reagent system [14], in dry ben-
zene, and the mixture was heated at 50 °C for 24 hours.
Work-up of the reaction mixture gave the tetraazathiapen-
talene derivative 3 as a colorless solid in 46% yield from 1,
together with tetraazathiapentalene derivative 2 in 33%
yield. Compounds 2 and 3 were stable in air and highly
soluble in organic solvents.
pounds [5]. The reaction of 1 with NaBH and LiAlH
4
4
gave the ring-opened compound, 1,3-bis(methylthiocarba-
moyl)-perhydropyrimidine, in good yield with release of
the hypervalent sulfur [6]. Furthermore, treatment of 1
with acids gave the ring-opening product, 1,3-dimethyl
perhydropyrimidin-2-one, in high yield with release of the
hypervalent sulfur [7]. The alkaline hydrolysis of the
tetraazathiapentalene derivative that contains octyl group

1176
N. Matsumura, R. Hirase, S. Kamitani, Y. Okumura, and K. Mizuno
Vol. 42
Synthesis of Macrocyclic Compounds Bearing Hyperalent
Sulfur.
The ring closure reactions of 3 with an equimolar
amount of N,N'-dialkyl substituted diamines such as
1,2-bis(ethylamino)ethane (4a), 1,6-bis(methylamino)-
hexane (4b), 1,5-bis(ethylamino)-3-oxapentane (4c),
1,8-bis(ethylamino)-3,6-dioxaoctane (4d), and 2,6-
bis(ethylaminomethyl)pyridine (4e) were carried out in
DMSO at room temperature for 48 hours (Scheme 2).
The 23-29 membered macrocyclic compounds 5a-e that
bear the tetraazathiapentalene ring were obtained in
good yields (Table 1) with the recovery of a small
amount of 3.

Sep-Oct 2005
Synthesis and Properties of New Macrocyclic Compounds
1177
1
lent sulfur in fair to good yields (Table 3).
In the H-NMR spectra of 6a-e (Table 4), a charac-
In the H-NMR spectra of 5a-e (Table 2), all the com-
pounds showed a singlet at 4.67-4.88 ppm due to benzyl
protons attached to the 2,3-positions in the tetraazathiapen-
talene ring, indicating that these compounds are symmetri-
cal molecules. They are also soluble in polar solvents and
stable in air. The reaction of 3 with primary diamines gave
complex mixtures.
1
teristic peak due to the N-CH -N protons was
2
observed as a singlet at around 5.6 ppm, indicating
that the molecules possess the ring-expanded struc-
tures as represented in Scheme 3 with release of the
hypervalent sulfur.
Ring Expansion of 5 by use of Sodium Borohydride.
Ring Opening Reaction of 5e in Acidic Conditions.
Previously, we found that 1 is converted into the ring-
opened compound, 1,3-bis(methylthiocarbamoyl)-
perhydropyrimidine, by reductive elimination of the
Previously, we found that treatment of 10-S-3 tetraaza-
thiapentalene derivatives under acidic conditions affords
the ring-opening products, 1,3-disubstituted perhydropy-
rimidin-2-ones, in high yields with release of the hyperva-
lent sulfur [7]. For example, 1 undergoes a ring-opening
reaction by treating with 10% hydrochloric acid to give
1,3-bis(methylthiocarbamoyl)perhydropyrimidin-2-one
with release of the hypervalent sulfur [7]. We applied this
reaction to the ring opening reaction of the macrocyclic
hypervalent sulfur with NaBH [6].
4
We applied this reaction to the ring-opening reaction of
the macrocyclic compounds 5a-e. Sodium borohydride
was added in large excess (ten equiv.) to solutions of 5a-e
in DMSO or 2-propanol at room temperature. The solu-
tions changed immediately from colorless to emerald
green. After complete fading of the color, the mixtures
were stirred for 48 hours. Usual work-up of the reaction
mixtures gave the stable ring expanded 27-33 membered
macrocyclic compounds 6a-e with release of the hyperva-
compound 5e (Scheme 4).
The ring-opening reaction of 5e with 10% hydrochloric
acid under similar conditions did not proceed successfully.
However, when a solution of 5e in 50% aqueous trifluo-

1178
N. Matsumura, R. Hirase, S. Kamitani, Y. Okumura, and K. Mizuno
Vol. 42
1
Furthermore, in the H- NMR spectrum, a new broad NH
peak appeared at 10.72 ppm. These results suggest that a
hydrogen bond between NH and CO groups is forming.
Conclusions.
In this investigation, we successfully synthesized the
reactive hypervalent sulfur compound 3 that bears the p-
xylyleneisothiocyanate function at the 2,3-positions of the
tetraazathiapentalene derivative. Compound 3 was con-
verted into the new macrocyclic compounds 5a-e by the
reaction with substituted diamines containing various spac-
ers. The macrocycles 5a-e were further converted into ring-
expanded macrocyclic compounds. Treatment of 5a-e with
sodium borohydride afforded the new ring-opened macro-
roacetic acid was stirred at 50 °C for 24 hours, the carbonyl-
containing product 7 was obtained in 30% yield along with
50% recovery of 5e. Reactions of 5c-d with aqueous triflu-
oroacetic acid under similar conditions gave complex mix-
tures. In the IR spectrum of 7, a carbonyl absorption due to
cyclic compounds 6a-e that bear the thiourea function and
various spacers such as alkyl chain, ether chain, and pyri-
dine ring. Hydrolysis of 5e with trifluoloacetic acid pro-
moted the ring-opening reaction to give the macrocyclic
compound 7 that bears the 1,3-disubstituted perhydropyrim-
idin-2-one ring in the molecule. The macrocyclic
-1
the N-CO-N moiety was observed at 1650 cm .

Sep-Oct 2005
Synthesis and Properties of New Macrocyclic Compounds
1179
Compound 3 had a mp 244-246 °C (decomp.); ir (KBr): 2180,
compounds synthesized in this paper are expected to have a
potential utility in the field of complexation and host-guest
chemistry. The reported methodology provides a useful tool
for the synthesis of macrocyclic compounds.
2100, 1580, 1530, 1480, 1420, 1330, 1310, 1240, 1145, 915, 805,
-1
1
740, and 715 cm
;
H nmr (CDCl ) δ 2.36 (m, 2H,
3
NCH CH CH N), 4.40 (t, 4H, NCH CH CH N, J = 6.0 Hz),
2
2
2
2
2
2
4.71 (s, 4H, 2x NCH ), 4.88 (s, 4H, 2x CH NCS), 7.27-7.36 (m,
2
2
13
8H, aromatic); C nmr (CDCl ) δ 19.98, 44.97, 48.47, 48.73,
127.20, 127.51, 129.32, 133.89, 136.84, 156.59, 170.00.
3
EXPERIMENTAL
Anal. Calcd. for C
H N S : C, 51.96; H, 4.00; N, 5.15.
24 22 6 5
All the solvents used in this study were purified by usual proce-
dures. Column chromatography was performed on silica gel
Found: C, 51.80; H, 3.79; N, 14.85.
Ring Closure Reactions of 3 with Substituted Diamines 4.
Typical Procedure.
1
13
(Merck, 70-230 mesh). H-NMR and C-NMR spectra were
recorded on a JEOL JNM-GX (270 MHz) using TMS as an internal
standard. IR spectra were obtained with a PERKIN ELMER 1600
FT IR spectrometer. Mass spectra were obtained using a JEOL-
DX303HF spectrometer with FAB ionization. Melting points were
determined on a Yanagimoto MP-S3 melting point apparatus and
were uncorrected. Elemental analyses were recorded on a
Yanagimoto MT-3 CHN recorder. Purifications of products were
conducted by column chromatography on silica gel (Wakogel C-
300) or by preparative tlc on silica gel (Merck Kieselgel 60 GF 254).
To a solution of 3 (60 mg, 0.108 mmol) in DMSO (30 mL) was
added an equimolar amount of 2,6-bis(ethylaminomethyl)pyridine
(4e) (20.9 mg, 0.108 mmol). The reaction mixture was stirred at
room temperature for 48 hours, poured into water, and the solution
was extracted with chloroform. The extract was washed with
water, dried over sodium sulfate, and concentrated under reduced
pressure. The residue was chromatographed on a silica gel column
with dichloromethane/ethylacetate (4/1) to give the macrocylic
compound 5e (55.7 mg, 69%). Recrystallization from chloro-
form/n-hexane gave an analytically pure compound.
Materials.
IV
2,3-Dimethyl-6,7-dihydro-5H-2a-thia(2a-S )-2,3,4a,7a-
tetraazacyclopent[cd]indene-1,4 (2H,3H)-dithione (1) [14], p-
xylylenediisothiocyanate [11-12], 1,5-bis(ethylamino)-3-oxapen-
tane (4c) [15], 1,8-bis(ethylamino)-3,6-dioxaoctane (4d) [16],
and 2,6-bis(ethylaminomethyl)pyridine (4e) [17] were prepared
according to the procedures described in the literature.
Reduction of Macrocylic Compounds 5 with Sodium
Borohydride.
A typical Procedure.
Ten equivalents of sodium borohydride (36 mg, 0.94 mmol) was
added to a stirred solution of 5c (67.2 mg, 0.094 mmol) in dry
DMSO (30 mL), and the mixture was stirred at room temperature for
48 hours. The reaction mixture was poured into water, and the solu-
tion was extracted with chloroform. The extract was washed with
water, dried over sodium sulfate and concentrated under reduced
pressure. The residue was chromatographed on a silica gel column
with dichloromethane/ethylacetate (4/1) to give the ring-opened
macrocylic compound 6c (42.5 mg, 66%). Recrystallization from
n-hexane/chloroform afforded an analytically pure compound.
Reaction of 1 with p-Xylylenediisothiocyanate.
p-Xylylene diisothiocyanate (881 mg, 4.0 mmol) was added to
a stirred solution of 1 (104 mg, 0.40 mmol) in dry benzene (20
mL) and the mixture was heated at 50 °C for 24 hours. After
removal of benzene under reduced pressure, the residue was chro-
matographed on silica gel with chloroform to give 2,3-bis[(p-
isothiocyanatomethylphenyl)methyl]-6,7-dihydro-5H-2a-thia(2a-
IV
S )-2,3,4a,7a-tetra-azacyclopent[cd]indene-1,4(2H,3H)-dithione
(3) (101 mg, 46%) and 2-methyl-3-[(p-isothiocyanatomethyl-
IV
Ring-opening Reaction of Macrocylic Compound 5e under
phenyl)methyl]-6,7-dihydro-5H-2a-thia(2a-S )-2,3,4a,7a-tetra-
Acidic Conditions.
azacyclopent[cd]indene-1,4(2H,3H)-dithione (2) (54 mg, 33%) as
colorless solids together with the recovery of a small amount of 1.
Recrystallization of 2 and 3 from chloroform/n-hexane gave the
analytically pure compounds.
Compound 5e (55 mg, 0.074 mmol) was stirred in 50% triflu-
oroacetic acid (20 mL) at 50 °C for 24 hours. After cooling to
room temperature, the reaction mixture was poured into water
and neutralized with a saturated aqueous solution of sodium car-
bonate. The mixture was extracted several times with chloro-
form. The chloroform layers were combined, washed with water,
dried over sodium sulfate, and concentrated under reduced pres-
sure. The residue was chromatographed on a silica gel column
with dichloromethane/ethylacetate (4/1) to give 7 (16.3 mg,
30%). Recrystallization from chloroform/n-hexane gave an ana-
lytically pure compound; mp 191-192 °C (decomp.); IR (KBr):
3250, 2930, 1650, 1535, 1405, 1335, 1280, 1190, 1100, 1060,
2-Methyl-3-[(p-isothiocyanatomethyphenyl)methyl]-6,7-dihy-
IV
dro-5H-2a-thia(2a-S )-2,3,4a,7a-tetraazacyclopent[cd]indene-
1,4 (2H,3H)-dithione (2).
Compound 2 had a mp 247-248 °C (decomp.); ir (KBr):
2180, 2100, 1580, 1540, 1490, 1400, 1360, 1315, 1245, 1190,
-1
1
1150, 1050, 955, 940, and 740 cm ; H nmr (CDCl ): δ 2.36
3
(m, 2H, NCH CH CH N), 3.18 (s, 3H, CH ), 4.40 (t, 2H,
2
2
2
3
NCH CH CH N, J= 6.1 Hz), 4.43 (t, 2H, NCH CH CH N,
2
2
2
2
2
2
J=6.1Hz), 4.69 (s, 2H, NCH C H ), 4.94 (s, 2H,C H -
2
6
4
6
4
-1
1
960, 860, and 750 cm ; H NMR (CDCl ): δ 1.19 (t, 6H, 2x
3
13
CH NCS), 7.27-7.41 (m, 4H, aromatic); C nmr (CDCl ): δ
20.02, 31.18, 44.95, 48.38, 48.45, 127.18, 128.98, 133.67,
137.09, 156.27, 169.71, 170.20.
2
3
NCH CH , J = 7.0 Hz), 2.11 (m, 2H, NCH CH CH N), 3.82 (q,
2
3
2
2
2
4H, 2x NCH CH , J = 7.1 Hz), 4.37 (t, 4H, NCH CH CH N, J =
2
3
2
2
2
6.1 Hz), 4.72 (s, 4H, 2x NCH C H N), 4.81 (d, 4H, 2x
2
5
3
Anal. Calcd. for C H N S : C, 47.15; H, 4.20; N, 17.18.
16 17
5 4
C H CH NH, J = 4.9 Hz), 4.89 (d, 4H, 2x NHCH C H , J = 3.1
6
4
2
2 6 4
Found: C, 46.92; H, 3.98; N, 16.90.
Hz), 7.05-7.78 (m, 13H, aromatic, 2x C H CH NH), 10.72 (brs,
6
4
2
13
2,3-Bis[(p-isothiocyanatomethylphenyl)methyl]-6,7-dihydro-
2H, 2x C H CH NHCSNCO); C NMR (CDCl ): δ 12.44,
6
4
2
3
IV
5H-2a-thia(2a-S )-2,3,4a,7a-tetraazacyclopent[cd]indene-
22.67, 47.07, 49.12, 49.50, 51.28, 55.00, 121.70, 128.27, 128.35,
135.53, 138.36, 138.79, 156.49, 157.36, 183.16, 183.42.
1,4(2H,3H)-dithione (3).

1180
N. Matsumura, R. Hirase, S. Kamitani, Y. Okumura, and K. Mizuno
Vol. 42
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Found: C, 57.54; H, 5.98; N, 17.36.
35 43
9
4
Acknowledgment.
This work was supported by a Grant-in Aid for Scientific
Research from the Ministry of Education, Science, Sports and
Culture of Japan, to which the authors wish to express their grate-
ful acknowledgment.
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