Synthesis and separation of stereoisomeric 2,4,6,8-tetrasubstituted 3,7-dithia-1,5-diazabicyclo[3.3.0]octanes

Article abstract of DOI:10.1007/s11172-012-0020-y

Heterocyclization of hydrazine with aldehydes R-CHO (R = Me, Et, Pr ⁿ, Buⁿ, n-C₅H₁₁, Ph, 4-MeOC ₆H₄, 3-Py) and H₂S leads to stereoisomeric 2,4,6,8-tetrasubstituted 3,7-dithia- 1,

Full text of DOI:10.1007/s11172-012-0020-y

Russian Chemical Bulletin, International Edition, Vol. 61, No. 1, pp. 141—147, January, 2012
141
Synthesis and separation of stereoisomeric 2,4,6,8ꢀtetrasubstituted
3,7ꢀdithiaꢀ1,5ꢀdiazabicyclo[3.3.0]octanes
V. R. Akhmetova,a N. N. Murzakova,a G. R. Khabibullina,a T. V. Tyumkina,a Z. A. Starikova,b
I. S. Bushmarinov,b and L. F. Korzhovac
aInstitute of Petrochemistry and Catalysis, Russian Academy of Sciences,
141 prosp. Oktyabrya, 450075 Ufa, Russian Federation.
Fax: +7 (347) 284 2750. Eꢀmail: ink@anrb.ru
bA. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences,
28 ul. Vavilova, 119991 Moscow, Russian Federation.
Fax: +7 (499) 135 5085. Eꢀmail: star@xray.ineos.ac.ru
cBashkir Republican Research Environmental Center,
147 prosp. Oktyabrya, 450075 Ufa, Russian Federation.
Fax: +7 (347) 284 3503. Eꢀmail: ecocnt@diaspro.ru
Heterocyclization of hydrazine with aldehydes R—CHO (R = Me, Et, Prn, Bun, nꢀC5H11
,
Ph, 4ꢀMeOC6H4, 3ꢀPy) and H2S leads to stereoisomeric 2,4,6,8ꢀtetrasubstituted 3,7ꢀdithiaꢀ
1,5ꢀdiazabicyclo[3.3.0]octanes, which were separated by column chromatography. The
transꢀtransoidꢀtransꢀconfiguration of tetramethyl(ꢀethyl,ꢀpropyl)ꢀ3,7ꢀdithiaꢀ1,5ꢀdiazabicycloꢀ
[3.3.0]octanes was inferred from the Xꢀray diffraction and 1H and 13C NMR spectroscopic data.
Key words: heterocyclization, hydrazine, aldehydes, hydrogen sulfide, 2,4,6,8ꢀtetraꢀ
alkyl(aryl)ꢀ3,7ꢀdithiaꢀ1,5ꢀdiazabicyclo[3.3.0]octanes, Xꢀray diffraction analysis.
Heterocycles1,2 of thiadiazolidine series exhibit various
biological activity. 3,7ꢀDithiaꢀ1,5ꢀdiazabicyclo[3.3.0]ꢀ
octane containing fused thiadiazolidine rings was for the
first time3 synthesized from hydrazine, formaldehyde, and
H2S in 11% yield. Recently,4,5 we have suggested imꢀ
proved methods for its preparation in 76 and 80% yields.
We studied conformational features of this bicyclane in
both the crystalline phase6 and the solution.4 In the crysꢀ
tal, molecules of this compound adopt the cisꢀconformaꢀ
tion and retain the second order symmetry C2h. In CDCl3
solution at 24.5 C, a conformational equilibrium between
the cisꢀforms of 3,7ꢀdithiaꢀ1,5ꢀdiazabicyclo[3.3.0]octane
is observed due to the inversion of the nitrogen atoms.
To develop efficient methods for the synthesis of alkylꢀ
and arylꢀsubstituted 3,7ꢀdithiaꢀ1,5ꢀdiazabicyclo[3.3.0]ꢀ
octanes, we studied a thiomethylation reaction of hydraꢀ
zine with aliphatic and aromatic aldehydes and H2S, as
well as stereochemistry of the crystalline 2,4,6,8ꢀtetrasubꢀ
stituted 3,7ꢀdithiaꢀ1,5ꢀdiazabicyclo[3.3.0]octanes.
order of mixing the starting reagents7) leads to heteroꢀ
cycles of 1,3,4ꢀthiadiazolidine and 1,3,5ꢀdithiazinane
series.
In the present work, we show that a preliminary bubꢀ
bling hydrogen sulfide through acetic aldehyde 1 with subꢀ
sequent dropwise addition of hydrazine at temperatures
below –10 C regiospecifically leads to 2,4,6,8ꢀtetramethylꢀ
3,7ꢀdithiaꢀ1,5ꢀdiazabicyclo[3.3.0]octane 2 (R = Me) in more
than 64% yield. According to the 1H and 13C NMR specꢀ
troscopic data and GCꢀMS analysis, bicycle 2 is formed
as a mixture of stereoisomers 2a—d (Scheme 1, Table 1).
Scheme 1
Results and Discussion
Earlier, we have found that cyclothiomethylation of
hydrazine with formaldehyde and H2S, depending on the
molar ratio of the starting reagents, temperature,4 and
medium pH5 (in the case of acetic aldehyde, also on the
R = Me (1, 2); Et (3, 7); Prn (4, 8); Bun (5, 9); nꢀC5H11 (6, 10);
Ph (11, 14); 4ꢀMeOC6H4 (12, 15); 3ꢀPy (13, 16)
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 1, pp. 139—145, January, 2012.
1066ꢀ5285/12/6101ꢀ141 © 2012 Springer Science+Business Media, Inc.

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Akhmetova et al.
Table 1. Conditions of separation by column chromatography, physicochemical characteristics, and yields of stereoꢀ
isomeric 2,4,6,8ꢀtetraalkylꢀ3,7ꢀdithiaꢀ1,5ꢀdiazabicyclo[3.3.0]octanes 2 and 7—10
R1
Separation conditions
Support Eluent
Product
Rf
Physical
state
Yield
(%)
Me
SiO2—
—AgNO3
(5%)
nꢀC6H14—EtOAc—
—СHСl3 (5 : 1 : 1)
2a
2b
2c
2d
7а
7b
7c
7d
8a
8b
8c
8d
9b
9c
0.55
0.59
0.61
0.63
0.58
0.63
0.67
0.53
0.53
0.62
0.69
0.57
0.56
0.66
0.78
0.57
0.68
0.75
Crystal
Oil
Oil
31
18
7
7
Et
Activated
charcoal
(AGꢀ5)
CH2Cl2—
—СHСl3 (2 : 1)
Crystal
Oil
Oil
42
21
8
8
Prn
Bun
Activated
charcoal
(AGꢀ5)
CH2Cl2—
—СHСl3 (2 : 1)
Crystal
Oil
Oil
48
17
11
11
52
20
22
54
34
12
SiO2—
—AgNO3
(5%)
Light petroleum
—CH2Cl2 (5 : 3)
Oil
Oil
Oil
Oil
Oil
Oil
9d
10b
10c
10d
nꢀC5H11 SiO2—
—AgNO3
(5%)
nꢀC6H14—EtOAc—
—СHСl3 (5 : 1 : 1)
Heterocyclization of hydrazine with other aliphatic
scopy. The crystalline compounds 2a and 8a were studied
by Xꢀray diffraction, too (Figs 1 and 2).
aldehydes RCHO (R = Et (3), Prn (4), Bun (5), nꢀC5H11 (6))
and H2S similarly gave a series of the correspondꢀ
ing 2,4,6,8ꢀtetraalkylꢀ3,7ꢀdithiaꢀ1,5ꢀdiazabicyclo[3.3.0]ꢀ
octanes 7—10 as mixtures of stereoisomers. At the same
time, the condensation of hydrazine with aromatic aldeꢀ
hydes RCHO 11, 13 (R = Ph, 3ꢀPy) and H2S gave only
one stereoisomer of 2,4,6,8ꢀtetraarylꢀ3,7ꢀdithiaꢀ1,5ꢀdiꢀ
azabicyclo[3.3.0]octanes 14, 16, whereas in the case
of anisaldehyde 12 (R = 4ꢀMeOC6H4), stereoisomeric
2,4,6,8ꢀtetrakis(4ꢀmethoxyphenyl)ꢀ3,7ꢀdithiaꢀ1,5ꢀdiazaꢀ
bicyclo[3.3.0]octanes 15 were obtained.
The 1H NMR spectrum of the unseparated stereoꢀ
isomeric mixture of bicycle 2 at 20 C exhibits two broad
signals corresponding to the methyl (H 1.13—1.82,
W1/2 = 60 Hz) and methine groups (H 4.10—4.90,
W1/2 = 60 Hz) in the indicative regions, whereas in the
relatively lowꢀfield, narrow region of the 13C NMR specꢀ
trum  61.30—69.50, seven signals for the CH carbon
atoms are observed, as well as seven resonances for the
methyl groups (C 18.10—25.90). The GCꢀMS data show
that 2,4,6,8ꢀtetraalkylꢀ3,7ꢀdithiaꢀ1,5ꢀdiazabicyclo[3.3.0]ꢀ
octanes 2, 7, and 8 were obtained as mixtures of four
isomers with different configuration of alkyl substituents,
whereas 9 and 10, as mixtures of three isomers. The mass
spectra of stereoisomeric bicyclanes 2a—d are identical,
but differ in the Kovach indices.8 Thus, for isomers 2a, 2b,
and 2c, the Kovach indices, determined experimentally
(GCꢀMS), are 1500, 1550, and 1530, respectively.
Obviously, formation of bicyclanes proceeds via the
intermediacy of compounds 17—19 (Scheme 2). Cyclizaꢀ
tion of intermediates 18 and 19 is effected with eliminaꢀ
tion of water (see Scheme 2).
The stereoisomeric mixtures of compounds 2 and 7—10
were characterized by 1H and 13C NMR spectra and anaꢀ
lyzed by gas chromatoꢀmass spectrometry (GCꢀMS). Inꢀ
dividual stereoisomers of the synthesized bicycles 2 and
7—10 were isolated by column chromatography (see
Table 1) and characterized by 1H and 13C NMR spectroꢀ
For the isolation of individual stereoisomeric bicycles
(2 and 7—10), we selected conditions for their efficient
separation by column chromatography (see Table 1).
Scheme 2

3,7ꢀDithiaꢀ1,5ꢀdiazabicyclo[3.3.0]octanes
Russ.Chem.Bull., Int.Ed., Vol. 61, No. 1, January, 2012
143
C(7)
C(10)
O(5)
C(6)
C(6)
C(5)
C(9)
S(1)
C(1)
N(1)
C(8)
C(2´)
C(3)
C(2)
O(3´)
C(2)
N(2)
C(3)
N(1)
S(1)
S(2)
C(4)
C(11)
C(14)
C(16)
N(2)
S(2)
C(15)
C(13)
C(12)
C(1´)
C(4)
C(4´)
C(1)
Fig. 2. Molecular structure of 8a. The atoms are given as thermal
ellipsoids with p = 50%.
C(7)
C(8)
major fragment. Both fiveꢀmembered rings are in the twistꢀ
envelope conformation, and the net conformation of the
bicycle can be described as the endoꢀendo kind, with all
the methyl groups being in the equatorial positions TTT.
Fig. 1. Molecular structure of 2a. The atoms are shown as therꢀ
mal ellipsoids with p = 50%, the minor disordered position are
shown in the dashed lines.
1
In the H NMR spectrum of compound 2a, the CH3
and CH groups are found as four magnetically nonequivaꢀ
lent signals: two singlets at H 1.40, 1.50 and two unsplited
singlets at H 4.50, 5.20, respectively. The 13C NMR specꢀ
trum also contains two signals both in the highꢀfield and
both in the lowꢀfield regions at C 18.50, 26.40 and 64.76,
66.30, respectively. The shape of the signals indicates
a slow conformational exchange in the NMR time scale
between conformers A and B (Scheme 3).4 Quantum
chemical calculations (B3LYP/6ꢀ31G(d,p), Gamess)
show that conformer A predominates.
Activated charcoal, Al2O3, SiO2, as well as SiO2 imꢀ
pregnated with AgNO3—H2O, were used as adsorbents.
The best results in the separation of isomeric dithiadiꢀ
azabicyclooctanes 2 were obtained with column chromatoꢀ
graphy on SiO2 impregnated with AgNO3—H2O (5%).9
A gradual evaporation at room temperature of the eluꢀ
ent from the fraction with Rf 0.55 afforded crystals, which
were studied by Xꢀray diffraction. The compound was deꢀ
termined to be the transꢀtransoidꢀtransꢀisomer (TTT) 2a.
Bicycle 2a is disordered, with the population of the
major and the minor positions being 0.887 and 0.113, reꢀ
spectively. The two disordered fragments possess identical
conformations and can be described as enantiomers with
common of the sulfur and the nitrogen atoms and the
methyl groups (see Fig. 1). In our further descriptions of
the bicycle geometry, we will use the data for only the
1
The H and 13C NMR spectra of the second stereoꢀ
isomer 2b (an oily product with Rf 0.59) exhibit two sigꢀ
nals each: at H 1.45 (J = 4 Hz), 4.52 (3J = 4 Hz) and C
29.80, 61.90. Taking into account molecular symmetry, it
was suggested that two signals can be attributed to the
cisꢀcisoidꢀcisꢀisomers (CCC) 2b, with either equatorial or
axial arrangement of the methyl groups.
Scheme 3

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Russ.Chem.Bull., Int.Ed., Vol. 61, No. 1, January, 2012
Akhmetova et al.
1
In each of H and 13C NMR spectra of the third oily
values are close in the unsubstituted dithiadiazabicycloꢀ
octane, where the difference is6 0.0462 Å. The C—N bond
distances considerably differ too: N(1)—C(2) (1.448(2) Å),
N(1)—C(3) (1.514(2) Å) and N(2)—C(4) (1.451(1) Å),
N(2)—C(1) (1.515(2) Å) in the molecule of 2a,
N(1)—C(1) (1.459(7) Å), N(1)—C(4) (1.507(7) Å) and
N(2)—C(3) (1.471(7) Å), N(2)—C(2) (1.499(8) Å) in the
molecule of 8a. Therefore, the difference in the lengths of
chemically equivalent C—N bonds is 0.066 and 0.064 Å in
the molecule of 2a, 0.048 and 0.028 Å in the molecule of
8a. In the unsubstituted dithiadiazabicyclooctane, this difꢀ
ference is 0.0458 Å. The observed differences in the equivꢀ
alent C—S and C—N bonds is accounted for by different
stereoelectron interactions of the lone pair of electrons on
the nitrogen atom lpꢀN—C—S.7
isomer 2c (the fraction with Rf 0.61), three signals are
observed: at H 4.37, 4.39, 5.34 and C 61.80, 67.30, 69.30.
The signals for the methine carbon atoms of the ring are
found in the lowꢀfield region of the spectrum, the signals
at C 17.60, 23.40, 25.86, and 28.10 due to the Me substitꢀ
uents are found, as well.
These conditions selected for the column chromatoꢀ
graphy separation did not allow us to isolate the fourth
isomer 2d in the individual state, therefore, the correꢀ
sponding to it signals were obtained by subtraction of the
signals assigned earlier for three other isomers 2a—c from
the spectrum of the unseparated mixture of isomers. In
addition, we used homoꢀ and heteronuclear experiments
COSY and HSQC to reveal the H—H spin systems and
the C—H interactions. Thus, the signals at C 25.1 and
66.0 in the 13C NMR spectrum and at H 1.50 and 4.35
in the 1H NMR spectrum were assigned to the fourth
stereomer.
The crystal packing in the structures of interest is mainꢀ
ly determined by the van der Waals interactions between
alkyl substituents, the shortest contacts are S...H 3.11 Å,
N...H 2.58 Å (see Fig. 3).
It should be noted that in the 1H NMR spectra of
stereoisomers 2b—d recorded in the temperature interval
20—60 C, a clear splitting of the signals for the methane
and methyl protons is observed. It indicates that the conꢀ
formational equilibrium is shifted toward the endoꢀendoꢀ
conformer A (see Scheme 3) already at room temperature.
To sum up, heterocyclization of hydrazine with acetic
aldehyde and H2S leads to four isomers of 2,4,6,8ꢀtetraꢀ
methylꢀ3,7ꢀdithiaꢀ1,5ꢀdiazabicyclo[3.3.0]octane 2a—d in
the endoꢀendoꢀconformation with different configurations
of the methyl groups, three of these isomers were isolated
by column chromatography in the individual state
(see Table 1).
Similar pattern is observed in the reaction of hydrꢀ
azine with propionaldehyde (3) or butyraldehyde (4) and
H2S (see Scheme 1): four stereoisomeric 2,4,6,8ꢀtetraꢀ
ethylꢀ and tetrapropylꢀsubstituted bicyclanes 7 and 8
were synthesized, whose isolation was performed by
column chromatography on AGꢀ5 activated charcoal (see
Table 1).
According to the Xꢀray diffraction data, the molecule
of 2,4,6,8ꢀtetrapropylꢀ3,7ꢀdithiaꢀ1,5ꢀdiazabicyclo[3.3.0]ꢀ
octane (8a), likewise the molecule of 2a, is in the endoꢀ
endoꢀconformation with the TTTꢀconfiguration of the
propyl groups (see Fig. 2).
Conformation and geometry of the bicyclic fragments
in compounds 2a and 8a are similar to those in the unsubꢀ
stituted 3,7ꢀdithiaꢀ1,5ꢀdiazabicyclo[3.3.0]octane.6 The
distances of chemically equivalent C—S bonds are found
to significantly differ: by 0.068 Å (the bonds S(1)—C(1)
(1.800(1) Å) and S(1)—C(2) (1.868(1) Å)) and by 0.050 Å
(the bonds S(2)—C(3) (1.802(2) Å) and S(2)—C(4)
(1.851(2) Å)) in the molecule of 2a; by 0.015 Å (the bonds
C(1)—S(1) (1.836(7) Å) and C(2)—S(1) (1.821(6) Å))
and by 0.056 Å (the bonds C(4)—S(2) (1.799(6) Å) and
C(3)—S(2) (1.855(6) Å)) in the molecule of 8a. These
The spectra of four individual isomers of tetraethylꢀ
(7a—d) and tetrapropylbicyclanes (8a—d) resemble the
spectra of configurational isomers of tetramethylꢀsubstiꢀ
tuted bicyclanes 2a—d. A total yield of stereoisomeric tetraꢀ
alkylꢀsubstituted bicyclanes 7—10 increases from 80% to
quantitative with the increase in the alkyl chain size in the
starting aldehydes.
Note that in the case of valeraldehyde (5) and caproalꢀ
dehyde (6), only three isomers 9b—d and 10b—d, respecꢀ
tively, are formed. These isomeric bicyclanes were also
isolated in the individual state by column chromatography
(see Table 1), in which case all three stereoisomeric fracꢀ
tions of tetrabutylꢀ and tetrapentylꢀsubstituted bicyclanes
are oily liquids. It is obvious that the bulky substituents
(Bun, nꢀC5H11) hinder formation of the crystalline (TTT)
2,4,6,8ꢀtetrabutylꢀ and 2,4,6,8ꢀtetrapentylꢀ3,7ꢀdithiaꢀ1,5ꢀ
diazabicyclo[3.3.0]octanes 9a and 10a because of the transꢀ
annular10 strain.
The reactions of hydrazine and H2S with aromatic
benzaldehyde 11 and pyridineꢀ3ꢀcarbaldehyde 13 were found
to stereoselectively form the corresponding 2,4,6,8ꢀtetraꢀ
arylꢀsubstituted 3,7ꢀdithiaꢀ1,5ꢀdiazabicyclo[3.3.0]octanes
14 and 16. Additional spectroscopic studies showed that
in the temperature range –10—60 C, positions of the sigꢀ
nals for the methine protons of the thiadiazolidine ring in
the molecules of 14 (H 4.79) and 16 (H 4.55) remain
unchanged. Apparently, the configuration of the aryl subꢀ
stituents in compounds 14 and 16 is CCC, since in the 1H
and 13C NMR spectra, like in the corresponding spectra of
compound 2b, the thiadiazolidine carbon and hydrogen
atoms give one set of signals each. At the same time, the
reaction with anisaldehyde 12 proceeds with the formaꢀ
tion of three stereoisomeric bicyclooctanes 15a—c (the
1H, 13C, HSQC and HPLC NMR spectroscopic data).
The ratio of the signals for the endocyclic protons of the
CH groups at H 5.69, 5.99, and 5.31, corresponding to

3,7ꢀDithiaꢀ1,5ꢀdiazabicyclo[3.3.0]octanes
Russ.Chem.Bull., Int.Ed., Vol. 61, No. 1, January, 2012
145
0a
c
b
Fig. 3. Packing of molecules in crystal of 8a.
isomers 15a, 15b, and 15c, is 1 : 2 : 1. The heteronuclear
correlation HSQCꢀexperiments revealed the following corꢀ
relations (: H(5.69)  C(55.56), H(5.99)  C(51.00),
and H(5.31)  C(58.41).
Note that because a decrease in the reactivity of
the aromatic aldehydes (the conversion of 40%) as comꢀ
pared to the aliphatic counterparts (the conversion of up
to 100%), a total yield of 2,4,6,8ꢀtetraarylꢀsubstituted
3,7ꢀdithiaꢀ1,5ꢀdiazabicyclo[3.3.0]octanes 14—16 did not
exceed 30%.
In conclusion, a series of stereoisomeric 2,4,6,8ꢀtetraꢀ
alkyl(aryl)ꢀ3,7ꢀdithiaꢀ1,5ꢀdiazabicyclo[3.3.0]octanes 2,
7—10 and 14—16 was synthesized for the first time; condiꢀ
tions for the separation of 2,4,6,8ꢀtetraalkylꢀsubstituted
stereoisomers 2 and 7—10 by column chromatography
were developed.
Experimental
Products were analyzed by GLC on a Chromꢀ5 chromatoꢀ
graph with a flameꢀionizing detector and a 2400×3 mm packed
steel column, an SEꢀ30 (5%) stationary phase on a Chromaton
NꢀAWꢀHMDS support, 50—270 C at 8 C min–1 temperature
programming, helium carrier gas. 1H and 13C NMR spectra were
recorded on a Bruker Avance 400 spectrometer (13C, 100.62;
1H, 400.13 MHz) in CDCl3. Homoꢀ (H—H COSY) and heteroꢀ
nuclear (H—C: HSQC, HMBC) experiments were performed
using standard Bruker programs. IR spectra were recorded on
a Specord 75 IR spectrophotometer (KBr pellets). GLCꢀMS
spectral analysis of compounds 2b—d was performed on a Finiꢀ
gan model 4021 instrument (a 50000×0.25 mm glass capillary
column, HPꢀ5 stationary phase, helium carrier gas, 50 to 300 C
at 5 C min–1 temperature programming, 280 C injector temꢀ
perature, 250 C temperature of the source of ions, 70 eV), whereꢀ

146
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Akhmetova et al.
as analysis of compound 2a was carried out on a Shimadzu
LCMSꢀ2010EV instrument. Elemental analysis of the samples
was performed on a Karlo Erba elemental analyzer (model No.
1106). Isomeric mixtures of 15a—c were analyzed by HPLC on
a Shimadzu QPꢀ2010Plus chromatograph, a Supelco PTEꢀ5 capꢀ
illary column (30 m × 0.25 mm). Column chromatography was
conducted on KSKG silica gel impregnated with solution of
AgNO3.9 TLC was performed on Silufol Wꢀ254 plates, visualiꢀ
zing in iodine vapors.
(20 C), : 1.50 (d, 12 H, Me); 4.35 (s, 4 H, CH). 13C NMR, :
25.10, 66.00. MS, m/z (Irel (%)): 204 [M]+ (90), 119
[N2H3CH(Me)SCMe]+ (98), 74 [NCH(Me)S]+ (8), 57
[N2CH(Me)]+ (97).
2,4,6,8ꢀTetraethylꢀ3,7ꢀdithiaꢀ1,5ꢀdiazabicyclo[3.3.0]octane
(7a). Colorless crystals, the yield was 42%, m.p. 58—59 C,
Rf 0.58, Cact (AGꢀ5), CH2Cl2—CHCl3 (2 : 1). IR, /cm–1: 690,
750, 885, 1120, 1380, 2940. 1H NMR (CDCl3), : 0.95 (m, 12 H,
Me); 1.56 (d, 8 H, CH2, J = 6.58 Hz); 4.79 (br.s, 4 H, CH,
W1/2 = 18 Hz). 13C NMR, : 11.39, 11.75, 25.54, 31.44, 69.71,
72.4. Found (%): C, 55.27; H, 9.18; N, 10.63; S, 24.54. C12H24N2S2.
Calculated (%): C, 55.34; H, 9.29; N, 10.76; S, 24.68.
Compound 7b. Light yellow oil, the yield was 8%, Rf 0.67,
Cact (AGꢀ5), CH2Cl2—CHCl3 (2 : 1). 1H NMR (CDCl3), : 0.94
(t, 12 H, Me, J = 7.2 Hz); 1.72—1.67 (m, 8 H, CH2); 4.57 (q, 4 H,
CH, J = 5.8 Hz). 13C NMR, : 13.99, 28.52, 72.80.
Compound 7c. Light yellow oil, the yield was 21%, Rf 0.63,
Cact (AGꢀ5), CH2Cl2—CHCl3 (2 : 1). 1H NMR (CDCl3), : 0.79
(m, 12 H, Me); 1.52 (m, 8 H, CH2); 4.00 (s, 1 H, CH); 4.78 (s, 1 H,
CH); 4.90 (s, 2 H, CH). 13C NMR, : 15.03, 15.46, 16.60, 29.26,
33.82, 35.13, 70.84, 73.29, 76.02.
Xꢀray diffraction analysis of compounds 2a and 8a. The meaꢀ
surements were performed on Bruker APEX2 CCD at 100 K
(2a) and Bruker SMART 1000 CCD at 120 K (8a) diffractoꢀ
meters ((MoꢀK) = 0.71073 Å, ꢀscan technique). For crystals
of 2a, preliminary data are given in the work.7 Crystals of 8a are
colorless, C16H32N2S2 (FW = 316.56), monoclinic, space group
P21/c, at 120 K a = 9.905(4), b = 10.748(4), c = 17.344(6) Å,
3
 = 99.834 (8), V = 1819.3 (11) Å , Z = 4, dcalc = 1.156 g cm3,
(MoꢀK) = 0.287 cm–1, F(000) = 696. Experimental set of
15462 reflections (2 < 52) was obtained from a very small
single crystal 0.10×0.10×0.05 mm in size; 3577 independent reꢀ
flections (Rint = 0,1439) were used for the structure solution and
refinement. The structure was solved by direct method, nonꢀ
hydrogen atoms were refined in anisotropic approximation, hyꢀ
drogen atoms were placed in the geometrically calculated posiꢀ
tions and made allowance for in isotropic approximation in the
strictly fixed model. The final Rꢀfactors are: wR2 = 0.1385 for all
the independent reflections, R1 = 0.0696 for 1029 observed reꢀ
Compound 7d. Light yellow oil, the yield was 8%, Rf 0.53,
Cact (AGꢀ5), CH2Cl2—CHCl3 (2 : 1). 1H NMR (20 C), : 1.04
(t, 12 H, Me, J = 7.2 Hz); 1.72—1.67 (m, 8 H, CH2); 4.50 (q, 4 H,
CH, J = 5.8 Hz). 13C NMR, : 12.99, 27.50, 72.80.
2,4,6,8ꢀTetrapropylꢀ3,7ꢀdithiaꢀ1,5ꢀdiazabicyclo[3.3.0]ꢀ
octane (8a). Colorless crystals, the yield was 48%, m.p.
61—62 C, Rf 0.53, Cact (AGꢀ5), CH2Cl2—CHCl3 (2 : 1). IR,
flections with I > 2(I), 185 refined parameters, GOF = 0.889,
–3
1
the residual electron density 0.428 and –0.373 e Å
.
/cm–1: 650, 780, 870, 1150, 1460, 2840. H NMR (20 C), :
All the calculations were performed using the SHELXTLꢀ
Plus 5.0 program.11
0.83 (m, 12 H, Me); 1.41 (m, 8 H, CH2); 2.25 (s, 8 H, CH2);
4.17 (dd, 2 H, CH, J = 4.8 Hz, J = 8.4 Hz); 4.74 (q, 2 H, CH,
J = 4.8 Hz). 13C NMR, : 13.93, 21.38, 21.94, 41.54, 42.91,
69.49, 72.77. Found (%): C, 60.27; H, 10.15; N, 8.53; S, 20.24.
C16H32N2S2. Calculated (%): C, 60.70; H, 10.19; N, 8.85;
S, 20.26.
Compound 8b. Light green oil, the yield was 17%, Rf 0.62,
Cact (AGꢀ5), CH2Cl2—CHCl3 (2 : 1). 1H NMR (20 C, CDCl3),
: 0.96 (m, 12 H, Me); 2.36—2.44 (m, 16 H, CH2); 4.83 (d, 4 H,
CH, J = 4 Hz). 13C NMR, : 13.80, 20.83, 41.18, 68.31.
Compound 8c. Light green oil, the yield was 11%, Rf 0.69,
Cact (AGꢀ5), CH2Cl2—CHCl3 (2 : 1). 1H NMR (20 C, CDCl3),
: 0.96 (m, 12 H, Me); 2.36—2.44 (m, 16 H, CH2); 4.83 (dd, 4 H,
CH, J1 = 5.2 Hz, J2 = 5.6 Hz). 13C NMR, : 13.80, 20.83, 41.18,
72.53, 72.99, 73.89.
Cyclothiomethylation of N2H4•H2O with aldehydes RCHO
(R = Me, Et, Prn, Bun, nꢀC5H11, Ph, 4ꢀMeOC6H4, 3ꢀPy) (genꢀ
eral procedure). An aldehyde (0.2 mol) was saturated with hyꢀ
drogen sulfide (0.2 mol) at temperature  –10 C over 15—20 min,
then hydrazine hydrate (0.05 mol) was added dropwise. The
reaction mixture was stirred for 3 h at a given temperature, then
extracted with chloroform (3×50 mL), the extract was concenꢀ
trated on a rotary evaporator. The obtained products 2 and 7—10
were purified by column chromatography.
2,4,6,8ꢀTetramethylꢀ3,7ꢀdithiaꢀ1,5ꢀdiazabicyclo[3.3.0]ꢀ
octane (2a), the yield was 31%. The spectral characteristics are
identical to those reported in the work,7 Ik = 1500.
Compound 2b. Light yellow oil, the yield was 18%, Rf 0.59,
SiO2—AgNO3, nꢀC6H14—EtOAc—CHCl3 (5 : 1 : 1). IR, /cm–1
:
Compound 8d. Light green oil, the yield was 11%, Rf 0.57,
Cact (AGꢀ5), CH2Cl2—CHCl3 (2 : 1). 1H NMR (20 C, CDCl3),
: 0.84 (m, 12 H, Me); 2.48—3.20 (m, 16 H, CH2); 4.53 (d, 4 H,
CH, J = 4.6 Hz). 13C NMR, : 13.80, 23.80, 42.01, 71.20.
2,4,6,8ꢀTetrabutylꢀ3,7ꢀdithiaꢀ1,5ꢀdiazabicyclo[3.3.0]octane
(9b). Red oil, the yield was 52%, Rf 0.56, SiO2—AgNO3, light
670, 740, 880, 1120, 1450, 2972. 1H NMR (20 C), : 1.45 (d, 12 H,
Me, J = 4 Hz)); 4.52 (q, 4 H, CH, J = 4 Hz). 13C NMR, :
29.80, 61.90. Ik = 1550. MS, m/z (Irel (%)): 204 [M]+ (90), 119
[N2H3CHMeSCMe]+ (98), 74 [NCHMeS]+ (8), 57 [N2CHMe]+
(97). Found (%): C, 46.93; H, 7.52; N, 13.63; S, 31.18. C8H16N2S2.
Calculated (%): C, 47.02; H, 7.89; N, 13.71; S, 31.38.
1
petroleum—CH2Cl2 (5 : 3). H NMR (20 C), : 0.81 (m, 6 H,
Compound 2c. Light yellow oil, the yield was 7%. Rf 0.61,
SiO2—AgNO3, nꢀC6H14—EtOAc—CHCl3 (5 : 1 : 1). 1H NMR
(20 C), : 1.41 (m, 3 H, Me); 1.48 (s, 3 H, Me); 1.41 (s, 3 H,
Me); 1.66 (s, 3 H, Me); 4.38 (br.s, 1 H, CH); 4.39 (br.s, 2 H,
CH); 5.34 (br.s, 1 H, CH). 13C NMR, : 17.6, 23.4, 25.86, 28.1,
61.80, 67.30, 69.30. Ik = 1530. MS, m/z (Irel (%)): 204 [M]+ (90),
119 [N2H3CH(Me)SC(Me)]+ (98), 74 [NCH(Me)S]+ (8), 57
[N2CH(Me)]+ (97).
Me); 0.82 (s, 6 H, Me); 1.31 (br.s, 24 H, CH2, W1/2 = 90 Hz);
4.42 (s, 2 H, CH); 4.80 (s, 2 H, CH). 13C NMR, : 13.67, 13.76,
22.16, 22.26, 26.82, 28.02, 34.47, 35.45, 72.86, 73.74. Found (%):
C, 64.27; H, 10.28; N, 7.50; S, 17.19. C20H40N2S2. Calculatꢀ
ed (%): C, 64.46; H, 10.82; N, 7.52; S, 17.24. IR, /cm–1: 670,
740, 880, 1120, 1450, 2972.
Compound 9c. Red oil, the yield was 20%, Rf 0.66,
SiO2—AgNO3, light petroleum—CH2Cl2 (5 : 3). 1H NMR (20 C),
: 0.74 (m, 3 H, Me); 0.88 (q, 3 H, Me, J = 5.61 Hz); 0.94 (m, 6 H,
Me); 1.22 (m, 2 H, CH2); 1.51 (m, 2 H, CH2); 1.88 (m, 4 H,
Compound 2d. Light yellow oil, the yield was 7%, Rf 0.63,
SiO2—AgNO3, nꢀC6H14—EtOAc—CHCl3 (5 : 1 : 1). 1H NMR

3,7ꢀDithiaꢀ1,5ꢀdiazabicyclo[3.3.0]octanes
Russ.Chem.Bull., Int.Ed., Vol. 61, No. 1, January, 2012
147
CH2); 2.25 (br.s, 16 H, CH2); 4.67 (s, 1 H, CH); 4.76 (t, 1 H,
CH, J = 5.13 Hz); 4.87 (s, 2 H, CH). 13C NMR, : 13.69, 13.70,
13.73, 22.17, 22.19, 22.26, 25.45, 25.54, 25.71, 33.36, 33.67,
33.95, 68.17, 71.11, 72.37.
Compound 9d. Dark orange oil, the yield was 22%, Rf 0.78,
SiO2—AgNO3, light petroleum—CH2Cl2 (5 : 3). 1H NMR (20 C),
: 0.84 (m, 12 H, Me); 1.29 (m, 24 H, CH2); 4.23 (br.s, 4 H,
CH). 13C NMR, : 13.67, 22.36, 26.66, 27.08, 27.63, 31.12,
31.41, 31.40, 37.76, 38.50, 38.80, 71.10.
2,4,6,8ꢀTetra(pyridinꢀ3ꢀyl)ꢀ3,7ꢀdithiaꢀ1,5ꢀdiazabicycloꢀ
[3.3.0]octane (16). Orange crystals, the yield was 24%, m.p.
79—80 C. 1H NMR (20 C), : 4.55 (br.s, 4 H, CH, W1/2
=
= 17.9 Hz); 7.12 (br.s, 4 H, CH); 7.30 (d, 4 H, CH, J = 7.6 Hz);
8.42 (br.s, 4 H, CH); 8.58 (s, 4 H, CH). 13C NMR, : 51.17,
123.78, 129.65, 134.88, 150.30, 151.91. Found (%): C, 63.06;
H, 4. 12; N, 18.30; S, 14.01. C24H20N6S2. Calculated (%):
C, 63.13; H, 4.42; N, 18.41; S, 14.05.
The authors are grateful to U. M. Dzhemilev and L. M.
Khalilov for discussing the results.
This work was financially supported by the Division of
Chemistry and Materials Science of the Russian Academy
of Sciences (Program No. 7).
2,4,6,8ꢀTetrapentylꢀ3,7ꢀdithiaꢀ1,5ꢀdiazabicyclo[3.3.0]ꢀ
octane (10b). Dark orange oil, the yield was 54%, Rf 0.57,
SiO2—AgNO3, nꢀC6H14—EtOAc—CHCl3 (5 : 1 : 1). 1H NMR
(20 C), : 0.84 (m, 12 H, Me); 1.10—1.50 (m, 16 H, CH2);
1.50—2.00 (m, 16 H, CH2); 4.24 (br.s, 4 H, CH). 13C NMR, :
13.80, 22.43, 27.22, 31.51, 38.91, 71.21. Found (%): C, 67.16;
H, 11.22; N, 6.52; S, 14.24. C24H48N2S2. Calculated (%):
C, 67.23; H, 11.28; N, 6.53; S, 14.96.
References
Compound 10c. Dark orange oil, the yield was 34%, Rf 0.68,
SiO2—AgNO3, nꢀC6H14—EtOAc—CHCl3 (5 : 1 : 1). 1H NMR
(20 C), : 0.84 (br.s, 12 H, Me); 1.29 (m, 32 H, CH2); 4.23
(m, 3 H, CH); 5.15 (s, 1 H, CH). 13C NMR, : 13.67, 22.36,
26.66, 27.08, 27.63, 31.12, 31.41, 31.40, 37.76, 38.50, 38.80,
68.17, 71.10, 72.37.
Compound 10d. Dark orange oil, the yield was 12%, Rf 0.75,
SiO2—AgNO3, nꢀC6H14—EtOAc—CHCl3 (5 : 1 : 1). 1H NMR
(20 C), : 0.84 (m, 12 H, Me); 1.10—1.50 (m, 16 H, CH2);
1.50—2.00 (m, 16 H, CH2); 4.24 (br.s, 4 H, CH). 13C NMR, :
13.80, 22.43, 27.22, 31.51, 38.91, 71.21.
2,4,6,8ꢀTetraphenylꢀ3,7ꢀdithiaꢀ1,5ꢀdiazabicyclo[3.3.0]ꢀ
octane (14). Orange crystals, the yield was 19%, m.p. 88—89 C.
IR, /cm–1: 690, 750, 1620, 2900. 1H NMR (20 C), : 4.79
(br.s, 4 H, CH, W1/2 = 17.9 Hz); 7.41 (m, 4 H, CHAr); 7.51
(d, 4 H, CHAr, J = 2.29 Hz); 7.90 (s, 12 H, CHAr). 13C NMR, :
53.39, 128.09, 128.41, 128.74, 131.18, 140.00. Found (%):
C, 74.14; H, 5.21; N, 6.05; S, 14.10. C28H24N2S2. Calculatꢀ
ed (%): C, 74.30; H, 5.34; N, 6.19; S, 14.17.
2,4,6,8ꢀTetrakis(4ꢀmethoxyphenyl)ꢀ3,7ꢀdithiaꢀ1,5ꢀdiazaꢀ
bicyclo[3.3.0]octanes (15a—c). Orange crystals, the yield was
22%, the ratio 15a : 15b : 15c = 1 : 2 : 1. 1H NMR (20 C), :
3.85 (s, 12 H, OMe) for 15a; 3.83 (s, 12 H, OMe) for 15b; and
3.76 (s, 12 H, OMe) for 15c; 5.69 (br.s, 4 H, CH) for 15a; 5.99
(br.s, 4 H, CH) for 15b; and 5.31 (br.s, 4 H, CH) for 15c; 6.85 (d,
8 H, CHAr, J = 7.2 Hz) for 15a; 6.95 (d, 8 H, CH, J = 8.8 Hz) for
15b; and 6.99 (d, 8 H, CHAr, J = 7.81 Hz) for 15c; 7.27—7.83
(m, 8 H, CHAr). 13C NMR, : 52.73, 55.56 for 15a; 51.00 for
15b; and 58.41 for 15c; 114.30 for 15a; 114.25 for 15b; and
116.25 for 15c; 129.19 for 15a and 15c; 129.50 for 15b; 130.46
for 15a; 130.30 for 15b; and 130.20 for 15c; 131.99 for 15a;
132.30 for 15b; and 132.00 for 15c; 162.14 for 15a; 161.12 for
15b; and 159.86 for 15c.
1. M. R. Stillings, A. P. Welbourn, D. S. Walter, J. Med. Chem.,
1986, 29, 2280.
2. M. Küdwai, N. Negi, S. R. Chaudhary, Acta Pharma, 1995,
45, 511.
3. K.Rshlmann, J. Prakt. Chem., 1959, 8, 285.
4. S. R. Khafisova, V. R. Akhmetova, T. V. Tyumkina, L. M.
Khalilov, R. V. Kunakova, U. M. Dzhemilev, Izv. Akad.
Nauk, Ser. Khim., 2004, 1652 [Russ. Chem. Bull., Int. Ed.,
2004, 53, 1717].
5. V. R. Akhmetova, G. R. Nadyrgulova, S. R. Khafisova, R. R.
Khairullina, E. A. Paramonov, R. V. Kunakova, U. M.
Dzhemilev, Zh. Org. Khim., 2006, 42, 151 [Russ. J. Org. Chem.
(Engl. Transl.), 2006, 42].
6. I. S. Bushmarinov, M. Y. Antipin, V. R. Akhmetova, G. R.
Nadyrgulova, K. A. Lyssenko, J. Phyz. Chem. A, 2008,
22, 5017.
7. V. R. Akhmetova, G. R. Nadyrgulova, N. N. Murzakova,
Z. A. Starikova, M. Yu. Antipin, R. V. Kunakova, Izv. Akad.
Nauk, Ser. Khim., 2009, 1063 [Russ. Chem. Bull., Int. Ed.,
2009, 58, 1091].
8. M. S. Vigdegauz, L. V. Semenchenko, V. A. Ezrets, Yu. N.
Bogoslovskii, Kachestvennyi gazokhromatograficheskii analiz
[Qualitative Gas Chromatographic Analysis], Nauka, Moscow,
1978, 244 pp. (in Russian).
9. A. Cupta, S. Pev, J. Chromatogr., 1963, 12, 189.
10. E. L. Eliel, S. H. Wilen, M. P. Doyle, Basic Organic Stereoꢀ
chemistry, John Wiley and Sons, Inc., New York, 2001.
11. G. Sheldrick, Acta Crystallogr., Sect. A, 2008, 64, 112.
Received December 23, 2010;
in revised form September 29, 2011