Insertion of carbon disulfide into the diaziridine ring of 6-aryl-1,5-diazabicylo[3.1.0]hexanes assisted by ionic liquids

Article abstract of DOI:10.1016/j.mencom.2008.01.016

3-(4-Aryl)dihydro-5H-pyrazolo[1,2-c][1,3,4]thiadiazole-1-thiones have been synthesised by the title reaction catalysed by Et₂O·BF₃.

Full text of DOI:10.1016/j.mencom.2008.01.016

Mendeleev
Communications
Mendeleev Commun., 2008, 18, 42–44
Insertion of carbon disulfide into the diaziridine ring of
6-aryl-1,5-diazabicylo[3.1.0]hexanes assisted by ionic liquids
Yuliya S. Syroeshkina,a Vladimir V. Kuznetsov,a
Konstantin A. Lyssenkob and Nina N. Makhova*a
a N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 119991 Moscow, Russian
Federation. Fax: +7 499 135 5328; e-mail: mnn@ioc.ac.ru
b A. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, 119991 Moscow,
Russian Federation. Fax: +7 499 135 5085; e-mail: kostya@xrlab.ineos.ac.ru
DOI: 10.1016/j.mencom.2008.01.016
3-(4-Aryl)dihydro-5H-pyrazolo[1,2-c][1,3,4]thiadiazole-1-thiones have been synthesised by the title reaction catalysed by
Et2O·BF3.
The reactions of diaziridines with electrophilic reagents occur
via a zwitter-ionic intermediate, the transformation of which
can result in the expansion of the diaziridine ring to give
nitrogen-containing heterocycles with a greater number of ring
atoms.1–3 We have recently shown that the conversion of readily
available 1,2-dialkyldiaziridines and their bicyclic analogues,
1,5-diazabicyclo[3.1.0]hexanes, with heterocumulenes (ketenes,
isocyanates and isothiocyanates) offers new simple methods
for the synthesis of 1,3-dialkylimidazolidin-4-ones, 1-mono-
and 1,2-diacylpyrazolidines, 4-aroyl-1,2,4-triazolidin-3-ones and
4-benzoyl-1,2,3-trialkyl-1,2,4,6-tetrazepan-5-thiones.4–7 Note
that, depending on the heterocumulene used and the structure
of the starting diaziridine derivatives, the three-membered ring
in monocyclic diaziridines 1 is opened at both N–N and C–N
bonds, whereas in bicyclic diaziridines 2 it is opened at the
C–N bond. In this work, we continued studies on the reactions
of 1,2-dialkyldiaziridines 1 and 1,5-diazabicyclo[3.1.0]hexanes 2
with electrophilic reagents using carbon disulfide. Based on the
data obtained previously,4–7 it could be expected that possible con-
version products of 1,2-dialkyldiaziridines 1 include 1,2,4-thia-
diazolinine-5-thione derivatives 3 or 1,3,4-thiadiazolinine-2-thione
derivatives 4, whereas the reaction of bicyclic compounds 2 with
carbon disulfide most likely involves the C–N bond cleavage to
give bicyclic system 5 (Scheme 1).
studied and was returned unchanged from the reaction mixture.
The failure of these experiments is presumably due to the rather
low electrophilicity of CS2.
Various conditions were used to intensify the reaction of
diaziridine 1a with CS2, in particular, heating in acetonitrile in
a sealed tube at 100 °C and stirring at 20 °C in the ionic liquid
[bmim][BF4] or without a solvent but in the presence of a
catalytic amount of Et2O·BF3; in all cases, the optimum molar
ratio 1a:CS2 was 1:4. Complete conversion of diaziridine 1a took
10 days in acetonitrile, 4 days in the ionic liquid and 25 days in
the presence of Et2O·BF3. However, in all cases, instead of
expected compounds 3 or 4, 3,4-di(2-phenylethyl)-1,3,4-thia-
diazolidine-2,5-dithione 6 was obtained in 30–35% yields.
3,4-Disubstituted 1,3,4-thiadiazolidin-2,5-dithiones have been
obtained by reactions of 1,2-disubstituted hydrazines with an
excess of CS2.8 Apparently, diaziridine 1a undergoes hydrolysis
under the test conditions to give 1,2-di(2-phenylethyl)hydrazine
7, which then reacts with CS2 (Scheme 2). Hydrolysis to give
hydrazines is a typical reaction of diaziridines.9
CH2Ph
H2O
N
N
Ph(CH2)2NH–NH(CH2)2Ph
PhH2C
1a
7
i–iii
CS2
S
R
R
R
R
S
S
CS2
CS2
N
N N
N
N
N
N
N
R
S
S
S
R
S
PhH2C
CH2Ph
6
3
1
4
S
Scheme 2 Reagents and conditions: i, MeCN, 100 °C, 10 days; ii, [bmim][BF4]
,
R
20 °C, 4 days; iii, without solvent, Et2O·BF3, 20 °C, 25 days.
N
N
N
S
N
To study the insertion of CS2 into the diaziridine ring of
1,5-diazabicyclo[3.1.0]hexane derivatives 2, conditions found
elsewhere10,11 for a similar reaction of 6-aryl-1,5-diazabicyclo-
[3.1.0]hexanes 8 with reactive dipolarophiles (N-arylmalein-
imides) were chosen. The catalytic diaziridine ring opening
in compounds 8 on treatment with Lewis acids [Et2O·BF3 or
In(OTf)3] results in dipolar intermediate 9, which undergoes
1,3-dipolar cycloaddition to N-arylmaleinimides to give product
10 as a mixture of cis–trans isomers. If no dipolarophile is
present, intermediate 9 gives dimer 11 (Scheme 3). These reactions
R
2
5
Scheme 1
The study started with an attempt to insert CS2 into the three-
membered ring of 1,2-dialkyldiaziridines 1 using compound 1a
(R = CH2CH2Ph) as an example. For this purpose, a mixture of
the reagents was kept for 20–72 h at 20 °C or refluxed with an
excess of CS2 in the presence of bases (TEA, NaOH). However,
diaziridine 1a did not react with CS2 under the conditions
– 42 –
© 2008 Mendeleev Communications. All rights reserved.

Mendeleev Commun., 2008, 18, 42–44
Ar1
O
reactions were continued until the complete conversion of starting
O
compounds 8; TLC monitoring showed that an intermediate
was formed in all cases. The reaction time and the resulting
yields of bicyclic compounds 5b–e depended on the type of
substituent in the aromatic moiety of starting compounds 8
(Table 1, Scheme 5).†,‡ Nearly quantitative yields are observed with
electron-donating substituents (compounds 8c,d), whereas with
Ar = 4-ClC6H4 (compound 8e), the yield of corresponding bicyclic
compound 5e is as low as 30%; furthermore, p-ClC6H4CHO
was isolated as a by-product.
Ar1
N
N
Ar
N
O
O
Ar
Lewis
acid
Ar
N
N
N N
N
8
9
10
N
N
N
N
9
Ar
Ar
Table 1 shows that for bicycles 8a–d the longest reaction
time was observed in case of compound 8d. Therefore, the
reaction of compound 8d with CS2 was chosen to separate
intermediate and final products. The mixture of two reaction
products was extracted from the ionic liquid at the initial stage
of the process, and they could be separated by column chromato-
graphy on SiO2. It was found that the intermediate, both in an
individual state obtained after evaporating the solvent and in
11
Scheme 3
were carried out at room temperature in dipolar aprotic solvents,
such as THF, diethyl ether and acetonitrile.
Furthermore, the possibility of CS2 addition to intermediate
12, which is structurally similar to intermediate 9, followed
by cyclization into tricyclic system 13 has been shown experi-
mentally.12 Compound 12 was synthesised by passing a solution
of diazenium perchlorate 14 through a column with alkaline
alumina (Scheme 4).
†
All the new compounds exhibited satisfactory elemental analyses.
IR spectra were measured on a UR-20 spectrometer. H and 13C NMR
spectra were recorded on a Bruker AM-300 (300 MHz for H; 75.5 MHz
1
1
for 13C) spectrometer (CDCl3 was used as an internal standard). 13C NMR
spectra were recorded under proton decoupling conditions. Signals in the
13C NMR spectra of compounds 5 were assigned using the selective
heteronuclear double resonance method, while those in the 1H NMR
spectra were assigned using the NOE.DIFF method for compound 5c as
an example. Mass spectra were measured on a Finnigan MAT INCOS-50
instrument. TLC was carried out on Silufol UV-254 plates. Melting points
were measured on a Gallenkam.p. instrument (Sanyo).
Ph
Base
N
N
CH(Ph)2
N
Ph
N
N
ClO4
14
12 (38%)
Ph
Ph
3-(4-Methoxyphenyl)dihydro-5H-pyrazolo[1,2-c][1,3,4]thiadiazole-
1-thione 5a: Rf 0.71 [n-hexane–ethyl acetate, 2:1 (v/v)], mp 131.5–132.0 °C.
1H NMR (CDCl3) d: 2.55 (m, 2H, NCH2CH2, 2J 9.2 Hz, 3J 5.5 Hz),
2.75, 3.15 (2m, 2H, ArCNCH2, 2J 9.3 Hz, 3J 5.5 Hz, ∆n 112.7 Hz), 3.78,
3.93 (2m, 2H, SCNCH2, 2J 9.2 Hz, 3J 5.5 Hz, ∆n 46.2 Hz), 3.83 (s, 3H,
OMe), 5.75 (s, 1H, SCH), 6.80, 7.50 (2d, 4H, CArH, 3J 10.4 Hz). 13C NMR
(CDCl3) d: 27.66 (NCC), 45.82 (SCNCC), 51.35 (ArCNCC), 55.46 (ArOC),
74.76 (ArCring), 114.37, 129.28, 126.04, 132.07 (Ar), 180.30 (C=S).
IR (n/cm–1): 1060, 1132, 1168, 1356, 1440, 1508, 1612. MS, m/z (%):
266 (M, 6), 190 (M – CS2, 60), 121 [M – CS2 – N2C3H5(ring), 100], 76
(CS2 or C6H4, 86).
CS2
N
S
S
13
Scheme 4
The catalytic opening of 1,5-diazabicyclo[3.1.0]hexanes 2
with an excess of CS2 in the presence of Et2O·BF3 was first
carried out for 6-(4-methoxyphenyl)-1,5-diazabicyclo[3.1.0]-
hexane 8a in acetonitrile at 20 °C. This reaction gave target
4-aryl-3-thia-1,5-diazabicyclo[3.3.0]octane-2-thione 5a,† but the
complete conversion of compound 8a took as long as 20 days.
To accelerate the process, the same reaction was carried out in
the ionic liquid [bmim][BF4] or [bmim][PF6], which accelerate
1,3-dipolar cycloaddition reactions.13,14 The reaction of bicyclic
compound 8a with CS2 in ionic liquids was carried out at room
temperature and the molar ratio 8a:CS2 of 1:6. The reaction
was monitored by TLC until complete conversion of bicyclic
compound 8a. TLC monitoring of this reaction showed that
the first reaction steps produce two compounds with Rf 0.40
and Rf 0.70 in hexane–ethyl acetate (2:1). The first compound
predominates initially but disappears as the reaction proceeds,
whereas the amount of the second compound, presumably target
3-(4-Methylphenyl)dihydro-5H-pyrazolo[1,2-c][1,3,4]thiadiazole-1-thione
5d: Rf 0.72 [n-hexane–ethyl acetate, 2:1 (v/v)], mp 110.0–110.5 °C. 1H NMR
(CDCl3) d: 2.35 (s, 3H, Me), 2.55 (m, 2H, NCH2CH2, 2J 9.8 Hz, 3J 4.9 Hz),
2.75, 3.15 (2m, 2H, ArCNCH2, 2J 9.9 Hz, 3J 5.2 Hz, ∆n 74.5 Hz), 3.78,
3.93 (2m, 2H, SCNCH2, 2J 9.9 Hz, 3J 5.2 Hz, ∆n 38.7 Hz), 5.75 (s, 1H,
SCH), 6.80, 7.50 (2d, 4H, CArH, 3J 10.1 Hz). 13C NMR (CDCl3) d: 21.25
(MeAr), 27.56 (NCH2C), 45.81 (SCNCC), 51.29 (ArCNCC), 74.67
(ArCring), 127.72, 129,74, 131.34, 139.78 (Ar). IR (n/cm–1): 1060, 1132,
1172, 1352, 1444, 1504. MS, m/z (%): 250 (M, 60), 173 (M – CS2 – H,
100), 105 (MeC6H4CH, 30), 91 (MeC6H4, 32), 76 (CS2, 12), 76 (C6H4, 17).
3,4-Bis(2-phenylethyl)-1,3,4-thiadiazolidine-2,5-dithione 6: yield 30–35%,
Rf 0.69 [n-hexane–ethyl acetate, 4:1 (v/v)], mp 159.5–160.5 °C. 1H NMR
(CDCl3) d: 3.05 (t, 4H, ArCH2, 3J 8.6 Hz), 4.33 (t, 4H, NCH2, 3J 8.6 Hz),
7.28 (m, 10H, Ph). 13C NMR (CDCl3) d: 32.84 (PhC), 50.88 (NCH2),
127.67 (p-CAr), 128.75 (m-CAr), 129.19 (o-CAr), 135.89 (ipso-CAr), 180.96
(C=S). IR (n/cm–1): 1074, 1148, 1164, 1212, 1350, 1444, 1496, 1604.
MS, m/z (%): 358 (M, 15), 254 [M – Ph(CH2)2 – H, 40], 104 (PhCH2CH,
100), 91 (PhCH2, 60).
1
bicycle 5a, increases. The H NMR spectrum of a mixture of
these products exhibited the signals of both compounds. The
signals belonging to product 5a are 2.55 (m, 2H, NCH2CH2),
2.75, 3.15 (2m, 2H, ArCNCH2), 3.78, 3.93 (2m, 2H, SCNCH2)
and 5.75 (s, 1H, SCH). The signals of substituents at the aromatic
ring in the 1H NMR spectrum of the second compound are
shifted downfield by 0.1 ppm, there is no singlet near d 5.75,
but a singlet appears at about d 9.85–10.0 and the aromatic
proton signals are shifted downfield. Obviously, the second
compound with Rf 0.4 is an intermediate reaction product. The
reaction was completed in 4 h to give compound 5a in a nearly
quantitative yield.
For characteristics of 5b, 5c and 5e see Online Supplementary Materials.
‡
6-Aryl-1,5-diazabicyclo[3.1.0]hexanes 8a,d,e were synthesised by the
published method.15 New compounds 8b,c were obtained in the same
way (see Online Supplementary Materials).
2-(4-Methylbenzylidene)pyrazolidin-2-ium-1-carbodithioate 15d: Rf 0.42
[n-hexane–ethyl acetate, 2:1 (v/v)]. 1H NMR (CDCl3) d: 2.45 (s, 3H,
Me), 0.55, 0.90 (2m, 2H, S–CNCH2), 1.55 (m, 2H, NCCH2), 3.15, 3.60
(2m, 2H, N+CH2), 6.88, 7.81 (2d, 4H, CArH, 3J 9.7 Hz), 9.95 (s, 1H,
ArCH=N). 13C NMR (CDCl3) d: 14.21 (MeAr), 31.59 (NCH2C), 48.36,
60.36 (2NCH2), 129.62, 129.85, 134.20, 145.50 (Ar), 192.10 (ArCH=N+).
Found (%): C, 57.65; H, 5.64; N, 11.05; S, 25.71. Calc. for C12H14N2S2
(%): C, 57.57; H, 5.64; N, 11.19; S, 25.61.
Other 6-aryl-1,5-diazabicyclo[3.1.0]hexanes 8b–e were also
used in the reaction with CS2 under the conditions found. The
– 43 –

Mendeleev Commun., 2008, 18, 42–44
Table 1 Duration of the reaction and the yields of compounds 5.
C(15)
C(12)
C(13)
Reaction
time/h
Yield of
compound 5 (%)
C(14)
C(9)
Compound
Ar
S(3)
N(5)
C(11)
S(1)
C(2)
N(1)
8a
8b
8c
8d
8e
4-MeOC6H4
4-EtOC6H4
4-PriOC6H4
4-MeC6H4
4-ClC6H4
4
2
4
7
7
~99
~99
~99
~99
30
C(4)
C(10)
C(8)
C(6)
C(7)
solution, underwent gradual conversion into final bicyclic com-
pound 5d. Nevertheless, we performed elemental analysis and
recorded the 1H and 13C NMR spectra of each of the compounds.
Figure 1 General view of a molecule of 5d.
results from the conjugation of a lone electron pair at N(1) with
the C=S bond. Note that the lone electron pairs at both S(1) and
N(5) are antiperiplanar to the C(4)–H(4) bond; thus, one can
suppose that the latter hydrogen atom has a considerable acidic
nature.
Thus, this study allowed us to develop the synthesis of
3-(4-aryl)dihydro-5H-pyrazolo[1,2-c][1,3,4]thiadiazole-1-thiones
5a–e by Et2O·BF3-catalysed CS2 insertion into the C–N bond
of the diaziridine ring in 6-aryl-1,5-diazabicyclo[3.1.0]hexanes
8a–e. We found that this reaction requires ionic liquids to be
used as the reaction medium. In the synthesis of compound 5d,
we succeeded in isolating and characterising intermediate 15d,
a direct precursor of the end product.
1
The H NMR spectra were similar to those obtained for the
mixture of the corresponding compounds in the reaction of bicyclic
compound 8a. A comparison of the 13C NMR spectra of com-
pound 5d and its precursor shows that both spectra contain the
signals of carbon atoms of the pyrazolidine and benzene rings,
but they are shifted downfield in the spectrum of the inter-
mediate in comparison with that of compound 5d. The spectrum
of the latter contains a signal with a chemical shift of 180.7 ppm
corresponding to the carbon atom of the C=S moiety and a
signal with a chemical shift of 74.6 ppm corresponding to the CH
moiety of the thiazolidine ring in compound 5d. In the 13C NMR
spectrum of the intermediate, the signal of the CH moiety is
shifted downfield (192.1 ppm), whereas the signal of the carbon
atom in the C=S moiety is absent. Based on the spectral data
and the easy conversion to give end product 5d, it can be
assumed that the structure of the intermediate is 15d (Scheme 5).
The absence of the signal of the carbon atom in the C=S moiety
in assumed intermediate 15 is apparently due to electron density
delocalisation between both sulfur atoms.
This study was partially supported by the Presidium of the
Russian Academy of Sciences, the programme ‘Development
of Methods for Synthesising Chemical Compounds and Creating
New Materials’.
We are grateful to Dr. M. I. Struchkova for recording the
NMR spectra.
S
S
Online Supplementary Materials
Supplementary data associated with this article can be found
in the online version at doi:10.1016/j.mencom.2008.01.016.
Ar
S
N
N
S
N
N
Ar
i
N
N
Ar
8a–e
15a–e
5a–e
References
1
2
E. Schmitz, Adv. Heterocycl. Chem., 1979, 24, 63.
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Scheme 5 Reagents and conditions: i, CS2 (excess), [bmim][BF4] or
[bmim][PF6], Et2O·BF3, 20 °C.
3
4
5
H. W. Heine, in Small Ring Heterocycles, part 2, ed. A. Hassner, Wiley-
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firmed by a combination of elemental analyses and spectral
data, including those for compound 15d; furthermore, X-ray
diffraction analysis was carried out for compound 5d.§
According to X-ray diffraction analysis, the pyrazolidine
ring is characterised by an envelope conformation, where the
C(6) atom deviates by 0.59 Å from the plane of the rest of the
atoms. In turn, the sulfur-containing five-memebred ring has a
distorted twisted conformation with deviations of the N(5) and
C(4) atoms by 0.50 and 0.17 Å in opposite directions. The
nitrogen atoms in 5d differ significantly. Indeed, the N(1) atom
is characterised by a planar trigonal configuration; in contrast,
the N(5) atom has a pyramidal configuration with the sum of
bond angles equal to 325.6(1)°. This drastic difference clearly
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§
X-ray diffraction data. Crystals of 5d (C12H14N2S2, M = 250.37) are
monoclinic, space group P21/c, at 100(2) K: a = 14.8215(14), b = 7.4625(7)
and c = 11.8230(10) Å, b = 112.039(5)°, V = 1212.13(19) Å3, Z = 4, dcalc
=
= 1.372 g cm–3, m(MoKα) = 4.12 cm–1, F(000) = 528. Intensities of 8641
reflections were measured with a Bruker Smart APEX II diffractometer
(w-scans, 2q < 58°), 3178 independent reflections (Rint = 0.0378) were
used in the further refinement. The refinement converged to wR2 = 0.0886
and GOF = 0.990 for all independent reflections [R1 = 0.0334 was calcu-
lated against F for 10362 observed reflections with I > 2s(I)]. All calcula-
tions were performed using SHELXTL PLUS 5.0.
CCDC 671036 contains the supplementary crystallographic data for this
paper. These data can be obtained free of charge from The Cambridge
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Received: 5th June 2007; Com. 07/2955
– 44 –