4-Thio derivatives of sydnone imines

Article abstract of DOI:10.1016/j.mencom.2009.11.009

4-Thio derivatives of sydnone imines were obtained by the reaction of 4-lithiosydnone imines with elemental sulfur and subsequent treatment of the reaction mixture with electrophiles.

Full text of DOI:10.1016/j.mencom.2009.11.009

Mendeleev
Communications
Mendeleev Commun., 2009, 19, 322–323
4-Thio derivatives of sydnone imines
Ilya A. Cherepanov, Sergey N. Lebedev, Alina S. Samarskaya,
Ivan A. Godovikov, Yulia V. Nelyubina and Valery N. Kalinin*
A. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, 119991 Moscow,
Russian Federation. Fax: +7 499 135 6549; e-mail: vkalin@ineos.ac.ru
DOI: 10.1016/j.mencom.2009.11.009
4-Thio derivatives of sydnone imines were obtained by the reaction of 4-lithiosydnone imines with elemental sulfur and
subsequent treatment of the reaction mixture with electrophiles.
Sydnone imines (5-amino-1,2,3-oxadiazolium betaine) are the
most studied substances among mesoionic heterocyclic com-
Li
SLi
pounds.1,2 Their synthesis and characterization are of great
interest because of the broad spectrum of sydnone imine
pharmacological activity.2 Recently, it was shown that sydnone
imines are effective exogenous donors of nitrogen oxide (NO),
which is a unique intracellular regulator of the metabolism in
living organisms.3–5
N
N
i
N
N
N
N
O
O
Ph
Ph
O
O
4
ii
iii
Unfortunately, sydnone imines with a heteroatom (S, P, N,
etc.) as a substituent at the 4-position are unknown. Introduc-
tion of a sulfur atom as a substituent at the 4-position of the
sydnone imine ring can significantly change the pharmaco-
logical activity of these promising heterocyclic compounds.
The aim of this study was to develop a synthetic approach to
previously unknown 4-mercapto derivatives of sydnone imines
and to investigate their reactivity.
SH
SMe
N
N
N
N
N
N
O
O
Ph
Ph
O
O
5, 80%
6g, 83%
We have already mentioned that N6-derivatives of sydnone
imines 1, which bear no substituent at the C4-position, are
smoothly metalated by the action of n-BuLi giving corre-
sponding 4-lithio derivatives6 2 whose interaction with electro-
philes yields sydnone imines 3 functionalized at the 4-position
(Scheme 1).
Scheme 2 Reagents and conditions: i, S8, THF, –90 °C ® room tem-
perature, 30 min; ii, H2O; iii, MeI, THF, 20 °C, 2 h.
bond by up to 11.6°. There is a pseudo-inversion center relating
the independent species in such a way that there are two
pseudosymmetric pairs of molecules; it is displaced from the
exact symmetry element8 by 0.42 Å. Supramolecular organiza-
tion in the crystal of 6g follows exactly the same trend; i.e., the
species within these pairs form nearly the same intermolecular
contacts while the chemical patterns of those belonging to the
different pairs markedly vary.
R
R
R
H
Li
E
3
N
4
N
N
i
ii
2 N
N
N
N6
N
N
5
O
O
O
1
R'
R'
R'
Other 4-mercapto derivatives of sydnone imines were obtained
by an analogous way. However, these derivatives are unstable,
1
2
3
Scheme 1 Reagents and conditions: i, n-BuLi, THF, –90 °C, 30 min;
†
Crystals of 6g (C13H15N3O2S, M = 277.34) are triclinic, space group
ii, E+, THF, –90 °C, 2 h.
–
P1, at 100 K: a = 10.2520(4), b = 11.2447(4) and c = 23.8900(8) Å,
a = 103.240(5)°, b = 91.368(5)°, g = 90.574(5)°, V = 2679.75(17) Å3,
Z = 8 (Z' = 4), dcalc = 1.375 g cm–3, (MoKα) = 2.43 cm–1, F(000) = 1168.
Intensities of 384485 reflections were measured with a Bruker SMART
APEX2 CCD diffractometer [l(MoKα) = 0.71072 Å, w-scans, 2q < 90°]
and 43867 independent reflections (Rint = 0.0354) were used in the further
refinement. The structure was solved by a direct method and refined by
the full-matrix least-squares technique against F2 in the anisotropic-iso-
tropic approximation. Hydrogen atoms were located from the Fourier
synthesis of the electron density and refined in the isotropic approxima-
tion. For 6g the refinement converged to wR2 = 0.1239 and GOF = 1.004
for all independent reflections [R1 = 0.0396 was calculated against F for
35309 observed reflections with I > 2s(I)]. All calculations were performed
using SHELXTL PLUS 5.0.9
We supposed that, as in the case of sydnones whose 4-lithio
derivatives easily react with elemental sulfur,7 4-lithio deriva-
tives of sydnone imines should also undergo this reaction.
The treatment of the 4-lithio derivative of 3-isopropyl-
N6-benzoylsydnone imine with elemental sulfur gives lithium
thiolate 4, whereas the consequent acidification of the reaction
mixture gives free thiol 5 in high yield (Scheme 2).
The treatment of lithium thiolate 4 formed in the reaction with
methyl iodide gives heteryl methyl sulfide 6g in a high yield.
The structure of the product was confirmed by X-ray diffraction
analysis† (Figure 1), which showed that sulfide 6 crystallizes
with four independent molecules in an asymmetric unit. Their
geometrical parameters are typical of the compounds of this
type and close to each other with the main difference being
observed for the phenyl group which rotates around the C(7)–C(9)
CCDC 737013 contains the supplementary crystallographic data for this
paper. These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
For details, see ‘Notice to Authors’, Mendeleev Commun., Issue 1, 2009.
– 322 –
© 2009 Mendeleev Communications. All rights reserved.

Mendeleev Commun., 2009, 19, 322–323
Table 1 Synthesis of 4-thio derivatives of sydnone imines.
R
R
R
H
SLi
S R''
i, n-BuLi
R'' X
ii, S8
N
N
N
N
N
N
N
N
N
O
O
O
R'
R'
R'
1
6
Product
R
R'
R'' X
R''
Yield (%)
mp/°C
6a
6b
6c
6d
6e
6f
Bun
Bun
Bun
NMe2
NMe2
Pri
C(O)Ph
C(O)CF3
C(O)But
C(O)Me
C(O)Ph
C(O)Me
C(O)Ph
C(O)Ph
MeI
MeI
MeI
MeI
MeI
MeI
MeI
Me
Me
Me
Me
Me
Me
Me
68
58
70
83
68
54
83
75
78–79
50–51
48–49
75–76
79–80
108–109
73–74
81–82
6g
6h
Pri
Pri
PhCH2Br
PhCH2
6i
6j
Pri
Pri
C(O)Ph
89
Oil
CH2Br
N
CH2
Cl
Cl
N
Cl
Cl
C(O)Ph
83
135–136
S
S
O
O
NO2
NO2
6k
Pri
C(O)Ph
76
179–180
O
O
and they quickly decomposed on isolation and storage. Thus,
the further isolation of their pure forms was not carried out.
Lithium thiolate 4 formed in the reaction was in situ treated
with organohalides and corresponding sulfide 6 was isolated as
a reaction product. The results are given in Table 1.‡
According to these data, the properties of the intermediate
4-lithiothiolates of sydnone imines are typical of such a type of
compounds. They are smoothly alkylated with alkyl halides
giving 4-thioalkyl-substituted sydnone imines. On the interac-
tion with aryl or heteroaryl halides, the active halogen atom is
substituted giving corresponding sulfides 6k, 6j. Note that both
chlorine atoms can be replaced in the case of 2,4-dichloro-
5-formylthiazole. However, the reverse addition, i.e., the addi-
tion of a lithium thiolate solution to organic halide, allowed
monosubstituted substance 6j to be obtained in a high yield.
The presence of an aldehyde function in sulfides 6j and 6k
or that of the replaceable chlorine atom in 6j gives additional
possibilities for the functionalization of the 4-thio derivatives of
sydnone imines thus obtained. This is significant for a search
for new physiologically active derivatives among mesoionic
heterocyclic compounds.
Thus, preparative methods for the synthesis of previously
unknown 4-mercapto-, 4-thioalkyl-, 4-thioaryl- and 4-thio-
heteryl derivatives of sydnone imines were elaborated.
Online Supplementary Materials
Supplementary data associated with this article can be found
in the online version at doi:10.1016/j.mencom.2009.11.009.
C(19)
C(11)
C(10)
C(12)
S(18)
N(3)
C(17)
C(15)
C(9)
References
N(6)
C(4)
C(5)
C(13)
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C(14)
C(7)
O(1)
3 K. Schonafinger, Il Farmaco, 1999, 54, 316.
N(2)
C(16)
O(8)
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Figure 1 General view of compound 6g in representation of atoms via
thermal ellipsoids at 50% probability level.
‡
Standard procedure: 2.1 mmol of n-BuLi solution in hexane was added
to 2.0 mmol of sydnone imine in 50 ml of dry THF at –85 °C. The
solution was stirred at –85 °C for 15 min; then, 2.2 mmol of powdered
sulfur was added. The resulting mixture was stirred at –85 °C for 15 min
and heated to room temperature in a bath; then, 3 mmol of organohalide
were added. The reaction mixture was stirred for additional 2–24 h for
completing the reaction (control by TLC) and quenched with 1 ml of
water. The solvent was evaporated at reduced pressure, the residue was
dissolved in 50 ml of methylene chloride, and the solution was filtered
through a layer of Al2O3. The solvent was evaporated, the residue was
purified by chromatography on a SiO2 column (chloroform–ethyl acetate,
5:1). The product was crystallized from isopropanol–hexane. Satisfactory
data of elemental analysis, 1H and 13C NMR spectroscopy were obtained
for all of the new substances (see Online Supplementary Materials).
Received: 8th June 2009; Com. 09/3347
– 323 –