Thionation of a cyanoxime derivative to form the sulphur-containing derivative, a novel ligand for complexation with transitional metal ions

Article abstract of DOI:10.1007/s11224-016-0865-z

2-Cyano-2-(hydroxyimino)dithioacetic acid was prepared starting from cyanoacetic acid methylester via 2-cyano-2-(hydroxyimino)acetic acid methylester. Before thionation, the ester had to be hydrolyzed. The optimum conditions for each reaction were identified. P₄S₁₀ was found to be the efficient thionation reactant resulting in the formation of the dithionated product. Its structure was verified with IR, NMR and mass spectrometric measurements.

Full text of DOI:10.1007/s11224-016-0865-z

Struct Chem
DOI 10.1007/s11224-016-0865-z
ORIGINAL RESEARCH
Thionation of a cyanoxime derivative to form
the sulphur-containing derivative, a novel ligand for complexation
with transitional metal ions
Truong Ngoc Hung1,2 & Adél Ádám1,2 & Gábor Varga1,2 & Csilla Dudás2,3 & Zoltán Kele4
Pál Sipos2,3 & István Pálinkó1,2
&
Received: 30 September 2016 /Accepted: 15 October 2016
#
Springer Science+Business Media New York 2016
Abstract 2-Cyano-2-(hydroxyimino)dithioacetic acid was
prepared starting from cyanoacetic acid methylester via 2-cy-
ano-2-(hydroxyimino)acetic acid methylester. Before
thionation, the ester had to be hydrolyzed. The optimum con-
ditions for each reaction were identified. P4S10 was found to
be the efficient thionation reactant resulting in the formation of
the dithionated product. Its structure was verified with IR,
NMR and mass spectrometric measurements.
engineering, medicine, agriculture, etc. They form a large va-
riety of mononuclear (with Na, K, Rb, Cs, Ba, Sn(IV), Te(IV),
Sb(V), Cu, Ni, Co, Fe, Pd, Pt, lanthanoids) as well as polynu-
clear (with Ni(II), organotin(IV), Ag(I), Th(I)) complexes, in
which the cyanoximes exhibit a large scale of coordination
modes. For a recent review describing these structural features
and many more in detail by their principle investigator, please
see ref. [1].
If sulphur derivatives of the cyanoximes can be made, one
may expect even better coordination ability and a larger vari-
ety of coordination modes being the sulphur atom larger and
thus having a more polarizable electron cloud. Surprisingly,
sulphur-containing derivatives except the thioamide deriva-
tives are not known. Possibly, the replacement of one or more
oxygens for sulphur atom(s) in these compounds is not an
easy exercise, even if there is a number of thionating agents
that are in the hands of chemists.
The most often used and best known thionation agents are
S8 [2], P4S10 1 (Berzelius reagent [3–5]) and the Lawesson’s
reagent 2 [6–10]. (It is to be noted that the Lawesson’s reagent
is prepared from the reaction of methylphenyl ether and
P4S10.) (Fig. 1).
.
.
.
Keywords Cyanoxime derivative Thionation P4S10
Dithionated product
Introduction
Cyanoximes represent a recently synthesized novel subclass
of oximes. They have the general formula of NCC(=NOH)-R,
where R is an electron-withdrawing group such as CN, amide/
thioamide, keto, carboxylic ester, and a variety of aryls and
heterocycles. They were prepared (40 representatives) with
the aim of investigating their ability to form coordination com-
pounds useful in various fields like proteomic research, crystal
Other not so frequently applied thionation reagents have
also been developed like hexamethyldisilathiane together with
CoCl2·6H2O co-catalyst [11], the combination of P4S10 and
hexamethyldisiloxane [12], P4S10-pyridyne complex [13] and
many others reviewed by Polshettiwar and Kaushik [14].
Interestingly, in many of them, P4S10 is the major component.
Most of the thionation agents, especially P4S10 and the
Lawesson’s reagent, are used most often for C=O to C=S
exchange in compounds containing carbonyl group (ketones,
carboxylic acids, esters amides, etc.). P4S10 and the
Lawesson’s reagent dissociate during the reaction, and the
formation of the strong P=O bond drives the reaction (for
details, see ref. [10] and any other reviews cited). These
* István Pálinkó
palinko@chem.u-szeged.hu
1
Department of Organic Chemistry, University of Szeged, Dóm tér 8,
Szeged H-6720, Hungary
2
Material and Solution Structure Research Group, Institute of
Chemistry, University of Szeged, Aradi Vértanúk ter 1,
Szeged H-720, Hungary
3
Department of Inorganic and Analytical Chemistry, University of
Szeged, Dóm tér 7, Szeged H-6720, Hungary
4
Institute of medical Chemistry, University of Szeged, Dóm tér 8,
Szeged H-6720, Hungary

Struct Chem
introduced into the MS by applying direct injection method:
the built-in syringe pump of the instrument with a 25-mL
Hamilton syringe was used. The electrospray needle was ad-
justed to 3 kVand N2 was used as nebulizer gas. The computer
program used to simulate the theoretical isotope distributions
is included in the Masslynx software package.
Fig. 1 The Berzelius (P4S10 1) and the Lawesson’s (2,4-bis(p-
methoxyphenyl)-1,3-dithiadi-phosphetane-2,4-disulfide 2) reagents
The syntheses of the intermediates and the final product
were prepared by the following recipes:
reactants are able to replace both oxygens in esters or carbox-
ylic acids [8]. However, the replacement of oxygen to sulphfur
in oximes under ambient conditions is not feasible, because
the corresponding thio-oxime is only stable at –70 °C or be-
low [15].
In this contribution, we intend to show a convenient way of
preparing 2-cyano-2-(hydroxyimino)dithioacetic acid starting
from the easily accessible cyanoacetic acid methylester via 2-
cyano-2-(hydroxyimino)acetic acid methylester. The ester
could be thionated at the carboxylic end leaving the =N–OH
group intact.
2-Cyano-2-(hydroxyimino)acetic acid methylester
Phosphoric acid (4 mL) was added drop-wise to a 0 °C sus-
pension of methyl cyanoacetate (10 g) and sodium nitrite (6 g)
in H2O (80 mL). The reaction was allowed to warm up to
40 °C in 1 h. The mixture was then cooled and cc. HCl
(8 mL) was added gradually. The solution was extracted with
ethyl acetate, and the organic phase was collected, dried over
Na2SO4 and concentrated in vacou to give the product, which
was purified by recrystallization from toluene. White crystals
were obtained with a yield of 91 %.
2-Cyano-2-(hydroxyimino)acetic acid Method 1: A mixture
of 3 g of 2-cyano-2-(hydroxyimino)acetic acid methylester
and 12 mL of methanol was stirred and maintained at 35 °C
in a 50-mL two-neck round-bottom flask; 2.65 g of KOH was
added and the contents were stirred for 2 h and then were
concentrated in vacou. Twenty-five millilitres of water was
added. The mixture was acidified to pH = 2 with 6 M HCl
extracted with ethyl acetate. After drying over Na2SO4, the
solvent was evaporated and the crude 2-cyano-
2-(hydroxyimino)acetic acid was obtained. It was purified
by column chromatography (eluent: n-hexane: ethylacetate
=1:1). White crystals were obtained with a yield of 76 %.
M e t h o d 2 : A m i x t u r e o f 4 . 3 g o f 2 - c y a n o -
2-(hydroxyimino)acetic acid methylester in 40 mL of ethanol
was added to a solution of 8 g of NaOH in 80 mL of H2O. The
mixture was refluxed for 4 h, then cooled to room temperature
and diluted with 40 mL of THF and acidified to pH = 2 with
6 M HCl. The mixture was then extracted with ethyl acetate.
The organic fraction was separated, dried over Na2SO4, and
the solvent was removed under reduced pressure to give the
crude of 2-cyano-2-(hydroxyimino)acetic acid, which was re-
fined the same way as in Method 1. White crystals were ob-
tained with a yield of 74 %.
Experimental
The reactants were either the products of Aldrich Chemical
Co. (P4S10, cyanoacetic acid methylester, NaNO2, KOH,
NaOH) or VWR (HCl, H3PO4, glacial acetic acid). The sol-
vents (toluene, methanol, ethanol, hexane, ethyl acetate and
DMSO-d6) were purchased from VWR. They had over 98 %
purity and were used without further purification.
The thionation reactions were performed in Ar atmosphere.
The reactions were followed by thin-layer chromatography
(TLC, silica gel, Aldrich; eluent: n-hexane:ethyl acetate =1:1).
The products were purified with column chromatography with
the eluent used in TLC in solution or recrystallization when
solid. TLC was performed on a plastic sheet precoated with
silica gel 60 F254. Silica gel (pore size 60 Å, 60–100 mesh
particle size, Sigma-Aldrich) was used for column
chromatography.
Infrared (IR) measurements were carried out on a Bio-Rad
FTS-40 FT-IR spectrometer, working in the reflection mode,
using 1 % of the sample in KBr (spectroscopic grade, Aldrich
Chem. Co.). Two hundred fifty-six scans were collected for
the spectra at 4-cm−1 resolution.
NMR measurements were performed in 0.5 mL DMSO-d6
or acetone-d6 (99.96 atom% D, from Sigma-Aldrich
Chemical Co.) using Bruker Avance 500, 500-MHz NMR
spectrometer with 5-mm glass NMR tubes from Wilmad.
Electrospray ionization mass spectrometric (ESI-MS) mea-
surements were performed using a Micromass Q-TOF
Premier (Waters MS Technologies) mass spectrometer
equipped with electrospray ion source. The sample was
Fig. 2 The reaction used for the synthesis of the cyanoxime derivative
(2-cyano-2-(hydroxyimino)-acetic acid methylester)

Struct Chem
Fig. 3 The 1H (a) and the 13C (b)
NMR spectra of the purified 2-
cyano-2-(hydroxyimino)acetic
acid methylester
(a)
(b)
2-Cyano-2-(hydroxyimino)dithioacetic acid A mixture of
0.34 g of 2-cyano-2-(hydroxyimino)acetic acid and 0.4 g of
phosphorus pentasulfide in 20 mL of anhydrous toluene was
refluxed for 2 h. After cooling to room temperature, the reac-
tion mixture was placed on silica gel column and the toluene
was eluted with n-hexane. The product 2-cyano-
2-(hydroxyimino)dithioacetic acid formed was then eluted
with n-hexane:ethylacetate =2:1. Orange-coloured crystal
with a yield of 39 % was obtained.
The structure of the purified product was verified by 1H
and 13C NMR spectroscopies (Fig. 3). All lines in the spec-
tra could be assigned to the functional groups of the
cyanoxime.
As it seen in the figure, the oxime (C=N) and the cyanide
carbons (C≡N) are well separated from each other in the 13
C
NMR spectrum. The C=O carbon, as it is expected, appears at
the deshielded end, while the methoxy carbon, being the most
shielded, is seen at relatively low chemical shifts. Due to fast
1
exchange, the oxime proton is not observed in the H NMR
spectrum; however, the methoxy protons are easily identified.
The hydrolysis of the ester was performed by two similar
methods. Method 2, hydrolysis in methanolic KOH at 35 °C
in 2 h, proved to be better, since there was no by-product
formation. To achieve similar yield, the reaction with
ethanolic NaOH required higher temperature (100 °C) and
longer reaction time (4 h).
Structural identification was performed by IR as well as
13C NMR spectroscopies (Fig. 4).
Again, the functional groups could be easily identified. The
hydrogen-bonded OH groups gave the typical wide absorp-
tion band in the 3400–2400-cm−1 region.
Results and discussion
The intermediate cyanoxime could be prepared from
cyanoacetic acid methyl ester with in situ formed HNO2 at
or near room temperature [16] (Fig. 2). When glacial acetic
acid was used, a 4-h reaction time was needed to gain accept-
able yield of the product, and care had to be taken of avoiding
excess acid. Using a mixture of concentrated H3PO4 and HCl
afforded high yield in 2 h at somewhat higher reaction tem-
perature (35 °C).
Fig. 4 The IR (a) and the 13
NMR (b) spectra of the purified
2-cyano-2-(hydroxyimino)acetic
acid
C
(a)
(b)

Struct Chem
Fig. 5 The IR spectrum of the
crude product after thionation (a)
and the 1H NMR spectrum of the
purified thionated product (b)
(a)
(b)
Then, the thionation reactions were performed with the 2-
cyano-2-(hydroxyimino)acetic acid intermediate. ESI-MS
mass spectroscopic result indicated that there were two sul-
phur atoms in the product, since the molecular ion was found
at M/z = 146. The IR spectra (Fig. 5a) of the crude product
indicated the presence of diminished C=O vibration at
1750 cm−1, increased C=S vibration at 863 cm−1, an S–H
vibration at 2613 cm−1 and a broad band in the 3500–2500-
cm−1 range indicating H-bonded OH groups from the residual
acid reactant and the unchanged =N–OH. The 1H NMR spec-
trum of the recrystallized product verified the presence of the –
SH and the unchanged =N–OH functional groups (Fig. 5b).
These observations mean that both oxygens of the carboxylic
group were replaced by sulphur, while, as expected, the oxy-
gen in the =N–OH group was not. The product was 2-cyano-
2-(hydroxyimino)dithioacetic acid.
References
1. Gerasimchuk NN, Guzei I, Sipos P (2015) Curr Inorg Chem 5:38–
63
2. Brillon D (1992) Sulfur Rep 12:297–332
3. Berzelius J (1843) Liebigs Ann Chem 46:129–154
4. Berzelius J (1843) Liebigs Ann Chem 46:251–281
5. Ozturk T, Ertas E, Mert O (2010) Chem Rev 110:3419–3478
6. Pedersen BS, Scheibye S, Nilson NH, Lawesson S-O (1978) Bull
Soc Chim Belg 87:223–228
7. Scheibye S, Pedersen BS, Lawesson S-O (1978) Bull Soc Chim
Belg 87:229–238
8. Pedersen BS, Scheibye S, Nilson NH, Clausen K, Lawesson S-O
(1978) Bull Soc Chim Belg 87:293–297
9. Scheibye S, Pedersen BS, Lawesson S-O (1978) Bull Soc Chim
Belg 87:299–306
10. Ozturk T, Ertas E, Mert O (2007) Chem Rev 107:5210–5278
11. Innocenti AD, Capperucci A, Mordini A, Reginato G, Ricci A,
Cerreta F (1993) Tetrahedron Lett 34:873–876
12. Curphey TJ (2002) J Org Chem 67:6461–6473
13. Bergman J, Petterson B, Hasimbegovic V, Svensson PH (2011) J
Org Chem 76:1546–1553
Conclusions
14. Polshettiwar V, Kaushik MP (2006) J Sulfur Chem 27:353–386
15. Barton DR, Magnus PD, Pennanen SI (1974) JCS Chem Com
1007–1008
16. Clayden J, Greeves N, Warren S (2012) Organic chemistry, 2nd
edn. Oxford University Press, Oxford, pp. 464–465
A convenient reaction sequence was elaborated for the syn-
thesis of a novel thionated cyanoxime derivative. The
cyanoxime carboxylic acid prepared from cyano acetic acid
could be thionated with P4S10 by replacing both oxygens in
the carboxylic group. At the same time, the oxygen in the =N–
OH functional group was preserved. The sulphur-containing
novel compound is a promising ligand in future complexation
studies.