Mechanism of the sulfurisation of phosphines and phosphites using 3-amino-1,2,4-dithiazole-5-thione (xanthane hydride)

Article abstract of DOI:10.1039/b616298c

Contrary to a previous report, the sulfurisation of phosphorus(iii) derivatives by 3-amino-1,2,4-dithiazole-5-thione (xanthane hydride) does not yield carbon disulfide and cyanamide as the additional reaction products. The reaction of xanthane hydride with triphenyl phosphine or trimethyl phosphite yields triphenyl phosphine sulfide or trimethyl thiophosphate, respectively, and thiocarbamoyl isothiocyanate which has been trapped with nucleophiles. The reaction pathway involves initial nucleophilic attack of the phosphorus at sulfur next to the thiocarbonyl group of xanthane hydride followed by decomposition of the phosphonium intermediate formed to products. The Hammett ρ-values for the sulfurisation of substituted triphenyl phosphines and triphenyl phosphites in acetonitrile are ～ -1.0. The entropies of activation are very negative (-114 ± 15 J mol^-1 K^-1) with little dependence on solvent which is consistent with a bimolecular association step leading to the transition state. The negative values of ΔS ^≠ and ρ values indicate that the rate limiting step of the sulfurisation reaction is formation of the phosphonium ion intermediate which has an early transition state with little covalent bond formation. The site of nucleophilic attack has been also confirmed using computational calculations. The Royal Society of Chemistry 2007.

Full text of DOI:10.1039/b616298c

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www.rsc.org/obc | Organic & Biomolecular Chemistry
Mechanism of the sulfurisation of phosphines and phosphites using
3-amino-1,2,4-dithiazole-5-thione (xanthane hydride)†‡
Jirˇ´ı Hanusek,a Mark A. Russell,b Andrew P. Laws,b Petr Jansa,c John H. Atherton,b Kevin Fettesd and
Michael I. Page*b
Received 7th November 2006, Accepted 30th November 2006
First published as an Advance Article on the web 18th December 2006
DOI: 10.1039/b616298c
Contrary to a previous report, the sulfurisation of phosphorus(III) derivatives by
3-amino-1,2,4-dithiazole-5-thione (xanthane hydride) does not yield carbon disulfide and cyanamide as
the additional reaction products. The reaction of xanthane hydride with triphenyl phosphine or
trimethyl phosphite yields triphenyl phosphine sulfide or trimethyl thiophosphate, respectively, and
thiocarbamoyl isothiocyanate which has been trapped with nucleophiles. The reaction pathway involves
initial nucleophilic attack of the phosphorus at sulfur next to the thiocarbonyl group of xanthane
hydride followed by decomposition of the phosphonium intermediate formed to products. The
Hammett q-values for the sulfurisation of substituted triphenyl phosphines and triphenyl phosphites in
acetonitrile are ∼ −1.0. The entropies of activation are very negative (−114 15 J mol−1 K−1) with little
dependence on solvent which is consistent with a bimolecular association step leading to the transition
state. The negative values of DS= and q values indicate that the rate limiting step of the sulfurisation
reaction is formation of the phosphonium ion intermediate which has an early transition state with
little covalent bond formation. The site of nucleophilic attack has been also confirmed using
computational calculations.
compounds has been achieved with a number of reagents such as:
phenylacetyl disulfide (PADS),5 3H-1,2-benzodithiol-3-one-1,1-
Introduction
dioxide (Beaucage reagent),6 tetraethylthiuram disulfide (TETD),7
dibenzoyl tetrasulfide,8 bis(O,O-diisopropoxyphosphinothioyl)
disulfide (S-Tetra),9 benzyltriethylammonium tetrathiomolybdate
(BTTM),10 bis(p-toluenesulfonyl) disulfide,11 3-ethoxy-1,2,4-
dithiazoline-5-one (EDITH),12 1,2,4-dithiazolidine-3,5-dione
(DTSNH),12 bis(ethoxythiocarbonyl)tetrasulfide,13 3-methyl-
There is increasing use of phosphorothioate analogues of
oligonucleotides in nucleic acid research.1 The stability of
the phosphorothioate linkage and its resistance to hydrolysis
by nucleases together with the improved pharmacokinetic
profiles of these analogues have led to their incorporation into
therapeutic oligonucleotides.2 Phosphorothioates have been used
as inhibitors of gene expression3 and have also been introduced
into oligonucleotides for mechanistic studies on DNA–protein
and RNA–protein interactions.4 Therefore, the synthesis of
oligonucleotide phosphorothioate analogues is of considerable
interest. Synthesis is normally achieved by the sulfurisation of the
corresponding nucleotide-phosphite through reaction of the P(III)
analogue, supported on a solid support, with an organic sulfurising
agent which is present in an organic solvent. As with all the steps
involved in the synthesis of oligonucleotide based phosphoroth-
ioates, the sulfurisation step of the synthesis must be rapid and
have a near quantitative yield. The sulfurisation of phosphorus(III)
1,2,4-dithiazolin-5-one (MEDITH)14
and 3-amino-1,2,4-
dithiazole-5-thione (1a) (ADTT, xanthane hydride).15 The last
reagent, in particular, appears to have an optimal combination of
properties that suggest it will be an advantageous alternative to
existing sulfurising reagents.15
To date there have been very few mechanistic studies of the
sulfurisation reactions of phosphorus(III) analogues using hete-
rocyclic sulfurisation reagents. We report here the results of our
product and kinetic studies which provide a detailed mechanism
for the sulfurisation of substituted triphenyl phosphines (2a–g),
triphenyl phosphites (3a–e) and trialkyl phosphites (4a–f) with 3-
amino-1,2,4-dithiazole-5-thione (1a) and 3-dimethylamino-1,2,4-
dithiazole-5-thione (1b) (Scheme 1).
aDepartment of Organic Chemistry, Faculty of Chemical Technology,
ˇ
University of Pardubice, Na´m. Cs. Legi´ı 565, 532 10, Pardubice, Czech
Republic. E-mail: Jiri.Hanusek@upce.cz; Fax: +420 603 037 068; Tel: +420
603 037015
Results and discussion
bDepartment of Chemical and Biological Sciences, University of Hudders-
field,Queensgate,Huddersfield,UKHD13DH.E-mail: m.i.page@hud.ac.uk
Products of the sulfurisation reaction
cInstitute of Organic Chemistry and Biochemistry, Academy of Sciences of
the Czech Republic, Flemingovo na´m. 2, 166 10, Praha 6, Czech Republic.
E-mail: jansap.@email.cz
Sulfurisation reactions of triphenyl phosphines (2a–g), triph-
enyl phosphites (3a–e) and trialkyl phosphites (4a–f) with 3-
amino-1,2,4-dithiazole-5-thione (1a) and 3-dimethylamino-1,2,4-
dithiazole-5-thione (1b) were studied in acetonitrile, ethanol and
dichloromethane at 25 ◦C. Under these conditions sulfurisation
proceeds smoothly and the yield of the corresponding phosphine
dAvecia Biotechnology, Milford, MA 01757, USA
ˇ
† Dedicated to Professor Vojeslav Steˇrba on the occasion of his 85th
birthday
‡ Electronicsupplementaryinformation(ESI)available:Observedratecon-
stants, details of computational calculations. See DOI: 10.1039/b616298c
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Scheme 1
Scheme 2
sulfide or phosphorothioate is almost quantitative. In reporting
the use of 3-amino-1,2,4-dithiazole-5-thione (1a) as a sulfurisation
agent Tang et al. proposed15 that carbon disulfide and cyanamide
or carbodiimide were additional reaction products and that the
reaction likely proceeded via nucleophilic attack at the sulfur
adjacent to the amino group, to generate an intermediate phospho-
nium ion (Scheme 2). Although this suggestion has been widely
accepted, no evidence was provided for the proposed reaction
products or the mechanism.
In the current study, the reactions of triphenyl phosphine (2d)
with 1a and triphenyl phosphite (3d) with 1a in acetonitrile were
analysed by 1H, 13C and 31P NMR and by GC-MS. All attempts to
detect carbon disulfide and cyanamide or carbodiimide failed.
A possible explanation of this result could lie in the possible
formation of N-cyanocarbonimidodithioic acid (5b) instead of
carbodiimide and carbon disulfide. N-Cyanocarbonimidodithioic
acid (5b) is a tautomer of the proposed intermediate carbodiimide
(5a) (Scheme 3).
ful. On the other hand, the dipotassium salt of (5b) is stable and is
easily available from the reaction of cyanamide and carbon disul-
fide in aqueous or ethanolic potassium hydroxide16,17 solutions or
by hydrolysis of 3-amino-1,2,4-dithiazole-5-thione (1a) in aqueous
potassium hydroxide.16 Although N-cyanocarbonimidodithioic
acid (5b) itself is an unstable compound, it is an important
intermediate18 during synthesis of 1a. The analysis of the reaction
products from the sulfurisation of triphenyl phosphine (2d) with
1a in acetonitrile, after work up with potassium hydroxide, showed
only trace levels of the dipotassium salt of 5b.
1
The H and 13C NMR spectra of the crude by-products show
=
major signals that are more typical of a H2N–(C S)–N grouping,
1
i.e. two broad singlets at 7.85 and 8.43 ppm in H NMR, and
a signal at 186.7 ppm in 13C NMR. This is not consistent
with the previously proposed products and mechanism15 and
an alternative reaction pathway must occur. A possible reac-
tion pathway involves nucleophilic attack of the phosphorus at
sulfur next to the thiocarbonyl group of 1a and subsequent
decomposition of the phosphonium intermediate formed into
triphenyl phosphine sulfide and thiocarbamoyl isothiocyanate (6)
(Scheme 4).
Thiocarbamoyl isothiocyanate (6) itself has not been described
in the literature, presumably because of its high reactivity and
instability. N,N-Dimethylthiocarbamoyl isothiocyanate has been
characterised and is stable for a couple of days19 at −15 ◦C;
at ambient temperature N,N-dimethylthiocarbamoyl isothio-
cyanate readily undergoes19,20 dimerisation ([4 + 2] cycloaddition)
Scheme 3
N-Cyanocarbonimidodithioic acid (5b) is an unstable
compound16 and its characterisation in a pure state was unsuccess-
Scheme 4
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to give 2-dimethylamino-5-dimethylthiocarbamoyl-1,3,5-thiadia-
zine-4,6-dithione.
(1b) in ethanol gives the expected O-ethyl N,N-dimethylthiourea-
Nꢁ-thiocarboxylate (9) (Scheme 7) and
a small amount
To prove the presence of the reactive thiocarbamoyl isothio-
cyanate (6) during the course of the sulfurisation reaction we added
an external nucleophile, 4-nitroaniline, to the reaction mixture to
act as a trap. After reaction work up, 1-(4-nitrophenyl)dithiobiuret
was obtained which is the expected product of nucleophilic
addition of 4-nitroaniline to thiocarbamoyl isothiocyanate
(Scheme 5). The analogous product (i.e. 1-(4-nitrophenyl)-5,5-
dimethyldithiobiuret) was obtained when 3-dimethylamino-1,2,4-
dithiazole-5-thione (1b) was reacted with triphenyl phosphine (2d)
in the presence of 4-nitroaniline. Further evidence supporting
the involvement of thiocarbamoyl isothiocyanate as a reaction
product was sought from performing the reaction in ethanol as
solvent. Although ethanol is a weak nucleophile a reaction with
the reactive thiocarbamoyl isothiocyanate was possible. However,
the desired ethyl thiourea N-thiocarboxylate was not isolated
after 24 hours at ambient temperature, but instead, O-ethyl-S-
potassium N-cyanocarbonimidothioate (8) was obtained as the
main by-product (Scheme 6).
of the dimer (2-dimethylamino-5-dimethylthiocarbamoyl-1,3,5-
thiadiazine-4,6-dithione).
Scheme 7
In order to gain more information about the site of attack
the selenium analogue of 1a, i.e. 3-amino-1,2,4-thiaselenazole-
5-thione (10), was prepared. Reaction of this compound with
triphenyl phosphine in acetonitrile-d3 was monitored using 31P
NMR spectroscopy. It was found that the major product was
triphenyl phosphine sulfide (96%) and less than 5% triphenyl
phosphine selenide was generated. In methanol-d3 the ratio of
products was similar (93% of triphenyl phosphine sulfide and 7%
of triphenyl phosphine selenide). The formation of the sulfide in
preference to the selenide supports nucleophilic attack on sulfur
adjacent to the thione.
The site of nucleophilic attack has been also confirmed using
computational calculations—GAUSSIAN 03 as described in the
Experimental section. The structures of 1a, 1b and 10 as depicted
in Scheme 8 were found to be the most stable tautomers (99.998%).
In the case of 1a and 1b, both in acetonitrile as well as in ethanol,
there is lower electron density at sulfur close to the thiocarbonyl
group (S-1) than at the sulfur (S-2) close to the amino group
(Scheme 8) based on both Mulliken charges and charges calculated
using natural bond analysis (NBO). Presumably this is due to the
electrons at S-1 being more involved in conjugation with the –
Scheme 5
=
C S– grouping compared with the level of conjugation between
=
S-2 and C N. This is consistent with differences in bond lengths
between (C-5)–(S-1) and (C-3)–(S-2) determined in the crystal21
structure. Population analysis also shows higher electron density
between S-1 and C-5 than between S-2 and C-3. Such differences
in conjugation will lead to a polarisation of the S–S bond which
is comparable with the polarisation of a C–S bond. From the
data presented in Scheme 7 it is also clear that the solvent has little
influence on the electron densities at either of the two sulfur atoms.
Scheme 6
There are two possible explanations of this unexpected be-
haviour. One explanation is that changing the solvent alters
the site of attack; attack at the sulfur adjacent to the amino
group would generate N-cyanocarbonimidodithioic acid (5b)
which could undergo esterification with ethanol to give a half
ester which, after work up with potassium hydroxide, gives
(8). Our preferred explanation involves initial formation of the
unstable thiocarbamoyl isothiocyanate (6) which then undergoes
a slow intramolecular cyclisation giving intermediate 4-imino-
1,3-thiazolidine-2-thione (7) which ring opens18 to generate N-
cyanocarbonimidodithioic acid (5b) (Scheme 6).
N-Substituted xanthane hydrides, such as 3-dimethylamino-
1,2,4-dithiazole-5-thione (1b), cannot form the corresponding N-
cyanocarbonimidodithioic acid (5) because the tautomerisation
of the thiocarbamoyl isothiocyanate (6) (Scheme 3) via the
intermediate (7) is not possible. Confirmation of our proposed
pathway comes from the observation that the sulfurisation of
Scheme 8 Mulliken charges and natural bond analysis (NBO) charges in
acetonitrile and ethanol (values given in parentheses) for 1a, 1b and 10.
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Mulliken charges were calculated and NBO analysis was also
performed for 3-amino-1,2,4-thiaselenazole-5-thione (10) in ace-
tonitrile (Scheme 8). In this case the electron densities at sulfur and
selenium are almost the same in terms of Mulliken charges and,
using NBO analysis, the positive charge at selenium is predicted to
be larger and this is probably caused by the lower electronegativity
of selenium. This result could suggest nucleophilic attack might
be expected to occur at both selenium and sulfur. In order to get
a further insight into the factors that control the reactivity of 10,
we made use of the NBO analysis. Valence electrons at selenium
are further away from the core and are therefore less involved in
A Hammett plot for the data, the logarithm of the second-order
rate constants against r, is presented in Fig. 1 for seven substituted
triphenyl phosphines (2a–g). The plot is linear, for both of the
sulfurisation agents, (1a) and its dimethyl derivative (1b), the slope
of which generates reaction constants q(1a) = −0.86 and q(1b) =
−0.92 (Fig. 1). A similar value is also seen for the sulfurisation
of substituted triphenyl phosphites (3a–e) in acetonitrile, q(1a) =
−1.10. The correlation shown is against r− which is better than that
against r, presumably because there is some conjugation between
the P lone pair and the aromatic ring.
=
conjugation with –C N– as compared with conjugation of (S-1)
=
with C S. The calculated shapes and energy levels of the LUMO
orbitals at sulfur and selenium indicate that the electron density
at selenium, in the direction of potential nucleophilic attack, is
approximately three times higher than at the adjacent sulfur.
Kinetic studies of the sulfurisation reaction
The kinetics of the sulfurisation reaction were determined by
monitoring the decrease in concentration of 1a, 1b and 10 spec-
trophotometrically at 360 nm in various solvents in the presence
of excess phosphine or phosphite. The absorbance decreased
exponentially with time from which was obtained a pseudo-first-
order rate constant which varied linearly with the concentration of
the phosphorus(III) derivative to give the corresponding second-
order rate constant. Rate constants were determined for the
sulfurisation reactions of substituted triphenyl phosphines (2a–g),
triphenyl phosphites (3a–e) and trialkyl phosphites (4a–f) using
1a, 1b and 10 as sulfurisation agents (Tables 1 and 2).
Fig. 1 Hammett correlation for sulfurisation of triphenyl phosphine (2d)
with 1a (solid points and solid line) and with 1b (open points and dashed
line).
The single exponential decay of absorbance both for phosphites
and phosphines indicates that the reaction proceeds in one
observable step, which is also supported by the observation that
no consecutive reactions are seen at any wavelength in the UV-Vis
spectrum. It is concluded that if the reaction proceeds through a
reactive intermediate then its concentration is negligible compared
to that of the reactants throughout the entire reaction time.
The interpretation of the Hammett q-value in terms of charge
distribution in the transition state requires a reference reaction,
ideally a corresponding q-value for an equilibrium reaction. There
are a limited number of Hammett correlations in the literature
which relate to reactions of phosphorus(III) species, but they
include kinetic values measured for the reaction of: aryldiethyl
phosphines with ethyl iodide,22 q = −1.0; triaryl phosphines with
elemental sulfur,23 q = −2.5; and triaryl phosphines and triaryl
phosphites with24 diphenyl trisulfide, q = −1.1. In determining
possible transition state structures these values can be compared
with equilibrium data measured for the protonation of phosphines,
measured in nitromethane using Taft substituent constants25 q* =
−2.6 which is very similar to the reaction constant determined for
protonation of amines,26 q = −2.77.
Table 1 Second order rate constants k (l mol−1 s−1) for reaction of 1a,
1b and 10 with substituted triphenyl phosphines (2a–g) in acetonitrile at
25 ◦
C
Phosphine
k(1a) × 10−4
k(1b) × 10−4
k(8) × 10−4
2a
2b
2c
2d
2e
2f
5.947
3.404
1.782
1.323
0.787
0.410
0.026
4.465
2.791
1.335
1.220
0.519
0.251
0.015
—
—
—
0.041
—
—
—
It is likely that the sulfurisation reaction proceeds by initial
nucleophilic attack of phosphorus(III) on the disulfide linkage to
generate a phosphonium ion intermediate as shown in Scheme 4.
Either formation or breakdown of the intermediate could be the
rate limiting step and both steps would have transition states with
positively charged phosphorus compared with the reactant state.
The relatively small reaction constant measured here of about
−1.0 indicates the development of a partial positive charge on
phosphorus in the transition state. If the first step is rate limiting
then the observed q-value suggests an early transition state with
little build up of charge on phosphorus. If the second step is rate
limiting then the reaction constant is the sum of two values for the
two steps (Scheme 4), probably with opposite signs. The reaction
constant for the formation of intermediate q is expected to be
about −2.8. It is therefore unlikely that the second step is rate
2g
Table 2 Second order rate constants k (l mol−1 s−1) for reaction of 1a with
substituted triphenyl phosphites (3a–e, 4a–f) in acetonitrile at 30 ◦
C
Phosphite
k(1a)
Phosphite
k(1a)
3a
3b
3c
3d
3e
26.24
6.746
3.991
3.263
0.509
4a
4b
4c
4d
4e
4f
3030
3122
3655
3870
5.641
702.3
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limiting and the observed q-value is indicative of rate limiting
formation of the phosphonium ion with less than half of the unit
positive charge developed on phosphorus in the transition state as
a result of bond formation.
triarylphosphines, triaryl phosphinites and triaryl phosphonites
with diphenyl trisulfide.24
In order to support this conclusion activation parameters
for the sulfurisation reaction were also determined. Activation
parameters were measured in both acetonitrile and ethanol for the
sulfurisation of triphenyl phosphine (2d) and triphenyl phosphite
(3d) with 1a and 1b. The measurements were carried out at four
temperatures (Table 3) and from the dependence of ln(k/T) vs.
1/T activation enthalpies and entropies at 30 ◦C were calculated
(Table 4). The entropies of activation are very negative (−114
15 J mol−1 K−1) and are consistent with a bimolecular association
step leading to the transition state. This is consistent with the
first step being rate limiting but may also contain a contribution
from the entropy change associated with increased solvation of
charge in the transition state. From Tables 3 and 4 it is clear
that both the rate constants and activation parameters are only
slightly dependent on solvent. To confirm this observation the
kinetics of sulfurisation of triphenyl phosphine (2d) with 1b in
dichloromethane were also determined. The second order rate
constant k = 1.16 × 104 l mol−1 s−1 is similar to that in acetonitrile
(Table 1). From this it can be concluded that the transition state
of the rate limiting step is not very polar. For the reaction of
triphenyl phosphines and phosphites with benzhydrylium cations
in dichloromethane, where charge is neither created nor destroyed
values of activation entropy DS= around −90 J mol−1 K−1 have been
reported.27 The rate constants for this reaction in dichloromethane
and acetonitrile are also similar.
Conclusions
In summary, it can be concluded that the sulfurisation reaction
involves nucleophilic attack of the phosphorus at sulfur next to
the thiocarbonyl group of 1a and 1b to form a phosphonium in-
termediate. The intermediate then breakdowns in a unimolecular
step by carbon–sulfur bond fission to generate the thiophosphoryl
product and thiocarbamoyl isothiocyanate (Scheme 4). The nega-
tive values of DS= and q values indicate that the rate limiting step
of the sulfurisation reaction is formation of the phosphonium ion
intermediate which has an early transition state with little covalent
bond formation.
Experimental
1H, 13C, 31P and 77Se NMR spectra were recorded on a Bruker
400 MHz or Bruker AVANCE 500 MHz instrument. Chemical
shifts d are referenced to solvent residual peaks d(DMSO-d6) =
2.50 (1H) and 39.6 ppm (13C), and d(CDCl3) = 7.27 (1H) and
77.0 (13C). 31P NMR shifts are referenced to 85% phosphoric acid
(external standard) and 77Se NMR shifts are referenced to H2Se.
Coupling constants J are quoted in Hz.
The kinetic measurements were carried out on a Diode Array
Stopped-Flow SX.18 MV-R (Applied Photophysics) spectropho-
tometer at 25 ◦C. The observed pseudo-first-order rate constants
kobs were calculated from the measured time dependence of
absorbance at 360 nm with the help of an optimisation program.
Quantum chemical computations were carried out with the
GAUSSIAN 03 program28 employing the hybrid density func-
tional B3LYP.29 Full geometry optimisations were performed
by using the TZVP basis set.30 The nature of the stationary
points was verified by analytical computations of harmonic
vibrational frequencies. Solvation effects were included using the
polarizable continuum model (PCM).31 A natural bond orbital
(NBO) analysis32 was invoked using the population keyword in
GAUSSIAN 03.
The second order rate constants obtained for triphenyl phos-
phines (2a–g) are more than three orders of magnitude higher
than those for the corresponding triphenyl phosphites (3a–e) and
more than one order of magnitude higher than those for trialkyl
phosphites (4a–f) (Tables 1 and 2) which is consistent with the
higher nucleophilicity of phosphines. Even greater rate differences
have been observed in the case of reactions of triphenyl phosphines
and triphenyl phosphites with various carbocations.27 Despite the
rate differences we observe here, the q-values for both reaction
series are very similar. This is also the case for the reaction of
Triphenylphosphines (2a–g), triphenyl phosphite (3d) and tri-
alkyl phosphites (4a–d) were purchased from Sigma-Aldrich and
used without further purification. Triphenyl phosphites (3a–c,
3e) and trialkyl phosphites (4e–f) were prepared and purified
according to ref. 33. Due to potential oxidation of all phos-
phorus(III) compounds all the solutions were freshly prepared
just before kinetic measurements. Solvents used were of HPLC
quality. 3-Amino-1,2,4-dithiazole-5-thione (1a) was obtained from
Avecia Biotechnology, Grangemouth, UK and recrystallised from
a mixture of water and dimethyl sulfoxide. Dipotassium N-
cyanocarbonimidodithioate was prepared according to ref. 17.
Table 3 Bimolecular rate constants k (l mol−1 s−1) for reaction of 1a
and 1b with triphenyl phosphine (2d) in acetonitrile and ethanol and for
reaction of 1a and triphenyl phosphite (3d) at 25, 30, 35 and 40 ◦
C
k(1a) × 10−4
k(1b) × 10−4
k(1a) × 10−4
k(1a + 3d)
(acetonitrile)
T/◦C (acetonitrile) (acetonitrile)
(ethanol)
25
30
35
40
1.323
1.439
1.603
1.781
1.220
1.339
1.466
1.605
0.394
0.465
0.551
0.644
2.648
3.263
4.231
5.410
Table 4 Activation parameters DH= and DS= for reaction of 1a and 1b with triphenyl phosphine (2d) and triphenyl phosphite (3d) in acetonitrile (ACN)
and ethanol (EtOH) at 30 ◦
C
1a + 2d (ACN)
1b + 2d (ACN)
1a + 2d (EtOH)
1a + 3d (ACN)
DH=/kJ mol−1
13.3
−121
11.7
−128
23
−99
36.5
−115
DS=/J mol−1 K−1
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3-Dimethylamino-1,2,4-dithiazole-5-thione (1b)
at 30 ◦C and a solution containing 2.62 g (0.01 mol) of triphenyl
phosphine (2d) in 100 ml of acetonitrile was added in one
portion. The reaction mixture was stirred for 5 min and then
1.38 g (0.01 mol) of 4-nitroaniline in 30 ml of acetonitrile
was added. After 20 hours precipitated 1-(4-nitrophenyl)-5,5-
dimethyldithiobiuret (1.25 g) was filtered off and the acetonitrile
was removed. The solid residue was quickly extracted with 2 ×
50 ml portions of 3% aqueous potassium hydroxide solution. After
filtration, the insoluble material pure triphenyl phosphine sulfide
(2.9 g, 98%) was recovered and the filtrate was immediately acid-
ified by the addition of concentrated HCl (pH = 3). Precipitated
1-(4-nitrophenyl)-5,5-dimethyldithiobiuret (1.2 g) was filtered off
and dried. Overall yield 2.45 g (87%). Mp 155–156 ◦C (ref. 19 gives
mp 188 C). H NMR (DMSO-d6, 500 MHz) d 3.31 (s, 6H, 2 ×
NCH3), 7.97 (AAꢁXXꢁ, J 9.1, 2H, Ar-2H), 8.24 (AAꢁXXꢁ, J 9.1,
2H, Ar-2H), 10.33 (bs, 1H, NH), 11.76 (bs, 1H, NH). 13C NMR
(DMSO-d6, 125 MHz) d 41.5, 42.4, 122.1, 124.3, 143.2, 144.9,
178.6, 178.9. m/z (ESI) 283.0313 (M+. C10H11N4O2S2 requires
283.0318).
This compound was prepared according to ref. 34 and purified by
crystallisation from acetonitrile. 1H NMR (DMSO-d6, 400 MHz)
d 3.26 and 3.36 (2 × s, 6H, 2 × NCH3). 13C NMR (DMSO-d6, 100
MHz) d 42.2, 42.7, 181.7, 206.6.
3-Amino-1,2,4-thiaselenazole-5-thione (10)
This compound was prepared according to ref. 18 and used
immediately for reaction with triphenyl phosphine. 1H NMR
(DMSO-d6, 400 MHz) d 9.37 and 10.00 (2 × bs, 2H, NH2). 13C
NMR (DMSO-d6, 100 MHz) d 181.9, 209.6. 77Se NMR (DMSO-
d6, 95 MHz) d 738.2 (d, J 11.4).
◦
1
Sulfurisations in acetonitrile
Reaction of 1a with triphenyl phosphine (2d). 3-Amino-1,2,4-
dithiazole-5-thione (1a) (1 g, 6.7 mmol) was dissolved in 400 ml of
acetonitrile under a nitrogen atmosphere at 30 ◦C and a solution
containing 1.75 g (6.7 mmol) of triphenyl phosphine (2d) in 100 ml
of acetonitrile was added in one portion. The reaction mixture was
stirred for 40 min. and then acetonitrile was removed. The solid
residue was mixed with 30 ml of aqueous potassium hydroxide
solution. After filtration the insoluble material was practically
pure triphenyl phosphine sulfide (1.8 g), the filtrate was evaporated
to give a crude mixture of by-products. 1H NMR (D2O, 400
MHz) d 7.85 and 8.43 (2 × bs, 2H, NH2). 13C NMR (D2O, 100
MHz) d 133.5, 186.7 (major signals), 121.6, 228.4 (minor signals
corresponding17 to dipotassium N-cyanocarbonimidodithioate)
and 160.6, 171.1 (minor signals of unknown compound, possibly
(7)).
Reaction of 10 with triphenyl phosphine (2d) (31P NMR study).
3-Amino-1,2,4-thiaselenazole-5-thione (10) (21 mg, 106 lmol)
was dissolved in 3 ml of acetonitrile-d3 and 0.5 ml of DMSO-
d6. Triphenyl phosphine (2d) (28 mg, 107 lmol) in 0.5 ml of
acetonitrile-d3 was added and a 31P NMR spectrum was recorded
after 15 min, 45 min and 24 hours. All spectra contained two
singlets belonging to triphenyl phosphine sulfide (43.2 ppm;
in accordance with ref. 30) and triphenyl phosphine selenide
(35.5 ppm; in accordance with refs. 30,31) in the ratio 23 : 1.
Sulfurisations in ethanol
Reaction of 1a with triphenyl phosphine (2d). 3-Amino-1,2,4-
dithiazole-5-thione (1a) (1 g, 6.7 mmol) was dissolved in 200 ml of
ethanol under a nitrogen atmosphere at 30 ◦C and a solution con-
taining 1.75 g (6.7 mmol) of triphenyl phosphine (2d) in 100 ml of
ethanol was added in one portion. The reaction mixture was stirred
for 17 hours and then precipitated triphenyl phosphine sulfide was
filtered off (0.7 g). Ethanol was removed and the solid residue was
mixed with 30 ml of 3% aqueous potassium hydroxide solution.
After filtration the insoluble triphenyl phosphine sulfide (1.1 g,
overall yield 92%) was recovered and the filtrate was evaporated
to dryness. The resulting solid was washed with ethanol to give
0.7 g (67%) of O-ethyl-S-potassium N-cyanocarbonimidothioate
Reaction of 1a with triphenyl phosphine (2d) and 4-nitroaniline.
3-Amino-1,2,4-dithiazole-5-thione (1a) (1 g, 6.7 mmol) was dis-
solved in 400 ml of acetonitrile under a nitrogen atmosphere at
30 ◦C and a solution containing 1.75 g (6.7 mmol) of triphenyl
phosphine (2d) in 100 ml of acetonitrile was added in one portion.
The reaction mixture was stirred for 5 min. and then 0.92 g
(6.7 mmol) of 4-nitroaniline in 20 ml acetonitrile was added.
After 15 hours the acetonitrile was removed and the solid residue
was quickly extracted with 3 × 40 ml of 3% aqueous potassium
hydroxide solution. After filtration the insoluble material, pure
triphenyl phosphine sulfide (1.85 g, 94%), was recovered. The
filtrate was immediately acidified by addition of concentrated HCl
(pH = 3). Precipitated 1-(4-nitrophenyl)dithiobiuret was filtered
1
(8). H NMR (DMSO-d6, 400 MHz) d 1.13 (t, J 7.1, 3H, CH3),
4.08 (q, J 7.1, 2H, OCH2). 13C NMR (DMSO-d6, 125 MHz) d
14.6, 64.4, 120.2, 197.1. m/z (ESI) 129.0156 (M − K+. C4H5N2OS
requires 129.0117). m/z (ESI) 206.9398 (M + K+. C4H5K2N2OS
requires 206.9391).
◦
1
off and dried. Yield 1.65 g (97%). Mp 168–170 C. H NMR
(DMSO-d6, 500 MHz) d 7.97 (AAꢁXXꢁ, J 9.05, 2H, Ar-2H), 8.25
(AAꢁXXꢁ, J 9.1, 2H, Ar-2H), 9.1 and 9.42 (2 × bs, 2H, NH2),
11.01 (bs, 1H, NH), 13.22 (bs, 1H, NH). 13C NMR (DMSO-d6,
125 MHz) d 123.3, 124.6, 143.7, 144.3, 177.3, 179.2. m/z (ESI)
255.0016 (M−.C8H7N4O2S2 requires 255.0005).
Reaction of 1b with triphenyl phosphine (2d). 3-
Dimethylamino-1,2,4-dithiazole-5-thione (1b) (1.78 g, 0.01 mol)
was suspended in 500 ml of ethanol under a nitrogen atmosphere
at 30 ◦C and a solution containing 2.62 g (0.01 mol) of triphenyl
phosphine (2d) in 100 ml of ethanol was added in one portion. The
reaction mixture was stirred for 23 hours and then precipitated
triphenyl phosphine sulfide was filtered off. The volume of the
reaction mixture was reduced to 50 ml and the rest of the solid
triphenyl phosphine sulfide (2.8 g, overall yield 95%), was filtered
Reaction of 1a with trimethyl phosphite (4a) and 4-nitroaniline.
The reaction was carried out in the same way as for triphenyl
phosphine. Yield of isolated 1-(4-nitrophenyl)dithiobiuret was
1.35 g (80%).
Reaction of 1b with triphenyl phosphine (2d) and 4-nitroaniline.
3-Dimethylamino-1,2,4-dithiazole-5-thione (1b) (1.78 g, 0.01 mol)
was dissolved in 200 ml of acetonitrile under a nitrogen atmosphere
1
off. The filtrate was evaporated to give a yellow oil. H NMR
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The Royal Society of Chemistry 2007
Org. Biomol. Chem., 2007, 5, 478–484 | 483
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(CDCl3, 500 MHz) d 1.33 (t, J 7.2, 3H, CH3), 3.23 and 3.41 (2 × s,
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Acknowledgements
The authors acknowledge the financial support from the Ministry
of Education, Youth and Sports of the Czech Republic (project
no. MSM 002 162 7501), EPSRC and Avecia Biotechnology.
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