A thionation process and a thionating agent
Field of the invention
The present invention relates to a thionation process. More specifically, the invention relates
to a process for transforming an oxo group (>C=0) in a compound into a thio group (>C=S)
or a tautomeric form of said thio group.
Background of the invention
In 1951, Klingsberg 1 et al described the use of P4S10 dissolved in pyridine as a thionating
agent. Pyridine and P4S10 react readily to form a zwitter-ionic, non-smelling compound, the
composition of which, P2 S 5-2 C5H5N, was studied as early as 1967-1968 by German inorganic
chemists2'3who obtained evidence for its structure by 1P NMRdata 4 as well as by comparison
with related molecules.
In spite of the teachings of Klingsberg et al., the predominantly used agent in the reaction of
thionation of compounds containing an oxo group has been the so-called Lawesson's reagent
(IUPAC name: 2,4-bis(4-methoxyphenyl)-l,3,2,4-dithiadiphosphetane-2,4-dithione), herein
below referred to as LR. LR was introduced in 1968 for transformations in organic chemistry
and was used with a considerable number of reactants, such as amides and ketones, which
were thionated in fair yields. However, LR as a thionating agent suffers from a number of
drawbacks. For example, its thermal stability is mediocre; it has even been reported that LR
starts to decompose above 110 °C5'6. Further, LR has a generally low solubility, which quite
often has necessitated the use of hexamethylphosphoramide (HMPA) as a solvent. HMPA is
suspected of being carcinogenic to humans and its use is prohibited in many countries.
Additional drawbacks with LR are the strong, unpleasant smell of the compound in itself and
the fact that during a reaction, there tends to be formation of foul-smelling side-products that
are difficult to separate from the desired reaction products (column chromatography is often
required).
It appears that there still remains a need for an improved process for the thionation of an oxo
group-containing compound as well as an improved thionating agent for use in such process.
Summary of the invention
According to a first aspect there is provided a process for transforming a group >C=0 (I) in a
compound into a group >C=S (II) or a tautomeric form of group (II), in a reaction giving a
thionated reaction product, by use of crystalline P2S5-2 C5H5N as a thionating agent.
According to a further aspect, a thionating agent is provided, which is crystalline P2S5-2
C5H5N .
Brief description of the drawings
Figure 1 shows (A) the molecular structure and (B) the crystal structure of P2S5-2 C5H5N .
Figure 2 shows (A) the molecular structure and (B) the crystal structure of pyridinium
dihydrogenmonothiophosphate.
Detailed description of the invention
The present inventors have determined the crystal structure of P2S5-2 C5H5N by X-ray
analysis, the details of which are given in the Experimental Section. An Ortep representation
of the molecular structure of the compound is shown in Figure 1. The molecules are linked
together via several van der Waals interactions. The strongest van der Waals contact (CH...
S) links the molecules together into and infinite chain along the c-axis. The packing
coefficient (percent filled van der Waals space in the unit-cell) is 67.7 %, indicating an
efficient molecular framework in the solid state. The molecular packing is facilitated by the
aromatic p stacking. The distance between the planes of two adjacent aromatic moieties is
approximately 3.5 A.
As mentioned herein above, the present invention provides a thionating agent consisting of
crystalline P2S5-2 C5H5N . Very advantageously, this agent is storable for long period of times
and moreover is free from impurities inherent in the conventional thionating agent because
these impurities (from P4S10) are removed via the pyridine mother liquor.
The improved purity will result in cleaner thionation products and more facile work-up
procedures. A particular advantage is the fact that the thionating agent can be transferred to
solvents such as acetonitrile and dimethylsulfone.
Indeed, the zwitterionic crystalline compound has fair solubility in hot acetonitrile and a good
solubility in hot pyridine. It also has a good solubility in cyclic sulfones or in lower alkyl
sulfones, such as dimethylsulfone.
In one embodiment of the process of the invention, the thionating agent and the compound to
be thionated are allowed to react in a liquid solvent medium for the compound and for the
thionating agent. In other words, the thionating agent is used dissolved in a liquid solvent
medium.
In one embodiment of the process of the invention, the thionating agent is used as a melt,
mixed with the compound to be thionated. In this embodiment, the thionating agent is heated
to its melting temperature (167-169 °C) and the compound to be thionated is mixed with the
thionating agent before, after or during heating.
The solvent medium should be selected from aprotic solvents. In one embodiment, the liquid
solvent medium is an organic solvent that is liquid at room temperature and that may be
heated to a suitable reaction temperature, e.g. a temperature of 60-200 °C, e.g. 60-100 °C,
such as acetonitrile that is a liquid at room temperature (melting point -42 °C) and has a
boiling temperature of 82 °C. In this case, the crystalline P2S5-2 C5H5N and the compound to
be thionated are both dissolved in the organic solvent, which optionally is heated e.g. to
reflux.
In one embodiment, the crystalline P2S5-2 C5H5N is admixed with the solvent medium, at a
temperature below the melting point of the solvent medium and of the crystalline P2S5-2
C5H5N and the mixture is heated in order to obtain a liquid solution containing P2S5-2 C5H5N
dissolved in the liquid solvent medium.
The compound to be thionated may be admixed with the other components of the reaction
mixture at any point of the process, e.g. before or after melting and/or dissolution.
For example, the melting temperature of dimethylsulfone is 107-109°C. In case melted
dimethylsulfone is used as a liquid solvent medium for the reaction, crystalline P2S5-2 C5H5N
and solid dimethylsulfone may be mixed at e.g. room temperature and heated to a temperature
of at least about 109°C, at which time a solution of P2S5-2 C5H5N in liquid dimethylsulfone is
obtained. In this reaction medium, the thionation of the oxo group containing compound may
be performed.
An advantageous feature of P2S5-2 C5H5N is its thermal stability, which allows for performing
the thionating reaction at temperatures well over 100 °C, e.g. at a temperature of 100-200 °C,
or 115-180 °C, or at a temperature of 150-175 °C, in particular at a temperature of 165-175
°C, although also lower temperatures may be used, e.g. 60-100 °C. In some embodiments, the
reaction is performed at the boiling temperature of the liquid solvent medium.
It is at present not clear if it is P2S5-2 C5H5N per se that, after dissolution in the liquid solvent
medium, thionates the compound, or whether the reaction proceeds via dissociation to some
other intermediary, reactive species. For the purpose of the present invention, however, the
precise mechanism of the reaction is not essential, and by indication that the dissolved P2S5-2
C5H5N is allowed to react with the dissolved compound it is intended to include a reaction
proceeding by any possible intermediary leading to the desired thionated product.
In the presence of water or a protic solvent, such as a lower alcohol, e.g. methanol or ethanol,
P2S5-2 C5H5N quickly undergoes extensive degradation. For example, addition of water to a
hot solution/suspension of P2S5-2 C5H5N in acetonitrile will quickly result in a clear solution
of a salt of pyridine and phosphorothioic acid, viz. pyridinium
dihydrogenmonothiophosphate, of formula
This salt is readily soluble in water and its ready formation and high solubility can be
advantageously used during work-up of the thionated reaction product of the invention, e.g.
thioamides. Thus, in a typical reaction of the invention, four equivalents of an amide are
heated with 1.1 equivalents of crystalline P2S5-2 C5H5N in dry acetonitrile and in connection
with the work-up any remaining thionating agent is readily removed by addition of water.
P2S5-2 C5H5N will also decompose when treated with alcohols; e.g. treatment of P2S5-2
C5H5N with ethanol gives pyridinium 0,0-diethyldithiophosphonate, of formula
Thus, one advantage of the present invention is that the desired thionated product is easily
separated from any remaining thionating agent P2S5-2 C5H5N by treatment with a protic
solvent, such as water or a lower alcohol, e.g. ethanol.
Therefore, in one embodiment of the invention, there is provided a process for transforming a
group >C=0 (I) in a compound into a group >C=S (II) or a tautomeric form of group (II) by
bringing the compound into contact with P2S5-2 C5H5N so as to obtain a thionated reaction
product; comprising admixing crystalline P2S5-2 CsH Nwith said compound in a liquid
solvent medium for the compound and for the crystalline P2S5-2 C5H5N, so as to obtain a
liquid solution of the compound and P2S5-2 C5H5N and allowing the P2S5-2 C5H5N and
compound to react with each other in the solution, followed by adding a protic solvent to the
solution.
After addition of a protic solvent to the solution, the salt resulting from decomposition of any
remaining P2S5-2 C5H5N will be easily separated from the thionated compound, e.g. by
extraction with an aqueous solution or with water. In some embodiments, addition of a protic
solvent, such as water, will result in the precipitation of the thionated reaction product, which
may then be separated from the aqueous phase, e.g. by a simple filtration. Further purification
of the reaction product may optionally be performed, e.g. by recrystallization.
The group >C=0 (I) to be transformed into a group >C=S (II) may be present e.g. in a ketone
or an amide functional group and may be present in a compound comprising one or several
functional groups, in which case a selective thionation may be achievable, as will be shown in
the Examples herein below.
In one embodiment, the group (I) is present in an amide function, -C(0)-N<, e.g. in a
compound
wherein R e.g. may be selected from C1-C12 hydrocarbyls, and R' and R may be
independently selected from H and C1-C12 hydrocarbyls, or wherein R and R' and/or R'and
R" may be joined to each other to form, together with the amide carbon and/or nitrogen to
which they are attached, a mono- or polycyclic ring, e.g. a mono- or polycyclic 5-20
membered ring optionally containing one or several additional heteroatoms, e.g. one or
several heteroatoms selected from O, N and S, which ring may be saturated or unsaturated
and aromatic or non-aromatic.
In one embodiment, the compound is a peptide, an oligopeptide or a polypeptide, e.g. a
peptide comprising from 1 to 10 groups (I) in the backbone, or from 1 to 5 oxo groups (I).
In one embodiment, the group (I) is present in a ketone function, such as in a compound
wherein R and R' e.g. may be independently selected from H and C1-C12 hydrocarbyls, or
may be joined to each other to form, together with the ketone carbon, a mono- or polycyclic
ring, e.g. a mono- or polycyclic 5-20 membered ring optionally containing one or several
heteroatoms, e.g. one or several heteroatoms selected from O, N and S, which ring may be
saturated or unsaturated and aromatic or non-aromatic.
The groups R, R' and R" may optionally and independently be substituted by one or more
substituents, e.g. one or more further oxo groups or one or more other functional groups.
When the group (I) is present in a ketone function, there preferably should be at least one
electron donating group present in the compound, resulting in an increased electron density of
the group (I). Such electron donating group (EDG) e.g. may be a group having a lone electron
pair, capable of raising the electron density of the keto group by derealization of said
electron pair through one or several double bonds situated between the EDG and the keto
group. The electron density of the keto group also may be raised by inductive effects.
The product of the thionating reaction of the invention is a thionated compound comprising a
group >C=S (II) or a tautomer thereof, e.g. a group >C=C(SH)-.
The crystalline P2S5-2 C5H5N preferably is admixed at a molar ratio to the group (I) to be
transformed of 1 mole P2S5-2 C5H5N per 1-4 moles of group (I), e.g. 1 mole P2S5-2 C5H5N per
2-4 moles of group (I), in particular 1 mole P2S5-2 C5H5N per 3-4 moles of group (I).
Therefore, in case the compound contains more than one group (I) to be transformed into a
group (II), the molar ratio of P2S5-2 C5H5N to compound will be correspondingly higher. For
example, in case the compound contains 2 groups (I) to be transformed into 2 groups (II), the
crystalline P2S5-2 C5H5N preferably is admixed at a molar ratio with the compound to be
thionated of 1 mole P2S5-2 C5H5N per 0.5-2 moles of the compound, e.g. 1 mole P2S5-2
C5H5N per 1-2 moles of the compound, or 1 mole P2S5-2 C5H5N per 1.5-2 moles of the
compound.
Generally, for a compound containing n functions selected from e.g. ketone functions and
amide functions, e.g. n amide functions, the molar ratio between P2S5-2 C5H5N and the
compound may be from n/4 to n, or from n/4 to n/2, e.g. from n/4 to n/3.
An advantageous feature of P2S5-2 C5H5N as a thionating agent is its selectivity. Thus, for
example carboxylic ester functions generally do not react with P2S5-2 C5H5N, and therefore,
the present invention also provides a method of selectively thionating e.g. an amide or keto
function in a compound also comprising a carboxylic ester function.
The invention will be further described in the following, non-limiting examples.
EXAMPLE 1
Crystalline P2S 2 C H N
Tetraphosphorus decasulfide (P4S10, 44.5 g, 0.1 mol) was added in portions to dry pyridine
(560 mL) at 80 °C using stirring equipment. After a period of reflux (lh) a clear yellow
solution was obtained, which deposited light-yellow crystals when the solution was allowed
to cool. After 2h the crystals were collected, washed with dry acetonitrile and finally
transferred to an exsiccator (containing a beaker with cone sulfuric acid) to remove any
excess of pyridine, yield 62.3 g (84%), mp: 167-169 °C, IRv max: 3088, 3040, 1608, 1451,
1197, 1044, 723, 668 cm 1 ; cf. Fig.l.
Pyridinium dihydrogenmonothiophosphate
The crystalline P2S5-2 C5H 5N (3.80 g, 10 mmol) was heated at reflux temperature in
acetonitrile (35 mL) containing water (1.0 mL). The clear solution (obtained within 3 min)
was concentrated and the product allowed to crystallize, 3.15 g, (79%). The crystals were
suitable for X-ray crystallography, mp: 110-120 °C, decomp., with evolution of H2S; 1H NMR
(300 MHz, DMSO - ) d 7.51 (m, 2H, 3-H), 7.95 (dd, 1H, 4-H), 8.63 (d, 2H, 2-H), 9.7 (br s,
3H); 1 C NMR (75.5 MHz, OMSO-d ) d 124.7 (d), 138.5 (d), 147.8 (d); cf. Fig.2.
Pyridinium O,O-diethyldithiophosphonate
The crystalline P2S5-2 C5H5N (1.0 g) was heated at reflux in ethanol (5 mL) for 5 min, the
clear solution was evaporated to give an oil which soon solidified (100%).
IR Vmax: 2976, 2891, 1630, 1600, 1526, 1479, 1383, 1020, 920, 748, 681 cm 1
1H NMR (300 MHz, DMSO - ,) d 1.08 (t, J =7.1 Hz, 6H), 3.79 (m, 4H), 8.09 (m, 2H), 8.62
(m, 1H), 8.97 (m, 2H); 1 C NMR (75.5 MHz, DMSO - ) d 16.1 (q, JC-P = 8.8 Hz), 59.8 (t,
2JC-p = 7 .1 Hz), 127.2 (d), 142.5 (d), 146.0 (d).
EXAMPLE 2
(S)-ll-Thioxo-2,3,ll,lla-tetrahydro-lH-benzo[e]pyrrolo[l,2-a][l,4]diazepine-5- (10H)-
one (Table 1, entry 17).
To a MeCN-solution (200 mL) of 2,3-dihydro-lH-benzo[e]pyrrolo[l,2-a][l,4]diazepine-
5,1 1(10H,1 laH)-dione (4.0 g, 20 mmol) crystalline P2S 2 C5H5N (2.3 g, 6 mmol), was added
and heated to 60 °C for 3 h during which time a yellow precipitate was formed. The reaction
mixture was allowed to stand at room temperature overnight in order to precipitate fully. The
product was vacuum-filtered and washed with a little cold MeCN to give the title compound
(3.9 g, 85 %) as a pale-yellow solid, mp 268-270 °C; [a] D
23 +971° ( 0.16, MeOH); Ir vma :
3170, 2979, 1616, 1602, 1477, 1374, 1271, 1141, 831, 813, 752 cm 1 ;
1H NMR (300 MHz, DMSO - ,) d 1.89-1.94 (m, 1H), 1.99-2.16 (m, 2H), 2.84-2.94 (m, 1H),
3.40-3.50 (m, 1H), 3.53-3.60 (m, 1H), 4.27 (d, J =6.1 1 Hz, 1H), 7.22-7.27 (m, 1H), 7.30-7.37
(m, 1H), 7.55-7.60 (m, 1H), 7.80-7.85 (m, 1H), 12.46 (br s, 1H); 1 C NMR (75.5 MHz,
OMSO-d6) d 22.7(t), 29.0 (t), 46.8 (t), 59.8 (d), 121.8 (d), 125.7 (d), 127.8 (s), 130.2 (d),
132.2 (d),136.5 (s),164.2 (s), 201.9 (s).
EXAMPLE 3
2,5-Piperazinedithione from glycine (Table 2, entry 1).
Glycine (1.50 g, 20 mmol), crystalline P2S 2 C H N (9.12g, 28 mmol) and dimethylsulfone
(8.0 g) were heated at 165-170 °C for l h whereupon the reaction mixture (after cooling) was
treated with boiling water for 30 min. The brownish solid obtained was recrystallized from
ethanol/DMF, 1.85 g (63 %) mp 284 °C; 1H NMR (300 MHz, OMSO-d ) d 4.19 (s), 10.7 (s);
1 C NMR (75.5 MHz, DMSO-4) d 54.4 (q), 191.9 (s).
EXAMPLE 4
2,5-Piperazinedithione from 2,5-piperazinedione (Table 2, entry 2).
2,5-Piperazinedione (2.28 g, 20 mmol) and crystalline P2S 2 C H N ( 2.28 g, 8 mmol) were
heated at reflux in acetonitrile (50 mL) for 2h, when the mixture was concentrated and water
was added. The solid formed was collected after a stirring period of lh, 2.63 g (90 %).
Melting point and NMR data are identical to data reported above for 2,5-piperazinedithione
from glycine (Table 2, entry 1).
S,S -l,4-Diacetyl-2,5-bis-acetylthiolo-l,4-dihydropyrazine, 35.
The above 2,5-piperazinedithione (1.46 g, 10 mmol) was heated at reflux temperature in
acetic anhydride (20 mL) for 2h, whereupon the reaction mixture was concentrated and
treated with diisopropyl ether, 2.06 g (93 %), mp 190-192 °C; 1H NMR (300 MHz, DMSOd6)
d 2.17 (s, 6H), 2.45 (s, 6H), 6.99 (s, 2H); 1 C NMR (75.5 MHz, DMSO-4) d 22.2 (q), 29.4
(q), 117.0 (s), 131.6 (d), 166.3 (s), 193.7 (s); Elemental analysis calcd for Ci2Hi4N20 4S2, C,
45.75; H, 4.48; N, 8.88. Found C, 45.90; H, 4.32; N, 8.71.
Reductive cleavage of the tetrasulfide, 25.
The 3,3'-diindolyl-2,2'-tetrasulfide 25, (3.58 g, 10 mmol was dissolved in THF, 50 mL and
added to a mixture of NaBH (1.50 g, 40 mmol) in THF (75 mL). Evolution of gases
containing H2S ensued and the reaction mixture was stirred for 3 h at 40-45 °C under a
blanket of argon. This air-sensitive solution containing the dianion 26 was not stored but
directly transformed by operations described below.
2,2'-Bis(methylthio)-l H,l ,H-3,3'-biindole.
Dimethyl sulfate (1.51 g, 12 mmol) dissolved in MeOH (15 mL) was added dropwise to a
solution obtained by reductive cleavage of the tetrasulfide 25 (5 mmol) at 25 °C. After a
period (lh) of stirring the solution was evaporated and treated with water. The crude solid was
crystallized from MeOH-water to yield a yellow solid (0.45 g, 57%) mp 184-186 °C; 1H NMR
(300 MHz, OMSO-de) d 2.44 (s, 6H), 6.95-6.99 (m, 2H), 7.10-7.22 (m, 4H), 7.36-7.45 (m,
2H), 11.55 (s, 2H); 1 C NMR (75.5 MHz, DMSO-4) d 18.0 (q), 110.8 (s), 110.9 (d), 119.0
(d), 119.2 (d), 121.5 (d), 128.0 (s), 129.1 (s), 137.0 (s).
Synthesis of the cyclodisulfide, 23.
A solution obtained by reductive cleavage of the tetrasulfide 25 was, after addition of water
(50 mL), stirred for 24 h in contact with air. The yellow solid formed was collected and
crystallized from acetonitrile-DMF 4:1 yielding 2.20 g (77%) of a solid still containing DMF,
which was removed by drying under reduced pressure, mp >227-228 °C.
1H NMR (300 MHz, DMSO-4,) d 7.04-7.08 (m, 1H), 7.28-7.31 (m, 2H), 7.33-7.51 (m, 1H),
12.16 (s, 1H): 1 C NMR (75.5 MHz, DMSO-4) d 136.3 (s), 127.0 (s), 124.9 (s), 124.6 (d),
120.3 (d), 120.2 (d), 119.3 (s), 112.2 (d).
EXAMPLE 5
Cyclodisulfide 23 by thionation of oxindole at 160 °C (Table 3, entry 13).
Oxindole (1.33 g, 10 mmol) and crystalline P2S5-2 C5H5N (1.52 g, 4 mmol) were warmed
with dimethyl sulfone (4.0 g) and then heated at 160 °C for 5 min. The melt was allowed to
cool and then heated with water. The solid formed was crystallized from acetonitrile-DMF 4 :1
yielding 1.37 g (92 % ) mp > 227-228 °C. This material was identical with that obtained via
reductive cleavage of the tetrasulfide 25.
3,3'-Bithio-oxindole, 27.
The solution obtained from reductive cleavage of the tetrasulfide 25 was acidified with AcOH
which resulted in quick formation of the title compound as a yellow precipitate, 2.52 g (85
%). Which was recrystallized from acetonitrile, mp 180 °C decomp. This molecule is sensitive
towards aerial oxidation.
1H NMR (300 MHz, DMSO-4,) d 4.66 (s, 2H), 6.85-6.91 (m, 4H), 6.96-6.98 (m, 2H), 7.07-
7.13 (m, 2H), 13.06 (s, 2H); 1 C NMR (75.5 MHz, DMSO-4) d 60.8 (d), 110.4 (d), 123.0 (d),
123.4 (d), 128.6 (d), 130.2 (s), 144.2 (s), 204.3 (s). Elemental analysis calcd for C16 Hi2N2S2;
C, 64.60, H, 4.08, N, 9.43 Found C, 64.26, H, 3.99, N, 9.31.
EXAMPLE 6
Methyl 5-mercapto-4-(2-methoxy-2-oxoethyl)-2-methyl-lH-pyrrole-3-carboxylate, 34b.
The diester 33a (2.13g, 10 mmol) and crystalline P2S5-2 C5H5N (1.14g, 4 mmol) were heated
at reflux temperature in acetonitrile (50 mL) for lh. After concentration to 25 mL, water was
added and the solid formed collected and crystallized from 2-propanol, 1.85g (81%) mp. 185-
187 °C; IR max: 3273, 2954, 1742, 1724, 1707, 1681, 1562, 1440, 1341, 1269, 1200, 1173,
1117, 1080, 1003, 782 cm 1 ; 1H NMR (300 MHz, OMSO-d ) d 2.43 (s, 3H, CH3), 3.17 (s, 1H,
SH), 3.49 (s, 3H, OCH3), 3.64 (s, 3H, OCH3), 11.90 (s, 1H, H); 1 C NMR (75.5 MHz,
DMSO-4) d 13.4 (q), 30.6 (d), 50.4 (q), 51.4 (q), 111.2 (s), 117.1 (s), 126.9 (s), 139.9 (s),
164.4 (s), 171.1 (s) Elemental analysis calcd for C10 Hi3N0 4S; C, 49.37, H, 5.38, N 5.75
Found C, 49.25, H, 5.46, N, 5.61.
EXAMPLE 7
3-(lH-Indol-3-yl)-3,3'-biindoline-2-thione (Table 3, entry 9).
3-(lH-indol-3-yl)-3,3'-biindolin-2-one (728 mg, 2 mmol), crystalline P2S 2 C5H5N (228 mg,
0.6 mmol) and dimethyl sulfone (3.05 g) were heated (165-170 °C) for 20 min. The melt was
allowed to cool and then heated in water for 10 min. The solid formed was collected, 766 mg
(94 %), mp >260 °C. 1H NMR (300 MHz, OMSO-d ) d 7.09-7.15 (m, 2H), 7.18-7.20 (m, 5H),
7.24-7.30 (m, 7H), 13.00 (s, 1H); 1 C NMR (75.5 MHz, DMSO-4) d 72.7 (s), 111.2 (d),
124.4 (d), 126.5 (d), 127.5 (d), 128.6 (s), 128.7 (s), 129.0 (d), 129.1 (d), 129.1 (d), 139.2 (s),
143.0 (s), 143.5 (s), 145.3 (s, 2C), 208.4 (s). Elemental analysis calcd for C24Hi7N3S; C,
75.96, H, 4.51, N, 11.07; Found C, 76.10, H, 4.46, N, 11.00.
The outcome of a number of thionation reactions according to the invention, using crystalline
P2S5-2 C5H5N dissolved in hot acetonitrile, are listed in Table 1. In the exemplified reactions,
the ratio of crystalline P2S5-2 C5H5N to the compound to be thionated was 1.1:4. In some
cases direct comparisons with LR have been made. For instance e-caprolactam and P2S5-2
C5H5N gave the corresponding thioamide within 5 min, but LR thionates even faster.
Actually, a suspension of LR in hot acetonitrile can be titrated by addition of e-caprolactam.
The advantages of the thionating agent of the invention over LR are primarily that the
inventive thionating agent is easier to prepare, odourless (when sufficiently pure) and that the
thionated products are very pure. In the Examples described herein, formation of nitriles from
primary amides never was a problem. This type of side reaction can sometimes be
problematic when the thionating agent LR is used7'8. Thionation of the exemplified ketones
with P2 S 5-2 C5H5N worked well (Table 2, entries 3 and 4). The keto derivatives 20a and 21a
could be converted to 20b and 21b, respectively, when the thionating agent of the invention is
used in hot pyridine or as a melt or even better - when heated together with dimethylsulfone
(Table 1, entry 20 and Table 3, entry 3).
Whereas thionation of 3,3-dimethyloxindole (entry 7, Table 1) gave an excellent yield, the
parent compound, oxindole (entry 6, Table 1) gave unacceptably low yields (-10 %). Here,
formation of complexes of low solubility seems to be the cause of the problems. Synthesis of
3,3-diindolylindoline-2-thione also failed but could be effected with dimethylsulfone as
solvent (see Table 3). Thionation of 3-hydroxy-2-pyridone worked well without
complications to give the interesting class of 3-hydroxy-2-(lH)-pyridinethione, which for
several types of metal complexes (e.g. Zn2+) have been reported to show some promise
against diabetes mellitus.
In cases where more than one carbonyl group is present in the starting materials selectivity
could be achieved. Thus the monothionated molecules (Table 1, entries 12, 16 and 17) could
be obtained in good yields. Thionation of piperidine-2,6-dione gave the monothionated
product in hot acetonitrile whereas with an excess of the thionating agent in hot pyridine the
fully thionated product could be obtained.
Table 1. Thionation of amides with the inventive thionating agent in hot MeCN.

isolatec product contained two rotamers
Thionation of Gly-Gly as well as piperazine -2,5-dione both gave good yields of the
expected dithionated product (Table 2, entries 1 and 2). To further characterise the rather
insoluble product, it was acetylated in hot acetic anhydride, which yielded the
tetraacetylated product 35 which readily gave nice MR spectra.
Table 2. Thionation with the inventive thionating agent in hot pyridine
obtained from - 20
Thionations at quite high temperatures (165-175 °C) could be effected with e.g. P2S5-2 C5H5N
dissolved in dimethylsulfone (mp 107-109 °C, bp 238 °C). The results of some exemplifying
reactions of the invention are listed in Table 3 . In one case (Table 3, entry 6) the product was
partially converted to the highly insoluble disulfide 22. Similar observations have been
reported e.g. Stoyanov9 and Hino et al 0 . The latter workers found that a number of 3-
substituted indole-2-thiones readily could be oxidized to the corresponding disulfides.
Formation of oxidative products could be avoided by running the reactions under argon.
Benzaldehyde has been thionated many times in the past11 16 and the product has invariably
been isolated as the trimer (29) of the unstable primary product 30, and the trimer 29, was
indeed the product when benzaldehyde was reacted with the thionating agent of the invention
in dimethylsulfone.
29 30
Ester carbonyl groups are generally not attacked by P2S5-2 C5H Nas can be exemplified by
thionation (Table 3, entry 10) of the monoacetate of kojic acid (31) which selectively gave the
thione 32 (Table 1, entry 17). Thionation of the diester 33a offered another example, namely
the pyrrole-2-thiol derivative 34b
The starting material existed completely (NMR evidence) as the tautomer 33a, whereas the
product existed completely as the thiol tautomer 34b. But more importantly the two ester
functions were intact.
Due to low solubility and high melting point, 2,5-piperazinedithione (Table 3, entry 12) was
difficult to characterize, therefore the readily soluble tetraacetate 35 was prepared.
Table 3 . Thionation in dimethylsulfone with the inventive thionating agent at 165-175 °C
*experiment run under
In the light of the above general description and with further guidance from the illustrating
Examples, the person of ordinary skill in the art will be well capable of practicing the
invention within the full scope of the claims, using routine experimentation if necessary to
select suitable reaction conditions, e.g. in view of the functional groups that may be present in
the compound to be thionated. For example, the reaction may be performed under normal
ambient atmosphere or under an inert atmosphere of e.g. argon or nitrogen. Other parameters
that may be optimized or varied are e.g. the solvent medium, the reaction temperature and the
reaction time and all such modifications and variations are contemplated to be within the
scope of the present invention.
References
(1) Klingsberg, E.; Papa, D. J . Am. Chem. Soc. 1951, 73, 4988-4989.
(2) Meisel, M.; Grunze, H. Z. Anorg. Allg. Chemie, 1967, 360, 277-283.
(3) Fluck, E.; Binder, H. Z. Anorg. Allg. Chemie 1967, 354, 113-129.
(4) Brunei, E.; Monzur, J.; Retuert, J . J . Chem. Res (M) 1981, 3437-3445.
(5) Jesberger, M.; Davis, T. P.; Berner, L. Synthesis 2003, 1929-1958.
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b) Ozturk, T.; Erdal, E.; Olcay, M. Chem. Rev. 2010, 110, 3419-3478.
(7) Scheibye, S.; Shabana, R.; Lawesson, S. O.; Romming, C. Tetrahedron 1982,
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(8) Ley, S. V.; Leach, A. G.; Storer, R. I . J . Chem. Soc, Perkin Trans 1 2001, 358-
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(9) Stoyanov, S.; Petkov, ; Antonov, L.; T. Stoyanova; Karagiannidis, P.;
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(10) Hino, T.; Suzuki, T.; Nakagawa, M. Chem. Pharm. Bull 1974, 22, 1053-1060.
(11) Baumann, E.; From, E. Ber. 1889, 22, 2600-2609.
(12) Stanfield, J . A.; Reynolds, L. B. J . Am. Chem. Soc. 1952, 74, 2878-2880.
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Claims
1. A process for transforming a group >C=0 (I) in a compound into a group >C=S (II) or into
a tautomeric form of group (II) in a reaction giving a thionated reaction product, by use of
crystalline P2S5-2 C5H5N as a thionating agent.
2 . A process according to claim 1, wherein the thionating agent and the compound are
allowed to react with each other in a liquid solvent medium for the compound and for the
thionating agent.
3 . The process according to claim 1 or claim 2, wherein the liquid solvent medium comprises
pyridine, a C1-C3 alkylnitrile, a cyclic sulfone and/or a C1-C3 dialkylsulfone.
4 . The process according to any one of the claims 1-3, wherein the liquid solvent medium
comprises pyridine, sulfolane, dimethyl sulfone and/or acetonitrile.
5 . The process according to any one of the claims 1-4, wherein the reaction is performed at a
temperature of 60°C to 180°C.
6 . The process according to claim 5, wherein the reaction is performed at temperature of
115°C to 175°C.
7 . The process according to any one of the claims 1-6, wherein the compound comprises a
group (I) that is present in an amide function.
8 . The process according to any one of the claims 1-7, wherein the compound comprises a
group (I) that is present in a ketone function.
9 . The process according to any one of the claims 1-8, wherein the thionating agent is used at
a molar ratio to the group (I) to be transformed of 1 mole P2S5-2 C5H5N per 1-4 moles of
group (I).
10. The process according to any one of the claims 1-9, comprising separating the thionated
reaction product from the reaction.
11. The process according to claim 10, wherein water is added to the reaction and the
thionated reaction product is separated as a solid material, by precipitation or crystallization.
12. A thionating agent which is crystalline P2 S 5-2 C5H5N .