WO2012104415A1 - A thionation process and a thionating agent - Google Patents

A thionation process and a thionating agent Download PDF

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Publication number
WO2012104415A1
WO2012104415A1 PCT/EP2012/051864 EP2012051864W WO2012104415A1 WO 2012104415 A1 WO2012104415 A1 WO 2012104415A1 EP 2012051864 W EP2012051864 W EP 2012051864W WO 2012104415 A1 WO2012104415 A1 WO 2012104415A1
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WO
WIPO (PCT)
Prior art keywords
group
compound
reaction
process according
thionating agent
Prior art date
Application number
PCT/EP2012/051864
Other languages
French (fr)
Inventor
Birgitta Pettersson
Vedran Hasimbegovic
Per H. Svensson
Jan Bergman
Original Assignee
Vironova Ab
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to JP2013552218A priority Critical patent/JP5989674B2/en
Priority to BR112013019821-4A priority patent/BR112013019821B1/en
Priority to EP13175186.9A priority patent/EP2650274B1/en
Priority to DK12702531.0T priority patent/DK2569263T3/en
Priority to AU2012213417A priority patent/AU2012213417B2/en
Priority to CA2825257A priority patent/CA2825257C/en
Priority to CN201280002402.4A priority patent/CN103153917B/en
Priority to EP12702531.0A priority patent/EP2569263B1/en
Priority to US13/807,104 priority patent/US9221855B2/en
Priority to MEP-2014-13A priority patent/ME01570B/en
Application filed by Vironova Ab filed Critical Vironova Ab
Priority to PL12702531T priority patent/PL2569263T3/en
Priority to RU2013140771/04A priority patent/RU2605412C2/en
Priority to SI201230020T priority patent/SI2569263T1/en
Priority to RS20140055A priority patent/RS53186B/en
Priority to KR1020137023442A priority patent/KR101978703B1/en
Priority to ES12702531.0T priority patent/ES2445024T3/en
Publication of WO2012104415A1 publication Critical patent/WO2012104415A1/en
Priority to US13/936,423 priority patent/US9115158B2/en
Priority to HK13110785.3A priority patent/HK1183474A1/en
Priority to HRP20140124AT priority patent/HRP20140124T1/en
Priority to SM201400054T priority patent/SMT201400054B/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
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    • C07F9/58—Pyridine rings
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    • C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen directly attached to ring carbon atoms
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    • C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
    • C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
    • C07D243/14—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines
    • C07D243/16—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals
    • C07D243/18—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals substituted in position 2 by nitrogen, oxygen or sulfur atoms
    • C07D243/22—Sulfur atoms
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    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/34—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D309/36—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with oxygen atoms directly attached to ring carbon atoms
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    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/78—Ring systems having three or more relevant rings
    • C07D311/80—Dibenzopyrans; Hydrogenated dibenzopyrans
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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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Definitions

  • LR Lawesson's reagent
  • 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.
  • reactants such as amides and ketones
  • LR hexamethylphosphoramide
  • a thionating agent is provided, which is crystalline P 2 S 5 -2 C 5 H 5 N.
  • Figure 1 shows (A) the molecular structure and (B) the crystal structure of P 2 S 5 -2 C 5 H 5 N.
  • Figure 2 shows (A) the molecular structure and (B) the crystal structure of pyridinium dihydrogenmonothiophosphate.
  • the present inventors have determined the crystal structure of P 2 S 5 -2 C 5 H 5 N 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 (C- H... 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 ⁇ stacking.
  • the distance between the planes of two adjacent aromatic moieties is approximately 3.5 A.
  • the present invention provides a thionating agent consisting of crystalline P 2 S 5 -2 C 5 H 5 N.
  • 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 P 4 S 10 ) 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.
  • 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.
  • 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.
  • the thionating agent is used dissolved in a liquid solvent medium.
  • the thionating agent is used as a melt, mixed with the compound to be thionated.
  • 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.
  • 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.
  • 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.
  • the crystalline P 2 S 5 -2 C 5 H 5 N and the compound to be thionated are both dissolved in the organic solvent, which optionally is heated e.g. to reflux.
  • the crystalline P 2 S 5 -2 C 5 H 5 N is admixed with the solvent medium, at a temperature below the melting point of the solvent medium and of the crystalline P 2 S 5 -2 C 5 H 5 N and the mixture is heated in order to obtain a liquid solution containing P 2 S 5 -2 C 5 H 5 N 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.
  • the melting temperature of dimethylsulfone is 107-109°C.
  • crystalline P 2 S 5 -2 C 5 H 5 N 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 P 2 S 5 -2 C 5 H 5 N in liquid dimethylsulfone is obtained.
  • the thionation of the oxo group containing compound may be performed.
  • P 2 S 5 -2 C 5 H 5 N An advantageous feature of P 2 S 5 -2 C 5 H 5 N 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.
  • the reaction is performed at the boiling temperature of the liquid solvent medium. It is at present not clear if it is P 2 S 5 -2 C 5 H 5 N 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.
  • the precise mechanism of the reaction is not essential, and by indication that the dissolved P 2 S 5 -2 C 5 H 5 N 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.
  • P 2 S 5 -2 C 5 H 5 N quickly undergoes extensive degradation.
  • a protic solvent such as a lower alcohol, e.g. methanol or ethanol
  • P 2 S 5 -2 C 5 H 5 N quickly undergoes extensive degradation.
  • addition of water to a hot solution/suspension of P 2 S 5 -2 C 5 H 5 N in acetonitrile will quickly result in a clear solution of a salt of pyridine and phosphorothioic acid, viz. pyridinium
  • 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.
  • thionated reaction product of the invention e.g. thioamides.
  • four equivalents of an amide are heated with 1.1 equivalents of crystalline P 2 S 5 -2 C 5 H 5 N in dry acetonitrile and in connection with the work-up any remaining thionating agent is readily removed by addition of water.
  • P 2 S 5 -2 C 5 H 5 N will also decompose when treated with alcohols; e.g. treatment of P 2 S 5 -2 C 5 H 5 N with ethanol gives pyridinium 0,0-diethyldithiophosphonate, of formula
  • one advantage of the present invention is that the desired thionated product is easily separated from any remaining thionating agent P 2 S 5 -2 C 5 H 5 N by treatment with a protic solvent, such as water or a lower alcohol, e.g. ethanol.
  • a protic solvent such as water or a lower alcohol, e.g. ethanol.
  • the salt resulting from decomposition of any remaining P 2 S 5 -2 C 5 H 5 N will be easily separated from the thionated compound, e.g. by extraction with an aqueous solution or with water.
  • a protic solvent such as water
  • 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 (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.
  • R e.g. may be selected from C1-C12 hydrocarbyls
  • R ' and R " may be independently selected from H and C1-C12 hydrocarbyls, or wherein R and R'
  • 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).
  • the group (I) is present in a ketone function, such as in a compound
  • 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.
  • the group (I) 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 crystalline P 2 S 5 -2 C 5 H 5 N preferably is admixed at a molar ratio to the group (I) to be transformed of 1 mole P 2 S 5 -2 C 5 H 5 N per 1-4 moles of group (I), e.g. 1 mole P 2 S 5 -2 C 5 H 5 N per 2-4 moles of group (I), in particular 1 mole P 2 S 5 -2 C 5 H 5 N per 3-4 moles of group (I).
  • the molar ratio of P 2 S 5 -2 C 5 H 5 N to compound will be correspondingly higher.
  • the crystalline P 2 S 5 -2 C 5 H 5 N preferably is admixed at a molar ratio with the compound to be thionated of 1 mole P 2 S 5 -2 C 5 H 5 N per 0.5-2 moles of the compound, e.g. 1 mole P 2 S 5 -2 C 5 H 5 N per 1-2 moles of the compound, or 1 mole P 2 S 5 -2 C 5 H 5 N per 1.5-2 moles of the compound.
  • the molar ratio between P 2 S 5 -2 C 5 H 5 N 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.
  • P 2 S 5 -2 C 5 H 5 N as a thionating agent is its selectivity.
  • carboxylic ester functions generally do not react with P 2 S 5 -2 C 5 H 5 N, 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.
  • Tetraphosphorus decasulfide (P 4 S 10 , 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.
  • the crystalline P 2 S 5 -2 C 5 H 5 N (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%).
  • 2,5-Piperazinedione (2.28 g, 20 mmol) and crystalline P 2 S 5 -2 C 5 H 5 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 %).
  • 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 H 2 S 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.
  • 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.
  • Oxindole (1.33 g, 10 mmol) and crystalline P 2 S 5 -2 C 5 H 5 N (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.
  • the diester 33a (2.13g, 10 mmol) and crystalline P 2 S 5 -2 C 5 H 5 N (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.
  • a suspension of LR in hot acetonitrile can be titrated by addition of ⁇ -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.
  • formation of nitriles from primary amides never was a problem. This type of side reaction can sometimes be
  • Benzaldehyde has been thionated many times in the past 11"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.
  • Ester carbonyl groups are generally not attacked by P 2 S 5 -2 C 5 H 5 N as 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
  • reaction conditions e.g. in view of the functional groups that may be present in the compound to be thionated.
  • the reaction may be performed under normal ambient atmosphere or under an inert atmosphere of e.g. argon or nitrogen.
  • suitable reaction conditions e.g. in view of the functional groups that may be present in the compound to be thionated.
  • 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.

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Abstract

A process for transforming a group >C=O (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. A thionating agent which is crystalline P2S5·2 C5H5N

Description

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, Klingsberg1 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, P2S5-2 C5H5N, was studied as early as 1967-1968 by German inorganic chemists2'3 who obtained evidence for its structure by 31P MRdata4 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 (C- H... 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 π 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
dih drogenmonothiophosphate, of formula
Figure imgf000005_0001
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
Figure imgf000006_0001
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 CsH5Nwith 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
Figure imgf000006_0002
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
Figure imgf000007_0001
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 P2S5-2 C5H5N
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, IR vmax: 3088, 3040, 1608, 1451, 1197, 1044, 723, 668 cm"1; cf. Fig.l. Pyridinium dihydrogenmonothiophosphate
The crystalline P2S5-2 C5H5N (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-i ) δ 7.51 (m, 2H, 3-H), 7.95 (dd, 1H, 4-H), 8.63 (d, 2H, 2-H), 9.7 (br s, 3H); 13C NMR (75.5 MHz, OMSO-d6) δ 124.7 (d), 138.5 (d), 147.8 (d); cf. Fig.2.
Pyridinium Ο,Ο-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- ,) δ 1.08 (t, J= 7.1 Hz, 6H), 3.79 (m, 4H), 8.09 (m, 2H), 8.62 (m, 1H), 8.97 (m, 2H); 13C NMR (75.5 MHz, DMSO- ) δ 16.1 (q, 3JC-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, 11(10H, 1 laH)-dione (4.0 g, 20 mmol) crystalline P2S5-2 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° (c 0.16, MeOH); Ir vmax: 3170, 2979, 1616, 1602, 1477, 1374, 1271, 1141, 831, 813, 752 cm"1;
1H NMR (300 MHz, DMSO- ,) δ 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= 6.11 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); 13C NMR (75.5 MHz, OMSO-d6) δ 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 P2S5-2 C5H5N (9.12g, 28 mmol) and dimethylsulfone (8.0 g) were heated at 165-170 °C for lh 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-d6) δ 4.19 (s), 10.7 (s); 13C NMR (75.5 MHz, DMSO- ) δ 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 P2S5-2 C5H5N ( 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, DMSO- d6) δ 2.17 (s, 6H), 2.45 (s, 6H), 6.99 (s, 2H); 13C NMR (75.5 MHz, DMSO- ) δ 22.2 (q), 29.4 (q), 117.0 (s), 131.6 (d), 166.3 (s), 193.7 (s); Elemental analysis calcd for Ci2Hi4N204S2, 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)-lH,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) δ 2.44 (s, 6H), 6.95-6.99 (m, 2H), 7.10-7.22 (m, 4H), 7.36-7.45 (m, 2H), 1 1.55 (s, 2H); 13C NMR (75.5 MHz, DMSO- ) δ 18.0 (q), 1 10.8 (s), 1 10.9 (d), 1 19.0 (d), 1 19.2 (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- ,) δ 7.04-7.08 (m, 1H), 7.28-7.31 (m, 2H), 7.33-7.51 (m, 1H), 12.16 (s, 1H): 13C NMR (75.5 MHz, DMSO- ) δ 136.3 (s), 127.0 (s), 124.9 (s), 124.6 (d),
120.3 (d), 120.2 (d), 1 19.3 (s), 1 12.2 (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- ,) δ 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); 13C NMR (75.5 MHz, DMSO- ) δ 60.8 (d), 1 10.4 (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 umax: 3273, 2954, 1742, 1724, 1707, 1681, 1562, 1440, 1341, 1269, 1200, 1 173, 1 1 17, 1080, 1003, 782 cm"1; 1H NMR (300 MHz, OMSO-d6) δ 2.43 (s, 3H, CH3), 3.17 (s, 1H, SH), 3.49 (s, 3H, OCH3), 3.64 (s, 3H, OCH3), 1 1.90 (s, 1H, H); 13C NMR (75.5 MHz, DMSO- ) δ 13.4 (q), 30.6 (d), 50.4 (q), 51.4 (q), 1 1 1.2 (s), 117.1 (s), 126.9 (s), 139.9 (s), 164.4 (s), 171.1 (s) Elemental analysis calcd for C10 Hi3N04S; 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 P2S5-2 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-d6) δ 7.09-7.15 (m, 2H), 7.18-7.20 (m, 5H), 7.24-7.30 (m, 7H), 13.00 (s, 1H); 13C NMR (75.5 MHz, DMSO- ) δ 72.7 (s), 1 11.2 (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, 1 1.07; Found C, 76.10, H, 4.46, N, 1 1.00.
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 ε-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 ε-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 P2S5-2 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 dimethyl sulfone (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 dimethyl sulfone 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.
Figure imgf000013_0001
Figure imgf000014_0001
Figure imgf000015_0001
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
Figure imgf000016_0001
obtained from - 20 Thionations at quite high temperatures (165-175 °C) could be effected with e.g. P2S5-2 C5H5N dissolved in dimethyl sulfone (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 al10. 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.
Figure imgf000017_0001
29 30
Ester carbonyl groups are generally not attacked by P2S5-2 C5H5N as 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
Figure imgf000017_0002
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
Figure imgf000018_0001
Figure imgf000019_0001
* 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, 1 13-129.
(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.
(6) a) Ozturk, T.; Erdal, E.; Olcay, M. Chem. Rev. 2007, 107, 5210-5278.
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,
38, 993-1001.
(8) Ley, S. V.; Leach, A. G.; Storer, R. I. J. Chem. Soc, Perkin Trans 1 2001, 358- 361.
(9) Stoyanov, S.; Petkov, I; Antonov, L.; T. Stoyanova; Karagiannidis, P.;
Aslanidis, P. Can. J. Chem. 1990, 68, 1482-1489.
(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.
(13) Bottcher, B.; Bauer, F. Liebigs Ann. Chem. 1951, 574, 218-226.
(14) Takikawa, Y.; Shimoda, K.; Makabe, T.; Takizawa, S. Chem. Lett. 1983, 1503- 1506.
(15) Sekido, K.; Hirokawa, S. Acta. Cryst. C41 1985, 379-400.
(16) Bonini, B. F.; Mazzanti, G.; Zani, P.; Maccagani, G.; Foresti, E. J. Chem. Soc,
Perkin Trans 1, 1988, 1499-1502.

Claims

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 P2S5-2 C5H5N.
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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013171334A1 (en) 2012-05-18 2013-11-21 Vironova Ab Methanethione compounds having antiviral activity
WO2018033455A1 (en) 2016-08-15 2018-02-22 Bayer Cropscience Aktiengesellschaft Condensed bicyclic heterocycle derivatives as pest control agents
WO2023083465A1 (en) 2021-11-12 2023-05-19 Vironova Thionation Ab A stable formulation of p2s5·2c5h5n

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9520617B2 (en) 2013-03-14 2016-12-13 Advanced Technology Materials, Inc. Sulfolane mixtures as ambient aprotic polar solvents
CN103641834B (en) * 2013-12-12 2015-12-09 沈阳药科大学 Pyrrolobenzodiazepines * compounds and its preparation method and application
CN105884740B (en) * 2016-05-16 2017-12-12 山东师范大学 One kind detects hypochlorous fluorescence probe and its preparation method and application

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2932674A (en) * 1959-03-11 1960-04-12 Eastman Kodak Co Preparation of symmetrical conjugated compounds
JPS5695164A (en) * 1979-12-28 1981-08-01 Kumiai Chem Ind Co Ltd Thiobenzoic acid anilide derivative, its preparation, and fungicide comprising it
DE3006865A1 (en) * 1980-02-23 1981-09-10 Hoechst Ag, 6000 Frankfurt HETERO-IMINO-PROSTACYCLINE
DE3100083A1 (en) * 1981-01-03 1982-08-05 Hoechst Ag, 6000 Frankfurt "11-DESOXY-HETERO-IMINO-PROSTACYCLINE, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS A MEDICINAL PRODUCT"
US4757084A (en) * 1984-02-29 1988-07-12 Merck & Co., Inc. 2,5-diaryl tetrahydrothiophenes and analogs thereof as PAF-antagonists
DE10024938A1 (en) * 2000-05-19 2001-11-22 Bayer Ag New substituted iminoazine derivatives useful as herbicides, especially for weed control in crops
UY31685A (en) 2008-03-04 2009-11-10 Smithkline Beecham Corp ANTIVIRAL COMPOUNDS, COMPOSITIONS AND METHODS TO USE THEM

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
FLUCK, E.; BINDER, H.: "Chemische Reaktionen dr Perthiophosphonsäureanhydride", ZEITSCHR. ANORG. CHEM., vol. 354, no. 3-4, October 1967 (1967-10-01), pages 113 - 224, XP009150039 *
KLINGSBERG, E.PAPA, D.: "Thiation with Phosphorus Pentasulfide in Pyridine Solution", J. AM. CHEM. SOC., vol. 73, no. 10, October 1951 (1951-10-01), pages 4988 - 4989, XP002648408 *
MEISEL, M.; GRUNZE, H.: "Über Thiophosphorsäure-pyridiniumbetaine", ZEITSCHR. ANORG. CHEM., vol. 360, 1968, pages 277 - 283, XP009150048 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013171334A1 (en) 2012-05-18 2013-11-21 Vironova Ab Methanethione compounds having antiviral activity
WO2018033455A1 (en) 2016-08-15 2018-02-22 Bayer Cropscience Aktiengesellschaft Condensed bicyclic heterocycle derivatives as pest control agents
WO2023083465A1 (en) 2021-11-12 2023-05-19 Vironova Thionation Ab A stable formulation of p2s5·2c5h5n

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