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WO2007064869A2 - Catalyseurs destines a une synthese de sulfure d’aryle et procede de fabrication de sulfures d’aryle - Google Patents

Catalyseurs destines a une synthese de sulfure d’aryle et procede de fabrication de sulfures d’aryle Download PDF

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Publication number
WO2007064869A2
WO2007064869A2 PCT/US2006/045973 US2006045973W WO2007064869A2 WO 2007064869 A2 WO2007064869 A2 WO 2007064869A2 US 2006045973 W US2006045973 W US 2006045973W WO 2007064869 A2 WO2007064869 A2 WO 2007064869A2
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optionally substituted
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aryl
compound
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WO2007064869A3 (fr
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John F. Hartwig
Qilong Shen
Manuel Fernandez-Rodriguez
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Yale University
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Yale University
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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
    • C07F17/00—Metallocenes
    • C07F17/02—Metallocenes of metals of Groups 8, 9 or 10 of the Periodic Table

Definitions

  • the present invention relates to the formation of aryl sulfides and aryl thiols from aryl halides and thiols, thiolates or thiolate equivalents.
  • the present invention provides a catalyst for the coupling of aryl halides with alkyl or aryl thiols or a hydrogen sulfide equivalent to form aryl alkyl, aryl silyl or diaryl sulfides with turnover numbers in excess of 1000 for the coupling of chloroarenes and typically and typically in the range of 10,000 for the coupling of bromo and iodoarenes.
  • the reaction encompasses bromoarenes containing nitrile, ester, keto, free hydroxyl, free amino, free carboxylic acid and other common functionalities.
  • the invention can be used to prepare pharmaceutical compounds, especially including their intermediates, agricultural agents and aryl sulfide polymers.
  • Aryl sulfides'- 1" are valuable intermediates in organic synthesis of biologically and pharmaceutically active molecules, of organic materials, or intermediates to these molecules.
  • a number of aryl sulfides have shown potential clinical applications. These applications include the treatment of inflammation by acting as antagonists of the interaction between leukocyte function-associated antigen- 1 and both intracellular adhesion molecule- 1 (LFA- 1/ICAM-l) 13"41 and vascular cell adhesion molecule-1 (VCAM-1).
  • aryl sulfides also include treatment of Alzheimer's and Parkinson's diseases by acting as muscarinic ⁇ or nicotinic 1 - 71 receptor antagonists, treatment of asthma and obstructive pulmonary disease by acting as a 5 -lipoxygenase inhibitor, 1 - 8 - 1 treatment of human immunodeficiency virus (HIV) by inhibiting HIV-I protease (an enzyme involved in the virus maduration) [9J and treatment of cancer as tubulin polymerization inhibitors.
  • HIV-I protease an enzyme involved in the virus maduration
  • Nickel- and copper-catalyzed coupling of thiols with aryl halides has also been reported. [31"32] However, these processes require either high temperatures or high catalyst loadings. Further, these reactions have typically been conducted with aryl iodides. [33"34]
  • a more reactive catalyst for the coupling of thiolates might contain a bisphosphine that binds the metal strongly enough to prevent formation of anionic or bridging thiolate complexes I and II, while simultaneously promoting oxidative addition and reductive elimination.
  • Figure 1 shows the general mechanism for the palladium-catalyzed C-S bond forming reactions.
  • Figure 2 shows the effect of ligand on the coupling of aryl chlorides with thiols at 0.1 mol % catalyst loading. Reaction conditions: 4-chloroanisole (1 mmol), RSH (1 mmol), Pd(OAc) 2 /Ligand (0.1 mol %), NaOtBu (1.1 mmol) in DME (1.5 niL) at 110 0 C for 24 hours.
  • the present invention is directed to compounds which are catalysts or pre-catalysts according to the chemical structure:
  • R 1 and R 2 are each independently H or an optionally substituted C 1 -C 10 hydrocarbyl group, preferably a C 1 -C 6 alkyl group, an optionally substituted heterocyclic group, preferably an optionally substituted heteroaryl group, or said optionally substituted hydrocarbyl or optionally substituted heterocyclic group is bound to the benzylic carbon through carbon, oxygen, nitrogen, sulfur or phosphorus, and said group is preferably an optionally substituted C 1 -C 10 hydrocarbyl group, more preferably a C 1 -C 6 alkyl group;
  • Y is M or a PR 5 R 6 group;
  • R 3 , R 4 , R 5 and R 6 are each independently an optionally substituted C 1 -C 10 hydrocarbyl group or an optionally substituted 3-14 membered heterocyclic group bound to phosphorus through carbon, oxygen, nitrogen, or sulfur; more preferably an optionally substituted aryl group, an optionally substituted C 1 -C 6 alkyl group, an optionally substituted Ci-C 6 (preferably C 1 -C 3 ) alkoxy group, an optionally substituted phenoxy group, an amino group which is optionally substituted with one or two C 1 -C 6 alkyl or alkanol groups; an optionally substituted C 1 -Ci 0 vinyl group, an optionally substituted 3 to 14 membered heterocyclic group, or a heteroaryl group; most preferably an optionally substituted C 1 -C 6 alkyl group;
  • M is Pd, Ni or Pt, and M is substituted with X and L or X and a PHR 5 R 6 group and is linked through a bond to PR 3 R 4 or is M a PR 5 R 6 -M ! group where M 1 is Pd, Ni or Pt, M 1 is substituted with two X groups and is linked through a bond to PR 3 R 4 ;
  • X is a formally anionic 2-electron donor ligand;
  • L is a formally neutral 2-electronic donor ligand
  • CpFe is a cyclopentadienyl iron (ferrous) group.
  • a catalyst comprises a compound according to the formula:
  • R 1 , R 2 , R 3 , R 4 , R 5 and R 6 and CpFe are the same as set forth above.
  • a catalyst comprises a compound according to the formula:
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 L, X, M and CpFe are the same as set forth above.
  • M is Pd.
  • a catalyst comprises a compound according to the formula:
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , X 5 M and CpFe are the same as set forth above.
  • M is Pd.
  • a catalyst comprises a compound according to the formula:
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , X, M 1 and CpFe are the same as set forth above.
  • M 1 is Pd.
  • R and R are preferably a C 1 -C 4 hydrocarbyl group, more preferably a methyl, ethyl or propyl or a t-butyl group or a phenyl, a 3,5-xylyl, a 2,4-xylyl, p-tolyl or a 3,5-bis-trifluoromethylphenyl.
  • R 3 , R 4 , R 5 and R 6 are preferably a C 1 -C 8 hydrocarbyl group, more preferably a t-butyl group, a cyclohexyl group, or a phenyl, a 3,5-xylyl, a 2,4-xylyl, p-tolyl or a 3,5-bis-trifluoromethylphenyl group, a heteroaryl selected from the group consisting of a pyridyl (2, 3, or 4-pyridyl), a 2- or 3- thienyl group or a 2- or 3-furyl group, a methoxy, ethoxy, isopropoxy, or phenoxy group, or a dimethylamino group.
  • an aryl C-S bond or olefmic C-S bond is formed by reacting an aryl or olefmic compound containing a leaving group (e.g., a halogen such as Cl, Br, I or a sulfonate group such as tosyl (toluenesulfonyl), triflic (trifluoromethylsulfonyl) or a related sulfonate leaving group) with a thiol-containing compound (HSR)in the presence of a pre-catalyst or catalyst according to the present invention and optionally, a secondary phosphine compound or a metal or metal-containing compound containing Pd, Ni, or Pt to produce an aryl or olefin compound containing an S-R group in a solvent at ambient temperature or a temperature above or below ambient temperature.
  • a leaving group e.g., a halogen such as Cl, Br, I or a sulfonate group such
  • Ar is an aryl group, which term includes a heteroaryl group and fused bicyclic or polycyclic aryl or heteroaryl groups;
  • Each R' is a substituent on the aryl group, which may be the same or different and is an optionally substituted C 1 -C 12 hydrocarbyl group, optionally substituted alkyl or aryl alkoxides (preferably, unsubstituted or substituted C 1 -C 6 alkoxides or phenoxides), optionally substituted keto, ester or carboxylic acid groups, nitro, nitrile (CN), amines, which may be unsubstituted or substituted with one or two substituents otherwise disclosed herein (preferably including C 1 -C 3 alkyl groups or alkanol groups), halogens (F, Br, Cl, I), mono- and dialkylamido groups, mono- and diarylamido groups, amidates (preferably unsubstituted or substituted alkyl or aryl amidates), carboxylic acid groups, hydroxyl groups, among numerous others, including optionally substituted 3-14 membered heterocyclic groups.
  • substituents include unsubstituted or substituted C 1 -C 6 alkyl groups or aryl groups (especially halogenated alkyl groups such as fluoro-substituted alkyl groups), preferably phenyl groups, alkoxide groups, keto groups, keto esters, carboxyl groups or amino groups, which substituents, within context, may be attached to a further substituent in context, through carbon, oxygen, nitrogen or sulfur atoms.
  • substituent subsumes or incorporates O, S or N atoms within alkyl or alkylene chains or in aryl groups (heteroaryl); n is from 0 to 5, preferably 0 to 3;
  • X 1 is a leaving group, preferably a halogen selected from Cl, Br or I or a sulfonate group such as a tosylate, mesylate or triflate (trifluoromethylsulfonate) group; and
  • R is an optionally substituted C 1 -C 12 hydrocarbyl group, an optionally substituted 3- 14 membered heterocyclic group or a Si-containing group -SiR 1 R 2 R 3 group where R 1 , R 2 and R3 are the same or different and are selected from H or a C1-C6 hydrocarbyl group which is optionally substituted with a halogen group or with at least one C 1 -C 3 alkyl group with the proviso that not more than two OfR 1 , R 2 and R 3 is H and preferably none are H.
  • reactions to introduce C-S bonds onto olefins occur by the following reaction wherein a thiol-containing compound is reacted with an olefinic group having a leaving group (halogen or sulfonate, preferably Cl, Br, I or tosylate, mesylate or triflate group):
  • X 1 is a leaving group such as a halogen or sulfonate leaving group (Cl, Br, I, tosylate, mesylate or triflate);
  • R 7 , R 8 and R 9 are each independently selected from H, an optionally substituted C 1 - C 12 hydrocarbyl group, an optionally substituted alkyl or aryl alkoxide (preferably, unsubstituted or substituted C 1 -C 6 alkoxides or phenoxides), optionally substituted keto, ester or carboxylic acid groups, nitro, nitrile (CN), amines, which may be unsubstituted or substituted with one or two substituents otherwise disclosed herein (preferably including C 1 - C 3 alkyl groups or alkanol groups), halogens (F, Br, Cl, I), mono- and dialkylamido groups, mono- and diarylamido groups, amidates (preferably unsubstituted or substituted alkyl or aryl amidates), carboxylic acid groups, hydroxyl groups, among numerous others, including optionally substituted 3-14 membered heterocyclic groups.
  • an optionally substituted C 1 - C 12 hydrocarbyl group
  • substituents include unsubstituted or substituted C 1 -C 6 alkyl groups or aryl groups (especially halogenated alkyl groups such as fluoro-substituted alkyl groups), preferably phenyl groups, alkoxide groups, keto groups, keto esters, carboxyl groups or amino groups, which substituents, within context, may be attached to a further substituent in context, through carbon, oxygen, nitrogen or sulfur atoms.
  • substituent subsumes or incorporates O 5 S or N atoms within alkyl or alkylene chains or in aryl groups (heteroaryl).
  • the present invention provides a catalyst for the coupling of aromatic compounds which have halogen or sulfonate leaving groups with alkyl or aryl thiols or hydrogen sulfide equivalent to form aryl, alkyl or diaryl sulfides with turnover numbers in excess of 1000 for the coupling of chloroarenes and typically in the range of 10,000 for the coupling of bromo and iodoarenes.
  • the reaction encompasses an aryl group containing a leaving group with potentially a huge number of substituents including, for example, nitrile, ester, keto, hydroxyl, amino, carboxylic acid and other common functionality in many instances without the necessity of using protecting groups.
  • compound is used to describe any chemical compound or ligand, including a pre-catalyst or catalyst, which is used in the present invention and in context may refer to a purified or substantially pure compound or a less than pure compound or a compound complexed to a metal and coordinating ligand in a catalyst complex, hi addition, compounds according to the present invention may refer to all optical (including enantiomeric and diastereomeric) isomers, regioisomers and/or stereoisomers within the context of use or synthesis and may include racemic mixtures and/or enantiomerically enriched compounds, individually or as mixtures. Purified and isolated compounds according to the present invention are preferred in numerous embodiments.
  • an effective amount is used to describe an amount of a compound or component which is used or included within the context of its use to provide an intended result.
  • An effective amount may range quite broadly, within context, depending upon a number of factors, conditions, components and/or additives and the role that they play within the context of their use.
  • One of ordinary skill will be able to determine an effective amount by routine experimentation, where such amount is not explicitly described.
  • hydrocarbyl shall mean a saturated or unsaturated (containing at least one unsaturated) group containing carbon atoms and hydrogen atoms and includes alkyl groups, alkene groups, alkyne groups and aromatic groups (pheny, naphthyl, phenanthryl, anthracenyl).
  • alkyl is used herein to refer to a fully saturated, monovalent radical containing carbon and hydrogen, and which may be a straight chain, branched or cyclic.
  • alkyl groups include C 1 -C 7 alkyl groups such as methyl, ethyl, n- butyl, n-pentyl, n-heptyl, isopropyl, 2-methylpropyl, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclopentylethyl and cyclohexyl.
  • aromatic or aryl refers to a substituted or unsubstituted monovalent aromatic radical having a single ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl, anthracene, phenanthrene, etc.).
  • aromatic or aryl includes heteroaromatic or heteroaryl radicals with nitrogen, oxygen or sulfur or a combination of these atoms in the ring system.
  • heteroaryl groups have one or more nitrogen, oxygen, or sulfur atoms in the ring, such as imidazole, furyl, pyrrole, pyridyl, indole and fused ring systems such as indole and the like, among others, which may be substituted or unsubstituted.
  • heterocycle or “heterocyclic” shall mean an optionally substituted moiety which is cyclic and contains at least one atom other than a carbon atom, such as a nitrogen, sulfur, oxygen or other atom and contains from 3 to 14 atoms in the ring or fused-ring system (3 to 14-membered heterocyclic group).
  • a heterocyclic ring shall contain up to four atoms other than carbon selected from nitrogen, sulfur and oxygen. These rings may be saturated or have unsaturated bonds and if fully unsaturated are heteroaryl groups. Fused rings are also contemplated by the present invention.
  • a heterocycle according to the present invention is an optionally substituted imidazole, furan, pyrrole, imidazole, thiazole, oxazole, isoxazole, a piperazine (including piperazinone), piperidine group, all optionally substituted, among numerous others.
  • a heterocyclic ring may be saturated and/or unsaturated. In instances where a heterocyclic ring is fully unsaturated, there is overlap with the term "heteroaryF'or "aryl" as defined above.
  • substituted is used to describe a substituent which in context may be incorporated onto a group of the precatalyst or catalyst according to the present invention, or the reactants according to the present invention.
  • substituents which may be used in the present invention include C 1 -C 12 hydrocarbon groups such as alkyl, alkenyl or aryl (aromatic or heteroaromatic) groups, which themselves may be unsubstituted or substituted, alkyl or aryl alkoxides (preferably, unsubstituted or substituted C 1 -C 6 alkoxides or phenoxides), keto, ester or carboxylic acid groups, nitro, nitrile (CN), amines, which may be unsubstituted or substituted with one or two substituents otherwise disclosed herein (including C 1 -C 3 alkyl groups or alkanol groups), halogens (F, Br, Cl, I), mono- and dialkylamido groups, mono- and diarylamid
  • substituents include unsubstituted or substituted C 1 - C 6 alkyl groups or aryl groups (especially halogenated alkyl groups such as fluoro-substituted alkyl groups), preferably phenyl groups, alkoxide groups, keto groups, keto esters, carboxyl groups or amino groups, which substituents, within context, may be attached to a further substituent in context, through carbon, oxygen, nitrogen or sulfur atoms.
  • substituent subsumes or incorporates O, S or N atoms within alkyl or alkylene chains or in aryl groups (heteroaryl), many of which may be bound to phorphorous.
  • Substituents may also include heterocyclic groups (which may or may not be aromatic) containing one or more fused rings, which themselves may also be substituted.
  • the present invention is particularly useful in that most of the substituent groups may be maintained in the molecule throughout the reaction without protection.
  • olefin is used throughout the specification to describe certain reactants, which are used in C-S forming reactions according to the present invention.
  • An olefin is any compound with a carbon-carbon double bond containing a leaving group which can participate in C-S forming (thiolation) reactions according to the present invention, and includes terminal and internal alkenes (especially vinyl), vinylarenes, dienes, eneynes, and alpha-beta-unsaturated carbonyl compounds.
  • solvent shall mean any solvent used in methods according to the present invention consistent with producing pre-catalyst, catalyst or with introducing C-S bonds into aromatic and olefin groups in the present invention.
  • Exemplary solvents include toluene, benzene, chloroform, methylene chloride, dimethoxyethane (DME), tetrahydrofuran (THF), 1,4-dioxane, dimethylacetamide (DMA), dimethylformamide (DMF), acetonitrile, among numerous others.
  • DME and toluene are preferred solvents for use in the present invention.
  • base is used to describe a chemical species that donates electrons or hydroxide ions or that accepts protons.
  • a base is generally a strong base which is capable of extracting a proton (accepts protons) within the context of the reaction in which the base is used.
  • Exemplary bases for use in the present invention include stronger bases such as alkoxide bases, such as sodium or potassium t- butoxide (Na + " Ot-Bu or K + " Ot-Bu), NaHMDS (NaN(SiMe 3 ) 2 ), among others, or weaker bases including a carbonate base such as Na 2 CO 3 , K 2 CO 3 , or Cs 2 CO 3 base.
  • the term temperature shall mean at ambient temperature (i.e., at the temperature of the room at which a reaction is conducted), or above or below ambient temperature. In many instances in the present invention, the temperature is elevated to above ambient temperature and preferably less than about 125 C.
  • source of Pd, Ni or Pt shall mean a compound which contains palladium, nickel or platinum in a form which may be used in the present invention to produce a catalyst for introducing thiol-containing groups into aryl or olefin compounds.
  • Such source may be palladium metal (powder), nickel metal (powder) or platinum metal (powder) or palladium, nickel and platinum compounds such as Pd(OAc) 2 , Pd(dba) 2 (palladium dibenzylideneacetone), PdCl 2 , (CH 3 CN) 2 PdCl 2 , Ni(OAc) 2 , Nickel acetonylacetonate, NiCl 2 , Pt(OAc) 2 , PtCl 2 , among others.
  • 2-electron donor ligand is used to describe a ligand bonded to a metal in a pre-catalyst or catalyst compound according to the present invention that donates two electrons to the metal center, and when these electrons are attributed to the ligand, the ligand is anionic.
  • 2-electronic anionic ligands include, for example, Cl, Br, I, OTf (triflate), OTs (tosylate), OAc (acetate), trifluoroacetate, among others.
  • the term "formally neutral 2-electron donor ligand” is used to describe a ligand bonded to a metal in a pre-catalyst or catalyst compound according to the present invention that donates two electrons to the metal center and when these electrons are attributed to the ligand, the ligand is neutral.
  • ligands examples include phosphines (PR" 3 , where each R" is independently a C 1 -C 10 optionally substituted hydrocarbyl group, preferably methyl, ethyl, isopropyl, phenyl, p-tolyl, xylyl, mono- or bis-trifluoromethylphenyl, etc.), olefins (preferably, C 2 -C 10 ), amines (including mono- and di-alkyl or di-alkanol substituted amines) and ethers (preferably, C 2 -C 10 ), among others.
  • PR phosphines
  • R is independently a C 1 -C 10 optionally substituted hydrocarbyl group, preferably methyl, ethyl, isopropyl, phenyl, p-tolyl, xylyl, mono- or bis-trifluoromethylphenyl, etc.
  • olefins preferably, C 2 -C
  • thiol thiolate or thiolate equivalent
  • nucleophilic compounds containing sulfur nucleophiles or groups which are modified to obtain or create sulfur nucleophiles which, when reacted with compounds containing a leaving group according to the present invention in the presence of pre-catalysts and/or catalysts according to the present invention, produce C-S bonds in aryl compounds and olefins.
  • Thiolation reactions according to the present invention may be run in numerous solvents, including toluene, dimethoxyethane (DME), tetrahydrofuran (THF), 1,4-dioxane, dimethylacetamide (DMA), dimethylformamide, acetonitrile, among numerous others.
  • the reactions may be run at ambient temperature or above or below ambient temperature.
  • the precatalyst, catalyst and metal are used in catalytic amounts, generally ranging from about 0.001% to about 5 mol %, preferably about O.Olmol % to about 3 mol % the amount of aromatic reactant (containing leaving group) used in the reaction.
  • the present application relates to the coupling of aryl chlorides and related compounds with thiols, thiolates and equivalents using this catalyst system, as well as preformed catalyst precursors including (CyPF-t-Bu)PdCl 2 , under conditions of low catalyst loading.
  • Reactions at 110 °C occurred to higher conversions. Reactions at this temperature conducted with NaOtBu as base occurred to full conversion in less than 4 h and with an excellent yield of sulfide (Table 1, entry 4). In contrast, reactions conducted with KOtBu base proceeded to 94% conversion and 87% isolated yield after 18 h (Table 1, entry 5). Reactions conducted with NaOtBu in 1,4-dioxane occurred in high yield after similar times as the reactions with NaOtBu in DME (Table 1, entry 6), while reactions in other solvents, such as toluene, DMF or DMSO, formed only traces of the desired aryl sulfide.
  • the palladium source also affected the amount of side product. Reactions conducted with Pd(dba) 2 and Josiphos ligand 1 as catalyst generated only traces ( ⁇ 0.5%) of byproduct (Table 2, entry 10). Reactions conducted with only 0.1 mol % of Pd(dba) 2 and Josiphos ligand 1 occurred in high yield in less than 4 h to form the desired diaryl sulfide in essentially quantitative yield (Table 2, entry 11).
  • Scope of the reaction Coupling of unactivated aryl chlorides. Reactions of a series of aryl chlorides with aliphatic and aromatic thiols were conducted under the optimized reaction conditions with the combination of palladium and Josiphos ligand 1 as catalyst; the results are summarized in Tables 3 and 4.
  • (CyPF- ⁇ -Bu)PdCb as catalyst precursor.
  • the methodology developed revealed that an equimolecular combination of metal to ligand is adequate to promote the coupling of chloroarenes with both aliphatic and aromatic thiols.
  • a palladium complex containing a single CyPF-t-Bu ligand would be an alternative catalyst precursor for the C-S bond-forming reactions.
  • the use of such a compound would alleviate the need to generate the metal-ligand complex in situ.
  • (CyPF-t-Bu)PdCl 2 forms in high yield from (CH 3 CN) 2 PdCl 2 and Josiphos ligand 1 (Scheme 3). Studies on reactions catalyzed by this complex are presented in this section. We studied reactions of this compound because it is more stable over the long-term than the complex formed from ligand 1 and Pd(OAc) 2 .
  • the process exhibits a broad scope and a high tolerance for functionality, such as fluoro, cyano, keto, free carboxylate, amido, carboalkoxy, carboxaldehyde, aromatic and aliphatic hydroxyl and amino functionalities.
  • functionality such as fluoro, cyano, keto, free carboxylate, amido, carboalkoxy, carboxaldehyde, aromatic and aliphatic hydroxyl and amino functionalities.
  • Only reactions of hindered aryl chlorides with aromatic thiols and reactions of aromatic thiols with chloroarenes containing carboxaldehyde functionality proceed to partial conversion or form significant amounts of side products.
  • Related thiations of more reactive bromo- and iodoarenes which overcome these few limitations of the reactions of chloroarenes, as well as studies of the mechanism of the coupling process are in progress.
  • CyPF-Z-Bu (l-dicyclohexylphosphino-2-di-Z- butylphosphinoethylferroceno) as well as the other commercial available Josiphos-type ligands 3-6 were obtained from Solvias AG and Strem Chemicals and used without purification.
  • Pd(dba) 2 was prepared according to literature procedures. 1 ⁇ 42 - 1 Toluene was degassed by purging with nitrogen for 45 min and dried with a solvent purification system containing a i m column of activated alumina. 1,2-Dimethoxyethane (DME, 99.9% purity, HPLC grade) was used without further purification, but was stored under nitrogen. Other solvents were dried by standard methods.
  • Abbreviations for 1 H NMR splitting patterns are: s, singlet; bs, broad singlet; d, doublet; t, triplet; q, quartet; quint, quintet; sext, sextet; sept, septet; oct, octet; dd, doublet of doublets; dt, doublet of triplets; td, triplet of doublets; tt, triplet of triplets; m, multiple!
  • the coupling constants are reported in hertz (Hz). Flash column chromatography was carried out on silica gel (230-240 mesh). The yields of the coupled products included in all tables refer to isolated yields and are the average of two runs.
  • Josiphos type ligand 2 (l-dicyclohexyIphosphino-2-di-f- butylphosphinomethylferroceno): This bisphosphine was prepared according to literature procedures for related ferrocenyl ligands. [43] 95% yield. Yellow solid.
  • Methyl 3-cyclohexylsulfanylbenzoate (Table 5, entry 9). [25] 100 ⁇ L of stock solution A and NaOtBu (98 mg, 1.02 mmol) were used. A 50: 1 mixture of hexane/ethyl acetate was used as chromatography eluent. 56% yield. Pale yellow oil.
  • Methyl 3-phenylsulfanylbenzoate (Table 6, entry 5). [41] 250 ⁇ L of stock solution C and KOtBu (123 mg, 1.10 mmol) were used; the reaction was conducted in toluene (1.5 niL). 50:1 and 20:1 mixtures of hexane/ethyl acetate were used as successive chromatography eluents. 80% yield (10-15% of tert-butyl ester derivative was also observed). Colorless liquid.

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Abstract

La présente invention concerne la formation de sulfures d’aryle et d’arylthiols à partir d’halogénures d’aryles et de thiols, de thiolates ou d’équivalents de thiolate. La présente invention concerne un catalyseur destiné à coupler des halogénures d’aryle avec des alkylthiols ou des arylthiols ou un sulfure d’hydrogène équivalent en vue de former des alkylarylsulfures, des arylsilylsulfures ou des sulfures de diaryle. La réaction englobe des bromoarènes et d’autres composés similaires contenant des groupes partants ainsi que du nitrile, de l’ester, de la cétone, un groupe hydroxyle libre, un groupe amino libre, un acide carboxylique libre et d’autres fonctionnalités courantes. La présente invention peut être utilisée en vue de préparer des composés pharmaceutiques, incluant notamment leurs intermédiaires, des agents agricoles et polymères de sulfure d’aryle.
PCT/US2006/045973 2005-12-01 2006-12-01 Catalyseurs destines a une synthese de sulfure d’aryle et procede de fabrication de sulfures d’aryle Ceased WO2007064869A2 (fr)

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JP2010531821A (ja) * 2007-07-03 2010-09-30 サノフィ−アベンティス 末端アルキンとアリールトシラートとをパラジウム触媒カップリングする方法
JP2013014534A (ja) * 2011-07-04 2013-01-24 Daicel Corp ベンゾイルギ酸化合物、及びその製造方法
CN105001133A (zh) * 2015-07-07 2015-10-28 侯文峰 一种医药中间体二芳基硫醚化合物的合成方法
US10894797B2 (en) 2018-09-18 2021-01-19 Nikang Therapeutics, Inc. Fused tricyclic ring derivatives as SRC homology-2 phosphatase inhibitors

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JP2013014534A (ja) * 2011-07-04 2013-01-24 Daicel Corp ベンゾイルギ酸化合物、及びその製造方法
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