WO2020094440A1 - Procédé de synthèse d'arylhydrazines - Google Patents

Procédé de synthèse d'arylhydrazines Download PDF

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WO2020094440A1
WO2020094440A1 PCT/EP2019/079354 EP2019079354W WO2020094440A1 WO 2020094440 A1 WO2020094440 A1 WO 2020094440A1 EP 2019079354 W EP2019079354 W EP 2019079354W WO 2020094440 A1 WO2020094440 A1 WO 2020094440A1
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formula
alkyl
process according
aryl
cycloalkyl
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PCT/EP2019/079354
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Justin Wang
John F. Hartwig
Stephan ZUEND
Kailaskumar Borate
Harish SHINDE
Roland Goetz
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Basf Se
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three 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, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D231/18—One oxygen or sulfur atom
    • C07D231/20—One oxygen atom attached in position 3 or 5
    • C07D231/22—One oxygen atom attached in position 3 or 5 with aryl radicals attached to ring nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C243/00—Compounds containing chains of nitrogen atoms singly-bound to each other, e.g. hydrazines, triazanes
    • C07C243/10—Hydrazines
    • C07C243/22—Hydrazines having nitrogen atoms of hydrazine groups bound to carbon atoms of six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/76—Nitrogen atoms to which a second hetero atom is attached
    • C07D213/77—Hydrazine radicals

Definitions

  • the invention relates to a process for the synthesis of aryl hydrazines of formula I
  • Ar is an optionally substituted aryl or hetaryl group
  • R 1 , R 2 , and R 3 are independently selected from H, C-i-Cs-alkoxycarbonyl, fluorenylmethyloxy- carbonyl, arylsulfonyl, C-i-Cs-alkylsulfonyl, formyl, triflouroacetyl, C-i-Cs-alkyl, and C3-C6-cyclo- alkyl, which process comprises subjecting an arene of formula II
  • R 1 , R 2 , and R 3 are as defined for formula I;
  • the coupling reaction is conducted in the presence of a catalyst comprising palladium and a diphosphine ligand, wherein the phosphorus atoms are connected through two, three, four, or five atoms selected from carbon, nitrogen, oxygen or iron, and in which the non-connec- ting phosphorus substituents are Ci-Cio-alkyl or C3-Cio-cycloalkyl;
  • hydrazine derivatives particularly aryl hydrazines
  • heterocycles such as pyrazoles and indoles, which are sub- structures of active ingredients used, e.g., in crop protection and pharmaceutical applications.
  • a widely practiced route to prepare aryl hydrazines is described e.g. in Org. Proc. Res. Dev. 2015, 19, 892-896, and involves diazotization and reduction of an aniline derivative.
  • the aniline corn- pound is often prepared from the corresponding nitroarene; there are significant disadvantages to using such a route, e.g., that the subsequent diazotization and reduction displays poor atom economy and is accompanied by a large amount of salt waste.
  • objective task for the invention is to provide more economic and efficient routes to aryl hydrazines suitable for industrial application.
  • DeAngelis et al. (Angew. Chem. Int. Ed., 2013, 52, 3434-3437; D1) describe the synthesis of aryl hydrazines of formula I from arenes of formula II, using hydrazine, a Pd complex, a mono- phosphine ligand, and a base.
  • This report describes a continuous flow process in a specialized laboratory microfluidic system.
  • the use of a substrate with multiple leaving groups is described (Table 2, row 2, column 3; 1 ,3-dichlorobenzene), providing 86% yield.
  • footnote 20 suggests that 1 ,4-substituted arenes containing an electron-withdrawing group in addition to the leaving group provide low yield.
  • this document directs the skilled artisan away from fur- ther exploiting such conditions to 1 ,4-substituted arenes containing an electron-withdrawing group in addition to the leaving group.
  • WO2012/068335 (D2) describes a particular set of arylaminophosphine ligands, which in com- bination with a Pd complex may be used in C-N coupling reactions with arenes containing a leaving group. All examples provided in this document require 3 mol% or more Pd and ligand are used. The examples provided clearly show that the use of hydroxide as a base in coupling reactions of hydrazine results in low yields of no industrial relevance (page 57, Table 4, entry 9).
  • Lundgren and Stradiotto de-scribe the synthesis of aryl hydrazines of formula I from arenes of formula II, using hydrazine hydrate, a Pd complex, a ligand, and a base.
  • the base used is of R 1 -0-M (formula Va), wherein R 1 is tert.-butoxy (OtBu). 3 mol-% or more Pd is used.
  • MacLean et al. (Biorganic & Medicinal Chemistry Letters, 26, 2016, 100-104; D5) describe the synthesis of aryl hydrazines of formula I from arenes of formula II, using hydrazine hydrate, a Pd complex, an arylaminophosphine-ligand, and a base.
  • Reichelt et al. (Organic Letters, 2010, 12, 792-795) describes the reaction of 2-chloropyridine with benzoic hydrazide in the presence of a Pd complex, a base, and a diphosphine ligand to yield the corresponding benzoyl-protected 2-hydrazidopyridine.
  • ben- zoyl and related amides can be cleaved only under very harsh conditions, such as refluxing 6N HCI for 48h.
  • the invention provides several advantages over the above prior art: the invention is amenable to low catalyst loadings, the use of inexpensive hydroxide bases, and the prepara- tion of industrially valuable aryl hydrazines even from the corresponding aryl chlorides; and the invention is amendable to the selective reaction of 1 ,4-substituted arenes with multiple leaving groups.
  • the process can be used to make a variety of aryl hydrazines and is limited, a priori, only by the availability of the arene starting material.
  • the main advantage of the invention compared with the currently established technical pro- Waits for the synthesis of aryl hydrazines is the reduced salt waste and higher atom economy.
  • Potential disadvantages are catalyst cost and, in some cases, possibly lower availability of aryl chloride starting material.
  • the coupling reaction according to the invention is usually carried out at temperatures of from 20°C to 150°C, preferably from 100°C to 120°C, in the presence of a base and a catalyst, pref- erably in an inert solvent [cf. JACS 2008, 130, 6586].
  • Suitable solvents are aliphatic hydrocarbons such as pentane, hexane, cyclohexane, and pet- rol ether, aromatic hydrocarbons such as toluene, o-, m-, and p-xylene, and 1 ,2-dimethyoxy- benzene, halogenated hydrocarbons such as methylene chloride, chloroform, and chloroben- zene, ethers such as diethylether, diisopropylether, tert.-butylmethylether (MTBE), dioxane, ani- sole, and tetrahydrofuran (THF), 2-methyl-THF, cyclopropyl methyl ether (CPME), diisopropyl- ether (DIPE), diglyme, and monoglyme (dimethoxyethane, DME), nitriles such as acetonitrile, and propionitrile, ketones such as acetone,
  • -butyl methyl ketone alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, and tert. -butanol, esters such as ethyl acetate, moreover dimethyl sulphoxide (DMSO), dimethyl formamide (DMF), and dimethylacetamide (DMA), preferably cyclic ethers such as dioxane, 2- methyl-THF, and THF. It is also possible to use mixtures of the solvents mentioned.
  • DMSO dimethyl sulphoxide
  • DMF dimethyl formamide
  • DMA dimethylacetamide
  • cyclic ethers such as dioxane, 2- methyl-THF, and THF. It is also possible to use mixtures of the solvents mentioned.
  • Suitable bases are, in general, inorganic compounds, such as alkali metal and alkaline earth metal hydroxides, such as LiOH , NaOH, KOH , and Ca(OH)2, alkali metal and alkaline earth metal oxides, such as LhO, Na 2 0, CaO, and MgO, alkali metal and alkaline earth metal car- bonates, such as U2CO3, Na2C03, K2CO3, and CaC03, alkali metal bicarbonates, such as NaHCOs, alkali metal and alkaline earth metal phosphates, such as U3PO4, NasPC , K3PO4, moreover organic bases, for example tertiary amines, such as trimethylamine, triethylamine, diisopropylethylamine and N-methylpiperidine, pyridine, substituted pyridines, such as collidine, lutidine and 4-dimethylaminopyridine, and also bicyclic amines.
  • alkali metal hydroxides such as NaOH, or KOH.
  • the bases can be used in equimolar amounts relative to the arene of formula II, in excess or, if appropriate, as solvent.
  • Suitable Pd moieties used as a source of Pd are preferably Pd(OAc)2, Pd(OAc)2(PPh3)2, Pd(OCOt-Bu)2, Pd(OCOCF3)2, Palladium(ll) acetylacetonate [Pd(acac)2)], Palladium(n-cinn- amyl) chloride dimer [(Cinnamyl)PdCI]2], Pd(dba)2, Tris(dibenzylideneacetone)dipalladium(0) [Pd 2 (dba) 3 ], PdCI 2 , PdBr 2 , Pdl 2 , PdCI 2 (PhCN) 2 , PdCI 2 (PPh 3 )2, Pd[P(o-tolyl) 3 ] 2 , Pd(PPh 3 ) 4 , or any other Pd complex which may undergo a ligand exchange reaction with a diphosphine to gener- ate a complex containing palla
  • a source of Pd already containing a diphosphine ligand may be used.
  • Pd sources are:
  • Methanesulfonato ⁇ (R)-(-)-1 -[(S)-2-(dicyclohexylphosphino)ferro- cenyl]ethyldi-t-butylphosphine ⁇ (2'-amino-1 ,T-biphenyl-2-yl)palladium(ll) is commercially availa- ble; a general procedure for the preparation of such complexes is provided in US 8,981 ,086.
  • Suitable diphosphines are compounds in which the phosphorus atoms are connected through two, three, four, or five atoms, which are preferably carbon, nitrogen, oxygen or a transition metal such as iron, and in which one, two, three, or four (preferably four) of the non-connecting phosphorus substituents are Ci-Cio-alkyl or C3-Cio-cycloalkyl, preferably a-branched C3-C10- alkyl, a C3-Cio-cycloalkyl, or a-tertiary C4-Cio-alkyl.
  • a-branched C3-Cio-alkyl is preferably CH(CH 3 ) 2 .
  • C 3 -C 10-cycloalkyl is preferably cyclohexyl o-tertiary C4-Cio-alkyl is preferably C(CH 3 ) 3 .
  • diphosphines are compounds of formula IV:
  • R 4 , R 5 , R 7 , R 8 are independently selected from Ci-Cio-alkyl, C3-Cio-cycloalkyl, and aryl; prefera- bly a-branched C3-Cio-alkyl or C3-Cio-cycloalkyl;
  • R 6 , R 6a are independently selected from H, Ci-C4-alkyl, C3-C6-cycloalkyl, and aryl; preferably at least one of R 6 and R 6a is Ci-C4-alkyl, C3-C6-cycloalkyl, and aryl; particularly at least one is alkyl and one is H;
  • R 11 and R 12 are preferably part of a ring system, preferably at least an aryl or heteroaryl group, more preferably aryl group, particularly an aryl group complexed to a second transition metal as part of an organometallic sandwich compound, preferably a metallocene, more preferably a ferrocene.
  • Aryl groups are unsubstitued or partially or fully substituted with groups as defined for formula IVA below.
  • Sandwich compounds are known to the person skilled in the art (cf. Colacota et al, Z Anorg. AHg. Chem. 2005, 631 , 2659-2668).
  • Examples of such formula IV ligands are: 1 ,3-bisdicyclohexylphosphinopropane, 1 ,2-bis- dicyclohexylphosphinoethane, 1 ,3-bisdiisopropylphosphinopropane, 1 ,2-bisdiisopropyl- phosphinoethane, 1 ,1’-bis(ditertbutylphosphino)ferrocene, 1 ,1’-bis(diisopropylphosphino)ferro- cene, 1 ,1’-bis(dicyclohexylphosphino)ferrocene, NiXantphos (4,6-Bis(diphenylphosphino)phen- oxazine), or a Josiphos ligand of formula IVA.
  • the diphosphine ligand may also be the mono or bisphosphine oxide of the above ligands.
  • diphosphine ligand which is one of the ligands bound to palladium during at least part of the process is represented by formula IVA:
  • R 4 , R 5 , R 7 , R 8 are independently selected from Ci-Cio-alkyl, C3-Cio-cycloalkyl, and aryl; prefer- ably a-branched C3-Cio-alkyl or C3-Cio-cycloalkyl;
  • R 6 are independently selected from H, Ci-C 4 -alkyl, C3-Cio-cycloalkyl, and aryl;
  • each R 93 ⁇ R 9b , R 9c , R 9d , R 9e , R 9f , R 9 s, R 9h are independently selected from H and Ci-C 4 -alkyl; wherein each of said aryls is either unsubstituted or substituted at any substitutable position with one or more substituents independently selected from Ci-C 4 -alkyl, fluorinated Ci-C3-alkyl, OR 13 , SR 13 , and N(R 13a ) 2 ;
  • each R 13 is independently selected from Ci-C 4 -alkyl, ;
  • each R 13a is independently selected from Ci-C 4 -alkyl, or two R 13a groups together form C 4 -C 8 - alkylene, which carbon chain may contain 1 or 2 heteroatoms O and/or S;
  • any one substitutable position of any one of the groups R 4 , R 5 , R 6 , R 7 , R 8 and R 11 is a point of attachment, directly or via a tethering group, to a polymer or a solid phase support;
  • diphosphine ligand IVA which is one of the ligands bound to palladium dur- ing at least part of the process is represented by formula IVAa:
  • R 4 , R 5 , R 6 , R 7 , and R 8 are independently selected from Ci-Cio-alkyl, C3-Cio-cycloalkyl, and aryl, preferably selected from a-branched C3-Cio-alkyl, and C3-Cio-cycloalkyl, or is a mixture of two or more such compounds.
  • Formula IVAa compounds and its Pd complexes are known from US 6,235,938 and US 8,058,477. Such ligands are generally referred to as“Josiphos” lig ands (c.f. Blaser et al. Topic Cata/2002, 19, pp 3-16).
  • the starting materials are generally reacted with one another in equimolar amounts.
  • the order of adding the reagents has minor influence in the process; usually the catalyst is added to the solution of the arene with the base in the solvent, then hydrazine is added at 20- 25°C, then the mixture is heated to the reaction temperature.
  • the starting materials and cata- lysts / ligands required for preparing the compounds I are commercially available or can be pre- pared in accordance with the literature cited.
  • reaction mixtures are worked up in a customary manner, for example by mixing with wa- ter, separating the phases and, if appropriate, chromatographic purification of the crude prod- ucts.
  • Some of the intermediates and end products are obtained in the form of colourless or slightly brownish viscous oils which are purified or freed from volatile components under re- prised pressure and at moderately elevated temperature. If the intermediates and end products are obtained as solids, purification can also be carried out by recrystallization or digestion. If individual compounds I cannot be obtained by the routes described above, they can be pre- pared by derivatization of other compounds I.
  • the organic moieties mentioned in the above definitions of the variables are - like the term halogen - collective terms for individual listings of the individual group members.
  • the prefix C n - C m indicates in each case the possible number of carbon atoms in the group.
  • halogen denotes in each case fluorine, bromine, chlorine or iodine, in particular chlorine or bromine, preferably chlorine.
  • Salts of the compounds according to the invention are preferably agriculturally and/or veteri- nary acceptable salts, preferably agriculturally acceptable salts. They can be formed in a cus- tomary manner, e.g. by reacting the compound with an acid of the anion in question if the corn- pounds according to the invention have a basic functionality or by reacting acidic compounds according to the invention with a suitable base.
  • Veterinary and/or agriculturally useful salts of the compounds according to the invention en- compass especially the acid addition salts of those acids whose cations and anions, respective- ly, have no adverse effect on the pesticidal action of the compounds according to the invention.
  • Suitable cations are in particular the ions of the alkali metals, preferably Li, Na, and K, of the alkaline earth metals, preferably Ca, Mg, and Ba, and of the transition metals, preferably Mn,
  • Ci-C 4 -alkyl Ci-C 4 -hydroxyalkyl
  • Ci-C 4 -alkoxy Ci-C 4 -alk- oxy-Ci-C 4 -alkyl
  • hydroxy-Ci-C 4 -alkoxy-Ci-C 4 -alkyl phenyl or benzyl.
  • substituted ammonium ions comprise methylammonium, isopropylammonium, dimethylammonium, diiso- propylammonium, trimethylammonium, tetramethylammonium, tetraethylammonium, tetrabu- tylammonium, 2-hydroxyethylammonium, 2-(2-hydroxyethoxy)ethyl-ammonium, bis(2-hydroxy- ethyl)ammonium, benzyltrimethylammonium and benzyltriethylammonium, furthermore phos- phonium ions, sulfonium ions, preferably tri(Ci-C 4 -alkyl)sulfonium, and sulfoxonium ions, prefer- ably tri(Ci-C 4 -alkyl)sulfoxonium.
  • Anions of useful acid addition salts are primarily chloride, bromide, fluoride, hydrogensulfate, sulfate, dihydrogenphosphate, hydrogenphosphate, phosphate, nitrate, bicarbonate, carbonate, hexafluorosilicate, hexafluorophosphate, benzoate, and the anions of Ci-C 4 -alkanoic acids, preferably formate, acetate, propionate and butyrate. They can be formed by reacting corn- pounds according to the invention with an acid of the corresponding anion, preferably of hydro- chloric acid, hydrobromic acid, sulfuric acid, phosphoric acid or nitric acid.
  • alkyl as used herein and in the alkyl moieties of alkylamino, alkylcarbonyl, alkylthio, alkylsulfinyl, alkylsulfonyl and alkoxyalkyl denotes in each case a straight-chain or branched alkyl group having usually from 1 to 10 carbon atoms, frequently from 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, more preferably from 1 to 3 carbon atoms.
  • alkyl group examples include methyl (“Me”), ethyl (“Et”), n-propyl (“n-Pr”), iso-propyl (“i-Pr”), n-butyl, 2-butyl, iso- butyl, tert-butyl (“t-Bu”,“Bu”), n-pentyl, 1 -methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-di- methylpropyl, 1 -ethylpropyl, n-hexyl, 1 ,1 -dimethylpropyl, 1 ,2-dimethylpropyl, 1 -methylpentyl, 2- methylpentyl, 3-methylpentyl, 4-methylpentyl, 1 , 1 -dimethylbutyl, 1 ,2-dimethylbutyl, 1 ,3-dimethyl- butyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl,
  • haloalkyl moieties are Ci-C3-haloalkyl or Ci-C2-haloalkyl, in particular C1-C2- fluoroalkyl such as fluoromethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, and pentafluoroethyl.
  • cycloalkyl as used herein and in the cycloalkyl moieties of cycloalkoxy and cycloal- kylthio denotes in each case a mono-, bi- or tricyclic cycloaliphatic radical having usually from 3 to 10 or from 3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl (“Cy”), cycloheptyl, cyclooctyl, cyclononyl and cyclodecyl or adamantyl.
  • aryl includes mono-, bi- or tricyclic aromatic radicals having usually from 6 to 14, preferably 6, 10 or 14 carbon atoms.
  • aryl includes any substituents being bound to the aryl ring.
  • exemplary aryl groups include phenyl (“Ph”), naphthyl and anthracenyl. Phenyl is preferred as aryl group.
  • heteroaryl includes monocyclic 5- or 6-membered heteroaromatic radicals comprising as ring members 1 , 2, 3 or 4 heteroatoms selected from N, O and S.
  • hetaryl includes any substituents being bound to the hetaryl ring.
  • 5- or 6-membered heteroaromatic radicals include pyridyl, i.e. 2-, 3-, or 4-pyridyl, pyrimidinyl, i.e. 2-, 4- or 5-pyrimidinyl, pyrazinyl, pyridazinyl, i.e. 3- or 4-pyridazinyl, thienyl, i.e.
  • heteroaryl also includes bicyclic 8 to 10-membered heteroaromatic radi cals comprising as ring members 1 , 2 or 3 heteroatoms selected from N, O and S, wherein a 5- or 6-membered heteroaromatic ring is fused to a phenyl ring or to a 5- or 6-membered hetero- aromatic radical.
  • Examples of a 5- or 6-membered heteroaromatic ring fused to a phenyl ring or to a 5- or 6-membered heteroaromatic radical include benzofuranyl, benzothienyl, indolyl, ind- azolyl, benzimidazolyl, benzoxathiazolyl, benzoxadiazolyl, benzothiadiazolyl, benzoxazinyl, chinolinyl, isochinolinyl, purinyl, 1 ,8-naphthyridyl, pteridyl, pyrido[3,2-d]pyrimidyl or pyridoimid- azolyl and the like.
  • These fused hetaryl radicals may be bonded to the remainder of the mole- cule via any ring atom of 5- or 6-membered heteroaromatic ring or via a carbon atom of the fused phenyl moiety.
  • the particularly preferred embodiments of the intermediates cor- respond to those of the compounds of formula I.
  • the variables of the compounds of formula I have the following meanings, these meanings, both on their own and in combination with one another, being particular embodiments of the compounds of formula I:
  • One embodiment of the invention involves a process for the preparation of aryl hydrazines of formula I
  • R 1 , R 2 , and R 3 are independently selected from H, C-i-Cs-alkoxycarbonyl, fluorenylmethyloxy- carbonyl, arylsulfonyl, C-i-Cs-alkylsulfonyl, formyl, triflouroacetyl, C-i-Cs-alkyl, and C 3 -C 6 -cyclo- alkyl; or are other groups selected from nitrogen protecting groups.
  • Ar in formulae I and II is an aryl or hetaryl group, which is optionally substituted with (R a ) n , and optionally further substituted with (R b ) y ;
  • R is halogen, NO 2 , Ci-C 4 -haloalkyl such as CF 3 , CF 2 H, CFFh; SF 5 , CN, S(0) m R aa ,
  • R, R’ each are independently H, C-i-Cs-alkyl, phenyl which is unsubstituted or par- tially or fully substituted with halogen, CN, NO 2 , Ci-C 4 -haloalkyl, C 3 -C 6 -halo- cycloalkyl, C(0)R A , S(0) m R A , OS(0) m R A , or R b ;
  • n 1 , 2, 3, 4, or 5;
  • y is 0, 1 , 2, 3, 4, or 5; wherein the sum of n and y is up to 5;
  • one group R a stands preferably in para-position
  • R b is Ci-Ci 2 -alkyl, C 2 -Cio-alkenyl, C 2 -Cio-alkynyl, C 3 -Ci 2 -cycloalkyl, C-i-Cs-alkoxy, aryl, het- aryl, OCOR, NHC(0)R, NRC(0)R’, NRR’, S1R 3 , azido, which groups are unsubstituted or partially or fully substituted with halogen, NO 2 , CN, OH, Ci-C 6 -alkyl, Ci-C 6 -alkoxy, C 1 -C 6 - haloalkyl, Ci-C 6 -haloalkoxy, C 3 -C 6 -cycloalkyl, C 3 -C 6 -cycloalkoxy, C 3 -C 6 -halocycloalkyl, C 3 - C 6 -halocycloalkyl, C 3 - C 6 -
  • R A is H, Ci-C 4 -alkyl, Ci-C 4 -haloalkyl, C 3 -C 6 -cycloalkyl, or C 3 -C 6 -halocycloalkyl, NRR’, Ci-C 4 -alkoxy, Ci-C 4 -haloalkoxy, or phenyl which is unsubstituted or partially or fully substituted with R B ;
  • R B is H, Ci-C 4 -alkyl, Ci-C 4 -haloalkyl, C 3 -C 6 -cycloalkyl, or C 3 -C 6 -halocycloalkyl;
  • n 0, 1 , or 2.
  • the formula I compound may be formed as a mixture of two regioisomers, each of which corresponds to a formula I compound.
  • a preferred embodiment is the process for the preparation of aryl hydrazines of formula I which corresponds to formula la or a salt, such as hydrochloride, sulphate, or hydrobromide thereof, wherein Ar is as defined and preferred for formula I.
  • Ar in formulae I and II is preferably phenyl, which is partially or fully substituted with R a being preferably halogen, and is optionally furthermore substituted with one or more groups R b .
  • R a is chloride or fluoride.
  • Ar in formula I and II is an unsubstituted or substituted 3-, or 4-pyridyl or substituted 2-pyridyl, preferably substituted or unsubstituted 3-pyridyl. If present, substitution of hetaryl is (R a ) n , and (R b ) y .
  • R a is halogen, preferably Cl, and # denotes the bond to the hydrazine or the leaving group, resp., and R b y is as defined above.
  • aryl hydrazine of formula I preferably corresponds to formula 1.1 ,
  • R a is as defined above, preferably Cl;
  • R b1 , R b2 , R b3 , R b4 are selected from groups R b , preferably independently from one another, H, Ci-Ci2-alkyl, C-3-Ci2-cycloalkyl, aryl, hetaryl;
  • the aryl hydrazine more preferably is of formula 1.1 which corresponds to formula 1.1 a,
  • R a , R b1 , R b2 , R b3 , R b4 are H, Ci-Ci2-alkyl, C-3-Ci2-cycloalkyl, and phenyl;
  • R b1 , R b2 , R b3 , R b4 are all H, and R a is Cl.
  • Ar is a monocyclic 5- or 6-membered heteroaromatic radical compris- ing as ring members 1 , 2, 3, or 4 heteroatoms selected from N, O and S, which is unsubstituted or partially or fully substituted with (R a ) n and/or (R b ) y .
  • Ar is phenyl, naphthyl, pyridyl, quinoline, quinoxaline, or benzothio- phene, which rings are unsubstituted or more preferably substituted with halogen, Ci-C4-alkyl, C3-C 4 -alkenyl Ci-C 4 -alkoxy, Ci-C 4 -alkylthio, Ci-C 4 -haloalkyl, Ci-C 4 -alkylcarbonyl, Ci-C 4 - alkoxycarbonyl, or imidazo[1 ,2-a]pyridine.
  • Z in formula II is understood as a nucleophilic leaving group, preferably halogen, or OS(0) 2 R’, wherein R’ is Ci-C 4 -alkyl, Ci-C 4 -haloalkyl, or aryl which is unsubstituted or partially or fully sub- stituted with Ci-C 4 -alkyl.
  • R’ is Ci-C 4 -alkyl, Ci-C 4 -haloalkyl, or aryl which is unsubstituted or partially or fully sub- stituted with Ci-C 4 -alkyl.
  • Z is tosylate, triflate, mesylate, or halogen; more preferably Cl or Br, particularly Cl.
  • Z is halogen or tosylate; more preferably Cl or tosylate.
  • Z is halogen; more preferably Cl or Br, particularly Cl.
  • the coupling reaction is conducted optionally in the presence of an addi- tional organic reagent, eg. a phase transfer catalyst or reagent, such as tetra alkylammonium halide salt, or Ci-Ci2-alcohol such as methanol or ethanol.
  • an addi- tional organic reagent eg. a phase transfer catalyst or reagent, such as tetra alkylammonium halide salt, or Ci-Ci2-alcohol such as methanol or ethanol.
  • R 1 , R 2 , and R 3 are as defined and preferred for formula I.
  • the compound of formula III is hydrazine or a salt or hydrate thereof; all R 1 , R 2 , and R 3 are hydrogen.
  • two of R 1 , R 2 , R 3 are H, and exactly one of R 1 , R 2 , R 3 is selected from Ci- Ce-alkoxycarbonyl, fluorenylmethyloxycarbonyl, aryl- or alkylsulfonyl, formyl, trifluoroacetyl, Ci- Cs-alkyl, and C3-C6-cycloalkyl.
  • R 1 , R 2 , R 3 is selected from C-i-Cs-alk- oxycarbonyl, fluorenylmethyloxycarbonyl, aryl- or alkylsulfonyl, formyl, triflouroacetyl; particularly exactly one of R 1 , R 2 , R 3 is te/Abutoxycarbonyl.
  • the process may further comprise removal of the protecting groups or derivative groups of such protected or derivatized aryl hydrazine to yield the aryl hy- drazine of formula la.
  • the coupling reaction must be followed by a removal reac- tion, which can be in separate step or reactor, or as a one-pot reaction in the same vessel or can occur spontaneously during workup of the coupling reaction.
  • the deprotection or removal of the derivative group from aryl hydrazine is usually carried out at temperatures of from 0°C to 200°C, preferably from 20°C to 120°C, in an inert solvent, in the presence of a base, an acid, or a catalyst and hydrogen.
  • This reaction can be run in a separate step or vessel, or in the same vessel as the coupling reaction, or can occur spontaneously dur- ing workup.
  • Suitable solvent is either the same solvent as used in the coupling reaction, or aliphatic hydro- carbons such as pentane, hexane, cyclohexane, and petrol ether, aromatic hydrocarbons such as toluene, o-, m-, and p-xylene, halogenated hydrocarbons such as methylene chloride, chloro- form, and chlorobenzene, ethers such as diethylether, diisopropylether, tert.-butylmethylether, dioxane, anisole, and THF, nitriles such as acetonitrile, and propionitrile, ketones such as ace- tone, methyl ethyl ketone, diethyl ketone, and tert.-butyl methyl ketone, alcohols such as meth- anol, ethanol, n-propanol, isopropanol, n-butanol, and tert.
  • esters such as ethyl ace- tate, moreover DMSO, DMF, and DMA, preferably cyclic ethers such as dioxane, 2-methyl-THF, and THF. It is also possible to use mixtures of the solvents mentioned.
  • Suitable bases are, in general, inorganic compounds, such as alkali metal and alkaline earth metal hydroxides, such as LiOH, NaOH, KOH and Ca(OH) 2 , alkali metal and alkaline earth met- al oxides, such as LhO, Na 2 0, CaO, and MgO, alkali metal and alkaline earth metal hydrides, such as LiH, NaH, KH and CaH2, alkali metal and alkaline earth metal carbonates, such as U2CO3, Na2C03, K2CO3, and CaC03, and also alkali metal bicarbonates, such as NaHCOs, moreover organic bases, for example tertiary amines, such as trimethylamine, triethylamine, diisopropylethylamine and N-methylpiperidine, pyridine, substituted pyridines, such as collidine, lutidine and 4-dimethylaminopyridine, and also bicyclic amines. Particular preference is given to NaOH and KOH
  • Suitable acids and acidic catalysts are in general inorganic acids such as HF, HCI, HBr, sul- phuric acid und perchloric acid, Lewis acids, such as boron tri fluoride, aluminium tri chloride, iron III chloride, tin IV chloride, titanium IV chloride and zinc II chloride, moreover organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, toluene sulphonic acid, benzene sulphonic acid, camphor sulphonic acid, citric acid, and trifluoro acetic acid. Particular prefer- ence is given to hydrochloric acid and trifluoroacetic acid.
  • the acids are generally employed in equimolar amounts; however, they can also be used in in catalytic amounts, in excess or, if ap-litiste, as solvent.
  • the protective group is fe/7-butoxycarbonyl.
  • the deprotection is usually carried out in the presence of an acid such as hydrochloric acid or trifluoroacetic acid (cf. Org. Lett. 2004, 6, 3675-3678).
  • an acid such as hydrochloric acid or trifluoroacetic acid
  • the deprotection is usually carried out using a palladium on carbon catalyst and H2. If the protective group is fluorenylmethyloxycarbonyl, the deprotection is usually carried out us- ing amines such as cyclohexylamine, ethanolamine, piperidine, and piperazine in polar sol- vents.
  • the deprotection is usually carried out using a base such as KOH or NaOH or an acid such as HBr at 25 to 120 °C.
  • the deprotection is usually carried out using a base such as KOH or NaOH or an acid such as HCI at 25 to 120 C.
  • the deprotection is usually carried out using out using a base such as KOH, NaOH, K2CO3 or Na 2 C0 3 at 25 to 120°C.
  • the protection is usually carried out using a base such as KOH or NaOH or an acid such as HCI at 25 to 120°C.
  • the compound of formula III is hydrazine, or a salt or hydrate thereof, and is e.g. hydrazine, hydrazine monohydrate, hydrazine acetate, hydrazine monohydrochloride, hydrazine dihydrochloride, or hydrazine sulfate. It is employed into the process neat or as a solution of one of these compounds, e.g. in water.
  • the amount of Pd used is less than 0.5 mol-% relative to the amount of arene of formula II.
  • the amount of Pd used is less than 0.1 mol-% relative to the amount of arene of formula II.
  • the amount of Pd used is less than 0.01 mol-% relative to the amount of arene of formula II.
  • the amount of Pd used is less than 0.005 mol-% relative to the amount of arene of formula II.
  • the amount of Pd used is less than 0.001 mol-% relative to the amount of arene of formula II.
  • the amount of Pd used is at least 0.0005 mol-%.
  • the amount of Pd used is up to 0.5 mol-% relative to the amount of arene of formula II.
  • the amount of Pd used is up to 0.2 mol-% relative to the amount of arene of formula II.
  • the amount of Pd used is up to 0.1 mol-% relative to the amount of arene of formula II.
  • the amount of Pd used is up to 0.05 mol-% relative to the amount of arene of formula II.
  • the amount of Pd used is up to 0.01 mol-% relative to the amount of arene of formula II.
  • the amount of Pd used is up to 0.005 mol-% relative to the amount of arene of formula II.
  • the amount of Pd used is up to 0.001 mol-% relative to the amount of arene of formula II.
  • the catalyst comprising Pd and the diphosphine ligand employed in the process is utilized by, first, preparing a complex comprising Pd and the diphosphine lig and in substantially pure form, and second, introducing the complex to the reactor in which the coupling process is to be carried out.
  • the diphosphine ligand is of formula IVA, and is most preferably CyPF-t-Bu.
  • the complex comprising the Pd and the diphosphine ligand preferably has the structure (CyPF-t- Bu)Pd (Ar)(X), where Ar is unsubstituted or substituted aryl, particularly unsubstituted or substi- tuted phenyl and X is Cl, Br, or I; preferred substituents are Ci-C 4 -alkoxy and Ci-C4-alkyl, pref- erably in the 4-position.
  • (CyPF-t-Bu)Pd (4-OCHsPh)(Br) may be prepared as described in US 8,058,477, Ex. 30.
  • (CyPF-t-Bu)Pd (4-CHsPh)(Br) may be prepared as described in Alvaro & Hartwig, JACS200Q, 131, 7857-7868, p. S4 of Supporting Information.
  • (CyPF-t-Bu)Pd (4- CH3Ph)(CI) may be prepared as described in Alvaro & Hartwig, JACS2QQS, 131, 7857-7868, p. S2 of Supporting Information.
  • the complex comprising the Pd and the diphosphine ligand has the structure (CyPF-t-Bu)Pd X 2 , where X is selected from Cl, Br, and I.
  • (CyPF-t-Bu) PdCI 2 may be prepared as described in US 8,058,477.
  • the complex comprising the Pd and the diphosphine ligand of formula IVA preferably has the structure (ligand of formula IVA)Pd (Ar)(X), where Ar and X are as defined above; the complex comprising the Pd and the diphosphine ligand of formula IVA may also have the structure (ligand of formula IVA)Pd X 2 , where X is selected from Cl, Br, and I.
  • the catalyst comprising Pd and the diphosphine ligand employed in the coupling reaction is utilized by preparing a stock solution of a Pd source and a diphosphine ligand, which is subsequently introduced to the reactor in which the coupling process is to be carried out.
  • the diphosphine ligand is of formula IVA, and is most preferably CyPF-t-Bu.
  • a stock solution of Pd(P(o-tolyl)3)2 and (R)-1-[(Sp)-2-(Dicyclohexyl- phosphino)ferrocene-yl]ethyldi-tert-butylphosphine ((R)-(S)-CyPF-tBu) may be prepared as de- scribed in Ex. 1 or as in JACS 2008, 130, 13848 (page S1 of the Supporting Information).
  • a stock solution of Pd(OAc) 2 and CyPF-tBu may be prepared, as described in JACS 2008, 130, 6586 (page S2 of the Supporting Information).
  • the diphosphine ligand and the Pd source are added simultane- ously or independently from one another to the reactor containing some or all the other reagents or solvent required for the coupling reaction.
  • the diphosphine ligand displaces one or more of the lig ands bound to the Pd source prior to or during the process.
  • the diphosphine ligand is preferably a ligand of formula IVA, and is particularly CyPF-t-Bu. Such procedure is described in US 6,235,938.
  • Aryl in R 4 , R 5 , R 6 , R 7 , and R 8 is preferably selected from phenyl and substituted phenyl, such as 4-methoxyphenyl, 3,5-dimethylphenyl, 3,5-dimethyl-4-methoxyphenyl, 3,5-bis(trifluoro- methyl)phenyl, 1-napthyl, 2-napthyl, 1-furyl, and 2-furyl.
  • R 7 and R 8 are independently selected from cyclohexyl and tert-butyl
  • R 4 , R 5 , R 6 are independently selected from Ci-C 4 -alkyl, cyclohexyl, iso-propyl, tert-butyl, and phenyl which is unsubstituted or partially or fully substituted with (R b ) y wherein R b is OH, Ci-C 4 -alkyl, CF 3 , Ci-C 4 - alkoxy, or S(0) m R A .
  • R 4 , and R 5 are independently selected from cyclohexyl and tert-butyl
  • R 6 , R 7 , R 8 are independently selected from Ci-C 4 - alkyl, cyclohexyl, iso-propyl, tert-butyl, and phenyl which is unsubstituted or partially or fully substituted with (R b ) y wherein R b is OH, Ci-C 4 -alkyl, CF 3 , Ci-C 4 -alkoxy, or S(0) m R A .
  • the compound of formula IVA is selected from the struc- tures below:
  • the compound of formula IVA is CyPF-tBu selected from following structures:
  • CyPF-tBu Any mixture of one, two, three, or four of these compounds is referred to as CyPF- tBu.
  • the compound of formula IVA is (R,S Fc )-CyPF-tBu, (S,R Fc )-CyPF-tBu or is a mixture of (R,S Fc )-CyPF-tBu and (S,R Fc )-CyPF-tBu.
  • the Pd source usually consists of a Pd(0) or Pd(ll) moiety (precata- lyst), such as Pd(OAc)2, Pd(OAc)2(PPh3)2, Pd(OCOt-Bu)2, Pd(OCOCF3)2, Palladium(ll) acetyl- acetonate [Pd(acac)2)], Palladium(n-cinnamyl) chloride dimer [(Cinnamyl)PdCI]2], Tris(diben- zylideneacetone)dipalladium(O) [Pd2(dba)3], Pd(dba)2, PdCh, PdBr2, Pd , PdCl2(PhCN)2, PdCl2(PPh3)2, Pd[P(o-tolyl)3]2, Pd(PPh
  • approximately 1 molar equiva- lent of the diphosphine ligand relative to Pd is employed; in some cases, it may be preferable to use slightly more or slightly less than 1 molar equivalent of ligand relative to Pd; in some cases, up to 2 molar equivalents of ligands relative to Pd may be used.
  • the Pd source is usually Pd[P(o-tolyl)3]2,
  • the Pd source is usually Pd(OAc)2 or PdCl2(PhCN)2, and is preferably
  • the base in the coupling reaction is preferably of formula Va or Vb,
  • R, R 9 each independently are H, or Ci-C4-alkyl, preferably CH 3 , C2H 5 , CH2CH2CH 3 ,
  • M is an alkali or alkaline earth metal, preferably Na, K, or Ca.
  • R 9 in formula Va is selected from H, CH 3 , C2H 5 , CH2CH2CH 3 , and CH(CH 3 ) 2 , particularly H, CH3, and C2H5.
  • the base in the coupling reaction is an alkali metal or alkaline earth metal car- bonate or phosphate, such as Na2C03, K2CO3, NasPC , and K3PO4, or mixtures thereof.
  • the base is of formula Va.
  • M is an alkali metal, such as Na, K, Li and Cs, preferably Na or K.
  • the base of formula Va is particularly selected from NaOH and KOH.
  • the base is NaOH.
  • the base is KOH.
  • the base is of formula Vb, wherein
  • R and R 9 are independently preferably H, or CH 3 , particularly H, and
  • M is an alkaline earth metal, preferably Ca.
  • the base is usually employed in at least one equivalents based on formula II compound. In some cases, in may be beneficial in to employ greater than 2 equivalents of base, and in other cases, up to 5 equivalents of base may be beneficial to achieve the highest yield for aryl hydra- zine of formula I.
  • the coupling reaction is conducted in the presence of an additional or- ganic reagent, e.g. a phase-transfer catalyst or an organic reagent or solvent, such as an alco- hol like MeOH or EtOH, that has the ability to increase the solubility of certain salts, such as NaOH or KOH, in the inert organic solvent.
  • an additional or- ganic reagent e.g. a phase-transfer catalyst or an organic reagent or solvent, such as an alco- hol like MeOH or EtOH, that has the ability to increase the solubility of certain salts, such as NaOH or KOH, in the inert organic solvent.
  • the reaction temperature depends from the Pd amount and nature of ligands used, in general at least 20°C, preferred at least 40°C, more preferred at least 60°C, more preferred at least 80°C, more preferred at least 90°C, even more preferred at least 100°C, particularly is in the range of from 100 to 120°C.
  • the process is conducted in
  • a reagent that increases the solubility of the base in the organic sol- vent or facilitates (speeds up) dissolution of the base in the organic solvent is added, which may be a Ci-Ci 2 -alcohol, such as preferably CH 3 OH or C 2 H 5 OH, isopropanol, t-amyl alcohol, or tert- butanol, a salt of such alcohol, a quaternary ammonium salt such as tetraalkylammonium salt, preferably hexadecyltrimethylammonium bromide (CTAB), or another type of phase-transfer catalyst (PTC).
  • Ci-Ci 2 -alcohol such as preferably CH 3 OH or C 2 H 5 OH
  • isopropanol t-amyl alcohol, or tert- butanol
  • a salt of such alcohol a quaternary ammonium salt
  • tetraalkylammonium salt preferably hexadec
  • phase-transfer catalysts are described, for example, in JACS, 1975, 97, 2345 - 2349, and include, e.g., quaternary ammonium, phosphonium, antimonium, bismuthoni- um, and tertiary sulfonium, salts, wherein the anion is, e.g., fluoride, chloride, bromide, iodide, or sulfate, or may be crown ethers.
  • phase-transfer catalysts may be optionally be used in the presence of an alcohol or diol, such as pinacol.
  • the amount of the additional organic reagent is less than 50 mol-%, less than 20 mol-%, less than 10 mol-%, less than 5 mol-%, less than 2 mol-%, less than 1 mol-%, less than 0.5 mol-%, or less than 0.1 mol-% relative to the amount of arene of formula II.
  • R a , R b1 , R b2 , R b3 , and R b4 are as defined and preferred for formula 1.1 .
  • the aryl hydrazine of formula 1.1 is 4-chlorophenyl- hydrazine
  • the %-conversion of 1 ,4-dichlorobenzene is at least 80%, at least 90%, at least 95%, at least 97%, or at least 99%, and an aryl dihydrazine
  • Aryl hydrazines of formula I can be transformed by methods known in the art to N-aryl substi- tuted heterocyclic compounds, such as pyrazoles, triazoles or pyridazinones. Such compounds correspond to formula VI
  • HC is a 5- or 6-membered unsaturated heterocycle comprising as ring members 2, 3 or 4 het- eroatoms selected from N, O and S, which is unsubstituted or partially or fully substituted with R a and/or R b ; and
  • Ar is as defined in formula I.
  • HC preferably at least two ring members are N.
  • Particularly pyrazole derivatives of formula VI are valuable intermediates for active ingredients used, e.g., in crop protection and pharmaceuticals.
  • Table VI lists examples of hydrazines of formula I, compounds of formula VI which are obtain- able from such formula I compounds, and active compounds obtainable by further transfor- mation of such formula VI compound. In some cases, the formula VI compound itself is known as active ingredient.
  • 4-chlorophenylhydrazine 1.1a or a salt thereof is converted in one or more subsequent steps to 1-(4-chlorophenyl)pyrazol-3-ol of formula VI.1 :
  • the inventive process consists of further reacting the hydrazine of formula 1.1 un- der basic conditions with methyl propiolate to yield 1-(4-chlorophenyl)pyrazol-3-ol of formula VI.1.
  • the pyrazole derivative of formula VI.1 is an intermediate for active ingredients used, e.g., in crop protection and pharmaceuticals.
  • the pyrazole derivative of formula VI.1 is e.g. an intermediate for the preparation of N-[2-[[1- (4-chlorophenyl)pyrazol-3-yl]oxymethyl]phenyl]-N-methyl-acetamide of formula VII (common name: pyraclostrobin)
  • the pyrazole derivative of formula VI.1 also is a suitable intermediate for the preparation of 1- [2-[[1-(4-chlorophenyl)pyrazol-3-yl]oxymethyl]-3-methyl-phenyl]-4-methyl-tetrazol-5-one of for- mula VIII (common name: metyltetraprole):
  • GC method 100°C for 3 min, then ramp to 300°C at a rate of 40°C/min for 4 minutes. Then hold at 300°C for 3.5 minutes.
  • Column HP-5 column from Agilent, 25 m in length, 0.200mm diameter, 0.33mM film (part number 19091J-102).
  • GC apparatus Agilent 7820A Preparation Examples:
  • 1 ,4-dichlorobenzene was purchased from Alfa-Aesar (>99% purity) and used without purifica- tion.
  • 1 ,4-dioxane was purchased from Sigma-Aldrich (>99% purity, anhydrous), sparged for 1 hour with nitrogen, and stored inside an inert atmosphere glovebox.
  • KOH pellets were pur- chased from Fisher Scientific (>85% purity), imported into a glovebox, and was ground into a fine powder with a pestle and mortar. Hydrazine monohydrate (64-65% by weight, 98% purity, Sigma Aldrich) and (/x)-CyPF-/Bu (Strem Chemicals) were used without purification.
  • Pd(P(o-tolyl)3)2 was synthesized according to Li, et.al., J. Org. Lett., 2010, 12 3332-3335.
  • Example 2 Reaction of 1 ,4-dichlorobenzene with hydrazine.
  • Example 3 Reaction of various aryl halides with hydrazine, followed by pyrazole formation
  • a 5ml_ volumetric flask was charged with Pd[P(o-tolyl)3]2 (34.4mg, 0.0481 mmol) and CyPF-/Bu (26.7mg, 0.0481 mmol).
  • the flask was filled to the mark with 1 ,4-dioxane to obtain an orange suspension, and a Teflon-coated stir bar was added to the flask.
  • the flask was capped and stirred for 45 minutes to obtain a homogenous, red-orange solution.
  • Example 4 Reaction of 1 ,4-dichlorobenzene with hydrazine using a racemic mixture of (R)-1 - [(S)-2-dicyclopentylphosphinoferrocenyl]phenylmethyldi-te/f-butylphosphine and (S)-1 -[(R)-2-di- cyclopentylphosphinoferrocenyl]phenylmethyldi-te/f-butylphosphine (rac-CypPF-(Ph)/Bu); a ra- cemic mixture of (R)-1 -[(S)-2-dicyclohexylphosphinoferrocenyl]ethyldiadamantylphosphine and (S)-1 -[(R)-2-dicyclohexylphosphinoferrocenyl]ethyldiadamantylphosphine (rac-CyPF-Ad);
  • PhPF-/Bu a 4.82 mM solution of Pd[P(o-tolyl)3]2 and 4.82 mM solution of PhPF-/Bu was used.
  • ferrocenecarboxaldehyde (A, 500mg, 2.34mmol), morpholine (407pL, 4.68mmol), and dichloromethane (15 ml.) were combined in a 50ml_ oven-dried round bottomed flask along with a Teflon-coated stir bar. The resulting mixture was then capped with a septum, stirred at 20-25°C, and 2.34ml_ (2.34mmol) of a 1.0M solution of TiCI 4 in DCM was added to the solution. The reaction was then stirred for 24 h, cooled in an ice bath, and
  • NaBI-hCN (413mg, 6.57mmol) was added in one portion as a solution in 10ml_ methanol. The reaction was stirred for 1 h and the pH was adjusted to ⁇ 13 with aq. NaOH. The reaction was then extracted thrice with EtOAc (30ml_), and the organic fractions were combined and concen- trated via rotary evaporation. The crude product was then purified by automated column chro- matography with a linear gradient of 0-100% of EtOAC/hexanes to obtain B in 35% yield (231 mg, orange solid).
  • Comparative Example 1 shows that using the preferred monophosphine ligand of D1 , but us- ing only 0.01 mol% Pd, the reaction of hydrazine with 1 ,4-dichlorobenzene does not proceed.
  • Comparative Example 2 shows that using the preferred monophosphine ligand of D1 and 1 mol% Pd (the preferred Pd amount in D1), the reaction of 1 ,4-dichlorobenzene with hydrazine proceeds.
  • the disadvantage of this procedure is the high catalyst loading and the low yield (74% versus >95%), thus these conditions cannot be exploited industrially.
  • Comparative Example 3 shows that using the preferred monophosphine ligand of D1 and 1 mol% Pd (the preferred Pd amount in D1), the reaction of 1 ,4-dichlorobenzene with hydrazine proceeds.
  • the disadvantage of this procedure is the high catalyst loading and the low yield (74% versus >95%), thus these conditions cannot be exploited industrially.
  • Comparative Example 3 shows that using the preferred monophosphine ligand of D1 and 1 mol% Pd (the preferred Pd amount in D1), the reaction of 1 ,4-dichlorobenzene with hydrazine proceeds.
  • Comparative Example 4 shows that using the preferred ligand of D2, D3, and D5, and using 5 mol% Pd (the preferred Pd amount reported in D2), the reaction of 1 ,4-dichlorobenzene with hydrazine proceeds, but provides only low yield of product.

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Abstract

L'invention concerne un procédé de synthèse d'arylhydrazines de formule I ou un sel correspondant, lequel procédé consiste à soumettre un arène de formule II à une réaction de couplage avec une hydrazine ou un dérivé de celle-ci, la réaction de couplage étant effectuée en présence d'un catalyseur comprenant du palladium et un ligand de diphosphine, les atomes de phosphore étant reliés par deux, trois, quatre ou cinq atomes choisis parmi le carbone, l'azote, l'oxygène ou le fer, et les substituants de phosphore non reliés étant alkyle en C1- C 10- ou cycloalkyle en C3-C10, la quantité de Pd utilisé étant jusqu'à 0,5 % en moles par rapport à la quantité d'arène de formule II ; et une base.
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