Description

The invention relates to a process for the synthesis of aryl hydrazines of formula I

or a salt, such as hydrochloride, sulphate, or bromide thereof,

wherein Ar is an optionally substituted aryl or hetaryl group, and

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

Z-Ar II

wherein Ar is defined as in formula I, and Z is a leaving group, to a coupling reaction with hydrazine or a derivative thereof of formula

or salts thereof, wherein R ¹ , R ² , and R ³ are as defined for formula I;

wherein 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;

and a base.

The synthesis of hydrazine derivatives, particularly aryl hydrazines, is a problem, as such compounds can be converted to 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.

Routes based on aryl chlorides are particularly highly desirable, as aryl chlorides are also readily available, inexpensive starting materials. Routes based on efficient catalytic processes that use small amounts of catalyst, inexpensive reagents, and produce few other byproducts are especially desirable, as such routes could potentially be implemented on a technical scale and would be accompanied by little waste. Unfortunately, industrially viable routes that may be gen- erally applied to the synthesis of products or intermediates of industrial interest are not known.

Thus, 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 base used is of formula Va, wherein R ¹ = OtBu. 1 mol-% or more Pd is used. In one case, the use of a substrate with multiple leaving groups is described (Table 2, row 2, column 3; 1 ,3-dichlorobenzene), providing 86% yield. However, footnote 20 suggests that 1 ,4-substituted arenes containing an electron-withdrawing group in addition to the leaving group provide low yield. Thus, 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 (Angewandte Chemie Int. Ed., 2011 , 49, pp. 8686 - 8690; D3) 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. In Table 1 , entry 9, the use of KOH in- stead of NaOtBu as base is described, and it is found that the yield drops to 24% (compared with 73% when NaOtBu is used); on page 8687 it is stated that“other bases such as KOH and CS2CO3 were inferior to NaOtBu.” The results in this document require high catalyst loadings of 3 mol% or more and are thus of little industrial relevance. The document also shows that inex- pensive hydroxide bases cannot be used, and instead expensive tert-butoxide bases must be employed.

Wang et al. (Tetrahedron Letters, 1999, 40, 3543-3546; D4) describes the reaction of aryl bromides with fe/7-butylcarbazate (BOCNHNH2) in the presence of a Pd complex, a base, and a diphosphine ligand to yield fe/7-butyloxycarbonyl (BOC)-protected aryl hydrazines. Since it is known that the BOC protective group can be removed readily under mild conditions, this report provides a method for the synthesis of aryl hydrazines. However, the reported method requires the use of 2 mol% Pd as well as expensive CS2CO3 as base. The method is only applicable to expensive aryl bromides, and not to inexpensive aryl chlorides. In addition, as shown in entry 7 of Table 1 (1 ,3-bromochlorobenzene), this method enables the synthesis of BOC-protected aryl hydrazides substituted by a single chlorine atom only in low yield.

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. The base used is of formula Va, wherein R ¹ = OtBu. 2.5 mol-% or more Pd is used. No substrates containing more than one leaving group (e.g., Cl, Br, OTs) are reported.

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. However, it is known that ben- zoyl and related amides can be cleaved only under very harsh conditions, such as refluxing 6N HCI for 48h. In addition, the reported method requires the use of 2 mol% Pd, and is only appli cable to 2-chloropyridine, which is an exceptionally reactive substrate that undergoes substan- tial reaction with benzoic hydrazide even in the absence of a transition metal catalyst (Table 1 , entry 1 , 27% yield). Thus, this document does not enable a general synthesis of aryl hydra- zines.

In summary, 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- cesses 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 main advantages compared with other efforts of affect this transformation using homoge- neous Pd catalysts (described below) is the reduced catalyst loading, and that it enables the use of an inexpensive stoichiometric base. A further advantage is that inexpensive 1 ,4-dichloro- benzene may be used as a starting material, which enables the selective synthesis of particular- ly valuable agrochemical active ingredients, whereas the use of this or related substrates is not enabled by other methods described above.

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, methyl ethyl ketone, diethyl ketone, and tert. -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.

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.

Particular preference is given to 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 palladium and the diphosphine ligand. Such Pd moieties or Pd sources are also referred to as precatalysts. Typically, such Pd sources are in the formal Pd(0) or Pd(ll) oxidation state.

Alternatively, a source of Pd already containing a diphosphine ligand may be used. Examples of such Pd sources are:

(CyPF-/Bu)Pd[P(o-tolyl) ₃ ], and (CyPF-t-Bu)PdCI ₂ .

(CyPF-t-Bu)Pd (4-OCH ₃ Ph)(Br) is known from US 8,058,477. (CyPF-t-Bu)PdCl2 is known from US 8,058,477. (CyPF-/Bu)Pd[P(i>tolyl)3] is known from JACS 2003, 125, 8704-8705, p. S2 of the Supporting Information. 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 .

Such diphosphines are compounds of formula IV:

IV

wherein,

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.

Preferably the 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;

or 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;

or is a mixture of two or more such compounds.

More preferably the 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:

wherein 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. In terms of yield or rate of reaction, it may be advantageous to employ more than 1 equivalent of hydra- zine or its derivative, based on formula II compound. In some cases, it is advantageous to use approximately 2 equivalents of hydrazine or its derivatives, based on formula II compound.

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.

The 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- duced 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.

The term“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,

Cu, Zn, and Fe, and also ammonium (NH ₄ ⁺ ) and substituted ammonium in which one to four of the hydrogen atoms are replaced by 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. Examples of 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.

The term "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. Examples of an alkyl group are 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, 3,3-dimethylbutyl, 1 -ethylbutyl, 2-ethylbutyl, 1 ,1 ,2- trimethylpropyl, 1 ,2,2-trimethylpropyl, 1 -ethyl-1 -methylpropyl, and 1-ethyl-2-methylpropyl.

The term "haloalkyl" as used herein denotes in each case a straight-chain or branched alkyl group having usually from 1 to 6 carbon atoms, preferably from 1 to 4 carbon atoms, wherein the hydrogen atoms of this group are partially or totally replaced with halogen, preferably fluoro atoms. Preferred 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.

The term "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.

The term“aryl” includes mono-, bi- or tricyclic aromatic radicals having usually from 6 to 14, preferably 6, 10 or 14 carbon atoms. Optionally 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.

The term "hetaryl" includes monocyclic 5- or 6-membered heteroaromatic radicals comprising as ring members 1 , 2, 3 or 4 heteroatoms selected from N, O and S. Optionally hetaryl includes any substituents being bound to the hetaryl ring. Examples of 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. 2- or 3-thienyl, furyl, i.e. 2-or 3-furyl, pyrrolyl, i.e. 2- or 3-pyrrolyl, oxazolyl, i.e. 2-, 3- or 5-oxazolyl, isoxazolyl, i.e. 3-, 4- or 5-isoxazolyl, thiazolyl, i.e. 2- or 5-thiazolyl, isothiazolyl, i.e. 3-, 4- or 5-isothiazolyl, pyrazolyl, i.e. 1-, 3-, 4- or 5-pyrazo- lyl, i.e. 1 -, 2-, 4- or 5-imidazolyl, oxadiazolyl, e.g. 2- or 5-[1 ,3,4]oxadiazolyl, 4- or 5-(1 ,2,3-oxa- diazol)yl, 3- or 5-(1 ,2,4-oxadiazol)yl, 2- or 5-(1 ,3,4-thiadiazol)yl, thiadiazolyl, e.g. 2- or 5-(1 ,3,4- thiadiazol)yl, 4- or 5-(1 ,2,3-thiadiazol)yl, 3- or 5-(1 ,2,4-thiadiazol)yl, triazolyl, e.g. 1 H-, 2H- or 3H-1 ,2,3-triazol-4-yl, 2 H-triazol-3-yl , 1 H-, 2H-, or 4H-1 ,2,4-triazolyl and tetrazolyl, i.e. 1 H- or 2H-tetrazolyl. The term "hetaryl" 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.

With respect to the variables, the particularly preferred embodiments of the intermediates cor- respond to those of the compounds of formula I. In a particular embodiment, 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

or a salt, such as hydrochloride, sulphate, or hydrobromide thereof, wherein

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 ; wherein

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 ,

OS(0) _m R ^aa , C(0)R ^aa ;

R ^aa is C-i-Cs-alkyl, Ci-C ₄ -haloalkyl, C ₃ -C ₆ -cycloalkyl, C ₃ -C ₆ -halocycloalkyl, C ₂ -C ₈ -alkenyl, C ₂ -C ₈ -alkynyl, OH, C-i-Cs-alkoxy, NRR’, phenyl, phenoxy which rings are unsubsti- tuted or partially or fully substituted with R ^b ;

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 is 1 , 2, 3, 4, or 5; and

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; and

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 -halocycloalkoxy, C ₂ -C ₄ -alkenyl, C ₂ -C ₄ -alkynyl, C(0)NRR’, =0, =S, =NR ^B , =NOR ^B , or =NSR ^B , C(0)R, or OCOR;

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;

m is 0, 1 , or 2.

In cases in which exactly one of R ¹ , R ² , R ³ is not H; or R ¹ and R ³ or R ² and R ³ are both not H and are not identical, 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 .

In a preferred embodiment R ^a is chloride or fluoride.

In another preferred embodiment, 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 .

In a particularly preferred embodiment Ar in formulae I and II denotes a group P

P

wherein 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.

Accordingly, the aryl hydrazine of formula I preferably corresponds to formula 1.1 ,

1.1

wherein

R ^a is as defined above, preferably Cl; and

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;

or a salt thereof.

Accordingly, the aryl hydrazine more preferably is of formula 1.1 which corresponds to formula 1.1 a,

1.1 a

wherein the variables are as defined and preferred as for formula I, and 1.1.

In another embodiment the variables in formula 1.1 denote:

R ^a , R ^b1 , R ^b2 , R ^b3 , R ^b4 are H, Ci-Ci2-alkyl, C-3-Ci2-cycloalkyl, and phenyl;

or a salt thereof. Preferably in formula 1.1 groups R ^b1 , R ^b2 , R ^b3 , R ^b4 are all H, and R ^a is Cl.

In another embodiment 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 .

In another embodiment 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. Preferably Z is tosylate, triflate, mesylate, or halogen; more preferably Cl or Br, particularly Cl.

In another embodiment Z is halogen or tosylate; more preferably Cl or tosylate.

In another embodiment Z is halogen; more preferably Cl or Br, particularly Cl.

In one embodiment 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.

Hydrazine or the derivative thereof corresponds to formula III:

or are salts thereof, wherein R ¹ , R ² , and R ³ are as defined and preferred for formula I.

In an especially preferred embodiment the compound of formula III is hydrazine or a salt or hydrate thereof; all R ¹ , R ² , and R ³ are hydrogen.

In one embodiment, 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. Preferably exactly one of 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.

In case the hydrazine derivative includes any protecting groups or derivative groups (at least one of R ¹ , R ² , R ³ being not H) 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. In such case 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. -butanol, 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. The bases are generally employed in equimolar amounts; however, they can also be used in catalytic amounts, in excess or, if appropriate, as solvent.

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- propriate, as solvent.

Preferably, the protective group is fe/7-butoxycarbonyl.

If 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). E.g. the deprotection compound of formula 1.1 , where R ^a = CN, R ¹ and R ² = H, and R ³ = tert-butoxycarbonyl is described in US 8,071 ,607 (Compound 52B); the deprotection is achieved by at 20-25°C using 4N HCI in dioxane-dichloromethane to provide the hydrochloride salt of the free aryl hydrazine in 85% yield.

If the protective group is benzyloxy carbonyl, 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.

If the protective group is methyloxy carbonyl or ethyloxy carbonyl, 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.

If the protective group is formyl, 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.

If the protective group is trifluoroacetyl, 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.

If the protective group is tosyl or mesyl, 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.

Preferably 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.

In a preferred embodiment, the amount of Pd used is less than 0.5 mol-% relative to the amount of arene of formula II.

In a second embodiment, the amount of Pd used is less than 0.1 mol-% relative to the amount of arene of formula II.

In a third embodiment, the amount of Pd used is less than 0.05 mol-% relative to the amount of arene of formula II.

In a fourth embodiment, the amount of Pd used is less than 0.01 mol-% relative to the amount of arene of formula II.

In a fifth embodiment, the amount of Pd used is less than 0.005 mol-% relative to the amount of arene of formula II.

In a sixth embodiment, the amount of Pd used is less than 0.001 mol-% relative to the amount of arene of formula II.

In another preferred embodiment, the amount of Pd used is at least 0.0005 mol-%.

In another preferred embodiment, the amount of Pd used is up to 0.5 mol-% relative to the amount of arene of formula II.

In a second embodiment, the amount of Pd used is up to 0.2 mol-% relative to the amount of arene of formula II.

In a second embodiment, the amount of Pd used is up to 0.1 mol-% relative to the amount of arene of formula II.

In a third embodiment, the amount of Pd used is up to 0.05 mol-% relative to the amount of arene of formula II.

In a fourth embodiment, the amount of Pd used is up to 0.01 mol-% relative to the amount of arene of formula II.

In a fifth embodiment, the amount of Pd used is up to 0.005 mol-% relative to the amount of arene of formula II.

In a sixth embodiment, the amount of Pd used is up to 0.001 mol-% relative to the amount of arene of formula II. In a preferred embodiment, 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. In a preferred embodiment, the diphosphine ligand is of formula IVA, and is most preferably CyPF-t-Bu. In the case in which the ligand is 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. In a further embodiment, 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. In cases in which the ligand is another ligand of formula IV, 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.

In another embodiment, 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. In a preferred embodiment, the diphosphine ligand is of formula IVA, and is most preferably CyPF-t-Bu. E.g., 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). Alter- natively, 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).

In yet another embodiment, 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. In some cases, in may be particularly advantage- ous to add the diphosphine ligand and the Pd source to a reactor containing only some of the solvent, then later diluting this mixture with the remainder of the solvent necessary for carrying out the process. In this embodiment, 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. Preferably R ⁴ , R ⁵ , R ⁶ , R ⁷ , and 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-C4-alkyl, CF ₃ , Ci-C ₄ -alkoxy, or S(0) _m R ^A . In a particularly preferred embod- iment, R ⁷ and R ⁸ are independently selected from cyclohexyl and tert-butyl, and 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 . In another particularly preferred embodiment, R ⁴ , and R ⁵ are independently selected from cyclohexyl and tert-butyl, and 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 .

In an especially preferred embodiment, the compound of formula IVA is selected from the struc- tures below:

or is a mixture of any two or more of these compounds.

In a particularly preferred embodiment, the compound of formula IVA is CyPF-tBu selected from following structures:

or is a

CyPF-tBu. Any mixture of one, two, three, or four of these compounds is referred to as CyPF- tBu. Especially preferably, 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.

In the embodiments in which the catalyst comprising Pd and a diphosphine ligand is prepared as a stock solution or in situ, 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(PPh3) ₄ , cyclopentadienyl allyl palladium, or any other Pd com- plex which may undergo a ligand exchange reaction with a diphosphine to form a complex with a diphosphine ligand as defined and preferred above. Preferably, 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.

In case of Pd(0) the Pd source is usually Pd[P(o-tolyl)3]2,

Tris(dibenzylideneacetone)dipalladium(0) [Pd2(dba)3], or Pd(dba)2, and is preferably Pd[P(o- tolyl) ₃ ]2.

In case of Pd(ll) the Pd source is usually Pd(OAc)2 or PdCl2(PhCN)2, and is preferably

Pd(OAc) ₂ .

The base in the coupling reaction is preferably of formula Va or Vb,

wherein

R, R ⁹ each independently are H, or Ci-C4-alkyl, preferably CH ₃ , C2H ₅ , CH2CH2CH ₃ ,

CH(CH ₃ ) ₂ , CH2CH2CH2CH3, CH ₂ CH(CH ₃ ) ₂ , particularly H; and

M is an alkali or alkaline earth metal, preferably Na, K, or Ca.

In another embodiment 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.

Alternatively, 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.

More preferably the base is of formula Va.

In one preferred embodiment 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.

In another preferred embodiment the base is NaOH.

In another preferred embodiment the base is KOH.

In another embodiment 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.

In another embodiment 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.

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.

In further embodiments, the process is conducted in

• a batch mode of operation, or in

• a fed-batch mode of operation in which arene, hydrazine derivative or both are continu- ously fed to a solution of the catalyst in a reaction vessel, or in • a continuous mode in which all reactants and catalyst are continuously fed to a reaction vessel with or without recycling of parts of the reaction mass.

In a further embodiment, 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). Typical 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. Such phase-transfer catalysts may be optionally be used in the presence of an alcohol or diol, such as pinacol.

Preferably 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.

Preferably the arene of formula II is represented by formula 11.1 ,

wherein R ^a , R ^b1 , R ^b2 , R ^b3 , and R ^b4 are as defined and preferred for formula 1.1 .

In an additional, preferred embodiment, the aryl hydrazine of formula 1.1 is 4-chlorophenyl- hydrazine,

or a salt thereof,

and the corresponding arene of formula II is 1 ,4-dichlorobenzene,

In an especially preferred additional embodiment, 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

or a salt thereof, is formed as a byproduct,

and wherein the relative amounts of 4-chlorophenylhydrazine and the aryl dihydrazine formed during the process is at least 2:1 , at least 5:1 , at least 10:1 , at least 20:1 , at least 50:1 , at least 100:1 , or at least 200:1 . 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

AG-N' HC) VI

wherein

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.

In 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.

Table VI

In one preferred embodiment, 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 :

or a salt thereof.

The transformation of 4-chlorophenylhydrazine to yield 1-(4-chlorophenyl)pyrazol-3-ol is usual- ly carried out under basic conditions, e.g. using methyl propiolate [cf. US2015/0051 171] Alter- natively a pyrazolidinone can be formed using an acrylic ester [cf. EP680954] or acrylamide [cf. CN 103588708]. Subsequently, this is further processed to form the pyrazole of formula VI.

Accordingly 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-acet amide of formula VII (common name: pyraclostrobin)

or a salt thereof.

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-phen yl]-4-methyl-tetrazol-5-one of for- mula VIII (common name: metyltetraprole):

The following examples illustrate the invention.

Examples

I. Characterization

The yields of products shown below were characterized by gas chromatography (GC), or ¹ H- NMR.

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:

With appropriate modification of the starting materials and reaction parameters, the proce- dures given in the synthesis description were used to obtain further compounds I (Tables II and III). The compounds obtained in this manner are listed in the tables that follow, together with reaction parameters.

General Information

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 1 : Reaction of 1 ,4-dichlorobenzene with hydrazine, Pd[P(o-tolyl)3]2 + (R)-(S)-CyPF- /Bu and KOH in dioxane

a) Stock Solution of Pd(P(o-tolyl)3)2 and (/x)-1-[(5p)-2-(Dicyclohexylphosphino)ferrocene- yl]ethyldi-fe/7-butylphosphine ((R)-(S)-CyPF-ZBu)

In an inert atmosphere glovebox, a 4mL vial was charged with Pd(P(o-tolyl) ₃ ) ₂ (17.6mg, 0.0252mmol) and CyPF-/Bu (14.0mg, 0.0252mmol). A Teflon coated stir bar was added to the vial along with ca. 1 mL of 1 ,4-dioxane and the resulting yellow-orange suspension was stirred for 30mins at 20 to 25°C to obtain a homogenous, orange solution. This solution was then trans- ferred to a 10mL volumetric flask and was diluted to the mark with 1 ,4-dioxane to obtain a 5.04mM solution of (CyPF-/Bu) Pd(P(o-tolyl)3).

b) Synthesis of 4-chlorophenylhydrazine with 100 ppm of (CyPF-/Bu) Pd(P(o-tolyl)3) stock so- lution.

In an inert atmosphere glovebox, a 4mL vial was charged with a Teflon stir bar (12 x 4.5mm),

1 ,4-dichlorobenzene (17.7mg, 0.1204mmol), KOH (30.4mg, 0.541 mmol),15pL of dodecane, and 500pL of 1 ,4-dioxane. 5pL of a stock solution containing (CyPF-/Bu) Pd(P(o-tolyl)3) in 1 ,4-diox- ane (5.04M) was added to the 4mL vial followed by 18.1 pL of N2H4 monohydrate. The vial was then capped with a Teflon lined cap, exported from the glovebox, and warmed to 110°C with stirring (375rpm) for 24h. The reaction was cooled to 20 to 25°C and an aliquot of this reaction was taken for analysis by GC. The title compound was obtained in 85% yield.

Example 2: Reaction of 1 ,4-dichlorobenzene with hydrazine.

The reaction was carried out as described in Example 1 , except that the Pd catalyst, concen- tration, base, solvent, phase-transfer catalyst, temperature, and reaction time were varied, as shown in Table I. Example 3: Reaction of various aryl halides with hydrazine, followed by pyrazole formation

Catalyst Stock Solution

In an inert atmosphere glovebox, 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.

Reaction Procedure

In a representative experiment, an oven-dried 4ml_ vial was charged with powdered KOH (122mg, 2.17mmol, 4.50equiv) or NaOt-Bu (208mg, 2.17mmol, 4.50equiv), aryl halide

(0.482mmol, 1.00equiv), 1 ,4-dioxane (800pL), 5, 15, 40, or 80pL of catalyst stock solution (100, 300, 800, or 1600 ppm of catalyst), and a Teflon-coated stir bar in an inert atmosphere glove- box. Hydrazine monohydrate (70pL, 1.4mmol, 3.0equiv) was then added to the reaction. The 4ml_ vial was then capped with a Teflon-lined cap, and the reaction was warmed to 100 or 110°C for the indicated amount of time with stirring. The reaction was then cooled to 20-25°C and the yield was determined using one of the following procedures: (a) trimethoxybenzene (27.0mg, 0.161 mmol, 0.333equiv) was added to the reaction. The yield and conversion was then determined by ¹ H NMR spectroscopy.; (b) the reaction was imported into a nitrogen glove- box, and acetylacetone (444pL, 4.35mmol, 9.00equiv) was added to the reaction to obtain a white suspension. The reaction was then re-capped with a Teflon-lined cap, exported from the glovebox, and was warmed to 100°C for 6h with stirring. Afterwards, the reaction was loaded directly onto a silica chromatography column, and the product was isolated via automated col- umn chromatography with a linear gradient of EtOAc/hexanes. Details are given in Table II and

able I - Reaction of 1 ,4-dichlorobenzene with 2 eq. hydrazine and Pd catalyst

w

1 relative to 1 ,4-dichlorobenzene

onversion rate and yield was determined by ¹ H NMR or GC.

able II - Reaction of Ar-CI with 2 eq. hydrazine, 4.5 eq. base in dioxane, 1 10°C, 24h, substrate concentration = 0.60 M

onversion rate and yield was determined by ¹ H NMR or GC.

able III - Reaction of Ar-CI or Ar-Br with 3 equiv. hydrazine, 4.5 eq. base in dioxane, 100°C, substrate concentration = 0.60M followed by reaction ith 9 equiv acetylacetone for 6h. Yield of Ar-NH-NH ₂ intermediates are re ported where applicable nd = not determined n

onversion rate was determined by ¹ H NMR and yields are isolated yields unless noted otherwise.

CO

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-butylphos phine (rac-CypPF-(Ph)/Bu); a ra- cemic mixture of (R)-1 -[(S)-2-dicyclohexylphosphinoferrocenyl]ethyldiadamantylphos phine and (S)-1 -[(R)-2-dicyclohexylphosphinoferrocenyl]ethyldiadamantylphos phine (rac-CyPF-Ad); (R)-1 - [(S)-2-diphenylphosphinoferrocenyl]ethyldi-fe/7-butylphosphi ne (PhPF-/Bu); or a racemic mixture of 1 -[(R)-2-[dicyclohexylphosphino]ferrocenyl]methylmorpholine and 1 -[(S)-2-[dicyclohexylphos- phino]ferrocenyl]methylmorpholine (rac-CyPF-morph). a) Catalyst Stock Solution Preparation

In a representative experiment, a 5 or 1 ml. volumetric flask was charged with Pd[P(o- tolyl)3]2 and ligand. The flask was filled to the mark with 1 ,4-dioxane and then a Teflon-coated stir bar was added to the flask and the resulting suspension was stirred for 45 min to obtain an orange solution.

With rac-CypPF-(Ph)/Bu, a 6.41 mM solution of Pd[P(o-tolyl)3]2 and 6.73 mM solution of rac- CypPF-(Ph)/Bu was used.

With rac-CyPF-Ad, a 5.04 mM solution of Pd[P(o-tolyl)3]2 and 5.04 mM solution of rac-CyPF- Ad was used.

With PhPF-/Bu, a 4.82 mM solution of Pd[P(o-tolyl)3]2 and 4.82 mM solution of PhPF-/Bu was used.

With rac-CyPF-morph, a 2.41 mM solution of Pd[P(o-tolyl)3]2 and 3.13 mM solution of rac- CyPF-morph was used.

Arylation of hydrazine with 1 ,4-dichiorobenzene

With ligands rac-CypPF-(Ph)/Bu and rac-PhPF-/Bu: In a representative experiment, a 4ml_ vial was charged with 1 ,4-dichlorobenzene (35.4 mg, 0.241 mmol), KOH (60.4 mg, 1 .08 mmol), 1 ,4- dioxane (0.8 ml_), dodecane (30pL), catalyst stock solution (3.76pL with rac-CypPF-(Ph)/Bu or 5.00pL with PhPF-/Bu), hydrazine monohydrate (36.2pL, 0.723mmol), and a Teflon-coated stir bar. The vial was then capped with a Teflon-lined cap, and the reaction was then warmed to 1 10°C for 24h with stirring. The yield of the reaction was then determined by GC.

With ligands rac-CyPF-Ad and rac-CyPF-morph: In a representative experiment, a 4ml_ vial was charged with 1 ,4-dichlorobenzene (17.7mg, 0.120mmol), KOH (30.2mg, 0.542mmol), 1 ,4- dioxane (0.4ml_), dodecane (15pL), catalyst stock solution (2.40pL with rac-CyPF-Ad or 5.00pL with rac-CyPF-morph), hydrazine monohydrate (18.1 pL, 0.361 mmol), and a Teflon-coated stir bar. The vial was then capped with a Teflon-lined cap, and the reaction was then warmed to 1 10°C for 24h with stirring. The yield of the reaction was then determined by GC. The results are provided in Table IV. KOH (4. 5 equiv)

orph

Table IV

^* not according to invention (not a fully alkyl-substituted diphosphine)

* ^* not according to invention (not a diphosphine)

In an inert-atmosphere glovebox, benzoylferrocene (A, 1 .00g, 3.45mmol), dimethylamine hy- drochloride (281 mg, 3.45mmol), triethylamine (1 .44ml_, 10.3mmol), and dichloromethane

(20ml_) 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 3.45ml_ (3.45mmol) of a 1 .0M solution of TiCI ₄ in DCM was added to the solution. The reaction was then stirred for 24h, cooled in an ice bath, and NaBI-hCN (647mg, 10.3mmol) was added in one por- tion as a solution in 10ml_ of 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 or- ganic fractions were combined and concentrated via rotary evaporation. The crude product was then purified by automated column chromatography with a linear gradient of 0-30% of

EtOAC/hexanes to obtain rac- B in 55% yield (605mg, orange solid). ¹ H NMR (400 MHz, CDC ) d 7.50 (d, J= 7.1 Hz, 2H), 7.40 (t, J= 7.5 Hz, 2H), 7.31 (t, J= 7.2 Hz, 1 H), 4.19 (m 2H), 4.15 (s, 1 H), 4.10 (s, 1 H), 3.78 (s, 1 H), 3.72 (s, 5H), 2.08 (s, 6H).

In an inert atmosphere glovebox, a 50ml_ oven-dried round bottomed flask was charged with B (273mg, 0.854mmol), a Teflon-coated stir bar, and 12ml_ of anhydrous diethylether. The result- ing solution was capped with a septum, cooled in a dry ice/acetone cooling bath, and Abutyl- lithium (1 .6 M/pentane, 614mI_, 0.982mmol) was added to the solution with stirring. After 30 min, the solution was warmed to 20-25°C and stirred for 20h. Chlorodicyclopentylphosphine (229pL,

1 .20mmol) was then added to the reaction as a solution in 5ml_ of diethylether. The reaction was then stirred for 20h at 20-25°C, cooled in an ice/water cooling bath, and 3ml_ of saturated aq. NaHCOs was added to the reaction. The resulting mixture was extracted twice with diethyl ether (20ml_). The organic fractions were combined, dried with MgS0 ₄ , concentrated via rotary evaporation, and the crude product was purified by automated column chromatography with a linear gradient of 0-18% EtOAc/hexanes to give rac- C in 48% yield (199mg, orange solid). ¹ H NMR (600MHz, CDCIs) d 7.57 - 7.53 (m, 2H), 7.40 (t, J= 7.7 Hz, 2H), 7.30 - 7.26 (m, 1 H), 4.60 (br. s, 1 H), 4.43 (d, J= 4.5 Hz, 1 H), 4.29 (t, J= 2.5 Hz, 1 H), 4.19 (t, J= 1 .9 Hz, 1 H), 3.55 (s,

5H), 2.39 - 2.12 (m, 1 H), 2.08 (s, 6H), 1.84 - 1 .38 (m, 15H). ³¹ P NMR (243 MHz, CDCIs) d - 21.97.

In an inert atmosphere glovebox, a 50 ml. oven-dried Schlenk flask was charged with C (199mg, 0.408mmol), di-tertbutylphosphine (302mI_, 1 .63mmol), and a Teflon-coated stir bar. Degassed and anhydrous acetic acid (4ml_) was added to this mixture, and while under a flow of nitrogen, a reflux condenser was attached to the Schlenk flask. The reaction was then warmed to 100°C for 1 h with stirring and then concentrated under vacuum. Triethylamine (2ml_) was added to the crude reaction along with 10 mL of pentane and 20ml_ CHCI3. The reaction was filtered through Celite, and the Celite was washed with 20ml_ CHCI3. The organic fractions were combined and concentrated via rotary evaporation, and the resulting orange oil was dis solved in ethanol and cooled to -15°C overnight to obtain rac-CypPF-(Ph)/Bu as an orange powder (8%, 19.8 mg). ¹ H NMR (600 MHz, CDCI ₃ ) d 7.64 (br. s, 2H), 7.34 (t, J= 7.6 Hz, 2H), 7.20 (t, J= 7.3 Hz, 1 H), 4.75 (s, 1 H), 4.32 (t, J= 5.8 Hz, 1 H), 4.24 (t, J= 2.5 Hz, 1 H), 4.21 (s,

1 H), 3.45 (s, 5H), 2.37 - 2.14 (m, 3H), 2.07 - 1 .39 (m, 15H), 0.94 (d, J= 10.0 Hz, 9H), 0.86 (d, J = 9.6 Hz, 9H). ³¹ P NMR (243 MHz, CDCI ₃ ) d 64.00, -22.36.

Example 6: Synthesis of rac- CyPF-Ad

A B rac-CyPF-Ad

In an inert atmosphere glovebox, a 50 mL oven-dried round bottomed flask was charged with /sc-[1 -(Dimethylamino)ethyl]ferrocene (“Ugi’s amine”, 500mg, 1 .94mmol), diethyl ether (15mL), and a Teflon-coated stir bar. The reaction was capped with a septum, exported from the glove- box, and /T-BuLi (2.5M/hexanes, 854pL, 2.13mmol) was added to the reaction, which was then stirred for 9.5h at 20-25°C. Chlorodicyclohexylphosphine (428pL, 1 .94mmol) was added to the reaction via syringe as a solution in diethyl ether (4mL). The reaction was then stirred for 20h at 20-25°C, cooled in an ice/water cooling bath, and 3mL of saturated aq. NaHCOs was added to the reaction. The resulting mixture was extracted twice with diethylether (20mL). The organic fractions were combined, dried with MgS0 ₄ , concentrated via rotary evaporation, and the crude product was purified by automated column chromatography with a linear gradient of 0-40% EtOAc/hexanes to give crude B in 33% yield (288mg, orange-red oil). B was used without fur- ther purification.

In an inert atmosphere glovebox, a 50ml_ oven-dried Schlenk flask was charged with B (288mg, 0.636mmol), diadamantylphosphine (192mg, 0.636mmol), and a Teflon-coated stir bar. Degassed and anhydrous acetic acid (4ml_) was added to this mixture, and while under a flow of nitrogen, a reflux condenser was attached to the Schlenk flask. The reaction was then warmed to 100°C for 1 h with stirring and then concentrated under vacuum. Triethylamine (3 ml.) was added to the crude reaction along with 30ml_ of pentane. The reaction was filtered through Celite, and the Celite was washed with 20ml_ of pentane. The organic fractions were combined and concentrated via rotary evaporation, and the resulting orange oil was purified by automated column chromatography with a 0-10% linear gradient of EtOAc/hexanes to obtain rac- CyPF-Ad in 4% yield (17.9 mg, orange solid). ¹ H NMR (400 MHz, CDCb) 6 4.44 (d, J= 3.1 Hz, 1 H), 4.21 (t, 7= 2.5 Hz, 1 H), 4.12 (m, 6H), 3.29 - 3.16 (m, 1 H), 2.34 (s, 2H), 2.17 - 1.93 (m, 22H), 1.88 (s, 6H), 1.71 (m, 21 H), 1.52 - 1.40 (m, 4H). ³¹ P NMR (162 MHz, Chloroform-o) d 46.22 (d, J= 12.1 Hz), -14.88 (br. s).

Example 7: Synthesis of rac- CyPF-morph

A B rac-CyPF-morph

In an inert-atmosphere glovebox, 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). ¹ H NMR (400 MHz, CDCb) 6 4.18 (t, J= 1.8 Hz, 2H), 4.12 (m, 7H), 3.71 - 3.61 (m, 4H), 3.36 (s, 2H), 2.41 (s, 4H).

In an inert atmosphere glovebox, a 50ml_ oven-dried round bottomed flask was charged with B (231 mg, 0.808mmol), a Teflon-coated stir bar, and 12ml_ of anhydrous diethylether. The result- ing solution was capped with a septum and /7-butyllithium (2.5M/pentane, 356pL, 0.889mmol) was added to the solution with stirring. The solution was left to stir for 7.5h. Chlorodicyclohex- ylphosphine (179pL, 0.808mmol) was then added to the reaction as a solution in 5 ml. of diethy- lether. The reaction was then stirred for 20h at 20-25°C, cooled in an ice/water cooling bath, and 3ml_ of saturated aq. NaHCOs was added. The resulting mixture was extracted twice with diethylether (20ml_). The organic fractions were combined, dried with MgS0 ₄ , concentrated via rotary evaporation, and the crude product was purified by automated column chromatography with a linear gradient of 0-100% EtOAc/hexanes to give rac- CyPF-morph in 12% yield (48.2 mg, red solid). ¹ H NMR (700 MHz, Chloroform-o) d 4.30 (s, 1 H), 4.27 (t, J= 2.4 Hz, 1 H), 4.12 (d, J= 2.0 Hz, 1 H), 4.10 (s, 5H), 3.84 (dd, J= 12.6, 2.6 Hz, 1 H), 3.71 - 3.58 (m, 4H), 3.04 (d, J= 12.6 Hz, 1 H), 2.52 (s, 2H), 2.40 (s, 2H), 2.04 - 1.85 (m, 5H), 1.82 - 1.61 (m, 6H), 1.51 - 1.09 (m,

1 1 H). ³¹ P NMR (162 MHz, CDCIs) d -16.13.

Comparative Examples

Comparative Example 1 :

Cat 1 (100 m)

1 10 °C, 24 h

0% Yield and Conversion

A 4 mL vial was charged with 1 ,4-dichlorobenzene (17.6 mg, 0.120 mmol), KOH (30.4 mg, 0.542 mmol), 5.00 pL of a stock solution of Chloro[2-(dicyclohexylphosphino)-3,6-dimethoxy- 2,4,6-triisopropyM ,1-biphenyl][2-(2-aminoethyl)phenyl]palladium(ll) (Cat. 1 , known as “Brettphos G1 palladacycle", 2.4 mM) in 1 ,4-dioxane, dodecane (15 pL), hydrazine monohy- drate (18.2 pL, 0.360 mmol), 1 ,4-dioxane (400 pL), and a Teflon-coated stir bar. The reaction was then warmed to 110°C for 24 h with stirring, and the yield was determined by GC. No prod- uct is obtained.

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:

A 4 mL vial was charged with 1 ,4-dichlorobenzene (7.4 mg, 0.050 mmol), NaO/Bu (5.8 mg, 0.0.060 mmol), Chloro[2-(dicyclohexylphosphino)-3,6-dimethoxy-2,4,6-triisop ropyl-1 ,1-biphe- nyl][2-(2-aminoethyl)phenyl]palladium(ll) (Cat. 1 , commonly referred to as“Brettphos G1 pal- ladacycle", 2.4 mM), trimethoxybenzene (8.4 mg, 0.050 mmol), THF (107 pL), anhydrous hydra- zine (1.0 M solution in THF, 60 pL), and a Teflon-coated stir bar. The reaction was then stirred at 20-25°C for 15 min. The reaction was diluted with THF (ca. 0.5 ml.) and the yield was deter- mined by ¹ H NMR spectroscopy.

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:

[Pd(cinnamyl)CI] ₂ (50 ppm)

MorDalPhos (160 ppm)

1 10 °C, 24 h

0% Yield and Conversion

A solution of [Pd(cinnamyl)CI]2 (1 .2 mM) and MorDalPhos (3.7 mM) was made in 1 ,4-dioxane. The contents of this mixture were stirred for 1 h to obtain a homogeneous solution, and the stirred solution was used for subsequent reactions.

A 4 mL vial was charged with 1 ,4-dichlorobenzene (17.6 mg, 0.120 mmol), KOH (30.4 mg, 0.542 mmol), 5.00 mI_ of a stock solution of [Pd(cinnamyl)CI]2 (1 .2 mM) and Di(1 -adamantyl)-2- morpholinophenylphosphine (“MorDalPhos”, 3.7 mM) in 1 ,4-dioxane, dodecane (15 mI_), 1 ,4- dioxane (400 mI_), hydrazine monohydrate (18.2 mI_, 0.360 mmol), and a Teflon-coated stir bar. The reaction was then warmed to 1 10°C for 24 h with stirring, and the yield was determined by GC. No product was obtained.

Comparative Example 3 shows that using the preferred ligand of D2, D3, and D5, but using only 0.01 mol% Pd, the reaction of hydrazine and 1 ,4-dichlorobenzene gives no product.

Comparative Example 4:

[Pd(cinnamyl)CI] ₂ (2.5 mol%

MorDalPhos (7.5 mol%)

NaOfBu (3.5 equiv)

N ₂ H ₄ .HCI

2 equiv Toluene

65 °C

25% Yield, 1 h

17% Yield, 2.5 h

A 4 mL vial was charged with 1 ,4-dichlorobenzene (17.7 mg, 0.120 mmol), NaO/Bu (40.4 mg, 0.421 mmol), [Pd(cinnamyl)CI]2 (1 .6 mg, 0.0030 mmol), and Di(1 -adamantyl)-2- morpholinophenylphosphine (“MorDalPhos”, 4.2 mg, 0.0090 mmol), dodecane (15 pL), hydrazi- ne hydrochloride (16.5 mg, 0.241 mmol), toluene (240 pl_), and a Teflon-coated stir bar. The reaction was then warmed to 65°C for 1 or 2.5 h with stirring, and the yield was determined by GC.

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.