WO2010112211A1

WO2010112211A1 - Method for arylating ring-substituted phenols and phenylethers

Info

Publication number: WO2010112211A1
Application number: PCT/EP2010/002057
Authority: WO
Inventors: Markus Heinrich; Alexander Wetzel
Original assignee: Technische Universität München
Priority date: 2009-03-31
Filing date: 2010-03-31
Publication date: 2010-10-07
Also published as: DE102009015697A1

Abstract

The present invention relates to a method for producing biphenyl compounds substituted in the ring. The method can be performed in a cost-effective manner and provides good regioselectivity. Functionalized biphenyl compounds are of great interest in particular as pharmaceuticals and plant protection agents and as precursors of such active substances. Said method for producing a compound of the formula (3) is characterized in that a compound of the formula (1) is reacted with a compound of the formula (2).

Description

Process for the arylation of ring-substituted phenols and phenyl ethers

The present invention relates to a process for the arylation of ring-substituted phenols and phenyl ethers.

A wide range of organometallic methods is available today for the mild and efficient synthesis of biaryl compounds.

For reviews on organometallic biarylsynthesis: M. Beller, C. BoIm, Transition Metals for Organic Synthesis, 2 ^nd Ed., Wiley-VCH, Weinheim, 2004; A. de Meijere, F. Diederich, Metal-Catalyzed Cross-Coupling Reactions, 2 ^nd Ed., Wiley-VCH, Weinheim, 2004.

Recent developments in biaryl synthesis: T. Dohi, M. Ito, K. Morimoto, M. Iwata, Y. Kita, Angew. Chem. 2008, 120, 1321-1324, Angew. Chem. Int. Ed. 2008, 47, 1301-1304; M. Amatore, C. Gosmini, Angew. Chem. 2008, 120, 2119-2122, Angew. Chem. Int. Ed. 2008, 47, 2089-2092; J. Gooßen, N. Rodriguez, K. Gooßen, Angew. Chem. 2008, 120, 3144-3164, Angew. Chem. Int. Ed. 2008, 47, 3100-3120.

Biaryl coupling via C-H activation: G. Dyker, Handbook of C-H Transformations, Wiley-VCH, Weinheim, 2005; L. Ackermann, Top. Organomet. Chem. 2007, 24, 35-60; T. Vogler, A. Studer, Org. Lett. 2008, 10, 129-131; L. Ackermann, R. Vicente, A. Althammer, Org. Lett. 2008, 10, 2299-2302.

However, organometallic methods also have some disadvantages. Thus, their attractiveness is diminished by high cost of the starting materials, especially in palladium-catalyzed reactions, lack of environmental compatibility, as in the case of nickel, and low maturity, especially in catalysis with cobalt and iron compounds. Compared to this variety of transformations, addition reactions of aryl radicals to aromatic substrates have rarely been used.

For a review on radical biaryl synthesis: A. Studer, M. Brossart in Radicals in Organic Synthesis, Eds. P. Renaud, MP Sibi, l ^st ed, Wiley-VCH, Weinheim, 2001, Vol 2, 62-80..; WR Bowman, JMD Storey, Chem. Soc. Rev. 2007, 36, 1803-1822; J. Fossey, D. Lefort, J. Sorba, Free Radicals in Organic Chemistry, Wiley, Chiester, 1995, 167-180

In particular, intramolecular radical biaryl couplings are complicated by the comparatively slow rates of addition of aryl radicals to common substrates such as substituted benzenes, which consequently promotes side reactions (JC Scaiano, LC Stewart, J. Am.Chem.Soc., 1983, 105, 3609-3614 ). Successful biaryl syntheses are therefore often bound to specific conditions using the substrate as a solvent (A. Nunez, A. Sanchez, C. Burgos, J. Alvarez-Builla, Tetrahedron 2004, 60, 6217-6224, PTF McLoughlin, MA Clyne , F. Aldabbagh, Tetrahedron 2004, 60, 8065-8071) or the reaction is carried out intramolecularly (ML Bennasar, T. Roca, F. Ferrando, Tetrahedron Lett. 2004, 45, 5605-5609).

Biaryl coupling reactions with aryl diazonium salts as radical precursors are described as Gomberg-Bachmann (Gomberg M., WE Bachmann, J. Am. Chem. Soc. 1924, 46, 2339-2343, JR Beadle, SH Korzeniowski, DE Rosenberg, BJ Garcia-Slanga, GW Gokel , J. Org. Chem. 1984, 49, 1594-1603) or Pschorr reactions (R. Pschorr, Chem. Ber. 1896, 29, 496-501).

In these cases, the difficulty is always that a reductant is needed to generate the aryl radicals (C. Galli, Chem. Rev. 1988, 88, 765-792), while oxidative conditions are required for the rearomatization of the cyclohexadienyl intermediate (DP Curran, AI Keller, J. Am. Chem. Soc., 2006, 128, 13706-13707).

Although individual examples of addition reactions of aryl radicals to phenols are known, this method of synthesizing biaryl compounds has hitherto gained no importance. PW Wojtkowski (EI Du Pont de Nemours and Company, Wilmington, US4960957, 1990) describes, for example, the reaction of the diazonium salt of aniline with hydroquinone to form biphenyl-2,5-diol. Petrillo reports several times on the radical arylation of phenates, but in this process arylazosulfides have to be used in place of the readily available diazonium salts (see G. Petrillo, M. Novi, C. Dell'Erba, C. Tavani, Tetrahedron 1991, 47, 9297-9304 and preliminary work cited therein). In addition, this reaction is limited in terms of Arylazosulfide or their substitution pattern.

The disadvantage of many known radical biaryl couplings is that they are less selective.

It is an object of the present invention to provide simple processes for the preparation of nucleus-substituted biphenyl compounds and derivatives thereof. These procedures should also be cost-effective and based on selective implementation. Functionalized biphenyl compounds are of great interest in particular as pharmaceuticals and crop protection agents and as precursors of such active substances.

The object is achieved by the method for the preparation of substituted biphenyls described in more detail below.

Embodiments of the invention are:

A process for the preparation of a compound of formula 3

characterized in that a compound of formula 1

with a compound of formula 2

is implemented, where

E is - [CR ^a R ^b ] _z - or NR ^a '; Q is - [CR ^c R ^d ] _v - or NR ^C ';

m is O, 1, 2, 3, 4 or 5; z is O, 1, 2, 3, 4 or 5; v is O, 1, 2, 3, 4 or 5; q is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; r is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; s is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

each R ¹ is independently halogen, alkyl, haloalkyl, hydroxyalkyl,

Alkoxy, haloalkoxy, alkylthio, cycloalkyl, haloalkylthio, alkenyl, alkynyl, nitro, cyano, -SO ₃ R ⁵ , -SO ₂ NH ₂ , -SO ₂ NHR ⁴ , -SO ₂ NR ⁴ R ⁵ , - COOR ⁴ , -CONHR ⁴ , -CONR ⁴ R ⁵ , -COR ⁴ , -OCOR ⁴ , -NR ⁴ COR ⁵ , - NR ⁴ SO ₂ R ⁵ , alkylcarbonyl, haloalkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, haloalkoxycarbonyl, alkenyloxycarbonyl,

Alkylsulfonyl, haloalkylsulfonyl, alkylimino, aryl, aryloxy, arylcarbonyl, arylalkyl, arylmethoxycarbonyl, arylalkylimino, or heteroaryl, wherein the aryl group optionally bears 1, 2, 3 or 4 substituents selected from halogen, alkyl, haloalkyl, alkoxy or haloalkoxy;

or two radicals R ¹ together form a cyclic group, for example of the formula -O- (CR ^u R ¹² ) _t -O-, where t is 1, 2 or 3, R ^{11 is} hydrogen, alkyl or haloalkyl, R ^{12 is} R ^{1 1} and R ¹² together form a non-aromatic ring system containing 5, 6 or 7 carbon atoms;

Each R ^a independently represents H, halo, -SR ⁴ , -OR ⁴ , -NR ⁴ R ⁵ , alkyl,

Haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkylthio, cycloalkyl, haloalkylthio, alkenyl, alkynyl, nitro, cyano, -SO ₃ R ^5, -SO ₂ NH _2, - SO ₂ NHR ^4, -SO ₂ NR ⁴ R ^5, -COOR ⁴ , -CONHR ⁴ , -CONR ⁴ R ⁵ , -COR ⁴ , -OCOR ⁴ , -NR ⁴ COR ⁵ , -NR ⁴ SO ₂ R ⁵ , -PO ₃ R ⁴ R ⁵ , alkylcarbonyl, haloalkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl,

Haloalkoxycarbonyl, alkenyloxycarbonyl, alkylsulfonyl,

Haloalkylsulfonyl, alkylimino, aryl, aryloxy, arylcarbonyl, arylalkyl, arylmethoxycarbonyl, arylalkylimino, or heteroaryl, wherein the aryl group optionally carries 1, 2, 3 or 4 substituents selected from halogen, alkyl, haloalkyl, alkoxy or haloalkoxy;

R ^{a> is} H, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, alkenyl, alkynyl, -

SO ₃ R ⁵ , -SO ₂ NH ₂ , -SO ₂ NHR ⁴ , -SO ₂ NR ⁴ R ⁵ , -COOR ⁴ , -CONHR ⁴ , - CONR ⁴ R ⁵ , -COR ⁴ , alkylcarbonyl, haloalkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl , Haloalkoxycarbonyl, alkenyloxycarbonyl, Alkylsulfonyl, haloalkylsulfonyl, aryl, arylcarbonyl, arylalkyl, arylmethoxycarbonyl, or heteroaryl, wherein the aryl group optionally carries 1, 2, 3 or 4 substituents selected from halogen, alkyl, haloalkyl, alkoxy or haloalkoxy;

R ^{b are} each independently H, halogen, -SR ⁴ , -OR ⁴ , -NR ⁴ R ⁵ , alkyl,

Haloalkoxycarbonyl, alkenyloxycarbonyl, alkylsulfonyl,

R ^{c are} each independently H, halo, -SR ⁴ , -OR ⁴ , -NR ⁴ R ⁵ , alkyl,

Haloalkoxycarbonyl, alkenyloxycarbonyl, alkylsulfonyl,

Haloalkylsulfonyl, alkylimino, aryl, aryloxy, arylcarbonyl, arylalkyl, arylmethoxycarbonyl, arylalkylimino, or heteroaryl, wherein the aryl group optionally carries 1, 2, 3 or 4 substituents selected from halogen, alkyl, haloalkyl, alkoxy or haloalkoxy; R ^c 'is H, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, alkenyl, alkynyl,

SO ₃ R ⁵ , -SO ₂ NH ₂ , -SO ₂ NHR ⁴ , -SO ₂ NR ⁴ R ⁵ , -COOR ⁴ , -CONHR ⁴ , - CONR ⁴ R ⁵ , -COR ⁴ , alkylcarbonyl, haloalkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl , Haloalkoxycarbonyl, alkenyloxycarbonyl,

Alkylsulfonyl, haloalkylsulfonyl, aryl, arylcarbonyl, arylalkyl, arylmethoxycarbonyl, or heteroaryl, wherein the aryl group optionally carries 1, 2, 3 or 4 substituents selected from halogen, alkyl, haloalkyl, alkoxy or haloalkoxy;

R ^{d are} each independently H, halogen, -SR ⁴ , -OR ⁴ , -NR ⁴ R ⁵ , alkyl,

Haloalkoxycarbonyl, alkenyloxycarbonyl, alkylsulfonyl,

R ^{e are} each independently H, halogen, -SR ⁴ , -OR ⁴ , -NR ⁴ R ⁵ , alkyl,

Haloalkoxycarbonyl, alkenyloxycarbonyl, alkylsulfonyl,

Haloalkylsulfonyl, alkylimino, aryl, aryloxy, arylcarbonyl, arylalkyl, arylmethoxycarbonyl, arylalkylimino, or heteroaryl, wherein the aryl group optionally carries 1, 2, 3 or 4 substituents, which are selected from halogen, alkyl, haloalkyl, alkoxy or haloalkoxy;

R ^{f are} each independently H, halogen, -SR ⁴ , -OR ⁴ , -NR ⁴ R ⁵ , alkyl,

Haloalkoxycarbonyl, alkenyloxycarbonyl, alkylsulfonyl,

R ^{g are} each independently H, halo, -SR ⁴ , -OR ⁴ , -NR ⁴ R ⁵ , alkyl,

Haloalkoxycarbonyl, alkenyloxycarbonyl, alkylsulfonyl,

D is hydroxy, -NR ⁴ R ⁵ , -NHCOR ⁴ , -NR ⁴ COR ⁵ , OR ⁶ , alkoxy, thioalkyl,

Cycloalkoxy, haloalkyloxy, alkylcarbonyloxy, haloalkylcarbonyloxy or aryloxy, where the aryl group is optionally 1, 2, 3, 4 or 5 carries substituents selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxy, or alkoxycarbonyl;

X ^" for halide, sulfate, tetrafluoroborate, acetate, trifluoroacetate,

Hexafluorophosphate, hexafluoroantimonate, the anion of an aromatic 1,2-dicarboxylic acid imide or the anion of an aromatic 1,2-disulfonic acid imide;

R ^{4 are} each independently hydrogen, alkyl, alkoxy, hydroxyalkyl,

Cycloalkyl, aryl, heteroaryl, fluorenylmethoxycarbonyl (Fmoc) or haloalkyl;

R ^{5 are} each independently hydrogen, alkyl, alkoxy, hydroxyalkyl,

Cycloalkyl, aryl, heteroaryl, fluorenylmethoxycarbonyl (Fmoc) or haloalkyl;

R ^{6 is} hydrogen, alkyl, hydroxyalkyl, cycloalkyl, alkylcarbonyl,

Haloalkylcarbonyl, aryl, heteroaryl or haloalkyl.

R ^{10 are} each independently hydrogen, alkyl, halogen, hydroxy, -NR ⁴ R ⁵ , -

NHCOR ⁴ , -NR ⁴ COR ⁵ , alkoxy, haloalkoxy, alkylcarbonyloxy, hydroxyalkyl, cycloalkyl, aryl, substituted aryl, heteroaryl or haloalkyl.

In particular a process for the preparation of compounds of structure 3 by reacting substituted aryl diazonium salts of structure 1 with compounds of structure 2.

The compounds of structure 3 can be used, for example, as intermediates for the preparation of biologically active compounds.

Specially substituted biphenyl alcohols and biphenyl ethers 4 can be prepared inexpensively by the process described herein. In contrast, organometallic cross-coupling reactions leading to similar compounds must be carried out with relatively difficult (non-commercially available) starting materials.

in which R ^{6 is} hydrogen, alkyl, hydroxyalkyl, cycloalkyl, alkylcarbonyl, haloalkylcarbonyl, aryl, heteroaryl or haloalkyl.

Examples of biologically active compounds which have biphenyl alcohols or biphenyl ethers 4 as structural element and which can therefore be made accessible by the process described here are contained in the following references:

Arylomycin A2

TC Roberts, PA Smith, RT Cirz, FE Romesberg, Structural and Initial Biological Analysis of Synthetic Arylomycin A ₂ , J. Am. Chem. Soc. 2007, 129, 15830-15838.

MG Kelly, S. Xu, N. Xi, P. Miller, JF Kincaid, C. Ghiron, T. Coulter, Vreparation of arylalkylamines as calcium receptor modulators for the treatment of hyperparathyroidism and osteoporosis, PCT Int. Appl. 2003, WO 2003099776, Chem. Abstr. 140: 4840th

V. E. Pombo, M. Koller, S. Ofher, R. Swoboda, Preparation of biphenyl derivatives for the treatment of epilepsy, stroke, and brain or spinal trauma, PCT Int. Appl. 1999, WO 9923073, Chem. Abstr. 130: 325,091th

H. Chaki, H. Kuroda, S. Makino, J. Nitta, K. Tanaka, T. Inaba, Preparation and formulation of alkylsulfonylbiphenyl and aminosulfonylbiphenyl derivatives as selective COX-2 inhibitors PCT Int. Appl. 1996, WO 9626921, Chem. Abstr. 125: 300,608th

Furthermore, a process for the synthesis of a compound of structure 6 is described, characterized in that in a first step a compound of formula 7 is reacted with a compound of formula 8 to give a compound of formula 5 and in a further step the compound of formula 5 in a compound of formula 6 is überfuhrt. The preparation of diversely functionalized dibenzofurans 6 was reported by Schimmelschmidt in JL Ann. Chem. 1950, 566, 184-204 and Kawaguchi et al. in J. Org. Chem. 2007, 72, 5119-5128.

X ¹ = Cl, Br, I

Here, m is 0, 1, 2, 3 or 4. All other radicals are as defined above.

Preferred reaction conditions for the conversion of the compound of formula 5 into a compound of formula 6 are heating in the presence of bases such as sodium hydroxide, sodium / tert-butoxide or sodium acetate, or palladium-catalyzed reactions in the presence of the above mentioned. Bases.

Furthermore, a process for the preparation of compounds of formula 10 is described, characterized in that a compound of formula 9 is reacted with a compound of formula 2,

10 where t is 1, 2 or 3; m is O, 1, 2 or 3;

R "is hydrogen, alkyl or haloalkyl;

R ^{12 is} hydrogen, alkyl, haloalkyl or

R ^{1 1} UnCl R ^{1 form} a non-aromatic ring system which is 5, 6 or 7

Contains carbon atoms.

Furthermore, a process for the preparation of compounds of formula 12 is described, characterized in that a compound of formula 11 is reacted with a compound of formula 8.

11 8

wherein all radicals are as defined above and m is 0, 1, 2, 3 or 4.

In the context of the present invention, the terms used generically have the following meanings:

The prefix C _x -C _y denotes the number of possible carbon atoms in each case.

The term "halogen" denotes in each case fluorine, bromine, chlorine or iodine, especially fluorine, chlorine or bromine, more preferably fluorine or chlorine.

The term "alkyl" denotes a linear or branched alkyl radical comprising 1 to 20 carbon atoms, such as methyl, ethyl, propyl, 1-methylethyl (isopropyl), butyl, 1-methylpropyl (sec-butyl), 2-methylpropyl (isobutyl), 1,1-dimethylethyl (tert-butyl), pentyl, hexyl, heptyl, octyl, 2-ethylhexyl, nonyl, decyl or 2-propylheptyl and positional isomers thereof, preferably methyl, ethyl or propyl.

The term "haloalkyl" as used herein and in the haloalkyl moieties of haloalkoxy describes straight or branched alkyl groups having from 1 to 10 carbon atoms, the hydrogen atoms of these groups being partially or fully replaced by halogen atoms. Examples are chloromethyl, bromomethyl, Dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, chlorofluoromethyl, dichlorofluoromethyl, chlorodifluoromethyl, 1-chloroethyl, 1-bromoethyl, 1-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-chloroethyl 2-fluoroethyl, 2-chloro-2,2-difluoroethyl, 2,2-dichloro-2-fluoroethyl, 2,2,2-trichloroethyl, pentafluoroethyl, 3,3,3-trifluoroprop-1-yl, 1, l, l Trifluoroprop-2-yl, 3,3,3-trichloroprop-1-yl, heptafluoroisopropyl, 1-chlorobutyl, 2-chlorobutyl, 3-chlorobutyl, 4-chlorobutyl, 1-fluorobutyl, 2-fluorobutyl, 3-fluorobutyl, 4 Fluorobutyl and the like, preferably fluoromethyl, 2-fluoroethyl, or trifluoromethyl.

The term "alkenyl" denotes a monounsaturated, linear or branched aliphatic radical having 3 or 8 carbon atoms. Examples of these are propen-1-yl, propen-2-yl (allyl), but-1-en-1-yl, but-1-en-2-yl, but-1-en-3-yl, butanol. 1-en-4-yl, but-2-en-1-yl, but-2-en-2-yl, but-2-en-4-yl, 2-methylprop-1-en-1-yl, 2-methylprop-2-en-1-yl and the like, preferably propenyl or but-1-en-4-yl.

The term "cycloalkyl" denotes a saturated alicyclic radical having 3 to 10 carbon atoms as ring members. Examples are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl and cyclodecyl. The cycloalkyl radicals may carry 1, 2 or 3 substituents which are selected from alkyl, alkoxy or halogen, preferably cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

The term "alkoxy" denotes straight-chain or branched saturated alkyl groups comprising 1 to 10 carbon atoms which are bonded via an oxygen atom, the alkyl radical optionally carrying 1, 2 or 3 substituents which are selected from halogen, alkyl, haloalkyl, cycloalkyl, alkoxy , Haloalkoxy. Examples of alkoxy are methoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy), n-butoxy, 1-methylpropoxy (sec-butoxy), 2-methylpropoxy (isobutoxy) and 1,1-dimethylethoxy (tert-butoxy), preferably methoxy, ethoxy, n-propoxy, or -OCH ₂ -cyc / o-pentyl.

The term "haloalkoxy" describes straight-chain or branched saturated haloalkyl groups comprising 1 to 10 carbon atoms which are bonded via an oxygen atom. Examples of these are chloromethoxy, bromomethoxy, dichloromethoxy, Trichloromethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chlorofluoromethoxy, dichlorofluoromethoxy, chlorodifluoromethoxy, 1-chloroethoxy, 1-bromoethoxy,

1-fluoroethoxy, 2-fluoroethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, 2-chloro-2-fluoroethoxy, 2-chloro-2,2-difluoroethoxy, 2,2-dichloro-2-fluoroethoxy, 2,2,2-trichloroethoxy, 1,1,2,2-tetrafluoroethoxy, 1-chloro-1,2,2-trifluoroethoxy, pentafluoroethoxy, 3,3,3-trifluoroprop-1-oxy, 1, l, l Trifluoroprop-2-oxy, 3,3,3-trichloroprop-1-oxy, 1-chlorobutoxy, 2-chlorobutoxy, 3-chlorobutoxy, 4-chlorobutoxy, 1-fluorobutoxy, 2-fluorobutoxy, 3-fluorobutoxy, 4-fluorobutoxy, and the like, preferred are fluoromethoxy, difluoromethoxy or trifluoromethoxy.

The term "cycloalkoxy" refers to a saturated alicyclic radical having 3 to 10 carbon atoms as ring members bonded through an oxygen atom. Examples are cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, cyclooctyloxy, cyclononyloxy and cyclodecyloxy. The cycloalkyl radicals may carry 1, 2 or 3 substituents selected from alkyl and halogen. Preferred cycloalkoxy radicals are cyclopropyloxy, cyclobutyloxy, cyclopentyloxy or cyclohexyloxy.

The term "alkylcarbonyl" denotes alkyl radicals having from 1 to 10 carbon atoms bonded via a carbonyl group,. Examples of these are methylcarbonyl (acetyl), ethylcarbonyl, propylcarbonyl, isopropylcarbonyl, n-butylcarbonyl, sec-butylcarbonyl, isobutylcarbonyl and tert-butylcarbonyl, preferably methylcarbonyl or ethylcarbonyl.

The term "haloalkylcarbonyl" denotes haloalkyl radicals having 1 to 10 carbon atoms attached via a carbonyl group. Examples thereof are fluoromethylcarbonyl, difluoromethylcarbonyl, trifluoromethylcarbonyl, 1-fluoroethylcarbonyl, 2-fluoroethylcarbonyl, 1,1-difluoroethylcarbonyl, 2,2-difluoroethylcarbonyl, 2,2,2-trifluoroethylcarbonyl, pentafluoroethylcarbonyl and the like, preferred are fluoromethylcarbonyl, difluoromethylcarbonyl or trifluoromethylcarbonyl ,

The term "alkylcarbonyloxy" refers to alkyl radicals having from 1 to 10 carbon atoms attached via a carbonyloxy group, examples being methylcarbonyloxy (acetoxy), ethylcarbonyloxy, propylcarbonyloxy and isopropylcarbonyloxy, preferably methylcarbonyloxy or ethylcarbonyloxy. The term "haloalkylcarbonyloxy" denotes haloalkyl radicals having 1 to 10 carbon atoms attached via a carbonyloxy group, examples of which are fluoromethylcarbonyloxy, difluoromethylcarbonyloxy, trifluoromethylcarbonyloxy, 1-fluoroethylcarbonyloxy, 2-fluoroethylcarbonyloxy, 1,1-difluoroethylcarbonyloxy, 2,2-difluoroethylcarbonyloxy, 2,2, 2-trifluoroethylcarbonyloxy, pentafluoroethylcarbonyloxy and the like, preferred are fluoromethylcarbonyloxy, difluoromethylcarbonyloxy or trifluoromethylcarbonyloxy.

The term "alkenylcarbonyl" refers to alkenyl radicals having 3 or 6 carbon atoms attached via a carbonyl group. Examples of these are propen-1-ylcarbonyl, propen-2-ylcarbonyl (allylcarbonyl), but-1-en-1-ylcarbonyl, but-1-en-2-ylcarbonyl, but-1-en-3-ylcarbonyl, butylene 1-en-4-ylcarbonyl, but-2-en-1-ylcarbonyl, but-2-en-2-ylcarbonyl, but-2-en-4-ylcarbonyl, 2-methylprop-1-en-1-ylcarbonyl, 2-methylprop-2-en-1-ylcarbonyl and the like, propene-1-ylcarbonyl, propen-2-ylcarbonyl or but-l-en-4-ylcarbonyl are preferred.

The term "alkoxycarbonyl" denotes alkoxy radicals having 1 to 10 carbon atoms bonded via a carbonyl group, the alkyl radical optionally carrying 1, 2 or 3 substituents selected from halogen, alkyl, haloalkyl, cycloalkyl, alkoxy, haloalkoxy. Examples of these are methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, sec-butoxycarbonyl, isobutoxycarbonyl and tert-butoxycarbonyl, preferably methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl or isopropoxycarbonyl.

The term "haloalkoxycarbonyl" denotes haloalkoxy radicals having 1 to 10 carbon atoms attached via a carbonyl group. Examples thereof are fluoromethoxycarbonyl, difluoromethoxycarbonyl, trifluoromethoxycarbonyl, 1-fluoroethoxycarbonyl, 2-fluoroethoxycarbonyl, 1,1-difluoroethoxycarbonyl, 2,2-difluoroethoxycarbonyl, 2,2,2-trifluoroethoxycarbonyl, pentafluoroethoxycarbonyl and the like, preferred are fluoromethoxycarbonyl, difluoromethoxycarbonyl or trifluoromethoxycarbonyl , The term "alkenyloxycarbonyl" refers to alkenyloxy radicals having 3 or 8 carbon atoms attached via a carbonyl group. Examples of these are allyloxycarbonyl and methallyloxycarbonyl, preferably allyloxycarbonyl.

The term "alkylsulfonyl" refers to a sulfonyl group (SO ₂ ) bonded alkyl radicals having 1 to 10 carbon atoms, wherein the alkyl radical optionally 1, 2 or 3 substituents selected from halogen, alkyl, haloalkyl, cycloalkyl, alkoxy, haloalkoxy. Examples thereof are methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, n-butylsulfonyl, sec-butylsulfonyl, isobutylsulfonyl and tert-butylsulfonyl, preferably methylsulfonyl, ethylsulfonyl, propylsulfonyl or isopropylsulfonyl.

The term "haloalkylsulfonyl" refers to a sulfonyl group (SO ₂ ) bonded haloalkyl having 1 to 10 carbon atoms. Examples thereof are fluoromethylsulfonyl, difluoromethylsulfonyl, trifluoromethylsulfonyl, 1-fluoroethylsulfonyl, 2-fluoroethylsulfonyl, 1,1-difluoroethylsulfonyl, 2,2-difluoroethylsulfonyl, 2,2,2-trifluoroethylsulfonyl, pentafluoroethylsulfonyl and the like, preferably fluoromethylsulfonyl, difluoromethylsulfonyl or trifluoromethylsulfonyl.

The term "aryl" refers to carbocyclic aromatic radicals having 6 to 14 carbon atoms. Examples include phenyl, naphthyl, fluorenyl, azulenyl, anthracenyl and phenanthrenyl. Aryl is preferably phenyl or naphthyl and in particular phenyl.

The term "heteroaryl" denotes aromatic radicals having 1 to 4 heteroatoms selected from O, N, S and SO ₂ . Examples of these are 5- and 6-membered heteroaryl radicals having 1, 2, 3 or 4 heteroatoms selected from O, N, S and SO ₂ such as pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, Tetrazolyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidyl or triazinyl.

The term "arylcarbonyl" denotes aryl radicals which are bonded via a carbonyl group. Examples of these are phenylcarbonyl, 4-nitrophenylcarbonyl, 2- Methoxyphenylcarbonyl, 4-chlorophenylcarbonyl, 2,4-dichlorophenylcarbonyl, 4-nitrophenylcarbonyl or naphthylcarbonyl, preferably phenylcarbonyl.

The term "arylalkyl" denotes aryl radicals which are bonded via an alkyl group, the alkyl radical optionally bearing 1, 2 or 3 substituents which are selected from halogen, alkyl, haloalkyl, cycloalkyl, alkoxy, haloalkoxy. Examples of these are benzyl, 2-phenylethyl (phenethyl) and the like, preferably phenethyl.

The term "arylmethoxycarbonyl" refers to arylmethoxy radicals which are bonded via a carbonyl group. Examples of these are benzyloxycarbonyl or fluorenylmethoxycarbonyl.

The term "alkylimino" refers to a radical of the formula -N = R which is bonded via the nitrogen, wherein R is alkylene, such as = CH ₂ , = CHCH ₃ , = CHCH ₂ CH ₃ , = C (CH ₃ ) ₂ , ^ CHCH ₂ CH ₂ CH ₃ , = C (CH ₃ ) CH ₂ CH ₃ or = CHCH (CH ₃ ) ₂ .

The term "arylalkylimino" refers to a radical of the formula -N = R which is bonded via the nitrogen, where R is aryl-alkylene, such as benzylidene (R = CH-phenyl).

The term "hydroxyalkyl" refers to an -OR ⁴ radical attached via an alkyl group, wherein R ^{4 is} as defined above, preferably -CH ₂ OH, - (CH ₂ ) ₂ OH or - (CH ₂ ) ₃ OH.

The term "alkylthio" or "thioalkyl" denotes straight-chain or branched saturated alkyl groups comprising 1 to 10 carbon atoms which are bonded via a sulfur atom, the alkyl radical optionally carrying 1, 2 or 3 substituents which are selected from halogen, alkyl, haloalkyl , Cycloalkyl, alkoxy, haloalkoxy.

The term "haloalkylthio" describes straight-chain or branched saturated haloalkyl groups comprising 1 to 10 carbon atoms which are bonded via a sulfur atom. The term "aryloxy" denotes carbocyclic aromatic radicals having 6 to 14 carbon atoms which are bonded via an oxygen atom.

The term "cyclic group" refers to a saturated or unsaturated (e.g., aromatic) cyclic group having from 3 to 10 ring atoms selected from O, S, N and carbon atoms, preferably having 5, 6 or 7 ring atoms.

The term "alkynyl" refers to a linear or branched aliphatic radical having 2 or 3 to 8 carbon atoms and at least one triple bond.

Examples of the anion of an aromatic 1,2-dicarboxylic acid imide and the anion of an aromatic 1,2-disulfonic acid imide are:

Anion of an aromatic anion of an aromatic

1, 2-Dicarbonsäureimids 1, 2-Disulfonsäureimids

The term "substituted aryl" refers to an aryl substituted by one or more (eg 1, 2, 3, 4 or 5) of the following radicals: halo, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkylthio, cycloalkyl, haloalkylthio , Alkenyl, alkynyl, nitro, cyano, -SO ₃ R ⁵ , -SO ₂ NH ₂ , -SO ₂ NHR ⁴ , -SO ₂ NR ⁴ R ⁵ , -COOR ⁴ , -CONHR ⁴ , -CONR ⁴ R ⁵ , COR ⁴ , -OCOR ⁴ , -NR ⁴ COR ⁵ , -NR ⁴ SO ₂ R ⁵ , alkylcarbonyl, haloalkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, haloalkoxycarbonyl, alkenyloxycarbonyl, alkylsulfonyl, haloalkylsulfonyl, alkylimino, aryl, aryloxy, arylcarbonyl, arylalkyl, arylmethoxycarbonyl , Arylalkylimino, or heteroaryl, said aryl optionally carrying 1, 2, 3 or 4 substituents selected from halogen, alkyl, haloalkyl, alkoxy or haloalkoxy Alternatively or additionally, two radicals together may form a cyclic group substituted aryl group is a group of the formula:

where R ¹ and m are as defined above. The comments made below on preferred embodiments of the inventive method, in particular preferred embodiments of the residues of the various starting materials and products and the reaction conditions of the inventive method, both alone and in particular in any conceivable combination with each other.

The reactions described herein are carried out in reaction vessels customary for such reactions, it being possible for the reaction procedure to be carried out both continuously, semicontinuously and discontinuously. As a rule, the respective reactions will be carried out under atmospheric pressure. However, the reactions may also be carried out under reduced (e.g., 0.1 to 1.0 bar) or elevated pressure (eg, 1.0 to 10 bar).

In particular, it is preferable to combine the preferred embodiments in any combination with each other.

In the context of the present invention, m is preferably 1, 2, 3 or 5, in particular 1, 2 or 5. When m is 1, R ^{1 is} preferably in para or meta position to the diazonium substituent.

In the context of the present invention, z is preferably 0, 1, 2 or 3, in particular 0 or 1.

In the context of the present invention, v is preferably 0, 1, 2 or 3, in particular 0 or 1.

More preferably z is 0 or 1 and v is 0 or 1.

In the context of the present invention, q is preferably 0, 1, 2, 3, 4, 5 or 6, in particular 0, 1, 2, 3 or 4. More preferably, q is 0 or 1. In the context of the present invention, r is preferably 0, 1, 2, 3, 4, 5 or 6, in particular 0, 1, 2, 3 or 4. More preferably, r is 0 or 1.

In the context of the present invention, s is preferably 0, 1, 2, 3, 4, 5 or 6, in particular 0, 1, 2, 3 or 4. Particularly preferably s is 0 or 1.

The sum of q + z + r + v + s is particularly preferably 0, 1 or 2 (in particular 0 or 1) and the radicals R ^a , R ^b , R ^c and R ^d are H.

In the context of the present invention, R ^{1 is} preferably halogen, alkyl, hydroxyalkyl, haloalkyl, alkoxy, haloalkoxy, nitro, cyano or optionally with 1 to 5 substituents which are selected from halogen, alkyl or alkoxy-substituted aryloxy. More preferably, R ^{1 is} halo, alkoxy, haloalkoxy or aryloxy optionally substituted with halo, alkyl or alkoxy and more preferably chloro, bromo, fluoro, alkoxy or phenoxy. In particular, R ^{1 is} 2-Me, 3-Me, 4-Me, 2-F, 3-F, 4-F, 2-Cl, 3-Cl, 4-Cl, 2-Br, 3-Br, 4 -Br, 2-methoxy, 3-methoxy, 4-methoxy, 2-CF ₃ , 3-CF ₃ , 4-CF ₄ , 2-OCF ₃ , 3-OCF ₃ , or 4-OCF ₃ . The position information refers to the 1-position, via which the derived from the compound of formula 1, or of formula 7, or of formula 9, or the formula 11 aryl radical to the benzene ring of the compound of formula 2, or of the formula 8 or to the 1-position of the diazonium radical in the compound of the formula 1, or of the formula 7, or of the formula 9, or of the formula 11.

In the context of the present invention, X preferably represents a halide, such as chloride, bromide, iodide, BF ₄ ^" , PF ₆ ^" , sulfate ( ¹ A SO ₄ ^{2 "} ), acetate, the anion of an aromatic 1,2-dicarboximide or Anion of an aromatic 1,2-disulfonimide The anion is formed in the latter two cases by abstraction of the proton on the imide nitrogen atom. X is particularly preferably a halide, such as chloride, bromide, BF ₄ ^" or sulfate ( ¹ A SO ₄ ^{2 "} ).

In the context of the present invention, R ^{4 is} preferably hydrogen, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, or aryl, optionally with 1 to 5 substituents, which are selected from halogen, alkyl or alkoxy-substituted aryl. In the context of the present invention, R ^{5 is} preferably hydrogen, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, or aryl, optionally with 1 to 5 substituents, which are selected from halogen, alkyl or alkoxy-substituted aryl.

In the context of the present invention, R ^{6 is} preferably hydrogen, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, or aryl, optionally with 1 to 5 substituents, which are selected from halogen, alkyl or alkoxy-substituted aryl.

In the context of the present invention, R ¹⁰ preferably represents hydrogen, halogen, alkyl, haloalkyl, hydroxy, -NR ⁴ R ⁵ , -NHCOR ⁴ , -NR ⁴ COR ⁵ , alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, or aryl, optionally with 1 to 5 substituents which are selected from halogen, alkyl or alkoxy-substituted aryl, particularly preferably hydrogen, halogen or alkyl.

In the context of the present invention, D is preferably hydroxyl, -NR ⁴ R ⁵ , -NHCOR ⁴ , -NR ⁴ COR ⁵ , alkoxy, haloalkoxy, cycloalkoxy, alkylcarbonyloxy, haloalkylcarbonyloxy or aryloxy. Particularly preferred for D are: -OH, -OMe, -OCH ₂ F, -OCHF ₂ , -OCF ₃ , -OCF ₂ Cl, -OEt, -OCF ₂ CHClF, -OCF ₂ CHF ₂ , -O (CH ₂ ) ₂ C1, -OCH ₂ CF _3, -OCF ₂ CF _3, -O (CH ₂₎ ₂ CH _3, - OCH (CF ₃₎ _2, -O (CH ₂₎ ₂ OMe, -OCHMe _2, -O (CH ₂₎ ₂ CN, -O (CH ₂₎ ₃ CH _3, -OCMe _3, -OCH (Me) Et, -OCH ₂ CH Me _2, -O (CH ₂₎ ₂ OEt, -OCH (Me) CH ₂ OMe, -O (CH ₂ ) ₄ CH ₃ , -O (CH ₂ ) ₂ CHMe ₂ , - OCHEt ₂ , -OCH ₂ CMe ₃ , -O (CH ₂ ) ₂ O (CH ₂ ) ₂ Me, -O (CH ₂ ) ₂ O (CH ₂ ) ₂ OMe, -O (CH ₂ ) ₅ Me, - O (CH ₂ ) ₆ Me, -OCH (Me) (CH ₂ ) ₄ Me, -O (CH ₂ ) ₇ Me, - O (CH ₂₎ ₈ Me, -O (CH ₂₎ ₉ Me, -0 (CH ₂₎ n Me, -O (CH ₂₎ ₁₃ Me, -O (CH ₂₎ ₁₅ Me, -O (CH ₂₎ ₁₇ me,

In the context of the present invention, R ^{a is} preferably H, halogen, alkyl, Hydroxyalkyl, haloalkyl, alkoxy, haloalkoxy, nitro, cyano, CO ₂ R ⁴ , NR ⁴ R ⁵ , SO ₃ R ⁵ , SO ₂ NR ⁴ R ⁵ , CONR ⁴ R ⁵ , COR ⁴ , NR ⁴ SO ₂ R ⁵ , OCOR ⁴ , NR ⁴ COR ⁵ , OH or PO ₃ R ⁴ R ⁵ . More preferably, R ^{a is} H, hydroxyalkyl, alkoxy, nitro, cyano, CO ₂ R ⁴ , NR ⁴ R ⁵ , SO ₃ R ⁵ , SO ₂ NR ⁴ R ⁵ , CONR ⁴ R ⁵ , COR ⁴ , NR ⁴ SO ₂ R ⁵ , OCOR ⁴ , NR ⁴ COR ⁵ , OH or PO ₃ R ⁴ R ⁵ . In particular, R ^{a is} H, cyano, CO ₂ R ⁴ , NR ⁴ R ⁵ , CO ₂ Me, CO ₂ H, NH ₂ or OH.

In the context of the present invention, R ^{a is} preferably H, alkyl, hydroxyalkyl, haloalkyl, CO ₂ R ⁴ , SO ₃ R ⁵ , SO ₂ NR ⁴ R ⁵ , CONR ⁴ R ⁵ or COR ⁴ . R ^{a 'is} particularly preferably H, hydroxyalkyl, CO ₂ R ⁴ , SO ₃ R ⁵ , SO ₂ NR ⁴ R ⁵ , CONR ⁴ R ⁵ or COR ⁴ . In particular, R ^{a 'is} H, CO ₂ R ⁴ , CO ₂ Me or CO ₂ H.

In the context of the present invention, R ^{b is} preferably H, halogen, alkyl, hydroxyalkyl, haloalkyl, alkoxy, haloalkoxy, nitro, cyano, CO ₂ R ⁴ , NR ⁴ R ⁵ , SO ₃ R ⁵ , SO ₂ NR ⁴ R ⁵ , CONR ⁴ R ⁵ , COR ⁴ , NR ⁴ SO ₂ R ⁵ , OCOR ⁴ , NR ⁴ COR ⁵ , OH or PO ₃ R ⁴ R ⁵ . R ^b particularly preferably represents H, hydroxyalkyl, alkoxy, nitro, cyano, CO ₂ R ⁴ , NR ⁴ R ⁵ , SO ₃ R ⁵ , SO ₂ NR ⁴ R ⁵ , CONR ⁴ R ⁵ , COR ⁴ , NR ⁴ SO ₂ R ⁵ , OCOR ⁴ , NR ⁴ COR ⁵ , OH or PO ₃ R ⁴ R ⁵ . In particular, R ^{b is} H, cyano, CO ₂ R ⁴ , NR ⁴ R ⁵ , CO ₂ Me, CO ₂ H, NH ₂ or OH.

In the context of the present invention, R ^{c is} preferably H, halogen, alkyl, hydroxyalkyl, haloalkyl, alkoxy, haloalkoxy, nitro, cyano, CO ₂ R ⁴ , NR ⁴ R ⁵ , SO ₃ R ⁵ , SO ₂ NR ⁴ R ⁵ , CONR ⁴ R ⁵ , COR ⁴ , NR ⁴ SO ₂ R ⁵ , OCOR ⁴ , NR ⁴ COR ⁵ , OH or PO ₃ R ⁴ R ⁵ . Particularly preferably, R ^{c is} H, hydroxyalkyl, alkoxy, nitro, cyano, CO ₂ R ⁴ , NR ⁴ R ⁵ , SO ₃ R ⁵ , SO ₂ NR ⁴ R ⁵ , CONR ⁴ R ⁵ , COR ⁴ , NR ⁴ SO ₂ R ⁵ , OCOR ⁴ , NR ⁴ COR ⁵ , OH or PO ₃ R ⁴ R ⁵ . In particular, R ^{c is} H, cyano, CO ₂ R ⁴ , NR ⁴ R ⁵ , CO ₂ Me, CO ₂ H, NH ₂ or OH.

In the context of the present invention, R ^{c is} preferably H, alkyl, hydroxyalkyl, haloalkyl, CO ₂ R ⁴ , SO ₃ R ⁵ , SO ₂ NR ⁴ R ⁵ , CONR ⁴ R ⁵ or COR ⁴ . Particularly preferably, R ^{c 'is} H, hydroxyalkyl, CO ₂ R ⁴ , SO ₃ R ⁵ , SO ₂ NR ⁴ R ⁵ , CONR ⁴ R ⁵ or COR ⁴ . In particular, R ^{c 'is} H, CO ₂ R ⁴ , CO ₂ Me or CO ₂ H.

In the context of the present invention R ^{d is} preferably H, halogen, alkyl, hydroxyalkyl, haloalkyl, alkoxy, haloalkoxy, nitro, cyano, CO ₂ R ⁴ , NR ⁴ R ⁵ , SO ₃ R ⁵ , SO ₂ NR ⁴ R ⁵ , CONR ⁴ R ⁵ , COR ⁴ , NR ⁴ SO ₂ R ⁵ , OCOR ⁴ , NR ⁴ COR ⁵ , OH or PO ₃ R ⁴ R ⁵ . R ^{d is} particularly preferably H, hydroxyalkyl, alkoxy, nitro, cyano, CO ₂ R ⁴ , NR ⁴ R ⁵ , SO ₃ R ⁵ , SO ₂ NR ⁴ R ⁵ , CONR ⁴ R ⁵ , COR ⁴ , NR ⁴ SO ₂ R ⁵ , OCOR ⁴ , NR ⁴ COR ⁵ , OH or PO ₃ R ⁴ R ⁵ . In particular, R ^{d is} H, cyano, CO ₂ R ⁴ , NR ⁴ R ⁵ , CO ₂ Me, CO ₂ H, NH ₂ or OH.

In the context of the present invention, R ^{e is} preferably H, halogen, alkyl, hydroxyalkyl, haloalkyl, alkoxy, haloalkoxy, nitro, cyano, CO ₂ R ⁴ , NR ⁴ R ⁵ , SO ₃ R ⁵ , SO ₂ NR ⁴ R ⁵ , CONR ⁴ R ⁵ , COR ⁴ , NR ⁴ SO ₂ R ⁵ , OCOR ⁴ , NR ⁴ COR ⁵ , OH or PO ₃ R ⁴ R ⁵ . R ^e particularly preferably represents H, hydroxyalkyl, alkoxy, nitro, cyano, CO ₂ R ⁴ , NR ⁴ R ⁵ , SO ₃ R ⁵ , SO ₂ NR ⁴ R ⁵ , CONR ⁴ R ⁵ , COR ⁴ , NR ⁴ SO ₂ R ⁵ , OCOR ⁴ , NR ⁴ COR ⁵ , OH or PO ₃ R ⁴ R ⁵ . In particular, R ^{e is} H, cyano, CO ₂ R ⁴ , NR ⁴ R ⁵ , CO ₂ Me, CO ₂ H, NH ₂ or OH.

In the context of the present invention, R ^{f is} preferably H, halogen, alkyl, hydroxyalkyl, haloalkyl, alkoxy, haloalkoxy, nitro, cyano, CO ₂ R ⁴ , NR ⁴ R ⁵ , SO ₃ R ⁵ , SO ₂ NR ⁴ R ⁵ , CONR ⁴ R ⁵ , COR ⁴ , NR ⁴ SO ₂ R ⁵ , OCOR ⁴ , NR ⁴ COR ⁵ , OH or PO ₃ R ⁴ R ⁵ . More preferably, R ^{f is} H, hydroxyalkyl, alkoxy, nitro, cyano, CO ₂ R ⁴ , NR ⁴ R ⁵ , SO ₃ R ⁵ , SO ₂ NR ⁴ R ⁵ , CONR ⁴ R ⁵ , COR ⁴ , NR ⁴ SO ₂ R ⁵ , OCOR ⁴ , NR ⁴ COR ⁵ , OH or PO ₃ R ⁴ R ⁵ . In particular, R ^{f is} H, cyano, CO ₂ R ⁴ , NR ⁴ R ⁵ , CO ₂ Me, CO ₂ H, NH ₂ or OH.

In the context of the present invention, R ^{g is} preferably H, halogen, alkyl, hydroxyalkyl, haloalkyl, alkoxy, haloalkoxy, nitro, cyano, CO ₂ R ⁴ , NR ⁴ R ⁵ , SO ₃ R ⁵ , SO ₂ NR ⁴ R ⁵ , CONR ⁴ R ⁵ , COR ⁴ , NR ⁴ SO ₂ R ⁵ , OCOR ⁴ , NR ⁴ COR ⁵ , OH or PO ₃ R ⁴ R ⁵ . Particularly preferably, R ^{g is} H, hydroxyalkyl, alkoxy, nitro, cyano, CO ₂ R ⁴ , NR ⁴ R ⁵ , SO ₃ R ⁵ , SO ₂ NR ⁴ R ⁵ , CONR ⁴ R ⁵ , COR ⁴ , NR ⁴ SO ₂ R ⁵ , OCOR ⁴ , NR ⁴ COR ⁵ , OH or PO ₃ R ⁴ R ⁵ . In particular, R ^{8 is} H, cyano, CO ₂ R ⁴ , NR ⁴ R ⁵ , CO ₂ Me, CO ₂ H, NH ₂ or OH.

Most preferably, E is - [CR ^a R ^b ] _z - and Q is - [CR ^c R ^d ] _v -. Furthermore, E is preferably NR ^a> and Q is NR ^{0 '} . Again preferably E is - [CR ^a R ^b ] _z - and Q is NR ^C> Furthermore, E is preferably NR ^{a '} and Q is - [CR ^c R ^d ] _v -.

Furthermore, E is preferably - [CR ^a R ^D ] _z -, Q is - [CR ^c R ^α ] _v -, R ^a , R ^b , R ^c and R ^{d are} H, R ^e for H or COOR ⁴ , R ^f for H or COOR ⁴ , R ⁸ for NHR ⁵ and the sum of q + z + r + v + s for O 1 or 2 (in particular O or 1), where at least one of the radicals R ^e and R ^{f is} H. D is preferably -OMe or -OH.

The synthesis of compounds of the formula 3 in which R ^{1 is} a group of the formula:

is still preferred. These compounds may be prepared, for example, from a compound of formula 2 wherein R ^{10 is} H by reaction with a compound of formula 1, for example by a double arylation. If this double arylation is carried out sequentially, it is possible to provide different radicals R ¹ to the respective phenyl radicals of the compound of formula 3.

The term "reducing agent" refers to those elements and compounds which, as electron donors [also electron-donor complexes], tend to change to a lower-energy state by the release of electrons, in particular with the formation of stable electron shells, which is a measure of the strength of a reducing agent Examples of reducing agents are inorganic salts, metals, metal salts or reducing organic compounds.

If the reaction is carried out in the presence of a reducing agent, the reaction is preferably carried out in such a way that the compound of the formula 2 or of the formula 8 and the reducing agent are dissolved or dispersed, preferably in a solvent, and charged with the compound of the formula 1 or the formula 7, or the formula 9, or the formula 11 are successively offset. With regard to rate of addition, reaction temperature and solvent, reference is made to the following statements.

The reducing agent is preferably selected from reducing metal salts, metals and / or reducing anions; However, other reducing agents are also suitable whose reduction potential is sufficiently high to apply to the particular compound of formula 1 or formula 7 or formula 9 or formula 11 to transfer an electron. These include compounds as diverse as pyrene, ascorbic acid and hemoglobin. However, the use of reducing metals, metal salts and / or reducing anions is preferred.

In the context of the present invention, any reducing metal salts can be used as long as their reduction potential is sufficiently high to transfer an electron to the respectively used compound of formula 1, or of formula 7 or of formula 9, or of formula 11 ,

In the context of the present invention, reducing metal salts are understood as meaning those in which the most stable oxidation number of the metal is higher under the reaction conditions than in the employed form, so that the metal salt acts as a reducing agent.

Preferred metal salts are soluble in the reaction medium. Since the reaction medium is preferably aqueous, preferred metal reducing salts are accordingly water-soluble. Preferred counteranions of the metal salts are common water-soluble anions such as the halides, especially chloride, sulfate, nitrate, acetate and the like.

However, metal complexes such as hexacyanoferrate (II) or ferrocene are also suitable.

Particularly preferred reducing metal salts are selected from Ti (II) salts, Cu (I) salts, Fe (II) salts, tin (II) salts, chromium (IΙ) salts and vanadium (II) salts, and especially among Ti (! H) salts, Cu (I) salts and Fe (II) salts. Preferred among these are their water-soluble salts, such as the chlorides, sulfates, nitrates, acetates and the like. In particular, one uses Ti (iπ) salts and especially TiCl ₃ .

Preferred reducing metals are selected from iron, copper, cobalt, nickel, zinc, magnesium, titanium and chromium, more preferably iron and copper.

Preferably, the reducing metal salt (s) is employed in a total amount of from 0.005 to 8 moles, more preferably from 0.1 to 3 moles, more preferably from 0.1 to 1 mole, even more preferably from 0, From 25 to 1 mole and especially from 0.25 to 0.5 mole, based on 1 mol of the compound of formula 1, or of formula 7 or of formula 9 or of formula 11.

When the reaction is carried out in degassed (ie deoxygenated) solvents and under an inert gas atmosphere such as nitrogen or argon, the reducing metal salt may be used in minor amounts, for example, in an amount of from 0.005 to 4 moles, preferably from 0.01 to 1 mol, particularly preferably from 0.05 to 0.7 mol, more preferably from 0.05 to 0.5 mol and in particular from 0.05 to 0.4 mol, based on 1 mol of the compound of formula 1, or of formula 7 or of formula 9, or of formula 11.

Suitable reducing anions are, for example, bromide, iodide, sulfite, hydrogen sulfite, pyrosulfite, dithionite, thiosulfate, nitrite, phosphite, hypophosphite, ArS ^" , xanthates (ROCS ₂ ^' , R' = alkyl, aryl), alkoxides, such as methanolate, ethanolate, propoxide Of course, when the reaction is carried out under acidic conditions, the reducing anions are preferably selected from those whose reduction potential is still sufficient under these conditions to decompose the compound of formula 1 , or the formula 7 or the formula 9 or the formula 11 to effect.

The reducing anions are used in an amount of preferably 0.005 to 8 moles, more preferably from 0.01 to 6 moles and especially from 1 to 6 moles, relative to 1 mole of the compound of the formula 1 or of the formula 7 or of the formula 9 or the formula 11 used.

Alternatively or additionally, in a preferred embodiment of the method according to the invention carried out under the conditions of an electrochemical reduction. In this procedure, aryldiazenyl radicals are generated from the compound of the formula 1 or the formula 7 or the formula 9 or the formula 11 by anodic reduction, which initiates the decomposition of the abovementioned compounds.

The implementation is carried out, for example, that in the reaction vessel, which in a cathode and anode are arranged and during the successive addition of the compound of formula 1, or the formula 7 or the formula 9 or the formula 11 voltage is applied. The voltage and current density to be selected depend on various factors, such as rate of addition and solvent, and must be determined on a case-by-case basis, which can be achieved, for example, by means of preliminary tests. The solvents are suitably chosen so that they do not undergo any competing reaction at the electrodes under the given reaction conditions. Since the anodic reduction of protons is difficult to avoid even at very low current densities and voltages, preference is given to using nonprotonic, polar solvents, such as acetonitrile, dimethylformamide or acetone.

Of the measures mentioned, the implementation in the presence of at least one reducing agent and in particular at least one reducing metal salt or a reducing metal depending on the reaction conditions is preferred.

However, it is particularly preferred to use the abovementioned reducing metal salts or metals as reducing agents. With regard to suitable and preferred metal salts, reference is made to the above statements.

Alternatively or additionally, the process for the preparation of compounds of the structure 3, 4, 5, 10 or 12, characterized in that the reaction is carried out under irradiation with electromagnetic radiation in the visible and / or ultraviolet range. Preference is given to using electromagnetic radiation having a wavelength in the range from 100 to 400 nm, particularly preferably in the range from 200 to 380 nm and in particular in the range from 250 to 360 nm.

The irradiation is preferably carried out in such a manner that the compound of the formula 2 or of the formula 8 is initially introduced in a suitable solvent and during the successive addition of the compound of the formula 1, or of the formula 7, or of the formula 9 , or the formula 11 is irradiated under cooling. In particular, when UV radiation is used, the solvents are preferably used in degassed form, otherwise Oxygen radicals can arise, which can lead to undesirable products. Since water or aqueous solutions are not easily degasified, in this case, the below-mentioned organic solvents are preferable.

Alternatively or additionally, the process for the preparation of compounds of the formula 3, 4, 5, 10 or 12 is carried out in that the reaction is carried out using ultrasound. Like all sound waves, ultrasound also produces periodic compression and stretching of the medium; the molecules are compressed and stretched. Small bubbles form which grow and implode immediately. This phenomenon is called cavitation. Each imploding bubble emits shock waves and tiny jets of liquid at a speed of about 400 km / h, which affect the surrounding area. Cavitation, for example, can be exploited to accelerate chemical reactions and increase the solubility of products in a given medium.

The implementation using ultrasound, for example, carried out so that the reaction vessel in which the compound of formula 2, or the formula 8 is presented in a suitable solvent in an ultrasonic bath and the reaction mixture during the successive addition of the compound Formula 1, or the formula 7, or the formula 9, or the formula 11 is exposed to ultrasound. Instead of using an ultrasonic bath, a sonotrode (= device which forwards the ultrasonic vibrations generated by a sound transducer to the material to be sounded) can be placed in the reaction vessel in which the compound of formula 2 or formula 8 is initially charged in a suitable solvent become. The latter alternative is particularly suitable for larger approaches.

With regard to rate of addition, reaction temperature and solvent, preliminary experiments can advantageously be carried out.

Alternatively or additionally, in a preferred embodiment of the method according to the invention carried out under Radiolysebedingungen. Here, solvated electrons in aqueous solution by irradiation with γ-radiation for example, generated from a ⁶⁰ co-source. This procedure is described in more detail in JE Packer et al., J.Chem.Soc, Perkin Trans. 2, 1975, 751, and Aust. J. Chem. 1980, 33, 965, to which reference is hereby made in its entirety.

The term "solvent" (solvent, solvent) refers in the broadest sense to substances that can physically solubilize others, in the narrower sense inorganic and organic liquids that other gaseous, liquid or solid substances are capable of dissolving As a solvent, neither the solvent nor the dissolved substance changes chemically during the dissolution process, so that the components of the solution can be recovered by physical separation processes such as distillation, crystallization, sublimation, evaporation, absorption in the original form.

Inorganic and organic solvents are known, which are presented here in groups.

In the case of inorganic solvents, a distinction is made between proton-containing (protic) such as H ₂ O, liquid NH ₃ , H ₂ S, HF, HCN, HNO ₃ , and proton (hydrogen) -free (aprotic) solvents, such as, for example, liquid SO ₂ , N ₂ O ₄ , NOCl, SeOCl ₂ , ICl, BrF ₃ , AsCl ₃ , on the other hand aqueous and non-aqueous solvents (all except H ₂ O, with the subgroups aprotic, amphiprotic, protogenic, protophilic solvent).

Of course, the last-mentioned classifications apply even more to the organic solvents, of which only the most important ones can be listed here: alcohols (eg, methanol, ethanol, etc.) glycols (eg, ethylene glycol), ethers, and glycol ethers (eg. Diethyl ether, dioxane, tetrahydrofuran), ketones (eg acetone), amides and other nitrogen compounds (eg dimethylformamide), sulfur compounds (eg carbon disulfide, sulfolane), nitro compounds (eg nitromethane), halogenated hydrocarbons (eg. Dichloromethane, chloroform), hydrocarbons (e.g., gasolines, petroleum ethers, cyclohexane). Suitable solvents depend in detail on the choice of the particular reaction conditions for the decomposition of the compound of formula 1, or of formula 7, or of formula 9, or of formula 11, such as, for example, the reactants. However, it has generally proved to be advantageous as a solvent for the reaction of the compound of formula 1, or of formula 7, or of formula 9, or of formula 11 and the compound of formula 2, or of the formula 8 to use aqueous solvent.

In the context of the present invention, preferred organic solvents are, for example, short-chain nitriles, such as acetonitrile or propionitrile, amides, such as dimethylformamide, short-chain monohydric or polyhydric alcohols, such as methanol, ethanol, propanol, isopropanol, ethylene glycol or trifluoroethanol, short-chain carboxylic acids, such as glacial acetic acid, trifluoroacetic acid , short-chain ketones, such as acetone, and dimethyl sulfoxide or mixtures of these organic solvents with one another.

In the context of the present invention, preferred inorganic solvents are, for example, hydrochloric acid, sulfuric acid, phosphoric acid and hydrofluoric acid.

In the context of the process according to the invention, aqueous solvents are understood as meaning water and aqueous solvent systems are understood as meaning a mixture of water with water-miscible organic and / or inorganic solvents.

In the context of the present invention, furthermore, aqueous solvent systems acid solutions, in particular aqueous mineral acids, such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like are preferred. Preference is given here to non-oxidizing acids, such as hydrochloric acid or hydrobromic acid. In a preferred embodiment, the acid solutions are used in dilute form. "Diluted" in this context means in particular that the concentration of the acid is 0.1 to 20 wt .-%, in particular 3 to 15 wt .-% and especially 2 to 8 wt .-%, based on the total weight of the solvent.

The aqueous acid solutions can also be used in admixture with the abovementioned, water-miscible organic solvents. In a special In a preferred embodiment, the concentration of the acid in the aqueous solvent is chosen such that the pH of the reaction mixture is at most 7, for example 0 to 6 or 1 to 5 or 3 to 5 or 2 to 4.

In a preferred embodiment, the aqueous solvent system is a dilute mineral acid, i. in the aqueous solvent is a mineral acid in a concentration of usually 0.1 to 20 wt .-%, in particular from 3 to 15 wt .-% and especially from 2 to 8 wt .-% before. Hydrochloric acid or sulfuric acid are preferably used here as the mineral acid.

The concentration of the acid in the aqueous solvent system is preferably chosen such that a pH of at most 7, e.g. from 0 to 7, or 1 to 7, or 2 to 7, and especially of at most 5, e.g. from 0 to 5, or 1 to 5, or 2 to 5, or 3 to 4.

However, nonaqueous solvent systems, such as e.g. the o.g. organic solvents and mixtures of these solvents.

Another suitable solvent system is a two-phase solvent system comprising two substantially immiscible solvent systems. "Substantially immiscible" means that a first solvent, which is used in less or the same amount as a second solvent, in the second solvent at most 20 wt .-%, preferably at most 10 wt .-% and in particular at most 5 wt .-%, based on the total weight of the first solvent, dissolves. Examples are systems which contain, in addition to an aqueous solvent or solvent system as defined above, one or more water-immiscible solvents such as carboxylic acid esters, eg ethyl acetate, propyl acetate or ethyl propionate, open chain ethers such as diethyl ether, dipropyl ether, dibutyl ether, methyl isobutyl ether and methyl tert-butyl ether, aliphatic hydrocarbons, such as pentane, hexane, heptane and octane, and petroleum ethers, halogenated aliphatic hydrocarbons, such as methylene chloride, trichloromethane, dichloroethane and trichloroethane, cycloaliphatic hydrocarbons, such as cyclopentane and cyclohexane, and aromatic hydrocarbons, such as toluene, the xylenes, chlorobenzene, dichlorobenzenes and mesitylene.

Such a two-phase solvent system may suitably also contain at least one phase transfer catalyst.

Suitable phase transfer catalysts are well known to the person skilled in the art and include, for example, charged systems such as organic ammonium salts, for example tetra (C 1 -C ₁₈ -alkyl) ammonium chlorides or bromides, such as tetramethylammonium chloride or bromide, tetrabutylammonium chloride or bromide, hexadecyltrimethylammonium chloride or bromide, octadecyltrimethylammonium chloride or bromide, methyltrihexylammonium chloride or bromide, methyltrioctylammonium chloride or bromide or benzyltrimethylammonium hydroxide (Triton B), furthermore tetra (C 1 -C ₁₈ -alkyl) phosphonium chlorides or bromides such as tetraphenylphosphonium chloride or bromide, [(phenyl) _m - (C 1 -C ₁₈ -alkyl) _n ] -phosphonium chlorides or bromides, in which m = 1 to 3 and n = 1 to 3 and the sum m + n = 4, and also pyridinium salts, such as methylpyridinium chloride or bromide, and uncharged systems such as crown ethers or azacrown ethers, eg 12-crown-4, 15-crown-5, 18-crown-6, dibenzo-18-crown-6 or [2,2,2] -crypt and (222-cryptofix), cyclodextrins, calixarenes such as [1 ₄ ] -metacyclophane, calix [4] arene and p-tert-butyl-calix [4] arene, and cyclophanes.

Also suitable is the implementation in a two-phase system, wherein one of the phases preferably comprises at least one of the abovementioned solvents or Lösunsmittelsystem and the second phase with the first phase is substantially immiscible. The first phase preferably comprises at least one of the abovementioned protic solvents, such as water, alcohols or diols. More preferably, the first phase is an aqueous system, ie, water, an aqueous mineral acid such as hydrochloric, hydrobromic, nitric, sulfuric, phosphoric and the like, or a mixture of water or an aqueous acid with at least one water-miscible organic solvent For example, alcohols such as methanol, ethanol, propanol, isopropanol or trifluoroethanol, diols such as ethylene glycol, cyclic ethers such as tetrahydrofuran and dioxane, acetonitrile, amides such as dimethylformamide, carboxylic acids such as glacial acetic acid, and ketones such as acetone. In particular, the first phase comprises water or an aqueous mineral acid, wherein the mineral acid is preferably hydrochloric acid or Hydrobromic acid is.

The second phase is preferably selected from carboxylic acid esters, e.g. Ethyl acetate, propyl acetate or ethyl propionate, open-chain ethers, such as diethyl ether, dipropyl ether, dibutyl ether, methyl isobutyl ether and methyl tert-butyl ether, aliphatic hydrocarbons, such as pentane, hexane, heptane and octane, and petroleum ethers, halogenated aliphatic hydrocarbons, such as methylene chloride, trichloromethane, tetrachloromethane, dichloroethane and trichloroethane, cycloaliphatic hydrocarbons such as cyclopentane and cyclohexane, and aromatic hydrocarbons such as toluene, the xylenes, chlorobenzene or dichlorobenzene.

For the purposes of the present invention, non-polar (non-polar) solvents include, for example, carbon disulfide, carbon tetrachloride, most aromatic and saturated aliphatic hydrocarbons, and among the polar solvents all organic nitrogen and oxygen compounds.

The term "weakly polar solvents" denotes, for example, halogenated and some aromatic hydrocarbons The empirically determined polarity expressed in units of the so-called Eχ (30) scale increases, for example, from apolar n-hexane over toluene, chloroform, n-butanol, acetone , Ethanol, formamide to strongly polar water.

In the context of the present invention, "polar organic solvents" are understood as meaning, for example, short-chain nitriles, such as acetonitrile or propionitrile, amides, such as dimethylformamide, short-chain monohydric or polyhydric alcohols, such as methanol, ethanol, propanol, isopropanol, ethylene glycol or trifluoroethanol, short-chain carboxylic acids, such as glacial acetic acid, trifluoroacetic acid, short chain ketones such as acetone, and dimethyl sulfoxide.

In a preferred embodiment, the solvents are used in degassed (ie, especially deoxygenated) form. The degassing of solvents is known and can be carried out, for example, by single or multiple freezing of the solvent, thawing under vacuum (to remove the dissolved / dispersed in the solvent / gas) and compensated with an inert gas such as nitrogen or argon. Alternatively or In addition, the solvent can be treated with ultrasound. The latter approach is particularly suitable for water or aqueous solvents, since the expansion of water during freezing can lead to equipment problems.

Alternatively or additionally, in a preferred embodiment of the process according to the invention, the reaction is carried out in at least one solvent or solvent system which comprises the radical decomposition of the compound of formula 1 or of formula 7 or of formula 9 or of formula 11 in nitrogen and an aryl radical and / or promotes the reaction in a different manner. For example, "favored in another way" means that the solvent or solvent system promotes the formation of the aryl radical.

Solvent or solvent systems which promote the radical decomposition of the diazonium salt of formula 1 or of formula 7 or of formula 9 or of formula 11 into an aryl radical are characterized by a certain reductive potential and can be used in conjunction with a diazonium salt of formula 1, or of formula 7, or of formula 9, or of formula 11 as a reducing agent; ie the solvents themselves are oxidizable. Examples of such solvents are alcohols, for example C 1 -C ₄ -alcohols, such as methanol, ethanol, propanol, isopropanol, butanol, sec-butanol, isobutanol and tert-butanol, diols, such as ethylene glycol and diethylene glycol, open-chain ethers, such as diethyl ether, methyl isobutyl ether and methyl tert-butyl ether, cyclic ethers such as tetrahydrofuran and dioxane, nitrogen-containing heterocycles such as pyridine, and HMPT (hexamethyl phosphoric triamide), but also basic aqueous solutions. However, since basic solutions promote side reactions such as the azo coupling of the diazonium salt of formula 1, or of formula 7, or of formula 9, or of formula 11, or at least not prevent, the pH of the reaction mixture should not exceed a value of 9 , Suitable bases are inorganic bases, such as alkali metal hydroxides, for example lithium, sodium or potassium hydroxide, alkaline earth hydroxides, for example magnesium or calcium hydroxide, alkali metal carbonates, for example lithium, sodium or potassium carbonate, and alkali hydrogen carbonate, for example lithium, sodium or potassium carbonate , and organic bases, such as acetates, for example sodium acetate, or alcoholates, for example, sodium, sodium, sodium tert-butoxide or potassium tert-butoxide. The alcoholates are preferably as aqueous Solvent systems used.

Particularly suitable are those solvents or solvent systems which do not have readily abstractable hydrogen atoms, since they best protect a formed aryl radical from side reactions. At the same time, however, the solvents or solvent systems must also have sufficient dissolving power for the reactants. Examples of these are water and aqueous mineral acids, such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like, but also alcohols without hydrogen atoms in the α-position, such as tert-butanol, or comparatively inert organic solvents or solvent systems, such as acetonitrile, Acetic acid, trifluoroacetic acid, acetone, trifluoroethanol and / or dimethyl sulfoxide. In particular, an addition of water or aqueous mineral acids, such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like, generally has a stabilizing effect on the resulting aryl radicals, since they undergo virtually no side reactions with water. Water and aqueous mineral acids are therefore preferred as solvents without abstractable hydrogen atoms.

When solvents with readily abstractable hydrogen atoms, such as primary alcohols, are used, they are preferably used in admixture with a solvent which does not possess readily abstractable hydrogen atoms. Preferably, the non-inert organic solvents or solvent systems to the aryl radicals are in an amount of at most 50 wt .-%, more preferably of at most 20 wt .-% and in particular of at most 10 wt .-%, based on the weight of the mixture from reducing solvent or solvent system and solvents or solvent systems without readily abstractable hydrogen atoms. Since water or aqueous mineral acids are used as solvents or solvent systems without readily abstractable hydrogen atoms, the reducing solvents or solvent systems used in the mixtures are preferably those which are miscible with water (these are the abovementioned alcohols, diols and cydic ethers). ,

The solvents or solvent systems used are preferably those which the radical decomposition of the compound of formula 1, or of formula 7, or of formula 9, or of formula 11 in nitrogen and an aryl radical effect and / or favor the reaction in another way. Preferably, water, said aqueous mineral acids or mixtures of the above-mentioned organic, water-miscible, a certain reduction potential having solvent or solvent systems (those are the aforementioned alcohols, diols and cyclic ethers) with water or said aqueous acids.

Alternatively preferred is the implementation in (sole) presence of at least one solvent which causes the radical decomposition of the compound of formula 1, or of formula 7, or of formula 9, or of formula 11 in nitrogen and an aryl radical and / or the reaction in another way favors, in particular of water, one of the above-mentioned aqueous mineral acids or a mixture of said reductive, organic, water-miscible solvents with water or one of the above-mentioned aqueous mineral acids. The solvents are preferably used in degassed form. This embodiment is particularly suitable when a compound of formula 2, or of formula 8, is used with a relatively high reduction potential, which is used as reducing agent for the diazonium salt of formula 1, or of formula 7, or of formula 9, or the formula 11 acts.

In many cases one does not use the pure solvents, but mixtures, which unite the solution properties, or one resorts to solubilizers.

The term "solubilizer" refers to (surface-active) substances which by their presence render other compounds which are virtually insoluble in a solvent soluble or emulsifiable in this solvent: There are solubilizers which form a molecular compound with the sparingly soluble substance and those which are formed by micelles It can also be said that solubilizers give a so-called latent solvent its dissolving power For example, ethanol (as a latent solvent) dissolves cellulose acetate poorly, but much better after adding 2-nitropropane (as a solubilizer). The reaction according to the invention is carried out by reacting the compound of formula 1, or of formula 7, or of formula 9, or of formula 11 and a compound of formula 2, or of formula 8, preferably in a suitable solvent with each other Reaction conditions bring into contact, which cause a decomposition of the compound of formula 1, or of the formula 7, or the formula 9, or the formula 11 in nitrogen and an aryl radical.

The reactants can in principle be brought into contact with each other in a different order. Thus, for example, the compound of formula 2, or of formula 8 optionally dissolved or dispersed in a solvent or solvent system, initially charged and with the compound of formula 1, or of formula 7, or of formula 9, or the formula 11 or, conversely, the compound of the formula 1 or of the formula 7 or of the formula 9 or of the formula 11, if appropriate dissolved or dispersed in a solvent or solvent system, is initially charged and reacted with the compound of the formula 2 or . of Formula 8. However, it has generally proved to be advantageous to initially introduce the compound of the formula 2 or of the formula 8, if appropriate in a solvent or solvent system, and to prepare the compound of the formula 1 or of the formula 7 or of the formula 9, respectively to add to formula 11.

The reaction can be carried out both in a solvent or solvent system and in substance. In the latter case, for example, the compound of formula 2, or the formula 8 itself acts as a solvent or dispersant or, if its melting point is above room temperature (25 ° C), introduced as a melt and then with the compound of formula 1, or of formula 7, or of formula 9, or of formula 11 under suitable reaction conditions. However, the preferred embodiment is the implementation in a solvent or solvent system.

The compound of the formula 2 or of the formula 8 is preferably used directly. Alternatively, it can also be used, either completely or partially, in the form of one of its acid adducts or a mixture of such adducts, the hydrochloride of the compound of formula 2 or of formula 8 being particularly preferred. The implementation is carried out, for example, so that the compound of formula 2, or the formula 8 in such a solvent (system) and then presented the diazonium salt of formula 1, or of formula 7, or of formula 9, or the formula 11 is added successively or conversely the compound of formula 1, or of formula 7, or of formula 9, or of formula 11 in such a solvent (system) and then the compound of formula 2, or the formula is added, the first variant is preferred. With regard to rate of addition and reaction temperature, reference is made to the above statements. When carried out in a two-phase system, alternatively, the compound of formula 2 or of formula 8 in the solvent (system) of the one phase and the compound of formula 1, or of formula 7, or of formula 9, or of formula 11 be presented in the solvent (system) of the second phase respectively.

As already stated, in a preferred embodiment, the compound of formula 1 or of formula 7 or of formula 9 or of formula 11 is added to the compound of formula 2 or of formula 8 present in the original. The compound of formula 1, or of formula 7, or of formula 9, or of formula 11 can be added dissolved or dispersed either in substance or in a solvent or solvent system. As the solvent, water or the above-mentioned aqueous solvent systems or polar organic solvents may be used, with the aforementioned water-miscible organic solvents being preferred. The compound of formula 1, or of formula 7, or of formula 9, or of formula 11 is preferably added successively (in portions or continuously). The successive addition in many cases suppresses the formation of homocoupling products, i. of products which are formed by reaction of two or more compounds of the formula 1 or of the formula 7 or of the formula 9 or of the formula 11 with one another, because a low concentration of the compound of the formula 1 or of the formula 7 , or the formula 9, or the formula 11 in the reaction mixture ensures that its reaction with the compound of formula 2, or the formula 8 outweighs the reaction with itself.

The rate of addition is determined by several factors, such as batch size, temperature, reactivity of the starting materials and the nature of the reaction conditions selected, which is a decomposition of the compound of formula 1, or of formula 7, or of the formula 9, or of the formula 11 in nitrogen and an aryl radical, and can be determined by a person skilled in the individual case, for example by suitable preliminary experiments. Thus, low reactivity of the educts requires a slower rate of addition, but for example by a higher temperature and / or by the choice of reaction conditions, the decomposition of the compound of formula 1, or the formula 7, or the formula 9, or accelerate the formula 11, at least partially compensated.

The two aforementioned preferred measures, i. the use of the compound of formula 1, or of formula 7, or of the formula 9, or of the formula 11 in the deficit and their gradual addition, cause an advantageous reaction course, since they are the Homokupp development of the compound of formula 1, or of formula 7, or the formula 9, or the formula 11 push back.

According to the invention, the compound of the formula 1, or of the formula 7, or of the formula 9, or of the formula 11 and the compound of the formula 2, or of the formula 8 is reacted under reaction condition, which is a decomposition of the compound of the formula 1, or the formula 7, or the formula 9, or the formula 11 in nitrogen and an aryl radical effect. In this case, preference is given to using reaction conditions under which a single electron (SET, single electron transfer) is transferred to the diazonium salt of the formula 1 or of the formula 7 or of the formula 9 or of the formula 11.

Suitable conditions under which decomposition of the compound of the formula 1 or of the formula 7 or of the formula 9 or of the formula 11 into nitrogen and an aryl radical take place are generally known to the person skilled in the art. Thus, even the addition of the compound of formula 1, or of formula 7, or of formula 9, or of formula 11 to the compound of formula 2, or the formula 8 cause their decomposition in nitrogen and an aryl radical since at least part of the compound of formula 2 or of formula 8 has sufficient reductive potential. In this case, no special procedures need to be taken and the reaction can be carried out under the reaction conditions described above. If the reduction potential of the compound of formula 2, or of formula 8, is insufficient, it is necessary to take further procedural measures in order to obtain the Initiate reduction step. But even if the reduction potential of the compound of formula 2 or of the formula 8 used should be sufficient to the decomposition of the compound of formula 1, or of formula 7, or of formula 9, or of formula 11 in nitrogen and a Aryl radical initiate, it may be advantageous to take further procedural measures that ensure disintegration or degradation of the compound of formula 1, or of formula 7, or of formula 9, or of formula 11 in nitrogen and an aryl radical / accelerate or with respect to other possible reactions of the diazonium salt of the formula 1, or of the formula 7, or of the formula 9, or of the formula 11 (for example, azo coupling) preferably proceed.

The method measures are preferably selected from:

- Carrying out in the presence of at least one reducing agent;

- Implementation under irradiation with electromagnetic radiation in the visible and / or ultraviolet range;

- Implementation using ultrasound;

- Implementation under the conditions of an electrochemical reduction;

- Implementation in at least one solvent or solvent system which causes the radical decomposition of the compound of formula 1, or of formula 7, or of formula 9, or of formula 11 in nitrogen and an aryl radical and / or the reaction in one favored in another way;

- Carrying out under radiolysis conditions;

- and the combination of at least two of these measures.

If two or more of the above measures are combined, one of these measures is preferably to carry out in the presence of at least one reducing agent and in particular at least one reducing metal salt and / or carrying out in the presence of at least one solvent or solvent system, the radical decomposition of the compound of formula 1, or of the formula 7, or of the formula 9, or of the formula 11 in nitrogen and an aryl radical and / or favors the reaction in another manner. Particularly suitable is the combination of these two measures with each other and with the implementation using ultrasound. The reaction temperature is determined by a number of factors, such as the reactivity of the reactants used and the nature of the selected reaction condition, which is a decomposition of the compound of formula 1, or of formula 7, or of formula 9, or of formula 11 in nitrogen and an aryl radical, and can be determined by a person skilled in the individual case, for example by simple preliminary experiments. In general, the reaction of the compound of formula 1, or of formula 7, or of formula 9, or of formula 11 with the compound of formula 2, or of formula 8 at a temperature in the range of preferably -10 ° C to the boiling point of the reaction mixture, preferably from -78 ° C to 200 ° C, more preferably from 0 ⁰ C to 80 ° C and in particular from 0 ° C to 50 ° C by. These temperatures are for solution in solution; however, if it is carried out in substance and the melting point of the compound of the formula 2 or of the formula 8 above room temperature, the reaction temperature is of course at least the temperature of the melt of the reaction mixture.

In the process according to the invention for the preparation of compounds of the formula 3, 4, 5, 10 or 12, preference is given to using the compound of the formula 1 or of the formula 7 or of the formula 9 or of the formula 11 in an amount of 0.001 to 0.9 mol, particularly preferably from 0.1 to 0.7 mol and in particular from 0.1 to 0.5 mol, in each case based on 1 mol of the compound of formula 2, or of the formula 8.

Diazonium salts of the formula 1, or of the formula 7, or of the formula 9, or of the formula 11 are generally known and can be prepared according to conventional methods, as described for example in Organikum, Wiley VCH, 22nd edition. Thus, they are obtainable by diazotization of the corresponding aniline derivative, for example, by reacting such aniline derivative with nitrite in the presence of an acid, such as semi-concentrated sulfuric acid. Both corresponding aniline derivatives for the preparation of compounds of the formula 1 or of the formula 7 or of the formula 9 or of the formula 11 and of compounds of the formula 2 or of the formula 8 are known or can be prepared by known processes For example, by hydrogenating or homogeneously reduced correspondingly substituted nitrobenzenes in the presence of a suitable catalyst (for example with Sn (II) chloride / HCl, see Houben Weyl, "Methoden der Org. Chemie" 11/1, 422). Also, the preparation of azobenzenes and the substitution of suitable benzenes with Ammonia are common methods. The preparation of diazonium salts of the formula 1, or of the formula 7, or of the formula 9, or of the formula 11, in which the counteranions are selected from the anions of aromatic dicarboximides or disulfonimides, can be prepared analogously to M. Barbero et al. , Synthesis 1998, 1171-1175.

The workup of the resulting reaction mixtures and the isolation of the compounds of formula 3, 4, 5, 10 and 12 is carried out in the usual manner, for example by an extractive workup, by removing the solvent, for. B. under reduced pressure, or by a combination of these measures. Further purification can be carried out, for example, by crystallization, distillation or by chromatography.

Excess or unreacted starting materials (these are, in particular, the compound of the formula 2 or of the formula 8, which in relation to the compound of the formula 1, or of the formula 7, or of the formula 9, or The formula 11 is preferably used in excess) are preferably isolated in the workup and reused.

According to a preferred embodiment of the invention, the reaction mixture is extracted several times for work-up with a suitable, substantially water-immiscible organic solvent and the combined organic phases are concentrated. Examples of suitable substantially water-immiscible organic solvents are listed above. The product isolated in this way can then be kept ready for use or used directly, for example in a further reaction step, or further purified beforehand.

In particular, if the reaction is carried out in acidic solution, the reaction mixture is preferably at least partially neutralized before extraction with an organic solvent, which is usually carried out by adding a base. Examples of suitable bases are inorganic bases, such as alkali metal hydroxides, for example lithium, sodium or potassium hydroxide, alkaline earth metal hydroxides, for example magnesium or calcium hydroxide, or alkali metal and alkaline earth metal oxides, for example sodium, magnesium or calcium oxide; organic bases, such as alcoholates, for example sodium methoxide, sodium ethoxide, potassium tert-butoxide and the like; and amines, such as diethylamine, triethylamine or ethyldiisopropylamine. Preference is given to the said inorganic bases, which are preferably used as aqueous solution, and in particular the said alkali metal hydroxides, such as lithium, sodium or potassium hydroxide, preferably in the form of their aqueous solution.

Further preferred embodiments of the present invention are:

Al. Process for the preparation of a compound of formula 3

characterized in that a compound of formula 1

with a compound of formula 2

is implemented, where m is 0, 1, 2, 3, 4 or 5; z is 0, 1, 2, 3, 4 or 5; v is 0, 1, 2, 3, 4 or 5; q is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; r is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; s is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

each R ¹ is independently halogen, alkyl, haloalkyl, hydroxyalkyl,

Haloalkoxycarbonyl, alkenyloxycarbonyl, alkylsulfonyl,

Haloalkylsulfonyl, alkylimino, aryl, aryloxy, arylcarbonyl, arylalkyl, arylmethoxycarbonyl, arylalkylimino, or heteroaryl, wherein the aryl group optionally carries 1, 2, 3 or 4 substituents selected from halogen, alkyl, haloalkyl, alkoxy or haloalkoxy; R ^{b are} each independently H, halogen, -SR ⁴ , -OR ⁴ , -NR ⁴ R ⁵ , alkyl,

Haloalkoxycarbonyl, alkenyloxycarbonyl, alkylsulfonyl,

Haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkylthio, cycloalkyl, haloalkylthio, alkenyl, alkynyl, nitro, cyano, -SO ₃ R ^5, -SO ₂ NH _2, - SO ₂ NHR ^4, -SO ₂ NR ⁴ R ^5, -COOR ⁴ , -CONHR ⁴ , -CONR ⁴ R ⁵ , -COR ⁴ , -OCOR ⁴ , -NR ⁴ COR ⁵ , -NR ⁴ SO ₂ R ⁵ , -PO ₃ R ⁴ R ⁵ , alkylcarbonyl, haloalkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, Haloalkoxycarbonyl, alkenyloxycarbonyl, alkylsulfonyl,

Haloalkoxycarbonyl, alkenyloxycarbonyl, alkylsulfonyl,

Haloalkylsulfonyl, alkylimino, aryl, aryloxy, arylcarbonyl, arylalkyl, arylmethoxycarbonyl, arylalkylimino, or heteroaryl, wherein the aryl group optionally carries 1, 2, 3 or 4 substituents selected from halogen, alkyl, haloalkyl, alkoxy or haloalkoxy; R ^{g are} each independently H, halo, -SR ⁴ , -OR ⁴ , -NR ⁴ R ⁵ , alkyl,

Haloalkoxycarbonyl, alkenyloxycarbonyl, alkylsulfonyl,

D is hydroxy, -NR ⁴ R ⁵ , -NHCOR ⁴ , -NR ⁴ COR ⁵ , alkoxy, thioalkyl,

Haloalkyloxy, alkylcarbonyloxy, haloalkylcarbonyloxy or aryloxy, wherein the aryl group optionally carries 1, 2, 3, 4 or 5 substituents selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxy, or alkoxycarbonyl;

X for halide, sulfate, tetrafluoroborate, acetate, trifluoroacetate,

R ^{4 are} each independently hydrogen, alkyl, alkoxy, hydroxyalkyl,

Cycloalkyl, aryl, heteroaryl or haloalkyl;

R ^{5 are} each independently hydrogen, alkyl, alkoxy, hydroxyalkyl,

Cycloalkyl, aryl, heteroaryl or haloalkyl; Each R 10 is independently hydrogen, alkyl, hydroxy, -NR 4rR, 5, -NHCOR, -NR ⁴ COR ⁵ , alkoxy, alkylcarbonyloxy, halo, hydroxyalkyl, cycloalkyl, aryl, heteroaryl or haloalkyl.

A2. Process according to embodiment Al characterized in that D is a group of the formula -OR ⁶ , wherein R ^{6 represents} hydrogen, alkyl, hydroxyalkyl, alkylcarbonyl, haloalkylcarbonyl, cycloalkyl, aryl, heteroaryl or haloalkyl.

A3. Process for the preparation of a compound of formula 6

characterized in that in a first step a compound of the formula 7

with a compound of formula 8

8 is converted to a compound of formula 5,

in which

X is chlorine, bromine or iodine, the remaining radicals are as defined in embodiment A1,

and in a second step, a compound of formula 5 is converted to the compound of formula 6.

A4. Process for the preparation of a compound of formula 10

characterized in that a compound of formula 9

is reacted with a compound of formula 2, wherein

t is 1, 2 or 3;

R ¹ 'is hydrogen, alkyl or haloalkyl;

R ¹² is hydrogen, alkyl, haloalkyl or R ^{1 1} and R ¹² form a non-aromatic ring system containing 5, 6 or 7

Containing carbon atoms, and the remaining radicals are as defined in embodiment Al.

A5. Process for the preparation of a compound of formula 12

characterized in that a compound of formula 11

11 with a compound of formula 8

is reacted, wherein the radicals are defined as in embodiment Al.

A6. Method according to one of the preceding embodiments, characterized in that the reaction is carried out in multi-stage process in the first step, in the presence of at least one reducing agent.

A7. Method according to one of the preceding embodiments, characterized in that the reaction is carried out in multi-stage process in the first step in the presence of at least one solvent.

A8. Method according to one of the preceding embodiments, characterized in that the reaction in multi-stage process in the first step under irradiation, ultrasound or radiolysis is performed.

A9. Method according to one of the preceding embodiments, characterized in that the reaction in multi-stage process in the first step in a pH range of 0 to 11 is performed. AlO. Method according to one of the preceding embodiments, characterized in that the reaction is carried out in multi-stage process in the first step under inert gas.

11. The method according to any one of the preceding embodiments, characterized in that the reaction in multi-stage process in the first step in the temperature range of -78 ° C to 200 ° C is performed.

The present invention can be used, for example, in the following syntheses of useful compounds:

1. Synthesis of BACE-I Inhibitors:

Important structural fragments in BACE-I inhibitors are arylated tyramine derivatives 50. According to previously known processes, these have to be prepared from tyramine (51) via four stages (Bioorg. Med., Lett., 2008, 1304).

According to the process described here, arylated tyramine derivatives 50 are accessible from tyramine (51) in only one reaction step.

As can be seen from this example, the method according to the invention has the following advantages:

1) No need for protecting groups for aliphatic amines (i.e., short synthetic routes)

2) Favorable titanium (m) chloride as a catalyst instead of expensive Pd catalysts

3) Cheap anilines or diazonium salts 52 as coupling partners instead of expensive arylboronic acids 49

With the method according to the invention a wide variety of derivatives of structure 50 could be prepared. Thus, the broad tolerance of substituents on the aryl diazonium salt 52 could be demonstrated. It should be emphasized that halogen substituents on 52 (R ¹ = Cl, Br, I) are also tolerated. In contrast, Pd-catalyzed cross-coupling reactions with Cl, Br, and I substituents on 49 are difficult to carry out.

2. Building blocks for peptide synthesis:

By the method described, tyrosine methyl ester 53 can be added in one reaction step

Compound 54 can be arylated:

Two further simple reaction steps (protection with Fmoc, saponification) give the biphenyl compound 55, which is suitable for peptide synthesis. Known processes for preparing comparable peptide building blocks (at 55) proceed over significantly longer synthesis sequences (J. Org. Chem. 2006, 71, 5625). Since these processes are based on Pd-catalyzed cross-coupling, the process described here results in the advantages described under 1. above. Examples

Examples A:

Al. Preparation of the Diazoniumssalzlösung the example of 4-Chlorphenyldiazonium- chloride

To a solution of finely powdered 4-chloroaniline (2.55 g, 20.0 mmol) in water (20 ml) and 10% hydrochloric acid (20 ml, about 3M) (solvent mixture on a rotary evaporator evacuated three times and aerated with argon) is added dropwise at 0 ° C under argon, a solution of sodium nitrite (1.38 g, 20.0 mmol) in water (10 ml) (previously degassed with argon) over 10 minutes. The clear diazonium salt solution is stirred for a further 15 minutes at 0 ° C and kept under argon. For the following experiment, 5 ml of diazonium salt solution are removed (5 ml of saline solution contain about 2 mmol of diazonium salt and 2 mmol of hydrochloric acid).

A2. biaryl

5 ml of the previously prepared 0.4M aryldiazonium chloride solution (2 mmol) are added dropwise under syringe over 10 to 15 minutes to a solution of the phenol or phenyl ether (10.0 mmol) in water (6 ml, previously degassed) and titanium (ffl) chloride by syringe pump (4 ml, about 4 mmol, about IM solution in 3N hydrochloric acid). After completion of the addition, the reaction mixture is stirred for a further 10 minutes at room temperature and then treated with a solution of sodium hydroxide (2 g) and sodium sulfite (2 g) in 20 ml of water. After three extractions with ethyl acetate or diethyl ether (3x50 ml), the combined organic phases are washed with saturated sodium chloride solution and dried over sodium sulfate. The pure biarylamines are obtained after concentration in vacuo by column chromatography, sublimation, distillation or crystallization.

A2.1. (4'-chloro-6-methoxybiphen-3-yl) methylamine

C ₁₄ H ₁₄ CINO

M = 247.72 g / mol

Synthesis of 4-chloroaniline and / - methoxybenzylamine according to the general procedure. Purification by distillation under high vacuum (about 0.03 mbar) at 120 ° C gave (4'-chloro-6-methoxybiphen-3-yl) methylamine (342 mg, 1.38 mmol, 69%) and /? - methoxybenzylamine (875 mg, 6.38 mmol, 74% of the unreacted starting material).

¹ H-NMR (250 MHz, _CDCl3): 6 = 1:42 (s, 2 H), 3.71 (s, 3 H), 3.77 (s, 2 H), 6.86 (d, J = 8.3 Hz, 1 H) , 7.14-7.22 (m, 2H), 7.28 (d, J = 8.7 Hz, 2H), 7.38 (d, J = 8.7 Hz, 2H); ¹³ C NMR (63 MHz, CDCl ₃ ): δ = 45.8 (CH ₂ ), 55.7 (CH ₃ ), 111.3 (CH), 127.5 (CH), 128.1 (2 * CH), 129.4 (C _q ), 129.6 (CH), 130.7 (2><CH), 132.8 (C _q), 135.7 (C _q), 136.8 (C _q), 155.2 (C _q); MS (EI): m / z (%): 249 [ ³⁷ Cl-M ⁺ ] (32), 248 (42), 247 [M ⁺ ] (100), 246 (73), 230 (18), 216 ( 55), 205 (55), 184 (9), 181 (12), 168 (16), 152 (23), 136 (41), 122 (14), 105 (13), 98 (17), 78 ( 27), 63 (27), 44 (56); HRMS (EI): Ci ₄ H ₁₄ NO ³⁵ Cl [M ⁺ ] calc .: 247.0764; Found: 247.0758; C ₁₄ H ₁₃ NO ³⁵ Cl [M ⁺ -H] calc .: 246.0686; found: 246.0682.

A2.2. 2- (4'-chloro-6-methoxybiphen-3-yl) ethylamine

C ₁₅ H ₁₆ CINO

M = 261, 75 g / mol

Synthesis of 4-chloroaniiine and 2- (4-methoxyphenyl) ethylamine according to the general procedure. Purification by column chromatography on silica gel (CH ₂ Cl ₂ / MeOH / AcOH = 10: 1: 1) gave 2- (4'-chloro-6-methoxybiphen-3-yl) ethylamine (283 mg, 1.08 mmol, 54%). ¹ H-NMR (360 MHz, CDCl ₃ ): δ = 1.78 (s, 2 H), 2.75 (t, J-6.8 Hz, 2 H), 2.98 (t, J = 6.8 Hz, 2 H), 3.79 ( s, 3 H), 6.92 (d, J = 8.2 Hz, 1 H), 7.15 (m, 2 H), 7.36 (d, J = 7.8 Hz, 2 H), 7.46 (d, J = 7.8 Hz, 2 H); ¹³ C-NMR (90 MHz, CDCl _3): δ = 38.9 (CH _2), 43.6 _(CH2), 55.7 _(CH3), 111.5 (CH), 128.1 (2 * CH), 129.1 (CH), 129.4 (C _q), 130.8 (2><CH), 131.0 (CH), 132.0 (C _q), 132.9 (C _q), 136.9 (C _q), 154.9 (C _q); MS (EI): m / z (%): 263 (4) [ ³⁷ Cl-M ⁺ ], 261 [ ³⁵ Cl-M ⁺ ] (9), 234 (22), 233 (15), 232 (67) , 220 (32), 206 (22), 205 (100), 181 (13), 145 (9), 83 (17), 57 (39), 43 (15); HRMS (EI): C ₁₅ H ₁₆ ³⁵ ClNO [M ^+] calc .: 261.0920; Found: 261.0915.

A2.3. 2-amino-2- (4'-chloro-6-hydroxybiphenyl-3-yl) methyl acetate

C ₁₅ H ₁₄ CINO ₃

M = 291, 73 g / mol

Synthesis of 4-chloroaniline and 2-amino-2- (4-hydroxyphenyl) acetic acid methyl ester according to the general procedure. In the workup, the pH was first adjusted to pH = 9-10 with saturated sodium carbonate solution and then extracted several times with ethyl acetate. Purification by column chromatography on silica gel (CH ₂ Cl ₂ ZMeOH = 10: 1) gave methyl 2-amino-2- (4'-chloro-6-hydroxybiphenyl-3-yl) acetate (338 mg, 1.16 mmol, 58%). ,

¹ H-NMR (500 MHz, CD ₃ OD): δ = 3.71 (s, 3 H), 4.63 (s, 1 H), 6.90 (d, J = 8.4 Hz, 1 H), 7.20 (dd, J = 2.4 Hz, J = 8.4 Hz, 1 H), 7.29 (d, J = 2.4 Hz, 1 H), 7.38 (d, J = 8.7 Hz, 2 H), 7.55 (d, J = 8.7 Hz, 2 H) ; ¹³ C-NMR (90 MHz, MeOD): δ = 53.0 (CH), 58.6 _(CH3), 117.4 (CH), 128.8 (CH), 128.9 (C _q), 129.1 (2><CH), 130.5 ( CH), 131.0 (C _q), 131.9 (2 ^χ CH), 133.8 (C _q), 138.5 (C _q), 155.8 (C _q), 175.0 (C _q); MS (ESI): m / z = 292 [M ⁺ + H].

Examples B:

General procedure a) Preparation of the diazonium salt solution To a cooled in an ice bath and degassed with nitrogen solution of the aniline derivative (20.0 mmol) in hydrochloric acid (3 N, 20 mL) and water (20 mL) is over 10 minutes degassed with nitrogen solution of sodium nitrite (20.0 mmol, 1.38 g) Water (10 mL) added dropwise. The ice bath is stirred for a further 20 minutes, then the clear solution can be used for the further reaction. The concentration of the aryl diazonium chloride solution is 0.4 M (20.0 mmol / 50 mL). b) biaryl synthesis

While stirring vigorously, add to a nitrogen-degassed solution of the phenol or phenyl ether (10.0 mmol) in water (6 mL), titanium (III) chloride (IM in 3 N hydrochloric acid, 4.00 mmol, 4 mL) and acetonitrile (until complete) Solution) an aliquot (2.00 mmol, 5 mL) of the 0.4 M diazonium chloride solution is added dropwise by syringe pump over a period of 10 to 15 minutes. It is stirred for a further 10 minutes and then the pH of the reaction mixture is adjusted to 9 with saturated, aqueous sodium carbonate solution. Extraction is carried out with diethyl ether or ethyl acetate (3 x 75 mL). The combined organic phases are washed with saturated aqueous sodium chloride solution and dried over sodium sulfate. The solvent is removed under reduced pressure and the resulting product is dried in vacuo. The further purification of the products is carried out by preparative HPLC or column chromatography on silica gel.

2- (4'-chloro-6-hydroxybiphen-3-yl) ethylamiii

C ₁₄ H ₁₄ CINO 247.72

Oxygen 0.2 (CH ₂ Cl ₂ / MeOH / AcOH = 10: 1: 1) [UV].

¹ H-NMR (360 MHz, CD ₃ OD): δ = 2.68 (t, J = 6.9 Hz, 2 H), 2.84 (t, J = 6.3 Hz, 2 H),

6.84 (d, J = 8.1 Hz, 1 H), 7.00 (dd, J = 2.0 Hz, J = 8.1 Hz, 1 H), 7.08 (s, 1 H),

7.34 (d, J = 8.5 Hz, 2 H), 7.54 (d, J = 8.5 Hz, 2 H). MS (EI) m / z (%): 248 [M ⁺ + H].

HRMS (EI) calcd. for C ₁₄ H ₁₅ ³⁵ ClNO [M ⁺ ]: 248.0837, found: 248.0830.

2- (4'-fluoro-6-hydroxybiphen-3-yl) ethylamine

Ci ₄ H ₁₄ FNO 231, 27

¹ H-NMR (CDCl ₃ , 360 MHz): δ = 2.71 (t, J = 6.8 Hz, 2H), 2.96 (t, J - 6.8 Hz, 2H), 6.87 (d, J = 8.1 Hz, IH), 7.03 - 7.07 (m, 2H), 7.15 (t, J = 8.8 Hz, 2H), 7.45 (dd, J = 5.4 Hz, J = 8.8 Hz, 2H).

2- (3'-chloro-6-hydroxybiphen-3-yl) ethylamine

C ₁₄ H ₁₄ CINO 247.72

¹ H NMR (CDCl ₃ , 360 MHz): δ = 2.70 (t, J = 6.8 Hz, 2H), 2.96 (br t, 2H), 6.79 (d, J = 8.2 Hz, IH), 7.01 (dd , J = 2.2 Hz, J = 8.2 Hz, IH), 7.04 (d, J = 2.2 Hz, IH), 7.30 (ddd, J = 1.5 Hz, J = 1.9 Hz, J = 7.7 Hz, IH), 7.34 ( t, J = 7.7 Hz, IH), 7.39 (td, J = 1.5 Hz, J = 7.7 Hz, IH), 7.50 (dd, J = 1.5 Hz, J = 1.9 Hz, IH).

2- (3'-fluoro-6-hydroxybiphen-3-yl) ethylamine

C ₁₄ H ₁₄ FNO 231, 27

H-NMR (CDCl _3, 360 MHz): δ = 2.71 (t, J = 6.8 Hz, 2H), 2.96 (t, J = 6.8 Hz, 2H), 6.85 (d, J = 8.6 Hz, IH), 7:03 - 7.07 (m, 3H), 7.22 (ddd, J = 1.6 Hz, J = 2.5 Hz, J - 10.0 Hz, IH), 7.27 (ddd, J = 1.0 Hz, J = 1.6 Hz, J = 7.7 Hz, IH ), 7.39-7.43 (m, IH). - (4'-bromo-6-hydroxybiphen-3-yl) ethylamine

C ₁₄ H ₁₄ BrNO 292.17 H-NMR (CDCl ₃ , 360 MHz): δ = 2.71 (t, J = 6.8 Hz, 2H), 2.96 (t, J = 6.8 Hz, 2H), 6.84 (d, J = 8.2 Hz, IH), 7.01 - 7.07 (m, 2H), 7.37 (d, J = 8.6 Hz, 2H), 7.58 (d, J = 8.6 Hz, 2H). - (3'-bromo-6-hydroxybiphen-3-yl) ethylamine

Ci ₄ H ₁₄ BrNO 292.17 H NMR (CDCl ₃ , 360 MHz): δ = 2.72 (t, J = 6.8 Hz, 2H), 2.97 (t, J = 6.8 Hz, 2H), 6.86 (d, J = 8.2 Hz, IH), 7.04 - 7.08 (m, 2H), 7.32 (t, J = 7.8 Hz, IH), 7.42 - 7.44 (m, IH), 7.49 - 7.51 (m, IH), 7.66 (t, J = 1.8 Hz, IH). - (2'-chloro-6-hydroxybiphen-3-yl) ethylamine

C ₁₄ H ₁₄ CINO 247.72 H NMR (CDCl ₃ , 360 MHz): δ = 2.71 (t, J = 6.7 Hz, 2H), 2.95 (br t, 2H), 6.89 (d, J = 8.2 Hz , IH), 6.98 (d, J = 2.3 Hz, IH), 7.11 (dd, J = 2.3 Hz, J = 8.2 Hz, IH), 7.32 - 7.36 (m, 3H), 7.49 -7.52 (m, IH) , - (3 ', 4'-dichloro-6-hydroxybiphen-3-yl) ethylamine

Ci ₄ Hi ₃ CI ₂ NO 282,17

¹ H-NMR (CDCl _3, 360 MHz): δ = 2.72 (t, J = 6.7 Hz, 2H), 2.97 (br s., 2H), 6.80 (d, J = 8.6 Hz, IH), 7:04 to 7:06 (m, 2H), 7.35 (dd, J = 2.1 Hz, J = 8.3 Hz, IH), 7.49 (d, J = 8.3 Hz, IH), 7.61 (d, J = 2.1 Hz, IH).

C- (4'-chloro-6-methoxybiphen-3-yl) methylamine

Ci ₄ H ₁₄ CINO 247.72

¹ H-NMR (250 MHz, CDCl ₃ ): δ = 1.42 (s, 2H), 3.71 (s, 3H), 3.77 (s, 2H), 6.86 (d, J = 8.3 Hz, 1H) , 7.14-7.22 (m, 2 H), 7.28 (d, J = 8.7 Hz, 2 H), 7.38 (d, J = 8.7 Hz, 2 H).

¹³ C-NMR (63 MHz, CDCl _3): δ = 45.8 (CH _2), 55.7 _(CH3), 111.3 (CH), 127.5 (CH), 128.1 (2 ^χ CH), 129.4 (C _q), 129.6 (CH), 130.7 (2 ^χ CH), 132.8 (Cq), 135.7 (Cq), 136.8

MS (EI) m / z (%): 249 [ ³⁷ Cl-M ⁺ ] (32), 248 (42), 247 [M ⁺ ] (100), 246 (73), 230 (18), 216

(55), 205 (55), 184 (9), 181 (12), 168 (16), 152 (23), 136 (41), 122 (14), 105 (13), 98 (17), 78 (27), 63 (27), 44 (56).

2- (4'-chloro-6-methoxybiphen-3-yl) ethylamine

C ₁₅ H ₁₆ CINO 261, 75

¹ H-NMR (360 MHz, CDCl _3): δ = 1.78 (s, 2 H), 2.75 (t, J = 6.8 Hz, 2 H), 2.98 (t, J =

6.8 Hz, 2 H), 3.79 (s, 3 H), 6.92 (d, J = 8.2 Hz, 1 H), 7.15 (m, 2 H), 7.36 (d, J =

7.8 Hz, 2 H), 7.46 (d, J = 7.8 Hz, 2 H). 1 ³ C-NMR (90 MHz, CDCl ₃ ): δ = 38.9 (CH ₂ ), 43.6 (CH ₂ ), 55.7 (CH ₃ ), 111.5 (CH), 128.1

(2 ^χ CH), 129.1 (CH), 129.4 (C _q ), 130.8 (2 ^χ CH), 131.0 (CH), 132.0 (C _q ), 132.9

(C _q ), 136.9 (C _q ), 154.9 (C _q ). MS (EI) m / z (%): 263 (4) [ ³⁷ Cl-M ⁺ ], 261 [ ³⁵ Cl-M ⁺ ] (9), 234 (22), 233 (15), 232 (67),

220 (32), 206 (22), 205 (100), 181 (13), 145 (9), 83 (17), 57 (39), 43 (15).

5 '- (2-aminoethyl) -4,4' dichloro [l, l '; 3', l "] terphenyl-2'-ol

C ₂₀ H ₁₇ Cl ₂ NO 358.26

IH NMR (360 MHz, CD ₃ OD): δ = 2.94 (t, J = 7.5 Hz, 2H), 3.17 (t, J = 7.5 Hz, 2 H), 7.15 (s, 2H), 7:42 (d, J = 8.3 Hz, 4 H), 7.53 (d, J = 8.3 Hz, 4H).

MS (ESI) m / z: 360 r [i ^J l 'Cf I ³⁵ Cl-M ⁺ -HH], 358 [ ³⁵ C1 ₂ -M ⁺ + H]. 2- ^{(4,4-dichloro-5'M-methoxy-} [l, l '; 4 ^I, l ^M] terphen-2'-yl) ethylamine

C ₂ IH ₁₉ CI ₂ NO 372.29

¹ H-NMR (360 MHz, CDCl _3): δ = 2.66-2.80 (m, 4 H), 3.79 (s, 3 H), 6.79 (s, 1 H), 7.21 (s, 1 H), 7.30 ( d, J = 8.4Hz, 2H), 7.39 (d, J = 8.5Hz, 2H), 7.41 (d, J = 8.4Hz, 2H), 7.50 (d, J = 8.5Hz, 2H);

MS (ESI) m / z (%) = 374 [ ³⁷ C1 ³⁵ C1-M ⁺ + H], 372 [ ³⁵ C1 ₂ -M ⁺ + H].

Methyl 2-amino-2- (4'-chloro-6-hydroxybiphen-3-yl) acetate

¹ H-NMR (360 MHz, CD ₃ OD): δ = 3.71 (s, 3 H), 4.63 (s, 1 H), 6.90 (d, J = 8.4 Hz, 1 H),

7.20 (dd, J = 2.4 Hz, J = 8.4 Hz, 1 H), 7.29 (d, J = 2.4 Hz, 1 H), 7.38 (d, J =

8.7 Hz, 2 H), 7.55 (d, J = 8.7 Hz, 2 H);

13 C-NMR (90.6 MHz, CD ₃ OD): δ = 53.0 (CH), 58.6 (CH ₃ ), 117.4 (CH), 128.8 (CH),

128.9 (C _q), 129.1 (2xCH), 130.5 (CH), 131.0 (C _q), 131.9 (2><CH), 133.8 (C _q),

138.5 (C _q ), 155.8 (C _q ), 175.0 (C _q ); MS (EI) m / z (%) = 293 [ ³⁷ Cl-M ⁺ ] (1), 291 [ ³⁵ Cl-M ⁺ ] (2), 234 [ ³⁷ Cl-M ⁺ -59] (35), 232

[ ³⁵ Cl-M ⁺ -59] (100), 205 (6), 187 (3), 170 (9), 152 (13), 141 (6), 122 (11), 116

(5), 98 (11), 43 (16); HRMS (EI): calcd for C ₁₃ H ₁₁ NO ³⁵ Cl [M ⁺ -59]: 232.0529; found: 232.0522. Methyl 2-amino-3- (4'-fluoro-6-hydroxybiphen-3-yl) propanoate

C ₁₆ H ₁₆ FNO ₃ 289.30

IH-NMR (360 MHz, CDC13): δ (ppm) - 2.80 (dd, J = 7.7 Hz, J = 13.7 Hz, 1H), 3.05 (dd, J = 3.9 Hz, J = 13.7 Hz, 1H) , 3.72 (s, 4H), 6.74 (d, J = 8.1 Hz, 1H), 6.95 - 7.01 (m, 2H), 7.09 (t, J = 8.8 Hz, J _HF = 8.8 Hz, 2H) , 7.42 (dd, J _HF = 5.4 Hz, J = 8.9 Hz, 2 H).

13 C-NMR (91 MHz, CDC13): δ = 39.7 (CH ₂ ), 52.1 (CH ₃ ), 55.5 (CH), 115.5 (d,

J _CF = 21.0 Hz, 2 x CH), 116.4 (CH), 127.7 (C _q ), 128.5 (C _q ), 129.6 (CH), 130.8 (d, J _CF = 8.1 Hz, 2 x CH), 131.1 ( CH), 133.6 (d, J _CF = 2.9 Hz, C _q ), 152.1 (C _q ), 162.1 (d, J _CF = 245.8 Hz, Cq), 175.2 (Cq).

MS (EI) m / z (%): 290 (29) [M ⁺ + H ⁺ ], 289 (92) [M ⁺ ], 231 (25), 230 (100), 229 (30), 228 (14 ), 213 (15), 203 (49), 202 (100), 201 (100), 200 (32), 199 (45), 195 (32), 187 (12), 186 (17), 185 (22 ), 184 (17), 183 (70), 182 (15), 181 (60), 173 (11), 172 (15), 171 (33), 170 (40), 165 (15), 159 (25 ), 157 (19), 153 (21), 152 (45), 151 (12), 147 (11), 146 (27), 133 (42), 127 (11), 120 (12), 115 (74 ), 114 (38), 107 (22), 89 (52), 88 (94), 77 (15), 74 (19).

Methyl 2-amino-3- (4'-chloro-6-hydroxybiphen-3-yl) propanoate

C ₁₆ H ₁₆ CINO ₃ 305.76

¹ H-NMR (360 MHz, CD ₃ OD): δ = 2.94 (dd, J = 6.0 Hz, J = 13.9 Hz, 1 H), 3.02 (dd, J = 7.0 Hz, J = 13.9 Hz, 1 H) , 3.71 (s, 3 H), 3.83 (dd, J = 6.0 Hz, J = 7.0 Hz, 1 H), 6.85 (d, J = 8.5 Hz, 1 H), 7.01 (dd, J = 2.2 Hz, J = 8.5 Hz, 1 H), 7.09 (d, J = 2.2 Hz, 1 H), 7.37 (d, J = 8.6 Hz, 2 H), 7.54 (d, J = 8.6 Hz, 2 H);

¹³ C-NMR (91 MHz, CD ₃ OD): δ = 39.9 (CH ₂ ), 49.9 (CH ₃ ), 56.4 (CH), 117.3 (CH), 128.6 (C _q ), 128.7 (C _q ), 129.0 (CH), 130.7 (CH), 131.9 (CH), 132.4 (CH), 133.6 (C _q), 138.7 (C _q), 154.6 (C _q), 175.3 (C _q);

MS (ESI) m / z = 306 [ ³⁵ C1-M ⁺ + H]; MS (EI): m / z (%): 307 [ ³⁷ Cl-M ⁺ ] (3), 305 [ ³⁵ Cl-M ⁺ ] (8), 248 [ ³⁷ Cl-M ⁺ -59] (4), 246 [ ³⁵ Cl-M ⁺ -59] (10), 219 [ ³⁷ Cl-M ⁺ -88] (42), 217 [ ³⁵ Cl-M ⁺ -88] (100), 181 (15), 152 (10 ), 136 (10), 107 (58), 88 (58), 70 (9), 57 (21), 43 (60).

Methyl 2-amino-3- (4'-bromo-6-hydroxybiphen-3-yl) propanoate

C ₁₆ H ₁₆ BrNO ₃ 350.21

IH NMR (360 MHz, CDCl _3): δ (ppm) = 2.80 (dd, J = 7.7 Hz, J = 13.7 Hz, 1 H), 3:03 (dd, J = 4.2 Hz, J = 13.7 Hz, 1 H ), 3.70 (s, 4 H), 6.73 (d, J = 8.2 Hz, 1 H), 6.93 (dd, 2.2 Hz, J = 8.2 Hz, 1 H), 7.00 (d, J = 2.3 Hz, 1 H ), 7.36 (d, J = 8.7 Hz, 2 H), 7.48 (d, J = 8.7 Hz, 2 H). 13 C-NMR (91 MHz, CDCl ₃ ): δ = 39.9 (CH ₂ ), 51.2 (CH ₃ ), 55.4 (CH), 116.5 (CH), 121.0 (Cq), 127.4 (C _q ), 128.1 (C _q ), 129.6 (CH), 130.8 (2 x CH), 131.0 (CH), 131.3 (2 x CH), 152.4 (C _q), 162.7 (C _q) 175.0 (C _q).

MS (EI) m / z (%): 349 (9) [ ⁷⁹ Br-M ⁺ ], 292 (10), 290 (11), 264 (31), 263 (100), 262 (32), 261 ( 100), 194 (12), 183 (10), 182 (49), 181 (37), 152 (11), 89 (10), 88 (34).

Methyl 2-amino-3- (4'-iodo-6-hydroxybiphen-3-yl) propanoate

Ci ₆ Hi ₆ INO ₃ 397,21

IH NMR (360 MHz, CDCl _3): δ (ppm) = 2.80 (dd, J = 7.6 Hz, J = 13.7 Hz, 1 H), 3:04 (dd, J = 3.8 Hz, J = 13.7 Hz, 1 H ), 3.70 - 3.74 (m, 4 H), 6.68 (d, J = 8.2 Hz, 1 H), 6.95 (dd, J = 2.2 Hz, J = 8.2 Hz, 1 H), 6.98 (d, J = 2.1 Hz, 1 H), 7.19 -

7.22 (m, 2H), 7.68-7.71 (m, 2H).

13 C-NMR (91 MHz, CDCl ₃ ): δ = 39.5 (CH ₂ ), 52.1 (CH ₃ ), 55.2 (CH), 92.8 (C _q ), 116.5 (CH), 127.6 (C _q ), 128.6 (C _q), 129.6 (CH), 130.9 (CH), 131.0 (2 x CH), 137.3 (2 x CH), 137.5 (C _q), 152.3 (C _q), 174.9 (C _q).

MS (EI) m / z (%): 397 (4) [M ⁺ ], 330 (30), 310 (11), 309 (30), 184 (25), 183 (100), 182

(16), 181 (13), 136 (17), 108 (27), 181 (37), 107 (80), 91 (11), 88 (36), 77 (12), 34 (19), 33 (23).

Methyl 2-amino-3- (6-hydroxybiphen-3-yl) propanoate

Ci ₆ Hi ₇ NO ₃ 271, 31

IH-NMR (600 MHz, CDCl _3): δ (ppm) = 2.82 (dd, J = 7.8 Hz, J - 13.8 Hz, 1 H), 3:05 (dd, J = 5.0 Hz, J = 13.8 Hz, 1 H ), 3.69 - 3.72 (m, 4 H), 6.82 (d, J - 8.2 Hz, 1 H), 7.01 (dd, J = 2.3 Hz, J = 8.2 Hz, 1 H), 7.03 (d, J = 2.2 Hz, 1H), 7.33 - 7.37 (m, 1H), 7.41 - 7.45 (m, 4H).

13 C-NMR (151 MHz, CDCl ₃ ): δ = 39.9 (CH ₂ ), 52.1 (CH ₃ ), 55.6 (CH), 116.3 (CH), 127.7 (C _q ), 128.4 (CH), 128.7 (CH) , 129.0 (2 x CH), 129.1 (2 x CH), 129.7 (CH), 131.0 (C _q), 137.3 (C _q), 151.8 (Cq), 175.3 (C _q).

MS (EI) m / z (%): 271 (6) [M +], 212 (7), 184 (26), 183 (100), 165 (5), 128 (3), 107 (7),

106 (4), 105 (4), 88 (6).

Methyl 2-amino-3- (4'-cyano-6-hydroxybipheii-3-yl) propanoate

Ci ₇ H ₁₆ N ₂ O ₃ 296.32

IH NMR (360 MHz, CDCl _3): δ (ppm) = 2.81 (dd, J = 8.0 Hz, J = 13.9 Hz, 1 H), 3:08 (dd, J - 4.8 Hz, J = 13.9 Hz, 1 H ), 3.72 (m, 1 H), 3.74 (s, 3 H), 6.67 (d, J = 8.2 Hz, 1 H), 6.98 (dd, J = 2.3 Hz, J = 8.2 Hz, 1 H), 7.04 (d, J = 2.3 Hz, 1H), 7.57 - 7.64 (m, 4H).

13 C-NMR (151 MHz, CDCl ₃ ): δ = 39.5 (CH ₂ ), 52.2 (CH ₃ ), 55.4 (CH), 110.3 (C _q ), 116.7 (CH), 118.9 (C _q ), 126.8 (C _q), 128.4 (C _q), 129.9 (2 x CH), 130.4 (CH), 131.1 (CH), 131.9 (2 x CH), 143.1 (C _q), 152.5 (C _q), 175.1 (C _q) ,

MS (EI) m / z (%): 296 (11) [M ⁺ ], 237 (26), 210 (7), 209 (49), 208 (100), 206 (5), 190 (7), 119 (7), 89 (20), 88 (63).

Methyl 2-amino-3- (4'-methoxy-6-hydroxybiphen-3-yl) propanoate

301, 34

IH NMR (360 MHz, CDCl _3): δ (ppm) = 2.73 - 2.91 (m, 1 H), 2.96 - 3:06 (m, 1 H), 3.70 - 3.72 (m, 4 H), 3.82 (s, 3 H), 6.70 (dd, J - 2.1 Hz, J = 8.3 Hz, 1 H), 6.80 (d, J = 8.3 Hz, 1 H), 6.95 (d, J = 8.6 Hz, 2 H), 7.01 ( d, J = 2.1 Hz, 1 H), 7.41 (d, J = 8.6 Hz, 2 H).

13 C-NMR (151 MHz, CDCl ₃ ): δ = 39.6 (CH ₂ ), 52.0 (CH ₃ ), 55.2 (CH ₃ ), 55.3 (CH), 114.0 (2 x CH), 115.6 (CH), 127.3 ( C _q ), 128.0 (C _q ), 129.0 (CH), 130.2 (2 x CH), 130.4 (C _q ), 131.0 (CH), 155.6 (C _q ), 158.8 (C _q ), 175.0 (C _q ) ,

MS (EI) m / z (%): 301 (3) [M ⁺ ], 213 (27), 195 (8), 136 (19), 108 (33), 107 (100), 91

(10), 88 (27), 77 (9), 33 (9).

Preparation of the Fmoc acids from aryl tyrosine methyl ester a according to Lit .: J. Org. Chem. 1991, 56,

3447th 2-7V- (fluorenylmethoxycarbonyl) -3- (4'-chloro-6-hydroxybiphen-3-yl) propanoic acid

C ₃₀ H ₂₄ CINO ₅ 513.97

IH-NMR (600 MHz, CDCl _3): δ (ppm) = 3:05 (dd, J = 5.3 Hz, J = 13.8 Hz, 1 H), 3.16 (dd, J = 4.8 Hz, J = 13.8 Hz, 1 H ), 4.17 (t, J - 7.0 Hz, 1 H), 4.30 (dd, J = 7.0 Hz, J = 10.4 Hz, 1 H), 4.40 (dd, J = 7.0 Hz, J = 10.4 Hz, 1 H) , 4.53 -4.60 (m, 1 H), 6.83 (d, J = 7.9 Hz, 1 H), 7.00 (d, J = 7.9 Hz, 1 H), 7.07 (s, lH), 7.26 (t, J = 7.5 Hz, 2 H), 7.37 - 7.41 (m, 4 H), 7.46 (d, J = 8.5 Hz, 2 H), 7.52 - 7.57 (m, 2 H), 7.75 (d, J = 7.4 Hz, 2 H).

13 C-NMR (91 MHz, CDCl ₃ ): δ = 36.9 (CH ₂ ), 46.9 (CH), 54.9 (CH ₂ ), 66.7 (CH), 115.9 (CH), 119.7 (4 x CH), 124.8 (CH ), 126.8 (2 x CH), 127.5 (2 x CH), 128.2 (2 x CH), 129.6 (C _q), 130.3 (2 x CH), 131.2 (Cq), 132.7 (C _q), 136.5 (CH ), 141.0 (2 x Cq), 143.5 (2 x Cq), 143.6 (C _q ), 152.3 (Cq), 155.8 (C _q ), 175.1 (C _q ).

MS (EI) m / z (%): 179 (15), 178 (100), 177 (11), 176 (19), 152 (10), 151 (8), 89 (7), 88

(7), 76 (9), 46 (7).

Claims

claims

1. A process for the preparation of a compound of formula 3

characterized in that a compound of formula 1

with a compound of formula 2

is implemented, where

E is - [CR> a ^a Rr> b °] _z - or NR ³ '; Q is - [CR> c ^c p R> d ^a ] v or NR ⁰ '; m is 0, 1, 2, 3, 4 or 5; z is 0, 1, 2, 3, 4 or 5; v is 0, 1, 2, 3, 4 or 5; q is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; r is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; s is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

each R ¹ is independently halogen, alkyl, haloalkyl, hydroxyalkyl,

or two radicals R 'together form a cyclic group of, for example, the formula -O- (CR ^u R ¹² ) _t -O-, where t is 1, 2 or 3, R ^{11 is} hydrogen, alkyl or haloalkyl, R ^{12 is} R ¹¹ and R ¹² together form a non-aromatic ring system containing 5, 6 or 7 carbon atoms;

Haloalkoxycarbonyl, alkenyloxycarbonyl, alkylsulfonyl, Haloalkylsulfonyl, alkylimino, aryl, aryloxy, arylcarbonyl, arylalkyl, arylmethoxycarbonyl, arylalkylimino, or heteroaryl, wherein the aryl group optionally carries 1, 2, 3 or 4 substituents selected from halogen, alkyl, haloalkyl, alkoxy or haloalkoxy;

R ^a 'is H, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, alkenyl, alkynyl,

Haloalkoxycarbonyl, alkenyloxycarbonyl, alkylsulfonyl,

R ^c 'is H, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, alkenyl, alkynyl,

Haloalkoxycarbonyl, alkenyloxycarbonyl, alkylsulfonyl,

Haloalkylsulfonyl, alkylimino, aryl, aryloxy, arylcarbonyl, arylalkyl, arylmethoxycarbonyl, arylalkylimino, or heteroaryl, wherein the aryl group optionally carries 1, 2, 3 or 4 substituents selected from halogen, alkyl, haloalkyl, alkoxy or haloalkoxy; R ^{e are} each independently H, halogen, -SR ⁴ , -OR ⁴ , -NR ⁴ R ⁵ , alkyl,

Haloalkoxycarbonyl, alkenyloxycarbonyl, alkylsulfonyl,

D is hydroxy, -NR ⁴ R ⁵ , -NHCOR ⁴ , -NR ⁴ COR ⁵ , -OR ⁶ , alkoxy, thioalkyl,

Cycloalkoxy, haloalkyloxy, alkylcarbonyloxy, haloalkylcarbonyloxy or aryloxy, the aryl group optionally carrying 1, 2, 3, 4 or 5 substituents selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxy, or alkoxycarbonyl;

X ^" for halide, sulfate, tetrafluoroborate, acetate, trifluoroacetate,

R ^{4 are} each independently hydrogen, alkyl, alkoxy, hydroxyalkyl,

Cycloalkyl, aryl, heteroaryl, fluorenylmethoxycarbonyl (Fmoc) or haloalkyl;

R ^{5 are} each independently hydrogen, alkyl, alkoxy, hydroxyalkyl,

Cycloalkyl, aryl, heteroaryl, fluorenylmethoxycarbonyl (Fmoc) or haloalkyl;

R ^{6 is} hydrogen, alkyl, hydroxyalkyl, cycloalkyl, alkylcarbonyl,

Haloalkylcarbonyl, aryl, heteroaryl or haloalkyl.

2. The method according to claim 1, characterized in that D is a group of the formula - OR ⁶ , wherein R ^{6 is} hydrogen, alkyl, hydroxyalkyl, alkylcarbonyl, Haloalkylcarbonyl, cycloalkyl, aryl, heteroaryl or haloalkyl.

3. Process for the preparation of a compound of formula 6

characterized in that in a first step a compound of the formula 7

with a compound of formula 8

is converted to a compound of formula 5,

in which

X 'is chlorine, bromine or iodine, m is 0, 1, 2, 3 or 4 and the remaining radicals are as defined in claim 1,

4. Process for the preparation of a compound of formula 10

characterized in that a compound of formula 9

is reacted with a compound of formula 2,

where t is 1, 2 or 3; m is 0, 1, 2 or 3;

R 11 represents hydrogen, alkyl or haloalkyl; R 12 is hydrogen, alkyl, haloalkyl or R ¹¹ and R ^{12 form} a non-aromatic ring system which is 5, 6 or 7

Carbon atoms, and the remaining radicals are as defined in claim 1.

5. Process for the preparation of a compound of formula 12

12, characterized in that a compound of formula 11

11 with a compound of formula 8

is reacted, wherein m is 0, 1, 2, 3 or 4 and the remaining radicals are as defined in claim 1.

6. The method according to any one of the preceding claims, characterized in that E is - [CR ^a R ^b ] ₂ - and Q is - [CR ^c R ^d ] _v -.

7. The method according to any one of the preceding claims, characterized in that the reaction is carried out in multi-stage process in the first step in the presence of at least one reducing agent.

8. The method according to any one of the preceding claims, characterized in that the reaction is carried out in multi-stage process in the first step in the presence of at least one solvent.

9. The method according to any one of the preceding claims, characterized in that the reaction in multi-stage process in the first step under irradiation, ultrasound or radiolysis is performed.

10. The method according to any one of the preceding claims, characterized in that the reaction in multi-stage process in the first step in a pH range of 0 to 11 is performed.

11. The method according to any one of the preceding claims, characterized in that the reaction is carried out in multi-stage process in the first step under inert gas.

12. The method according to any one of the preceding claims, characterized in that the reaction in multi-stage process in the first step in the temperature range of -78 ° C to 200 ° C is performed.