DE4327749A1 - Process for the preparation of 2-fluoroarylonitrile derivatives - Google Patents

Abstract

The invention relates to a process for the preparation of 2-fluoroarylonitrile derivatives from the corresponding fluoroaryl derivatives, this substance being deprotonated with a strong base and the resulting anion being reacted with a sulphonyl cyanide, if desired after transmetallation.

Description

The invention relates to a process for the preparation of 2-Fluoroaryl-nitrile derivatives from the corresponding fluoroaryl derivatives, deproto this with a strong base and the resulting anion, if desired after Transmetallation, reacted with a sulfonyl cyanide.

In preparative organic chemistry are methods for Metalation of aromatics of increasing importance. It has have been shown that in substituted aromatics due to Orientation effects regioselective metallations possible are. Thus, for example, fluorobenzene, 1,2- and 1,3-Difluorobenzene each regiospecific in the ortho-Posi tion to 2-fluorophenyllithium, 2,3- or 2,6-difluorophenyllite metalize.

The lithiated compounds are stable below -50 ° C and provide valuable intermediates in the synthesis of many fluoroaromatics (eg, A.M. Roe, Chem., Comm. 22, 582, 1965).  

It has now surprisingly been found that in the 1-Posi tion suitably substituted 3-fluoroaryl selectively in the 4-position are metallizable. So you can use 4-substituted Produce 2-fluoroaryl nitriles by reacting in the 1-position substituted 3-fluorobenzenes with an organometallic Deprotonated reagent and reacted with a sulfonyl cyanide.

The previously known processes for the preparation of 2-fluoro Arylonitriles all lead to unsatisfactory results.

For this purpose, especially poor yields and z. T. difficult accessible starting compounds responsible. How to succeed For example, the preparation of 1-cyano-2-fluoro-4- (trans- 4-heptylcyclohexyl) benzene according to EP-0 119 756 from the corre sponding 1-acetyl compound only with a yield of approx. 1% d. Th.

In contrast, the cross-coupling of organometallic requires Compounds with 4-bromo-2-fluorobenzonitriles (eg. DE 36 32 410 or DE 37 36 489) the use of expensive Palla dium catalysts, which are often not recovered can.

In DE-OS 39 39 611 a process for the preparation of of 2-fluoroaryl nitriles, the fluoroaromatic is compounded in the ortho position to the fluorine atom, the 2-fluoroaryl metal derivative is formylated and then the formyl compound is converted into the nitrile becomes. The disadvantage of this method is that you have two stages needed to get from the metal derivative to the nitrile.

Object of the present invention was a manufacturing to find a method for the compounds of formula I, the the disadvantages of the previous method not described or only slightly.

Surprisingly, it has now been found that 1-substituted 3-fluoroaryl derivatives metallated regiospecifically in the 4-position and can be synthesized by means of sulfonyl cyanides in one step the derivatives of 2-Fluorarylonitrils can be converted.

The compounds obtainable by these processes of Depending on the substitution, formula I are valuable intermediates z. In the synthesis of liquid crystalline compounds, as the components of liquid-crystalline phases whose dielek improve tric anisotropy or other parameters. you are quite common as intermediates in industrial organic chemistry of interest.

The invention therefore relates to a process for the manufacture ment of 2-Fluorarylonitrildivate from the corresponding Fluoroaryl derivatives, this with a strong base deprotonated and the resulting anion, desired if reacted after Ummetallierung, with a sulfonyl cyanide.

The inventive method is easily accessible 2-fluoroaryl derivatives z. B. according to EP OS 02 80 902 Herge can be made.

Preferred embodiments are:

• a) method wherein the fluoroaryl derivative and the Sul Fonylcyanid presented in an inert solvent and to Add the strong base to this reaction mixture.
• b) Process wherein the fluoroaryl derivative in an inert Solvent presents, and the strong base and the Sul adds fonyl cyanide at the same time.
• c) method wherein the fluoroaryl derivative in an inert Solvent presents, and a tetraalkyl titanate and a to this mixture a strong base at the same time and then adding the sulfonyl cyanide.
• d) Process for the preparation of o-fluorobenzonitrile derivatives of Formula I

in which
R¹, H, C represents _1-18 -alkyl or alkoxy or a mesogenic group, and
L¹ and L² are H, each being F, Cl or Br
wherein a compound of formula II

optionally in the presence of a tetraalkyl titanate, treated with a strong base and the included organometallic compound of the formula III

in which
Met Li, K, Na or Ti (OR ') ₃ means
wherein R 'is C _1-6 -alkyl,
reacted with a sulfonyl cyanide.

• e) method wherein the reaction at temperatures between between -40 and + 60 ° C.
• f) process wherein 0.8 to 1.3 mol sulfonyl cyanide bezo gen on 1 mol of fluorobenzene derivative.

L 1 in the formulas I, II and III is preferably H or F, in particular F and L² is preferably H.  

The 2-fluoroaryl derivatives of the formula II are known Procedures, such as. In H. Gilmann, T.S. Soddy, J. Org. Chem. 22, 1715 (1957) are described in the corresponding Organometallic z. B. of formula III.

The reaction of the 2-fluoroaryl derivatives of the formula II takes place preferably in an inert solvent, for example Ethers such as diethyl ether, dimethoxyethane, tetrahydrofuran (THF), dioxane or tert-butyl methyl ether (TBME), char such as hexane, cyclohexane, benzene, toluene or Gemi rule of these solvents.

Deprotonation of the 2-fluoroaryl derivatives of the formula II are organometallic compounds and base systems that such compounds, alkali metal amides or alkali metal hy dride included, suitable. Among the organometallic Rea genzien are alkyl or aryl metal compounds, such as. Eg n, sec- or tert-butyllithium (BuLi) or phenyllithium or Alkali metal amides such as sodium amide, potassium amide, lithium diiso propylamide (LDA), lithium tetramethylpiperidide or potassium hexane amethyldisilazane particularly suitable. The base systems contain th additionally an activator, preferably complex formers such as amines or amides, such. Hexamethylphos phosphoric triamide (HMPT), tetramethylethylenediamine (TMEDA), N, N-dimethylpropyleneurea (DMPU), transmetalation reagent substances, such as As potassium tert-butoxide (KOT) or crown nether, such as B. 18-Crown-6.

The deprotonation of the compounds of formula II is carried out at Temperatures from -100 ° C to + 100 ° C, preferably at -40 ° C to + 60 ° C, especially at about 0 ° C, and is usually in finished a few minutes.  

Preferably, the metallation takes place in the presence of Sul fonylcyanides or a Ummetallierungsreagenzes. It will the metal derivative, e.g. B. the formula III formed in situ and quickly intercepted by the electrophile present. These Reaction is already with other electrophiles known, for. B. EP 04 40 082.

The term mesogenic group is familiar to the person skilled in the art (eg H. Kelker, H. Hatz, Handbook of Liquid Crystals) and stands for a so-called "rod-like" remainder consisting of ring glaze and possibly bridge piers and wing groups.

The mesogenic radical preferably denotes a radical of the formula VI

-Z¹-A¹- (Z²-A²) _n -R ° (VI)

wherein
A¹ and A² are each independently of one another unsubstituted or substituted by 1 to 2 fluorine atoms 1,4-phenylene, in which also one or two CH groups may be replaced by N, or unsubsti tuiertes or by a cyano group-substituted 1,4-cyclohexylene wherein also one or two CH₂ groups may be replaced by O or S, thiadiazole-2,5-diyl, 1,4-bicyclo [2,2,2] octylene,
Z¹ and Z² are each independently of one another -CO-O-, -O-CO-, -CH₂O-, -OCH₂-, -CH₂CH₂-, -C≡C- or a single bond,
R⁰ is an optionally halogenated alkyl, alkoxy, alkenyl or alkenyloxy group having 1 to 16 C-Ato and
n 0, 1, or 2
mean.

Preferred starting compounds of formula II are those of the formula II1 to II20

In the compounds of the preceding and following For R¹ or R⁰ is preferably an alkyl, alkenyl, Alkoxy or an oxaalkyl radical each having 1 to 12 carbon atoms or also a perfluoroalkyl radical having 1 to 12 C atoms.

If R¹ or R⁰ is alkyl or an alkoxy radical, then this can be straight-chain or branched. Preferably he straight-chain and therefore preferably methyl, ethyl, Propyl, butyl, pentyl, hexyl, heptyl, methoxy, ethoxy, Pro poxy, butoxy, petoxy, hexoxy or heptoxy, furthermore octyl, Nonyl, decyl, undecyl, dodecyl, octoxy, nonoxy, decoxy, Undecoxy.

Oxaalkyl is preferably straight-chain 2-oxapropyl (= Methoxymethyl), 2- (= ethoxymethyl) or 3-oxabutyl (= 2-Me thoxyethyl), 2-, 3- or 4-oxapentyl, 2-, 3-, 4- or 5-oxa hexyl, 2-, 3-, 4-, 5- or 6-oxaheptyl, 2-, 3-, 4-, 5-, 6- or 7-oxo-octyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-oxanonyl, 2-, 3-, 4-, 5-, 6-, 7-, 8- or 9-oxadecyl.

Branched groups of this type usually do not contain more than one chain branch. Preferred branched radicals R¹ and R⁰ are isopropyl, 2-butyl (= 1-methylpropyl), Iosbu tyl (= 2-methylpropyl), 2-methylbutyl, isopentyl (= 3-methyl butyl), 2-methylpentyl, 3-methylpentyl, 2-ethylhexyl,  2-propylpentyl, isopropoxy, 2-methylpropoxy, 2-methylbutoxy, 2-methylpentoxy, 3-methylpentoxy, 2-ethylhexoxy, 1-methyl hexoxy, 1-methylheptoxy.

If R⁰ is an alkylene radical, this can be straight be tig or branched. Preferably, it is straight-chain and has 2 to 10 carbon atoms. They therefore mean especially vinyl, Prop-1, or prop-2-enyl, but-1, 2- or but-3-enyl, Pent-1-, 2-, 3- or pent-4-enyl, hex-1, 2-, 3-, 4- or Hex-5-enyl, hept-1, 2-, 3-, 4-, 5- or hept-6-enyl, Oct-1, 2-, 3-, 4-, 5-, 6- or oct-7-enyl, non-1-, 2-, 3-, 4-, 5-, 6-, 7- or non-8-enyl, Dec-1, 2-, 3-, 4-, 5-, 6-, 7-, 8- or dec-9-enyl.

Met is preferably Li or K.

Z1 is preferably a single bond, -CH₂O-, -OCH₂- or -CH₂-CH₂-, in particular a single bond or -CH₂CH₂-.

The metal compounds of formula III are then at optionally metallized with the same temperatures and with the sulfonyl cyanide implemented.

Preferred sulfonyl cyanides are compounds of the formula IV,

R²-SO₂-CN IV

wherein
R² is alkyl or perfluoroalkyl having 1 to 7 carbon atoms or phenyl optionally substituted by 1 or more C _1-3 alkyl groups.

Particularly preferred are p-toluenesulfonyl cyanide (R² = 4-Me thylphenyl), mesyl cyanide R² = CH₃) and triflate cyanide (R² = CF₃).

Preferred transmetalation reagents are tetraalkylorthotite anate and trialkylorthotitanates of the formula V

(R 3 O) ₃Ti-X V

in which
X is Cl or OR³ and each independently
R³ has one of the meanings of R².

Particularly preferred are tetraalkyl orthotitanates of the formula V, wherein R³ is methyl or isopropyl.

The compounds of the formula II are known (for example DE 29 33 653, EP 02 80 902, JP 59042329, JP 59016840 the DE 31 39 130, EP 02 05 998) or can be literature produce known methods (eg Houben-Weyl, methods of Organic Chemistry, Georg Thieme Verlag, Stuttgart). there can also by known, not mentioned here Variants are used.  

The compounds of the formula I are suitable for use as liquid crystalline materials, such as. In EP 0 119 756, DE 35 30 126, where 89/12621, EP 03 17 175 and DE 40 02 609 disclosed, or may be used as intermediates for the manufacturers tion of other liquid crystalline compounds used become.

The following examples are intended to explain the invention in more detail, without limiting it.

Above and below, percentages are by weight; All temperatures are given in degrees Celsius.

The following abbreviations are used:

BuLi butyllithium I isotropic phase K crystalline-solid phase N nematic phase S smectic phase THF tetrahydrofuran TMEDA tetramethylethylenediamine LDA Lithium diisopropylamide (prepared from equimolar amounts of diisopropylamine and n-BuLi.

The numbers between the individual phase names indicate the phase transitions in degrees Celsius.  

Example 1 Preparation of 4- (trans-4-heptylcyclohexyl) 2-fluorobenzones tril

A mixture of 0.1 mol of 3- (trans-4-heptylcyclohexyl) fluoride benzene (prepared according to EP 01 19 756) and 200 ml of THF at 40 ° C simultaneously with a solution of 0.1 mol LDA in Hexane and a mixture of 0.1 mole p-toluenesulfonyl cyanide and 20 ml of THF. After warming to room temperature and usual workup gives the product as a colorless Solid, K 19 N 20 I, in a yield of 80% d. Th.

Analog are produced:

example 2 Preparation of 4- (trans-4-propylcyclohexyl) -2,6-difluoro-benzene zonitril Used substances

0.1 mol of 3- (trans-4-propylcyclohexyl) -1,5-difluorobenzene (PCH-3.FF)
0.11 mol LDA in hexane
140 ml of THF
0.11 mol of tetraisopropylorthotitranate (Ti (OiPr) ₄)
0.11 mol p-toluenesulfonyl cyanide (PTS-CN).

A mixture of 0.1 mol PCH-3.F.F. and 140 ml of THF is added 0 ° C simultaneously with 0.11 mol LDA and 0.11 mol of Ti (OiPr) ₄ added. After stirring for 10 minutes, 0.11 mol of PTS-CN are added dropwise added, allowed to warm to 10 ° C and worked up as usual. After chromatography with dichloromethane / hexane 1: 1 as Laufmit Tel gives the pure product, K 57 I in a yield from 70% d. Th.

Claims (7)

1. A process for the preparation of 2-Fluorarylonitrildivate from the corresponding Fluorarylderivaten, characterized in that deprotonated this with a strong base and the resulting anion, if desired, after transmetallation, with a sulfonyl cyanide. 2. The method according to claim 1, characterized in that the fluoroaryl derivative and the sulfonyl cyanide in one inert solvent and presents to this Reaktionsge mix the strong base. 3. The method according to claim 1, characterized in that the fluoroaryl derivative in an inert solvent and the strong base and sulfonyl cyanide adds at the same time. 4. The method according to claim 1, characterized in that the fluoroaryl derivative in an inert solvent and a tetraalkyl titanate and one to this Mixture adds a strong base at the same time, and then add the sulfonyl cyanide.   5. The method according to any one of claims 1 to 4 for the produc- tion of o-fluorobenzonitrile derivatives of the formula I. in which
R¹, H, C represents _1-18 -alkyl or alkoxy or a mesogenic group, and
L 1 and L 2 are each H, F, Cl or Br,
characterized in that a compound of the formula II optionally in the presence of a tetraalkyl titanate, treated with a strong base and the organometallic compound of formula III in which
Met Li, K, Na or Ti (OR ') ₃ means
wherein R 'is C _1-6 alkyl, reacted with a sulfonyl cyanide. 6. The method according to any one of claims 1 to 5, characterized characterized in that the reaction at temperatures between -40 and + 60 ° C performs. 7. The method according to any one of claims 1 to 6, characterized characterized in that 0.8 to 1.3 mol sulfonyl cyanide based on 1 mol of fluorobenzene derivative.