CA1334976C

CA1334976C - Process for the preparation of pyrrole derivative

Info

Publication number: CA1334976C
Application number: CA000593961A
Authority: CA
Inventors: Bruno Schaub; Hans-Ruedi Kanel; Peter Ackermann
Original assignee: Ciba Geigy AG
Current assignee: Syngenta Participations AG
Priority date: 1988-03-18
Filing date: 1989-03-16
Publication date: 1995-03-28
Anticipated expiration: 2012-03-28
Also published as: KR0128282B1; AU3146789A; IL89634A; EP0333661A2; EP0333661B1; EP0333661A3; AU624806B2; DE58907537D1; JP2791488B2; ZA892044B; KR890014530A; JPH01275577A; ATE104974T1; IL89634A0

Abstract

3-(2,2-difluorobenzodioxol-4-yl)-4-cyanopyrrole can be prepared by reacting 4-metallo-2,2-difluorobenzodioxole (III) with an unsaturated nitrile and then with a sulfonylmethyl isocyanide in a one-pot process.
The compounds III are novel intermediates.

Description

- 5-16952/+

Process for the preparation of a pyrrole derivative The present invention relates to a process for the preparation of 3-(2,2-difluorobenzodioxol-4-yl)-4-cyanopyrrole of formula I

~ CN (I), F/ \F
to the 4-metallo-2,2-difluorobenzodioxoles involved as intermediates of that process, and to a process for the preparation of those intermedi-ates.

It is known from D~-PS 2,927,480 that N-acyl-3-phenyl-4-cyanopyrroles have a fungicidal activity. ~P-A 206999 describes 3-(2,2-difluorobenzo-dioxol-4-yl)-4-cyanopyrrole as a fungicide.

A process for the preparation of 3-phenyl-4-cyanopyrroles starting froman ~-cyanocinnamic acid (or from a suitable ester of such an acid) by reaction with a substituted methyl isocyanide has been described in D~-OS 3,601,285.

The disadvantage of that process is that the benzaldehydes, which, as the starting materials, form the basis of the ~-cyanocinnamic acids, can be obtained only with difficulty in the case of certain substitutions in the nucleus. In such cases, a process based on that reaction sequence proves to be very difficult to carry out and uneconomical.

The aim of the present invention is to provide a process for the preparation of 3-(2,2-difluorobenzodioxol-4-yl)-4-cyanopyrrole which process is improved from the technical and economic point of view and can be applied generally.

Surprisingly, it has now been found that 3-(2,2-difluorobenzodioxol-4-yl)-4-cyanopyrrole of formula I

.~ ~. il il-CN (I) 0~ ;0 ~/

F F
can be very readily prepared in a one-pot process when a 4-metallo-2,2-difluorobenzodioxole of formula III, wherein Me is a metal, n is the valency of that metal and Y is an anionic radical which can also be a Cl-Cl4 organic basic radical, is reacted in a solvent phase, in the presence or absence of a complex-forming compound, first with an unsaturated nitrile of formula IV

~ n-l ~ ~ RlCH=C
F F \R2 III IV
wherein Rl is halogen, Cl-C4alkoxy, C 6-C loaryloxy, di-Cl-C4alkylamino, C1-C4-alkylsulfonyloxy, C6-Cloarylsulfonyloxy or Cl-C4alkylcarbonyloxy (=acyloxy) and R2 is a Cl-C4alkoxycarbonyl radical, and then with an isocyanide of formula V

R3-SOzCHzNC, (V) wherein R3 is an open-chain or cyclic, unsubstituted or substituted Cl-Clohydrocarbon.

It has also been found and is likewise a subject of the present invention that the compounds of formula III can be prepared very readily and regioselectively by reacting 2,2-difluorobenzodioxole of formula II in a suitable solvent phase, in the presence or absence of a complex-forming compound, with a metal or a metal compound, metallation not occurring to any appreciable extent in any position other than the 4-position.

_ 3 _ 1 3 3 4 ~ 7 6 - ~ + Me Y ~ $ n-l F F F F
(II) (III) In these formulae, Me, Y and n are as defined above, at least one Y being an organic basic radical. If a metal is used, n = 0 and Y does not apply.

The nature of the metal Me used and also of the metal compound MenYn used is not in principle subject to any restriction but metals of the alkali or AlkAl;ne earth groups are preferred, especially Li, Na, K, Cs, Ca and Mg and their compounds with a C1-Clohydrocarbon radical.

The reaction is carried out in a temperature range of from -70 to +150C, preferably at from -25 to +80C.

Suitable solvents are, for example, hydrocarbons (such as petroleum ether, toluene, hexane, heptane, etc.) and ethers (such as diethyl ether, dioxane, tetrahydrofuran) in addition to those specified hereinafter. If non-polar or weakly polar solvents are used in the metallation, then the use of complexing agents is necessary or at least advantageous if a high regioselectivity is to be obtained and ensured.

Of the process conditions, the use of a complex-forming compound selected from a group consisting of tert.-amines, cyclic ureas, ethers and N-substituted acid amides is preferred. Of those, hexamethylphosphoric acid triamide, ethylene glycol dimethyl ether, 1,3-dimethyl-2-imidazo-lone, dimethylethyleneurea, dimethylpropyleneurea and N,N,N',N'-tetra-methylethylenediamine are especially preferred.

The present invention relates also to the compounds of formula III which can be prepared by that process.

Conventional metallation processes, described in organic chemistry, foraromatic compounds generally take place non-selectively and result in a -_ 4 _ ~ ~3 ~ 9 7 6 mixture of isomeric organometallic compounds. It is therefore surprising that the metallation of 2,2-difluorobenzodioxole takes place selectively in the 4-position.

Compounds of formula III can also be obtained by trans-metallation of acompound of formula IIIa ~ (Me ) Yn_l (IIIa), 0~ ;0 F/ \F
with a compound of formula MenY , Me' being a metal other than Me. The meaning of the metal Me' and its compounds is limited essentially to metals of the alkali and Alk~l;ne earth group. Preferred are Li, Na, K, Cs and Mg, lithium being especially preferred. The present invention relates also to that transmetallation. Alkali metal and A 1 kA 1; ne earth metal derivatives of 2,2-difluorobenzodioxole can generally be obtained by direct metallation, while metals from the other groups are advantage-ously obtained from the former group by transmetallation. The present invention relates also to the 4-metallo-2,2-difluorobenzodioxole deriva-tives of formula III obtainable by transmetallation or direct metalla-tion, especially to those in which the metal is an alkali metal or an AlkAl;ne earth metal or is zinc, cadmium, copper, palladium, nickel, aluminium, silicon, tin, titanium or zirconium.

In such a transmetallation operation, for example 2,2-difluorobenzodi-oxole-lithium can be converted with magnesium bromide or with zinc chloride into 2,2-difluorobenzodioxole-magnesium bromide or 2,2-di-fluorobenzodioxole-zinc chloride, respectively.

Surprisingly, it has now been found that, starting from 2,2-difluoro-benzodioxole of formula II, the complete process for the preparation of the compounds of formula I can be effected in a one-pot process via the stage of the compounds of formula III despite the fact that the reactants are completely different and are added gradually and possibly under changing conditions, likewise without isolation of further products formed intermediately.

-_ 5 _ 1 3 3 4 9 7 6 The present invention accordingly relates also to a process for the preparation of 3-(2,2-difluorobenzodioxol-4-yl)-4-cyanopyrrole, wherein the 2,2-difluorobenzodioxole of formula II is converted in a solvent phase, in the presence or absence of a complex-forming compound, with an organometal compound or with a metal into a 4-metallo-2,2-difluorobenzo-dioxole of formula III which is reacted, without being isolated, first with an unsaturated nitrile of formula IV and then with an isocyanide of formula V.

Metal compounds of formula III are therefore the direct intermediates for compounds of formula I and are either introduced as such into the preparation process or are formed in the first step thereof.

Using the process according to the invention, 3-(2,2-difluorobenzodi-oxol-4-yl)-4-cyanopyrrole can be prepared in a high yield.

The Cl-C4alkyl representing the individual radicals Rl and Rz in formula IV as part of other radicals may be branched or straight-chained and is methyl, ethyl, propyl, isopropyl, butyl, sec.-butyl, isobutyl or tert.-butyl.

Rl as a C6-C1Garyloxy or a C6-Cloarylsulfonyloxy radical may be phenoxy, Cl-C4alkylphenoxy, a- or ~-naphtyloxy, further phenylsulfonyloxy, C1-C4-alkylsulfonyloxy or a- or ~-naphthylsulfonyloxy.

There may be mentioned as examples of the C1-Clohydrocarbon radical mentioned under R3 in formula V, without these constituting a limitation, methyl, ethyl, isopropyl, heptyl, octyl, cyclopentyl, cyclohexyl, decyl, methylcyclohexyl, phenyl, p-tolyl, l-naphthyl and 2-naphthyl.

In the metallation reagents MenY for the 2,2-difluorobenzodioxole, as mentioned, at least one Y is a strongly basic anion which may be C1-C1o-alkyl , preferably C1-C4alkyl , C6-C14aryl , C1-Cloalkoxy , preferably Cl-C4alkoxy , NHz , Cl-ClohydrocarbylNH or di(Cl-Clohydrocarbyl)N or also H .

- 6 - ~ 3 3 4 9 7 ~

Of these anions, alkyl , aryl (such as phenyl ), di-(Cl-C4alkyl)N , (C1-C4alkyl)(Cs-C6cycloalkyl)N and di- (Cs-C6cycloalkyl)N are pre-ferred. For transmetallation it is also possible to use metal compounds having anions such as halide, nitrate, sulfate, phosphate, acetate, formate, etc..

The following solvents are especially suitable for the preparation of the compounds of formula I in stepwise processes or in a one-pot process:

Aliphatic or aromatic hydrocarbons, ethers, tertiary amines, N-alkylated acid amides, lactams or cyclic ureas, sulfoxides, sulfones, nitriles, ketones, alcohols or mixtures thereof. ~xamples are pentane, isopentane, hexane, heptane, cyclohexane, methylcyclohexane, benzene, tol~ene, xylene, diethyl ether, dibutyl ether, tetrahydrofuran, dioxane, ethylene glycol dimethyl ether, triethylamine, N,N,N',N'-tetramethylethylenedi-amine, hexamethylphosphoric acid triamide, dimethylformamide, dimethyl-acetamide, N-methylpyrrolidone, ethylenedimethylurea, propylenedimethyl-urea, dimethyl sulfoxide, tetramethylenesulfone, acetonitrile, acetone, methyl ethyl ketone, methyl isobutyl ketone, cyclohexanone, methanol, ethanol, isopropanol and tert.-butanol.

When non-polar solvents are used, in order to ensure that the reaction proceeds smoothly it is almost always necessary to add a complexing agent, and when weakly polar solvents are used such action is at least advantageous. The complexing agent is added in an amount of from 0.01 mol. % to a tenfold excess, based on the compound of formula II.
Tertiary amines, N-substituted acid amides, lactams, cyclic ureas, alcoholates, sulfoxides or ethers, some of which have already been mentioned among the above solvents or earlier among the preferred complexing agents, are generally suitable.

Included among the ethers in the broader sense are also crown ethers, for example 15-crown-5; 18-crown-6; dibenzo-18-crown-6; dicyclohexyl-18-crown-6; dibenzo-24-crown-8; and dicyclohexyl-24-crown-8.

_ 7 _ 1 ~3 4 9 7 6 The processes according to the invention preferably take place under aninert gas in the presence of a complex-forming compound (= complexing agent) and in a solvent or a solvent mixture.

The preferred first step in each of the above-mentioned processes for the preparation of the compounds of formula III, IIIa or I is the metallation of the 2,2-difluorobenzodioxole of formula II with lithium or, prefer-ably, an organolithium compound. Accordingly, of the compounds of formula III, 2,2-difluorobenzodioxol-4-yl-lithium is especially preferred as intermediate.

One of the preferred forms of the complete process for the preparation of 3-(2,2-difluorobenzodioxol-4-yl)-4-cyanopyrrole is that wherein the 2,2-difluoro-1,3-benzodioxole dissolved in a hydrocarbon is added at from -25 to -5C to a mixture of approximately equimolar amounts of tetra-methylethylenediamine and n-butyllithium, and then an equimolar amount of ethoxymethylenecyanoacetic acid ethyl ester and subsequently an equimolar amount of p-toluenesulfonylmethyl isocyanide are added to the reaction mixture at from -25 to +25C. Tetrahydrofuran is advantageously used as a further solvent. Methanol may be mentioned as the preferred solvent for the last reactant.

One of the especially preferred forms of the complete process for the preparation of 3-(2,2-difluorobenzodioxol-4-yl)-4-cyanopyrrole is that wherein n-butyllithium is added at from -25 to -5C to a mixture, dissolved in a hydrocarbon, of approximately equimolar amounts of 2,2-difluorobenzodioxole and tetramethylethylenediamine, and then an equimolar amount of ethoxymethylenecyanoacetic acid ethyl ester and subsequently an equimolar amount of p-toluenesulfonylmethyl isocyanide are added to the reaction mixture at from -25 to +25C.

The organometal compounds of formula III, both in solution and in suspension, are stable for a time at low temperatures in the form of their corresponding complexes. It is known that, for example, organo-lithium compounds are often in the form of dimers. In addition, solvents or complexing agents that have free electron pairs, for example ethers or tert.-amines, are coordinatively bonded to the metal.

In the preparation according to the invention of the compounds of formula III from the compound of formula II, organometal compounds are to be given prominence as reactants. Of the organometal compounds, the organolithium compounds, especially methyllithium, n-butyllithium, sec.-butyllithium, tert.-butyllithium, phenyllithium, lithium diiso-propylamide and lithium dicyclohexylamide, are particularly preferred.

The metal compounds used for the preparation of the compounds of formula III, and the compounds of formulae II, IV and V are known products which are commercially available or can be prepared by con-ventional methods.

The process according to the invention is illustrated by the following Examples:

Example 1: Preparation of 2,2-difluoro-1,3-benzodioxol-4-yl-lithium a) First 13 g (110 mmol) of N,N,N',N'-tetramethylethylenediamine in 30 ml of toluene/tetrahydrofuran (2:1) and then 15.8 g (100 mmol) of 2,2-di-fluoro-1,3-benzodioxole, dissolved in 120 ml of toluene/tetrahydrofuran (2:1), are added dropwise under a nitrogen atmosphere at from -15 to -10C to 69 ml (110 mmol) of n-butyllithium (1.6 molar suspension in toluene), n-butane being formed.

A specimen of the resulting dissolved product of formula III is ident-ified by NMR spectroscopy.

Signals ~ ppm: 6.83 d (J ~ 7 Hz) corresponds to: H 7 7.10 dd (J ~ 7 Hz) corresponds to: H 6 7.80 d (J = 4 Hz) corresponds to: H 5 b) 94.0 g (272 mmol) of n-butyllithium (18.5 % in toluene) are added dropwise under a nitrogen atmosphere at from -15 to -10C to 29.5 g (254 mmol) of N,N,N',N'-tetramethylethylenediamine and 40.0 g (253 mmol) of 2,2-difluoro-1,3-benzodioxole in 35 ml of toluene, n-butane being formed in addition to the title compound.

c) 39.3 g (339 mmol) of N,N,N',N'-tetramethylethylenediamine are added dropwise under a nitrogen atmosphere at from -15 to -10C to 137.8 g (409 mmol) of n-butyllithium solution (19.0 % in toluene). The resulting reaction mixture is added dropwise at from -15 to -10C under a nitrogen atmosphere to a solution of 53.3 g (337 mmol) of 2,2-difluoro-1,3-benzo-dioxole in 46 ml of toluene, n-butane being formed in addition to the title compound.

The following compounds of formula III are prepared analogously to ~xample 1.

/~ \- MenY
~ ~ n-l (III) 0~ ~0 F/ \F

,~

Table: Compounds of formula III
compound Me Y position no. NMR: ~ (ppm) H atom 1 Li - 6,83 (d) (J=7Hz) 7 7,10 (dd) (J=7Hz) 6 7,80 (d) (J=4Hz) 5 2 Na 3 K - 6,85 (d) (J=7Hz) 7 7,05 (dd) (J=7Hz) 6 7,76 (d) (J=4Hz) 5 4 Cs Cl Mg Br 6,86 (d) (J=7Hz) 7 6,65 (dd) (J=7Hz) 6 7,42 (d) (J=4Hz) 5 6 Hg Cl 6,93 (d) (J=7Hz) 7 6,84 (dd) (J=7Hz) 6 7,05 (d) (J=4Hz) 5 7 Zn Cl 6,84 (d) (J=7Hz) 7 6,98 (dd) (J=7Hz) 6 7,14 (d) (J=4Hz) 5 8 Cu Cl Example 2: Preparation of 3-(2,2-difluorobenzodioxol-4-yl)-4-cyano-pyrrole a) First 48.2 g of N,N,N',N'-tetramethylethylenediamine, and then, after stirring for 30 minutes, 60 g of 2,2-difluoro-1,3-benzodioxole dissolved in 200 ml of hexane are added under an inert gas atmosphere at -20 to 261 ml of 1.6N n-butyllithium in hexane. After 15 minutes, 70.7 g of ethoxymethylenecyanoacetic acid ethyl ester dissolved in 250 ml of tetrahydrofuran are added at -15 within a period of 25 minutes. After a further 30 minutes, 81.5 g of p-toluenesulfonylmethyl isocyanide dis-solved in 220 ml of tetrahydrofuran are added to the resulting suspension at 0 over a period of 25 minutes. The solution is then heated to 25 and 400 ml of solvent are evaporated off in vacuo.

The residue is diluted with 500 ml of ethyl acetate and the resulting solution is washed twice with 300 ml of water and twice with 300 ml of saturated sodium chloride solution and dried over magnesium sulfate. The solvent is evaporated off in vacuo.

The residue is chromatographed over silica gel using hexane/ethyl acetate (3:1) as eluant.

After evaporation of the solvent in vacuo, the title compound having a melting point of 193-195C is obtained. Yield 70 % of the theoretical yield, based on 2,2-difluorobenzo-1,3-dioxole.

b) 106.2 g (307 mmol) of n-butyllithium solution (18.5 % in toluene) are added dropwise under a nitrogen atmosphere at from -15 to -10C to 29.5 g (254 mmol) of N,N,N',N'-tetramethylethylenediamine and 40 g (253 mmol) of 2,2-difluoro-1,3-benzodioxole in 35 ml of toluene. 52.1 g (308 mmol) of ethoxymethylenecyanoacetic acid ethyl ester in 115 ml of toluene are then added within a period of 2 hours at from -15 to -10C.
After 20 minutes, the resulting suspension is heated to 0C and 50 g (256 mmol) of p-toluenesulfonylmethyl isocyanide dissolved in 135 ml of tetrahydrofuran are added over a period of 30 minutes. The reaction mixture is then heated to 25C, added to 150 ml of water and filtered to obtain the title compound.

c) 39.3 g (339 mmol) of N,N,N',N'-tetramethylethylenediamine are added dropwise under a nitrogen atmosphere at from -15 to -10C to 137.8 g (409 mmol) of n-butyllithium solution (19.0 % in toluene). The resulting reaction mixture is metered at from -15 to -10C under a nitrogen atmosphere into a solution of 53.3 g (337 mmol) of 2,2-difluorobenzo-2,3-dioxole in 46 ml of toluene. 69.1 g (409 mmol) of ethoxymethylene-cyanoacetic acid ethyl ester in 150 ml of toluene are then metered in at from -15 to -10C. The resulting suspension is subsequently heated to 0C and 66.6 g (342 mmol) of p-toluenesulfonylmethyl isocyanide dissolved in 180 ml of tetrahydrofuran are added. The reaction mixture is then heated to 25C, added to 200 ml of water and filtered to obtain the title compound.

Claims

1. A process for the preparation of 3-(2,2-difluorobenzodioxol-4-yl)-4-cyanopyrrole of formula I
(I), wherein a 4-metallo-2,2-difluorobenzodioxole of formula III, wherein Me is a metal, n is the valency of that metal and Y is an anionic radical, is reacted in a suitable solvent phase, in the presence or absence of a complex-forming compound, first with an unsaturated nitrile of formula IV

III IV
wherein R1 is halogen, C1-C4alkoxy, C6-C10aryloxy, di-C1-C4alkylamino, C1-C4-alkylsulfonyloxy, C6-C10arylsulfonyloxy or C1-C4alkylcarbonyloxy and R2 is a C1-C4alkoxycarbonyl radical, and then with an isocyanide of formula V

R3-SO2CH2NC, (V), wherein R3 is an open-chain or cyclic, unsubstituted or substituted C1-C10hydrocarbon.

2. A process for the preparation of compounds of formula III according to claim 1, wherein 2,2-difluorobenzodioxole of formula II is reacted in a suitable solvent phase, in the presence or absence of a complex-forming compound, with a metal or a metal compound MenYn (II) (III) wherein Me is a metal, n is the valency of the metal and Y is an anionic radical and, if Y is present, at least one Y is an organic basic radical.

3. A process for the preparation of 3-(2,2-difluorobenzodioxol-4-yl)-4-cyanopyrrole, wherein, in a one-pot reaction, 2,2-difluorobenzodioxole is converted in a solvent phase, in the presence or absence of a complex-forming compound, with an organometal compound or with a metal into a

4-metallo-2,2-difluorobenzodioxole of formula III according to claim 1 which is reacted, without being isolated, first with an unsaturated nitrile of formula IV according to claim 1 and then with an isocyanide of formula V according to claim 1.

4. A process for the preparation of compounds of formula III according to claim 1, wherein a compound of formula IIIa (IIIa), wherein Me' is a metal other than Me, is reacted with a compound of formula MenYn.

5. A process according to claim 3, wherein the reaction is carried out under an inert gas atmosphere in a solvent selected from a group con-sisting of aliphatic and aromatic hydrocarbons, ethers, ketones and dipolar solvents.

6. A process according to claim 5, wherein the metallation and the subsequent reactions are carried out at from -70° to +150°C.

7. A process according to claim 6, wherein the operation is carried out at from -25° to +80°C.

8. A process according to claim 3, wherein the complex-forming compound is selected from a group consisting of ethers, tert.-amines, cyclic ureas and N-substituted acid amides.

9. A process according to claim 8, wherein the complex-forming compound is selected from a group consisting of ethylene glycol dimethyl ether, hexamethylphosphoric acid triamide, 1,3-dimethyl-2-imidazolone, dimethyl-ethyleneurea, dimethylpropyleneurea and N,N,N',N'-tetramethylethylenedi-amine, and an organolithium compound is used as the metal compound.

10. A process according to claim 9, wherein 2,2-difluoro-1,3-benzodioxole is added to a mixture of approximately equimolar amounts of tetramethyl-ethylenediamine and butyllithium at from -25° to -5°C and the reaction mixture is reacted in succession with an approximately equimolar amount of ethoxymethylenecyanoacetic acid ethyl ester and then with an approxi-mately equimolar amount of p-toluenesulfonylmethyl isocyanide at from -25° to +25°C.

11. A process according to claim 9, wherein n-butyllithium is added at from -25° to -5° to a mixture, dissolved in a hydrocarbon, of approxi-mately equimolar amounts of 2,2-difluoro-1,3-benzodioxole and tetra-methylethylenediamine and the reaction mixture is reacted in succession with an approximately equimolar amount of ethoxymethylenecyanoacetic acid ethyl ester and then with an approximately equimolar amount of p-toluene-sulfonylmethyl isocyanide at from -25° to +25°C.

12. The compounds of formula III which can be prepared by a process according to claim 2 or claim 4.

13. Compounds according to claim 12, wherein Me is a metal selected from a group consisting of Li, Na, K, Cs, Mg, Ba, Zn and Cu, n being 1 or 2 and Y being chloride or bromide.

14. 2,2-difluoro-1,3-benzodioxol-4-yl-lithium.

15. A process according to claim 2, wherein an organolithium compound is used as the metal compound MenYn.

16. A process according to claim 15, wherein an organolithium compound selected from a group consisting of methyllithium, n-butyllithium, sec.-butyllithium, tert.-butyllithium, phenyllithium, lithium diisopropylamide and lithium dicyclohexylamide is used.

17. A process according to claim 2, wherein the compound of formula II is reacted with a complex prepared from equimolar amounts of an organometal compound and a tert.-amine or an amide.

18. A process according to claim 17, wherein the organometal compound is selected from a group consisting of organo-Li, -Na, -K, -Cs and -Mg compounds.