Intermediates for the production of a benzofuran or benzothiophene type derivative nitrated in the 5 position, and use thereof

Abstract

The invention concerns novel nitroaromatic compounds of general formula (I′) wherein: R, R′1, R2, Z and n are as defined in claim 38. The invention also concerns a method for preparing nitroaromatic compounds nitrated in position 4. The invention further concerns the use of said compounds for preparing heterocyclic benzofuran or benzothiophene derivatives nitrated in position 5. The invention concerns particularly the preparation of 2-alkyl-5-nitrobezofuran

1 . A process for preparing nitroaromatic compounds with formula (I):  
       
         
           
           
               
               
           
         
       
       in which: 
 R 1  represents a hydrogen atom, a linear or branched alkyl group containing 1 to 12 carbon atoms, a phenyl group that may be substituted by an alkyl group containing 1 to 4 carbon atoms, or a halogenophenyl group;  
 R 2  represents a hydrogen atom, a hydrocarbon group containing 1 to 12 carbon atoms, which may be a linear or branched alkyl group, a cycloalkyl group, a phenyl group or a phenylalkyl group;  
 Z represents an oxygen or sulphur atom;  
 R represents a hydrogen atom or a substituent;  
 n is a number equal to 0, 1, 2 or 3, preferably 0;  
 when n is greater than 1, two groups R and the successive 2 atoms of the benzene ring can together form a saturated, unsaturated or aromatic cycle containing 5 to 7 carbon atoms;  
 characterized in that it consists of carrying out selective nitration in the 4 position, using a source of NO 2   +  and in the presence of sulphuric acid, of an aromatic compound with formula (II):  
                     
 in which formula (II), R, R 1 , R 2 , Z and n have the meanings given above.  
 
     
     
         2 . A process according to  claim 1 , characterized in that the starting substrate has formula (II), in which R represents a hydrogen atom or one of the following groups: 
 a hydroxyl group;    a linear or branched alkyl group containing 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl;    an alkoxy group containing 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms;    an ester group containing 1 to 10 carbon atoms, preferably 1 to 4 carbon atoms;    an alkylamide group containing 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms;    a carboxamide group;    a halogen atom;    a trifluoromethyl group.    
     
     
         3 . A process according to  claim 1 , characterized in that the starting substrate has formula (II) in which R represents a hydrogen atom, a methyl or ethyl group, or a methoxy or ethoxy group.  
     
     
         4 . A process according to  claim 1 , characterized in that the starting substrate has formula (II) in which R 1  represents an alkyl group containing 1 to 4 carbon atoms.  
     
     
         5 . A process according to  claim 1 , characterized in that the starting substrate has formula (II) in which R 2  represents an alkyl group containing 1 to 4 carbon atoms.  
     
     
         6 . A process according to  claim 1 , characterized in that the starting substrate has formula (II) in which Z is an oxygen atom.  
     
     
         7 . A process according to  claim 1 , characterized in that nitration of the compound with formula (II) is carried out by reacting it with a source of NO 2   +  in the presence or absence of an organic solvent, preferably an aliphatic halogenated hydrocarbon, more preferably dichloromethane.  
     
     
         8 . A process according to  claim 7 , characterized in that the nitrating reagent is any source of NO 2   + , preferably nitrogen dioxide NO 2 , nitrous anhydride N 2 O 3 , dinitrogen tetroxide N 2 O 4 , nitric oxide NO associated with an oxidising agent such as nitric acid, nitrogen dioxide or oxygen; nitrous acid, nitrosyl sulphate or a nitrous salt, preferably an alkali metal salt, still more preferably, sodium or an alkyl nitrite.  
     
     
         9 . A process according to  claim 7 , characterized in that the quantity of nitrating reagent employed is a nitrating mixture.  
     
     
         10 . A process according to  claim 7 , characterized in that the quantity of nitric acid, expressed as the mole ratio of the aromatic O- or S-alkylated compound/nitric acid is in the range 0.9 to 1.1, preferably in the range 0.95 to 1.05.  
     
     
         11 . A process according to  claim 7 , characterized in that the quantity of sulphuric acid, expressed as the mole ratio of the aromatic O- or S-alkylated compound/sulphuric acid is in the range 0.9 to 1.1, preferably in the range 0.95 to 1.05.  
     
     
         12 . A process according to  claim 7 , characterized in that the nitration reaction temperature is in the range −10° C. to 20° C., preferably in the range −5° C. to 10° C.  
     
     
         13 . A process for preparing a compound with formula (II) as defined in  claim 1 , characterized in that it is obtained by reacting: 
 a compound of the 2-hydroxy- or 2-thiobenzaldehyde-type with formula (III):                          in which formula (III), R, Z and n have the meanings given above in any one of  claims 1  to  3 ;    and a carboxylic acid or a derivative with formula (IV):                          in which formula (IV):    Y represents a leaving group, preferably a halogen atom or a sulphonic ester group with formula —OSO 2 -  where   is a hydrocarbon group;    R 1 , R 2  have the meanings given above in any one of claims  1 ,  4  and  5 .    
     
     
         14  A process according to  claim 13 , characterized in that the compound with formula (III) is salicylic anhydride and the carboxylic acid or derivative with formula (IV) is methyl or ethyl 2-bromohexanoate.  
     
     
         15  A process according to  claim 13 , characterized in that mole ratio between the compound with formula (III) and the compound with formula (IV) is between 1 and 1.2.  
     
     
         16  A process according to  claim 13 , characterized in that an aromatic compound with formula (III) is reacted with a carboxylic acid or a derivative with formula (IV), the reaction being carried out in the presence of a base, preferably in an organic solvent.  
     
     
         17  A process according to  claim 16 , characterized in that the base can be a mineral base, preferably an alkali metal or alkaline-earth metal salt, preferably an alkali or alkaline-earth metal hydroxide which may be sodium, potassium or calcium hydroxide; or an alkali metal carbonate or bicarbonate, preferably sodium carbonate; or an organic base, preferably a quaternary ammonium hydroxide or a tertiary amine.  
     
     
         18  A process according to  claim 17 , characterized in that the base employed is sodium or potassium carbonate.  
     
     
         19  A process according to  claim 16 , characterized in that the compound with formula (III) in its salt form and the compound with formula (IV) are reacted in an organic solvent preferably selected from aromatic hydrocarbons that may or may not be halogenated, aliphatic, cycloaliphatic or aromatic ether-oxides, aliphatic or aromatic nitrites; linear or cyclic carboxamides, preferably N,N-dimethylacetamide or dimethylformamide.  
     
     
         20  A process according to  claim 18 , characterized in that iodide ions are added, preferably alkali metal iodides, more preferably potassium iodide.  
     
     
         21  A process according to any one of  claims 13  to  20 , characterized in that the reaction between the compound with formula (III) and the compound with formula (IV) is carried out at a temperature in the range 0° C. to 100° C., preferably in the range 25° C. to 50° C.  
     
     
         22  A process according to  claim 13 , characterized in that an aromatic compound with formula (III) is reacted with a carboxylic acid or a derivative thereof, in an aqueous medium, in the presence of a base and a phase transfer catalyst.  
     
     
         23  A process according to  claim 22 , characterized in that the phase transfer catalyst is a tris(ether-amine), preferably tris(3,3-dioxaheptyl)amine.  
     
     
         24  A process according to  claim 22 , characterized in that the phase transfer catalyst is an onium salt wherein the onium has one of the following formulae:  
       
         
           
           
               
               
           
         
       
       in which formulae: 
 Z represents N, P or As;  
 Y represents S, O, Se or C;  
 X 1 , X 2 , X 3  and X 4 , which may be identical or different, represent: 
 a linear or branched alkyl group containing 1 to 16 carbon atoms, optionally substituted by one or more phenyl, hydroxyl, halogen, nitro, alkoxy or alkoxycarbonyl groups, the alkoxy groups containing 1 to 4 carbon atoms;  
 a linear or branched alkenyl group containing 2 to 12 carbon atoms;  
 an aryl group containing 6 to 10 carbon atoms, optionally substituted by one or more alkyl groups containing 1 to 4 carbon atoms, an alkoxy group, an alkoxycarbonyl group, the alkoxy group containing 1 to 4 carbon atoms, or a halogen;  
 
 two of said groups X 1  to X 4  can together form a linear or branched alkylene, alkenylene or alkadienylene group containing 3 to 6 carbon atoms.  
 
     
     
         25 . A process according to  claim 24 , characterized in that the anion of said onium salts is selected from the following ions: F − , ClO 4   − , PF 6   − , BF 4   − , SnCl 6   − , SbCl 6   − , B(Ph) 4   − , PO 4   3− , HPO 4   2− , H 2 PO 4   − , CH 3 SO 3   − , Ph—SO 3   − , HSO 4   − , NO 3   − , SO 4   2− , Cl − , Br − , I − , OH − , Ph representing a phenyl group; the anion for said onium salts preferably being selected from Br − , Cl −  and OH −  ions.  
     
     
         26 . A process according to  claim 22 , characterized in that the phase transfer catalyst is selected from: tributylbenzylammonium or phosphonium chloride or bromide; tetramethylammonium or phosphonium chloride or bromide; tetraethylammonium or phosphonium chloride or bromide, tetrabutylammonium or phosphonium chloride or bromide, and preferably represents tributylbenzylammonium chloride or bromide.  
     
     
         27 . A process according to  claim 22 , characterized in that the base is selected from potassium carbonate, sodium carbonate and ammonia, preferably potassium carbonate.  
     
     
         28 . A process according to  claim 22 , characterized in that the mole ratio between said catalyst and the compound with formula (III) is in the range 0.01 to 0.50, preferably in the range 0.05 to 0.2.  
     
     
         29 . A process according to  claim 22 , characterized in that the reaction is carried out in an aqueous medium.  
     
     
         30 . A process according to  claim 22 , characterized in that the reaction temperature is between ambient temperature and 80° C., preferably between 50° C. and 65° C.  
     
     
         31 . A process for preparing a heterocyclic compound with general formula (V):  
       
         
           
           
               
               
           
         
       
       in which formula (V), R, R 1 , Z and n have the meanings given above in any one of  claims 1  to  4 ;  
       characterized in that the compound with formula (I) or (I′) is optionally saponified when R 2  is an ester function, followed by cyclisation.  
     
     
         32 . A process according to  claim 31 , characterized in that the compound with formula (I) or (I′) is cyclised in the presence of sodium acetate and in an acetic anhydride medium.  
     
     
         33 . A process according to  claim 31 , characterized in that the compound with formula (I) or (I′) is cyclised in the presence of sodium or potassium carbonate and in an acetic anhydride medium.  
     
     
         34 . A process according to  claim 31 , characterized in that it is obtained: 
 by preparing the compound with formula (II) by reacting a compound with formula (III) with a carboxylic acid or derivative thereof with formula (IV) in the presence of a base and optionally, a phase transfer catalyst;    by carrying out selective nitration of the compound with formula (II) in the 4 position using the process described in any one of  claims 1  to  12 ;    if necessary, by saponifying the compound obtained with formula (I) or (I′) in the case when R 2  is an ester function;    cyclising the product obtained.    
     
     
         35 . A process according to  claim 31 , characterized in that it is obtained: 
 by preparing the compound with formula (II) by reacting a compound with formula (III) with a carboxylic acid or derivative thereof with formula (IV) in the presence of a base and optionally, a phase transfer catalyst;    if necessary, by saponifying the compound obtained with formula (II) in the case when R 2  is an ester function;    by carrying out selective nitration of the compound with formula (II) in which R 2  is a hydrogen atom, using the process described in any one of  claims 1  to  12 ;    cyclising the product obtained.    
     
     
         36 . A process according to  claim 35  or  claim 36 , characterized in that cyclisation is carried out using the process defined in  claim 32  or  claim 33 .  
     
     
         37 . A process according to any one of  claims 31  to  36 , characterized in that the compound with formula (V) is 2-n-butyl-5-nitrobenzofuran.  
     
     
         38 . Novel nitroaromatic compounds with general formula:  
       
         
           
           
               
               
           
         
       
       in which: 
 R′ 1  represents a linear or branched alkyl group containing 1 to 12 carbon atoms, a phenyl group that may be substituted by an alkyl group containing 1 to 4 carbon atoms, or a halogenophenyl group;  
 R 2  represents a hydrogen atom, a hydrocarbon group containing 1 to 12 carbon atoms, which may be a linear or branched alkyl group, a cycloalkyl group, a phenyl group or a phenylalkyl group;  
 Z represents an oxygen or sulphur atom;  
 R represents a hydrogen atom or a substituent;  
 n is a number equal to 0, 1, 2 or 3, preferably 0;  
 when n is greater than 1, two groups R and the successive 2 atoms of the benzene ring can together form a saturated, unsaturated or aromatic cycle containing 5 to 7 carbon atoms;  
 
     
     
         39 . Novel nitroaromatic compounds according to  claim 38 , characterized in that R represents a hydrogen atom or one of the following groups: 
 a hydroxyl group;    a linear or branched alkyl group containing 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl;    an alkoxy group containing 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms;    an ester group containing 1 to 10 carbon atoms, preferably 1 to 4 carbon atoms;    an alkylamide group containing 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms;    a carboxamide group;    a halogen atom;    a trifluoromethyl group.    
     
     
         40 . Novel nitroaromatic compounds according to  claim 38 , characterized in that R represents a hydrogen atom, a methyl or ethyl group, or a methoxy or ethoxy group.  
     
     
         41 . Novel nitroaromatic compounds according to  claim 38 , characterized in that R′ 1  represents an alkyl group containing 1 to 4 carbon atoms.  
     
     
         42 . Novel nitroaromatic compounds according to  claim 38 , characterized in that R 2  represents an alkyl group containing 1 to 4 carbon atoms.