IE901826A1 - Preparation of n-arylsubstituted amides - Google Patents

Description

The present invention is concerned with the preparation of N-aryl-substituted amides. It is more particularly concerned with the preparation of such amides by reductive N-acylation of nitroaromatic compounds by means of carboxylic acids and carbon monoxide. N5 substituted amides are a class of products particularly useful as intermediate compounds in the synthesis of various active substances in the pharmaceutical and phytosanitary fields.

It has already been proposed that N-aryl-substituted amides should be prepared by reductive N-acylation of nitroaromatic compounds, thus in Bulletin of the Chemical Society of Japan, Vol. 42, 827-828 (1969)” it has been indicated that nitrobenzene can be converted, by reaction with carbon monoxide and acetic or propionic acid, to acetanilide or propionanilide, at a temperature at above 300°C and at initial carbon monoxide pressures of 50 to 100 kg/cm (measured at ambient temperature) in the presence of nickel tetracarbonyl, dicobait octacarbonyl or iron pentacarbonyl. However, the development of such a technique on the industrial scale is difficult, particularly because excessively severe operating conditions (temperature and pressure) are required .

More recently, in J. Org. Chem. 1984, 49, 4461-4455 (1984) an alternative catalytic system to that previously used has been proposed. It comprises a platinum complex such as PtCi2(PPh^)2 and stannic chloride or another Lewis acid such as SnC^, FeCl^, VCl^, AlCl^ or ZnC^· IT the presence of such Lewis acids is essential in order to obtain a suitable selectivity towards acetanilide, a temperature of at least 18O°C is necessary in order that an appreciable transformation of the nitro compounds may be observed; moreover, the transformation is very often accompanied by the formation of aniline, which is not desired. The necessity for the presence of platinum complexes, which 3u are rare and difficult to use, also compromises the development of such a procedure in the industrial state.

For these reasons research has been carried out to find an alternative to the catalytic systems previously proposed.

It has now been found that N-aryl-substitutea amides can be prepared by the reaction of carbon monoxide and at least one carboxylic acid on at least one nitroaromatic compound under conditions of pressure and temperature that are less severe than tnose previously proposed, at the same time limiting the coproduction of aromatic amines, by using a catalytic system based on palladium or a palladium compound ana at least one additive whose nature is specified below.

In accordance with the present invention there is provided a 5 process for the preparation of N-aryi-substituted amides by reaction in the liquid phase, under superatmospheric pressure, of carbon monoxide and at least one carboxylic acid with at least one nitroaromatic compound in the presence of a catalytic quantity of palladium or a palladium compound and at least one additive of the formula: G G. Ν '—-^C - C N in which each of G and G', which are the same or different, represents a bridging group containing three or four atoms of which at least two are carbon atoms, or in which G and G1 are joined to one another. In accordance with a preferred embodiment of the present invention, N-aryl-substituted formamides are prepared by reaction of carbon monoxide and formic acid on at least one nitroaromatic compound in the presence of the said catalytic system.

Also in accordance with the present invention p-acetamidophenol is prepared by reaction of carbon monoxide and acetic acid on pnitrophenol in the presence of the said catalytic system.

The process in accordance with the present invention can by schematically represented by the following stoichiometric equation: IE 9018^6 2 in which each of R and R , which are the same or different, represents a hydrogen or halogen atom, a hydroxyl or nitro group, a C-] alkoxy radical or a alkyl radical that may be straight or branched and may contain one or more halo substituents; R^ represents a hydrogen atom or a alkyl radical which may be straight or branched and may contain one or more naio substituents. R^ 1 2 may be the same as or different from R and/or R . 2 Preferably, R and R , which are the same or dilferent, represent hydrogen, hydroxy, nitro or C-|_^ alkyl containing at least one fluorine, chlorine and/or bromine substituent. It is particularly 1 2 preferred that when R represents hydroxy or nitro, R is hydrogen or a alkyl radical.

Examples of nitroaromatic compounds that can be used in the process of the present invention are: nitrobenzene, p-nitrotoluene, o15 nitrotoluene, dinltro-2,4-toluene, p-nitroanisole, p-nitrophenol, pnitrochlorobenzene and p-(trifluoromethyl)nitrobenzene.

The procedure requires the presence, as a reactant, of a carboxylic acid of formula R^COOH, where is as defined above. I“tre particularly, R^ is a nydrogen atom or a alkyl radical. Examples of carboxylic acids that can be used in the process of the invention are formic, acetic and propionic acids.

The stoichiometric equation proposed above involves equimoiecular quantities of nitroaromatic compound and carboxylic acid. The amount of carboxylic acid used can vary widely from the 1:1 molecular proportion, and the precise quantity of acid used will generally be greater than 1:1. The excess of carboxylic acid over that expected to be used in the reaction depends in large measure on the precise nature of the carboxylic acid selected and on various other parameters that influence the way in which the reaction proceeds.

Thus, for example, when formic acid is used, good results can be obtained wich a molar ratio of acid:nitroaromatic compound between 1:1 and 10:1, preferably around 2:1 to 4 :1.

On the other hand, when acetic acid is used, good results are obtained with this molar ratio substantially greater than 10:1.

Carrying out the procedure in accordance with the present invention necessitates the presence of a catalytic quantity of palladium or a palladium compound. It does not matter what source of palladium Is used. Metallic palladium as such or deposited on an inert support, such as carbon black or alumina, or salts or complexes of palladium, can be used. Under the conditions of the reaction most sources of palladium are soluble in the reaction medium. Examples of palladium compounds that it is convenient to use in the present process are palladium carboxylates, preferably in which the anion contains up to twelve carbon atoms, in particular palladium acetate and palladium propionate; palladium halides, in particular palladium chloride and palladium bromide; palladium acetylacetonate, palladium complexes, e.g. the dibenzylideneacetone (Pd(dba)^). Palladium acetate is particular suitable for use in accordance with Che invention.

The exact quantity of palladium to be used varies over large limits and is usually chosen as a compromise between the efficacy desired and the cost of the catalyst, as well as the conditions chosen for the reaction.

A molar ratio of Pd between 1000:1 and 200:1 is usually satisfactory; if the ratio is greater than 1000:1 the strength of the reaction is diminished, and if it less than 200:1 there is a risk of encumbering the total economy of the procedure.

The invention also requires the presence of at least one additive of the formula given above. In that formula, G and/or G1 preferably comprise(s) one or two atoms different from carbon atoms, these atoms preferably being nitrogen. G and G' can also be joined by a group containing two carbon atoms to produce an additive of the formula above giving the skeleton of 1,10-phenanthroline. Examples of compounds having the general formula given above are 2,2'-bipyridy1, 4,4'dimethyl-2,2'-bipyridyl, 4,4'-dimethoxy-2,2’-bipyridyl, 4,4'-dicarboxy2,2 ' -bipyridyl, 4,4'-dichloro-2,2'-bipyridy1, 2,2'-biquinolyl, 1,10phenanthroline , 4,7-diphenyl-1,10-phenanthroline, 3,4,7,8-tetramethyl30 1,10-phenanthroline and 4,7-dimethyl-1,10-phenanthroline. 1,10Phenanthroline and its 2- and 9- unsubstituted derivatives are most particularly suitable as additives in the process of the present invention.

The quantity of additive can vary within large limits. It is usually such that the molar ratio additive:palladium is from 1:1 to 100:1, preferably 4:1 to 20:1.

The reaction temperature depends particularly on the reactivity of the nitroaromatic compound. A temperature of at least 110°C appears to be necessary to obtain acceptable conversion and there is no advantage in operating at above 18O°C, at which temperature a noticeable diminution of the selectivity of the reaction towards amide is observed. Preferably, the temperature is between 120 and 16O°C.

The reaction is conducted in the liquid phase under superatmospheric pressure. A partial pressure of carbon monoxide at the temperature of the order of 30 bars (3 MPa) has an appreciable effect on the good operation of the reaction. There is no point exceeding 150 bars (15 MPa). The pressure is advantageously between 30 and 120 bars (3 and 12 MPa). Substantially pure carbon monoxide, such as that obtained commercially, is used, although minor quantities of inert gases such as nitrogen, argon and carbon dioxide are quite tolerable. The presence of hydrogen in substantial quantities is not suitable to the good running of the reaction because it induces a diminution in the selectivity to the desired products.

The reaction can be conducted in the presence of a solvent or diluent that is inert with respect to the reaction products and the reactants. Examples of such solvents and diluents are chlorinated and unsubstituted aromatic hydrocarbons, e.g. benzene and odichlorobenzene, aliphatic or cyclic ethers, N , N-disubstituted amides, sulphones and esters.

Certain reactant carboxylic acids, particularly acetic acids, can be used in large excess with respect to stoichiometry mentioned above, and can play some sort of supplementary role as solvent or diluent.

At the end of the reaction period the desired amide is separated from the reaction medium by any suitable means, for example, extraction and/or distillation.

The following Examples illustrate but do not limit the present invent ion.

EXAMPLES Examples 1 to 8: Preparation of N-phenylformamide The following description applies to Example 2. mmol of nitrobenzene, 0.36 g-atom of palladium as PdiOAc^, mmol of 1, 10-pnenanthroline (phen.), 72 mmol of formic acia and o-dichlorobenzene (odcb) make 30 ml are introduced into a 125-ml Hastelloy B2 autoclave. The autoclave is purged with carbon monoxide and then raised to 14O°C with stirring under a constant pressure of 60 bars (6 MPa) of carbon monoxide. After one hour reaction at the temperature indicated, the autoclave is cooled and the pressure released. The reaction mass is removed, diluted to 100 ml with ethanol and analysed by gas-phase chromatography. Examples 1, 3 and 8 are carried out in an analogous manner.

The particular conditions and the results obtained are set forth in Table I in which the initial amounts of starting material are based on 1 mole of nitrobenzene and the abbreviations have the following meanings : T t P TT % RT % (NPF) RT T. (A) reaction temperature in UC duration of reaction in hours pressure of carbon monoxide at the reaction temperature in bars percentage transformation of nitrobenzene number of moles of N-phenylformamide formed for every 100 moles of nitrobenzene transformed number of moles of aniline formed for every 100 moles of nitrobenzene transformed Example 9 Example 2 is repeated, but the 1 ,1ΰ-phenanthroline is replaced by an equivalent quantity of 2,2'-bipyridyl . The following results are obta ined : TT ? : 59 RT ί (NPF) : 79 RT £ (A) : 2 Examples 10 to 12: Preparation of various N-arylformamides (NAF) In the apparatus defined above and proceeding in the same manner, a series of tests at 14O°C under 60 bars pressure is carried out starting with three different nitroaromatic compounds.

Example 10 starts from o-nitrotoluene; Example 11 starts from 2,4-dinitrotoluene and Example 13 starts from 4-trifluoromethy1nitrobenzene.

At the end of each run, the reaction mass is removed and evaporated, then distilled. The distillate is analysed by gas-phase chromatography, by connected CPG/Mass Spectroscopy and by Nuclear Magnetic Resonance.

The special conditions and the results obtained are set out in Table II in which the initial amounts of starting material are related to 1 mole of nitroaromatic compound and in which TT ί is the rate of transformation of the nitroaromatic compounds used, and RT ί (NAF) is the number of moles of N-arylformamide produced for 100 moles of nitroaromatic compound transformed.

Examples 13 and 14: Preparation of acetanilide and p-acetylaminophenol In the apparatus described above and proceeding in an analogous manner, two syntheses at 140°C under 60 bars pressure are carried out in the absence of o-dicnlorobenzene. Analysis after synthesis of the acetanilide is carried out as indicated for Examples 1 to 8; that corresponding to the synthesis of p-acetamidophenol is carried out by CLHP on the reaction mass after its removal and evaporation as above.

The particular conditions under which the results are obtained are set out in Table III.

Table I ·* o o 0.5 CM o CM o b* CU z & l·- az 42 CO 83 38 84 84 CO ! Q9 I I * H t- o in ID 40 cn 38 CS T-* M· GO 54 OPERATING CONDITIONS _I cu 09 09 09 60 30 09 60 09 n CM VH u 0 140 [ 140 i_ 140 140 1 140 Oil o co 140 AMOUNTS OF STARTING MATERIALS E 0 U T3 0 1 o UJ 700 o co C4 o lO ID 650 650 650 mol phen. 0.085 0.085 1 0.085 ι 1 0.085 1 0.085 0.085 0.085 0.085 CL o • o 0.01 0.01 0.01 0.01 _ 0.01 0.01 0.005 HCOOH I 20 -- .. -________1 CM 1.2 10 CM CM CM CM CM s T“* T—· Ref rH CM LO ID r- co Table II Table III » • — * Λ ts σ 61 • * fc o o co σ> •u IT • CO CO υ 0 H o o ·* Qu o tfi o C - £ 2 a co o o co o o -P (0 •ο l 0. tr co o o o cc o o o H3COOH ol 1 co co NITRO-AROMATIC COMPOUND 0 ε IDENTITY o 2 ά N g Φ o X M-i Pi n Ί» of nitroaromatic compound

Claims (14)

1. A process for preparing N-arylsubstituted amides by reaction in liquid phase under superatmospheric pressure of carbon monoxide and at least one carboxylic acid on at least one nitroaromatic compound, in which the reaction is carried out in the presence of a catalytic quantity of palladium or of a compound of palladium and at least one additive of the formula: in which each of G and G', which are the same or different, represents a bridging group containing three or four atoms of which at least two are carbon atoms, or in which G and G' are joined to one another.

2. A process according to Claim 1, in which the reaction temperature is in the range 110 to 18O°C.

3. A process according to Claim 1 or 2, in which the partial pressure of carbon monoxide measured at the reaction temperature is at least 30 bars (3 MPa). M. A process according to any one of the preceding claims, in which the partial pressure of carbon monoxide measured at the reaction temperature does not exceed 120 bars (12 MPa).

4. 5. A process according to any one of the preceding claims, in which the aromatic compound is nitrobenzene, a nitrotoluene, a dinitrotoluene, p-(tri fluoromethyl)nitrobenzene or p-nitrophenol.

5. 6. A process according to any one of Claims 1 to 5, in which the carboxylic acid is acetic acid.

6. 7. A process according to any one of Claims 1 to 5, in which the carboxylic acid is formic acid.

7. 8. A process according to any one of Claims 1 to 7, in which the nitroaromatic compound is p-nitrophenol.

8. 9. A process according to any one of the preceding claims, in which the additive is 2,2'-bipyridyl, 4,4'-dimethyl-2,2'-bipyridyl, 4,4'dimethoxy-2,2'-bipyridyl, 4,4'-dicarboxy-2,2'-bipyridyl, 4,4'-dichloro2,2'-bipyridy1, 2,2 '-biquinolyl, 1, 10-phenanthroiine, 4,7-diphenyΙΙ, 10-phenanthrol ine, 3,4,7,8-tetramethyl-1,10-phenanthroline or 4,7dimethyl-1,10-phenanthroline.

9. 10. A process according to Claim 9, in which the additive is 1,10phenanthroline .

10. 11. A process according to any one of the preceding claims, in which the molar ratio of Νθ£ group to Pd is from 1000:1 to 200:1.

11. 12. A process according to any one of the preceding claims, in which the molar ratio of the additive to Pd is from 1:1 to 100:1.

12. 13. A process according to Claim 1 substantially as hereinbefore described in any one of the foregoing Examples.

13.

14. An N-aryl-substituted amide wnen prepared by a process according to any one of the preceding claims.