WO2002096856A1

WO2002096856A1 - Catalyst and synthetic process for carboxamides by nitrile hydrolysis

Info

Publication number: WO2002096856A1
Application number: PCT/PT2002/000009
Authority: WO
Inventors: Armando J. L. Pombeiro; Vadim Yu Kukushkin; Maximilian N. Kopylovich; João J. R. FRAUSTO DA SILVA
Original assignee: Instituto Superior Tecnico
Priority date: 2001-05-30
Filing date: 2002-05-29
Publication date: 2002-12-05
Also published as: PT102618A

Abstract

A catalyst is obtained for the hydrolysis of nitriles NCR (R=alkyl, benzyl or aryl) to give the corresponding carboxamides (RCONH2) that are synthesized by a process according to the general reaction (I). The catalyst is formed by the association of an oxime, R'2C=NOH (R'=alkyl) with a metal ion salt such as Zn(NO3)2.6H2O, ZnCl2 or Zn(CF3SO3)2. (I)

Description

DESCRIPTION

"CATALYST AND SYNTHETIC PROCESS FOR CARBOXAMIDES BY

NITRILE HYDROLYSIS"

Field

Areas of Inorganic, Coordination and Organic Chemistries.

Origin

A collaboration has been set up between Prof. AJ.L. Pombeiro (Centra de Quimica Estrutural, Instituto Superior Tecnico) and Prof. V. Yu. Kukushkin (St. Petersburg State University) involving namely the investigation of the coordination chemistry of oximes and nitriles. It has allowed to establish, for the first time, that the latter compounds, when activated by coordination to a suitable metal centre (in particular of platinum(II) [1], platinum(IV) [2], rhenium(IV) [3] or rhodium [4]), react with the former to produce complexes with imine ligands upon nucleophilic addition reactions. These reactions have been extended to other nucleophiles such as nitrones which, by [2+3] cycloaddition reactions with nitrile ligands, in mild conditions, form Δ⁴- 1,2,4- oxadiazolines [5], a process (with various advantages over the other known synthetic methods for oxadiazolines) which has been the object of a patent application [6].

Within the extension of the nitrile-oxime coupling studies to different types of metal sites, it has recently been observed [7] that Co(II)- ketoxime system is able to induce the conversion of alkyl nitriles, NCR, into the corresponding amidines, RC(=NH)NH₂, and carboxylic acids, RCOOH. It was also detected the formation, although not catalytic, of carboxamides when the nitrile was diluted in water [8]. This triggered the interest on the search for a catalytic metal system for the synthesis of carboxamides by hydrolysis of nitriles, in mild conditions, without the need to use strongly acidic or basic media and without the production of polluting salts, similarly to what is achieved by some enzymes (nitrile hydrolases).

The system presented herein (already submitted for publication [9]) is based on the combination of the Zn(II) ion with an oxime and has resulted from the post-doc. research of Dr. M.N. Kopylovich carried out at the Centro de

Qufmica Estrutural, within the above joint project involving Prof. AJ.L.

Pombeiro and Prof. JJ.R. Fraύsto da Silva, in this Centre, and Prof. V. Yu.

Kukushkin (University of St. Petersburg) in visit to the same Centre as an Invited Scientist.

Objective and advantages of the invention

The present invention concerns a new catalytic system for the hydrolysis of nitriles (NCR), formed by the combination of an oxime with a metal salt, and its application in a synthetic process for carboxamides (RCONH₂).

The main general advantages of this process for the synthesis of carboxamides in comparison with the previous ones are as follows: use of easily accessible starting materials, high simplicity and low cost. Other common advantages over alternative methods include the environmentally friendly character, without formation of polluting inorganic salts, the operation in neutral, environmental and considerably mild conditions (without the need of a strongly acidic or basic medium, or of operating in an air-free or inert gas atmosphere) and/or the preferential formation of carboxamides relatively to the products of the complete hydrolysis (corresponding carboxylic acids and ammonia).

In fact, the usual processes for the synthesis of amides are based on the reaction between a carboxylic acid and an amine or ammonia [10]. An alternative method consists on the hydrolysis of nitriles, requiring strong acids or bases [10], but generally the reaction leads mainly to carboxylic acids or carboxylate salts because the hydrolysis of the formed amides (which thus convert into carboxylic acids or carboxylate salts) is faster than the preceding hydrolysis of nitriles (conversion to amides), i.e. the reaction does not stop at the desired amide stage, although in a few cases, in concentrated acid, it is possible to get the amides; however, it is then required a tight control of the temperature and of the reagents ratio in order to avoid the formation of polymers that is promoted by the exothermic character of the hydrolysis reaction; moreover, the final neutralization of the acid leads to an extensive salt formation with product contamination and pollution effects [11].

These difficulties in principle can be overcome with the use of a metal ion which can activate the nitrile toward nucleophilic attack by water (or hydroxide). This leads to a promotion of the rate of hydrolysis usually in the range of

[12] or even higher when involving an intramolecular attack by an hydroxide ligand, e.g. 10¹⁰ upon nitrile coordination to a tetraaza macrocyclic Co(III) centre [13a] or 10¹⁸ by coordination to Hg(II) [13b]. However, these systems generally are not catalytic or their catalytic activity is very low. However, the following ones are noticeworthy in view of their catalytic activity: some platinum(II) phosphinito-complexes, typically

[PtH(Me₂PO...H...OPMe₂)(PMe₂OH)] (the most active one) which acts as a catalyst not only for the nitrile hydrolysis to amides [14] but also for the amidation of nitriles to N-substituted amides [15]; some platinum(II) phosphine complexes (and analogous of palladium and nickel), less active than the above phosphinito complexes, such as [PtH(H₂0)(PR₃)₂]OH (R = Me or Et) [16] derived from the hydrolysis of trans- [PtHCl(PR₃)₂] in basic medium and also active for the hydrolysis of alkenes to primary alcohols [16b]; or, with lower activity, complexes derived from the hydrolysis of [Pt(PR₃)₂] [PR₃ = P(C Hι ι)₃ or PPhBu^] or [Pt(PR₃)₃] (R = Et or Pr¹) [17]; dipalladium(II) complexes with N,S- coordinated ligands (with thiolate bridge) [18 a] and, less effective, various mononuclear Pd(II) complexes with aqua, amine, methylester of methionine, etc. [18b], apart from some hydride phosphine complexes of low valent ruthenium or iridium [19].

Heterogeneous systems with solid catalysts have also been applied, in particular with black copper (Raney copper, Ullmann copper or others with reduced copper) or with metal oxides [16,20] but their use in industry has presented several difficulties, namely due to the formation of secondary products (e.g. occurrence of polymerisation) and to the low selectivity (mainly when a higher temperature has to be used in order to get a significant catalytic activity), and also as a result of the need to concentration and purification of the product, with a high cost, in spite of the developments that have been achieved not only in the operation procedures [21a] but also in the catalysts namely by using various activators and promoters [21b-21e].

A biological route, by taking - advantage of the usually high enzymatic selectivity, has also been considered: the enzymatic hydrolysis of nitriles by nitrile-hydratases [22]. Various enzymatic processes for the preparation of amides have already been patented [23] and the possibility of industrial application e.g. in the synthesis of acrylamide has been recognized. However, the abovementioned chemical or biological catalysts in general present various limitations such as, besides those already mentioned, the high cost and/or the considerable experimental difficulties associated to their preparation or use (in contrast with the low cost, availability and simplicity of our metal salt/oxime system) which have hampered their laboratory and industrial applications, in spite of the various registered patents.

The current interest of the theme is still justified by the search for the establishment of inorganic mimetic models of the enzymatic systems (nitrile hydratases) [22], as well as by the synthetic and industrial relevance of carboxamides [10, 14, 16], namely as intermediates in the synthesis of products with application in medicine and in agriculture, and in dyes and fine chemicals.

Innovatory features

The unprecedent association of an oxime (e.g. acetoxime) with a metal salt (such as zinc nitrate, zinc chloride or zinc triflate) allows to obtain a new type of catalyst for the hydrolysis of nitriles to carboxamides. None of the individual reagents exhibits, separately, any catalytic activity.

The obtained catalytic system, with a high simplicity, is formed by cheap, easily available and non-polluting reagents, operates in neutral (without requiring the use of acids or bases) and relatively mild conditions, in an easy way, in air and without the need of an inert gas atmosphere. It presents a noticeworthy generality and is applied to a variety of nitriles, alkyl (with or without steric hindrance), benzyl and aryl ones, leading to the high yield synthesis of the corresponding carboxamides. It thus overcomes various difficulties associated to the other types of catalysts, as indicated above. Technical description

The invention concerns the preparation of a catalyst for the hydrolysis of nitriles NCR (R = alkyl, benzyl or aryl) to the corresponding carboxamides (RCONH₂) which are synthesized by a process according to the general reaction (I). The catalyst is formed by the association of an oxime, R'₂G=NOH [R'₂ = alkyls, e.g. (CH₃)₂ or C₅H₁₀], with a metal salt, such as Zn(N0₃)₂.6H₂0, ZnCl₂ or Zn(CF₃S0₃)₂. The hydrolysis does not occur when any of the reagents is used separately from the others.

_{NCR + H2θ} CatZW C→TOH, JL^ _{X)

Active intermediates of the type [ZnX₂(oxime)₂] (X = N0₃ or Cl) have been isolated and although the mechanism has not yet been established, it is possible, on the basis of the knowledge [1-7] on the activation of nitriles to nucleophilic attack by oximes and on the chemistry of the derived aminoacyl ligands, to propose a plausible catalytic cycle for the conversion of nitriles into carboxamides (Scheme 1, in which [Zn] denotes the binding metal centre with other co-ligands e.g. oximes). Ligation of the nitrile to the zinc(II) centre (a strong Lewis acid) results in its activation toward nucleophilic attack by an oxime leading to an iminoacylated intermediate which, on hydrolysis, regenerates the oxime and yields the carboxamide ligand (in the iminol or derived carbonyl form) which is liberated on displacement by water or nitrile, regenerating an active species in the catalytic cycle. Hence, the process has a catalytic nature for both the metal and the oxime. An alternative mechanism could involve metal binding of both a nitrile and a water molecule followed by the intramolecular hydration of NCR and release of the carboxamide formed, but the need for two more equivalents (see below) of the oxime would then not be easily explained.

N≡CR

[Zn]-OH₂ [Zn]-N≡CR

Scheme 1

Typically the process involves the use of the zinc salt, ZnX₂ (e.g. X = N0₃, Cl, CF₃S0₃), and the oxime in the 1:4 molar ratio, the former being, relatively to the nitrile, in a molar ratio below 0.7%. Water is added in the stoichiometric amount of the catalytic cycle (2:1 relatively to the nitrile, although the overall quantity can reach a slight excess when it is present in the zinc salt), and the process does not require the use of an excess of water. The (oxime)zinc(II) complexes [ZnX₂(oxime)₂], which are believed to be intermediates in the reaction, can be prepared and also act as catalysts, replacing the zinc salt (2 equivalents of the oxime are then needed, instead of 4).

The reaction system is biphasic, except in the case of acetonitrile when an homogeneous system is obtained, and requires efficient stirring and heating to reflux. The values of the turnover number (TON) are usually not higher than 100 (for a 10 h reaction time) and the isolated yields are high (commonly in the 65-90 % range), although the corresponding carboxylic acids are also formed (5-9 % yield, except in the cases of NCMe and NCCH₂C1 when they are ca. 20%). However, these acid products are easily removed by recrystallization.

The hydrolysis of NCCH₂C₆H₄θMe-4 is the most favourable one

(higher TON and yield), being facilitated by precipitation of the corresponding carboxamide, 4-MeOC₆H₄CH₂C(=0)NH₂. Moreover, if the precipitate is removed by filtration and if a new portion of the nitrile and water is added to the filtered solution, the catalytic process continues and a TON value of ca. 1,000 can be reached.

Examples

Synthesis of carboxamides

In view of the generality of the process, its description is also given in general terms for the typical cases of using 2-propanone oxime (Me₂C=NOH) as the oxime, and Zn(N0₃)₂ as the zinc(II) salt, for the synthesis of the following carboxamides: RC(=0)NH₂ (R = Me, C1CH₂, Et, n-Pr, t^'-Pr, Λ-BU, *-BU, Ph or 4- MeOC₆H₄CH₂).

2-propanone oxime (1.37 mmol) is added to a stirred mixture of NCR (50 mmol) (R = Me, C1CH₂, Et, «-Pr, -Pr, «-Bu, t-Bu, Ph or 4- MeOC₆H₄CH₂) and Zn(N0₃)₂.6H₂0 (0.33 mmol) and the system becomes homogeneous within 10 minutes (in the case of NCMe, in which the zinc salt is soluble, an homogeneous solution is immediately formed). Water (0.10 mol) is then added dropwise for 1 h to the vigorously stirred mixture forming a biphasic system (in the case of NCMe the addition of water does not result in the separation of a second phase) that is refluxed for 10 h whereafter the reaction mixture is cooled to room temperature, the solvent removed in vacuo and the solid residue purified by recrystallization.

Similar procedures, leading to comparable yields and TONs, are followed when using other zinc(II) salts, ZnX₂ (X = Cl or CF₃S0₃), or the

(oxime)zinc(II) complexes [ZnX₂(oxime)₂] (X = N0₃, Cl or CF₃S0₃), in the latter case only two equivalents of the oxime being needed. These complexes can be prepared as follows.

Synthesis of (oxime)Zn(II) catalysts

The oxime R₂C=NOH (4 mmol) is added to the zinc salt ZnX₂ (2 mmol), whereupon acetone (10 ml) is added. The stirred obtained slurry within ca. 1 minute turns into a colourless solution that is refluxed for 8 h, the solvent is then removed in vacuo at room temperature and the solid residue of [ZnX₂(oxime)₂] is washed with three 5 ml portions of diethyl ether (yields are 90-97% based on the metal).

References

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Claims

1. Catalyst system for the hydrolysis reaction of nitriles (NCR) to carboxamides (RCONH₂), characterized by the association of an oxime

(R₂'C=NOH) to a metal ion, in the presence of water and of the substrate (nitrile).

2. System according to claim 1 characterized by the use of a ketoxime R₂'C=NOH [R₂' = alkyls, e.g. (CH₃)₂ or C₅H₁₀].

3. System according to claim 1 characterized by the use of the Zn(II) ion or a Zn(II) salt.

4. System according to claim 1 characterized by the use of an oxime-zinc(II) complex.

5. System according to claim 4 characterized by the use of a complex of the type [ZnX₂(oxime)₂] (e.g. X = N0₃, Cl or CF₃S0₃).

6. Process of synthesis of alkyl, benzyl or aryl carboxamides

RCONH₂ (R = alkyl, benzyl or aryl, without or with appreciable steric hindrance), according to claims 1,2,3,4 or 5, characterized by the use of the corresponding nitriles (NCR).