QUATERNARY AMMONIUM SALTS USED AS PHASE TRANSFER CATALYSTS

Abstract: Quaternary ammonium salts of general formula (I) wherein: R is a saturated or unsaturated, linear or branched alkyl radical of C₁ to C₈. R′ is a saturated or unsaturated, linear or branched alkyl radical of C₁ to C₁₂, or a benzyl radical. n is a number equal to 2 or 3. X ⊖ is a halogenide anion, such as Cl ⊖ , Br ⊖ , I ⊖ , are used as phase transfer catalysts, in heterogeneous ionic reactions wherein the reagents are in different pha­ se and have different polarity.

Description: 1. Field of the Invention The present invention refers to the use of a series of quaternary ammonium salts as phase transfer catalysts, in heterogeneous ionic reactions wherein the reagents are in different phases and have different polarity. These catalysts are specifically used, this not meaning a limitation, for improving the reaction among re­ agents in a medium wherein one of them is in a solid state or is an aqueous phase, being substantially inmiscible with an adjacent organic phase, wherein the other reagent is. Consequently, a reaction in-between can only occur at the separation interphase or by transfer of a compound from one phase to another. 2. Background . The quaternary ammoniym salts of the elements of Group V of the Periodic System, are characterized by being, generally, very stable strong alkalis, which are highly io­ nized in aqueous solution in order to form stable cations containing the pentavalent element bound to the hydrocarbon­ ed sustituents by covalent bonds. It is known that these quaternary salts are, in so­ me cases, more reactive than the corresponding K or Na salts. On the other hand, if the configuration and the or­ ganic chains of the quaternary salts are adequate, these com­ pounds are easily soluble in organic solvents. The capability of these quaternary salts to cata­ lyze transfer reactions has been widely studied (Starks, Ch. M. and Liotta, CH. "Phase Transfer Catalysis". Academic Press (1978)). In general, the phase transfer catalysis is carried out in a two-phase system, an organic phase and the other an aqueous or solid phase. The reagent being present, for instance, in the aqueous phase, is transferred to the organic one, by the transfer catalyst, according to the schedule: The reactions which can be carried out by this me­ thod are numerous and, as an example, the following can be cited: C-alkylizations, O-alkylizations, esterifications, halogen exchange, ester and chloride hydrolisis, carbene reactions and, in general, nucleophilic displacements of the kind: R X + Y ⊕ → R Y + X ⊕ wherein Y can be for instance: Cl⁻, Br⁻, I⁻, -CCO⁻, -NO₂⁻, -NCO⁻, -OH⁻, -CN⁻, -SCN⁻. A great number of these reactions are described by Keller, W.E. "Compendium of Phase-Transfer Reactions and Related Synthetic Methods", Fluka A.G. (1979). The ammonium salt amount necessary to catalyze a reaction varies substantially depending on the type of reac­ tion and the catalyst used. The reaction rate generally in­ creases when the catalyst amount, the temperature or both, are increased. In general, the catalyst amount used varies in the range between the 0.01% and the 50% by weight, referred to the lest polar phase reagent. Besides ammonium salts, the following compounds may be used as phase transfer catalysts: phosphonium salts, crown ethers, macrobicyclic compounds and polyethylene glycols. Each one of them has specific disadvantages: qua­ ternary salts usually have little stability, crown ethers and macrobicyclic compounds are expensive and toxic and polyethylene glycols are little effective. 3. Description of the Invention . The present invention refers to the use of a series of quaternary ammonioum salts as phase transfer catalysts. These quaternary ammonium salts have a general struc­ ture (I) wherein: R is a saturated or unsaturated, linear or branched, alkyl radical of C₁ to C₈. R′ is a saturated or unsaturated, linear or branched, al­ kyl radical of C₁ to C₁₂, or a benzyl radical. n is a number equal to 2 or 3. X ⊖ is a halogenide: Cl ⊖ , Br ⊖ , I ⊖ . Some of the derivatives included in general formula (I) are shown below: a) Bis-[2-(N-benzyl-N,N-diethylammonium)ethyl]ether, dichloride (compound 1) b) Bis-[2-(N-benzyl-N,N-diethylammonium)ethyl]ether, dibromide (compound 2). c) Bis-[2-(N,N-diethyl-N-methylammonium)ethyl]ether, diiodide (compound 3). d) Bis-[3-(N-benzyl-N,N-dimethyl)1-propyl]ether, di­ chloride (compound 4). e) Bis-[2-(N-benzyl-N,N-dimethyl)ethyl]ether dichlo­ ride (compound 5). f) Bis-[2-(N,N,N-triethyl)-ethyl]ether, dibromide (compound 6). g) Bis-[3-(N,N-dimethyl-N-ethyl)-1-propyl]ether, dibromide (compound 7). h) Bis-[2-[N,N-diethyl-N-(1-propyl)]ethyl]ether, di­ bromide (compound 8). i) Bis-[3-[N,N-dimethyl-N-(1-propyl)]1-propyl]ether, dibromide (compound 9). j) Bis-[2-[N,N-dimethyl-N-(1-propyl)]ethyl]ether, dibromide (compound 10). k) Bis-[2-[N,N-diethyl-N-(1-butyl)]ethyl]ether, di­ bromide (compound 11). l) Bis-[3-[N,N-dimethyl-N-(1-butyl)]1-propyl]ether, dibromide (compound 12). m) Bis-[2-[N,N-diethyl-N-(1-pentyl)]ethyl}ether, dibromide (compound 13). n) Bis-[3-[N,N-dimethyl-N-(1-penthyl)]propyl]ether, dibromide (compound 14). o) Bis-[2-[N,N-diethyl-N-(1-hexyl)]ethyl]ether, di­ bromide (compound 15). p) Bis-[3-[N,N-dimethyl-N-(1-hexyl)]propyl]ether, dibromide (compound 16). q) Bis-[2-[N,N-diethyl-N-(1-octyl)]ethyl]ether, di­ bromide (compound 17). r) Bis-[3-[N,N-dimethyl-N-(1-octyl)]propyl]ether, dibromide (compound 18). s) Bis-[2-[N,N-dimethyl-N-(1-octyl)]ethyl]ether, dibromide (compound 19). t) Bis-[2-(N,N-diisopropyl-N-methyl)ethyl]ether, diiodide (compound 20). u) Bis-[3-[N,N,N-trimethyl)propyl]ether, diiode (compound 21). In examples 1 to 26, hereinafter exposed, the use, in different reactions, of some of the catalysts obtained, is illustrated, comparing the effectiveness thereof with that of others already known: C-ALKYLATION . Example 1 : Phenylacetonitrile (5.85 g, 0.05 mol), 0.1 mol of 1-bromobutane, 50% aqueous sodium hydroxide (20 ml) and 0.0015 mol of compound 1 were stirred at room temperature for 24 hours. At the end of that time, the reaction mix­ ture was diluted with methylene chloride (20 ml) and the organic phase was separated, washed with water (3x10 ml) and dried over magnesium sulphate. The solvent and the ex­ cess of alkylating agent were removed under reduced pressu­ re and the residue was analyzed by GLC. Monoalkylated pro­ duct: 70%. Dialkylated product: 22%. The same conditions as above using tetra-n-buylam­ monium bromide as catalyst yielded 61% of monoalkylation product and 27% of dialkylation product. O-ALKYLATION l Examples 2 to 5 : A mixture of phenol (1.89 g, 20 mmol), alkylating agent (40 mmol), 5% aqueous sodium hydroxide solution (50 ml), 1 mmol of the catalyst and the suitable solvent (40 ml) was stirred under the conditions given in Table 1. The organic layer was then separated and the aqueous layer extracted twice with 20 ml portions of the solvent used in the reac­ tion. The combined organic extracts were evaporated, the re­ sidue mixed with water and the mixture extracted with ether. The organic extract was washed twice with 2N ammonia solu­ tion (when dimethyl sulphate was used as alkylating agent), 2N sodium hydroxide solution, and finally with saturated so­ dium chloride solution. After drying with sodium sulphate, the solvent was evaporated and the residual ether purified by distillation. Examples 6 to 10 : Benzoic acid (2.44 g, 0.02 mol), benzyl chloride (0.021-0.063 mol), finely powdered potassium carbonate (26.56 g, 0.19 mol), dichloromethane (30 ml) and 0.8 mmol of the catalyst were stirred under reflux for the time indi­ cated in Table 2. The reaction was stopped by careful ad­ dition of water (30 ml) and the organic phase was separated. The aqueous layer was extracted with dichloromethane (2x15 ml) and the combined organic extracts were washed with sodium hydrogen carbonate, dried over magnesium sulphate and evaporated to give the benzyl benzoate, which was puri­ fied by distillation. Example 11 : A mixture of n-butanol (0.74 g, 0.01 mol), benzyl chloride (2.53 g, 0.02 mol), 50% aqueous sodium hydroxide solution (10 ml) and 0.5 mol of compound 1 was stirred at 50°-60°C for 4 hours. The reaction mixture was allowed to cool to room temperature and diluted with dichloromethane (10 ml). The organic layer was separated and the aqueous layer extracted twice with 10 ml portions of dichlorome­ thane. The combined organic extracts were evaporated, the residue mixed with water and the mixture extracted with ether. The organic extract was washed twice with 2N sodium hydroxide solution and saturated sodium chloride solution. After drying with magnesium sulphate, the solvent was eva­ porated and the residual benzyl-n-butyl ether purified by distillation. Yield: 90%. The same conditions as above, using tetra-n-butyl­ ammonium bromide as catalyst yielded 76% of the ether. Example 12 : A mixture of benzophenone oxime (1.97 g, 0.01 mol), benzyl chloride (1.58 g, 0.0125 mol), 50% sodium hydroxide solution (8 ml), benzene (5 ml) and compound 1 (0.5 mol) was stirred at 80°C for 4 hours and then poured into hot wa­ ter and left overnight at room temperature. The solid thus obtained was filtered off, washed with water and dried. Re­ crystallization from methanol gave pure benzophenone o-(ben­ zyl)oxime. Yield : 90%. m.p.: 56-58°C. The reaction and work-up were also carried out as above described, using tetra-n-butylammonium bromide as ca­ talyst. Yield: 87%. N-ALKYLATION . Examples 13 and 14 : 1-Bromobutane (1.51 g, 0.011 mol) in benzene (10 ml) was slowly added to a refluxing mixture of benzamide (1.21 g, 0.01 mol), 50% aqueous sodium hydroxide solution (10 ml) and 1 mmol of the catalyst (Table 3). After the addition of has been completed, refluxing is continued for 4 hours. The reaction mixture ws then cooled to room temperature and di­ luted with water (20 ml). The organic phase is separated, washed with water (3x10 ml) until neutral, dried over magne­ sium sulphate and evaporated to give pure N-n-butylbenzami­ de. Yields are given in Table 3. Examples 15 and 16 : n-Butyl bromide or benzyl chloride (0.0125 mol) was added to a mixture of carbazole (1.67 g, 0.01 mol), 50% aqueous sodium hydroxide (10 ml), benzene (2 ml) and 0.3 mmol of the catalyst (Table 4).The reaction mixture was stirred at 70-80°C for 1 hour and then poured into hot water and left overnight ar room temperature. The solid thus obtained was filtered off, washed with water and dried. Recrystallization from ethanol afforded N-alkylated carbazoles. Example 17 : Benzyl chloride (2.78 g, 0.022 mol) in benzene (10 ml) was added with efficient stirring to a refluxing mixture of benzene sulfonamide (1.57 g, 0.01 mol), 50% aqueous sodium hydroxide (10 ml) and 1 mmol of compound 1. The reaction mixture was heated under reflux for 4 hours and then allowed to cool to room temperature. After dilution with water (20 ml), the organic phase was separated, washed with water (3x10 ml) until neutral, dried with magnesium sulphate and evaporated to give a solid residue which was recrystallized from ethanol to yield pure N,N-dibenzylsulfo­ namide. Yield: 82%. m.p.: 67-68°C. The reaction and work-up were carried out as above described using tetra-n-butylammonium bromide as catalyst. Yield: 87%. Example 18 : Indole (1.17 g, 0.01 mol) was added to a mixture of benzyl chloride (1.90 g, 0.015 mol), 50% aqueous sodium hydroxide solution (5 ml), benzene (10 ml) and 0.5 mmol of compound 1. The mixture was stirred at 60-70°C for 5 hours, then cooled to room temperature and diluted with water (10 ml). The organic layer was separated, washed with dilu­ ted hydrochloric acid, water and dried over anhydrous mag­ nesium sulphate. The solvent and excess of benzyl chloride were removed under vacuo and the residue was chromatograph­ ed on silicagel using n-hexane to give the N-benzylindole (70%), m.p.: 43-45°C. Following this procedure, N-benzylindole was obtain­ ed in 85% and 90% yield using triethylbenzylammonium chlori­ de and tetra-n-butylammonium hydrogensulphate catalyst res­ pectively. Example 19 : A mixture of 2-methylbenzimidazole (1.32 g, 0.01 mol), 1-bromobutane (1.21 g, 0.01 mol), 50% aqueous sodium hydro­ xide (5 ml), toluene (20 ml) and 0.5 mmol of compound 1 was stirred at 80°-85°C for 3 hours. After that time, the result­ ing mixture was allowed to cool to room temperature and the organic layer was separated, extracted with concentrated hy­ drochloric acid (3x20 ml). The acidic solution was neutraliz­ ed with 20% sodium hydroxide, extracted with toluene (3x15 ml), dried over magnesium sulphate and evporated to give a re­ sidue which was distilled at reduced pressure (0.4-0.5 mm 162-6°C) to give 1-n-butyl-2-methylbenzimidazole. Yield: 65%. The reaction carried out using tetra-n-butylammonium bromide as catalyst afforded the alkylated product in 91% yield. S-ALKYLATION . Example 20 : Sodium sulphide nonahydrate (2.40 g, 0.01 mol), ben­ zyl chloride (1.26 g, 0.01 mol), water (3 ml) and compound 1 (0.5 mmol) were stirred at 70-78°C for 20 minutes. The reaction mixture was poured into water and left overnight at room temperature. The white crystals thus obtained were filtered off and dried to give 2.02 g of benzyl sulphide. Yield: 94%. m.p.: 47-48°C. Under the same conditions, the same yield was ob­ tained using tetra-n-butylammonium bromide as catalyst. Example 21 : A mixture of potassium thiocyanate (29.1 g, 0.3 mol), 1-bromobutane (19.1 g, 0.14 mol), water (30 ml) and compound 1 (4 mmol) was stirred under reflux for 75 minutes. Then, the mixture was cooled to room temperature, and organic lay­ er separated and the aqueous phase extracted with ether. After drying over magnesium sulphate and combined organic portions, the solvent was evaporated and the residue distil­ led at reduced pressure (30 mm) to give n-butyl thiocyanate (80% yield). Following this procedure, the alkylated thiocyanate was obtained in 84% yield if tetra-n-butylammonium bromide is used as catalyst. OXIDATION . Examples 22 and 23 : Potassium permanganate (3.16 g, 0.02 mol) in water (35 ml) was stirred for 10 minutes and then cooled in a wa­ ter bath while phenylacetonitrile or benzyl alcohol (0.011 mol), benzene (20 ml) and the catalyst (Table 5) (1 mmol) were added. The mixture was stirred for 3 hours at room tem­ perature and worked up by addition of 4% sodium bisulphite (60 ml), acidification with 2N hydrochloric acid, separa­ tion of organic layer and extraction of the aqueous layer with benzene (2x20 ml). The combined organic extracts were dried over magnesium sulphate and the solvent evaporated on a rotary evaporator. Recrystallization of the solid residue obtained gives pure benzoic acid. REDUCTION . Example 24 : Acetophenone (6g, 0.05 mol), benzene (15 ml), sodium borohydride (1.13 g, 0.03 mol), water (15 ml) and compound 1 (3 mmol) were vigorously stirred at room temperature for 6 hours. The organic layer was then separated, the aqueous phase extracted with dichloromethane (3x15 ml) and the com­ bined organic fractions dried over magnesium sulphate. Af­ ter evaporation of the solvent, the residue was chromato­ graphed on silica gel. Racemic 1-phenylethanol was eluted with n-hexane. Yield: 70%. Under the same conditions, the reduction of aceto­ phenone using tetra-n-butylammonium hydrogensulphate as cata­ lyst gave racemic 1-phenylethanol in 90% yield. ALDOL-TYPE REACTION . Example 25 : A mixture of 2-methylbenzothiazole (1.49 g, 0.01 mol), benzaldehyde (1.27 g, 0.012 mol), 50% sodium hydroxi­ de solution (3 ml), toluene (5 ml)and compound 1 (1 mmol) was stirred at reflux temperature for 4 hours. The reaction mixture was allowed to cool to room temperature and then di­ luted with water (10 ml). The organic layer was separated and the aqueous phase extracted with toluene. The combined organic portions were dried over magnesium sulphate and eva­ porated to give a solid residue which was crystallized from ethanol to give the corresponding 2-styrylbenzothiazole. Yield: 57%. m.p.: 109-110°C. The reaction carried out in the presence of tetra­ -n-butylammonium hydrogensulphate as catalyst gives styryl derivative in 72% yield. REFORMATSKY-TYPE REACTION . Example 26 : To a stirred mixture of cyclohexanone (5.39 g, 0.055 mol), 50% sodium hydroxide solution (10 ml) and com­ pound 1 (1 mmol) was added dropwise chloroacetonitrile (3.8 g, 0.05 mol) and stirring was continued for further 45 minutes. After that time, the resulting reaction mixture was diluted with dichloromethane (15 ml), the organic layer was separated and the aqueous phase extracted with dichloro­ methane (3x15 ml). The combined organic portions were dried over magnesium sulphate and evaporated to give a residue which upon distillation under reduced pressure gave 1-oxaspiro [2,5] octane-2-carbonitrile. Yield: 46%. b.p.: 85°C/5 mm Hg. The glicidic nitrile was obtained in 52% yield by using triethylbenzylammonium chloride as catalyst.

Claims: 1. Use of quaternary ammonium salts of general for­ mula (I) wherein: R is a saturated or unsaturated, linear or branched alkyl radical of C₁ to C₈. R′ is a saturated or unsaturated, linear or branched alkyl radical of C₁ to C₁₂, or a benzyl radical. n is a number equal to 2 or 3. X⊖ is a halogenide anion, such as Cl⊖, Br⊖, I⊖, characterized in that they may be used as phase transfer ca­ talysts.

Inventors: ALVAREZ-BUILLA, JULIO, DORREGO, FERNANDO, FAU DE CASA JUANA, MIGUEL, GALERA, CARLOS, PANDO, BASILIO, SUNKEL, CARLOS, VAQUERO, JUAN J., VAZQUEZ, MAR A L.
Applicants: ALTER, S.A.
Application year: 1987
Main classification: B01J31
IPC codes: C07C43, C07D209, C07C69, C07C27, C07C331, C07C319, C07C41, C07C33, C07C67, C07C311, C07B61, C07C29, C07C253, C07C251, C07C321, C07D277, C07C313, C07C255, C07C239, B01J31, C07C51, C07C233, C07C63