Title of Invention

"AN IMPROVED PROCESS FOR THE PREPARATION OF NITROXYL RADICALS"

Abstract

The present invention relates to an improved process for the preparation of nitroxyl radicals.. In the process amines are converted to their corresponding nitroxyl radicals, catalyzed by Vanadium Silicate (VS-1) in combination with aqueous H2O2 as oxidant. The catalyst Vanadium Silicate (VS-1) has been successfully employed for the first time for the catalytic oxidation of amines to their nitroxyl radicals. The catalyst Vanadium Silicate (VS-1) is truly heterogeneous one and the catalyst was recovered & successfully reused many number of times for the process without further purification. The process can be continuous one, operating at ambient temperature without affecting the yield & purity of the process.

Full Text

The present invention relates to an improved process for the preparation of nitroxyl radicals. This invention particularly relates to a process for the preparation of nitroxyl radicals catalyzed by heterogeneous catalyst. More particularly, the invention relates to a process for conversion of amines to their corresponding nitroxyl radicals, catalyzed by Vanadium Silicate (VS-1) in combination with aqueous H2O2 as oxidant. Nitroxyl radicals are very well known in the literature because of its wide synthetic utility. The use of nitroxyl radicals in the oxidation of alcohols becomes increasingly popular. Interest in the chemistry of nitroxyl radicals has also been stimulated in recent years by their application as probes in materials [Spin labeling theory (II) and appln 1976, 173], spin label biochem [Quart. Rev. Biophys 1970, 3,91] in organic synthesis [Organic Synthesis 1987; Synthesis 1996, 1153] and more recently as contrast agents in magnetic resonance imaging [J. Radiology 1990, 71, 125], or electron spin resonance imaging [J. Magn.Reson (b) 1995,106 (26) 122,] and in polymer chem [Polymer. Sci. 1996,4, 183] Hence the synthesis of these compounds become important and many new methods are developed for the betterment of yield and practicability of the process. All the methods reported so far for the synthesis of nitroxyl radicals suffer from drawbacks such as the use of commercially expensive reagents, toxic reagents, sealed tube reaction at higher temperature, more number of steps etc. In the prior art preparation of nitroxyl radicals was achieved by many methods and following are the few representative ones. 1. a) Several nitroxyl radicals were prepared from hydroxylamine by treating with potassium ferrycyanide [Ref: JACS 1944, 66, 1652. Ch]. Many other reagents such as air [Ref: Chem Ber 1938, 71, 1442], silver oxide,F, [Ref: JACS, 1965,87,802] Pb dioxide [Ref: Bull. Soc. Chem. France 1968,4679; JACS, 1968,90,1078], nickel peroxide [Ref: Tet Let .1965, 3879] are also known for oxidation of hydro xylamine to produce nitroxyl radicals. b) Nitroxyl radicals were prepared by oxidation of amines by using various oxidizing agents like hydroperoxide, lead tetroxide, various peracids, H2O2 with cerium, Ag2O alkaline solution of H2C2, pertungstate ion, benzoyl peroxide, meta chloroperbenzoic acid etc. [Ref: Tet. Let. 1995, 36, 5519 and references cited therein] Under basic condition using acetone, oxone, buffer and phase transfer catalyst, some secondary amines having no a-hydrogen are oxidized to their corresponding nitroxyl radicals. c) Hydroxyl amine was converted to nitroxyl radicals via fluorine oxidation at -70. In another method hydroxyl amine was passed through silver oxide at 200° to get nitroxyl radicals [Ref: JACS, 1965, 87, 802] d) Acylphenyl nitroxyl radicals were prepared by oxidation of the corresponding hydroxylamides with nickel peroxides [Ref: Tet Let 1965, 3879]. 2. a) Nitroxyl radicals were prepared by reduction of nitrocompound with metallic sodium or by polarographic technique [Ref: JACS 1961, 83,4671]. A similar strategy of reduction was also used by employing Grignard complex [Ref: Bull Soc. Chim. France. 1965, 444] and LAH [Ref: Tet Let. 1964, 3507.] b) Diphenyl nitroxyl radicals were also prepared from nitro derivatives in 3 steps. First step involves reduction of amine, 2nd step involves oxidation to nitroso derivative, which is decomposed in the 3rd step at 400°, under high pressure [Ref: Bull. Chem. Soc. Japan 1964,37, 1893]. 3. a) Diaryl nitroso radicals were prepared by photolysis [Ref: JOC 1967, 32, 3853]. b) Nitroxyl radicals were prepared in 2 steps, from hydrocarbon. In the 1st step, nitroso alkane is produced by photochemical nitrosation, and the 2nd step involves thermal reaction at 100°- 120°. [Ref: Tet 1967, 23, 4021; JACS 1967, 89, 5487.] Nitroxyl radicals were also prepared by photolysis of substituted nitrobenzene derivatives. c) Nitroxyl radicals were also prepared from nitrosyl chloride in tetrafluroethylene by irradiation for 5 days [JACS, 1966, 480]. 4. a) Nitroxyl radicals were prepared from dibenzyl hydroxylamine by using Tertiary butyl hydro peroxide (TBHP) in a sealed tube at 80° [JACS 1961, 83, 4900]. Nitroxyl radicals were also prepared from hydroxylamine and acetone in a sealed tube at 140°-150° for 8 - 10 hrs [Ref: Tet let 1968, 1065]. b) Nitroxyl radicals of sterically hindered amines were prepared by treating the amine with H2O2 added in portions in presence of Titanium containing catalyst and solvent. [Ref: Eur pat App E.P. 488403 (1992) The above mentioned processes in the prior art are known to be useful for the preparation of nitroxyl radicals, however they suffer from the following drawbacks. 1. In most of the methods oxidizing agents used are, HgO, Pb (IV) oxide, nickel peroxide, m- chloroperbenzoic acid, oxone which are toxic, commercially expensive and acidic, bulky molecule, so not suitable. 2. In some methods oxone is used which is inexpensive but the amount of KHSO4 used to produce one mole quantity of dioxirane would be enormous. Moreover, dimethyl dioxirane is potentially explosive to handle. 3. In some of the methods, halogenated reagents and excess of Grignard reagent, are used which are hazardous in nature. 4. In some of the reactions in the prior article, large amount of waste products containing transition metals like (Ni, W, Hg, Ag, Ti etc.) residues are generated in the processes which are difficult to dispose off. 5. In one of the methods metallic sodium is used which is expensive and dangerous to handle. 6. In one of the methods lithium aluminium hydride is used for reduction of nitro compound, wherein dry condition has to be maintained which is difficult. 7. In some methods very high temperature and high pressure is employed to decompose nitroso derivatives, which is hazardous to the environment and highly explosive in nature. 8. In one of the methods, the sealed tube and higher temperature is used which is again dangerous. 9. Most of the methods in prior art involve many number of steps. 10. Reagents like various peracids, hydroperoxides, lead tetroxides; mercuric oxides are used which are hazardous to the environment. 11. In some methods, irradiation technique is used which is very expensive, and safety is required while handling. In view of the above disadvantages of the prior art, it is desirable to provide a process that is safe, eco-friendly, inexpensive single step and simple. The main object of the present invention is to provide an improved process for the preparation of nitroxyl radicals, which obviates the drawbacks as detailed above. Another object of the present invention is to provide a safe process for the preparation of nitroxyl radical by treating various tetrasubstituted secondary amines with 30% H2C2, as oxidant and Vanadium Silicate (VS-1) as heterogeneous catalyst, which can easily be separated from the product and reused three times, without further purification. The catalyst used in the present invention is prepared by mixing tetraethyl ortho silicate (TBOS), telrapropyl ammonium hydroxide (TPA-OH), deionized water & vanadyl sulfate trihydrate. Accordingly the present invention provides an improved single step process for the preparation of nitroxyl radicals which comprises; mixing amine, such in herein described with 30% - 70% oxidant such as herein described in presence of a heterogeneous vanadium silicate catalyst reiluxing the mixture for a period of 6-20hrs, cooling the reaction mixture to ambient temperature, separating the catalyst, extracting with polar solvent such as herein described by conventional methods to get the corresponding nitroxyl radical. In one of the embodiment of the invention the amine used may be such as tetramcthylpiperidines, hydroxy- tetramethyl piperidines, oxazolidines, dimethyl anilines. In one of the embodiment of the present invention the oxidant used may be tertiarybutyl hydropcroxide (TBHP) of I H2C2In another embodiment, the polar solvent used may be selected from organic solvent such as dichloromethane, methanol, acetonitrile, acetone, dimethyl formamide. In yet another embodiment the heterogeneous catalyst used may be Vanadium silicate designated as (VS-1), claimed and prepared as per the process described in our co-pending application no 765/DEL/91. In a feature of the present invention the products isolated by filtering to remove the catalyst, then by extracting with dichloromethane, and removal of solvent and by passing through a column of silicagel to get the pure product. In still another embodiment the reaction temperature may be 0° to 150° C preferably 70° C. The process for the Invention is described below with reference to examples, which are illustrative only and should not be construed to limit the scope of the present invention in any manner. Example 1 To a solution 25g of tetraethyl ortho silicate (TEOS), lOg of tetrapropyl ammonium hydroxide (TPA-OH), 10ml of deionized water was added to hydrolyse the tetraethyl ortho silicate (TEOS). The mixture was stirred for about 30 minutes at 298K. To the above mixture, required quantity of vanadyl sulfate trihydrate in 5ml of deionized water was added slowly. Finally a solution of 5g of tetrapropyl ammonium hydroxide (TPA-OH), in 5ml of water was added. The clear green solution thus obtained was stirred for 3 hrs before adding 20ml of water and stirred for 90 minutes. The crystllization was carried out at 443k for 48 to 60 hrs under static condition. The material thus obtained was filtered, washed with distilled water and dried at 373K for 6hrs to get Vanadium silicate - 1 (yield 80%). Example 2 A mixture of 2,2,6,6- tetramethylpiperidine (0.5 g, 3.5 mmol), 30% l-^Ch (1.6 ml, 14 mmol) and 50 mg of VS-1 were taken in 10ml of methanol and refluxed for 12 hrs and worked it up by filtering to remove the catalyst, then by extraction with dichloromethane, and removal of solvent and by passing through a column of silicagel of the crude product with 10- 15% ethyl acetate- pet ether to get the pure product of 2,2,6,6-tetramethyl piperidine -1-oxyl 0.47 gm (85%). m.p. 36-38° Examples 3 A mixture of 4- hydroxy-2,2,6,6- tetramethylpiperidine (0.55 g, 3.5 mmol) , 30% H2C2 ( 1.6 ml, 14 mmol) and 50 mg of VS-1 were taken in 10ml of methanol and refluxed for 12 hrs. and worked it up by filtering to remove the catalyst, then by extraction with dichloro methane, and removal of solvent and by passing through a column of silicagel of the crude product with 10- 15% ethyl acetate - pet ether to get the pure product of 4- hydroxy-2,2,6,6-tetramethyl piperidine -1-ox.l. 0.42gm (71%) m.p. 68-69. Examples 4 A mixture of 2-spirocyclohexyl -4, 4- dimethyl-oxazolidine (0.59 g, 3.5 mmol), 30% H2O2 (1.6 ml, 14 mmol) and 50 mg of VS-1 were taken in 10ml of methanol and refluxed for 12 hrs. and worked it up by filtering to remove the catalyst, then by extraction with dichloromethane, and removal of solvent and by passing through a column of silicagel of the crude product with 10-15% ethyl acetate - pet ether to get the pure product of 2-spirocyclohexyl —4,4 - dimethyl - oxazolidine -1 - oxyl. 0.49 gm (78 %) m.p. 55- 57 Examples 5 A mixture of N, N -Dimethyl aniline (0.42 g, 3.5 mmol), 30% H2O2 (1.6 ml, 14 mmol) and 50 mg of VS-1 were taken in 10ml of methanol and refluxed for 12 hrs. and worked it up by filtering to remove the catalyst, then by extraction with dichloromethane, and removal of solvent and by passing through a column of silicagel of the crude product with 10- 15% ethyl acetate- pet ether to get the pure product of N, N - dimethyl aniline - N -oxide. 0.33gm(72%). Examples 6 A mixture of 2,2,6,6- tetramethylpiperidine (0.5 g, 3.5 mmol), 70% TBHP (2 ml, 14 mmol) and 50 mg of VS-1 were taken in 10ml of methanol and refluxed for 12 hrs and worked it up by filtering to remove the catalyst, then by extraction with dichloromethane, and removal of solvent and by passing through a column of silicagel of the crude product with 10- 15% ethyl acetate- pet ether to get the pure product of 2,2,6,6-tetramethyl piperidine -1-oxyl 0.5 gm (90%). m.p. 36-38° Novelty and inventive step. 1. This is the first report in which a new heterogeneous catalyst Vanadium Silicate (VS-1) has been successfully employed for the catalytic oxidation of amines to their nitroxyl radicals. 2. Only catalytic amount of oxidant has been used in the reaction. 3. The catalyst Vanadium Silicate (VS-1) is truly heterogeneous one, infact the catalyst was recovered & successfully reused many number of times for the process without further purification. 4. The process can be continues one, operating at ambient temperature without affecting the yield & purity of the process. The advantages of present invention are as follows: 1. The process is economically viable. 2. It is environmentally safe 3. It is easy to handle 4. No transition metal or heavy metals (Ni, Pb, W, Ag etc.) are used in the present process, so problem of disposal of such metal does arise. 5. It is a single step process. We Claim: 1. An improved single step process for the preparation of nitroxyl radicals which comprises; mixing amine such in herein described with 30% - 70% oxidant such as herein described in presence of a heterogeneous vanadium silicate catalyst, refluxing the mixture for a period of 6-20hrs, cooling the reaction mixture to ambient temperature, separating the catalyst, extracting with polar solvent such as herein described by conventional methods to get the corresponding nitroxyl radical. 2. A process as claimed in claim 1 wherein the amine used is selected from tetramcthylpiperidines, hydroxy- tetramethyl piperidines, oxazolidines, dimethyl anilines. 3. A process as claimed in claim 1-2 wherein the oxidant used is selected from tertiarybutyl hydroperoxide ('TBI IP) and Hydrogen peroxide (H2O2). 4. A process as claimed in claims 1-3 wherein, the polar solvent used is selected from organic solvent such as dichloromethane, methanol, acetonitrile, acetone, dimethyl form amide. 5. A process for preparation of nitroxyl radicals substantially as herein described with reference to example.

Documents:

1033-del-2000-abstract.pdf

1033-del-2000-claims.pdf

1033-del-2000-correspondence-others.pdf

1033-del-2000-correspondence-po.pdf

1033-del-2000-description (complete).pdf

1033-del-2000-form-1.pdf

1033-del-2000-form-19.pdf

1033-del-2000-form-2.pdf

1033-del-2000-form-3.pdf