N-tert-butyl-1-phenylmethanimine oxide

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a dry 3 liter, 3-necked, round bottom flask equipped with a mechanical paddle stirrer, a nitrogen gas flow, and a condenser was added 87 gm (83.5 ml; 0.82 moles) of benzaldehyde and 63 gm (90.5 ml; 0.86 moles) of t-butylamine. The mixture was stirred for about 4 hours at room temperature to allow complete formation of N-benzylidene-t-butylamine. After removal of the nitrogen gas flow and the condenser, the reaction flask was evacuated under an aspirator (about 24″ Hg vacuum) for about 15 minutes. The aspirator was detached and 288 gm (3.428 moles) of sodium bicarbonate followed by 500 ml of water and 500 ml of acetone were added to the 3-liter flask. The condenser was reattached to the flask and carefully about 600 gm (0.98 moles) of Oxone® was added portion-wise through a powder-addition funnel to the stirring reaction over a period of about 10 minutes. The reaction began to slowly foam from the evolution of carbon dioxide and turn to a bluish tinge as the temperature rose to about 35° C. The reaction was stirred for one hour after the Oxone® addition, and a GC analysis revealed a trace amount of starting imine (3.72 minutes) and a large peak representing 2-t-butyl-3-phenyl oxaziridine (4.45 minutes). The reaction was poured into a beaker containing a 2-phase solution of 3000 ml water and 300 ml toluene. Insoluble salts were filtered out and the aqueous layer separated in a separatory funnel. The upper toluene layer was placed in a 1-liter single-neck, round bottom flask and concentrated over a 30-minute period on a rotary evaporator at 50° C. under vacuum (about 24″ Hg) to remove traces of acetone and water. Several silicon carbide boiling chips were added to the concentrated oxaziridine and the oxaziridine/toluene solution was refluxed at 115° C. -125° C. for 2-3 hours to form the desired N-t-butylphenylnitrone product. The excess toluene was removed under vacuum and the resulting clear brown liquid N-t-butylphenylnitrone was poured into a crystallizing dish and placed in a fume hood. Crystallization was almost immediate, affording 113.1 gm of crude crystalline N-t-butylphenylnitrone (78% theoretical yield). To a dry 3 liter, 3-necked, round bottom flask equipped with a mechanical paddle stirrer After removal of the nitrogen gas flow the condenser, the reaction flask was evacuated under an aspirator (about 24″ Hg vacuum) for about 15 minutes were added to the 3-liter flask was added portion-wise through a powder-addition funnel to the stirring reaction over a period of about 10 minutes rose to about 35° C The reaction was stirred for one hour The reaction was poured into a beaker Insoluble salts were filtered out the aqueous layer separated in a separatory funnel The upper toluene layer was placed in a 1-liter single-neck, round bottom flask concentrated over a 30-minute period on a rotary evaporator at 50° C. under vacuum (about 24″ Hg) to remove traces of acetone and water Several silicon carbide boiling chips were added to the concentrated oxaziridine the oxaziridine/toluene solution was refluxed at 115° C. -125° C. for 2-3 hours

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a nitrogen charged 250 ml, 3-necked, round bottom flask equipped with a magnetic stir bar, nitrogen gas flow, pot thermometer, and condenser was added 119.3 gm (0.674 moles) of the 2-t-butyl-3-phenyloxaziridine as prepared in Example 2 and several silicon carbide boiling chips. The system was continuously flushed with nitrogen while gradually heated to 120° C. Upon reaching 120°, the heat was removed as the exothermic rearrangement brought the reaction temperature to about 134° C. before slowly subsiding. The pale yellow 2-t-butyl-3-phenyloxaziridine gradually turned to a clear, dark brown color. The reaction was cooled after a total reaction time of about 1 hour and a GC analysis, as described in Example 1, of the crude product 25 indicated a complete conversion to the corresponding nitrone (a peak having a retention time of 6.45 minutes). Upon cooling, the liquid N-t-butylphenylnitrone crystallized to form a solid having a crude yield of 109.4 gm (91.7% of theoretical yield). To a nitrogen charged 250 ml 3-necked, round bottom flask equipped with a magnetic stir bar The system was continuously flushed with nitrogen Upon reaching 120° the heat was removed as the exothermic rearrangement to about 134° C. The reaction was cooled after a total reaction time of about 1 hour Upon cooling the liquid N-t-butylphenylnitrone crystallized to form a solid a crude yield of 109.4 gm (91.7% of theoretical yield)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The imine starting material may be commercially purchased or synthetically prepared. If desired, the imine may be prepared by a condensation reaction between an aldehyde and a primary amine. In one embodiment of the present invention, the imine precursor for α-phenyl-N-tert-butyl nitrone (PBN) is prepared by combining benzaldehyde and t-butyl amine at room temperature, in the absence of a solvent, to form the corresponding benzylidene-t-butyl amine (imine) and water. It was found that the resulting imine was sufficiently pure for use in the next step without the need for purification or removal of water by-product contained therein. Thus, the present method reduces time and cost, and improves efficiency, in comparison with traditional transformations. synthetically prepared at room temperature

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: N-tert-butylphenylnitrone (44.8 g, 0.25 mol) was dissolved in toluene (134 g) in a 500 ml bottle. Sulphuric acid (27.5 g, 95 to 97%, 0.27 mol, 1.1 equiv.) was diluted in water (134 g) and added to the reaction bottle. The two-phase mixture was then heated to +50° C. and stirred vigorously for approximately 2 h. At that time, GC indicated that only 0.2 area % of N-tert-butylphenylnitrone remained. After cooling to +20° C., the dark red organic phase was discarded and the clear, yellow water phase was extracted once with toluene (46 g). To the remaining water phase was then added acetic acid (14.8 g, 0.25 mol, 1.0 equiv.) followed by sodium hydroxide (45% aqueous solution) until the pH of the water phase was approximately 5.5. Ethyl acetate (224 g) was then added and the mixture was stirred vigorously. The organic phase was then separated and the aqueous phase was extracted once more with ethyl acetate. The combined organic fractions were then evaporated to leave an oil (35.2 g). This material was purified by distillation under reduced pressure. A stable distillation point was achieved at 19 mbar/ +78° C. Fraction 1, retrieved below +70° C., contained 2.7 g and fraction 2, collected between +70° C. and +80° C., con a highly viscous oil (28.7 g, 76%) that crystallized as a white solid upon standing. pKa 6.4 Chromatographic purity (GC): 99.4 area % added to the reaction bottle The two-phase mixture was then heated to +50° C. After cooling to +20° C. the clear, yellow water phase was extracted once with toluene (46 g) the mixture was stirred vigorously The organic phase was then separated the aqueous phase was extracted once more with ethyl acetate The combined organic fractions were then evaporated

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Following the general procedure of Example 1, N-benzyl-N-tert-butylamine is oxidized using a solution of 3-chloroperoxybenzoic acid dissolved in methylene chloride to give N-tert-butyl-alpha-phenyl nitrone as a white solid melting at 70°-72° C. This is the nitrone described in Japanese Sho No. 59-11345.