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1. Department of Chemistry, Harvard University, Cambridge, Massachusetts 02138.
2. Department of Chemistry, Yale University, New Haven, Connecticut 06520.
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H. Oldenziel, J. Wildeman, and A. M. Van Leusen, Org. Syn., 57, 8 (1977).
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ORGANIC SYNTHESES—VOL. 58
Chemical Abstracts Nomenclature (Collective Index Number; Registry Numbers)
Cyclohexanecarbonitrile (8,9); (766-05-2)
Hydrogen cyanide: Hydrocyanic acid (8,9); (74-90-8)
Carbazic acid, 2-(l-cyanocyclohexyl)-, methyl ester (8); Hy-drazinecarboxylic acid, 2-(l-cyanocyclohexyl)-, methyl ester (9); ( —) Methyl carbazate: Carbazic acid, methyl ester (8); Hydrazinecar-boxylic acid, methyl ester (9); (6294-89-9)
Cyclohexanone (8,9); (108-94-1)
Formic acid, [(l-cyanocyclohexyl)azo]-, methyl ester (8); Diazenecarboxylic acid, 2-(l-cyanocyclohexyl)-, methyl ester (9); (33670-04-1)
Sodium methoxide: Methanol, sodium salt (8,9); (124-41-4) Tosylmethylisocyanide: Methyl isocyanide, p-tolylsulfonyl- (8); Benzene, l-[(isocyanomethyl)sulfonyl]-4-methyl- (9); (36635-61-
4H-l,2,4-Triazole-3,5-dione, 4-phenyl- (8,9); (4233-33-4) Jerf-Butyl hypochlorite: Hypochlorous acid, ferf-butyl ester (8); Hypochlorous acid, 1,1-dimethylethyl ester (9); (507-40-4)
NITRONES FOR INTRAMOLECULAR 1,3-DIPOLAR CYCLOADDITIONS: HEXAHYDRO-l,3,3,6-TETRAMETHYL-
(CH3)2C=CHCH2CH2CH(CH3)CH2CHO + CH3NHOHHCI
Submitted by Norman A. LeBel and Dorothy Hwang1 Checked by Christopher K. VanCantfort and Robert M. Coates
NITRONES FOR INTRAMOLECULAR 1,3-DIPOLAR CYCLOADDITIONS 107
A 1-1., three-necked, round-bottomed flask is fitted with a mechanical stirrer, a reflux condenser attached to a Dean-Stark water separator,' and a 250-ml. dropping funnel. The flask is charged with 25.0 g. (0.16 mole) of 3,7-dimethyl-6-octenal (Note 1) and 500 ml. of toluene. The solution is heated to reflux with stirring, and a solution of N-methylhydroxylamine, methanol, and toluene is added (see below).
To a cooled and magnetically stirred solution of 23.4 g. (0.28 mole) of N-methylhydroxylamine hydrochloride (Notes 2 and 3) in 40 ml. of methanol is added 15.3 g. (0.282 mole) of sodium methoxide. The cooling bath is removed, and the mixture is stirred at room temperature for 15 minutes. The mixture is filtered rapidly through a 35-mm., coarse, sintered-glass funnel, and the filter cake is washed with 10 ml. of methanol. The filtrates are combined, refiltered, and mixed with 150 ml. of toluene.
The two-phase mixture containing N-methylhydroxylamine is added dropwise to the refluxing toluene solution of the aldehyde over 3 hours. During this time the distillate is collected and discarded in 25-ml. portions until the last such portion collected and discarded is clear (Note 4). Reflux and stirring are continued for an additional 3 hours, and then the clear reaction mixture is allowed to cool. The product is extracted with three 80-ml. portions of 10% aqueous hydrochloric acid. The extracts are combined, and the pH of the solution is adjusted to >12 by the slow addition of 30% aqueous potassium hydroxide. The basic mixture is extracted with two 120-ml. portions of pentane (Note 5), and the combined extracts are washed once with 100 ml. of water and dried over anhydrous potassium carbonate. The pentane is removed on a rotary evaporator and the residue is distilled through a short Vigreux column under reduced pressure to give 19.1-19.6 g. (64-67%) (Note 6) of hexahydro-l,3,3,6-tetramethyl-2,l-benz-isoxazoline, b.p. 90-92° (9 mm.) (Note 7).
1. Matheson Coleman and Bell technical-grade 3,7-dimethyl-6-octenal (citronellal), b.p. 87-90° (10 mm.), is used after a simple distillation.
ORGANIC SYNTHESES—VOL. 58
2. This quantity amounts to an 0.72 molar excess. A molar excess of at least 0.5 is desirable to maximize the yield.