Org. Synth. 1966, 46, 127
Submitted by Ingrid Brüning, Rudolf Grashey, Hans Hauck, Rolf Huisgen, and Helmut Seidl1
Checked by George E. Davis, Wayland E. Noland, and William E. Parham.
. A solution of 27.3 g. (0.25 mole) of pure N-phenylhydroxylamine2 (Note 1)
in 50 ml. of ethanol
is prepared in a 200-ml. Erlenmeyer flask
by swirling a mixture of the two and warming it briefly to 40–60° (Note 2)
. To the clear, lightly colored solution is added 26.5 g. (25.3 ml., 0.25 mole) of freshly distilled benzaldehyde
(exothermic reaction). The flask is stoppered and kept overnight at room temperature in the dark. The colorless needles of N,α-diphenylnitrone
are collected on a Büchner funnel
and washed once with 20 ml. of ethanol
. There is obtained 42–43 g.
) of product (m.p. 111–113°
), which can be further purified by dissolving the crude material in 80 ml. of ethanol
and allowing the solution to cool for several hours in the ice box
. In this manner there is produced 35–39 g.
) of pure crystalline nitrone, m.p. 113–114° (Note 3)
B. 2,3,5-Triphenylisoxazolidine. In a 100-ml. two-necked flask provided with a reflux condenser and a gas-inlet tube are placed 20.0 g. (0.101 mole) of pure N,α-diphenylnitrone and 50 ml. (0.43 mole) of freshly distilled styrene (Note 4). The flask is heated at 60° for 40 hours a slow nitrogen stream. The mixture is then cooled, and most of the excess styrene is removed (Note 5) from the clear orange solution by heating at a bath temperature of 55° (12 mm.). The warm residue is poured into 40 ml. of petroleum ether (40–60°), whereupon the isoxazolidine crystallizes immediately (Note 6). The flask is rinsed twice with 20-ml. portions of petroleum ether, and the washings are combined with the product. The resulting mixture is cooled for 1 hour in the ice box, and the lightly colored crystals are collected on a Büchner funnel and washed with two 20-ml. portions of petroleum ether. The yield of crude air-dried isoxazolidine (m.p. 96–98°) is 28–30 g. (92–99%).
For further purification the product is dissolved in 40 ml. of methylene chloride in a 250-ml. Erlenmeyer flask. The solution is heated to boiling, and 30 ml. of methanol is added (Note 7). When the solution has cooled to room temperature, 70 ml. of methanol is added to complete the crystallization, and the solution is kept in the ice box for 3 hours. The colorless needles are collected by vacuum filtration and washed with two 30-ml. portions of cold methanol. There is obtained 23–25 g. (76–82%) of product which melts at 99–100° (Note 8),(Note 9),(Note 10).
should be free of sodium chloride
. This is easily attained by dissolution of the compound in benzene
followed by filtration and then addition of petroleum ether
to cause rapid crystallization.
On prolonged heating, N-phenylhydroxylamine
begins to decompose.
The compound is light-sensitive and should be kept in a brown container
should be redistilled and stabilized with 0.1% hydroquinone
just prior to use; otherwise the final product will be contaminated with polystyrene
. The checkers used approximately 60 ml. (0.52 mole) of styrene
The checkers found that, if all the styrene
is removed, the product may become too viscous to pour.
By this method the formation of a thick crustaceous material, which is difficult to pulverize or wash, is avoided.
In this way the boiling solution is kept clear.
From the mother liquor a second diastereoisomer can be isolated (m.p. 78.5–79.5°
) in about 10%
yield by fractional crystallization.
In an analogous manner several other isoxazolidines can be prepared. From the reaction of N,α-diphenylnitrone
is obtained. As above, 10.0 g. (50.7 mmoles) of diphenylnitrone
is heated under a nitrogen
atmosphere for 24 hours at 85° with 15.3 g. (15.0 ml., 85.0 mmole) of 1,1-diphenylethylene
The excess olefin is removed at 105–130° (bath temperature) under high vacuum (0.005 mm.). The yellow-gold viscous residue is dissolved by warming it in a mixture of 15 ml. of methylene chloride
and 30 ml. of methanol
; on cooling, crystallization commences. After 2 hours another 10 ml. of methanol
is added, and the mixture is cooled overnight in the ice box. The colorless crystals are collected on a Büchner funnel and washed twice with 20-ml. portions of methanol
. The yield of air-dried product (m.p. 113–115°
) is 14–16 g.
). The compound can be further purified by adding methanol (30 ml.)
to a boiling solution in methylene chloride (15 ml.)
. After the solution has cooled to room temperature, another 10 ml. of methanol
is added; the mixture is kept in the ice box for several hours and then filtered. The pure compound melts at 115–116°
, yield 13–15 g.
The preparation of the oily ethyl 2,3-diphenyl-5-methylisoxazolidine-4-carboxylate
provides another example of this reaction. As in the procedure described with styrene
, 10.0 g. (50.7 mmoles) of N,α-diphenylnitrone
is heated under nitrogen
for 24 hours at 90–100° with 35.0 g. (38.0 ml., 307 mmoles) of ethyl crotonate
. The excess olefin, b.p. 45° (12 mm.)
is removed on the water pump
, and the red-orange residue, while still warm, is transferred to a 50-ml. Claisen flask
as a rinse. After removal of the solvent, 13–14 g.
) of the isoxazolidine is obtained as an orange oil by high-vacuum distillation at 163–173° (0.003 mm.). Redistillation of this material yields 2–3 g.
of fore-run and a purer product obtained as a yellow oil, b.p. 165–170° (0.003 mm.)
was first obtained by Bamberger4
. The procedure described above is analogous to that of Wheeler and Gore.5
, and ethyl 2,3-diphenyl-5-methylisoxazolidine-4-carboxylate
have been prepared only by this method.6
4. Merits of the Preparation
The procedure described illustrates the use of 1,3-dipolar addition7
of nitrones to olefins for the preparation of isoxazolidines. The preparations of 2,3,5,5-tetraphenylisoxazolidine
and ethyl 2,3-diphenyl-5-methylisoxazolidine-4-carboxylate
, as described in (Note 9)
and (Note 10)
, respectively, indicate the versatility of the method.
Chemical Abstracts Nomenclature (Collective Index Number);
sodium chloride (7647-14-5)
methylene chloride (75-09-2)
ethyl crotonate (623-70-1)
Isoxazolidine, 2,3,5-triphenyl- (13787-96-7)
ethyl 2,3-diphenyl-5-methylisoxazolidine-4-carboxylate (19744-10-6)
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