Organic Syntheses, CV 7, 8
ELECTROPHILIC
N-AMINATION OF IMIDE SODIUM SALTS WITH
O-DIPHENYLPHOSPHINYLHYDROXYLAMINE (DPH):
7-AMINOTHEOPHYLLINE
Submitted by W. Klötzer, J. Stadlwieser, and J. Raneburger
1.
Checked by Michael J. Luzzio and Andrew S. Kende.
1. Procedure
A.
O-Diphenylphosphinylhydroxylamine.2 A
500-mL, round-bottomed flask, equipped with a
reflux condenser,
drying tube, an
efficient mechanical stirrer, a
dropping funnel, and a
nitrogen-inlet tube, is charged with
300 mL of anhydrous methylene chloride,
16.5 g (0.5 mol) of hydroxylamine base (Note
1), and
1.0 g of dry sodium bicarbonate. While the suspension is stirred vigorously at −30°C (bath temperature), a solution of
52.06 g (0.22 mol) of diphenylphosphinyl chloride (Note
2) in
70 mL of anhydrous methylene chloride is added under a
nitrogen atmosphere at a constant rate within 30 min. The resulting thick suspension is stirred at −30°C for 2 hr and for an additional 2 hr after the
cooling bath is removed. The reaction mixture is filtered through a
sintered-glass funnel (porosity 3) and the residue is washed with two
80-mL portions of methylene chloride. The
methylene chloride is removed from the colorless solid by a stream of air for 2 hr. The dry solid, still on the funnel, is then mixed thoroughly with 200 mL of deionized water. The water is removed by suction. The same operation is performed sequentially with
150 mL of 5% aqueous sodium bicarbonate solution and then with two 150-mL portions of water. This solid, which retains water tenaciously, is dried by suction and by pressing down on the funnel for several hours, followed by drying in a
phosphorus pentoxide-charged vacuum desiccator until its weight is constant (24 hr) to give
36 g (
70%) of impure
O-diphenylphosphinylhydroxylamine, mp
120–135°C, with decomposition.
A
500-mL, two-necked flask, equipped with a reflux condenser and a drying tube, is charged with
240 mL of anhydrous ethanol. The solvent is preheated to 70°C and a 12-g portion of this finely powdered dry product is added all at once. The resulting suspension is refluxed for 2–3 min when almost all of the solid has dissolved. The hot solution is filtered as quickly as possible through a sintered-glass funnel (porosity 3) and the filtrate is chilled to 0°C for 30 min. Isolation of the crystalline deposit and washing with
20 mL of ether provides
7.8 g of pure product. Recrystallization of three 12-g portions furnishes
23.4 g (
44%) of
O-diphenylphosphinylhydroxylamine, mp
>140°C, with decomposition (Note
3).
B.
7-Benzylideneaminotheophylline. A
2000-mL, round-bottomed flask, equipped with an efficient mechanical stirrer,
thermometer, and drying tube, is charged with
600 mL of anhydrous N-methylpyrrolidone (Note
4) and
20.2 g (0.1 mol) of anhydrous theophylline sodium salt (Note
5). The flask is cooled with an
ice–salt bath to 0°C (internal temperature). Then
23.4 g (0.1 mol) of O-diphenylphosphinylhydroxylamine is added in three equal portions while the suspension is stirred vigorously. After the ice–salt bath is removed, the resulting viscous suspension is stirred for 6 hr at 20°C.
After the solution is diluted with 1200 mL of water, the pH is adjusted to 1–2 with concentrated
hydrochloric acid and the mixture stirred at 5°C for 1 hr. The precipitated
diphenylphosphinic acid is isolated by filtration and washed with 50 mL of water (Note
6). The filtrate is placed in a 2000-mL, round-bottomed flask, equipped with a reflux condenser and an efficient mechanical stirrer. A solution of
20 mL of benzaldehyde in
50 mL of ether is added and the mixture is stirred vigorously for 20 min. The precipitate that forms is isolated by filtration and washed sequentially with 50 mL of water and
50 mL of ether to yield
19.6 g (
69%) of
7-benzylideneaminotheophylline, mp
207–209°C.
3 An analytical sample may be prepared by recrystallization from
ethanol (mp
209°C).
C.
7-Aminotheophylline. The reaction flask of a steam distillation apparatus is charged with
19.6 g (0.069 mol) of 7-benzylideneaminotheophylline and
100 mL (0.1 mol) of 1 N hydrochloric acid. The suspension is steam-distilled until no more
benzaldehyde is detected in the distillate (Note
7). The resulting clear solution in the reaction flask is concentrated by rotary evaporation to a volume of 30 mL, adjusted to pH 10 with concentrated
ammonium hydroxide, transferred to a
separatory funnel, and extracted with five
60-mL portions of chloroform. The combined
chloroform extracts are dried with anhydrous
sodium sulfate, filtered, and concentrated to dryness by rotary evaporation. The residue is recrystallized from 75 mL of water to afford
11.3 g (
84%) of
7-aminotheophylline, mp
222°C.
3
2. Notes
1.
Hydroxylamine base has been prepared by the method of Lecher and Hofmann.
4 The free base can be stored in a tightly stoppered flask at −20°C for several days. The checkers found it expedient to prepare free
hydroxylamine by a modification of the Lecher–Hofmann procedure in which a Schlenk tube under dry N
2 was used to filter the NaCl precipitate and the NH
2OH base was crystallized from the filtrate at −30°C, then isolated by inverting the Schlenk apparatus and filtering the product (74% yield from the hydrochloride).
3. The recrystallization should be performed as quickly as possible in portions below 15 g. Prolonged heating in ethanolic solution causes substantial losses. The pure, dry compound can be stored in a tightly stoppered flask at 0°C for at least 6 months without loss of aminating capacity. The submitters report that the pure compound showed no signs of spontaneous decomposition during 4 years of use, except when heated to >140°C, where the compound decomposes with effervescence.
3. Discussion
Electrophilic
N-aminations of imide salts have been performed with
hydroxylamine-O-sulfonic acid (HOSA),
8,9,10 O-(2,4-dinitrophenyl) hydroxylamine,
11,
12 and
O-mesitylenesulfonylhydroxylamine (MSH).
11 The use of HOSA is mainly restricted to aqueous reaction media.
8,
9 O-(2,4-Dinitrophenyl) hydroxylamine, MSH, and
O-diphenylphosphinylhydroxylamine (DPH) can be applied in anhydrous or even nonpolar solvents.
O-(2,4-Dinitrophenyl) hydroxylamine and MSH require
N-protected
hydroxylamine for their preparation.
11,
12 MSH has been found to be explosive.
13,
14 DPH has the advantage of being prepared directly from unprotected
hydroxylamine and seems to have no tendency toward spontaneous decomposition. The possibility of recycling
diphenylphosphinic acid may be regarded as a further advantage. The advantage of using unprotected
hydroxylamine to prepare DPH is partially negated by the required somewhat delicate preparation and handling of the free
hydroxylamine base. The large amount of solvent that is sometimes required because of the low solubility of DPH and the resulting
diphenylphosphinic acid salt may be regarded as a disadvantage, too.
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