Checked by Gordon Hill and K. Barry Sharpless.
1. Procedure
Caution! Reactions using peroxides should be performed behind a safety shield to minimize explosion hazards (Note 1). Hexamethylphosphoric triamide (HMPA) and methanol are toxic and must be handled in a hood (Note 2).
A.
Oxodiperoxymolybdenum(aqua)(hexamethylphosphoric triamide), MoO5·H2O·HMPA.
2 A
500-mL, three-necked flask is fitted with an
internal thermometer and a
mechanical paddle stirrer. The flask is charged, with stirring, with
30 g (0.2 mol) of molybdenum oxide (MoO3) (Note
3) and
150 mL of 30% hydrogen peroxide (H2O2) (Note
4). An
oil bath equilibrated at 40°C is placed under the rection mixture and heating is continued until the internal temperature reaches 35°C. The heating bath is removed and replaced by a
water bath to control the mildly exothermic reaction so that an internal temperature of 35–40°C is maintained. After the initial exothermic period (approximately 30 min), the reaction flask is placed in the 40°C oil bath and stirred a total of 3.5 hr to form a yellow solution with a small amount of suspended white solid (Note
5).
After cooling to 20°C, the solution is filtered through a
1-cm mat of Celite pressed into a
coarse-porosity sintered-glass filter. The yellow filtrate is cooled to 10°C (with an
ice bath and magnetic stirring) and
37.3 g (0.21 mol) of hexamethylphosphoric triamide (HMPA) (Note
2) is added dropwise over 5 min, resulting in the formation of a yellow crystalline precipitate. Stirring is continued for a total of 15 min at 10°C, and the product is filtered using a
Büchner funnel and pressed dry with a
spatula. After 30 min in the funnel (aspirator vacuum), the filtercake is transferred to a
1-L Erlenmeyer flask.
Methanol (20 mL) is added and the mixture is stirred in the 40°C bath. More
methanol is slowly added until the crystals have dissolved. Cooling the saturated solution in the
refrigerator gives yellow needles. The crystal mass is broken up with a spatula, the product is filtered and washed with
20–30 mL of cold methanol to give
MoO5·H2O·HMPA,
46–50 g (
59–64%) (Note
5) and (Note
6).
B.
Oxodiperoxymolybdenum(pyridine)(hexamethylphosphoric triamide) MoO5·Py·HMPA=MoOPH.
2 The recrystallized product from above is dried over
phosphorus oxide (P2O5) in a
vacuum desiccator, shielded from the light, for 24 hr at 0.2 mm to give a somewhat hygroscopic yellow solid,
MoO5·HMPA. A
36.0-g (0.101 mol) portion of MoO5·HMPA is dissolved in
150 mL of dry tetrahydrofuran (THF) (Note
7) and the solution is filtered through a Celite mat, if needed, to remove a small amount of amorphous precipitate. The filtrate is then stirred magnetically in a 20°C water bath while
8.0 g (0.101 mol) of dry pyridine (Note
8) is added over 10 min. The crystalline, yellow product is collected on a Büchner funnel, washed with dry
tetrahydrofuran (25 mL) and anhydrous
ether (200 mL) and dried in a vacuum desiccator (1 hr, 0.2 mm) to yield
36–38 g (
51–53% overall from MoO
3) of finely divided yellow crystalline
MoO5·Py·HMPA (Note
9).
The product is stored in a
dark glass jar inside a second
container partly filled with Drierite, and the container is kept in the refrigerator. Before opening the jar, the container is allowed to warm to room temperature to avoid condensation of moisture inside. Properly stored
MoOPH is a freely flowing crystalline powder and can be used over a period of several months (Note
10).
An aliquot of
47.1 mL (35.3 mmol) of LDA solution is transferred by nitrogen-filled syringe into a nitrogen-swept, 500-mL, three-necked flask equipped with a magnetic stirrer and a device for addition of solid
MoOPH. The latter is an L-shaped glass tube with male joints at each end. A
round-bottomed flask containing
20.9 g (48.1 mmol) of MoOPH is wired to the
L-tube, which is wired to the reaction vessel at such an angle that rotation of the L-tube causes addition of
MoOPH to the enolate. The
MoOPH container is temporarily suspended using clamps, and the entire apparatus is maintained under a slow flow of
nitrogen. After the
LDA solution is cooled in a dry ice–acetone bath,
4.88 g (32.1 mmol) of camphor (Note
13) in
200 mL of dry THF is added dropwise with stirring over 0.5 hr. Then 10 min later the reaction is placed in a
dry ice–carbon tetrachloride bath and after 15 min the
MoOPH is added over 1–2 min by rotating the L-tube and gently tapping it to dislodge the powder. The reaction immediately turns orange and eventually fades to a pale tan (Note
14). Stirring is continued at approximately −23°C for 20 min, and the reaction is quenched by adding
100 mL of saturated aqueous sodium sulfite (Na2SO3). Vigorous stirring is maintained and the mixture is allowed to warm to room temperature. After 10 min at 20°C, the mixture is shaken with
100 mL of saturated sodium chloride solution, and the aqueous layer is extracted twice with
70 mL of ether. The combined organic layers are washed once with a mixture of
50 mL of 10% aqueous hydrochloric acid and
50 mL of saturated sodium chloride solution. The
hydrochloric acid–
sodium chloride aqueous layer is back-extracted with
50 mL of ether, and the combined organic layers are dried over
MgSO4, filtered, and evaporated under an aspirator to yield a blue–green oil. Residual molybdenum salts are removed by filtration over 100 g of silica gel (Note
15) in a
2.5-cm column wet-packed and eluted with 1:1
ether–
hexane. The product is eluted with approximately
750 mL of ether–hexane. Evaporation (aspirator) yields a white semisolid, which is crystallized from
15 mL of hexane at −20°C and collected by washing with
hexane cooled to −70°C. The mother liquors are crystallized in a similar manner from
2-4 mL of hexane to give a total of five crops,
4.14 g (
77%) of colorless needles, mp
170–183°C, a 5:1 mixture of endo : exo isomers (Note
16). Recrystallization did not affect the isomer ratio (literature mp; endo,
192–195°C, exo,
210–211°C).
3
2. Notes
1. There are no reports that
MoO5·H2O·HMPA,
MoO5·HMPA, or
MoO5·Py·HMPA are shock-sensitive. On heating on a hot plate, the crystalline solids ignite and burn, but do not detonate. These compounds can be stored in a refrigerator with precautions to exclude light. Prolonged storage at room temperature in the light may cause decomposition with gas evolution and an exotherm sufficient to crack a
glass container.
5. Failure to maintain the internal temperature below 40°C results in formation of amorphous, insoluble products.
6. The purity of this material is decisive because the quality of subsequent products cannot be improved by recrystallization because of some decomposition.
9. The product melts with vigorous evolution of gas at
103–105°C.
10. Prolonged exposure to light, or failure to control exothermic reactions in prior steps, results in a sticky product that smells of
pyridine. No method for purifying partly decomposed
MoOPH has been found, and "sticky" product should not be used for enolate hydroxylation. Suspect material can be decomposed by stirring with aqueous
sodium sulfite (Na
2SO
3) solution.
11.
Butyllithium was obtained from the Foote Mineral Company.
13.
Camphor was obtained from Eastman Organic Chemicals.
14. The colors are somewhat substrate-dependent. Some enolate hydroxylations acquire a green–blue color.
15.
Silica gel, 60–200 mesh, was obtained from Davison Chemical Division.
16. The endo : exo ratio is determined by comparing the NMR CHOH signal areas of the endo (4.21 ppm, d,
J = 4.8 Hz) and exo (3.75 ppm, br s) isomers.
3. Discussion
Enolate hydroxylation is a problem of long standing. Direct oxygenation succeeds with the fully substituted enolates of certain α,α-disubstituted ketones
4 and a variety of carboxylic acid derivatives (ester anions, acid dianions, amide anions),
5 but the reaction of enolates, RCH=C(O
−)R' or CH
2=C(O
−)R', with
oxygen results in complex products of overoxidation. The stable
molybdenum peroxide reagent
MoO5·Py·HMPA (MoOPH),
2 first prepared by Mimoun, allows the conversion of RCH=C(OLi)R' into RCH(OH)COR' in generally good yields (Table I).
6 In some cases, the α-diketone is formed as a by-product. The
MoOPH reagent also hydroxylates branched or unbranched ester, amide, and nitrile anions.
6,7 For unknown reasons,
MoOPH hydroxylations seldom give complete conversion of enolates into products, and recovery of 5–15% of the starting carbonyl substrate is to be expected.
Appendix
Compounds Referenced (Chemical Abstracts Registry Number)
silica gel
Oxodiperoxymolybdenum(aqua)(hexamethylphosphoric triamide), MoO5·H2O·HMPA
molybdenum oxide (MoO3)
hydrogen peroxide (H2O2)
MoO5·H2O·HMPA
Oxodiperoxymolybdenum(pyridine)(hexamethylphosphoric triamide) MoO5·Py·HMPA=MoOPH
MoO5·HMPA
MoO5·Py·HMPA
MoOPH
LDA
MoO5·Py·HMPA (MoOPH)
meta-chloroperbenzoic acid
OXODIPEROXYMOLYBDENUM(PYRIDINE)(HEXAMETHYLPHOSPHORIC TRIAMIDE), MoO5·Py·HMPA(MoOPH)
menthoxide
hydrochloric acid (7647-01-0)
methanol (67-56-1)
ether (60-29-7)
sodium sulfite (7757-83-7)
sodium chloride (7647-14-5)
oxygen (7782-44-7)
barium oxide
nitrogen (7727-37-9)
pyridine (110-86-1)
Benzophenone (119-61-9)
sodium (13966-32-0)
hydrogen peroxide (7722-84-1)
menthol (15356-60-2)
MgSO4 (7487-88-9)
camphor (21368-68-3)
butyllithium (109-72-8)
Tetrahydrofuran,
THF (109-99-9)
α-Tetralone (529-34-0)
hexane (110-54-3)
deoxybenzoin (451-40-1)
2-phenylcyclohexanone (1444-65-1)
oxaziridine
phenanthroline
hexamethylphosphoric triamide (680-31-9)
isobutyrophenone (611-70-1)
lithium diisopropylamide (4111-54-0)
diisopropylamine (108-18-9)
3-Hydroxy-1,7,7-trimethylbicyclo[2.2.1]heptan-2-one,
Bicyclo[2.2.1]heptan-2-one, 3-hydroxy-1,7,7-trimethyl-,
1,7,7-trimethyl-3-hydroxybicyclo[2.2.1]-heptan-2-one (21488-68-6)
molybdenum oxide
phosphorus oxide (1314-56-3)
molybdenum peroxide
Valerophenone (1009-14-9)
4,4-Diphenylcyclo-hexanone (4528-68-1)
Copyright © 1921-2002, Organic Syntheses, Inc. All Rights Reserved