Checked by Catherine Gasparski and Larry E. Overman.
1. Procedure
A.
4-Bromo-2,6-di-tert-butylphenol. A
dry, 1-L, three-necked, round-bottomed flask is fitted with a
gas inlet,
rubber septum,
pressure-equalizing dropping funnel,
magnetic stirring bar, and a
gas outlet tube that is connected to a
gas trap containing 0.5 M
sodium hydroxide (NaOH). The flask is charged with
103.2 g (500 mmol) of 2,6-di-tert-butylphenol (Note
1) and flushed with
argon, after which
200 mL of dry dichloromethane (Note
2) is added. The dropping funnel is charged with
28.2 mL (550 mmol) of bromine and
20 mL of dry dichloromethane. The reaction vessel is immersed in an
ice-water bath, stirring is initiated, and
bromine in
dichloromethane is added over 1 hr. The reaction mixture is stirred at 0°C for 10–20 min (Note
3). Then
60 mL of saturated aqueous sodium sulfite is added slowly at 0°C and stirring is continued at room temperature until the light orange color of
bromine is discharged, The mixture is poured into a
1-L separatory funnel containing
400 mL of saturated aqueous sodium bicarbonate (Note
4). The heavier organic layer is separated and the aqueous layer is extracted with two
75-mL portions of dichloromethane. The combined extracts are dried over
sodium sulfate and concentrated with a vacuum
rotary evaporator. The residue is recrystallized twice from ethanol-water (first with
130 mL of ethanol and 18 mL of water, then with
110 mL of ethanol and 11 mL of water) to furnish
109 g (
76% yield) of
4-bromo-2,6-di-tert-butylphenol (Note
5) as light yellow crystals, mp
83–85°C. Pure
4-bromo-2,6-di-tert-butylphenol is reported to melt at
81–82°C.
2
B.
Diphenylacetaldehyde. A
dry, 1-L, three-necked, round-bottomed flask is equipped with a gas inlet, rubber septum, pressure-equalizing dropping funnel, and a magnetic stirring bar. The flask is charged with
3.42 g (12 mmol) of 4-bromo-2,6-di-tert-butylphenol and flushed with
argon, after which
600 mL of freshly distilled dichloromethane is added. The mixture is stirred, degassed under vacuum, flushed with
argon, and
3 mL (6 mmol) of a 2 M hexane solution of
trimethylaluminum (Me
3Al, (Note
6)) is injected through the septum to the flask at room temperature. The resulting solution is stirred at this temperature for 1 hr to give
methylaluminum bis(4-bromo-2,6-di-tert-butylphenoxide) almost quantitatively (Note
7). The reaction vessel is cooled to a temperature of −20°C in a
dry ice/
o-xylene bath (Note
8). Then
11.8 g (60 mmol) of trans-stilbene oxide (Note
9) is dissolved in
25 mL of dry dichloromethane, transferred to the dropping funnel, and added over 15–20 min at −20°C. The mixture is stirred at −20°C for 4 hr. After addition of
1.01 g (24 mmol) of sodium fluoride, 324 μL (18 mmol) of water is injected dropwise at −20°C (Note
10). The entire mixture is vigorously stirred at −20°C for 5 min and at 0°C for 30 min. The contents of the flask are filtered with the aid of three
50-mL portions of dichloromethane (Note
11),(Note
12),(Note
13),(Note
14),(Note
15). The combined filtrates are concentrated to ca. 100 mL under reduced pressure with a rotary evaporator.
Silica gel (35 g) is added and the remainder of the
dichloromethane is removed using a rotary evaporator. The residue is layered on a
column of silica gel (500 g, column diameter: 9.5 cm) (Note
12) and eluted (
ether/
dichloromethane/
hexane, 1:2:20 to 1:1:10 as eluants) to give
10.3 g (
87%) of
diphenylacetaldehyde as a colorless oil (Note
16) and (Note
17).
2. Notes
2.
Solvent grade dichloromethane was dried and stored over Linde type 4 Å molecular sieves.
3. The reaction is conveniently followed by TLC (silica gel, 10:1:1
hexane-CH
2Cl
2-
ether).
4. The extractive workup is performed carefully to avoid vigorous evolution of
carbon dioxide gas.
5. The product has the following spectral properties:
1H NMR (200 MHz, CDCl
3) δ: 1.39 (s, 18 H, 2 t-Bu), 5.15 (s, 1 H, OH), 7.24 (s, 2 H, Ar-H).
6. Neat
trimethylaluminum was obtained from Toso-Akzo Chemical Company Ltd. (Japan) and used as a 2 M
hexane solution. The checkers used similar material obtained from Aldrich Chemical Company, Inc.
9.
trans-Stilbene oxide was obtained from Aldrich Chemical Company, Inc., and used without any purification.
10. To avoid excessive foaming on hydrolysis water should be added carefully by syringe.
11. The
sodium fluoride-water workup offers an excellent method for large-scale preparations, and is generally applicable to product isolation in the reaction of organoaluminum compounds.
3
12. The checkers report that GLC analysis (Note
13) at this point shows that the product is contaminated with ca. 4% of
trans-stilbene oxide and <1% of the Tischenko product (Note
14).
13. Gas chromatography conditions are as follows:
Supelco fused silica capillary SPB-1 column (30 m, 0.32-mm ID, 0.25 micrometers df), 100°C initial temperature, 280°C final temperature, 10°C/min. The following retention times were obtained:
diphenylacetaldehyde (6.7 min),
trans-stilbene oxide (7.4 min),
Tischenko product (18.2 min).
14. The
Tischenko product, Ph
2CHCO
2CH
2CHPh
2, has the following properties: mp,
95–98°C,
1H NMR (300 MHz, CDCl
3) δ: 4.35 (t, 1 H, J = 7.5), 4.70 (d, 2 H, J = 7.5), 4.92 (s, 1 H), 7.11–7.40 (m, 20 H);
13C NMR (75 MHz, CDCl
3) δ: 49.7, 57.2, 67.4, 126.8, 127.1, 128.2, 128.47, 128.53, 138.3, 140.8, 172.2; HRMS (CI, isobutane) Calcd for C
28H
24O
2: 393.1854 (MH); Found: 393.1829; IR (CCl
4) cm
−1: 3094–2906, 1737, 1600, 1494, 1450, 1144.
15. Merck Kieselgel 60 (Art. 9385) was used. The checkers found that loading the column in this way avoids precipitation of a by-product during column elution. The chromatography removes a few percent of remaining epoxide and
4-bromo-2,6-di-tert-butylphenol.
16. The product is >99% pure by capillary GLC analysis (Note
13) and has the following spectral characteristics:
1H NMR (200 MHz, CDCl
3) δ: 4.92 (d, 1 H, J = 2.6, CH), 7.20–7.49 (m, 10 H, 2 Ph), 9.98 (d, 1 H, J = 2.6, CHO).
17. The rearrangement is considerably faster when the reaction solution is more concentrated. If
480 mL of dichloromethane is used, the rearrangement is complete within 20 min at −20°C. However, the checkers found that the crude product is contaminated with 3–10% of the
Tischenko product (Note
14), which is difficult to remove by chromatography. This by-product can be removed by vacuum distillation (bp
136–144°C, 2 mm). Using this combined purification procedure, the checkers obtained
9.6 g (
81%) of
diphenylacetaldehyde of >99% purity by capillary GLC analysis (Note
13).
All toxic materials were disposed of in accordance with "Prudent Practices in the Laboratory"; National Academy Press; Washington, DC, 1995.
3. Discussion
This catalytic procedure illustrates a general method for preparing a wide range of carbonyl compounds by the selective rearrangement of epoxides under the influence of the exceptionally bulky, oxygenophilic
methylaluminum bis(4-bromo-2,6-di-tert-butylphenoxide) (MABR) as catalyst.
4 The advantages of catalytic versions include economy, ease of large-scale preparation and isolation, and the synthetic potential for in situ derivatization of the carbonyl products. Use of a
sodium fluoride-water (NaF-H
2O) workup
3 further simplifies the experimental operation. As revealed in Tables I and II, the amount of the catalyst varies from 5 to 20 mol% depending on the epoxy substrates. Yields when MABR is used stoichiometrically are also included for comparison. Certain epoxy substrates require stoichiometric MABR. Neither epoxides derived from monsubstituted olefins nor from certain internal dialkyl-substituted olefins can be rearranged by MABR, however, even using two equivalents.
The MABR-promoted rearrangement, when applied to optically active epoxy substrates, has been shown to proceed with rigorous transfer of the epoxide chirality. Accordingly, used in combination with the Sharpless asymmetric epoxidation of allylic alcohols,
5 this rearrangement represents a new approach to the synthesis of various optically active β-siloxy aldehydes, useful intermediates in natural product synthesis (Table II).
4,6
The stronger coordination of a carbonyl oxygen than an epoxide
oxygen to an aluminum reagent requires the stoichiometric use of MABR at low temperature. The key element of the present modification is the use of a higher reaction temperature (though still at or below 0°C) than the previously reported conditions
7 in order to induce dissociation of the aluminum reagent-carbonyl complex, thereby allowing regeneration of MABR as catalyst for further use in the catalytic cycle of the reaction. The facile dissociation of the organoaluminum-carbonyl complex as well as the smooth rearrangement of epoxides is apparently ascribable to the exceptional bulkiness of MABR compared to other ordinary Lewis acids.
8 The less bulky
methylaluminum bis(4-bromo-2,6-diisopropylphenoxide) was found to be totally ineffective for the rearrangement of the
tert-butyldimethylsilyl ether of
epoxy geraniol.
Appendix
Compounds Referenced (Chemical Abstracts Registry Number)
methylaluminum bis(4-bromo-2,6-di-tert-butylphenoxide) (MABR)
Dry Ice
ethanol (64-17-5)
ether (60-29-7)
sodium sulfite (7757-83-7)
sodium hydroxide (1310-73-2)
sodium bicarbonate (144-55-8)
bromine (7726-95-6)
sodium sulfate (7757-82-6)
oxygen (7782-44-7)
carbon tetrachloride (56-23-5)
carbon dioxide (124-38-9)
methane (7782-42-5)
dichloromethane (75-09-2)
sodium fluoride (7681-49-4)
hexane (110-54-3)
Diphenylacetaldehyde,
Benzeneacetaldehyde, α-phenyl- (947-91-1)
argon (7440-37-1)
trimethylaluminum (75-24-1)
trans-Stilbene oxide,
Oxirane, 2,3-diphenyl-, trans- (1439-07-2)
Methylaluminum bis(4-bromo-2,6-di-tert-butylphenoxide) (118495-99-1)
4-Bromo-2,6-di-tert-butylphenol (1139-52-2)
2,6-di-tert-butylphenol (128-39-2)
o-Xylene (95-47-6)
Methylaluminum bis(4-bromo-2,6-diisopropylphenoxide)
tert-butyldimethylsilyl ether
epoxy geraniol
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