Organic Syntheses, CV 8, 367
Submitted by Pier Lucio Anelli, Fernando Montanari, and Silvio Quici
1.
Checked by Katsumasa Nonoshita and Hisashi Yamamoto.
1. Procedure
A
1-L, three-necked, round-bottomed flask is fitted with a
mechanical stirrer,
pressure-equalizing dropping funnel, and a
thermometer. The flask is charged with
44.05 g (0.50 mol) of (S)-(−)-2-methyl-1-butanol (Note
1),
0.78 g (5 mmol) of 2,2,6,6-tetramethylpiperidin-1-oxyl (Note
2),
170 mL of dichloromethane, and a solution of
5.95 g (0.050 mol) of potassium bromide in 25 mL of water (Note
3). The reaction mixture is vigorously stirred and cooled to −10°C with a
salt–ice bath, then
550 mL (0.55 mol) of 1 M aqueous sodium hypochlorite (Note
4) at pH 9.5 (Note
5) is added over 15–20 min (Note
6), keeping the temperature of the reaction mixture between 10 and 15°C. The mixture is stirred for a further 3 min (Note
7). The orange organic phase is separated and the aqueous phase (Note
8) is extracted with
50 mL of dichloromethane. The combined organic extracts are washed with
100 mL of 10% aqueous hydrochloric acid containing 1.6 g (0.010 mol) of potassium iodide (Note
9),
60 mL of 10% aqueous sodium thiosulfate (Note
10), and 60 mL of water (Note
11). The organic phase is dried over anhydrous
magnesium sulfate and then distilled at atmospheric pressure through a
20-cm Vigreux distilling column to give
35.3–36.3 g (
82–84%) (Note
12) of
(S)-(+)-2-methylbutanal as a colorless oil, bp
90–92°C (GC purity >99%) (Note
13),
[α]D22 +36.8° (
acetone,
c 2.5) (Note
14),(Note
15),(Note
16).
2. Notes
1.
(S)-(−)-2-Methyl-1-butanol (GC purity >99.5%);
[α]D20 −6.6±0.3° (
ethanol,
c 10) was purchased from Fluka Chemie AG. Esterification with
(R)-(+)-3,3,3-trifluoro-2-methoxy-2-phenylpropionic acid (Mosher's acid),
2 and subsequent
1H and
19F NMR analyses at 300 MHz of the resulting ester showed an enantiomeric purity of
(S)-(−)-2-methyl-1-butanol >99%.
2.
2,2,6,6-Tetramethylpiperidin-1-oxyl from Nacalai Tesque, Inc., Kyoto, Japan, also available from Janssen Chimica, Beerse, Belgium, was used.
4-Methoxy-2,2,6,6-tetramethylpiperidin-1-oxyl, prepared according to the procedure of Endo,
3 can also be used.
4
4. Concentrations of aqueous
sodium hypochlorite in the range 0.3–2.0
M have been used successfully.
6. If the reaction is carried out on a 1–10-mmol scale, the temperature is easily maintained at 0°C and the reaction is over in a few minutes.
4 On a larger scale, a very efficient cooling system is required to maintain the temperature at about 0°C. When conventional laboratory equipment is used, the conditions described in this procedure are a reasonable compromise between two requirements: (a) fast addition of the aqueous
sodium hypochlorite and (b) temperature in the reaction medium low enough to minimize the catalyst decomposition.
4 Longer reaction times increase slightly the formation of
2-methylbutanoic acid.
7. At this stage the reaction can be monitored by GC: 1 m × 3 mm OV 101 5% on Chromosorb HP 100–120-mesh column, 50°C (2 min), then 50–90°C (15°C/min).
10. Washing with
10% aqueous sodium thiosulfate leads to a colorless organic phase, indicating total elimination of the catalyst.
11. The aqueous phase must be neutral. Acidic impurities catalyze trimerization of the anhydrous aldehyde
7 8 in the distillation stage.
12. Yields can be further increased with a more efficient separation of the
(S)-(+)-2-methyl-1-butanal contained in the top fractions.
13. The spectral properties of
(S)-(+)-2-methylbutanal are as follows: IR (film) cm
−1: 2970, 2940, 2890, 2820, 2710, 1725, 1460;
1H NMR (300 MHz, CDCl
3) δ: 0.94 (t, 3 H), 1.09 (d, 3 H), 1.33–1.54 (m, 1 H), 1.64–1.85 (m, 1 H), 2.18–2.33 (m, 1 H), 9.63 (d, 1 H).
14. Reduction with
borane/tetrahydrofuran9 regenerated enantiomerically pure
(S)-(−)-2-methyl-1-butanol, as shown by esterification with
Mosher's acid and subsequent NMR analysis of the ester (see (Note
1).
15. When practical,
(S)-(−)-2-methyl-1-butanol (GC purity 95%);
[α]D20 −6.3 ± 0.5° (EtOH,
c 10) from Fluka Chemie was used, and
(S)-(+)-2-methylbutanal having
[α]D20 +33.1° (
acetone,
c 2.5) was obtained.
3. Discussion
Oxammonium salts
1 have been used extensively either in stoichiometric or in catalytic amounts
13 for the oxidation of primary and secondary alcohols to the corresponding carbonyl derivatives.
Oxammonium salt
1, the effective oxidant species, is continuously generated from nitroxyl radical
2 by
hypochlorous acid in the organic phase. Radical
2 is one of the most stable radicals known, and is easily prepared from the inexpensive triacetoneamine
3.15 16 17 18 The oxidation is very exothermic; for this reason scale-up of the reaction needs a very efficient cooling system to maintain the temperature in the optimum 0–15°C range. One one-hundredth (0.01) molar equivalent of nitroxyl radical
2 is generally used, but on this reaction scale the amount of catalyst can be reduced to 0.002 molar equivalent, without substantially affecting the reaction time.
Sodium hypochlorite is used in only slight excess and is entirely consumed, an unusual occurrence for reactions carried out under aqueous, organic two-phase conditions.
19 20

Conversion of saturated, primary alkyl and aryl alkyl alcohols into the corresponding aldehydes can be achieved by this method provided that the alcohols are entirely dissolved in the organic phase. Relatively unstable protective groups are not affected, as in the oxidation of the
acetonide of 1,2,6-hexanetriol, whereas conjugated and isolated double bonds give rise to side reactions that considerably decrease selectivities and yields.
4 Some examples of aldehydes synthesized with this method are reported in Table I. Under the same conditions, secondary alcohols are oxidized to ketones. Addition of catalytic amounts of quaternary onium salts allows fast and total conversion of primary alcohols and aldehydes into carboxylic acids making this methodology very versatile.
4
When the limitations outlined above are considered, the procedure described here appears to be easier and cheaper than most methods in the condensed phase known to date.
21 Furthermore, alkali halides are almost the only contaminants in the waste water, making the scale up of this method very attractive.
Very hydrophilic alcohols are conveniently oxidized under solid–liquid two-phase conditions (LiOCl–CH
2Cl
2) in the presence of
NaHCO3 and 0.01 molar equiv of
2,2,6,6-tetramethylpiperidin-1-oxyl or its 4-methoxy derivative.
22 Commercial solid LiOCl contains 7% of water so that the reaction conditions can be assimilated to those of a pseudo solid–liquid system.
23
24
Appendix
Compounds Referenced (Chemical Abstracts Registry Number)
(S)-(−)-2-methyl-1-butanol
(R)-(+)-3,3,3-trifluoro-2-methoxy-2-phenylpropionic acid (Mosher's acid)
Mosher's acid
acetonide of 1,2,6-hexanetriol
m-Nitrobenyl alcohol
alcohol,
ethanol (64-17-5)
hydrochloric acid (7647-01-0)
sodium hydrogen carbonate,
NaHCO3 (144-55-8)
potassium iodide (7681-11-0)
sodium thiosulfate (7772-98-7)
1-butanol (71-36-3)
acetone (67-64-1)
Benzyl alcohol (100-51-6)
potassium bromide (7758-02-3)
butanal (123-72-8)
hypochlorous acid (7790-92-3)
1,5-Pentanediol (111-29-5)
1-heptanol (111-70-6)
sodium hypochlorite,
NaOCl (7681-52-9)
dichloromethane (75-09-2)
2-methylbutanoic acid (600-07-7)
magnesium sulfate (7487-88-9)
chromium (7440-47-3)
borane (7440-42-8)
1-Octanol (111-87-5)
Tetrahydrofuran (109-99-9)
1,4-butanediol
tributylamine (102-82-9)
p-Nitrobenzyl alcohol (619-73-8)
2,2,6,6-tetramethylpiperidin-1-oxyl (2564-83-2)
4-Methoxy-2,2,6,6-tetramethylpiperidin-1-oxyl (95407-69-5)
1,10-undecanediol
10-hydroxyundecanal
10-oxoundecanal
10-oxoundecanoic acid
1-Nonanol (143-08-8)
1-Undecanol (112-42-5)
(S)-(+)-2-METHYLBUTANAL,
Butanal, 2-methyl-, (S)-,
(S)-(+)-2-methyl-1-butanal,
S-(+)-2-methylbutanal (1730-97-8)
(S)-(+)-2-Methylbutanoic acid
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