Organic Syntheses, CV 8, 71
Submitted by Christina M. J. Fox and Steven V. Ley
1.
Checked by Anura P. Dantanarayana and James D. White.
1. Procedure
A.
S-tert-Butyl 3-oxobutanthioate. A dry,
2-L, three-necked, round-bottomed flask (Note
1) fitted with a
100-mL pressure-equalizing dropping funnel, a thermometer, a magnetic stirring bar, and an argon inlet is charged with
9.8 g (0.24 mol) of sodium hydride as a 60% dispersion in oil (Note
2). The system is flushed with, and kept under, dry
argon. The
sodium hydride is washed with two
40-mL portions of sodium-dried pentane and the system is purged with dry
argon to remove traces of
pentane. To the flask is then added
900 mL of dry tetrahydrofuran (Note
3).
The flask is cooled in an
ice–salt bath to −5°C and a solution of
20 g (25 mL, 0.22 mol) of 2-methylpropane-2-thiol (Note
2) in
20 mL of dry tetrahydrofuran is added at such a rate as to maintain a steady evolution of
hydrogen. The slightly exothermic reaction causes the temperature to rise to 0°C and the colorless solution is stirred at this temperature for 15 min to ensure complete formation of the thiolate. The reaction mixture is then recooled to −5°C and
20.3 g (18.8 mL, 0.24 mol) of diketene (Note
2) is added over 15 min to give a yellow-green solution. The
cooling bath is removed and the solution allowed to warm to room temperature.
The reaction is quenched and excess
sodium hydride is destroyed by careful addition of
300 mL of saturated ammonium chloride solution. The two-phase mixture is transferred to a
2-L separatory funnel charged with
400 mL of ether. The layers are separated and the organic phase is washed with 300-mL portions of water, saturated
sodium bicarbonate solution, and
Brine. The aqueous washes are reextracted with a
400-mL portion of ether and the combined organic layers are dried over anhydrous
sodium sulfate. The solvent is removed with a
rotary evaporator to give the crude product as a deep-red oil. Bulb-to-bulb distillation (Note
4) at 95–100°C (0.9 mm) gives
22 g (
57%) of
S-tert-butyl 3-oxobutanthioate as a colorless oil (Note
5).
B.
1-Carbomethoxy-1-methylethyl 3-oxobutanoate. A
500-mL, round-bottomed flask equipped with a magnetic stirring bar is charged with
10 g (0.085 mol) of methyl 2-hydroxyisobutyrate (Note
2),
17.7 g (0.102 mol) of S-tert-butyl 3-oxobutanthioate, and
250 mL of dry tetrahydrofuran. The flask is placed in the dark and
22.5 g (0.102 mol) of freshly prepared silver(I) trifluoroacetate (Note
6) is added in two portions. The resulting dark-brown suspension is stirred for 15 min (Note
7) and then concentrated to approximately 50 mL with a rotary evaporator. The concentrated mixture is diluted with
200 mL of hexane and the resulting orange-brown precipitate is removed by filtration. The filtered solid is washed with two
50-mL portions of hexane and the combined filtrate and washings concentrated with a rotary evaporator to give an orange-brown oil.
The crude product is chromatographed on 350 g of silica (Note
8) using
1 : 1 ether-petroleum ether (40–60) as eluant. The chromatography is monitored by TLC (Note
9) and the appropriate fractions are combined. Removal of the solvent with a rotary evaporator gives a pale-orange oil (Note
10), which was further purified by distillation to give
11.7 g (
68%) of the
O-ester, bp
69–72°C (0.2 mm) (Note
11).
C.
3-Acetyl-4-hydroxy-5,5-dimethylfuran-2(5H)-one. A
100-mL, round-bottomed flask equipped with a 50-mL pressure-equalizing dropping funnel and a magnetic stirring bar is charged with
5 g (0.025 mol) of the acetoacetate and
37 mL (0.037 mol) of tetrabutylammonium fluoride (1 M solution in THF) (Note
2) is added over 5 min. The resulting solution is stirred vigorously for 3 hr (Note
12) and then transferred to a
250-mL separatory funnel containing
50 mL of 6 M hydrochloric acid. The acidified mixture is extracted with three
30-mL portions of ether, each extract being washed with
10 mL of Brine. The combined organic extracts are dried over anhydrous
sodium sulfate and concentrated with a rotary evaporator to give
4.3 g of the crude
tetronic acid as a yellow solid. Recrystallization from
25 mL of hot 5% ether–petroleum ether gives
1.9 g of the
tetronic acid as pale-yellow plates, mp
66–67°C (lit.
2: mp
64–65°C) (Note
13). Concentration of the mother liquor affords a second crop of
0.4 g, mp
63–65°C, giving a combined yield of
54%.
2. Notes
1. The apparatus was oven-dried, assembled while hot, and cooled under a stream of dry
argon.
3.
Tetrahydrofuran was refluxed over and distilled from
sodium/benzophenone immediately prior to use.
4. A
Kugelrohr apparatus was used for the distillation. The reported temperature is the oven temperature.
5. The checkers found that the yield of this material was substantially higher (83%) when the reaction was conducted at

scale. Spectral properties of the product
3 4 are as follows: IR (neat) cm
−1: 1712, 1676, 1621;
1H NMR (60 MHz, CDCl
3) δ: 1.5 (s, 9 H, (CH
3)
3C), 2.3 (s, 3 H, COCH
3), 3.6 (s, 2 H, COCH
2CO), 5.3 (s, COCH=C(OH)).
6.
Silver(I) trifluoroacetate may be obtained commercially, but it is recommended that it be freshly prepared.
5 Trifluoracetic acid (18 mL, 0.24 mol) is added to
silver(I) oxide (0.12 mol), freshly precipitated from
silver nitrate (20 g, 0.12 mol) and
sodium hydroxide (4.7 g, 0.12 mol) in water (30 mL). The solution is filtered and evaporated to dryness under reduced pressure. The crude product is purified by dissolving it in
ether (150 mL), filtering through decolorizing charcoal and evaporation to give the product as a white crystalline solid (
19.3 g,
74%).
7. The time reported represents the average reaction time. The reaction can be followed by TLC, visualizing with
iodine and
10% phosphomolybdic acid in
ethanol followed by heating on a hot plate.
8. Merck Kieselgel 60 silica gel (230–400 mesh) was used.
9. Merck precoated silica gel 60 F-254 plates were used, visualizing with
iodine.
10. In some cases, the product is contaminated with a yellow solid even after chromatography. This is removed prior to distillation by filtering through a short pad of Celite.
11. The spectral properties of the product
2 are as follows: IR (neat) cm
−1: 1745, 1720;
1H NMR δ (90 MHz, CDCl
3): 1.57 (s, 6 H, (CH
3)
2C), 2.28 (s, 3 H, COCH
3), 3.44 (s, 2 H, COCH
2CO), 3.72 (s, 3 H, CO
2CH
3).
12. The reaction is monitored by TLC and quenched when starting material has been consumed.
13. Spectral properties of the product
2 are as follows: IR (KBr) cm
−1: 1758, 1685, 1610;
1H NMR (60 MHz, CDCl
3) δ: 1.50 and 1.51 [2 s, 6 H, C(CH
3)
2], 2.5 (s, 3 H, COCH
3), 9.25 (br s, 1 H, OH).
3. Discussion
Selective alkylation of β-keto esters via either anions or dianions is an important synthetic transformation.
6 Equally, thioesters may be transesterified in the presence of thiophilic metal cations.
7 These two features can be usefully combined in one substrate,
tert-butyl acetothioacetate, the subject of this Organic Syntheses procedure.
Alkylation at the 2-position can be achieved by formation of the anion with
sodium hydride in
1,2-dimethyoxyethane (DME) at 0°C followed by reaction with an alkyl halide at room temperature. Alternatively, selective alkylation at C-4 involves sequential treatment with
sodium hydride (at −10°C) and
butyllithium in DME (at −40°C) to form the dianion, followed by kinetic alkylation with an alkyl halide (or carbonyl compound).
8
The choice of DME as solvent in these reactions is important as other ether solvents are much less successful and lead to unwanted side products.
Transesterification of the resulting alkylated β-keto thioesters to the corresponding oxo esters is readily achieved using alcohols under various metal catalysis.
7
The alcohols used may also contain fairly sensitive functional groups, such as esters, halides, and silyl ethers. In this work, therefore,
tert-butyl acetothioacetate is behaving as a synthetic equivalent to
diketene. When this methodology is used, it is possible to devise very short syntheses of acyl tetronic acids
8 and novel macrocyclic structures.
9
Copyright © 1921-2002, Organic Syntheses, Inc. All Rights Reserved