Checked by K. Matsuo and G. Büchi.
1. Procedure
A
3-l., four-necked, round-bottomed flask equipped with a sealed
mechanical stirrer, a
pressure-equalizing dropping funnel, a
thermometer, and a condenser fitted with a
nitrogen-inlet tube is charged with
48.6 g. (2.00 g.-atoms) of magnesium turnings (Note
5). The flask is flushed with dry
nitrogen and thoroughly dried with a heat gun, and
300 ml. of anhydrous tetrahydrofuran (Note
6) is added. The Grignard reaction is initiated by adding about 10% of a solution of
243.0 g. (1.98 moles) of 3-chloro-N,N-dimethyl-1-propylamine in
300 ml. of anhydrous tetrahydrofuran (Note
6), and
4 ml. of ethyl bromide while gently heating the flask with the drier (Note
7). The remainder of the
3-chloro-N,N-dimethyl-1-propylamine solution is added over a period of approximately 1 hour so as to maintain gentle reflux. The reaction mixture is heated at reflux for 3 hours, after which time most of the
magnesium has reacted. The dark gray solution is cooled to 0° before a solution of
107.3 g. (81.29 ml., 0.5994 mole) of dichlorophenylphosphine (Note
8) in
200 ml. of anhydrous tetrahydrofuran (Note
6) is added dropwise, with efficient stirring, over a 1 hour period so that the temperature does not exceed 5° (Note
9). A greenish precipitate is formed locally where the
phosphine is added. After the addition is complete, the reaction mixture is stirred and heated at reflux for 2 hours, during which time a heavy, greenish precipitate is formed. After cooling to room temperature,
600 ml. of ether (Note
10) is added, and the reaction mixture is left standing overnight, during which time the precipitate separates to the bottom of the flask. The solution is decanted into a 3-l. separatory funnel containing
300 ml. of 40% aqueous potassium hydroxide and 1 kg. of ice. The remainder of the reaction product is suction filtered with the aid of
1200 ml. of 5:1 ether–dichloromethane through a 3-cm. layer of
Celite® (Note
11). The filtrate is added to the separatory funnel, and the organic layer is separated and washed twice with
600-ml. portions of saturated aqueous sodium chloride. The aqueous layer is extracted four times with
700-ml. portions of 5:1 ether–dichloromethane. The combined organic extracts are dried over anhydrous
sodium sulfate, and the solvent is removed with a
rotary evaporator. The crude yellow oil is distilled at high vacuum through a
14-cm. Vigreux column, yielding
109–116 g. (
65–69%, based on
phenylphosphonous dichloride) of
bis(3-dimethylaminopropyl)phenylphosphine as a colorless liquid, b.p.
100–108° (0.005 mm.) (Note
12). Redistillation furnishes
94–97 g. (
56–58%) of product, b.p.
102–105° (0.005 mm.) (Note
13),
n24D 1.5265.
B.
S-(2-Oxobut-3-yl) Butanethioate. A
750-ml., four-necked, round-bottomed flask equipped with a sealed mechanical stirrer, a pressure-equalizing dropping funnel, a thermometer, and a condenser fitted with a nitrogen-inlet tube is charged with
10.4 g. (0.100 mole) of thiobutyric acid (Note
14) in
300 ml. of anhydrous ether (Note
10). With stirring,
10.1 g. (0.100 mole) of triethylamine (Note
15) is added in one portion. Over a 15-minute period (Note
16),
15.1 g. (0.100 mole) of 3-bromo-2-butanone (Note
17) is added dropwise from the dropping funnel. The solution is heated at reflux with stirring for 1.5 hours and filtered through
Celite®; the precipitate is washed with
60 ml. of ether. The ether solution is concentrated on a rotary evaporator. The residual orange-yellow oil is dissolved in
20 ml. of 5:1 benzene–ether and filtered through
70 g. of silica gel (Note
18), using 500 ml. of this solvent mixture as eluent. The solvent is removed on a rotary evaporator, yielding
17.0–17.4 g. (
98–100%) of the thiol ester as a pale yellow oil which can be used without further purification in the next step. (Note
19) and (Note
20).
C.
3-Methyl-2,4-heptanedione. A dry,
500-ml., three-necked, round-bottomed flask equipped with a
magnetic stirring bar, a pressure-equalizing dropping funnel, a thermometer, and a condenser fitted with a nitrogen-inlet tube is charged with
17.8 g. (0.204 mole) of anhydrous lithium bromide (Note
21). Under a
nitrogen atmosphere,
34.8 g. (0.218 mole) of S-(2-oxobut-3-yl)butanethioate dissolved in
120 ml. of anhydrous acetonitrile (Note
22) is added to the flask. With stirring, the mixture is heated with a drier until a homogeneous solution is obtained. From the dropping funnel,
67 g. (69 ml., 0.24 mole) of redistilled bis(3-dimethylaminopropyl)phenylphosphine is added in one portion to the warm (
ca. 60°) solution. The temperature rises to about 70°, and after 1–2 minutes a thick, white precipitate appears. The reaction mixture is stirred at 70° for 15 hours (Note
23). After cooling to room temperature, the reaction mixture is transferred with
600 ml. of 5:1 ether–dichloromethane into a separatory funnel containing
900 ml. of cold 1 N hydrochloric acid. The organic layer is separated and washed three times with
500-ml. portions of saturated aqueous sodium chloride. The aqueous phase is washed twice with
600-ml. portions of 5:1 ether–dichloromethane. The combined organic layer is dried over anhydrous
sodium sulfate, and the solvent removed on a rotary evaporator, the temperature of the bath not exceeding 30°. The crude yellow oil is distilled through a
10-cm. Vigreux column under reduced pressure, yielding
23.5–24.7 g. (
83–87%) of
3-methyl-2,4-heptanedione as a colorless liquid, b.p.
74–76° (9 mm.),
n23D 1.4455 (Note
24).
2. Notes
2. The fractions may be analyzed by GC for absence of solvent; a
300 cm. by 0.3 cm. glass column packed with XE-60 (1.5% w/w) coated on Chromosorb G AW DCMS (80/100 mesh) was employed.
3. The spectral properties of the product are as follows; IR (neat) cm.
−1: 1470, 1465, 1265, 1040;
1H NMR (CDCl
3), δ (multiplicity, coupling constant
J in Hz., number of protons): 1.8–2.6 (m, 4H), 2.2 (s, 6H), 3.6 (t,
J = 6, 2H).
4. It is advisable to distill the solvent one day, store the residue overnight under
nitrogen at 0°, and distill the product the next morning, allowing ample time for the following Grignard reaction. On standing at room temperature a white solid precipitates.
5.
Magnesium turnings were purchased from E. Merck & Company, Inc., Darmstadt, Germany or J. T. Baker Chemical Company.
7. It is advisable to have available an
ice bath for cooling, should the reaction become violent.
9. The reaction is very exothermic and cooling with an
ice–sodium chloride bath is necessary.
10. Anhydrous
ether was purchased from Fluka AG or J. T. Baker Chemical Company.
11. During this operation, the reaction vessel is washed with 5:1
ether–
dichloromethane several times.
12. The colorless forerun weighs
12–20 g.; the dark brown residue weighs
13–22 g.
13. The reported b.p. is
102–105° (0.005 mm.); a full spectroscopic characterization is given in the original paper.
3
14. The
thiobutyric acid was prepared
4 as follows: A rapid stream of
hydrogen sulfide is passed, with vigorous stirring at −30°, through
200 ml. of anhydrous pyridine, contained in a
four-necked, round-bottomed flask equipped with a sealed mechanical stirrer, a
gas-inlet tube, a pressure-equalizing dropping funnel, and a thermometer. Over approximately 1 hour,
50 g. of 1-butyryl chloride is added dropwise to this solution. Approximately
400 ml. of 5 N sulfuric acid is added slowly until the pH is

5. The organic acid, which separates as a yellow oil, is taken up in
ether and dried over anhydrous
sodium sulfate. After removal of the ether on a rotary evaporator, the product is distilled through a 14-cm. Vigreux column under a
nitrogen atmosphere, yielding
23.1–32.1 g. (
43–65%, not optimized by the submitters) of
thiobutyric acid as a colorless liquid, b.p.
119–121°.
15.
Triethylamine was purchased from Fluka AG or J. T. Baker Chemical Company.
17.
3-Bromo-2-butanone was purchased from Fisher Scientific Company. The submitters prepared it according to the literature
5 and checked its purity (>95%) by GC (Note
2).
18. Silica gel (70–230 mesh ASTM) purchased from E. Merck & Company, Inc., Darmstadt, Germany was used in a 2.5-cm. diameter column.
19. GC analysis (Note
2) indicated <2% impurities. IR (neat) cm.
−1: 1720, 1695.
20. The submitters obtained a similar yield on ten times the scale.
21. The absence of water in the
lithium bromide is of great importance. Traces of water lower the yield of product by 10–20%.
Lithium bromide dihydride (purchased from E. Merck & Company, Inc., Darmstadt or City Chemical Corporation) was dissolved three times in anhydrous 1:1
acetonitrile–
benzene, and the solvents were removed each time with a rotary evaporator. The
lithium bromide was dried under high vacuum at 100° for 1 hour, ground to a fine powder with a
mortar and pestle while still warm, and again dried at 100°, as above, for 3 hours.
23. The reaction is followed best by GC analysis (Note
2). Traces of water seem to slow down the rate of the reaction.
24. By GC analysis (Note
2) the product is >98% pure. In the literature,
3 a full spectroscopic characterization is given. IR (neat) cm.
−1: 1725, 1700, 1600, 1360.
3. Discussion
This procedure illustrates a broadly applicable method which is essentially that found in the literature
3 for the synthesis of enolizable β-dicarbonyl compounds.
3 Although there are various methods for the preparation of β-dicarbonyl systems,
6 sulfide contraction widens the spectrum of available methods. The procedure can also be utilized in the sycnthesis of aza and diaza analogs of β-dicarbonyl systems. Eschenmoser
3 has utilized the method to produce vinylogous amides and amidines in connection with the total synthesis of corrins and vitamin B
12.
7,8
S-Alkylation of a thiocarboxylic acid with an α-halogenated carbonyl compound gives a thiol ester in which the two carbons to be connected are linked
via a sulfur bridge (see the scheme below). Enolization and formation of the episulfide creates the desired carbon–carbon bond. Removal of atomic sulfur by a thiophile, either a phosphine or a phosphite, liberates the β-dicarbonyl compound. The addition of base is necessary in most cases; however, in the vinylogous amidine systems
7,8 electrophilic catalysis was employed. Normally a teritary alkoxide is utilized in the contraction. The addition of anhydrous
lithium bromide or
lithium perchlorate allows the reaction to proceed with the use of a tertiary amine as the base. Presumably, the lithium salts complex with the carbonyl groups, enhancing the enolization and/or contraction step.
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