Checked by Anthony G. Schaefer and Leo A. Paquette.
1. Procedure
A.
(3-Methyl-2-butenyl)propanedioic acid, dimethyl ester (1). To a
500-mL, flame-dried, three-necked, round-bottomed flask under an
argon atmosphere and fitted with a
thermometer, a pressure-equalizing addition funnel, and a
magnetic stirring bar is added
250 mL of methanol (Note
1). The flask is immersed in an
ice bath, and
6.7 g (0.29 mol) of sodium is added cautiously (Note
2). After the
sodium has dissolved, the ice bath is removed,
36.9 g (0.28 mol) of dimethyl malonate (Note
1) is added at room temperature, and the solution is stirred for 0.5 hr. The reaction mixture is cooled to 0°C, and
45.8 g (0.31 mol) of 3,3-dimethylallyl bromide (Note
1) is added dropwise while the temperature is maintained near 5°C (Note
3). After 1 hr (Note
4), the reaction mixture is transferred to a
1-L, one-necked, round-bottomed flask with the aid of a small amount of
methanol and concentrated with a
rotary evaporator. The white residue is taken up in
400 mL of ether and
300 mL of a saturated salt/saturated sodium bicarbonate (1 : 1) solution and is transferred to a
separatory funnel. The
ether layer is separated, and the aqueous layer is extracted with
ether (1 × 200 mL). The
ether layers are combined, dried over
magnesium sulfate, filtered, and concentrated with a rotary evaporator. Distillation of the residue through a
6-in. Vigreux column (after a small forerun is collected) yields
43.9–44.5 g (
78–79%) of
1, bp
60–63°C (0.15 mm) (Note
5).
B.
(3-Methyl-2-butenyl)(2-propynyl)propanedioic acid, dimethyl ester (2). To a
1-L, flame-dried, three-necked, round-bottomed flask, equipped with a magnetic stirring bar (Note
6) and under an
argon atmosphere, is added
9.0 g (0.19 mol) of sodium hydride dispersion (Note
7). The
sodium hydride is washed with
petroleum ether (4 × 30 mL), removing the
petroleum ether by
pipette after the
sodium hydride has settled. The flask is then fitted with a thermometer and an
over-dried pressure-equalizing addition funnel and charged with
500 mL of tetrahydrofuran (Note
7). The heterogenous mixture is cooled with an ice bath, and
36.4 g (0.18 mol) of the monoalkyl diester (1.htm) is added dropwise at the rate of 1 drop/2–3 sec (Note
2). The cooling bath is removed when the addition is complete, and the solution is stirred until no more gas evolves (ca. 1 hr). The reaction mixture is recooled to 0°C, and
22 mL of propargyl bromide solution (0.20 mol) (Note
7) is added dropwise while the temperature is maintained at 0–10°C.
Sodium bromide begins to precipitate within 20 min. The ice bath is removed, and the reaction mixture is stirred overnight (Note
8). After careful addition of 50 mL of water (Note
9) and removal of the stirring bar, the solution is transferred to a 1-L, one-necked, round-bottomed flask and concentrated with a rotary evaporator. The residue is taken up in
500 mL of ether and washed with water (3 × 300 mL) and saturated salt solution (1 × 100 mL). The aqueous layers are combined, saturated with salt, and extracted with
ether (2 × 150 mL). The
ether layers are combined, dried over
magnesium sulfate, filtered, and concentrated with a rotary evaporator. The residue is distilled through a short-path distillation apparatus at 80°C (0.25 mm) to yield
34.0–34.2 g (
79–80%) of (Note
10).
C.
(Z)-3-Tributylstannylmethylene-4-isopropyl-1,1-cyclopentanedicarboxylic acid, dimethyl ester (3). A
flame-dried, 100-mL, round-bottomed flask equipped with a magnetic stirring bar is charged with
argon, and
23.8 g (0.100 mol) of dialkylmalonate diester (2.htm),
30.2 g (<0.104 mol) of tributyltin hydride (Note
11), and
40 mg (0.25 mmol) of azobisisobutyronitrile (AIBN) (Note
12) are added neat (Note
13) and (Note
14). The entire assembly is lowered into an
oil bath maintained at 75–85°C, and the mixture is stirred. After an induction period of less than 30 min, an exothermic reaction occurs and produces a small amount of gas and a rise in the temperature of the oil bath (as much as 20°C for a small bath). After this point TLC shows that the reaction is essentially complete (Note
15)(Note
16)(Note
17). Unpurified 3 thus obtained is suitable for protodestannylation.
D.
3-Methylene-4-isopropyl-1,1-cyclopentanedicarboxylic acid, dimethyl ester (4). Crude vinylstannane (3) is transferred to a
2-L Erlenmeyer flask containing
1 L of dichloromethane,
350 g of silica (Note
18), and a
large (7 × 3-cm, egg-shaped) stirring bar. The flask is stoppered, and the mixture is stirred for 24–48 hr (Note
19). The mixture is divided into three portions. Each portion is filtered under reduced pressure with a
600-mL glass frit, and the
silica is washed with
ethyl acetate (8 × 200 mL) to extract all of the desired product (Note
20). The solution is filtered through Celite and the solvent is removed with a rotary evaporator. Distillation through a short-path distillation apparatus (with no forerun) gives
19.8–20.5 g of
4 (
83–85% overall from
2), bp
80°–85°C (0.2 mm) (Note
21).
2. Notes
1. The use of less solvent can result in gel formation.
Methanol was freshly distilled from
calcium hydride or
magnesium metal.
Dimethyl malonate (Aldrich Chemical Company, Inc.) was distilled before use.
3,3-Dimethyallyl bromide may be purchased from Aldrich Chemical Company, Inc. or Wiley Organics.
2. The apparatus should be vented.
Hydrogen gas formation causes vigorous bubling.
3. At higher temperature more dialkylation occurs.
4. The reaction can be monitored by TLC eluting with
10% ethyl acetate/petroleum ether.
5. The physical properties are as follows: IR (neat) cm
−1: 2980, 1730–1760, 1435, 1040;
1H 200 MHz NMR (CDCl
3) δ: 1.62 (s, 3 H), 1.65 (s, 3 H), 2.56 (t, 2 H,
J = 7), 3.34 (t, 1 H,
J = 7), 3.70 (s, 6 H), 5.06 (bt, 1 H,
J = 7).
6. Unless a sufficiently large stirring bar is used the precipitate may be impossible to stir. An overhead mechanical stirrer can be substituted.
8. The reaction is generally complete sooner, but because it progress is difficult to monitor by TLC (since the starting material and product have similar
Rf values) the submitters routinely allow more than enough time.
9. Trace amounts of
sodium hydride may still be present. If the water is added too quickly, a vigorous reaction results.
10. The checkers observed a boiling point of
99–100°C (0.35 mm) for this material. The physical properties are as follows: IR (neat) cm
−1: 3290, 2960, 1740, 1440;
1H 300 MHz NMR (CDCl
3) δ: 1.61 (s, 3 H), 1.65 (s, 3 H), 1.97 (t, 1 H,
J = 3), 2.7 (m, 4 H), 3.69 (s, 6 H), 4.9 (t, 1 H
J = 7).
11.
Tributyltin hydride 97%, was purchased from Aldrich Chemical Company, Inc. and used directly. A minimal excess of this reagent is desired in order to ensure clean distillation of 4. If the product is to be purified by chromatography, a
10% excess of tributyltin hydride can be used.
12.
Azobisisobutyronitrile (AIBN) was purchased from Aldrich Chemical Company, Inc. and recrystallized from
chloroform. To exclude the possibility of a violent reaction, no more than twice this amount should be used on this scale.
13. These reactions can also be run in
benzene, which is preferable in cases where transfer of
hydrogen to the vinyl radical is competitive with cyclization.
14. The submitters routinely interposed a Vigreux column between the reaction flask and the
argon line to protect the
argon line in the event of bumping.
15. The reaction mixture is routinely stirred hot for an additional 30 min to ensure complete conversion.
16. Vinylstannane (
3) may protodestannylate on TLC, which could be confusing when monitoring Reaction C since dialkylmalonate diester (
2) and protodestannylated product (
4) have similar
Rf values. The submitters found that TLC plates stored in the open air (as opposed to desiccator-stored plates) caused negligible protodestannylation.
17. Although vinylstannane
3 protodestannylates on
silica, it may be isolated by flash chromatography in greater than
90% yield: IR (neat) cm
−1: 2960, 2930, 2880, 2860, 1740, 1615, 1465, 1435;
1H 200 MHz NMR (CDCl
3) δ: 3.71 (s, 3 H), 3.73 (s, 3 H), 5.62 (bs, 1 H) with satellites.
18. The submitters employed Silica Woelm 32-63 purchased from Universal Scientific, Inc.; the checkers used Merck silica gel 60 (40–60 μm in size). Before use the silica was oven dried for several days at 160°C. Undried silica may be used, but larger quantities and/or longer reaction times are necessary.
19. TLC plates stored in the open air should be used (see (Note
16)) to monitor Reaction D accurately. Approximately 4% of noncyclized hydrostannylation product is produced in Reaction C. This material forms cospots with
3 (
2.5% ethyl acetate in petroleum ether), but protodestannylates much more slowly. Therefore, by TLC Reaction D may appear not to go to completion.
20. A larger glass frit would obviate division of the mixture. In any case, the silica should be washed until by TLC the filtrate no longer contains
4.
21. The checkers observed a boiling point of
98–105°C (0.35 mm) for this product: IR (neat) cm
−1: 3080, 2960, 2875, 1735, 1655, 1435, 1385, 1365, 890. MS (CI) M + l = 241;
1H 300 MHz NMR (CDCl
3) δ: 0.75 (d, 3 H,
J = 7), 0.85 (d, 3 H,
J = 7), 1.80 (m, 2 H), 2.40 (m, 2 H), 2.84 (m, 2 H), 3.64 (s, 3 H), 3.65 (s, 3 H), 4.72 (bs, 1 H), 4.90 (bs, 1 H).
3. Discussion
Vinylstannanes
20 21 22 23 24 25 26 27 28 29 30 31 are versatile synthetic intermediates. They serve as a source of stereospecific vinyl anions and vinyl cuprates.
20,23,32 33 34 In the presence of Pd(0), vinylstannanes can be acylated
35,36 or alkylated.
37,38 Epoxidation followed by rearrangement converts vinylstannanes into carbonyl compounds.
39 Treatment with halogens or
N-halosuccinimides yields vinyl halides.
20,21,22,23,34,40 Deuterium-labeled olefins result from deuterolysis of vinyl stannanes with AcOD or DCl.
23 Olefins identical to those produced in vinyl halide reductions are obtained on protodestannylation with silica gel, which, unlike simple acid treatment, solves the problem of separation from tin residues.
41
Appendix
Compounds Referenced (Chemical Abstracts Registry Number)
petroleum ether
silica
3,3-Dimethyallyl bromide
Benzene (71-43-2)
ethyl acetate (141-78-6)
methanol (67-56-1)
ether (60-29-7)
hydrogen (1333-74-0)
chloroform (67-66-3)
sodium bicarbonate (144-55-8)
magnesium (7439-95-4)
sodium bromide (7647-15-6)
toluene (108-88-3)
Benzophenone (119-61-9)
sodium (13966-32-0)
dichloromethane (75-09-2)
magnesium sulfate (7487-88-9)
Tetrahydrofuran (109-99-9)
sodium hydride (7646-69-7)
calcium hydride (7789-78-8)
argon (7440-37-1)
propargyl bromide (106-96-7)
tributyltin hydride (688-73-3)
dimethyl malonate (108-59-8)
3-Methylene-4-isopropyl-1,1-cyclopentanedicarboxylic acid, dimethyl ester,
1,1-Cyclopentanedicarboxylic acid, 3-methylene-4-(1-methylethyl)-, dimethyl ester (107473-16-5)
3,3-dimethylallyl bromide (870-63-3)
azobisisobutyronitrile (78-67-1)
(3-Methyl-2-butenyl)propanedioic acid, dimethyl ester (43219-18-7)
(3-Methyl-2-butenyl)(2-propynyl)propanedioic acid, dimethyl ester (107473-14-3)
(Z)-3-Tributylstannylmethylene-4-isopropyl-1,1-cyclopentanedicarboxylic acid, dimethyl ester
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