Organic Syntheses, Vol. 77, 107
Checked by Yan Dong and Steven Wolff.
1. Procedure
2. Notes
3.
Dimethyl sulfide was used as purchased from the Aldrich Chemical Company, Inc.
4. Dropwise addition via syringe successfully avoids such problems as rapid precipitation of the
NBS·(CH3)2S complex, high exothermicity, and loss of stirring efficiency.
5.
Methyl 3-hydroxy-4-methyl-2-methylenepentanoate5 was obtained by the means of a Baylis-Hillman reaction
6 7,8 as follows. To a
500-mL, one-necked, round-bottomed flask equipped with a magnetic stir bar were added
82.3 g (1.14 mol) of isobutyraldehyde,
109.2 g (1.27 mol) of methyl acrylate,
7.28 g (0.057 mol) of 3-hydroxyquinuclidine, and
20 mL of chloroform (to predissolve the catalyst). The mixture was stirred at room temperature for 48 hr and concentrated to give the hydroxy ester (
50.0 g,
28%) as a pale yellow oil. The product can be distilled (bp
83-87°C at 3 torr) or used in Part A without further purification. In the latter event, yields are
10-20% lower.
6.
Reagent grade pentane was used as purchased from Fisher Scientific Company.
7. Anhydrous
MgSO4 was used as purchased from Fisher Scientific Company.
8.
ICN (230-400 mesh) silica gel was purchased from Bodman Industries.
9.
Silica gel (300 g) was packed to form a column of dimensions 19 cm × 6.5 cm. Elution was accomplished with
hexanes:ethyl acetate (19:1), both of which were used as purchased from Mallinckrodt Inc. The flow rate was 4 drops/sec. After collection of 300 mL of eluant, 20-mL fractions were collected. The pure, UV-active product (10.0 g) eluted in fractions 34-48 (R
f = 0.29;
silica gel developed with
p-anisaldehyde). Fractions 13-33 and 49-57 were combined and concentrated to give
6.9 g of material which was purified by chromatography over
200 g of silica gel to afford an additional
4.5 g of pure bromide.
10. Spectral data were as follows:
1H NMR (300 MHz, CDCl
3) δ: 1.09 (d, 6 H, J = 6.6), 2.71-2.83 (m, 1 H), 3.80 (s, 3 H), 4.23 (s, 2 H), 6.77 (d, 1 H, J = 10.5);
13C NMR (75 MHz, CDCl
3) δ: 21.6, 24.2, 28.5, 52.1, 127.0, 154.4, 166.3; IR (CH
2Cl
2) cm
−1: 3035 (w), 2980 (s), 2886 (m), 1740 (s), 1648 (m), 1470 (s), 1370 (m), 715 (s); MS (EI, 70 eV): m/z (M
+OCH
3) calcd 141.0915, obsd 141.0916 (100%).
11.
THF was used as purchased from Mallinckrodt Inc.
12.
Formaldehyde solution was used as purchased from EM Science.
13.
Indium powder (99.99%) was used as purchased from the Aldrich Chemical Company, Inc.
15.
Technical grade ethyl acetate was used as purchased from Mallinckrodt Inc.
16. Anhydrous
Na2SO4was used as purchased from Fisher Scientific Company.
17.
Silica gel (275 g) was packed to form a column of dimensions 16 cm × 6.5 cm. Elution was accomplished with
technical grade hexanes:ethyl acetate (7:3), both of which were used as purchased from Mallinckrodt Inc. The flow rate was 4 drops/sec. After collection of 150 mL of eluant, 20-mL fractions were collected. The UV-active product eluted in fractions 17-34 (R
f = 0.30; developed with I
2/SiO
2).
18. The submitters indicate that yields are
5-10% higher on smaller scale. The use of excess
formaldehyde solution led to polymerization and lower yields of the desired product.
19. Spectral data are as follows:
1H NMR (300 MHz, CDCl
3) δ: 0.84 (d, 3 H, J = 6.9), 0.96 (d, 3 H, J = 6.9), 1.90 (m, 2 H), 2.45 (m, 1 H), 3.74 (dd, 1 H, J = 7, 3), 3.75 (s, 3 H), 3.77 (dd, 1 H, J = 7, 3), 5.60 (dd, 1 H, J = 0.75, 1.1), 6.29 (d, 1 H, J = 1.2);
13C NMR (75 MHz, CDCl
3) δ: 20.1, 20.5, 27.6, 50.5, 51.6, 62.7, 126.2, 140.8, 168.3; IR (CHCl
3) cm
−1: 3619 (m), 3444 (w), 2964 (s), 1714 (s), 1624 (m), 1440 (m), 1159 (m); MS (EI): m/e 173 (MH
+); Anal. Calcd for C
9H
16O
3: C, 62.77; H, 9.36. Found: C, 62.59; H, 9.57.
The malodorous aqueous phase from the work-up of reaction A was treated with commercial bleach before disposal. Metallic indium from reaction B was treated with concd HCl and diluted before disposal.
3. Discussion
This procedure exemplifies a general method
9 10 11 12 for effecting carbon-carbon bond formation between a wide range of reactive halides and aldehydes or appropriately activated ketones
13 14 15 in aqueous media. The properties of
indium metal, most notably its first ionization potential (5.785 eV),
16 inertness to dissolution in hot alkali
17 and air oxidation,
18 and low toxicity contribute well to smooth coupling of the derived allylindium reagents. The latter are slow to hydrolyze, amenable to chelation control under the proper circumstances,
13,14,15,19 20 and conducive to long-range asymmetric induction.
5,21 Significantly,
indium(0) can easily be recovered from its salts by simple, conventional electrolysis.
22
Indium-promoted organometallic reactions are greatly accelerated in water, especially when the coreactant carbonyl compound also has good water solubility. Otherwise, aqueous
tetrahydrofuran can be used. To date,
indium is the most effective metal for promoting Barbier-type reactions under aqueous conditions. As illustrated here, this is of particular value where
formaldehyde is concerned, since the need to generate monomeric
formaldehyde by thermal cracking is avoided.
Appendix
Chemical Abstracts Nomenclature (Collective Index Number);
(Registry Number)
Dimethyl sulfide: Methyl sulfide (8); Methane, thiobis- (9); (75-18-3)
Formaldehyde (8,9); (50-00-0)
Methyl Z-2-(bromomethyl)-4-methylpent-2-enoate: 2-Pentenoic acid,
2-(bromomethyl)-4-methyl-, methyl ester, (Z)- (12); (137104-39-3)
N-Bromosuccinimide: Succinimide, N-bromo- (8); 2,5-Pyrrolidinedione,
1-bromo- (9); (128-08-5)
Methyl 3-hydroxy-4-methyl-2-methylenepentanoate: Pentanoic acid, 3-hydroxy-4-methyl-2-methylene-, methyl ester (10); (71385-30-1)
Indium (8,9); (7440-74-6)
Isobutyraldehyde (8); Propanal, 2-methyl- (9); (78-84-2)
Methyl acrylate: Acrylic acid, methyl ester (8); 2-Propenoic acid, methyl ester
(9); (96-33-3)
3-Hydroxyquinuclidine: 1-Azabicyclo[2.2.2]octan-3-ol (9); (1619-34-7)
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