Organic Syntheses, Coll. Vol. 10, p.541 (2004); Vol. 77, p.107 (2000).
Dimethyl sulfide was used as purchased from the Aldrich Chemical Company, Inc.
Dropwise addition via syringe successfully avoids such problems as rapid precipitation of the NBS·(CH3)2S complex
, high exothermicity, and loss of stirring efficiency.
was obtained by the means of a Baylis-Hillman reaction6
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
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
) 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%
pentane was used as purchased from Fisher Scientific Company
Anhydrous MgSO4 was used as purchased from Fisher Scientific Company
ICN (230-400 mesh) silica gel was purchased from Bodman Industries
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 (Rf
= 0.29; silica gel
). 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.
Spectral data were as follows:
H NMR (300 MHz, CDCl3
) 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)
C NMR (75 MHz, CDCl3
) δ: 21.6, 24.2, 28.5, 52.1, 127.0, 154.4, 166.3
; IR (CH2
: 3035 (w), 2980 (s), 2886 (m), 1740 (s), 1648 (m), 1470 (s), 1370 (m), 715 (s)
; MS (EI, 70 eV): m/z (M+
) calcd 141.0915, obsd 141.0916 (100%)
THF was used as purchased from Mallinckrodt Inc.
Formaldehyde solution was used as purchased from EM Science
Indium powder (99.99%) was used as purchased from the Aldrich Chemical Company, Inc.
ethyl acetate was used as purchased from Mallinckrodt Inc.
was used as purchased from Fisher Scientific Company
Silica gel (275 g)
was packed to form a column of dimensions 16 cm × 6.5 cm. Elution was accomplished with
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 (Rf
= 0.30; developed with I2
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.
Spectral data are as follows:
H NMR (300 MHz, CDCl3
) 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)
C NMR (75 MHz, CDCl3
) δ: 20.1, 20.5, 27.6, 50.5, 51.6, 62.7, 126.2, 140.8, 168.3
; IR (CHCl3
: 3619 (m), 3444 (w), 2964 (s), 1714 (s), 1624 (m), 1440 (m), 1159 (m)
; MS (EI): m/e 173 (MH+
; Anal. Calcd for C9
: 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.
This procedure exemplifies a general method9
for effecting carbon-carbon bond formation between a wide range of reactive halides and aldehydes or appropriately activated ketones13
in aqueous media. The properties of indium
metal, most notably its first ionization potential (5.785 eV),16
inertness to dissolution in hot alkali17
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
and conducive to long-range asymmetric induction.5,21
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.
Chemical Abstracts Nomenclature (Collective Index Number);
Methyl sulfide (8);
Methane, thiobis- (9); (75-18-3)
Formaldehyde (8,9); (50-00-0)
2-(bromomethyl)-4-methyl-, methyl ester, (Z)- (12); (137104-39-3)
Succinimide, N-bromo- (8);
1-bromo- (9); (128-08-5)
Pentanoic acid, 3-hydroxy-4-methyl-2-methylene-, methyl ester (10); (71385-30-1)
Indium (8,9); (7440-74-6)
Propanal, 2-methyl- (9); (78-84-2)
Acrylic acid, methyl ester (8);
2-Propenoic acid, methyl ester
1-Azabicyclo[2.2.2]octan-3-ol (9); (1619-34-7)
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