Checked by Shuyong Chen and Amos B. Smith, III.
1. Procedure
A.
1-Chloro-1-[(dimethyl)phenylsilyl]hexane. An
oven-dried, 500-mL, round-bottomed flask, equipped with a
magnetic stirring bar and a
rubber septum, is purged with
argon via an
inlet hose equipped with a needle and an
outlet hose equipped with a needle leading to an
oil bubbler. The flask is charged with
250 mL of dry tetrahydrofuran (THF) (Note
1) and
7.37 g of lithium wire (1.06 mol) cut into small pieces (Note
2). After cooling the reaction mixture to 0°C in a
CryoCool bath (Note
3),
30 g (29.1 mL, 176 mmol) of phenyldimethylsilyl chloride is added via syringe and the reaction mixture is stirred at 0°C for 16 hr (Note
4).
2 Within 0.5 hr, the reaction mixture turns from clear and colorless to dark red. An
oven-dried, 1-L, round-bottomed flask, equipped with a magnetic stirring bar and a rubber septum, is purged with
argon via an inlet needle and an outlet needle to an oil bubbler, charged with
16.78 g (20.0 mL, 167.5 mmol) of hexanal and
400 mL of dry THF (Note
5), and cooled to −78°C with a
dry ice-acetone bath. The solution of
phenyldimethylsilyllithium in THF prepared above is then added via
cannula. After addition, the red reaction mixture is warmed to 0°C and stirred for 1 hr. A saturated aqueous
ammonium chloride solution (250 mL) is then added in one portion and the resulting mixture is poured into a
2-L separatory funnel containing
250 mL of diethyl ether. The organic layer is washed with saturated aqueous
ammonium chloride (3 × 250-mL) and
brine (250 mL), dried over MgSO
4, and concentrated under reduced pressure. Purification via flash column chromatography (silica gel 230-400 mesh, 450 g of oil, loaded with hexanes, eluant 10:1
hexanes:
diethyl ether) yields a total of
32.6 g (
82%) of
1-[(dimethyl)phenylsilyl]-1-hexanol as a colorless oil (a second
column with 250 g of silica gel may be required for rechromatography of tailing fractions).
An oven-dried, 1-L, round-bottomed flask, equipped with a magnetic stirring bar, is charged with
500 mL of dry THF and
1-[(dimethyl)phenylsilyl]-1-hexanol (32.6 g, 138 mmol).
Carbon tetrachloride (53.20 g, 33.4 mL, 345.9 mmol) and
triphenylphosphine (54.30 g, 207 mmol) are added and the flask is equipped with a
condenser and a rubber septum and purged with
argon via inlet needle and outlet needle to an oil bubbler.
3 The reaction mixture is heated to reflux under
argon for 12 hr. After the reaction mixture is allowed to cool to room temperature, the volatiles are removed under reduced pressure, and the residue is triturated with
hexanes (3 × 300-mL). Concentration of the extracts under reduced pressure and purification via flash column chromatography (
silica gel 230-400 mesh, 450 g, eluant hexanes) yields
30.4–31.7 g of
1-chloro-1-[(dimethyl)phenylsilyl]hexane (
71–74% from
hexanal) as a colorless oil (Note
6)
B.
6-Methyl-6-dodecene. An oven-dried, 1-L, three-necked, round-bottomed flask is equipped with a condenser, a
125-mL, pressure-equalizing addition funnel, a magnetic stirring bar, and a rubber septum. The flask is purged with
argon and charged with
96.23 g (373 mmol) of magnesium bromide etherate (MgBr
2·Et
2O) (Note
2) and
250 mL of dry THF. A total of
26.67 g (682 mmol) of potassium metal, freshly rinsed with
60 mL of dry THF, is added piecewise (Note
7). The reaction mixture is heated at reflux with stirring for 3 hr, at which time the activated
magnesium has formed as a finely divided black powder (Note
8). The activated
magnesium is allowed to cool and settle. The supernatant THF layer is carefully transferred via cannula into a
500-mL Erlenmeyer flask containing
250 mL of isopropyl alcohol. The activated
magnesium is rinsed with dry
diethyl ether (2 × 200-mL) and diluted with
100 mL of dry diethyl ether all via cannula. The crude
1-chloro-1-[(dimethyl)phenylsilyl]hexane (31.58 g, 124 mmol) is diluted with
100 mL of dry diethyl ether and transferred via cannula to the addition funnel. The ethereal solution of the
α-silyl chloride is added to the activated
magnesium slurry in
diethyl ether slowly in portions causing the reaction mixture to reflux gently (Note
9). Upon completion of the addition, the reaction mixture is stirred for 15 min (Note
10).
An oven-dried, 1-L, round-bottomed flask is equipped with a magnetic stirring bar and a rubber septum. The flask is charged with
25.61 g of copper bromide-dimethyl sulfide complex (124 mmol) and
250 mL of dry diethyl ether, and the resulting slurry is cooled to −78°C with a dry ice-acetone bath. The Grignard reagent solution prepared above is added to the
copper bromide-dimethyl sulfide slurry via cannula (Note
11). The residual activated
magnesium is rinsed once with
200 mL of dry diethyl ether, and the supernatant layer is transferred via cannula to the
copper bromide-dimethyl sulfide slurry (Note
12). The reaction mixture is slowly warmed to −10°C, and then
16.78 g (17.42 mL, 125 mmol) of hexanoyl chloride is added dropwise via syringe after which the reaction mixture is warmed to room temperature. After stirring for 3 hr, the reaction mixture is filtered through a
75-g layer of Celite 545 (Note
13) and the filter cake rinsed with three
100-mL portions of diethyl ether. Concentration of the filtrate under reduced pressure yields the
α-silyl ketone which is utilized without further purification (Note
14).
(1) Acidic Elimination:
An oven-dried, 1-L, three-necked, round-bottomed flask is equipped with a 125-mL pressure-equalizing addition funnel, a magnetic stirring bar, and a rubber septum, and the system is purged with
argon. The flask is charged with the crude
α-silyl ketone prepared above and
500 mL of dry THF. Via cannula, a
125-mL (175 mmol) portion of a 1.4 M solution of methyllithium in hexanes is transferred to the addition funnel . After the
α-silyl ketone solution is cooled to −78°C with a dry ice-acetone bath, the
methyllithium solution is added dropwise over approximately 1 hr, and the reaction mixture is stirred for 0.5 hr at −78°C. A second, oven-dried, 1-L, round-bottomed flask is equipped with a magnetic stirring bar and a rubber septum. The second flask is charged with
47.39 g (249 mmol) of p-toluenesulfonic acid monohydrate and
100 mL of dry THF, and purged with
argon. The β-alkoxysilane solution prepared above is transferred to the flask containing the solution of
p-toluenesulfonic acid monohydrate in THF via cannula and stirred for 2 hr. The reaction mixture is then poured into a separatory funnel containing a biphasic mixture of
500 mL of saturated aqueous sodium bicarbonate and
250 mL of diethyl ether. The resulting organic layer is washed with saturated aqueous
sodium bicarbonate (3 × 250-mL) and
brine (250 mL), dried over MgSO
4, and concentrated under reduced pressure. Purification of the residue via flash column chromatography (silica gel 230-400 mesh, 450 g, eluant hexanes) yields
11.31–11.75 g of
(Z)-6-methyl-6-dodecene (
50–52% from the
α-silyl chloride) as a 92:8 Z/E ratio of isomers (Note
15) and (Note
16).
(2) Basic Elimination:
An oven-dried, 1-L, three-necked flask is equipped with a 125-mL pressure-equalizing addition funnel, a magnetic stirring bar, and a rubber septum. The flask is purged with
argon and is charged with the crude
α-silyl ketone (from
30.00 g, 118 mmol of α-silyl chloride) and dry
THF (500 mL).
Methyllithium (1.4 M, 118 mL, 165 mmol) is added to the addition funnel via cannula. The
α-silyl ketone solution is cooled to −78°C with a dry ice-acetone bath, and
methyllithium is added dropwise over approximately 1 hr after which the reaction mixture is stirred for 0.5 hr. A second, oven-dried, 1-L, round-bottomed flask, equipped with a magnetic stirring bar and a rubber septum, is charged with
27 g of potassium hydride (35% wt/wt dispersion in oil which is rinsed with three
100-mL portions of dry diethyl ether), and diluted with
100 mL of dry THF, and
0.200 g of 18-crown-6 (0.76 mmol) is added. The β-alkoxysilane solution prepared above is added to the
potassium hydride slurry via cannula, and the mixture is stirred for 16 hr. Excess
potassium hydride is quenched with
isopropyl alcohol (
50 mL) until no further
hydrogen gas is evolved (Note
17). Saturated aqueous
ammonium chloride (250-mL) is added to the reaction mixture which is then combined with
250 mL of diethyl ether in a separatory funnel. The organic layer is washed successively with three
250-mL portions of saturated aqueous ammonium chloride and
250 mL of brine, dried over MgSO
4, and concentrated under reduced pressure. Purification of the residue via flash column chromatography (silica gel 230-400 mesh, 450 g, eluant hexanes) provides
11.19–11.62 g (E)-6-methyl-6-dodecene, (
52–54% from the
α-silyl chloride) as a 95:5 E/Z ratio of isomers (Note
15) and (Note
18).
2. Notes
2.
Lithium wire (3.2 mm diam.), carbon tetrachloride, triphenylphosphine, MgBr·Et2O, copper bromide-dimethyl sulfide complex, hexanoyl chloride, methyllithium, p-toluenesulfonic acid monohydrate, potassium hydride, and 18-crown-6 were purchased from Aldrich Chemical Company, Inc. and used without further purification.
3. The CryoCool bath may be obtained from CryoCool CC-80II Neslab Instruments, Inc. Portsmouth, N.H. 03801, USA. The reaction may be run in an
ice bath under supervision.
5.
Hexanal was purchased from the Aldrich Chemical Company Inc. and distilled (bp
131°C) before use.
6. The product exhibits the following properties: IR (film) cm
−1: 3016, 2968, 2940, 2866, 1465, 1430, 1253, 1117;
1H NMR (400 MHz, CDCl
3) δ: 0.40 (s, 3 H), 0.41 (s, 3 H), 0.85 (t, 3 H, J = 7.1), 1.17–1.34 (m, 5 H), 1.58–1.68 (m, 3 H), 3.42 (dd, 1 H, J = 2.9, 11.2), 7.35–7.39 (m, 3 H), 7.54–7.56 (m, 2 H);
13C NMR (75 MHz, CDCl
3) δ: −5.7, −4.6, 14.0, 22.5, 27.4, 31.0, 33.1, 51.2, 127.8, 129.5, 134.1, 136.0; high resolution mass spectrum (CI, NH
3) m/z 272.1615 [(M
+NH
4)
+; calcd for C
14H
27NSiCl: 272.1602].
7.
Potassium metal, purified, was purchased from J.T. Baker Chemical Company.
CAUTION: Potassium metal is pyrophoric and reacts violently with water.
9.
CAUTION: The reaction is exothermic.
10. The Grignard solution may be stored overnight under
argon.
11. Care should be taken not to add excess activated
magnesium, although a small amount does not seem to affect cuprate formation.
13. The Celite used is NOT the acid-washed reagent. Acid-washed Celite will cause some desilylation of the
α-silyl ketone intermediate.
15. The ratio of isomers was determined by GC/MS (Hewlett Packard 5890 Series II Gas Chromatograph/5870 Series Mass Selective Detector).
16. The product exhibits the following properties: IR (film) cm
−1: 2966, 2935, 2867, 1460, 1379;
1H NMR (500 MHz, CDCl
3) δ: 0.89 (t, 3 H, J = 7.1, overlapping 0.88 (t, 3 H, J = 6.9)), 1.23–1.39 (m, 12 H), 1.58 (s, 0.26 H, E-methyl), 1.67 (s, 2.74 H, Z-methyl), 1.94–2.01 (m, 4 H), 5.11 (t, 1 H, J = 7.1);
13C NMR (125 MHz, CDCl
3) δ: 14.10, 22.63, 22.64, 23.40, 27.75, 27.77, 29.80, 31.60, 31.70, 31.80, 125.30, 135.40; high resolution mass spectrum (CI, NH
3) m/z 182.2029 [(M)
+; calcd for C
13H
26: 182.2035].
17.
CAUTION: Hydrogen gas is flammable and should be vented into a fume hood.
18. The product exhibits the following properties: IR (film) cm
−1: 2968, 2936, 2867, 1460, 1380;
1H NMR (500 MHz, CDCl
3) δ: 0.89 (t, 6 H, J = 7.0), 1.21–1.41 (m, 12 H), 1.58 (s, 2.73 H, E-methyl), 1.67 (s, 0.27 H, Z-methyl), 1.94–1.99 (m, 4 H), 5.11 (t, 1 H, J = 7.1);
13C NMR (125 MHz, CDCl
3) δ: 14.1, 15.8, 22.6, 27.7, 27.9, 29.6, 29.9, 31.6, 31.7, 31.8, 39.7, 124.6, 135.1; high resolution mass spectrum (CI, NH
3) m/z 182.2026 [(M)
+; calcd for C
13H
26: 182.2035].
All toxic materials were disposed of in accordance with "Prudent Practices in the Laboratory"; National Academy Press; Washington, DC, 1995.
3. Discussion
The acid or base elimination of a diastereoisomerically pure β-hydroxysilane,
1, (the Peterson olefination reaction
4 For reviews see:
5,6,7,8,9) provides one of the very best methods for the stereoselective formation of alkenes. Either the E- or Z-isomer may be prepared with excellent geometric selectivity from a single precursor (Scheme 1). The widespread use of the Peterson olefination reaction in synthesis has been limited, however, by the fact that there are few experimentally simple methods available for the formation of diastereoisomerically pure β-hydroxysilanes.
10,11,12,13 Also see:
14,15,16,17,18,19 One reliable route is the Cram controlled addition of nucleophiles to α-silyl ketones,
18,19 but such an approach is complicated by difficulties in the preparation of (α-silylalkyl)lithium species or the corresponding Grignard reagents. These difficulties have been resolved by the development of a simple method for the preparation and reductive acylation of (α-chloroalkyl)silanes.
20
The procedure shown here describes the preparation of α-silyl ketones from aldehydes and acyl chlorides. The α-silyl ketones undergo Cram addition of various nucleophiles to produce diastereoselectively β-hydroxysilanes. These compounds are then subjected directly to elimination in situ under basic or acidic conditions to produce the corresponding alkenes.
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