Organic Syntheses, CV 9, 121
Submitted by Wha Chen, E. Kyle Stephenson, Michael P. Cava
1, and Yvette A. Jackson
2.
Checked by Wei He and Leo A. Paquette.
1. Procedure
A.
N-tert-Butoxycarbonyl-2-bromopyrrole. A dry,
500-mL, three-necked, round-bottomed flask is equipped with a
magnetic stirring bar,
two solid addition funnels, and a
three-way stopcock attached to a balloon filled with
nitrogen. To the flask are added
4.5 g (67.2 mmol) of pyrrole (Note
1) and
180 mL of tetrahydrofuran (Note
2). The flask is evacuated and purged with
nitrogen (Note
3). The stirred solution is cooled to −78°C with a
dry ice-acetone bath (Note
4) and a catalytic amount
(ca. 0.1 g) of azoisobutyronitrile (AIBN) (Note
5) is added via a solids addition funnel. After 5 min,
9.57 g (33.6 mmol) of 1,3-dibromo-5,5-dimethylhydantoin (Note
6) is added over a 20-min period via a solids addition funnel. The light-green mixture is stirred for an additional 10 min, then allowed to stand for 2 hr, keeping the temperature below −50°C. The solution is filtered by suction into a dry, 500-mL, round-bottomed flask that has been cooled to −78°C in a dry ice-acetone bath. The flask is equipped with a magnetic stirring bar and a three-way stopcock attached to a balloon filled with
nitrogen. To the stirred dark-green solution is added
2.71 g (26.9 mmol) of triethylamine followed immediately by addition of
20.4 g (93.9 mmol) of di-tert-butyl dicarbonate and a catalytic amount
(ca. 0.1 g) of 4-dimethylaminopyridine (Note
7). The flask is evacuated and purged with
nitrogen (Note
3). The mixture is stirred for 8 hr while it is allowed to warm to room temperature (Note
8). The solvent is removed under reduced pressure at room temperature and
100 mL of hexane is added to the crude product, which is washed with deionized water (3 × 100 mL), dried over
sodium sulfate, and concentrated under reduced pressure at room temperature. The crude product is purified by chromatography on amine-treated neutral silica (270 g) using
hexane as the eluent (Note
9). The fractions containing the product are identified by TLC, combined, and concentrated under reduced pressure at room temperature to yield compound
1 as a colorless oil (
13.5–14.7 g,
82–89%) (Note
10).
B.
N-tert-Butoxycarbonyl-2-trimethylsilylpyrrole. A solution of
N-tert-butoxycarbonyl-2-bromopyrrole (13.5 g, 54.9 mmol) in 40 mL of hexane is added to
200 mL of tetrahydrofuran (Note
2) in a dry,
500-mL, two-necked, round-bottomed flask equipped with a magnetic stirring bar,
rubber septum, and a three-way stopcock attached to a balloon of
nitrogen. The flask is evacuated and purged with
nitrogen (Note
3). The stirred mixture is cooled to −78°C and
34.3 mL of 1.6 M butyllithium in hexane (Note
10) is added slowly via syringe over a 10-min period, during which time the colorless solution becomes brown. After an additional 10 min,
13.4 g (124 mmol) of chlorotrimethylsilane (Note 11) in 10 mL of tetrahydrofuran (Note
3) is added via syringe over a 10-min period. Stirring is continued and the mixture is allowed to warm to −30°C over a 1-hr period. The reaction mixture is quenched with saturated aqueous
sodium bicarbonate (10 mL) at which point a dark red-purple color develops. After warming to 0°C, the solvent is removed under reduced pressure and the product is extracted into
300 mL of hexane. The organic layer is washed twice with 150 mL of water and then dried over anhydrous
sodium sulfate. The solvent is removed under reduced pressure, and the residue is distilled twice using a
Kugelrohr oven at 85°C and 0.15 mm to give the pure product
2 (
10.5–11.1 g,
80–85%) (Note
12).
2. Notes
1.
Pyrrole (Aldrich Chemical Company, Inc.) was freshly distilled before use.
3. The apparatus is maintained under a
nitrogen atmosphere during the course of the reaction.
4. The level of the reaction mixture must remain below the level of the cooling bath to avoid partial decomposition of the bromination product.
6.
Commercial 1,3-dibromo-5,5-dimethylhydantoin (Aldrich Chemical Company, Inc.) (22.0 g) was stirred for 12 hr at room temperature with
400 mL of 5% aqueous sodium bicarbonate, then stirred with 400 mL of deionized water for 8 hr, filtered, washed with 500 mL of deionized water and dried over
phosphorus pentoxide to constant weight. The checkers used the commercial brominating agent as received from Aldrich Chemical Company, Inc.
8. The checkers found that the reaction mixture must be stirred at room temperature for at least 2 hr prior to workup. It is advisable to monitor the progress of reaction by TLC.
9. The column is packed with
hexane and pretreated with
500 mL of 5% triethylamine in hexane, then washed with
700 mL of hexane before addition of the compound.
10. Although this N-Boc derivative is far more stable than
2-bromopyrrole, it is best stored as a 20–25% solution in
hexane at −10°C. Under these conditions, solutions show no sign of decomposition after many months. The product shows the following spectrum:
1H NMR (CDCl
3) δ: 1.61 (s, 9 H), 6.14 (t, 1 H, J = 3.5), 6.29 (dd, 1 H, J = 2.0, 3.5), 7.30 (dd, 1 H, J = 2.0, 3.5).
12. The spectral properties for
2-trimethylsilyl-N-Boc pyrrole are as follows:
1H NMR (CDCl
3) δ: 0.27 (s, 9 H), 1.60 (2, 9 H), 6.21 (t, 1 H, J = 3.0), 6.46 (dd, 1 H, J = 1.5, 3.0), 7.38 (dd, 1 H, J = 1.5, 3.0).
Waste Disposal Information
All toxic materials were disposed of in accordance with "Prudent Practices in the Laboratory"; National Academy Press; Washington, DC, 1995.
3. Discussion
The N-tert-butoxycarbonyl protecting group of substituted pyrroles can be removed readily by methoxide ion
3 or, when electron-withdrawing substituents are present, by mild thermolysis.
6
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