Organic Syntheses, Vol. 75, 106
Checked by Kei Manabe and Kenji Koga.
1. Procedure
D. N-Benzyl-3-(Z/E)-ethylideneazetidin-2-one. Into a dry,
250-mL, one-necked, round-bottomed flask, fitted with a magnetic stirring bar, is placed
9.60 g (0.047 mol) of N-benzyl-3-(1-hydroxyethyl)azetidin-2-one,
125 mL of dry dichloromethane (Note
10), and
13.0 mL (0.093 mol) of triethylamine. The solution is cooled in an ice bath before
4.0 mL (0.052 mol) of methanesulfonyl chloride (Note
11) is introduced. The mixture is stirred at 0°C for 1 hr, transferred to a
separatory funnel, and washed with saturated
sodium bicarbonate solution (2 × 150 mL) and
brine (200 mL). The organic phase is dried over anhydrous
magnesium sulfate, filtered, and evaporated under reduced pressure to leave 14.3 of orange oil (Note
12).
The oil is immediately dissolved in
200 mL of dry benzene and transferred to a 500-mL, one-necked, round-bottomed flask to which is added
7.73 g (0.051 mol) of 1,8-diazabicyclo[5.4.0]undec-7-ene, DBU (Note
13). The flask is fitted with a condenser, heated at reflux for 8 hr, allowed to cool to room temperature, and washed with 200 mL of water and
200 mL of brine. The organic phase is dried over anhydrous
magnesium sulfate, filtered, and evaporated to leave a dark brown oil. This material is chromatographed on silica gel (elution with
30% ethyl acetate in hexanes) (Note
14) and (Note
15) to give
7.02 g (
79.9% for the two steps) as a very pale yellow oil.
2. Notes
2. The product exhibits the following spectroscopic properties; IR (CHCl
3) cm
−1: 3500, 1720, 1635;
1H NMR (300 MHz, CDCl
3) δ: 1.33 (d, 3 H, J = 6.5), 2.80 (br s, 1 H), 3.74 (s, 3 H), 4.57 (q, 1 H, J = 6.5), 5.79 (s, 1 H), 6.16 (s, 1 H).
3. The progress of this reaction can be conveniently monitored by
1H NMR spectroscopy. A small aliquot is evaporated to dryness and the disappearance of the vinyl protons at δ 5.79 and 6.16 (CDCl
3 solution) is followed.
4. The spectroscopic properties of this diastereomeric mixture are as follows:
1H NMR (300 MHz, CDCl
3) δ: 1.14-1.20 (two sets of doublets, 3 H, J = 6.3), 2.43-2.49 (m, 2 H), 2.98-3.04 (m, 2 H), 3.66 (s, 3 H), 3.74 (s, 2 H), 4.15-4.19 (m, 1 H), 7.25 (m, 5 H).
5.
Tetrahydrofuran was dried by distillation from
sodium benzophenone ketyl.
7. If unreacted
magnesium remains at this time, more
tert-butyl chloride is introduced in order to achieve complete conversion to the Grignard reagent.
8. It is essential to have good stirring during this step. If the reaction mixture becomes significantly turbid, a change to mechanical stirring is advisable.
9. This compound has the following properties: R
f = 0.3 (5%
ethanol in
dichloromethane; IR (CHCl
3) cm
−1: 3500-3300, 1740;
1H NMR (300 MHz, CDCl
3) δ: 1.24 (d, 3 H, J = 6.3), 2.65 (br s, 1 H), 3.14-3.22 (m, 3 H), 4.17 (m, 1 H), 4.37 (m, 2 H), 7.22-7.36 (m, 5 H).
11.
Methanesulfonyl chloride was obtained from the Mallinckrodt Company and distilled under reduced pressure before use.
12. This product is unstable and should be used without delay. It exhibits the following
1H NMR spectrum: (80 MHz, CDCl
3) δ: 1.5 (m, 3 H), 3.0 (s, 3 H), 3.3 (m, 3 H), 4.4 (s, 2 H), 5.0 (m, 1 H), 7.3 (s, 5 H).
13.
DBU (96%) was obtained from the Aldrich Chemical Company, Inc., and distilled under reduced pressure before use.
14. The Z- and E-isomers have quite different R
f values in 3:1
hexane-
ethyl acetate (0.25 and 0.10, respectively) and can easily be separated if desired.
1H NMR for the Z-isomer (300 MHz, CDCl
3) δ is as follows: 2.03 (d, 3 H, J = 7.1), 3.52 (s, 2 H), 4.46 (s, 2 H), 5.58 (q, 1 H, J = 7.1), 7.53 (s, 5 H); for the E-isomer (300 MHz, CDCl
3) δ: 1.66 (d, 3 H, J = 7.0), 3.59 (s, 2 H), 4.45 (s, 2 H), 6.13 (q, 1 H, J = 7.0), 7.20-7.34 (m, 5 H).
15. The product can alternatively be purified by Kugelrohr distillation (165°C, 0.5-1.0 mm). However, the yield is significantly lower (52%).
18. The spectral data are as follows: IR (CHCl
3) cm
−1: 1830, 1768;
1H NMR (300 MHz, CD
3COCD
3) δ: 3.93 (s, 2 H), 4.79 (s, 2 H), 7.30-7.39 (m, 5 H);
13C NMR (75 MHz, CD
3COCD
3) δ: 47.0, 59.9, 128.7, 129.1, 129.7, 135.8, 164.4, 195.6. The dione is stable for several weeks when kept in the dark at 5°C.
All toxic materials were disposed of in accordance with "Prudent Practices in the Laboratory"; National Academy Press; Washington, DC, 1995.
3. Discussion
Appendix
Chemical Abstracts Nomenclature (Collective Index Number);
(Registry Number)
N-Benzyl-2,3-azetidinedione: 2,3-Azetidinedione, 1-(phenylmethyl)- (10);
(75986-07-1)
Methyl 3-hydroxy-2-methylenebutanoate: Butyric acid, 3-hydroxy-2-methylene-, methyl ester (8): Butanoic acid, 3-hydroxy-2-methylene-, methyl ester (9);
(18020-65-0)
Methyl acrylate: Acrylic acid, methyl ester (8); 2-Propenoic acid, methyl ester (9);
(96-33-3)
Acetaldehyde (8,9);
(75-07-0)
1,4-Diazabicyclo[2.2.2]octane [DABCO] (8,9);
(280-57-9)
Benzylamine (8); Benzenemethanamine (9);
(100-46-9)
Magnesium (8,9);
(7439-95-4)
tert-Butyl chloride: Propane, 2-chloro-2-methyl- (8,9);
(507-20-0)
N-Benzyl-3-(Z/E)-ethylideneazetidin-2-one: 2-Azetidinone, 3-ethylidene-1-(phenylmethyl)- (12);
(115870-02-5)
Triethylamine (8); Ethanamine, N,N-diethyl- (9);
(121-44-8)
Methanesulfonyl chloride (8,9);
(124-63-0)
1,8-Diazabicyclo[5.4.0]undec-7-ene [DBU]: Pyrimido[1,2-a]azepine, 2,3,4,6,7,8,9,10-octahydro- (8,9);
(6674-22-2)
Sodium metaperiodate: Periodic acid, sodium salt (8,9);
(7790-28-5)
Osmium tetroxide: Osmium oxide (8); Osmium oxide, (T-4)- (9);
(20816-12-0)
Methyl 2-(benzylamino)methyl-3-hydroxybutanoate: Butanoic acid, 3-hydroxy-2-[[(phenylmethyl)amino]methyl]-, methyl ester (12); (R*,R*)-
(118559-03-8);
(R*,S*)-
(118558-99-9)
N-Benzyl-3-(1-hyrdoxyethyl)azetidin-2-one: 2-Azetidinone, 3-(1-hydroxyethyl)-1-(phenylmethyl)-, (11); (R*,R*)-
(89368-08-1); (R*,S*)-
(89368-09-2)
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