M. Muthukrishnan et al. / Tetrahedron 63 (2007) 1872–1876
1875
6% ammonia solution (5 mL). The crude (S)-metoprolol 1
free base was purified by column chromatography (silica gel,
DCM/MeOH¼98/2) (0.77 g; 97%), colorless solid; [a]D
ꢁ8.10 (c 10, CHCl3) {lit.7g [a]D ꢁ8.70 (c 10, CHCl3)}; ee
96% [chiral HPLC analysis; DAICEL CHIRALCEL OD
(0.46ꢃ25 cm) column; eluent: hexane/ethylalcohol/di-
ethylamine¼70/30/0.1; flow rate: 0.5 mL/min; detector:
254 nm (tR¼9.7 min) (tS¼11.77 min)]; IR (neat): n 3327,
3045, 2981, 2866, 1611, 1585, 1512, 1472, 1383, 1298,
1383, 1298, 1243, 1216, 1178, 1092, 930, 828, 756 cmꢁ1; 1H
NMR (500 MHz, CDCl3): d 0.20 (m, 2H), 0.52 (m, 2H), 1.06
(m, 8H), 2.70–2.75 (m, 1H), 2.83–2.93 (m, 3H), 3.27 (d,
J¼7.2 Hz, 2H), 3.61 (t, J¼7.3 Hz, 2H), 3.90 (d, J¼5.6 Hz,
3H), 3.98–4.02 (m, 1H), 6.84 (d, J¼8.7 Hz, 2H), 7.13 (d,
J¼8.7 Hz, 2H); l3C NMR (CDCl3): d 156.9, 131.0, 129.5,
114.2, 75.3, 71.5, 70.6, 68.2, 49.5, 48.7, 35.0, 22.7, 10.4,
2.7; MS m/z: 307 (M+). Anal. Calcd for C18H29NO3: C,
70.32; H, 9.51; N, 4.56. Found: C, 69.91; H, 9.74; N, 4.15.
1
1243, 1216, 1178, 1092, 930, 828, 756 cmꢁ1; H NMR
(200 MHz, CDCl3): d 1.15 (d, J¼6 Hz, 6H), 2.73–2.96 (m,
5H), 3.35 (s, 3H), 3.57 (t, J¼8 Hz, 2H), 3.94–3.97 (m,
2H), 4.02–4.10 (m, 1H), 6.84 (d, J¼8.0 Hz, 2H), 7.13
(d, J¼8.0 Hz, 2H); l3C NMR (CDCl3): d 156.9, 131.0,
129.5, 114.2, 75.3, 71.5, 70.6, 68.2, 49.5, 48.7, 35.0, 22.7;
MS m/z: 267 (M+). Anal. Calcd for C15H25NO3: C, 67.38;
H, 9.42; N, 5.24. Found: C, 67.51; H, 9.74; N, 5.15.
Acknowledgements
The authors thank Dr. M. K. Gurjar, Head, Organic Chemis-
try: Technology division for his support and encouragement.
References and notes
4.1.5. (S)-2-[4-(2-Cyclopropylmethoxy ethyl)phenoxy-
methyl]oxirane (8). A reaction flask was charged with
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(S)-1-[4-(2-hydroxyethyl)phenoxy]-2,3-epoxypropane
3
(1 g, 0.005 mol), bromomethylcyclopropane (0.83 g,
0.006 mol), and N,N-dimethylacetamide (10 mL). The mix-
ture was blanketed under nitrogen and stirred at room tem-
perature for 15 min and then cooled to ꢁ5 ꢂC. Potassium
tert-butoxide (0.87 g, 0.007 mol) was slowly added. After
the addition was completed, the reaction mixture was main-
tained at 0 ꢂC for 3 h. The reaction mixture was diluted with
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ture was extracted three times with 25 mL portions of ether.
The combined organic extracts were washed twice with
10 mL of water, dried over Na2SO4, evaporated, and the resi-
due was purified by column chromatography (silica gel,
petroleum ether/EtOAc¼98/2) to provide 8 as a colorless
oil (1.29 g; 96%); [a]D +2.05 (c 1, CHCl3); ee >99% [chiral
HPLC analysis; DAICEL CHIRALCEL OD (0.46ꢃ25 cm)
column; eluent: hexane/isopropanol¼97.5/2.5; flow rate:
1.0 mL/min; detector: 254 nm (tR¼9.25 min) (tS¼10.25 min)];
IR (neat): n 3078, 3004, 2928, 2861, 1723, 1612, 1583, 1512,
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1H NMR (200 MHz, CDCl3): d 0.20 (m, 2H), 0.54 (m,
2H), 1.06 (m, 1H), 2.70–2.75 (m, 1H), 2.83 (t, J¼7.3 Hz,
2H), 2.88–2.93 (m, 1H), 3.26 (d, J¼6.8 Hz, 2H), 3.28–
3.36 (m, 1H), 3.61 (t, J¼7.3 Hz, 2H), 3.95 (dd, J¼11.1
and 5.5 Hz, 1H), 4.15 (dd, J¼11.1 and 3.2 Hz, 1H), 6.87
(d, J¼8.2 Hz, 2H), 7.16 (d, J¼8.2 Hz, 2H); l3C NMR
(CDCl3): d 156.8, 131.5, 129.8, 114.4, 75.5, 71.6,
68.6, 50.1, 44.6, 35.3, 10.5, 2.9; MS m/z: 248 (M+). Anal.
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H, 8.42.
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4.1.6. (S)-Betaxolol (2). A solution of (S)-8 (0.7 g,
0.003 mol) in i-PrNH2 (2.5 mL) and H2O (2–3 drops) was
refluxed until TLC showed the reaction had gone to comple-
tion (10 h). Removal of the solvent yielded the crude (S)-
betaxolol 2 as a free base, which was purified by column
chromatography (silica gel, DCM/MeOH¼98/2) (0.83 g;
96%), colorless solid; [a]D ꢁ7.13 (c 1, CHCl3) {lit.8b [a]D
ꢁ5.4 (c 1, CHCl3)}; ee >99% [chiral HPLC analysis;
DAICEL CHIRALCEL OD (0.46ꢃ25 cm) column; eluent:
hexane/isopropanol/diethylamine¼60/40/0.1; flow rate:
0.5 mL/min; detector: 228 nm (tR¼8.53 min) (tS¼10.61 min)];
IR (neat): n 3327, 3045, 2981, 2866, 1611, 1585, 1512, 1472,
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