580
G. Blay et al. / Tetrahedron: Asymmetry 21 (2010) 578–581
0.5 mmol). The reaction mixture was stirred at ꢀ30 °C for 4 days.
Then the solvent was removed under reduced pressure and the
product was isolated by column chromatography eluting with hex-
ane/EtOAc mixtures (7:3–5:5) to give 25 mg of recovered starting
material and 85 mg (65% yield, 87% yield respect to consumed
was introduced in a bath at ꢀ50 °C. After 5 min, nitromethane
(1.1 mL, 20 mmol) was added followed by DIPEA (348 L,
l
2.0 mmol). After 27 h, the solvent was removed under reduced
pressure and the reaction product was isolated by column chroma-
tography eluting with hexane/EtOAc (9:1–6:4) to give 453 mg
starting material) of compound 5: ½a D25
ꢁ
¼ þ19:5 (c 0.54, MeOH,
(99%) of compound 8: ½a D25
ꢁ
¼ ꢀ27:1 (c 2.01, CH2Cl2, 96% ee), lit.21
92% ee); 1H NMR (300 MHz, DMSO-d6) d 9.78 (br s, 1H), 7.40 (d,
J = 8.7 Hz, 2H), 7.19 (d, J = 8.7 Hz, 2H), 6.05 (d, J = 4.8 Hz, 1H),
5.25–5.19 (m, 1H), 4.81 (dd, J = 12.3, 3.0 Hz, 1H), 4.54 (dd,
J = 12.3, 9.9 Hz, 1H), 2.98 (s, 3H); 13C NMR (75.5 MHz, DMSO-d6)
d 138.0 (C), 135.7 (C), 127.2 (2 ꢃ CH), 119.5 (2 ꢃ CH), 81.8 (CH2),
69.5 (CH), 39.2 (CH3); MS(EI) m/z (%) 242 (M+-H2O, 0.6), 199
(100), 120 (33), 92 (41); HRMS: 242.0370 (M+ꢀH2O), C9H10N2O4S
requires 242.0361; ee (92%) was determined by HPLC (Chiralcel
AD–H), hexane–i-PrOH 80:20, 1 mL/min, major enantiomer (S)
tr = 14.7 min, minor enantiomer (R) tr = 16.7 min.
½
a 2D5
ꢁ
¼ þ26:8 (c 2.02, CH2Cl2, 78% ee, (S)-enantiomer); 1H NMR
(300 MHz, CDCl3) d 6.91–6.89 (m, 2H), 6.85–6.83 (m, 1H), 5.38
(dt, J = 9.3, 2.7 Hz, 1H), 4.59 (dd, J = 12.9, 9.3 Hz, 1H), 4.47 (dd,
J = 12.9, 3.0 Hz, 1H), 3.86 (s, 3H), 3.85 (s, 3H) 2.99 (d, J = 2.4 Hz,
1H); 13C NMR (75.5 MHz, CDCl3) d 149.3 (C), 130.7 (C), 118.3
(CH), 111.3 (CH), 108.8 (CH), 81.3 (CH2), 78.8 (CH), 55.9
(2 ꢃ CH3); ee (96%) was determined by HPLC (Chiralcel OD–H),
hexane–i-PrOH 80:20, 1 mL/min, major enantiomer (R) tr = 15.9 min,
minor enantiomer (S) tr = 20.8 min.
3.6. (R)-(ꢀ)-2-Amino-1-(3,4-dimethoxyphenyl)ethanol 9
3.3. (S)-(+)-N-[4-(2-Amino-1-hydroxyethyl)phenyl]
methanesulfonamide 6
To a solution of compound 8 (399 mg, 1.76 mmol) in EtOH
(20 mL) was added 10% Pd/C (135 mg). The mixture was stirred un-
der a hydrogen atmosphere (balloon) for 22 h. The mixture was fil-
tered through a short pad of Celite to remove the catalyst. Removal
of the solvent under reduced pressure afforded 345 mg (99%) of
To a solution of compound 5 (99 mg, 0.38 mmol) in MeOH
(1.5 mL) and EtOH (3 mL) was added 10% Pd/C (35 mg). The mix-
ture was stirred under a hydrogen atmosphere (balloon) for 16 h.
After this time, the catalyst was removed upon filtration through
a short pad of Celite. The pad was washed with MeOH. Concentra-
tion of the filtrates under reduced pressure gave 88 mg (>99%
compound 9. ½a 2D5
ꢁ
¼ ꢀ24:0 (c 1.08, EtOH, 96% ee), lit.22
½
a 2D5
ꢁ
¼
ꢀ29:7 (c 0.72, EtOH); 1H NMR (300 MHz, DMSO-d6) d 6.91–6.89
(m, 2H), 6.81 (dd, J = 8.1, 1.8 Hz, 1H), 5.13 (br s, 1H), 4.36 (dd,
J = 7.2, 4.5 Hz, 1H), 3.74 (s, 3H), 3.72 (s, 3H), 2.63 (dd, J = 12.9,
4.5 Hz, 1H), 2.55 (dd, J = 12.9, 7.5 Hz, 1H); 13C NMR (75.5 MHz,
CDCl3) d 149.0 (C), 148.4 (C), 135.1 (C), 118.0 (CH), 111.0 (CH),
109.0 (CH), 74.0 (CH), 55.9 (CH3), 55.8 (CH3), 49.2 (CH2).
yield) of compound 6: ½a D25
ꢁ
¼ þ23:6 (c 1.03, MeOH, 92% ee); 1H
NMR (300 MHz, DMSO-d6) d 7.26 (d, J = 8.4 Hz, 2H), 7.13 (d,
J = 8.4 Hz, 2H), 4.39 (dd, J = 7.8, 4.5 Hz, 1H), 2.93 (s, 3H), 2.64 (dd,
J = 12.9, 4.5 Hz, 1H), 2.55 (dd, J = 12.9, 7.8 Hz, 1H); 1H NMR
(300 MHz, MeOH-d4) d 7.26 (d, J = 8.4 Hz, 2H), 7.15 (d, J = 8.4 Hz,
2H), 2.71 (unresolved m, 2H); 13C NMR (75.5 MHz, MeOH-d4) d
140.2 (C), 139.5 (C), 128.2 (2 ꢃ CH), 121.8 (2 ꢃ CH), 75.1 (CH),
49.9 (CH2), 39.2 (CH3); MS(EI) m/z (%): 230 (M+, 0.1), 212 (27),
200 (17), 133 (100), 122 (16); HRMS: 230.0724 (M+), C9H12N2O3S
requires 230.0725.
3.7. (R)-(ꢀ)-1-(3,4-Dimethoxyphenyl)-2-
(isopropylamino)ethanol 10
A solution of 9 (316 mg, 1.60 mmol) and acetone (293 lL,
2.7 mmol) in EtOH (2 mL) was stirred at rt for 1 h. Then, the reac-
tion mixture was cooled to 0 °C (ice bath) and NaBH4 (91 mg,
2.4 mmol) was added. After stirring for 1 h, the reaction mixture
was chromatographed on silica gel (AcOEt/MeOH) to give 361 mg
3.4. (S)-(+)-Sotalol 1
A
solution of 6 (80 mg, 0.35 mmol) and acetone (64 lL,
(94%) of compound 10. ½a D25
ꢁ
¼ ꢀ32:7 (c 3.00, acetone, 96% ee); 1H
0.58 mmol) in EtOH (0.8 mL) was stirred at rt for 1 h. Then, the
reaction mixture was cooled to 0 °C (ice bath) and NaBH4 (20 mg,
0.52 mmol) was added. After stirring for 1 h, the reaction mixture
was filtered through silica gel eluting with MeOH to give 94 mg
NMR (300 MHz, CDCl3) d 6.93 (d, J = 1.5 Hz, 1H), 6.87 (dd, J = 8.4,
1.5 Hz, 1H), 6.82 (d, J = 8.4 Hz, 1H), 4.59 (dd, J = 9.0, 3.6 Hz, 1H),
3.88 (s, 3H), 3.86 (s, 3H), 3.44 (br s, 1H), 2.87 (dd, J = 12.0, 3.9 Hz,
1H), 2.80 (m, J = 6.3 Hz, 1H), 2.63 (dd, J = 12.0, 9.0 Hz, 1H), 1.06
(d, J = 6.3 Hz, 6H); 13C NMR (75.5 MHz, CDCl3) d 149.0 (C), 148.3
(C), 135.5 (C), 117.9 (CH), 111.0 (CH), 108.9 (CH), 71.8 (CH), 55.9
(CH3), 55.8 (CH3), 54.6 (CH2), 48.5 (CH), 23.1 (CH3), 23.0 (CH3);
ee (96%) was determined by HPLC (Chiralpak AY-H), hexane–i-
PrOH 90:10, 1 mL/min, major enantiomer (R) tr = 13.6 min, minor
enantiomer (S) tr = 18.9 min.
(>99% yield) of (S)-(+)-sotalol: ½a D25
¼ þ19:3 (c 0.27, MeOH, 92%
ꢁ
ee); 1H NMR (300 MHz, DMSO-d6) d 7.21 (d, J = 8.4 Hz, 2H), 7.06
(d, J = 8.4 Hz, 2H), 5.16 (br s, 1H), 4.49 (dd, J = 8.1, 4.2 Hz, 1H),
3.36 (br s, 1H), 2.85 (s, 3H), 2.71 (m, J = 6.3 Hz, 1H), 2.61 (dd,
J = 11.7, 4.2 Hz, 1H), 2.54 (dd, J = 11.7, 8.1 Hz, 1H), 0.95 (d,
J = 6.3 Hz, 6H); 13C NMR (75.5 MHz, MeOD) d 141.3 (C), 139.5 (C),
128.0 (2 ꢃ CH), 121.9 (2 ꢃ CH), 73.0 (CH), 55.6 (CH2), 49.7 (CH),
39.1 (CH3), 22.6 (CH3), 22.4 (CH3); MS(EI) m/z (%) 272 (M+, 2.2),
254 (42), 185 (42), 175 (87), 106 (100), 72 (81); HRMS: 272.1198
(M+), C12H20N2O3S requires 272.1195; ee (92%) was determined
by HPLC (Chiralpak AD–H), hexane–i-PrOH 85:15, 1 mL/min, major
enantiomer (S) tr = 16.2 min, minor enantiomer (R) tr = 20.4 min.
This compound was treated with 5% aqueous HCl (1 equiv) to
Acknowledgments
Financial support from the Ministerio de Educación y Ciencia
and FEDER (CTQ 2006-14199) and from Generalitat Valenciana
(ACOMP/2009/338) is gratefully acknowledged. V.H.-O. thanks
the Universitat de València for a pre-doctoral grant (V segles
program).
give (S)-(+)-sotalol hydrochloride quantitatively: ½a D25
¼ þ28:7 (c
ꢁ
1.05, H2O, 92% ee), lit.8
½
a 2D5
ꢁ
¼ þ34:4 (c 1.00, H2O).
3.5. (R)-(ꢀ)-1-(3,4-Dimethoxyphenyl)-2-nitroethanol 8
References and notes
Ligand ent-3 (27 mg, 0.11 mmol) dissolved in absolute EtOH
(8 mL) was added to Cu(OAc)2ꢂH2O (20 mg, 0.10 mmol) and the
mixture was stirred for 1 h to give a deep blue solution. 3,4-Dime-
thoxybenzaldehyde 7 (336 mg, 2.0 mmol) was added and the flask
1. Pharmaceutical Chemistry of Antihypertension Agents; Szasz, G., Budvari-Barany,
Z., Eds.; CRC Press: Boston, 1991.
2. (a) Taggart, P.; Sutton, P.; Donaldson, R. Clin. Sci. 1985, 69, 631–636; (b) Foster,
R. T.; Carr, R. A. Anal. Profiles Drug Subst. Excip. 1992, 21, 501–533; (c) Midha, K.