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Synlett 2009(12): 1923-1928  
DOI: 10.1055/s-0029-1217538
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Synthesis of β-Amino Alcohols via the Reduction of Lactamides Derived from Ethyl (2S)-Lactate with Borane-Methyl Sulfide

Frank W. Lewis, Matthias C. Eichler, David H. Grayson*
Centre for Synthesis and Chemical Biology, University Chemical Laboratory, Trinity College, Dublin 2, Ireland
Fax: +353(1671)2826; e-Mail: dgrayson@tcd.ie;
Further Information

Publication History

Received 30 March 2009
Publication Date:
03 July 2009 (online)

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Abstract

Reactions of ethyl (2S)-lactate with various amines affords lactamides that are reduced with borane-methyl sulfide in the presence of boron trifluoride etherate to generate enantiomerically pure β-amino alcohols in good yield.

Key words

lactamides - borane-methyl sulfide - amino alcohols - asymmetric synthesis - reductions

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1

New address: F. W. Lewis, Department of Chemistry, University of Reading, Whiteknights, Reading RG6 6AD, UK.

12

Cost per gram from Aldrich Chemical Company: ethyl (2S)-lactate: £0.05; (2S)-2-methyloxirane: £8.66.

17

Synthesis of Lactamides 8a-n - General Procedure
Ethyl (2S)-lactate (7, 88.2 mmol, 1 equiv) and the appropriate amine (114.6 mmol, 1.3 equiv) were placed in a flask and heated under reflux for 24 h. The solution was allowed to cool to r.t., the volatiles were removed under reduced pressure (1.33˙10-4 bar), and the lactamide was purified by vacuum distillation or recrystallization. For the synthesis of bislactamides 8k and 8l, 0.5 equiv of amine were used. Compounds 8a-d,f-j,l-n are known.²0 Characterization Data for 8e
Yellow oil, bp 101-104 ˚C (1.33˙10-4 bar). [α]D ¹6 -16.6 (c 1.31, CHCl3). IR (neat): 3308 (OH, NH), 2978, 1655 (C=O), 1532, 1457, 1364, 1275, 1124, 1048, 978 cm-¹. ¹H NMR (400.1 MHz, CDCl3): δ = 6.90 (s, 1 H, exch. D2O, NH), 4.18 (q, J = 6.5 Hz, 1 H, CHOH), 3.84 (br s, 1 H, exch. D2O, OH), 2.67-2.74 (m, 1 H, CH), 1.39 (d, J = 6.5 Hz, 3 H, CH3), 0.72-0.84 (m, 2 H, CH2), 0.46-0.58 (m, 2 H, CH2). ¹³C NMR (100.6 MHz, CDCl3): δ = 176.1 (C=O), 67.7 (CHOH), 21.6 (CH), 20.6 (CH3), 5.9 (CH2), 5.8 (CH2). HRMS (EI, MeOH): m/z calcd for C6H11NO2 [M + Na]+: 152.0687; found: 152.0680.
Characterization Data for 8k
White solid, mp 97-98 ˚C (10% EtOH in THF). [α]D ¹6 -24.7 (c 1.96, MeOH). IR (Nujol): 3323 (OH), 3086 (NH), 2926, 1662 (C=O), 1561, 1458, 1368, 1310, 1274, 1223, 1129, 1079, 937 cm-¹. ¹H NMR (400.1 MHz, DMSO-d 6): δ = 7.81 (s, 1 H, exch. D2O, NH), 5.48 (s, 1 H, exch. D2O, NH), 3.94 (q, J = 6.5 Hz, 2 H, 2 × CHOH), 3.36 (br s, 2 H, exch. D2O, 2 × OH), 3.16 (app t, J = 2.5 Hz, 4 H, 2 × CH 2NH), 1.19 (d, J = 6.5 Hz, 6 H, 2 × CH3). ¹³C NMR (100.6 MHz, DMSO-d 6): δ = 174.8 (2 × C=O), 67.2 (2 × CHOH), 38.2 (2 × CH2NH), 21.0 (2 × CH3). HRMS (EI, MeOH): m/z calcd for C8H16N2O4 [M + Na]+: 227.1008; found: 227.1010.

18

Synthesis of β-Amino Alcohols 9a-n - General Procedure
The lactamide 8 (23.7 mmol, 1 equiv) was dissolved in dry 1,2-dimethoxyethane (15 mL/g) in an oven-dried flask equipped with a Dean-Stark trap and reflux condenser under a nitrogen atmosphere. Boron trifluoride etherate (47.5 mmol, 2 equiv) was added, and then borane-methyl sulfide (47.5 mmol, 2 equiv) was added dropwise via syringe. Once the evolution of H2 had ceased, the solution was heated under reflux for 24 h (ca. 2-3 mL of distillate collected) and the solvents were removed in vacuo. The resulting colorless oil was carefully diluted with 6 M HCl (15 mL/g) and boiled for ca. 5 min. The resulting clear solution was neutralized while still hot with 6 M NaOH (15 mL/g) and then allowed to cool to r.t. before being saturated with solid K2CO3 and extracted with CHCl3 (3 × 50 mL). The combined organic extracts were dried over MgSO4 and evaporated to afford the crude β-amino alcohol 9 which was purified by vacuum distillation or recrystallization. In the case of bislactamides 8k and 8l, 4 equiv of both boron trifluoride etherate and borane-methyl sulfide were used. Compounds 9a-d,f-k are known.²¹ Characterization Data for 9e
Colorless liquid, bp 76 ˚C (1.33˙10-² to 2.66˙10-² bar). [α]D ¹6 +41.9 (c 4.95, CHCl3). IR (neat): 3307 (OH, NH), 2965, 2931, 1451, 1373, 1141, 1103, 1066, 1015, 917, 816 cm-¹. ¹H NMR (400.1 MHz, CDCl3): δ = 3.79 (dqd, J = 10.0, 6.5, 3.0 Hz, 1 H, CHOH), 2.83 (dd, J = 12.0, 3.0 Hz, 1 H, CH 2NH), 2.50 (dd, J = 12.0, 10.0 Hz, 1 H, CH 2NH), 2.28 (br s, 2 H, exch. D2O, OH and NH), 2.13-2.18 (m, 1 H, CH), 1.16 (d, J = 6.5 Hz, 3 H, CH3), 0.41-0.51 (m, 2 H, CH2), 0.29-0.40 (m, 2 H, CH2). ¹³C NMR (100.6 MHz, CDCl3): δ = 65.0 (CHOH), 56.4 (CH2NH), 29.8 (CH), 19.9 (CH3), 6.5 (CH2), 5.4 (CH2). Anal. Calcd for C6H13NO: C, 62.61; H, 11.30; N, 12.17. Found: C, 62.39; H, 11.58; N, 11.95.
Characterization Data for 9l
White solid, mp 83-84 ˚C (CHCl3). [α]D ¹7 +34.2 (c 3.99, CHCl3). IR (Nujol): 3273 (OH), 3181 (NH), 2914, 1456, 1366, 1135, 1084, 985, 935, 900, 846 cm-¹. ¹H NMR (400.1 MHz, CDCl3): δ = 3.80 (dqd, J = 9.5, 6.0, 3.0 Hz, 2 H, 2 × CHOH), 2.93 (br s, 4 H, exch. D2O, 2 × NH and 2 × OH), 2.70 (dd, J = 12.0, 3.0 Hz, 2 H, CH 2CHOH), 2.53-2.70 (m, 4 H, 2 × CH 2NH), 2.42 (dd, J = 12.0, 9.5 Hz, 2 H, CH 2CHOH), 1.46-1.57 (m, 4 H, 2 × CH 2CH2NH), 1.31-1.39 (m, 4 H, 2 × CH 2CH2CH2NH), 1.16 (d, J = 6.0 Hz, 6 H, 2 × CH3). ¹³C NMR (100.6 MHz, CDCl3): δ = 65.3 (2 × CHOH), 56.8 (2 × CH2NH), 49.4 (2 × CH2CHOH), 29.8 (2 × CH2CH2NH), 27.0 (2 × CH2CH2CH2NH), 20.7 (2 × CH3). HRMS (EI, MeOH): m/z calcd for C12H28N2O2 [M + H]+: 233.2229; found: 233.2234.
Characterization Data for 9m
Colorless liquid, bp 62 ˚C (1.33˙10-4 bar). [α]D ¹6 +34.2 (c 3.61, CHCl3). IR (neat): 3304 (OH, NH), 2942, 2818, 1460, 1370, 1277, 1129, 1055, 846, 778 cm-¹. ¹H NMR (400.1 MHz, CDCl3): δ = 3.78 (dqd, J = 9.5, 6.0, 3.0 Hz, 1 H, CHOH), 2.65-2.78 (m, 3 H, CH 2CHOH and CH 2NH), 2.42 (dd, J = 12.0, 9.5 Hz, 1 H, CH 2CHOH), 2.37-2.46 [m, 2 H, CH 2N(CH3)2], 2.23 [s, 6 H, N(CH3)2], 1.15 (d, J = 6.0 Hz, 3 H, CH3). ¹³C NMR (100.6 MHz, CDCl3): δ = 65.1 (CHOH), 58.7 [CH2N(CH3)2], 56.5 (CH2CHOH), 46.3 (CH2NH), 45.0 [N(CH3)2], 20.0 (CH3). HRMS (EI, MeOH): m/z calcd for C7H18N2O [M + H]+: 146.1181; found: 146.1187.
Characterization Data for 9n
Colorless liquid, bp 72-76 ˚C (1.33˙10-4 bar). [α]D ¹6 +37.2 (c 1.68, CHCl3). IR (neat): 3303 (OH, NH), 2941, 2816, 1461, 1372, 1265, 1127, 1061, 839 cm-¹. ¹H NMR (400.1 MHz, CDCl3): δ = 3.79 (dqd, J = 9.5, 6.3, 3.0 Hz, 1 H, CHOH), 2.70 (dd, J = 12.1, 3.0 Hz, 1 H, CH 2CHOH), 2.61-2.75 (m, 2 H, CH 2NH), 2.41 (dd, J = 12.1, 9.5 Hz, 1 H, CH 2CHOH), 2.34 [t, J = 7.2 Hz, 2 H, CH 2N(CH3)2], 2.23 [s, 6 H, N(CH 3)2], 1.66 (q, J = 7.0 Hz, 2 H, CH2), 1.15 (d, J = 6.3 Hz, 3 H, CH3). ¹³C NMR (100.6 MHz, CDCl3): δ = 65.3 (CHOH), 57.7 [CH2N(CH3)2], 56.7 (CH2CHOH), 47.6 (CH2NH), 45.5 [N(CH3)2], 27.9 (CH2), 20.4 (CH3). HRMS (EI, MeOH): m/z calcd for C8H20N2O [M + H]+: 161.1654; found: 161.1646.