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Synlett 2004(14): 2606-2608  
DOI: 10.1055/s-2004-834827
LETTER
© Georg Thieme Verlag Stuttgart · New York

The Efficient Synthesis of Alkoxy-esters from Hydroxy Carboxylic Acids Using Dimsyllithium in Dimethylsulfoxide Followed by Alkylation with an Alkyl Halide

Philip C. Bulman Page, Yohan Chan, Harry Heaney*, Matthew J. McGrath, Eduardo Moreno
Department of Chemistry, Loughborough University, Loughborough, Leicestershire, LE11 3TU, UK
Fax: +44(1509)223926; e-Mail: h.heaney@lboro.ac.uk;
Further Information

Publication History

Received 10 August 2004
Publication Date:
20 October 2004 (online)

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Abstract

Hydroxy acids are converted directly into the related alkyl ether-alkyl esters in high yields in a single operation by ­double deprotonation using dimsyllithium in dimethylsulfoxide ­followed by treatment with an alkyl halide.

Key words

hydroxy acids - alkoxyesters - butyllithium - dimethylsulfoxide - dimsyllithium - alkyl halide

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  • 14a

    IR: νmax = 1747 cm-1. 1H NMR (400 MHz, CDCl3): δ = 1.54 (3 H, d, J = 6.9 Hz), 4.19 (1 H, q, J = 6.9 Hz), 4.53 and 4.77 (2 H, AB, J = 11.6 Hz), 5.27 and 5.28 (2 H, AB, J = 12.3 Hz), 7.39-7.45 (10, m) ppm. 13C NMR (100 MHz, CDCl3): δ = 19.2 (Me), 66.5 (CH2), 72.0 (CH2), 74.1 (CH), 127.9 (CH), 128.1 (CH), 128.3 (CH), 128.4 (CH), 128.5 (CH), 128.7 (CH), 135.9 (C), 137.7 (C), 173.0 (C=O) ppm. HRMS (FAB): m/z calcd for C17H19O3: 271.13393. Found: 271.13350 [M + 1]. [α]D -63.3 (c 1.6, CHCl3).
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13

A hexane solution of n-BuLi (83 mL, 207.0 mmol, 2.5 M. 2.1 equiv) was added carefully to anhyd DMSO (150 mL) in a 500 mL round-bottomed flask. (R)-(-)-Mandelic acid (15 g, 98.7 mmol) was added and the resulting solution was stirred under nitrogen for 2 h. MeI (32.2 g, 227.0 mmol, 2.3 equiv) was then added and the reaction mixture was stirred overnight, poured into H2O and extracted with Et2O. The combined ethereal layers were washed with brine, dried over anhyd MgSO4 and concentrated to afford (R)-(-)-methyl
2-methoxy-2-phenylacetate (17.8 g, 98.7 mmol, 100%). IR: νmax = 1740 cm-1. 1H NMR (400 MHz, CDCl3): δ = 3.41 (s, 3 H), 3.72 (s, 3 H), 4.78 (s, 1 H), 7,34-7.45 (m, 5 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 52.7, 57.8, 82.9, 127.6, 129.1, 129.2, 136.6, 171.6 (C=O) ppm. [α]D -113 (c 1.0, CHCl3). HPLC on ‘Chiracel OD-H’, eluting with hexane-propan-2-ol 99:1.

15

n-BuLi (3.7 mL, 9.25 mmol, 2.2 equiv) was added slowly to dry DMSO (7 mL) under nitrogen in a dry 25 mL round-bottomed flask. 2-Hydroxy-3-methylbutanoic acid (500 mg, 4.23 mmol, 1 equiv) in DMSO (7 mL) was then added. The solution was stirred during 2 h before MeI (630 µL, 10.16 mmol, 2.40 equiv) was added slowly. The reaction mixture was allowed to stir overnight and H2O (50 mL) and Et2O (20 mL) were then added to the mixture. The organic phase was separated, washed with brine, dried over Na2SO4 and concentrated under reduced pressure to afford the methyl
2-methoxy-3-methylbutanoate as a pale yellow liquid (620 mg, 100%). IR: νmax = 1750 cm-1. 1H NMR (400 MHz, CDCl3): δ = 0.86 (d, 3 H, J = 5.0 Hz), 0.88 (d, 3 H, J = 5.0 Hz), 1.96 (m, 1 H), 3.30 (s, 3 H), 3.44 (d, 1 H, J = 5.4 Hz), and 3.68 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 17.5 (Me), 18.5 (Me), 31.5 (CH), 51.4 (Me), 58.4 (Me), 95.9 (CH), 172.7 (C=O) ppm. HRMS (EI): m/z calcd for C7H14O3: 146.09430. Found: 146.09460.

16

IR: νmax = 1745 cm-1. 1H NMR (400 MHz, CDCl3): δ = 0.82 (3 H, d, J = 6.9 Hz), 0.84 (3 H, d, J = 6.8 Hz), 1.99 (1 H, m), 3.61 (1 H, d, J = 5.5 Hz), 4.23 and 4.55 (2 H, AB, J = 11.7 Hz), 5.04 and 5.06 (2 H, AB, J = 12.2 Hz),7.19-7.22 (10 H, m) ppm. 13C NMR (100 MHz, CDCl3): δ = 17.8 (Me), 18.9 (Me), 31.7 (CH), 66.4 (CH2), 72.5 (CH2), 83.3 (CH), 127.8 (CH), 128.1 (CH), 128.3 (8) (CH), 128.4 (2) (CH), 128.5 (CH), 128.6 (CH), 135.9 (C), 137.8 (C), and 172.3 (C=O) ppm. HRMS (FAB): m/z calcd for C17H19O3: 299.16443. Found: 299.16406 [M + 1].

17

IR: νmax = 1736 cm-1. 1H NMR (400 MHz, CDCl3): δ = 1.18 (3 H, d, J = 6.2 Hz), 2.40 and 2.61 (2 H, o, AB of ABX,
J A-B = -15.09 Hz, J A-X = 7.52 Hz, JB-X = 5.51 Hz), 3.95 (1 H, q × q, J = 6.2, 5.51, 7.52 Hz), 4.39 and 4.45 (2 H, AB, J = 11.6 Hz), 5.04 and 5.05 (2 H, AB, J = 12.3 Hz), and 7.23-7.26 (10 H, m) ppm. 13C NMR (100 MHz, CDCl3):
δ = 19.9 (Me), 42.2 (CH2), 66.4 (CH2), 70.9 (CH2), 72.2 (CH), 127.5 (CH), 127.7 (CH), 128.2 (CH), 128.2 (5) (CH), 128.3 (CH), 128.6 (CH), 136.0 (C), 138.5 (C), 171.3 (C=O) ppm. HRMS (FAB): m/z calcd for C18H21O3 285.14907. Found: 285.14941 [M + 1].