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Synlett 2004(14): 2636-2638  
DOI: 10.1055/s-2004-832846
LETTER
© Georg Thieme Verlag Stuttgart · New York

C(6)-Alkylation of 3-Hydroxypiperidine via Reductive and Homolytic Cleavage of N,S-Acetals

Marc Bartels, Julian Zapico, Timothy Gallagher*
School of Chemistry, University of Bristol, Bristol BS8 1TS, UK
Fax: +44(117)9298611; e-Mail: t.gallagher@bristol.ac.uk;
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Publication History

Received 20 June 2004
Publication Date:
24 September 2004 (online)

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Abstract

N-Carboxymethyl 3-hydroxypiperidine (6) undergoes substitution at C(6) via reductive cleavage of N,S-acetal 8a with lithium naphthalenide (LN) and trapping of the resulting carbanionic intermediate 9 with different electrophiles to give adducts 10. N,S-Acetal 8a also undergoes C-S homolysis and trapping of the resulting radical provides an alternative entry to 2-substituted-5-­hydroxypiperidines.

Key words

piperidines - alkylation - anodic oxidation - radical

    References

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7

Procedure for Electrochemical Oxidation of 6 to 7a,b and Conversion of 7a,b to 8a,b:
A solution of N-methoxycarbonyl-3-hydroxypiperidine (6, 2.0 g, 12.60 mmol) and tetraethylammonium tosylate (189 mg, 0.63 mmol, 5 mol%) in dry MeOH (20 mL) was placed into a beaker-type undivided electrolysis cell equipped with a graphite anode and cathode. A constant current of 0.1 A (10-12 V) was passed through the solution at 15 °C until 2.34 Fmol-1 of electricity had passed (approx. 8 h). The electrolyzed solution was concentrated in vacuo and the crude product purified by flash chromatography (silica gel; hexane-EtOAc 3:1) to give 7a,b (1.26 g, 53%) as a pale yellow oil.
A mixture of 7a,b (1.0 g, 5.40 mmol) in CH2Cl2 (35 mL) was cooled to 0 °C and TsOH·H2O (1.1 g, 5.90 mmol) was added followed by thiophenol (0.74 mL, 7.00 mmol). After 2 h at 0 °C, the mixture was quenched with H2O (30 mL) and extracted with CH2Cl2 (3 × 15 mL). The organic layer was dried (Na2SO4) and concentrated in vacuo and the residue was purified by flash chromatography (hexane-EtOAc 3:2) to afford 2-phenylthio-N-carbomethoxy-3-hydroxy-piperidine (8b, 275 mg, 19%) as a mixture of diastereo-isomers and as colorless oil. Continued elution gave 2-phenylthio-N-carbomethoxy-5-hydroxypiperidine (8a, 880 mg, 61%) as a mixture of diastereoisomers and as a colorless oil.

8

1H NMR and 13C NMR data for the cis and trans isomers of 8a are presented here, and 1H NMR assignments are based on a COSY analysis. While it was possible to separate the cis and trans isomers of 8a, but we have been unable to individually and unambiguously assign configurations to these compounds. Isomer A: 1H NMR (300 MHz, CDCl3, some doubling due to rotameric populations): δ = 1.72-2.12 (4 H, m, 3-H2 and 4-H2), 3.10-3.32 (4 H, m, 6-H and OMe), 3.61 (1 H, m, 5-H), 3.99, 4.31 (1 H, br s, 6-H), 5.66, 6.08 (1 H, br s, 2-H), 7.21-7.56 (5 H, m). 13C NMR (75 MHz, CDCl3): δ = 28.8, 29.2, 44.8, 45.5, 52.5, 61.1, 62.1, 66.8, 128.8, 132.6, 133.8, 135.3, 155.5. Isomer B: 1H NMR (300 MHz, CDCl3, some doubling due to rotameric populations): δ = 1.47-2.50 (4 H, m, 3-H2 and 4-H2), 3.02-3.81 (5 H, m, 6-H and OMe), 3.89, 4.12 (1 H, br s, 6-H), 5.79, 6.10 (1 H, br s, 2-H), 7.26-7.51 (5 H, m). 13C NMR (75 MHz, CDCl3): δ = 24.4, 25.9, 44.4, 44.9, 52.4, 62.1, 63.1, 63.8, 127.9, 128.8, 131.9, 132.7, 156.4. Both isomers of 8a gave satisfactory HRMS data.
1H NMR and 13C NMR data for 8b (mixture of diastereomers): 1H NMR (300 MHz, CDCl3, also some doubling due to rotameric populations): δ = 7.72-7.19 (10 H, m, Ar), 6.15-5.49 (2 H, 4 × br s, 2-H), 4.24-3.51 (6 H, m, 3-H and 6-H2), 3.23 (6 H, br s, OCH3) and 2.15-1.48 (8 H, m, 4-H2 and 5-H2). 13C NMR (75 MHz, CDCl3): δ = 156.4, 155.5, 135.0, 134.6, 133.3, 132.9, 129.3, 129.0, 128.9, 127.5, 72.2, 70.7, 69.3, 67.3, 52.9, 52.4, 39.3, 38.3, 29.4, 23.9, 23.4. Compound 8b also gave satisfactory HRMS data.

9

Typical Experimental Procedure: N,S-Acetal 8a (149 mg, 0.56 mmol) in THF (5 mL) was cooled to -78 °C and BuLi (0.28 mL, 2 M in hexanes, 0.56 mmol) was added slowly followed after 2 min by freshly prepared lithium naphthalenide (2.23 mL, 1 M in THF, 2.23 mmol) [prepared from Li metal (70.0 mg, 10.0 mmol) and naphthalene (1.28 g, 10.0 mmol) in THF (10 mL)]. After 2 min, allyl bromide (0.24 mL, 338 mg, 2.79 mmol) was added and the mixture was stirred for 1 h at -78 °C, then slowly warmed to r.t. After addition of 10 mL of H2O, the organic layer was separated and the aqueous layer extracted with EtOAc (3 × 10 mL). The combined organic layers were dried (Na2SO4), concentrated and the residue was purified by flash chromatography (silica gel, hexane-EtOAc 5:1) to give trans-10a (52 mg, 46%) and cis-10a (16 mg, 14%). trans-10a: 1H NMR (300 MHz, CDCl3): δ = 2.08-1.38 (4 H, m, 3-H2 and 4-H2), 2.24 (1 H, m, 1′-H) 2.38 (1 H, m, 1′-H), 3.04 (1 H, dd, J = 14.1 and 1.2 Hz, 6-H ax ), 3.69 (3 H, s, OCH3), 3.96 (1 H, br s, 5-H), 4.06 (1 H, br d, J = 14.6 Hz, 6-H eq ), 4.32 (1 H, br s, 2-H), 5.10-5.01 (2 H, m, 3′-H2) and 5.73 (1 H, ddd, J = 17.2, 10.5 and 7.1 Hz, 2′-H). 13C NMR (100 MHz, CDCl3): δ = 26.0, 28.5, 34.1, 45.6, 49.4, 52.6, 67.2, 117.2, 134.8, 156.4. MS (CI): m/z calcd for C10H18NO3 [MH+]: 200.1287; found: 200.1277. cis-10a: 1H NMR (300 MHz, CDCl3): δ = 1.92-1.42 (4 H, m, 3-H2 and 4-H2), 2.25 (1 H, m, 1′-H), 2.39 (1 H, m, 1′-H), 2.62 (1 H, dd, J = 13.1 and 10.9 Hz, 6-H ax ), 3.60 (1 H, m, 5-H), 3.68 (3 H, s, OCH3), 4.31-4.08 (2 H, m, 6-H eq and 2-H), 5.14-4.98 (2 H, m, 3′-H2) and 5.17 (1 H, ddt, J = 17.2, 10.5 and 7.2 Hz, 2′-H). 13C NMR (100 MHz, CDCl3): δ = 21.3, 25.5, 34.0, 45.1, 50.8, 52.7, 64.4, 117.1, 135.0, 157.0. MS (CI): m/z calcd for C10H18NO3 [MH+]: 200.1287; found: 200.1283. The environment (chemical shift and coupling constants) associated with 6-H ax is a useful diagnostic probe for cis/trans stereochemistry in this and related disubstituted piperidines.10

11

N,S-Acetal 8a also provided access to the corresponding N-acyl imimium ion under Lewis acid-mediated conditions. Accordingly, reaction of 8a with allyl trimethylsilane in the presence of TMSOTf gave 10a as a 6:1 mixture of cis and trans isomer in a combined yield of 77%. Note that under these conditions, cis-10a predominated.

12

Radical addition adducts 10d-f were obtained as approx. 1:1 mixtures of cis and trans isomers which were separable by chromatography. Styrene is generally a poor trap for nucleophilic radicals, and the major byproduct in this case was 6.