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

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

• 1a Buffat MGP. Tetrahedron  2004,  60:  1701 
• 1b Weintraub PM. Sabol JS. Kane JA. Borcherding DR. Tetrahedron  2003,  59:  2953 
• 1c Laschat S. Dickner T. Synthesis  2000,  1781 
• 1d Bailey PD. Millwood PA. Smith PD. J. Chem. Soc., Chem. Commun.  1998,  633 
• 2a Sunose M. Peakman TM. Charmant JPH. Gallagher T. Macdonald SJF. J. Chem. Soc., Chem. Commun.  1998,  1723 
• 2b For earlier work which incorrectly assigned the regiochemistry of the lithiation of 1, see: Pandey G. Chakrabarti D. Tetrahedron Lett.  1996,  37:  2285.  See also: Pandey G. Lakshmalah G. Synlett  1994,  277 
• 3 Beak P. Lee WK. J. Org. Chem.  1993,  58:  1109 
• 4a Shono T. In Best Synthetic Methods   Katritzky AR. Meth-Cohn O. Rees CW. Academic Press; London: 1991.  p.63 
• 4b Matsumura Y. Kanda Y. Shirai K. Onomura O. Maki T. Tetrahedron  2000,  56:  7411 
• 4c Barrett AT. Pilipauskas D. J. Org. Chem.  1991,  56:  2787 
• 4d Shono T. Matsumura Y. Tsubata K. J. Am. Chem. Soc.  1981,  103:  1172 
• 4e Shono T. Hamaguchi H. Matsumura Y. J. Am. Chem. Soc.  1975,  97:  4264 
• The anodic oxidation of N-carboxymethyl 3-hydroxy-pyrrolidine has been described and exploited for the synthesis of pyrrolizidine alkaloids:
• 5a Thaning M. Wistrand L.-G. Acta Chem. Scand.  1989,  53:  290 
• 5b A 1:1 mixture of regioisomers was obtained, analogous to oxidation of 6 leading to 7a and 7b. See: Thaning M. Wistrand L.-G. J. Org. Chem.  1990,  55:  1406 
• 6a Chiba T. Takata Y. J. Org. Chem.  1977,  42:  2973 
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• 13 The N,Se-acetal corresponding to 8a is generated from 7a,b under similar conditions to those used for 8a and 8b and has also been used as a source of a nucleophilic α-aza radical by C-Se homolysis to provide 10d-f in similar yields to those obtained from 8a. The use of an N,Se-acetal as a source of nucleophilic radical reactivity adjacent to nitrogen within a pyrrolidine framework has been described. See: Barrett AGM. Pilipauskas D. J. Org. Chem.  1991,  56:  2787 

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.