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Synlett 2006(9): 1347-1350  
DOI: 10.1055/s-2006-939726
LETTER
© Georg Thieme Verlag Stuttgart · New York

An Aza-Enolate Alkylation Strategy for the Synthesis of α-Alkyl-δ-amino Esters and α-Alkyl Valerolactams

Piers J. M. Taylora, Steven D. Bull*a, Philip C. Andrewsb
a Department of Chemistry, University of Bath, Bath, BA2 7AY, UK
Fax: +44(1225)386231; e-Mail: s.d.bull@bath.ac.uk;
b School of Chemistry, Monash University, P.O. Box 23, Clayton, Melbourne, Vic. 3800, Australia
Further Information

Publication History

Received 13 February 2006
Publication Date:
22 May 2006 (online)

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Abstract

Alkylation of the aza-enolate of valerolactim methyl ether with electrophiles affords α-alkyl lactims that may be hydro­lysed under mild acidic conditions to afford their corresponding α-alkyl-δ-amino esters as their hydrochloride salts. Neutralisation of these salts with base results in smooth intramolecular cyclisation to afford their corresponding α-alkyl lactams in excellent yield.

Key words

lactim ether - aza-enolate - alkylation - α-alkyl-δ-amino ester - α-alkyl lactams

    References and Notes

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11

Representative Experimental Procedure.
A solution of t-BuLi in hexane (1.1 equiv) was added to a stirred solution of lactim ether 1 (1 equiv, 2.0 mmol) in THF (10 mL) at -78 °C under nitrogen. The reaction was warmed to 0 °C for 15 min, recooled to -78 °C, an electrophile (3 equiv) added dropwise and the reaction was allowed to warm to r.t. overnight. The reaction was quenched with H2O (pH >8), extracted with Et2O (3×), dried (MgSO4), and concentrated in vacuo before Kugelrohr distillation in vacuo to afford α-alkyl lactim ethers 5.

12

All new compounds were fully characterised. Selected data for new compounds follows.
3,4,5,6-Tetrahydro-2-methoxy-3-(prop-2-ynyl)pyridine ( 5d). 1H NMR (300 MHz, CDCl3): δ = 1.39-1.55 (1 H, br m, H5A), 1.56-1.76 (2 H, br m, H4A and H5B), 1.83-1.88 (1 H, m, H4B), 1.92 (1 H, t, J = 2.6 Hz, CºCH), 2.34 (2 H, m, CH A HBCºCH and H3), 2.52 (1 H, app ddd, J = 12.6 Hz, 7.4 Hz, 2.6 Hz, CHA H BCºCH), 3.36-3.45 (2 H, m, 2 × H6), 3.54, (3 H, s, OMe). 13C NMR (100 MHz, CDCl3): δ = 21.7, 22.0, 26.2, 35.9, 47.4, 52.5, 70.2, 82.1, 163.2. HRMS (EI): m/z calcd [MH]+: 152.1070; found: 152.1070.
Methyl 5-Amino-2-methylpentanoate Hydrochloride ( 6b): 1H NMR (300 MHz, CD3OD): δ = 1.07 (3 H, d, J = 7.0 Hz, CHCH 3), 1.30-1.68 (4 H, br m, 2 × CH 2), 2.41 (1 H, app hept, J = 7.0 Hz, CHCH3), 2.80 (2 H, t, J = 6.8 Hz, CH 2NH2), 3.56 (3 H, s, OCH3). 13C NMR (100 MHz, CD3OD): δ = 17.9, 26.7, 31.8, 40.5, 41.0, 52.6, 178.6. HRMS (EI): m/z calcd [MH]+: 146.1176; found: 146.1172.
3-Benzylpiperidin-2-one ( 7a): 1H NMR (300 MHz, CDCl3): δ = 1.32-1.46 (1 H, br m, H4A), 1.51-1.81 (3 H, br m, H4B and 2 × H5), 2.48 (1 H, tdd, J = 10.0, 5.5, 3.8 Hz, H3), 2.61 (1 H, dd, J = 13.4, 10.0 Hz, CH A HBPh), 3.17-3.25 (2 H, m, 2 × H6), 3.34 (1 H, dd, J = 13.4, 3.6 Hz, CHA H B Ph), 5.76 (1 H, br s, NH), 7.10-7.27 (5 H, br m, Ar-H). 13C NMR (100 MHz, CDCl3): δ = 18.5, 22.1, 30.3, 37.5, 48.8, 127.9, 130.0, 130.8, 141.3, 179.3. HRMS (EI): m/z calcd [MH]+: 190.1229; found: 190.1226.

13

Numerous attempts to alkylate the aza-enolate of eight-membered enantholactim methyl ether using a range of bases and conditions with benzyl bromide as an electrophile were unsuccessful, returning unreacted starting material in good yield.

14

Representative Experimental Procedure.
An α-alkyl lactim ether 5 (0.125 mmol) was dissolved in CHCl3 (1.5 mL) and then 0.1 M aq HCl (1.5 mL) added. The resultant biphasic solution was stirred rapidly overnight, before solvents were removed in vacuo to afford a δ-amino-α-alkyl methyl ester hydrochloride salt 6.

16

Representative Experimental Procedure.
A δ-amino-α-alkyl methyl ester hydrochloride salt 6 (0.018 mmol) was dissolved in MeOH (0.6 mL) and then added to a solution of K2CO3( aq) (0.2 mL) before stirring for 24 h. The resulting solution was neutralised to pH 7.0, extracted with EtOAc, dried (MgSO4) and the solvent was removed in vacuo to afford the desired α-alkyl lactam 7.