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

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

• 1a Li Z.-H. Bulychev A. Kotra LP. Massova I. Mobashery S. J. Am. Chem. Soc.  1998,  120:  13003 
• 1b Seebach D. Schaeffer L. Brenner M. Hoyer D. Angew. Chem. Int. Ed.  2003,  42:  776 
• 2 Langenhan JM. Gellman SH. J. Org. Chem.  2003,  68:  6440 
• 3a Meissner RS. Perkins JJ. Duong LT. Hartman GD. Hoffman WF. Huff JR. Ihle NC. Leu C.-T. Nagy RM. Naylor-Olsen A. Rodan GA. Rodan SB. Whitman DB. Wesolowski GA. Duggan ME. Bioorg. Med. Chem. Lett.  2002,  12:  25 
• 3b Ting PC. Lee JF. Anthes JC. Shih N.-Y. Bioorg. Med. Chem. Lett.  2001,  11:  491 
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• 4b Appleby I. Boulton LT. Cobley CJ. Hill C. Hughes ML. De Koning PD. Lennon IC. Praquin C. Ramsden JA. Samuel HJ. Willis N. Org. Lett.  2005,  7:  1931 
• 5a Yue T.-Y. Nugent WA. J. Am. Chem. Soc.  2002,  124:  13692 
• 5b Suh Y.-G. Kim S.-A. Jung J.-K. Shin D.-Y. Min K.-H. Koo B.-A. Kim H.-S. Angew. Chem. Int. Ed.  1999,  38:  3545 
• 5c Enders D. Groebner R. Raabe G. Runsink J. Synthesis  1996,  941 
• 6 Trost BM. Kunz RA. J. Org. Chem.  1974,  39:  2475 
• 7 Menezes R. Smith MB. Synth. Commun.  1988,  18:  1625 
• 8 Lactim ethers 1, 15 and 16 were prepared using a protocol previously employed to prepare bis-lactim ether 8, see: Bull SD. Davies SG. Moss WO. Tetrahedron: Asymmetry  1998,  9:  321 
• 9 Schöllkopf U. Hartwig W. Pospischil KH. Kehne H. Synthesis  1981,  966 
• 10 Zezza CA. Smith MB. Ross BA. Arhin A. Cronin PLE. J. Org. Chem.  1984,  49:  4397 
• 15 An alternative mechanism involving hydrolysis of 13 to its corresponding α,α-dialkyl-ω-amino ester hydrochloride, followed by in situ ring closure to afford 20 was discounted because α,α-dialkyl-ω-amino ester hydrochloride salts are known to be stable under acidic conditions, see: Maligres PE. Chartrain MM. Upadhyay V. Cohen D. Reamer RA. Askin D. Volante RP. Reider PJ. J. Org. Chem.  1998,  63:  9548 

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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.

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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, H_5A), 1.56-1.76 (2 H, br m, H_4A and H_5B), 1.83-1.88 (1 H, m, H_4B), 1.92 (1 H, t, J = 2.6 Hz, CºCH), 2.34 (2 H, m, CH _A H_BCºCH and H₃), 2.52 (1 H, app ddd, J = 12.6 Hz, 7.4 Hz, 2.6 Hz, CH_A 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, H_4A), 1.51-1.81 (3 H, br m, H_4B 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 H_BPh), 3.17-3.25 (2 H, m, 2 × H₆), 3.34 (1 H, dd, J = 13.4, 3.6 Hz, CH_A 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.

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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.

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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.

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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 K₂CO_{3( 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.