Direct Chemo-, Regio-, and Diastereoselective Synthesis of β-Keto Ethers from Acrylonitrile by Cascade Aldol/Oxo-Michael Reaction with Cyclododecanone

Abstract

This paper describes the utility of mild metal hydroxides for the catalytic chemo-, regio-, and diastereoselective transformation of cyclododecanone into β-keto ethers through a cascade aldol/oxo-­Michael reaction. The choice of acrylonitrile as a co-reactant is critical in achieving chain extension in the C–C bond-formation reaction. Metal hydroxides are effective catalysts for delivering a single product in a high yield (≤86%), and with excellent diastereoselectivity (≤95:5) under solvent-free conditions.

Key words

cascade reaction - aldol reaction - oxo-Michael reaction - solvent-free - cyclododecanone - acrylonitrile

• References and Notes

• 1a Resconi L, Cavallo L, Fait A, Piemontesi F. Chem. Rev. 2000; 100: 1253-1253
• 1b Mlynarski CS, Schuster HC, Morken PJ. Nature 2014; 505: 386-386
• 2 Gray KW, Smail RF, Hitzler GM, Ross KS, Poliakoff M. J. Am. Chem. Soc. 1999; 121: 10711-10711
• 3a Smith MB, March J. March’s Advanced Organic Chemistry: Reactions, Mechanism, and Structure. 5th ed. Wiley; New York: 2001
• 3b Baggett N. In Comprehensive Organic Chemistry . Vol. 1. Barton DH. R, Ollis WD. Pergamon; Oxford: 1979: 799
• 4 Garavelas A, Mavropoulos I, Perlmutter P, Westman G. Tetrahedron Lett. 1995; 36: 463-463
• 5a Hartwig JF. Angew. Chem. Int. Ed. 1998; 37: 2046-2046
• 5b Ley SV, Thomas AW. Angew. Chem. Int. Ed. 2003; 42: 5400-5400
• 5c Maligres PE, Li J, Krska SW, Schreier DJ, Raheem IR. Angew. Chem. Int. Ed. 2012; 51: 9071-9071
• 6a Rosenfeld CD, Shekhar S, Takemiya A, Utsunomiya M, Hartwig FJ. Org. Lett. 2006; 8: 4179-4179
• 6b Tejero J, Creus E, Iborra M, Cunill F, Izquierdo FJ, Fité C. Catal. Today 2001; 65: 381-381
• 6c Fité C, Tejero J, Iborra M, Cunill F, Izquierdo JF, Parra D. Appl. Catal., A 1998; 169: 165-165
• 6d Verevkin SP, Krasnykh EL, Vasitsova TV, Heintz A. J. Chem. Eng. Data 2003; 48: 591-591
• 6e Klepáčová K, Mravec D, Kazonyi A, Bajus M. Appl. Catal., A 2007; 328: 1-1
• 6f Liu JF, Yi PG, Qi YS. J. Mol. Catal. A: Chem. 2001; 170: 109-109
• 6g Patrini R, Lami M, Marchinna M, Benvenuti F, Galleti AM. R, Sbrana G. J. Mol. Catal. A: Chem. 1998; 129: 179-179
• 7a Sathesh V, Umamahesh B, Ramachandran G, Rathore RS, Sathiyanarayanan KI. New J. Chem. 2012; 36: 2292-2292
• 7b Sathesh V, Karthikeyan NS, Rathore RS, Giridharan P, Sathiyanarayanan KI. Med. Chem. Res. 2014; 23: 5086-5086
• 7c Sathesh V, Sathiyanarayanan KI. New J. Chem. 2016; 40: 3833-3833
• 7d Goodman MJ, Hoffman HM. R, Vinte GJ. Tetrahedron Lett. 1995; 36: 7757-7757
• 7e Rawdah TN. Tetrahedron 1991; 47: 8579-8579
• 7f Rawdah TN. Tetrahedron 1990; 46: 4101-4101
• 7g Ledaal L. Tetrahedron Lett. 1968; 9: 651-651
• 7h Tsuritani T, Ito S, Shinokubo H, Oshima K. J. Org. Chem. 2000; 65: 5066-5066
• 8a Harmange J.-C, Figadère B. Tetrahedron: Asymmetry 1993; 4: 1711-1711
• 8b Cardillo G, Orena M. Tetrahedron 1990; 46: 3321-3321
• 8c Hanessian S, Cooke GN, DeHoff B, Sakito Y. J. Am. Chem. Soc. 1990; 112: 5276-5276
• 8d Evans DA, Dow RL, Shih LT, Takacs JM, Zahler R. J. Am. Chem. Soc. 1990; 112: 5290-5290
• 9 Bratt K, Garavelas A, Perlmutter P, Westman G. J. Org. Chem. 1996; 61: 2109-2109
• 10a Haibach MC, Guan C, Wang DY, Li B, Lease N, Steffens AM, Krogh-Jespersen K, Goldman AS. J. Am. Chem. Soc. 2013; 135: 15062-15062
• 10b Yi CS, Yun SY, He Z. Organometallics 2003; 22: 3031-3031
• 11 Sathesh V, Sathishkumar M, Ramachandran G, Rathore RS, Sathiyanarayanan KI. RSC Adv. 2013; 3: 23035-23035
• 12 β-Keto Ethers 5a–m; General ProcedureA dry conical flask equipped with a stopcock and mechanical stirrer was charged with cyclododecanone (1; 5 mmol), the appropriate aryl aldehyde 2 (5 mmol), acrylonitrile (3; 15 mmol), and NaOH (1 mol%). The mixture was stirred at r.t. while the reaction was monitored by TLC. The mixture was then neutralized with 0.1 M aq HCl and extracted with CHCl₃ (2 × 15 mL). The organic layer was dried (Na₂SO₄) and concentrated under vacuum to give a crude product that was purified by crystallization from a mixture of solvents. anti-3-[(2-Oxocyclododecyl)(phenyl)methoxy]propanenitrile (5a)The crude white solid was crystallized from 1:1 CHCl₃–EtOH; yield: 1.35 g (79%; dr 98:2); mp 89–91 °C; R_f = 0.5 (hexane–EtOAc, 4:1). FTIR (KBr): 3025, 2927, 2250, 1701 (C=O), 1620, 1105 (C–O_ether) cm^–1. ¹ H NMR (400 MHz, CDCl₃): δ = 7.35 (d, J = 8 Hz, 2 H, Ar–CH), 7.26 (d, J = 8 Hz, 3 H, Ar-CH), 4.36 (d, J = 8 Hz, 1 H, β-CH*), 3.71–3.36 (m, 2 H, β-CH*–O–CH₂), 2.91 (t, J = 20 Hz, 1 H, α-CH*), 2.83–2.77 (m, 1 H, CH₂–CN), 2.62–2.50 (m, 1 H, CH₂–CN), 2.49–2.40 (m, 2 H, α′-CH₂), 2.16 (s, 1 H, β-CH₂), 1.83 (s, 1 H, β-CH₂), 1.67 (s, 1 H, CH_2ali), 1.43–1.23 (m, 13 H, CH_2ali), 1.05 (s, 2 H, CH_2ali). ¹³C NMR (100 MHz, CDCl₃): δ = 213.0 (C=O), 137.5 (Ar-C), 134.5, 129.1, 129.0, 117.7 (CN), 83.5 (β-CH*), 63.3 (–OCH₂), 57.9 (α-CH*), 40.4 (α′-CH_2ali-ring), 31.0, 26.9, 26.4, 26.1, 24.3, 24.2, 22.9, 22.3, 21.8 (β′-CH_2ali-ring), 18.8 (CH₂–CN). HRMS (EI): m/z [M⁺] calcd for C₂₂H₃₁NO₂: 341.2355; found: 341.2349.