Tertiary Amine Promoted Aziridination: Preparation of NH-Aziridines from Aliphatic α,β-Unsaturated Ketones

Dedicated to Professor Steven V. Ley on the occasion of his 70^th birthday

Abstract

trans-NH-Aziridines were prepared from aliphatic α,β-unsaturated ketones using a tertiary amine promoted reaction via in situ generated N,N-ylides. Through use of modified conditions the reaction proved to be applicable for the diastereoselective aziridination of a range of enolisable aliphatic α,β-unsaturated ketones of varying substitution patterns.

Key words

aziridines - organocatalysis - enones - aminimine - ylides - stereoselective

• References and Notes

• 1 Current address: Dr. R. D. C. Pullin, Vertex Pharmaceuticals (Europe) Ltd., 86-88 Jubilee Avenue, Milton Park, Abingdon, Oxfordshire, OX14 4RW, UK.
• 2 For a review, see: Lowden PA. S. In Aziridines and Epoxides in Organic Synthesis . Yudin AK. Wiley-VCH; Weinheim: 2006: 399

For reviews see:
• 3a McCoull W, Davis FA. Synthesis 2000; 1347
• 3b Hu XE. Tetrahedron 2004; 60: 2701

For recent reviews, see:
• 4a Pellissier H. Tetrahedron 2010; 66: 1509
• 4b Pellissier H. Adv. Synth. Catal. 2014; 356: 1899
• 4c Degennaro L, Trinchera P, Luisi R. Chem. Rev. 2014; 114: 7881

For selected examples, see:
• 5a Evans DA, Faul MM, Bilodeau MT, Anderson BA, Barnes DM. J. Am. Chem. Soc. 1993; 115: 5328
• 5b Gillespie KM, Sanders CJ, O’Shaughnessy P, Westmoreland I, Thickitt CP, Scott P. J. Org. Chem. 2002; 67: 3450
• 5c Wang X, Ding K. Chem. Eur. J. 2006; 12: 4568

For example:
• 6a Ma L, Du D.-M, Xu J. J. Org. Chem. 2005; 70: 10155
• 6b Ma L, Jiao P, Zhang Q, Xu J. Tetrahedron: Asymmetry 2005; 16: 3718

For examples, see:
• 7a Vesely J, Ibrahem I, Zhao GL, Rios R, Córdova A. Angew. Chem. Int. Ed. 2007; 46: 778
• 7b Arai H, Sugaya N, Sasaki N, Makino K, Lectard S, Hamada Y. Tetrahedron Lett. 2009; 50: 3329
• 7c Deiana L, Zhao G.-L, Lin S, Dziedzic P, Zhang Q, Leijonmarck H, Córdova A. Adv. Synth. Catal. 2010; 352: 3201
• 7d Deiana L, Dziedzic P, Zhao G.-L, Vesely J, Ibrahem I, Rios R, Sun J, Córdova A. Chem. Eur. J. 2011; 17: 7904
• 7e Desmarchelier A, Pereira de Sant’Ana D, Terrasson V, Campagne JM, Moreau X, Greck C, Marcia de Figueiredo R. Eur. J. Org. Chem. 2011; 4046
• 7f Molnar IG, Tanzer E.-M, Daniliuc C, Gilmour R. Chem. Eur. J. 2014; 20: 794

Isolated examples have been reported, examples include:
• 8a Fioravanti S, Pellacani L, Tabanella S, Tardella PA. Tetrahedron 1998; 54: 14105
• 8b Tung S, Yudin AK. J. Am. Chem. Soc. 2002; 124: 530
• 8c Chen D, Timmons C, Guo L, Xu X, Li G. Synthesis 2004; 2479
• 8d Zibinsky M, Stewart T, Prakash GK. S, Kuznetsov MA. Eur. J. Org. Chem. 2009; 3635
• 9 Pesciaioli F, De Vincentiis F, Galzerano P, Bencivenni G, Bartoli G, Mazzanti A, Melchiorre P. Angew. Chem. Int. Ed. 2008; 47: 8703
• 10 De Vincentiis F, Bencivenni G, Pesciaioli F, Mazzanti A, Bartoli G, Galzerano P, Melchiorre P. Chem. Asian. J. 2010; 5: 1652
• 11 Ikeda I, Machii Y, Okahara M. Synthesis 1980; 650
• 12 Xu J, Jiao P. J. Chem. Soc., Perkin Trans. 1 2002; 1491
• 13 Armstrong A, Carbery DR, Lamont SG, Pape AR, Wincewicz R. Synlett 2006; 2504
• 14a Armstrong A, Baxter CA, Lamont SG, Pape AR, Wincewicz R. Org. Lett. 2007; 9: 351
• 14b Armstrong A, Pullin RD. C, Jenner CR, Scutt JN. J. Org. Chem. 2010; 75: 3499
• 14c Armstrong A, Ferguson A. Beilstein J. Org. Chem. 2012; 8: 1747
• 14d Armstrong A, Pullin RD. C, Jenner CR, Foo K, White AJ. P, Scutt JN. Tetrahedron: Asymmetry 2014; 25: 74

See also:
• 15a Shen Y.-M, Zhao M.-X, Xu J, Shi Y. Angew. Chem. Int. Ed. 2006; 45: 8005
• 15b Page PC. B, Bordogna C, Strutt I, Chan Y, Buckley BR. Synlett 2013; 24: 2067
• 16 Diastereoselectivity determined to be >95:5 by ¹H NMR spectroscopy. The cis and trans diastereoselectivity was determined by analysis of the ³ J coupling constants of the aziridine ring; generally trans-aziridines have ³ J = 2–4 Hz, cis-aziridines ³ J = 5–9 Hz. All aziridines prepared were determined be a single dia­stereoisomer.
• 17 Fioravanti S, Mascia MG, Pellacani L, Tardella PA. Tetrahedron 2004; 60: 8073
• 18 Menjo Y, Hamajima A, Sasaki N, Hamada Y. Org. Lett. 2011; 13: 5744

For the aziridination certain cyclic enones using N,N-ylides, see:
• 19a Oves D, Ferrero M, Fernandez S, Gotor V. J. Org. Chem. 2002; 68: 1154
• 19b De SR, Ghorai SK, Mal D. J. Org. Chem. 2009; 74: 1598
• 20 Aziridine 4e was resubmitted to the reaction conditions in place of the enone substrate and was recovered in quantitative amounts.
• 21 Representative Procedure for Enone Aziridination N-Methylmorpholine (14 μL, 0.125 mmol) was added dropwise to a solution of DppONH₂ (56.0 mg, 0.24 mmol) in CH₂Cl₂ (2 mL) at r.t., and the mixture was stirred for 0.5 h. i-PrOH (28 μL, 0.36 mmol) and NaH (60% dispersion in mineral oil, 14.4 mg, 0.36 mmol) were then added sequentially followed by addition of trans-4-phenylbut-3-en-2-one (3a, 17.5 mg, 0.12 mmol) in CH₂Cl₂ (1 mL) and the mixture allowed to stir at r.t. for 16 h. The reaction was quenched by the addition of sat. aq NH₄Cl solution and the aqueous layer separated and extracted with CH₂Cl₂, dried (Na₂SO₄), filtered and concentrated in vacuo. Purification by flash column chromatography (15% EtOAc–n-hexane) afforded (2R*,3S*)-1-(3-phenylaziridin-2-yl)ethanone (4a, 15.6 mg, 80%) as a colourless oil; R_f = 0.30 (15% EtOAc–n-hexane). ¹H NMR (400 MHz, CDCl₃): δ = 7.38–7.27 (5 H, m, 5 × PhH), 3.04 (1 H, d, J = 2.0 Hz, 3-CHN), 2.86 (1 H, d, J = 2.1 Hz, 2-CHN), 2.38 (3 H, s, CH₃), 2.29 (1 H, br, NH). ¹³C NMR (100 MHz, CDCl₃): δ = 204.5, 138.2, 128.5, 127.8, 126.1, 46.8, 43.0, 29.6.