Synthesis of β-Lactams via Enantioselective Allylation of Anilines with Morita–Baylis–Hillman Carbonates

Published as part of the ISySyCat2019 Special Issue

Abstract

Enantioenriched β-lactams are accessed via enantioselective allylation of anilines with Morita–Baylis–Hillman carbonates followed by a base-promoted cyclization. The resulting 3-methyleneazetidin-2-ones are amenable to diastereoselective functionalization to produce analogues of biologically active β-lactams. The use of nearly equimolar quantities of the starting materials make this method efficient and straightforward.

Key words

β-lactams - allylic substitution - allylation - Lewis base catalysis

• References and Notes

• 1 González-Bello C, Rodríguez D, Pernas M, Rodríguez Á, Colchón E. J. Med. Chem. 2019; in press; DOI: DOI: 10.1021/acs.jmedchem.9b01279.
• 2 Yimer EM, Hishe HZ, Tuem KB. Front. Neurosci. 2019; 13: 236
• 3a O’Boyle NM, Carr M, Greene LM, Bergin O, Nathwani SM, McCabe T, Lloyd DG, Zisterer DM, Meegan MJ. J. Med. Chem. 2010; 53: 8569
• 3b O’Boyle NM, Greene LM, Bergin O, Fichet J.-B, McCabe T, Lloyd DG, Zisterer DM, Meegan MJ. Bioorg. Med. Chem. 2011; 19: 2306
• 3c Zhou P, Liang Y, Zhang H, Jiang H, Feng K, Xu P, Wang J, Wang X, Ding K, Luo C. Eur. J. Med. Chem. 2018; 144: 817
• 4 Pitts CR, Lectka T. Chem. Rev. 2014; 114: 7930
• 5a Zi Y, Lange M, Schultz C, Vilotijevic I. Angew. Chem. Int. Ed. 2019; 58: 10727
• 5b Lange M, Zi Y, Vilotijevic I. J. Org. Chem. 2019; in press; DOI: DOI: 10.1021/acs.joc.9b02819.
• 6a Ma G.-N, Jiang J.-J, Shi M, Wei Y. Chem. Commun. 2009; 5496
• 6b Basavaiah D, Reddy BS, Badsara SS. Chem. Rev. 2010; 110: 5447
• 6c Wei Y, Shi M. Chem. Rev. 2013; 113: 6659
• 6d Wei Y, Shi M. Acc. Chem. Res. 2010; 43: 1005
• 6e Xie P, Huang Y. Org. Biomol. Chem. 2015; 13: 8578
• 6f Tang Q, Tu A, Deng Z, Hu M, Zhong W. Chin. J. Org. Chem. 2013; 33: 954
• 7a Rajesh S, Banerji B, Iqbal J. J. Org. Chem. 2002; 67: 7852
• 7b Kim J.-M, Kim S.-H, Kim S.-H, Kim J.-N. Bull. Korean Chem. Soc. 2008; 29: 1583
• 7c Wang X, Meng F, Wang Y, Han Z, Chen YJ, Liu L, Wang Z, Ding K. Angew. Chem. Int. Ed. 2012; 51: 9276
• 7d Wang Y, Liu L, Wang D, Chen Y.-J. Org. Biomol. Chem. 2012; 10: 6908
• 7e Wang Y, Zhang T, Liu L. Chin. J. Chem. 2012; 30: 2641
• 7f Wang X, Guo P, Han Z, Wang X, Wang Z, Ding K. J. Am. Chem. Soc. 2013; 136: 405
• 7g Zhu L, Hu H, Qi L, Zheng Y, Zhong W. Eur. J. Org. Chem. 2016; 2139
• 7h Sundararaju B, Achard M, Bruneau C. Chem. Soc. Rev. 2012; 41: 4467
• 8a Shi M, Xu YM. Angew. Chem. Int. Ed. 2002; 41: 4507
• 8b Matsui K, Takizawa S, Sasai H. J. Am. Chem. Soc. 2005; 127: 3680
• 8c Masson G, Housseman C, Zhu J. Angew. Chem. Int. Ed. 2007; 46: 4614
• 8d Shi Y.-L, Shi M. Eur. J. Org. Chem. 2007; 2905
• 8e Declerck V, Martinez J, Lamaty F. Chem. Rev. 2009; 109: 1
• 9a Li J, Wang X, Zhang Y. Tetrahedron Lett. 2005; 46: 5233
• 9b Zhang T.-Z, Dai L.-X, Hou X.-L. Tetrahedron: Asymmetry 2007; 18: 1990
• 9c Sun W, Ma X, Hong L, Wang R. J. Org. Chem. 2011; 76: 7826
• 9d Ma G, Sibi MP. Org. Chem. Front. 2014; 1: 1152
• 9e Yao L, Wang C.-J. Adv. Synth. Catal. 2015; 357: 384
• 9f Kamlar M, Císařová I, Hybelbauerová S, Veselý J. Eur. J. Org. Chem. 2017; 1926
• 9g Dočekal V, Šimek M, Dračínský M, Veselý J. Chem. Eur. J. 2018; 24: 13441
• 9h Li Z, Frings M, Yu H, Raabe G, Bolm C. Org. Lett. 2018; 20: 7367
• 9i Li Z, Frings M, Yu H, Bolm C. Org. Lett. 2019; 21: 3119
• 10 Bordwell FG, Algrim DJ. J. Am. Chem. Soc. 1988; 110: 2964
• 11a Bakthadoss M, Srinivasan J, Selvakumar R. Aust. J. Chem. 2014; 67: 295
• 11b Kim JN, Lee HJ, Lee KY, Gong JH. Synlett 2002; 173
• 12a Chen H.-Y, Patkar LN, Ueng S.-H, Lin C.-C, Lee AS.-Y. Synlett 2005; 2035
• 12b Lee CG, Lee KY, Lee S, Kim JN. Tetrahedron 2005; 61: 1493
• 12c Lee C.-G, Gowrisankar S, Kim J.-N. Bull. Korean Chem. Soc. 2005; 26: 481
• 12d Kim S.-C, Gowrisankar S, Kim J.-N. Bull. Korean Chem. Soc. 2005; 26: 1001
• 12e Pathak R, Madapa S, Batra S. Tetrahedron 2007; 63: 451
• 12f Gowrisankar S, Lee HS, Kim JM, Kim JN. Tetrahedron Lett. 2008; 49: 1670
• 13a Du Y, Han X, Lu X. Tetrahedron Lett. 2004; 45: 4967
• 13b Lin A, Mao H, Zhu X, Ge H, Tan R, Zhu C, Cheng Y. Adv. Synth. Catal. 2011; 353: 3301
• 13c Pei C.-K, Zhang X.-C, Shi M. Eur. J. Org. Chem. 2011; 4479
• 13d Liu TY, Xie M, Chen YC. Chem. Soc. Rev. 2012; 41: 4101
• 13e Zhao M.-X, Chen M.-X, Tang W.-H, Wei D.-K, Dai T.-L, Shi M. Eur. J. Org. Chem. 2012; 3598
• 13f Putaj P, Tichá I, Císařová I, Veselý J. Eur. J. Org. Chem. 2014; 6615

During the preparation of this manuscript, two independent reports describing similar reactions of anilines and MBH carbonates were published. These methods use 10 mol% of β-isocupreidine as the catalyst in toluene (1.5 equiv of carbonate) and 20 mol% of (DHQD)₂AQN as the catalyst in p-xylene in the presence of CaF₂ (2 equiv of carbonate). In comparison, our protocol uses a lower catalyst loading and avoids the use of superstoichiometric quantities of MBH carbonate, as is the case in these two previous reports, see:
• 14a Formánek B, Šimek M, Kamlar M, Císařová I, Veselý J. Synthesis 2019; 51: 907
• 14b Zhao S, Chen Z.-L, Rui X, Gao M.-M, Chen X. Synlett 2019; 703
• 15a Puylaert P, van Heck R, Fan Y, Spannenberg A, Baumann W, Beller M, Medlock J, Bonrath W, Lefort L, Hinze S. Chem. Eur. J. 2017; 23: 8473
• 15b Schömberg F, Zi Y, Vilotijevic I. Chem. Commun. 2018; 54: 3266
• 15c Zi Y, Schömberg F, Seifert F, Görls H, Vilotijevic I. Org. Biomol. Chem. 2018; 16: 6341
• 16 Enantioselective Allylation of Anilines; General Procedure Carbonate 7 (1 equiv), aniline 8 (1.1 equiv) and (DHQD)₂AQN (10 mol%) were added to a vial containing a stir bar. The vial was evacuated and refilled with nitrogen 3 times. The reaction mixture was then stirred at room temperature after adding cyclohexane (0.4 M). After completion of the reaction, the solvent was removed under reduced pressure. The crude residue was purified by column chromatography (eluent: 5% ethyl acetate in petroleum ether). Methyl 2-{[(4-Chlorophenyl)amino](phenyl)methyl}acrylate (9a) Yield: 28 mg (94%); pale yellow oil; 93:7 er (determined by HPLC analysis) [Phenomenex Lux Cellulose-1, n-hexane/i-PrOH = 95:5, 1.0 mL/min, λ = 253 nm, t _R (major) = 18.73 min, t _R (minor) = 14.92 min]. ¹H NMR (300 MHz, CDCl₃): δ = 7.48–7.27 (m, 5 H), 7.18–7.04 (m, 2 H), 6.57–6.44 (m, 2 H), 6.40 (s, 1 H), 5.92 (s, 1 H), 5.39 (s, 1 H), 4.24 (s, 1 H), 3.72 (s, 3 H). ¹³C NMR (75 MHz, CDCl₃): δ = 166.58, 145.23, 140.21, 139.80, 129.07, 128.88, 128.01, 127.51, 126.37, 122.60, 114.63, 59.13, 52.06.
• 17 Cyclization to β-Lactams 10; General Procedure To a solution of 9 (1.0 equiv) in toluene was added Sn[HMDS]₂ (1.5 equiv). The mixture was refluxed for 2 h and the solution then cooled and concentrated. The residue was purified by flash chromatography on silica gel (eluent: 5% ethyl acetate in petroleum ether) to afford the desired product. (R)-1-(3-Methoxyphenyl)-3-methylene-4-phenylazetidin-2-one (10i) Yield: 14 mg (85%); white solid. IR (ATR): 2927, 2360, 1743, 1597, 1492, 1454, 1369, 1249, 1114, 848, 752 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 7.46–7.32 (m, 5 H), 7.17 (t, J = 8.1 Hz, 1 H), 7.06 (t, J = 2.2 Hz, 1 H), 6.84 (dd, J = 8.0, 1.9 Hz, 1 H), 6.63 (dd, J = 8.2, 2.5 Hz, 1 H), 5.86 (t, J = 1.9 Hz, 1 H), 5.41 (d, J = 1.6 Hz, 1 H), 5.19 (d, J = 1.6 Hz, 1 H), 3.77 (s, 3 H). ¹³C NMR (101 MHz, CDCl₃): δ = 161.01, 160.13, 149.77, 138.68, 136.45, 129.92, 129.10, 128.81, 126.61, 111.01, 110.11, 109.41, 103.00, 63.72, 55.28. HRMS (EI): m/z [M]⁺ calcd for C₁₇H₁₅NO₂: 265.1103; found: 265.1094.
• 18 Reduction to β-lactams 11; General Procedure To a degassed ethyl acetate solution of 10 (1 equiv) was added (10 mol%) Pd/C and the reaction flask was furnished with a H₂ balloon. After stirring for 30 min, the reaction mixture was filtered over Celite and evaporated. The crude residue was purified by flash column chromatography (eluent: 5% ethyl acetate in petroleum ether). (3S,4S)-1-(4-Chlorophenyl)-3-methyl-4-(naphthalen-2-yl)azetidin-2-one (11x) Yield: 25 mg (98%); white solid. IR (ATR): 2974, 1728, 1597, 1492, 1381, 1365, 1161, 1091, 813, 744 cm^–1. ¹H NMR (300 MHz, CDCl₃): δ = 7.92–7.77 (m, 3 H), 7.73–7.67 (m, 1 H), 7.53 (dt, J = 6.3, 3.4 Hz, 2 H), 7.37–7.28 (m, 3 H), 7.25–7.16 (m, 2 H), 5.35 (d, J = 6.0 Hz, 1 H), 3.80 (qd, J = 7.6, 5.9 Hz, 1 H), 0.93 (d, J = 7.6 Hz, 3 H). ¹³C NMR (75 MHz, CDCl₃): δ = 168.44, 136.28, 133.18, 132.13, 129.16, 128.80, 128.72, 127.89, 127.82, 126.66, 126.45, 126.22, 124.36, 118.34, 58.74, 49.79, 9.79. HRMS (EI): m/z [M]⁺ calcd for C₂₀H₁₆ClNO: 321.0920; found: 321.0916.