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Synlett 2020; 31(06): 575-580
DOI: 10.1055/s-0039-1691570
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© Georg Thieme Verlag Stuttgart · New York

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

You Zi
a   Institute of Organic Chemistry and Macromolecular Chemistry, Friedrich Schiller University Jena, Humboldtstrasse 10, 07743 Jena, Germany   Email: ivan.vilotijevic@uni-jena.de
,
Markus Lange
a   Institute of Organic Chemistry and Macromolecular Chemistry, Friedrich Schiller University Jena, Humboldtstrasse 10, 07743 Jena, Germany   Email: ivan.vilotijevic@uni-jena.de
,
Philipp Schüler
b   Institute of Inorganic and Analytical Chemistry, Friedrich Schiller University Jena, Humboldtstrasse 8, 07743 Jena, Germany
,
Sven Krieck
b   Institute of Inorganic and Analytical Chemistry, Friedrich Schiller University Jena, Humboldtstrasse 8, 07743 Jena, Germany
,
Matthias Westerhausen 
b   Institute of Inorganic and Analytical Chemistry, Friedrich Schiller University Jena, Humboldtstrasse 8, 07743 Jena, Germany
,
Ivan Vilotijevic  ∗
a   Institute of Organic Chemistry and Macromolecular Chemistry, Friedrich Schiller University Jena, Humboldtstrasse 10, 07743 Jena, Germany   Email: ivan.vilotijevic@uni-jena.de
› Author Affiliations
Financial support from the Carl-Zeiss-Stiftung (Carl-Zeiss Foundation) (endowed professorship to I.V.), Friedrich-Schiller-Universität Jena and the State of Thuringia (graduate fellowship to M.L.) is gratefully acknowledged. P.S. is grateful to the Deutsche Bundesstiftung Umwelt (DBU) (German Environment Foundation) (Grant No. 20018/578) for a generous Ph.D. grant.
Further Information

Publication History

Received: 14 November 2019

Accepted after revision: 20 December 2019

Publication Date:
16 January 2020 (online)

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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

Supporting Information

    Supporting information for this article is available online at https://doi.org/10.1055/s-0039-1691570.
  • Supporting Information
 

  • References and Notes

  • 1 González-Bello C, Rodríguez D, Pernas M, Rodríguez Á, Colchón E. J. Med. Chem. 2019; in press; DOI:
    CrossrefPubMed
  • 2 Yimer EM, Hishe HZ, Tuem KB. Front. Neurosci. 2019; 13: 236
    CrossrefPubMedSearch in Google Scholar
  • 4 Pitts CR, Lectka T. Chem. Rev. 2014; 114: 7930
    CrossrefPubMedSearch in Google Scholar
  • 10 Bordwell FG, Algrim DJ. J. Am. Chem. Soc. 1988; 110: 2964
    CrossrefSearch in Google Scholar
    • 13a Du Y, Han X, Lu X. Tetrahedron Lett. 2004; 45: 4967
      CrossrefSearch in Google Scholar
    • 13b Lin A, Mao H, Zhu X, Ge H, Tan R, Zhu C, Cheng Y. Adv. Synth. Catal. 2011; 353: 3301
      CrossrefSearch in Google Scholar
    • 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
      CrossrefPubMedSearch in Google Scholar
    • 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
      Thieme ConnectSearch in Google Scholar
    • 14b Zhao S, Chen Z.-L, Rui X, Gao M.-M, Chen X. Synlett 2019; 703
      Thieme Connect
  • 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.