Synthesis 2013; 45(2): 153-166
DOI: 10.1055/s-0032-1317589
feature article
© Georg Thieme Verlag Stuttgart · New York

Step-Efficient Access to Chiral Primary Amines

Thomas C. Nugent*
Department of Chemistry, School of Engineering and Science, Jacobs University Bremen, Campus Ring 1, 28759 Bremen, Germany   Fax: +49(421)2003229   Email: t.nugent@jacobs-university.de
,
Sofiya M. Marinova
Department of Chemistry, School of Engineering and Science, Jacobs University Bremen, Campus Ring 1, 28759 Bremen, Germany   Fax: +49(421)2003229   Email: t.nugent@jacobs-university.de
› Author Affiliations
Further Information

Publication History

Received: 02 October 2012

Accepted after revision: 23 October 2012

Publication Date:
02 January 2013 (online)


Abstract

Routes to enantioenriched amines are outlined that employ reductive amination and carbanion addition methods. The strategies require either one or two reaction steps from prochiral carbonyl compounds for the synthesis of the corresponding chiral primary amines.

 
  • References


    • For very recent reviews, see:
    • 1a Xie J.-H, Zhu S.-F, Zhou Q.-L. Chem. Soc. Rev. 2012; 41: 4126
    • 1b Jones S, Warner CJ. A. Org. Biomol. Chem. 2012; 10: 2189
    • 1c Mathew S, Yun H. ACS Catalysis 2012; 2: 993
    • 1d Xie J.-H, Zhu S.-F, Zhou Q.-L. Chem. Rev. 2011; 111: 1713
    • 1e Tufvesson P, Lima-Ramos J, Jensen JS, Al-Haque N, Neto W, Woodley JM. Biotechnol. Bioeng. 2011; 108: 1479
    • 1f Robak MT, Herbage MA, Ellman JA. Chem. Rev. 2010; 110: 3600
    • 1g Fleury-Brégeot N, de La Fuente V, Castillón S, Claver C. ChemCatChem 2010; 2: 1346
    • 1h Hesp KD, Stradiotto M. ChemCatChem 2010; 2: 1192
    • 1i Nugent TC, El-Shazly M. Adv. Synth. Catal. 2010; 352: 753
    • 1j Koszelewski D, Tauber K, Faber K, Kroutil W. Trends Biotechnol. 2010; 28: 324
  • 2 We have demonstrated this for primary amines 4p and 4q, i.e., Pd/C (6.0 mol%), AcOH, low hydrogen pressures (4 bar), r.t., allowed hydrogenolysis; see the procedure for 4p (experimental section) for an example. Note that the racemization of chiral amines is possible in the presence of Pd, see ref. 3.
  • 3 Parvulescu AN, Jacobs PA, De Vos DE. Chem.–Eur. J. 2007; 13: 2034

    • For supportive examples, see:
    • 4a Nugent TC, Seemayer R. Org. Process Res. Dev. 2006; 10: 142
    • 4b Neidigh KA, Avery MA, Williamson JS, Bhattacharyya S. J. Chem. Soc., Perkin Trans. 1 1998; 2527
    • 4c Bhattacharyya S, Chatterjee A, Williamson JS. Synlett 1995; 1079
    • 4d Seebach D, Hungerbuehler E, Naef R, Schnurrenberger P, Weidmann B, Zueger M. Synthesis 1982; 138
  • 5 For the reductive amination of keto esters, see: Nugent TC, Ghosh A. Eur. J. Org. Chem. 2007; 3863
  • 6 See the following reference which strongly implies that chloro-, bromo-, and presumably iodoaromatic moieties would be hydrogenolyzed when using our methods: Bringmann G, Geisler J.-P, Geuder T, Künkel G, Kinzinger L. Liebigs Ann. Chem. 1990; 795
  • 7 Nugent TC, Negru DE, El-Shazly M, Hu D, Sadiq A, Bibi A, Umar MN. Adv. Synth. Catal. 2011; 353: 2085 ; and supporting information therein
  • 8 See ref. 7, p 2087 for the text discussion of compound 2a.
  • 9 See ref. 7, compounds 2d and 3d (Tables 1 and 2).
  • 10 See ref. 6, p 797, in reference to aromatic halide removal: ‘This well-known hydro-dehalogenation can be prevented only by application of a special catalyst mixture Rh2O3/PtO2 (3:2), which thus allows the preparation of the corresponding secondary amine 9m with a still significant stereoselectivity (see Table 1).’
  • 11 Process for the preparation of (S,S)-cis-2-benzhydryl-3-benzylaminoquinuclidine: Nugent TC, Seemayer R. WO 2004035575, 2004
  • 12 See refs. 7 and 4a for examples of success using crystallization to impart high de, in particular in the supporting information of those references.
  • 13 From greater than 20 examples, one substrate remains an oddity regarding the inconsistency of its stereoselectivity, in particular 3o (see Figure 4). We have previously reported its de as 94%, see ref. 14, but more recent unpublished research results of ours have shown that the de, and consequently the ee for this substrate, actually ranges between 84–94% de (average = 89% de). It is difficult to speculate on the source of the problem because other alkyl aryl ketones, e.g. o-substituted acetophenones, required the same reaction conditions or slightly harsher (albeit using a different solvent), and show no discrepancies in stereoselectivity. Racemization events can occur in the presence of Pd/C at high temperatures, e.g., see ref. 3.
  • 14 Nugent TC, Ghosh AK, Wakchaure VN, Mohanty RR. Adv. Synth. Catal. 2006; 348: 1289 ; and supporting information therein
  • 15 Nugent TC, Wakchaure VN, Ghosh AK, Mohanty RR. Org. Lett. 2005; 7: 4967 ; and supporting information therein
  • 16 The experimental description, ref. 7, for compounds 3m and 4m lacked an important detail, i.e., prestirring of the reagents and starting materials neat at elevated temperature (50 °C, 4 h) before pressurization with H2. See the experimental section provided here for the procedures for 3m and 4m for further details.
  • 17 Reeves JT, Tan Z, Han ZS, Li G, Zhang Y, Xu Y, Reeves DC, Gonnella NC, Ma S, Lee H, Lu BZ, Senanayake CH. Angew. Chem. Int. Ed. 2012; 51: 1400
  • 18 Nugent TC, El-Shazly M, Wakchaure VN. J. Org. Chem. 2008; 73: 1297
  • 19 See ref. 18, p 1302, the text and footnote 34, for specific examples.
  • 20 We cannot rule out the possibility that a one-pot reductive amination–hydrogenolysis has been previously achieved, but our attempts to use key word and phrase searches failed to identify anything regarding this topic in the literature. To see our research in this area, see ref. 7.
  • 21 Wakchaure VN, Mohanty RR, Shaikh AJ, Nugent TC. Eur. J. Org. Chem. 2007; 959
  • 22 Here our educated guess is that 3v would be produced in ~85% de using reductive amination with the appropriate ketone precursor.
    • 23a Nugent TC, Umar MN, Bibi A. Org. Biomol. Chem. 2010; 8: 4085
    • 23b Nugent TC, Bibi A, Sadiq A, Shoaib M, Umar MN, Tehrani FN. Org. Biomol. Chem. 2012; 10: 9287