Synthesis 2017; 49(24): 5285-5306
DOI: 10.1055/s-0036-1590909
short review
© Georg Thieme Verlag Stuttgart · New York

Computer-Aided Insight into the Relative Stability of Enamines

Alejandro Castro-Alvarez, Héctor Carneros, Anna M Costa, Jaume Vilarrasa*
  • Organic Chemistry Section, Facultat de Química, Universitat de Barcelona, Diagonal 645, 08028 Barcelona, Catalonia, Spain   Email: jvilarrasa@ub.edu
The authors acknowledge the Spanish Government for financial support (CTQ2015-71506R, FEDER). A.C.A. is grateful to Fundació Privada Cellex de Barcelona for a fellowship. H.C. has a studentship of the Spanish Government (CTQ2012-39230, FEDER).
Further Information

Publication History

Received: 10 July 2017

Accepted after revision: 23 August 2017

Publication Date:
04 October 2017 (eFirst)

Dedicated to Pere Mir, in memoriam

Abstract

Venerable aldol, Michael, and Mannich reactions have undergone a renaissance in the past fifteen years, as a consequence of the development of direct organocatalytic versions, mediated by chiral amines. Chiral enamines are key intermediates in these reactions. This review focuses on the formation of enamines from secondary amines and their relative thermodynamic stability, as well as on the reverse reactions (hydrolysis). Experimental results and predictions based on MO calculations are reviewed to show which enamine forms may predominate in the reaction medium and to compare several secondary amines as organocatalysts.

1 Introduction

2 Relative Stability of Enamines as Determined Experimentally

3 Pyrrolidine Enamines

4 Enamines of the Jørgensen–Hayashi Catalyst

5 Proline Enamines

6 Free Enthalpies and Polar Solvent Effects

7 Comparison of Organocatalysts

8 Summary and Outlook

9 Appendix

 
  • References


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    • Also see:
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    • For pioneering works, see:
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    • For some very recent papers focused on acetone reactions, see:
    • 28g Ref. 8e.
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    • 29e Triandafillidi I. Bisticha A. Voutyritsa E. Galiatsatou G. Kokotos CG. Tetrahedron 2015; 71: 932
    • 30a With the J–H catalyst, the related values, in kcal/mol, are as follows: propanedial, ΔE –19.7, ΔG ѳ –18.6, ΔG ѳ(DMSO) –20.5, ΔG ѳ(H2O) –22.1; PhCH2CHO, ΔE –10.3, ΔG ѳ –10.4, ΔG ѳ(DMSO) –12.8, ΔG ѳ(H2O) –12.7; Me2CHCH2CHO, ΔE –5.0, ΔG ѳ –5.6, ΔG ѳ(DMSO) –7.3, ΔG ѳ(H2O) –6.6; Me3CCOMe, enamine ap, ΔE 6.3, ΔG ѳ 7.4, ΔG ѳ(DMSO) 7.5, ΔG ѳ(H2O) 7.6; Me3CCOMe, sc-exo, ΔE 10.3, ΔG ѳ 11.4, ΔG ѳ(DMSO) 10.5, ΔG ѳ (H2O) 9.9.
    • 30b With Pro, the values are as follows: propanedial, CO2H s-cis, ΔE –11.5, ΔG ѳ –13.4, ΔG ѳ(DMSO) –13.0, ΔG ѳ(H2O) –15.6; propanedial, s-trans, ΔE –8.7, ΔG ѳ –10.4, ΔG ѳ(DMSO) –12.6, ΔG ѳ(H2O) –14.3; PhCH2CHO, s-cis, ΔE –5.5, ΔG ѳ –6.7, ΔG ѳ(DMSO) –6.4, ΔG ѳ(H2O) –7.6; Me2CHCH2CHO, s-trans, ΔE –1.8, ΔG ѳ –2.9, ΔG ѳ(DMSO) –4.4, ΔG ѳ(H2O) –4.0; EtCHO, s-trans, ΔE –1.1, ΔG ѳ –1.6, ΔG ѳ(DMSO) –2.7, ΔG ѳ(H2O) –2.5; Me3CCOMe, s-cis, ΔE 9.4, ΔG ѳ 10.6, ΔG ѳ(DMSO) 12.3, ΔG ѳ(H2O) 11.2.
    • 31a Pyrrolidine-sulfonamide, nitro-Michael: Wang J. Li H. Lou B. Zu L. Guo H. Wang W. Chem. Eur. J. 2006; 12: 4321
    • 31b 5-(Pyrrolidin-2-yl)tetrazole: Arnó M. Zaragozá RJ. Domingo LR. Tetrahedron: Asymmetry 2007; 18: 157
    • 31c Pro-NHSO2Ar, Mannich: Veverková E. Strasserová J. Sebesta R. Toma S. Tetrahedron: Asymmetry 2010; 21: 58
    • 31d 4-OH-pyrrolidine derivatives, Mannich anti-selective: Gómez-Bengoa E. Maestro M. Mielgo A. Otazo I. Palomo C. Velilla I. Chem. Eur. J. 2010; 16: 5333
    • 31e Pyrrolidine-ureas, nitro-Michael: Cao X.-Y. Zheng J.-C. Li Y.-X. Shu Z.-C. Sun X.-L. Wang B.-Q. Tang Y. Tetrahedron 2010; 66: 9703
    • 31f 2-CHPh2 and 2-CPh2OMe, MVK: Patil MP. Sharma AK. Sunoj RB. J. Org. Chem. 2010; 75: 7310
    • 31g Thiaproline: Parasuk W. Parasuk V. Comput. Theor. Chem. 2011; 964: 133
    • 31h Mannich, thiaproline: Parasuk W. Parasuk V. Asian J. Org. Chem. 2013; 2: 85
    • 31i 4-OH-prolinamides, nitro-Michael: Watts J. Luu L. McKee V. Carey E. Kelleher F. Adv. Synth. Catal. 2012; 354: 1035
    • 31j Mannich, 2-(pyrrolidin-1-ylmethyl)pyrrolidine: ref. 26g.
    • 31k Pro dipeptides vs. Pro tripeptides, aldol: Szöllösi G. Csámpai A. Somlai C. Fekete M. Bartók M. J. Mol. Catal. A: Chem. 2014; 382: 86
    • 31l Pyrrolidinyl-oxazolecarboxamides: Kamal A. Sathish M. Srinivasulu V. Chetna J. Shekar KC. Nekkanti S. Tangella Y. Shankaraiah N. Org. Biomol. Chem. 2014; 12: 8008
    • 31m Pro-hydrazide, explicit water: Chakrabarty K. Ghosh A. Basak A. Das GK. Comput. Theor. Chem. 2015; 1062: 11
    • 31n For a review, see: ref. 26a.

      For studies on the nucleophilicity of enamines, see:
    • 32a Kempf B. Hampel N. Ofial AR. Mayr H. Chem. Eur. J. 2003; 9: 2209
    • 32b Ref. 4e.