Elsevier

Tetrahedron

Volume 64, Issue 29, 14 July 2008, Pages 6961-6972
Tetrahedron

A modular synthesis of chiral aminoindanol-derived imidazolium salts

Dedicated to Professor John Hartwig in honor of his 2007 Tetrahedron Young Investigator Award
https://doi.org/10.1016/j.tet.2008.03.072Get rights and content

Abstract

A modular synthesis of N-substituted chiral imidazolium salts derived from (1R,2S)-(+)-1-amino-2-indanol is described. A wide range of amines are amenable to late stage introduction of the N-substituent to provide N-aryl, N-alkyl, and N-amino imidazolium salts, which serve as precursors to chiral N-heterocyclic carbenes (NHCs). A multi-gram synthesis of the N-mesityl derivative provides an important imidazolium salt for ongoing studies aimed at the development and understanding of NHC-catalyzed annulations. Critical to the success of this synthetic strategy is a chemoselective alkylation, 6-exo-tet ring closure of a formamide onto an epoxide, and a heterocyclic interconversion strategy.

Introduction

Over the past two decades, N-heterocyclic carbenes (NHCs) have received increasing attention due to their storied role as ligands for transition metal complexes1, 1(a), 1(b), 1(c), 1(d), 1(e) and, more recently, their remarkable properties as catalysts in their own right.2, 2(a), 2(b), 2(c), 2(d), 3 As an increasing number of processes catalyzed by either NHCs or their transition metal complexes are reported, interest in developing highly enantioselective variants through the design and synthesis of chiral NHCs continues to grow.4, 4(a), 4(b), 4(c) To this end, important advances have been made by Grubbs,5 Hoveyda,6 Burgess,7 Glorius,4a Montgomery,8 and many others in the preparation and application of novel, chiral imidazolium-derived NHCs for catalytic applications (Fig. 1).

In our own studies, we have pioneered the development of novel NHC-catalyzed redox processes of α-functionalized aldehydes, resulting in conceptually novel approaches to ester9, 9(a), 9(b), 9(c), 10, 10(a), 10(b) and amide11, 12 formation and the development of a new generation of highly selective annulation reactions from simple starting materials.13, 13(a), 13(b), 14, 14(a), 14(b), 14(c), 14(d) Interestingly, these novel NHC-catalyzed reactions appear to fall into two discrete categories:15 those catalyzed by imidazolium-derived NHCs13, 13(a), 13(b) and those promoted by triazolium-derived NHCs.14, 14(a), 14(b), 14(c), 14(d) For example, our group13, 13(a), 13(b) and that of Glorius16, 16(a), 16(b) have independently documented the imidazolium-derived NHC-catalyzed generation of homoenolate equivalents from enals.17, 18, 18(a), 18(b), 18(c), 18(d), 18(e) These species undergo nucleophilic additions to aldehydes, activated ketones, imines, and enones to give stereochemically rich annulation products under exceptionally mild and simple reaction conditions (Fig. 2).

The use of a simple organic molecule as a catalyst raises the promises of developing enantioselective variants of these annulations through the design and synthesis of chiral NHC catalysts. Indeed, chiral triazolium-derived NHCs have been employed as highly selective catalysts for benzoin and intramolecular Stetter reactions.19, 19(a), 19(b), 19(c), 19(d), 19(e), 19(f), 19(g), 19(h), 20, 20(a), 20(b) Our group has also reported a number of novel annulation processes that employ chiral N-mesityl substituted aminoindanol-derived triazolium precatalyst 1 for highly enantioselective annulations for inverse electron demand hetero-Diels–Alder reactions and benzoin-oxy-Cope reactions (Fig. 3).14, 14(a), 14(b), 14(c), 14(d) In almost all cases, the NHC catalyst 1 affords the expected products in good yields and outstanding enantioselectivities.

In contrast, the use of 1 or other triazolium-derived NHCs uniformly fails to provide products arising from NHC-catalyzed generation of homoenolates. The lack of reactivity of the triazolium salts coupled with the relative difficulty in preparing chiral imidazolium salts that promote homoenolate-based annulations of enals has stymied the development of enantioselective variants of these promising annulation reactions.

In seeking to address this, we have recently developed a practical synthesis of chiral imidazolium-derived NHC precatalysts built onto the chiral aminoindanol backbone that has proved so successful for enantioselective NHC-catalyzed reactions. In this account, we document these studies in detail, including the application of this synthetic route to diverse chiral N-substituted imidazolium salts and their preparation on a multi-gram scale.

Section snippets

Retrosynthetic analysis

The intense interest in the development and understanding of N-heterocyclic carbenes and their complexes has led to a number of notable advances in their preparation.21, 22, 23 Unfortunately, in our hands, we were generally unable to extend these routes to the preparation of our desired chiral bicyclic imidazolium salts. During the course of these efforts, Fürstner reported a new synthetic entry into unsymmetrically N,N′-disubstituted imidazolium salts based on a heterocyclic interconversion

Conclusion

In summary, we have documented a modular, scalable route to the preparation of chiral aminoindanol-derived imidazolium salts, which will find use as precursors to N-heterocyclic carbene catalysts and ligands. Our eight-step route takes advantage of a chemoselective alkylation, intramolecular epoxide opening, and a modification of the Fürstner imidazolium synthesis to achieve a robust, scalable methodology for the preparation of N-aryl, N-alkyl, and N-amino imidazolium salts. We have recently

General methods

All reactions utilizing air- or moisture-sensitive reagents were performed in dried glassware under an atmosphere of dry nitrogen. Dichloromethane and 1,2-dichloroethane were distilled over CaH2. Toluene, THF, DMF, DMSO, and EtOAc were dried by passage over activated alumina under Ar atmosphere. Acetic anhydride was shaken over P2O5, separated, shaken over K2CO3, filtered, and then fractionally distilled. All commercially available anilines were fractionally distilled prior to use. Perchloric

Acknowledgements

Partial support for this work was provided by the National Science Foundation (CHE-0449587). Unrestricted support from Amgen, AstraZeneca, Boehringer-Ingelheim, Bristol Myers Squibb, and Eli Lilly is gratefully acknowledged. We thank Donald Gauthier of Merck & Co. for a generous gift of aminoindanol. We thank Michael Rommel for his studies on the stereoselective epoxidation and ring closure of 5. We thank Patrick J. Carroll for the X-ray crystallographic structure. J.W.B is a fellow of the

References and notes (34)

  • F. Glorius et al.

    Chem. Commun.

    (2002)
    C. Burstein et al.

    Tetrahedron

    (2005)
    F. Tewes et al.

    J. Organomet. Chem.

    (2007)
  • H.U. Vora et al.

    J. Am. Chem. Soc.

    (2007)
  • S.S. Sohn et al.

    J. Am. Chem. Soc.

    (2004)
    M. He et al.

    Org. Lett.

    (2005)
  • W.A. Herrmann et al.

    Angew. Chem., Int. Ed.

    (1997)
    W.A. Herrmann

    Angew. Chem., Int. Ed.

    (2002)
    V. César et al.

    Chem. Soc. Rev.

    (2004)
    S. Díez-González et al.

    Coord. Chem. Rev.

    (2007)
  • R. Breslow

    J. Am. Chem. Soc.

    (1958)
    D. Enders et al.

    Acc. Chem. Res.

    (2004)
    D. Enders et al.

    Chem. Rev.

    (2007)
    N. Marion et al.

    Angew. Chem., Int. Ed.

    (2007)
  • T.J. Seiders et al.

    Org. Lett.

    (2001)
  • D.G. Gillingham et al.

    Angew. Chem., Int. Ed.

    (2007)
  • D. Chen et al.

    Organometallics

    (2007)
  • M.R. Chaulagain et al.

    J. Am. Chem. Soc.

    (2007)
  • K.Y.-K. Chow et al.

    J. Am. Chem. Soc.

    (2004)
    S.S. Sohn et al.

    Org. Lett.

    (2005)
    S.S. Sohn et al.

    Angew. Chem., Int. Ed.

    (2006)
  • For related work,...N.T. Reynolds et al.

    J. Am. Chem. Soc.

    (2004)
    N.T. Reynolds et al.

    J. Am. Chem. Soc.

    (2005)
  • J.W. Bode et al.

    J. Am. Chem. Soc.

    (2007)
  • M. He et al.

    J. Am. Chem. Soc.

    (2006)
    M. He et al.

    J. Am. Chem. Soc.

    (2006)
    P.-C. Chiang et al.

    J. Am. Chem. Soc.

    (2007)
    M. He et al.

    J. Am. Chem. Soc.

    (2008)
  • J.R. Struble et al.

    Org. Lett.

    (2008)
  • C. Burstein et al.

    Angew. Chem., Int. Ed.

    (2004)
    C. Burstein et al.

    Synthesis

    (2006)
  • K. Zeitler

    Angew. Chem., Int. Ed.

    (2005)
  • Cited by (21)

    View all citing articles on Scopus
    View full text