Carbon-Carbon Bond Forming Reactions Via C-H Activation

Summary

Principal Investigator: Jonathan A Ellman
Affiliation: Yale University
Country: USA
Abstract: DESCRIPTION (provided by applicant): Transition metal catalyzed carbon-carbon bond forming reactions such as metal-catalyzed cross-coupling and alkene metathesis have become some of the most extensively used reactions in the synthesis of important pharmaceutical agents and naturally occurring bioactive compounds. The importance of these transformations is in large part due to their broad functional group compatibility combined with the large and diverse array of compounds that can serve as starting materials. Metal-catalyzed C-H bond activation followed by carbon-carbon bond formation has the potential to become exceptionally powerful for the synthesis of bioactive compounds. C-H activation processes catalyzed by late transition metals are highly functional group compatible. In addition, because virtually every organic compound contains C-H bonds, the availability of starting materials for C-H activation pathways is enormous. This proposal describes the development and application of powerful catalytic methods for C-H activation and functionalization of two very important classes of nitrogen-containing compounds. 1. Imine directed C-H activation. The catalytic alkylation of aromatic and 1,2-unsaturated imines will be performed to obtain useful and complex bioactive compounds. Catalytic enantioselective alkylation will enable the efficient synthesis of single enantiomers of drugs and drug candidates. Catalytic alkenylation of 1,2-unsaturated imines followed by electrocyclization will provide 1,2-dihydropyridines, which are extremely versatile intermediates in the synthesis of pyridines and piperidines. Due to the immense importance of pyridines and piperidines in drug discovery and production, the alkenylation/electrocyclization sequence will be developed for the rapid and practical synthesis of these compounds. 2. Nitrogen heterocycle C-H activation. Catalytic alkylation and arylation of nitrogen heterocycles will be performed. A particular emphasis will be placed on heterocycles of huge pharmaceutical importance such as pyridines, quinolines, benzodiazepines and azoles. Catalytic enantioselective alkylation will be developed as an efficient method to prepare single enantiomers of important drugs and drug candidates. Mechanistic studies designed to enhance the utility and generality of the chemistry will also be pursued. The majority of therapeutic agents used to treat human disease are composed of synthetic organic compounds. This proposal describes powerful and general new methods to rapidly prepare complex, drug-like compounds from simple precursors. The proposed methods will enable accelerated drug discovery and more cost effective drug production at the same time that undesired chemical waste byproducts are minimized.
Funding Period: ----------------2004 - ---------------2011-
more information: NIH RePORT

Top Publications

  1. pmc Regio- and stereoselective 1,2-dihydropyridine alkylation/addition sequence for the synthesis of piperidines with quaternary centers
    Simon Duttwyler
    Department of Chemistry, Yale University, 225 Prospect St, New Haven, CT 06520 USA
    Angew Chem Int Ed Engl 53:3877-80. 2014
  2. pmc Rh(I)-catalyzed direct arylation of pyridines and quinolines
    Ashley M Berman
    Department of Chemistry, University of California, Berkeley, California 94720, USA
    J Am Chem Soc 130:14926-7. 2008
  3. pmc The stereoselective formation of bicyclic enamines with bridgehead unsaturation via tandem C-H bond activation/alkenylation/electrocyclization
    Sirilata Yotphan
    Department of Chemistry, University of California, Berkeley, California 94720, USA
    J Am Chem Soc 130:2452-3. 2008
  4. pmc Enantioselective intramolecular hydroarylation of alkenes via directed C-H bond activation
    Hitoshi Harada
    Department of Chemistry, University of California, and Division of Chemical Sciences, Lawrence Berkeley National Laboratory, Berkeley, California 94720, USA
    J Org Chem 73:6772-9. 2008
  5. pmc Synthesis of dihydropyridines and pyridines from imines and alkynes via C-H activation
    Denise A Colby
    Department of Chemistry, University of California, and Division of Chemical Sciences, Lawrence Berkeley National Laboratory, Berkeley, California 94720, USA
    J Am Chem Soc 130:3645-51. 2008
  6. pmc Asymmetric synthesis of (-)-incarvillateine employing an intramolecular alkylation via Rh-catalyzed olefinic C-H bond activation
    Andy S Tsai
    Department of Chemistry, University of California, Berkeley, California 94720, USA
    J Am Chem Soc 130:6316-7. 2008
  7. pmc Direct functionalization of nitrogen heterocycles via Rh-catalyzed C-H bond activation
    Jared C Lewis
    Department of Chemistry and Chemical Engineering, California Insitute of Technology, 1200 East California Boulevard, MC 210 41, Pasadena, California 91125, USA
    Acc Chem Res 41:1013-25. 2008
  8. pmc Synthesis of potent bicyclic bisarylimidazole c-Jun N-terminal kinase inhibitors by catalytic C-H bond activation
    Jason C Rech
    Department of Chemistry, University of California, and Division of Chemical Sciences, Lawrence Berkeley National Laboratory, Berkeley, California 94729, USA
    J Am Chem Soc 129:490-1. 2007
  9. pmc Rh(I)-catalyzed arylation of heterocycles via C-H bond activation: expanded scope through mechanistic insight
    Jared C Lewis
    Department of Chemistry, University of California and Division of Chemical Sciences, Lawrence Berkeley National Laboratory, Berkeley, California 94720, USA
    J Am Chem Soc 130:2493-500. 2008
  10. pmc Rhodium catalyzed chelation-assisted C-H bond functionalization reactions
    Denise A Colby
    Division of Chemical Sciences, Lawrence Berkeley National Laboratory, and Department of Chemistry, University of California, Berkeley, California 94720, USA
    Acc Chem Res 45:814-25. 2012

Detail Information

Publications40

  1. pmc Regio- and stereoselective 1,2-dihydropyridine alkylation/addition sequence for the synthesis of piperidines with quaternary centers
    Simon Duttwyler
    Department of Chemistry, Yale University, 225 Prospect St, New Haven, CT 06520 USA
    Angew Chem Int Ed Engl 53:3877-80. 2014
    ..Carbon nucleophile addition results in an unprecedented level of substitution to provide piperidine rings with adjacent tetrasubstituted carbon atoms. ..
  2. pmc Rh(I)-catalyzed direct arylation of pyridines and quinolines
    Ashley M Berman
    Department of Chemistry, University of California, Berkeley, California 94720, USA
    J Am Chem Soc 130:14926-7. 2008
    ..The method provides rapid entry into an important class of substituted heterocycles employing inexpensive and readily available starting materials...
  3. pmc The stereoselective formation of bicyclic enamines with bridgehead unsaturation via tandem C-H bond activation/alkenylation/electrocyclization
    Sirilata Yotphan
    Department of Chemistry, University of California, Berkeley, California 94720, USA
    J Am Chem Soc 130:2452-3. 2008
  4. pmc Enantioselective intramolecular hydroarylation of alkenes via directed C-H bond activation
    Hitoshi Harada
    Department of Chemistry, University of California, and Division of Chemical Sciences, Lawrence Berkeley National Laboratory, Berkeley, California 94720, USA
    J Org Chem 73:6772-9. 2008
    ..This further enabled the highly stereoselective intramolecular alkylation of certain substrates containing Z/E-alkene mixtures via a Rh-catalyzed alkene isomerization with preferential cyclization of the Z-isomer...
  5. pmc Synthesis of dihydropyridines and pyridines from imines and alkynes via C-H activation
    Denise A Colby
    Department of Chemistry, University of California, and Division of Chemical Sciences, Lawrence Berkeley National Laboratory, Berkeley, California 94720, USA
    J Am Chem Soc 130:3645-51. 2008
    ....
  6. pmc Asymmetric synthesis of (-)-incarvillateine employing an intramolecular alkylation via Rh-catalyzed olefinic C-H bond activation
    Andy S Tsai
    Department of Chemistry, University of California, Berkeley, California 94720, USA
    J Am Chem Soc 130:6316-7. 2008
    ..Additionally, this transformation produces an exocyclic, tetrasubstituted alkene through which the bicyclic piperidine moiety can readily be accessed...
  7. pmc Direct functionalization of nitrogen heterocycles via Rh-catalyzed C-H bond activation
    Jared C Lewis
    Department of Chemistry and Chemical Engineering, California Insitute of Technology, 1200 East California Boulevard, MC 210 41, Pasadena, California 91125, USA
    Acc Chem Res 41:1013-25. 2008
    ....
  8. pmc Synthesis of potent bicyclic bisarylimidazole c-Jun N-terminal kinase inhibitors by catalytic C-H bond activation
    Jason C Rech
    Department of Chemistry, University of California, and Division of Chemical Sciences, Lawrence Berkeley National Laboratory, Berkeley, California 94729, USA
    J Am Chem Soc 129:490-1. 2007
  9. pmc Rh(I)-catalyzed arylation of heterocycles via C-H bond activation: expanded scope through mechanistic insight
    Jared C Lewis
    Department of Chemistry, University of California and Division of Chemical Sciences, Lawrence Berkeley National Laboratory, Berkeley, California 94720, USA
    J Am Chem Soc 130:2493-500. 2008
    ..The reactions are performed with heating in a microwave reactor to obtain excellent product yields in 2 h...
  10. pmc Rhodium catalyzed chelation-assisted C-H bond functionalization reactions
    Denise A Colby
    Division of Chemical Sciences, Lawrence Berkeley National Laboratory, and Department of Chemistry, University of California, Berkeley, California 94720, USA
    Acc Chem Res 45:814-25. 2012
    ....
  11. pmc Facile synthesis of unsymmetrical acridines and phenazines by a Rh(III)-catalyzed amination/cyclization/aromatization cascade
    Yajing Lian
    Department of Chemistry, Yale University, New Haven, Connecticut 06520, USA
    J Am Chem Soc 135:12548-51. 2013
    ..Acridines can be directly prepared from aromatic aldehydes by in situ imine formation using catalytic benzylamine. ..
  12. pmc Mechanistic study of the oxidative coupling of styrene with 2-phenylpyridine derivatives catalyzed by cationic rhodium(III) via C-H activation
    Mikaël Brasse
    Instituto de Investigaciones Quimicas, Consejo Superior de Investigaciones Científicas Universidad de Sevilla, c Americo Vespucio 49, 41092 Sevilla, Spain
    J Am Chem Soc 135:6427-30. 2013
    ..The reaction rate is solely dependent on the catalyst and alkene concentrations, and the turnover-limiting step is the migratory insertion of the alkene into a Rh-C(aryl) bond...
  13. pmc Rhodium(III)-catalyzed indazole synthesis by C-H bond functionalization and cyclative capture
    Yajing Lian
    Department of Chemistry, Yale University, New Haven, Connecticut 06520, USA
    J Am Chem Soc 135:7122-5. 2013
    ..The 2-aryl-2H-indazole products also represent a new class of readily prepared fluorophores for which initial spectroscopic characterization has been performed...
  14. pmc Rhodium(III)-catalyzed alkenyl C-H bond functionalization: convergent synthesis of furans and pyrroles
    Yajing Lian
    Department of Chemistry, Yale University, New Haven, CT 06520, USA
    Angew Chem Int Ed Engl 52:629-33. 2013
    ..Cyclization and aromatization occurs under the reaction conditions to provide access to biologically relevant furans and pyrroles in good yields. Cp*=C(5)Me(5), DCE=1,2-dichloroethane, THF=tetrahydrofuran...
  15. pmc Unstabilized azomethine ylides for the stereoselective synthesis of substituted piperidines, tropanes, and azabicyclo[3.1.0] systems
    Michael A Ischay
    Department of Chemistry, Yale University, New Haven, Connecticut 06520, USA
    J Am Chem Soc 135:2478-81. 2013
    ..1.0] systems...
  16. pmc Proton donor acidity controls selectivity in nonaromatic nitrogen heterocycle synthesis
    Simon Duttwyler
    Department of Chemistry, Yale University, New Haven, CT 06520, USA
    Science 339:678-82. 2013
    ....
  17. pmc Synthesis of isoquinuclidines from highly substituted dihydropyridines via the Diels-Alder reaction
    Rhia M Martin
    Department of Chemistry, Yale University, New Haven, Connecticut 06520, USA
    Org Lett 15:444-7. 2013
    ..This procedure affords the target compounds in high yields and diastereoselectivities...
  18. ncbi Chemistry. The direct approach
    Jonathan A Ellman
    Department of Chemistry, University of California, Berkeley, CA 94720, USA
    Science 316:1131-2. 2007
  19. pmc Rh(I)-catalyzed alkylation of quinolines and pyridines via C-H bond activation
    Jared C Lewis
    Department of Chemistry, University of California, California, USA
    J Am Chem Soc 129:5332-3. 2007
  20. pmc Experimental and computational studies on the mechanism of N-heterocycle C-H activation by Rh(I)
    Sean H Wiedemann
    Department of Chemistry, University of California, and Division of Chemical Sciences, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA
    J Am Chem Soc 128:2452-62. 2006
    ..The consequences of this mechanism for coupling reactions of N-heterocycles that occur via Rh-catalyzed C-H bond activation are discussed...
  21. ncbi Microwave-promoted rhodium-catalyzed arylation of heterocycles through C--H bond activation
    Jared C Lewis
    Department of Chemistry, University of California, Berkeley, Berkeley, CA 94720 1460, USA
    Angew Chem Int Ed Engl 45:1589-91. 2006
  22. pmc Stereoselective alkylation of alpha,beta-unsaturated imines via C-H bond activation
    Denise A Colby
    Department of Chemistry, University of California, and Division of Chemical Sciences, Lawrence Berkeley National Laboratory, Berkeley, California 94720, USA
    J Am Chem Soc 128:5604-5. 2006
    ..Alternatively, for beta-alkylation products of the N-benzyl imine of methacrolein, hydrolysis can be performed under conditions that provide complete isomerization to the E isomer...
  23. ncbi Enantioselective synthesis of a PKC inhibitor via catalytic C-H bond activation
    Rebecca M Wilson
    Department of Chemistry and Division of Chemical Sciences, Lawrence Berkeley National Laboratory, University of California, Berkeley, California 94720, USA
    Org Lett 8:1745-7. 2006
    ..Catalytic decarbonylation and direct indole/maleimide coupling provide efficient access to 2...
  24. ncbi Reassignment of the configuration of salvianolic acid B and establishment of its identity with lithospermic acid B
    Anja Watzke
    Department of Chemistry, University of California Berkeley, Berkeley, California 94720, USA
    J Nat Prod 69:1231-3. 2006
    ....
  25. ncbi Rhodium-catalyzed direct C-H addition of 3,4-dihydroquinazolines to alkenes and their use in the total synthesis of vasicoline
    Sean H Wiedemann
    Department of Chemistry, University of California, Berkeley, California 94720, USA
    J Org Chem 71:1969-76. 2006
    ..The key Rh-catalyzed cyclization step was made possible by the use of a rigid bicyclic phosphine ligand. The synthesis further demonstrates a challenging Cu-catalyzed amidation of an ortho-substituted aryl chloride...
  26. pmc Expedient synthesis of N-acyl anthranilamides and β-enamine amides by the Rh(III)-catalyzed amidation of aryl and vinyl C-H bonds with isocyanates
    Kevin D Hesp
    Department of Chemistry, Yale University, New Haven, Connecticut 06520, USA
    J Am Chem Soc 133:11430-3. 2011
    ..This method provides direct and efficient syntheses of N-acyl anthranilamides, enamine amides, and pyrimidin-4-one heterocycles...
  27. pmc Highly diastereoselective synthesis of tetrahydropyridines by a C-H activation-cyclization-reduction cascade
    Simon Duttwyler
    Department of Chemistry, Yale University, New Haven, Connecticut 06520, USA
    J Am Chem Soc 134:4064-7. 2012
    ..This one-pot procedure affords the target compounds in up to 95% yield with >95% diastereomeric purity...
  28. pmc Synthesis of pyridines from ketoximes and terminal alkynes via C-H bond functionalization
    Rhia M Martin
    Department of Chemistry, Yale University, New Haven, Connecticut 06520, USA
    J Org Chem 77:2501-7. 2012
    ..The use of electron-deficient phosphite ligands is important to suppress dimerization of the terminal alkynes to enynes...
  29. pmc Synthesis and coordination chemistry of tri-substituted benzamidrazones
    Mark R Crimmin
    Department of Chemistry, University of California, Berkeley, California 94720, USA
    Dalton Trans 40:514-22. 2011
    ..This latter complex could be isolated as a crystalline orange solid, full characterisation including single crystal X-ray diffraction demonstrated that the amidrazone coordinates in a κ(2)-N(2),C-coordination mode...
  30. pmc A facile, metal- and solvent-free, autoxidative coupling of quinolines with indoles and pyrroles
    Mikaël Brasse
    Department of Chemistry, University of California, Berkeley, California 94720, USA
    Chem Commun (Camb) 47:5019-21. 2011
    ..This atom economic method requires only a stoichiometric amount of inexpensive hydrochloric acid and does not require a catalyst...
  31. pmc Rhodium-catalyzed synthesis of branched amines by direct addition of benzamides to imines
    Kevin D Hesp
    Department of Chemistry, Yale University, New Haven, Connecticut 06520, United States
    Org Lett 14:2304-7. 2012
    ..The synthetic utility of the resulting branched amine products has also been demonstrated by the preparation of isoindoline and isoindolinone frameworks...
  32. pmc Rh(III)-catalyzed oxidative coupling of unactivated alkenes via C-H activation
    Andy S Tsai
    Department of Chemistry, Yale University, New Haven, Connecticut 06520, USA
    Org Lett 13:540-2. 2011
    ..Oxime directed aromatic C-H bond activation and oxidative coupling to alkenes is reported using a cationic Rh(III) catalyst. Significantly, the method can be used to oxidatively couple unactivated, aliphatic alkenes...
  33. pmc Rhodium(III)-catalyzed arylation of Boc-imines via C-H bond functionalization
    Andy S Tsai
    Department of Chemistry, Yale University, New Haven, Connecticut 06520, United States
    J Am Chem Soc 133:1248-50. 2011
    ..Use of a non-coordinating halide abstractor is important to obtain reactivity. Aryl-branched N-Boc-amines are formed, and a wide range of functionality is compatible with the reaction...
  34. pmc Mechanism of the rhodium(III)-catalyzed arylation of imines via C-H bond functionalization: inhibition by substrate
    Michael E Tauchert
    Department of Chemistry, Yale University, New Haven, Connecticut 06520, USA
    J Am Chem Soc 134:1482-5. 2012
    ..The reaction was found to be first order in the catalyst resting state and inverse first order in the C-H activation substrate...
  35. pmc Application of Daugulis copper-catalyzed direct arylation to the synthesis of 5-aryl benzotriazepines
    Sirilata Yotphan
    Department of Chemistry, University of California and Division of Chemical Sciences, Lawrence Berkeley National Laboratory, Berkeley, California 94720, USA
    Org Lett 11:1511-4. 2009
    ..The arylation reaction can also be performed outside a glovebox in air without a significant decrease in yield. Furthermore, convenient microwave conditions for carrying out this transformation are reported...
  36. pmc Synthesis of multicyclic pyridine and quinoline derivatives via intramolecular C-H bond functionalization
    Sirilata Yotphan
    Department of Chemistry, University of California and Division of Chemical Sciences, Lawrence Berkeley National Laboratory, Berkeley, California 94720, USA
    Org Lett 12:2978-81. 2010
    ..Starting materials capable of undergoing olefin isomerization to provide terminal 1,1-disubstituted alkenes also proved to be effective substrates...