Synthesis of Tetrahydronaphthyridines from Aldehydes and HARP Reagents via Radical Pictet-Spengler Reactions.

The combination of aldehydes with newly designed HARP (halogen amine radical protocol) reagents gives access to α-substituted tetrahydronaphthyridines. By using different HARP reagents, various regioisomeric structures can be prepared in a single operation. These products, which are of high value in medicinal chemistry, are formed in a predictable manner via a formal Pictet-Spengler reaction of electron-poor pyridines that would not participate in the corresponding polar reactions.

[1]  Christopher W Murray,et al.  Opportunity Knocks: Organic Chemistry for Fragment-Based Drug Discovery (FBDD). , 2016, Angewandte Chemie.

[2]  A. Studer,et al.  Catalysis of Radical Reactions: A Radical Chemistry Perspective. , 2016, Angewandte Chemie.

[3]  Dong Liu,et al.  Carbon-Centered Radical Addition to C=X Bonds for C-X Bond Formation. , 2015, Chemistry, an Asian journal.

[4]  J. Bode,et al.  Catalytic Synthesis of N-Unprotected Piperazines, Morpholines, and Thiomorpholines from Aldehydes and SnAP Reagents. , 2015, Angewandte Chemie.

[5]  Huanfeng Jiang,et al.  Ruthenium-Catalyzed Straightforward Synthesis of 1,2,3,4-Tetrahydronaphthyridines via Selective Transfer Hydrogenation of Pyridyl Ring with Alcohols. , 2015, Organic letters.

[6]  J. Bode,et al.  Bespoke SnAP reagents for the synthesis of C-substituted spirocyclic and bicyclic saturated N-heterocycles. , 2015, Organic letters.

[7]  J. Bode,et al.  One-step synthesis of saturated spirocyclic N-heterocycles with stannyl amine protocol (SnAP) reagents and ketones. , 2014, Journal of the American Chemical Society.

[8]  G. Basarab,et al.  Synthesis of a tetrahydronaphthyridine spiropyrimidinetrione DNA gyrase inhibiting antibacterial agent--differential substitution at all five carbon atoms of pyridine. , 2014, Organic letters.

[9]  J. T. Njardarson,et al.  Analysis of the structural diversity, substitution patterns, and frequency of nitrogen heterocycles among U.S. FDA approved pharmaceuticals. , 2014, Journal of medicinal chemistry.

[10]  J. Bode,et al.  SnAP reagents for the one-step synthesis of medium-ring saturated N-heterocycles from aldehydes. , 2014, Nature chemistry.

[11]  H. Monenschein,et al.  Optimization of potency and pharmacokinetic properties of tetrahydroisoquinoline transient receptor potential melastatin 8 (TRPM8) antagonists. , 2014, Journal of medicinal chemistry.

[12]  Richard D. Taylor,et al.  Rings in drugs. , 2014, Journal of medicinal chemistry.

[13]  J. Bode,et al.  SnAP reagents for the synthesis of piperazines and morpholines. , 2014, Organic letters.

[14]  Jingsong Zhang,et al.  Ultraviolet photodissociation dynamics of the o-pyridyl radical. , 2013, The journal of physical chemistry. A.

[15]  Quan Chen,et al.  Transition-metal-free BF3-mediated regioselective direct alkylation and arylation of functionalized pyridines using Grignard or organozinc reagents. , 2013, Journal of the American Chemical Society.

[16]  J. Bode,et al.  SnAP reagents for the transformation of aldehydes into substituted thiomorpholines--an alternative to cross-coupling with saturated heterocycles. , 2013, Angewandte Chemie.

[17]  V. Timokhin,et al.  Silanes as Reducing Reagents in Radical Chemistry , 2012 .

[18]  J. Lalevée,et al.  Recent Applications of the (TMS)3SiH Radical-Based Reagent , 2012, Molecules.

[19]  I. Raheem,et al.  Enantioselective Pictet-Spengler-type cyclizations of hydroxylactams: H-bond donor catalysis by anion binding. , 2007, Journal of the American Chemical Society.

[20]  B. Becattini,et al.  Boron: A key element in radical reactions , 2007 .

[21]  Steven S. Sharik,et al.  Total synthesis of (-)-normalindine via addition of metalated 4-methyl-3-cyanopyridine to an enantiopure sulfinimine. , 2006, The Journal of organic chemistry.

[22]  J. Neudörfl,et al.  Unveiling the "booster effect" of fluorinated alcohol solvents: aggregation-induced conformational changes and cooperatively enhanced H-bonding. , 2006, Journal of the American Chemical Society.

[23]  R. Troschütz,et al.  Synthesis of 5-phenyl-5,6,7,8-tetrahydro-1,6-naphthyridines and 5-phenyl-6,7,8,9-tetrahydro-5H-pyrido[3,2-c]azepines as potential D1 receptor ligands , 2004 .

[24]  J. N. Johnston,et al.  The first azacyclopentenyl carbinyl radical isomerizations (ACCRI): independent use of steric and electronic (polarization) effects as gating elements. , 2003, Journal of the American Chemical Society.

[25]  E. Prabhakaran,et al.  Free radical-mediated aryl amination and its use in a convergent [3 + 2] strategy for enantioselective indoline alpha-amino acid synthesis. , 2003, Journal of the American Chemical Society.

[26]  M. Palucki,et al.  A highly efficient synthesis of 2-[3-aminopropyl]-5,6,7,8-tetrahydronaphthyridine via a double Suzuki reaction and a Chichibabin cyclization , 2001 .

[27]  E. Prabhakaran,et al.  Nonconventional carbon additions to azomethines. aryl amination/indoline synthesis by direct aryl radical addition to azomethine nitrogen. , 2001, Organic letters.

[28]  D. B. Collum,et al.  BF3-Mediated Addition of Lithium Phenylacetylide to an Imine: Correlations of Structures and Reactivities. BF3·R3N Derivatives as Substitutes for BF3·Et2O , 2000 .

[29]  Harada,et al.  Aryl radical cyclizations of 1-(2'-bromobenzyl)isoquinolines with AIBN-Bu3SnH: formation of aporphines and indolo , 2000, Organic letters.

[30]  F. Radner,et al.  Making radical cations live longer , 1997 .

[31]  J. Warkentin,et al.  Rate constants for aryl radical cyclization to aldimines : synthesis of tetrahydroisoquinolines by fast 6-endo closures to carbon , 1992 .

[32]  A. Pictet,et al.  Über die Bildung von Isochinolin‐derivaten durch Einwirkung von Methylal auf Phenyl‐äthylamin, Phenyl‐alanin und Tyrosin , 1911 .

[33]  O. Kikuchi,et al.  An Ab Initio Molecular Orbital Study of Pyridyl Radicals , 1988 .

[34]  G. Fodor,et al.  Correlation of the von Braun, Ritter, Bischler-Napieralski, Beckmann and Schmidt reactions via nitrilium salt intermediates , 1980 .