Zoltán Novák Group Research Laboratory

Ethynyl-cyclohexanol: an efficient acetylene surrogate in Sonogashira coupling, Márton Csékei, Zoltán Novák, András Kotschy, Tetrahedron 2008, 64, 975-982. DOI: 10.1016/j.tet.2007.10.031 |

The Sonogashira coupling of aryl halides in the presence of 1-ethynyl-cyclohexanol as an acetylene source provides an efficient method for the synthesis of diarylacetylenes without the isolation of the appropriate arylacetylenes.

Quinoidal Tetrazines:  Formation of a Fascinating Compound Class, Beatrix Bostai, Zoltán Novák, Attila C. Bényei, András Kotschy, Org. Lett. 2007, 9, 3437-3439. DOI: 10.1021/ol701442h | [Full Text Link] [Supp. Info Link, CIF]

A series of different N-heterocyclic carbenes (NHCs) were reacted with 3,6-bis(3‘,5‘-dimethylpyrazolyl)-tetrazine in the presence of an inorganic carbonate to provide access to a hitherto unprecedented compound class. The formed tetrazine derivatives bearing the NHC in the 3-position and an oxygen in the 6-position show a quinoidal-like structure, according to physical examinations and X-ray crystallography.

A multidimensional overpressured layer chromatographic method for the characterization of tetrazine libraries, Naran Gombusuren, Zoltán Novák, András Kotschy, E. Mincsovics, Gábor Dibó, J. Biochem. Biophys. Methods 2007, 69, 239-249. DOI: 10.1016/j.jbbm.2005.12.005 | [Full Text Link]

The recent combinatorial approach in synthetic organic chemistry started a new age in drug discovery. The generation of compound libraries in combination with high-throughput screening has become the method of choice for the production of new pharmacological leads for chemical optimization. Characterization and separation of such pool of compounds have been lagging behind the synthetic and screening methodologies. Overpressured layer chromatography (OPLC) is an instrumentalized planar liquid chromatographic technique associated with the use of optimized layers prepared from particles of narrow particle size distribution and small diameter. On one hand, uni-directional OPLC allows the simultaneous separation of large number of samples in minutes. On the other hand, two-dimensional OPLC offers multidimensional separation on a single layer. This paper shows the complete multidimensional separation of a tetrazine library prepared by parallel combinatorial synthesis. In general, this approach may become the method of choice for the characterization of compound libraries.

Oxidative Kinetic Resolution-Claisen Rearrangement Sequence to ­Enantioenriched Arylcycloalkenes, David C. Ebner, Zoltán Novák, Brian M. Stoltz, Synlett 2006, 20, 3533-3539. DOI: 10.1055/s-2006-958415 | [Full Text Link]

The Pd-catalyzed oxidative kinetic resolution of secondary alcohols afforded enantioenriched allylic alcohols with high ­selectivity. These alcohols were transformed into arylcycloalkenes with enantioenriched tertiary and quaternary stereocenters through a two-step vinylation and Lewis acid promoted Claisen rearrangement. Subsequent Pd-catalyzed oxidative cyclization of a Claisen product afforded a 5,5-fused tetrahydrofuran.

Study of the Formation and Thermal Decomposition of an Azo-Bridged Tricyclic Ring System, Zoltán Novák, Zoltán Vincze, Zsuzsanna Czégény, Gábor Magyarfalvi, David M. Smith, András Kotschy, Eur. J. Org. Chem. 2006, 15, 3358-3363. DOI: 10.1002/ejoc.200600058 | [Full Text Link]

1-Amino-2-methyl-1,3-pentadienes were treated with dimethyl 1,2,4,5-tetrazine-3,6-dicarboxylate to give diazatricyclo[2.2.2.0]octenes and dimethyl 4-methylpyridazine-3,6-dicarboxylate, the product distribution being largely dependent on the nature of the amino substituent. Under similar conditions the analogous 1-morpholino-1,3-butadiene afforded dimethyl pyridazine-3,6-dicarboxylate as the major product. The tricyclic products underwent selective thermal decomposition to give dimethyl 4-methylpyridazine-3,6-dicarboxylate in excellent yield. The proposed mechanism of the formation as well as of the decomposition was supported by quantum chemical calculations and experimental evidence.

Sequential and domino Sonogashira coupling: Efficient tools for the synthesis of diarylalkynes, András Nagy, Zoltán Novák, András Kotschy, J. Organomet. Chem. 2005, 690, 4453-4461. DOI: 10.1016/j.jorganchem.2004.12.036 |

The Sonogashira coupling reaction of aryl halides with a masked acetylene, leading to the formation of diarylethynes is reviewed. The process is either run in a sequential coupling–deprotection–coupling manner, or sometimes it is carried out in one-pot, a reaction we coined domino coupling. The procedures were also extended to the synthesis of compound libraries.

Tandem Sonogashira Coupling: An Efficient Tool for the Synthesis of Diarylalkynes, Zoltán Novák, Péter Nemes, András Kotschy, Org. Lett. 2005, 6, 4917-4920. DOI: 10.1021/ol047983f | [Full Text Link] [Supp. Info Link]

The tandem Sonogashira coupling reaction of aryl halides provides an efficient method for the synthesis of diarylalkynes. Several aryl halides were coupled with 2-methyl-3-butyn-2-ol as acetylene source in the presence of PdCl₂(PPh₃)₂ and CuI. Following the deprotection of the acetylene moiety in the same pot using a strong base, the Sonogashira coupling of a second aryl halide led to the formation of the appropriate diarylakyne. The established protocoll was successfully extended to the preparation of compound libraries.

The 'one-pot' preparation of substituted benzofurans, Márton Csékei, Zoltán Novák, Géza Timári, András Kotschy, Arkivoc 2004, 5, 285-291. (SA-1110BP) | [Full Text Link]

A simple one-pot procedure has been elaborated for the preparation of substituted benzofurans starting from halogenated phenols, and this method has been applied successfully to the total synthesis of dehydrotremetone, a natural product of White Snakeroot.

Keywords: Benzofurans, Sonogashira coupling, natural product, synthesis.

János Faragó, Zoltán Novák, Gitta Schlosser, Antal Csámpai, András Kotschy, Tetrahedron 2004, 60, 1991. DOI: 10.1016/j.tet.2004.01.013 |

A series of tetrazines were reacted with organometallic reagents. Depending on the nature of the metal azaphilic addition, reduction of the tetrazine or simple complex formation was the predominant transformation and usually high selectivity was observed.

Correlation of the Chemical Reactivity of Some Tetrazine Derivatives with Their Reactivity toward Ortho-positronium Atoms and Their LUMO Energies, András Kotschy, Zoltán Novák, Béla Lévay, J. Phys. Chem. A 2004, 108, 1753-1756. DOI: 10.1021/jp0373649 | [Full Text Link]

Chemical reaction rate constants of the nucleophilic ortho-positronium (o-Ps) atom with a series of tetrazine derivatives were determined in dimethylformamide (DMF) solutions by positron annihilation lifetime spectroscopy. The observed rate constants are in the range that corresponds to that of the diffusion-controlled reactions. It was shown that this pronounced reactivity of tetrazines toward o-Ps stems from the electron-deficient tetrazine core. The introduction of electron-donating substituents onto the tetrazine ring, as expected, decreases the reactivity of the molecule toward o-Ps. The measured reaction rate constants of o-Ps resulted in a good linear correlation with the calculated LUMO energies of the tetrazines. The reactivity of tetrazines toward o-Ps correlated well also with their reactivity toward classical nucleophiles.

Selective Nucleophilic Substitutions on Tetrazines, Zoltán Novák, Beatrix Bostai, Márton Csékei, Krisztián Lőrincz, András Kotschy, Heterocycles 2003, 60, 2653-2668. DOI: 10.3987/COM-03-9875 | [Full Text Link]

A series of tetrazine derivatives bearing a leaving group were reacted with different nucleophiles to undergo either the expected substitution reaction or an unexpected exchange of the other substituent of the tetrazine ring selectively. The influence of the choice of nucleophile as well as the substituents on the tetrazine was examined in detail and the interpretation of the results was also supported by quantum chemical calculations.

First Cross-Coupling Reactions on Tetrazines, Zoltán Novák, András Kotschy, Org. Lett. 2003, 5, 3495-3497. DOI: 10.1021/ol035312w | [Full Text Link] [Supp. Info Link]

A series of substituted chlorotetrazines were reacted with different terminal alkynes under Sonogashira or Negishi coupling conditions to furnish alkynyl-tetrazines in good to moderate yield. The electron-donating properties of the substituent on the tetrazine core were found to have a significant influence on the success of the reaction. These results constitute the first cross-coupling reactions on tetrazines.

The first total synthesis of Cicerfuran utilizing a one-pot synthesis of hydroxylated benzofuranes, Zoltán Novák, Géza Timári, András Kotschy, Tetrahedron 2003, 59, 7509-7513. DOI: 10.1016/S0040-4020(03)01170-0 |

A simple one-pot procedure was elaborated for the preparation of hydroxylated benzofurans from halogenated phenols and was successfully applied to the first total synthesis of Cicerfuran, a natural defence agent of wild chickpea.

Sonogashira Coupling of Aryl Halides Catalyzed by Palladium on Charcoal, Zoltán Novák, András Szabó, József Répási, András Kotschy, J. Org. Chem. 2003, 68, 3327-3329. DOI: 10.1021/jo034149f | [Full Text Link] [Supp. Info Link]

With the proper choice of solvent, palladium on charcoal acts as an efficient catalyst in the Sonogashira cross-coupling reaction of aryl bromides. The catalytically active species in the process is probably palladium, which leaches into the solution but returns onto the surface of the charcoal at the end of the reaction.

Synthesis and alkylation of some [1,2,4]triazolo[4,3-b]tetrazines, Zoltán Novák, Antal Csámpai, András Kotschy, Arkivoc 2000, 1, 259-265. (GJ-12EP) | [Full Text Link]

Two [1,2,4]triazolo[4,3-b]tetrazines were synthesised and alkylated using various reagents. The formation of the ethylated [1,2,4]triazolo[4,3-b]tetrazinium salts and their structure was unambiguously established using correlational NMR spectroscopy. The product distribution was interpreted on the basis of quantum chemical calculations. The triazolotetrazinium salts were found to dealkylate on workup to give the corresponding tetrafluoroborate salts.

A novel double ‘inverse electron-demand’ Diels-Alder reaction of azolyldienamines and tetrazines, András Kotschy, Zoltán Novák, Zoltán Vincze, David M. Smith, György Hajós, Tetrahedron Lett. 1999, 40, 6313-6316. DOI: 10.1016/S0040-4039(99)01184-3 |

Appropriately substituted azolyldienamines were found to undergo double ‘inverse electron-demand’ Diels-Alder reactions with tetrazine derivatives, yielding azolypyridazines and dihydropyridazines as products.