Research Topics in the Hiyama Laboratory

Modern organic chemistry is the basic science, which provides us with functionalized organic agents and materials inevitable for the present and future human life.
In particular, organic synthesis based on the straightforward (step economical, highly selective) transformation is essential for environmentally benign manufacture, for invention of novel pharmaceuticals, agrochemicals and organoelectric materials, and ultimately for realization of sustainable society based on green chemistry.
Accordingly, exploitation of novel synthetic methods for organic synthesis is the main topic of our research group.

In view that all of the organic compounds are formed by the framework made of carbon-carbon bonds, we focus on the highly efficient and selective C-C bond formation.
Recent topics for this transformation are the cross-coupling reaction using palladium catalyst, organometallic reagents, and organic electrophiles as is known by the Nobel Prize for Chemistry for 2010 given to Professors Akira Suzuki, Ei-ichi Negishi, and Richard F. Heck.
We also have invented organosilicon-based cross coupling as well as hydroarylation/hydroheteroarylation and carbocyanation methodologies (Pure and Applied Chemistry, 2014, 86, 299).

Organosilicon-Based Cross-Coupling Reaction
The cross-coupling reaction with organosilicon compounds (Chem. Soc. Rev. 2011, 40, 4893; J. Synth. Org. Chem. Jpn., 2011, 1221) is considered to be promising for the future C?C bond forming reaction partic-ularly for the construction of π-conjugate system. We have shown that this is conveniently done with HOMSi [organo(2-hydroxymethylphenyl)dimethylsilane] reagents (J. Am. Chem. Soc., 2005, 127, 6952; ibid. 2007, 129, 9137), the silicon moiety being recovered and reused for synthesis of HOMSi reagents. Recently, the bisHOMSi reagents are prepared and applied to polymer synthesis suc-cessfully (Chem. Lett. 2013, 42, 45).

The protocol of the synthetic method for HOMSi reagents usually uses the reaction of organolithi-um or ?magnesium compounds with the cyclic silyl ether. Alternatively, the coupling reagents are found to be prepared using bis(2-alkoxymethylphenyl)tetramethyldisilane and bromoarenes. The new synthetic method allows to prepare HOMSi reagents that contain various functional groups which are sensitive to organolithum and/or -magnesium reagents (Chem. Lett. 2014, 43, 201).

Since triarylamines are key electron carrier materials for organic electronics, exploitation of novel and efficient synthetic method for triarylamines is growing to be a key synthetic issue. The Hart-wig-Buchwald protocol is well documented but it still appears renovation is still needed. We found N-trimethylsilyldiphenylamines smoothly undergo C?N coupling with aryl bromides in the presence of Pd catalyst and cesium fluoride (Chem. Lett. 2014, 43, 438). With bis(trimethylsilyl)anilines, double arylation readily takes place; with dibromides, bisamination proceeds without any problem.

Transformation of C-H Bonds to C-C Bonds
We consider the advanced (post cross coupling) methodology for the C-C bond formation is the direct transformation of C-H bonds into C-C bonds, which is long considered to be the holy grail in organic synthesis before the Muraifs discovery with acetophenone and Ru catalysts (Nature 1993, 366, 529). We have achieved various types of hydroheteroarylation of substituted alkynes and al-kenes. Among all, C4-selective alkylation of pyridines with terminal alkenes (J. Am. Chem. Soc. 2009, 131, 15996) and C1 homologation of terminal alkenes with N,N-dimethylformamide (Chem. Lett. 2012, 41, 298) are shown below.

Sicne 2010, we have been focusing on novel synthetic reactions starting with aryl ethynyl ethers and palladium catalysts as summarized below (J. Am. Chem. Soc. 2012, 134, 6124; Chem. Lett. 2014, 43, 181). It is remarkable that ortho-C-H bond activation by Pd(0) catalyst is taking place to allow the reaction with substituted alkynes, allenes, isocyanates to give chromane-annulation products. The resulting 1,2-bis-exo-methylene products readily undergo the Diels-Alder reaction to give tetracyclic con-densed ring structures.

If the ortho position is substituted by a methyl, intramolecular hydromethylation takes place to give unstable exo-methylene isomers of benzofurans, which can be utilized for various useful transfor-mations (Angew. Chem. Int. Ed. 2013, 52, 10611). This method can be applied to the synthesis of multi-condensed cycles.

Transformation of C-CN Bonds to C-C Bonds
Another holy grail in organic synthesis is activation of C-C bonds with a metal catalyst and convert them into new C-C bonds. We were lucky to find Ni(0)/Lewis acid catalyst is appropriate to realize the dreamed transformation (Pure Appl. Chem., 2008, 80, 1097). Various nitriles including benzo-nitrile and even acetonitrile undergo carbocyanation across alkynes and alkenes in some cases.

In view of hydroarylation of polyfluorobenzenes across disubstituted acetylenes, we were inter-essted in the reactivity of polyfluorobenzonitrile and to extend the π-cojugate system. Actually we were successful in achieving the following sequential transformation. It is remarkable that carbocyanation takes place before hydroarylation, oxidative addition to C-F bond being totally suppressed, although the last reaction is thermodynamically preferred process to make the nickel catalyst totally dead (Angew. Chem. Int. Ed. 2013, 52, 883). This process will find applications in synthesis of fluorinated π-cojugated systems versatile in organic electronics.