Merck-Banyu Lecture

Wednesday, October 17th
Professor Jun Terao
"New Methodologies for Carbon-Carbon and Carbon-Silicon Bond Forming Reactions Using Anionic Transition Metal Complexes as Active Catalytic Species"

4:15pm - 5:15pm
Braun Lecture Hall
S.G.Mudd Chemistry Building
Stanford University



This special lecture is hosted by Merck-Banyu Company in recognition of the most outstanding young academicians in Japan. The lecture is free and open to the public. All Stanford University Chemistry students are encouraged to attend this special event.

About the seminar
Anionic complexes formed by the reaction of neutral complexes with organometallic reagents possess high electron densities.
Consequently, it is expected that the nucleophilicity at the metal center or S-carbon ligand of anionic complexes, as well as their
electron-donating ability, should be much higher then the corresponding neutral complexes (Scheme 1).
We have developed new methodologies for C-C and C-Si bond forming reactions using alkyl halides and/or chlorosilanes as shown
in Scheme 2 by taking advantage of these characteristics of anionic complexes.
The representative accomplishments are summarized in three sections as stated below.


1. A new methodology for cross-coupling reaction by using an anionic complex.1-4
We have developed new catalytic systems that do not involve the oxidative addition of alkyl halides toward M(0) complexes but proceeds via an anionic complex of M(II) as key intermediate. A key to attain this new catalytic pathway is to use 1,3-butadienes instead of phosphine ligands as an additive. The present reaction proceeds as follows. Ni(0) reacts with 2 molar amounts of 1,3-butadiene to afford the bis-S-allyl nickel (II) complex, which reacts with Grignard reagents to form the anionic K1,K3-octadienediylnickel complex. This complexation enhances the nucleophilicity of Ni toward alkyl halides. A coupling product is formed by nucleophilic substitution of alkyl halides on the nickel of this anionic complex, followed by reductive elimination. Interestingly, alkyl chlorides and fluorides can also undergo this cross-coupling reaction giving rise to the desired products in good yields. It was found that the bis-dienes were effective also for the Ni-catalyzed cross-coupling reaction of organozinc reagents with alkyl halides. We also found that the first example of Cu-catalyzed cross-coupling reaction of alkyl chlorides with Grignard reagents in the presence of 1-phenylpropyne as an additive.

2. A new methodology for nucleophilic activation of S-carbon ligands by anionic complexes.
We proposed a new methodology for enhancing back-donation from metal by forming an anionic transition metal complex generated by the reaction of an olefin complex with organometallic reagents and succeeded in the development of zirconocene-catalyzed silylation of olefins involving the process of nucleophilic activation of coordinate olefins as a key step. When we applied this method to other transition metal complexes having S-unsaturated carbon ligands, such as allyl, 1,3-dienyl, and bis-S-allyl ligands, it was found that these ligands are also activated as nucleophiles which efficiently react with alkyl halides or chlorosilanes to achieve new C-C and C-Si bond forming reactions. In these reaction systems, alkyl and silyl groups are introduced to C2, C3, C4, or C8 units with high regioselectivity.

3. A new methodology for generation of alkyl radical species using anionic transition metal complexes and its application to catalytic reaction.
During the course of studies on anionic transition metal-catalyzed C-C bond forming reactions, we found that anionic Ti and Ni complexes have high electron donating abilities toward alkyl halides resulting in the formation of alkyl radical species and developed multi-component coupling reactions. Regioselective double alkylation of aryl alkenes proceeds in THF by the aid of dibutyltitanocene (III) as a key catalyst. When this reaction is performed in the presence of chlorosilanes, carbosilylation takes place. The present reactions involve one electron transfer from anionic dibutyltitanocene (III) complex to alkyl halides leading to cleavage of the C-X bond to give an alkyl radical. It should be noted that not only the addition reaction, substitution of H with an alkyl group, of aryl alkenes (Mizoroki-Heck type transformation) proceeds in ether under similar conditions. As an extension of this methodology to late transition complex, a new method for regioselective three-component cross-coupling reaction of alkyl halides, 1,3-butadienes, and aryl Grignard or zinc reagents has been developed by the use of a nickel catalyst.

These studies have high novelty and synthetic utility as mentioned below.
1. Regioselective alkylation and silylation of olefins and butadienes using alkyl halides and chlorosilanes:
Although alkyl halides and chlorosilanes have rarely been use in transition metal-catalyzed reactions, due mainly to slow oxidative addition of these compounds to metal complexes and the fast E-hydrogen elimination from alkylmetal intermediate. We have solved these problems by using anionic complexes have achieved alkylation and silylation toward carbon-carbon unsaturated units using alkyl halides and chlorosilanes.

2. A new use of Grignard reagents in organic synthesis: Grignard reagents (R-MgX) are of great importance as widely available reagents in organic synthesis. We developed a new catalytic system that allows a new way to use of Grignard reagents where an anionic complex of Zr, Ti, Ni, or Pd metal plays a key role in the C-C and C-Si bond forming reaction.

3. A new type of transition-metal catalyzed cross-coupling reaction: We have developed a unique cross-coupling reaction system using 1,3-butadienes providing the first example of catalytic cross-coupling reaction using alkyl chlorides and fluorides. This reaction proceeds by a new pathway which is in large contrast to conventional reactions using phosphine ligands. The present catalytic system is highly advantageous especially for large-scale production since the reaction proceeds efficiently using less expensive alkyl chlorides as the reagent, NiCl2 as the catalyst, and 1,3-butadiene as the additive instead of phosphines.

4. A New method for generation of alkyl and aryl radicals: We have developed a new methodology for generation of alkyl radical species from a variety of alkyl halides (R-X; R = primary, secondary, and tertiary alkyl; X = Cl, Br, and I) by single electron transfer from anionic Ti and Ni complexes. This system can be applied to generation of aryl radicals from aryl halides.

5. New multi-component coupling reactions: Multi-component coupling reactions in a single operation are advantageous environmentally and economically and would provide wide practical applications. We have achieved highly regioselective multi-component coupling reactions employing unsaturated hydrocarbons, alkyl halides and/or chlorosilanes, and Grignard reagents by the aid of anionic transition metal catalysts.

References
1. Terao, J.; Watanabe, H.; Ikumi, A.; Kuniyasu, H.; Kambe, N. J. Am. Chem. Soc., 2002, 124, 4222.
2. Terao, J.; Ikumi, A.; Kuniyasu, H.; Kambe, N. J. Am. Chem. Soc., 2003, 125, 5646.
3. Terao, J.; Todo, H.; Watanabe, H.; Kambe, N. Angew. Chem., Int. Ed., 2004, 43, 6180.
4. Terao, J.; Todo, H.; Begum, S. A.; Kuniyasu, H.; Kambe, N. Angew. Chem., Int. Ed., 2007, 46, 2086.
5. Terao, J.; Torii, K.; Saito, K.; Kambe, N.; Baba, A.; Sonoda, N. Angew. Chem., Int. Ed, 1998, 37, 2653.
6. Terao, J.; Oda, A.; Ikumi, A.; Nakamura, A.; Kambe, N. Angew. Chem., Int. Ed., 2003, 42, 3412.
7. Terao, J.; Watabe, H.; Watanabe, H.; Kambe, N. Adv. Synth. Catal., 2004, 346, 1674.
8. Terao, J.; Watabe, H.; Kambe, N. J. Am. Chem. Soc., 2005, 127, 3656.
9. Terao, J.; Saito, K.; Nii, S.; Kambe, N.; Sonoda, N. J. Am. Chem. Soc., 1998, 120, 11822.
10. Terao, J.; Nii, S.; Chowdhury, F. A.; Nakamura, A.; Kambe, N. Adv. Synth. Catal., 2004, 346, 905.


About Terao:
Education:
1990.4-1994.3 B.S. Department of Applied Chemistry, Faculty of Engineering, Osaka University
1994.4-1996.3 M.S.
Department of Applied Chemistry, Graduate School of Engineering, Osaka University
Thesis Advisor: Professor Noboru Sonoda
Dissertation: SYNTHESIS AND REACTION OF VINYLICTELLURIDES
1996.4-1999.3 Ph.D.
Department of Applied Chemistry, Graduate School of Engineering, Osaka University
Thesis Advisor: Professor Noboru Sonoda, Professor Nobuaki Kambe, Professor Akio Baba
Dissertation: STUDIES ON THE ALKYLATION AND SILYLATION OF ALKENES CATALYZED BY EARLY TRANSITION METALS

Research experience:
1999.4-1999.9 (1997.4-1999.3 JSPS Research Fellow)
Post-doctoral fellow at Catalysis Research Center, Hokkaido University
Research Advisor: Professor Nobuaki Kambe
1999.10-2007.8
Assistant Professor at Department of Applied Chemistry, Graduate School of Engineering, Osaka University
Research Advisor: Professor Tamotsu Takahashi
2002.3-2003.3
Academic Visitor at Dyson Perrins Laboratory, University of Oxford
Research Advisor: Professor Harry L. Anderson
2007.8-present
Associate Professor at Center for Atomic and Molecular Technologies, Graduate School of Engineering, Osaka University
Research Advisor: Professor Nobuaki Kambe<

Awards:
1. Merck Banyu Lectureship Award (2007/7/7)
2. The Young Scientists' Prize of the Commendation for Science and Technology by the Minister of Education, Culture, Sports, Science and Technology (2007/4/17)
3. Mitsui Chemicals Catalysis Science Award of Encouragement (2007/3/14)
4. Banyu Young Chemist Award (2006/11/18)
5. The Society of Silicon Chemistry Japan Award for Young Chemist (2006/11/11)
6. The Japan Petroleum Institute Award for Encouragement of Research and Development (2006/5/18)
7. The Chemical Society of Japan Award for Young Chemists (2005/3/27)
8. The Thieme Journal Award (2005/1/17)
9. Banyu Pharmaceutical Award in Synthetic Organic Chemistry, Japan (2001/2/20)


Questions
Please contact Patricia Dwyer at 650-723-4770.