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Synthesis of multi-fused aromatic compounds by sequential benzyne reactions

Research Project

Project/Area Number 16K08164
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Chemical pharmacy
Research InstitutionOsaka University

Principal Investigator

Ikawa Takashi  大阪大学, 薬学研究科, 准教授 (20453061)

Project Period (FY) 2016-04-01 – 2019-03-31
Project Status Completed (Fiscal Year 2018)
Budget Amount *help
¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000)
Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Keywordsベンザイン / ベンズジイン等価体 / リスペリドン / 高歪化合物 / 連続反応 / 多環式複素環化合物 / 収束合成 / 三重結合 / ポリフェノール / フラン / 位置選択性 / 付加環化反応 / ベンズジイン / アライノフィル / フェノール / ドミノ反応 / ベンゾジアゼピン / インドリン / 多環式芳香族化合物 / ノナフラート / レゾルシノール
Outline of Final Research Achievements

We have devised a novel benzdiyne equivalent, capable of quadruple functionalization by sequential benzyne generation and reaction with arynophiles. The key features of this method include the chemoselective generation of two triple bonds in a single benzene ring under fluoride-ion-mediated mild conditions, and the regiocontrol of each benzyne reaction by the substituent next to the triple bond. This method produced various benzo-fused heteroaromatic compounds via reactions with arynophiles, such as furans, azides, and diazo compounds. A validation of the method is given in the convergent synthesis of the antipsychotic drug risperidone.

Academic Significance and Societal Importance of the Research Achievements

ベンゼン環内に2つの三重結合を有するベンズジインは、極めて不安定なため、これらを有機合成に利用することは通常困難である。一方、同一ベンゼン環内に三重結合を2箇所で順次発生させることができれば、その後の反応によりベンゼン環に多様な官能基を導入する有用な手法となる。今回我々は、新しいベンズジイン等価体を開発し、これを医薬品リスペリドンの効率的な合成へと応用することに成功した。

Report

(4 results)
  • 2018 Annual Research Report   Final Research Report ( PDF )
  • 2017 Research-status Report
  • 2016 Research-status Report
  • Research Products

    (52 results)

All 2019 2018 2017 2016 Other

All Journal Article (7 results) (of which Peer Reviewed: 7 results,  Open Access: 5 results,  Acknowledgement Compliant: 3 results) Presentation (42 results) (of which Int'l Joint Research: 11 results,  Invited: 9 results) Remarks (3 results)

  • [Journal Article] Microflow Fluorinations of Benzynes: Efficient Synthesis of Fluoroaromatic Compounds2018

    • Author(s)
      Ikawa Takashi、Masuda Shigeaki、Akai Shuji
    • Journal Title

      Chemical and Pharmaceutical Bulletin

      Volume: 66 Issue: 12 Pages: 1153-1164

    • DOI

      10.1248/cpb.c18-00578

    • NAID

      130007539120

    • ISSN
      0009-2363, 1347-5223
    • Year and Date
      2018-12-01
    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] 3-(Triflyloxy)benzynes Enable the Regiocontrolled Cycloaddition of Cyclic Ureas to Synthesize 1,4-Benzodiazepine Derivatives2018

    • Author(s)
      Ikawa Takashi、Akai Shuji、Kaneko Hideki、Yamamoto Yuta、Arulmozhiraja Sundaram、Tokiwa Hiroaki
    • Journal Title

      Synlett

      Volume: 29 Issue: 07 Pages: 943-948

    • DOI

      10.1055/s-0036-1591924

    • Related Report
      2018 Annual Research Report 2017 Research-status Report
    • Peer Reviewed
  • [Journal Article] Inflamed site-specific drug delivery system based on the interaction of human serum albumin nanoparticles with myeloperoxidase in a murine model of experimental colitis2018

    • Author(s)
      Iwao Yasunori、Tomiguchi Izumi、Domura Ayaka、Mantaira Yusuke、Minami Akira、Suzuki Takashi、Ikawa Takashi、Kimura Shin-ichiro、Itai Shigeru
    • Journal Title

      European Journal of Pharmaceutics and Biopharmaceutics

      Volume: 125 Pages: 141-147

    • DOI

      10.1016/j.ejpb.2018.01.016

    • Related Report
      2018 Annual Research Report 2017 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Synthesis of Optically Active 2,3-Disubstituted Indoline ?Derivatives through Cycloaddition Reactions between Benzynes and α,β-Unsaturated γ-Aminobutyronitriles2018

    • Author(s)
      Ikawa Takashi、Akai Shuji、Sumii Yuta、Masuda Shigeaki、Wang Ding、Emi Yuto、Takagi Akira
    • Journal Title

      Synlett

      Volume: 29 Issue: 04 Pages: 530-536

    • DOI

      10.1055/s-0036-1591722

    • Related Report
      2018 Annual Research Report 2017 Research-status Report
    • Peer Reviewed
  • [Journal Article] Preparation of optically active cycloalkenes bearing all-carbon quaternary stereogenic centres via lipase/oxovanadium combo-catalysed dynamic kinetic resolution2017

    • Author(s)
      Shinji Kawanishi, Koji Sugiyama, Yasuhiro Oki, Takashi Ikawa and Shuji Akai
    • Journal Title

      Green Chemistry

      Volume: 19 Issue: 2 Pages: 411-417

    • DOI

      10.1039/c6gc01995a

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] 1,3- and 1,4-Benzdiyne equivalents for regioselective synthesis of polycyclic heterocycles2016

    • Author(s)
      Takashi Ikawa, Shigeaki Masuda, Akira Takagi, Shuji Akai
    • Journal Title

      Chemical Sience

      Volume: 7 Issue: 8 Pages: 5206-5211

    • DOI

      10.1021/acs.joc.7b00238

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] 1,3- and 1,4-Benzdiyne Equivalents for Regioselective Synthesis of Polycyclic Heterocycles2016

    • Author(s)
      Ikawa, T.; Masuda, S.; Takagi, A.; Akai, S.
    • Journal Title

      Chemical Science

      Volume: 7 Issue: 8 Pages: 1-1

    • DOI

      10.1039/c6sc00798h

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Presentation] Dispersion Controlled (2+2) Cyclodimerization of Benzynes: Synthesis of Helical Molecules2019

    • Author(s)
      Takashi Ikawa
    • Organizer
      The 8th Heron Island Conference on Reactive Intermediates and Unusual Molecules: Synthesis and Mechanism (Heron 8)
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Not determined yet2019

    • Author(s)
      Takashi Ikawa
    • Organizer
      The 2nd International Symposium on Middle Molecular Strategy for Young Scientists (ISMMSys-2)
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] 分散力が制御するベンザインの(2+2)付加環化反応2019

    • Author(s)
      井川貴詞
    • Organizer
      第8回分子構築法 夏の勉強会
    • Related Report
      2018 Annual Research Report
  • [Presentation] ピリダインの反応制御2019

    • Author(s)
      井川貴詞
    • Organizer
      第24回生理活性をあまり意図しない自由な天然物合成勉強会
    • Related Report
      2018 Annual Research Report
  • [Presentation] Direct Benzyne Generation from Phenol Derivatives: Synthesis of Aromatic Primary Amines2018

    • Author(s)
      Takashi Ikawa
    • Organizer
      International Congress on Pure & Applied Chemistry 2018 (ICPAC 2018)
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Nonafluorobutanesulfonyl Fluoride: A Key Player for Direct Benzyne Generation from Phenols That Enables Synthesis of Primary Aniline Derivatives2018

    • Author(s)
      Ikawa, Takashi; Masuda, Shigeaki; Akai, Shuji
    • Organizer
      28th International Symposium on the Organic Chemistry of Sulfur (ISOCS 2018)
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] One-pot Benzyne Generation from Commercially Available Phenylboronic Acids2018

    • Author(s)
      Takashi Ikawa, JingKai Sun, Akira Takagi, Shuji Akai
    • Organizer
      The 14th International Kyoto Conference on New Aspects of Organic Chemistry (ICKOC-14)
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 市販のフェニルボロン酸誘導体からの新規ベンザイン発生法2018

    • Author(s)
      井川貴詞,孫 靖凱,高木 晃,赤井周司
    • Organizer
      第44回反応と合成の進歩シンポジウム
    • Related Report
      2018 Annual Research Report
  • [Presentation] 多環式ベンザインによる付加環化反応の理論的反応解析2018

    • Author(s)
      山本雄大,井川貴詞,Arulmozhiraja Sundaram,Sladek Vladimir,松尾直也,村上智成,福元 豊,高木 晃,青山 浩,赤井周司,常盤広明
    • Organizer
      第16回次世代を担う有機化学シンポジウム
    • Related Report
      2018 Annual Research Report
  • [Presentation] ベンザインを用いるアロインの合成研究2018

    • Author(s)
      井川貴詞、衣斐勇人、野崎俊史、繁田 尭、守川由起、赤井周司
    • Organizer
      日本薬学会138年会
    • Related Report
      2018 Annual Research Report 2017 Research-status Report
  • [Presentation] ベンザイン発生法によるベンザイン反応制御法の開発2018

    • Author(s)
      増田茂明、井川貴詞、赤井周司
    • Organizer
      日本薬学会138年会
    • Related Report
      2018 Annual Research Report 2017 Research-status Report
  • [Presentation] Direct Benzyne Generation from Phenol Derivatives: Synthesis of Aromatic Primary Amines2018

    • Author(s)
      Ikawa, Takashi; Masuda, Shigeaki; Akai, Shuji
    • Organizer
      International Congress on Pure & Applied Chemistry 2018 (ICPAC 2018)
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] 遷移金属触媒を用いないフェノールの直接アミノ化反応2017

    • Author(s)
      増田茂樹、井川貴詞、赤井周司
    • Organizer
      日本薬学会第137年会
    • Place of Presentation
      仙台国際センター
    • Year and Date
      2017-03-24
    • Related Report
      2016 Research-status Report
  • [Presentation] ベンザインの(2+2)付加環化二量化反応とその配向制御2017

    • Author(s)
      井川貴詞、村上智成、福元 豊、高木 晃、青山 浩、山本雄大、常盤広明、赤井周司
    • Organizer
      日本薬学会第137年会
    • Place of Presentation
      仙台国際センター
    • Year and Date
      2017-03-24
    • Related Report
      2016 Research-status Report
  • [Presentation] ベンズジイン等価体を用いる多環芳香族炭化水素の合成2017

    • Author(s)
      井川貴詞、王 鼎、増田茂明、赤井周司
    • Organizer
      日本薬学会第137年会
    • Place of Presentation
      仙台国際センター
    • Year and Date
      2017-03-24
    • Related Report
      2016 Research-status Report
  • [Presentation] 多環式ベンザインによる(2+2)付加環化反応はなぜ進行するのか?2017

    • Author(s)
      山本雄大、井川貴詞、SUNDARAM Arulmozhiraja、VLADIMIR Sladek、松尾直也、村上智成、福元 豊、高木 晃、青山 浩、赤井周司、常盤広明
    • Organizer
      日本薬学会第137年会
    • Place of Presentation
      仙台国際センター
    • Year and Date
      2017-03-24
    • Related Report
      2016 Research-status Report
  • [Presentation] Aloinの合成研究2017

    • Author(s)
      井川貴詞
    • Organizer
      第21回生物活性をあまり意図しない自由な天然物合成勉強会
    • Place of Presentation
      アワーズイン阪急
    • Year and Date
      2017-03-04
    • Related Report
      2016 Research-status Report
  • [Presentation] フェノールからのベンザイン発生及びベンザインのアミノ化反応2017

    • Author(s)
      井川貴詞
    • Organizer
      第22回生物活性をあまり意図しない自由な天然物合成勉強会
    • Related Report
      2017 Research-status Report
  • [Presentation] ベンザインを用いるらせん分子構築法の開発2017

    • Author(s)
      井川貴詞
    • Organizer
      第7回分子構築法 夏の勉強会
    • Related Report
      2017 Research-status Report 2016 Research-status Report
  • [Presentation] ベンザインの(2+2)付加環化反応を用いる新規らせん構築法の開発2017

    • Author(s)
      井川貴詞, 村上智成, 福元 豊, 高木 晃, 青山 浩, 山本雄大, 常盤広明, 赤井周司
    • Organizer
      第43回反応と合成の進歩シンポジウム
    • Related Report
      2017 Research-status Report
  • [Presentation] ベンザインとγ-アミノ-α,β-不飽和ニトリルの立体選択的反応によるインドリン環構築2017

    • Author(s)
      井川貴詞・王 鼎・角居雄太・衣斐勇人・赤井周司
    • Organizer
      第43回反応と合成の進歩シンポジウム
    • Related Report
      2017 Research-status Report
  • [Presentation] 3-トリフルオキシベンザイの位置選択的付加環化反応:ベンゾジアゼピ類の合成2017

    • Author(s)
      金子 英樹・井川 貴詞・赤井 周司
    • Organizer
      第47回複素環化学討論会
    • Related Report
      2017 Research-status Report
  • [Presentation] ベンザインの連続利用を基盤とするアロインの効率的合成研究2017

    • Author(s)
      井川貴詞、衣斐勇人、野崎俊史、繁田 尭、守川由起、赤井周司
    • Organizer
      第67回日本薬学会近畿支部会
    • Related Report
      2017 Research-status Report
  • [Presentation] トリフリルオキシベンザインによる多置換ベンゾジアゼピン類の一段階合成2017

    • Author(s)
      金子英樹、井川貴詞、赤井周司
    • Organizer
      第15回次世代を担う有機化学シンポジウム
    • Related Report
      2017 Research-status Report 2016 Research-status Report
  • [Presentation] Synthesis of 2,3-disubstituited indolines through benzyne cycloadditions with alpha-amino-beta,gamma-unsaturated nitriles2017

    • Author(s)
      Ikawa, Takashi; Sumii, Yuta; Wang, Ding; Emi, Yuto; Masuda, Shigeaki; Akai, Shuji
    • Organizer
      26th French-Japanese Symposium on Medicinal & Fine Chemistry
    • Related Report
      2017 Research-status Report
  • [Presentation] How to handle violent benzynes?2017

    • Author(s)
      Ikawa, Takashi
    • Organizer
      The Institute of Chemical Research of Catalonia (ICIQ), Special Lecture
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] Experimental and Theoretical Studies toward Benzyne Regioselectivities2017

    • Author(s)
      Ikawa, Takashi
    • Organizer
      Heidelberg University, Special Lecture
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] Universal Control of Benzyne Reactions2017

    • Author(s)
      Ikawa, Takashi
    • Organizer
      Ghent University, Special Lecture
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] ベンザインの[2+2]環化付加反応による新規らせん分子の合成2016

    • Author(s)
      井川貴詞、村上智成、福元 豊、高木 晃、青山 浩、山本雄大、常盤広明、赤井周司
    • Organizer
      第110回有機合成シンポジウム
    • Place of Presentation
      早稲田国際会議場
    • Year and Date
      2016-11-10
    • Related Report
      2016 Research-status Report
  • [Presentation] フェノールからの直接ベンザイン発生とそのアミノ化2016

    • Author(s)
      増田茂樹、井川貴詞、赤井周司
    • Organizer
      第42回反応と合成の進歩シンポジウム
    • Place of Presentation
      清水テルサ
    • Year and Date
      2016-11-07
    • Related Report
      2016 Research-status Report
  • [Presentation] 2-ボリルフェニルノナフラートを前駆体とする温和な条件下でのベンザイン発生とベンゾ縮合複素環の合成2016

    • Author(s)
      高木 晃、井川貴詞、山本梨加、赤井周司
    • Organizer
      第46回複素環化学討論会
    • Place of Presentation
      金沢
    • Year and Date
      2016-09-26
    • Related Report
      2016 Research-status Report
  • [Presentation] Copper-catalyzed Regioselective Three-component Coupling Reactions of Borylbenzynes2016

    • Author(s)
      Akira Takagi, Takashi Ikawa, Kazunori Shimizu, Masahiko Goto, Hiroaki Tokiwa, Shuji Akai
    • Organizer
      第63回有機金属化学討論会
    • Place of Presentation
      早稲田大
    • Year and Date
      2016-09-14
    • Related Report
      2016 Research-status Report
  • [Presentation] 2-(トリメチルシリル)フェニル トリメチルシリルエーテルを前駆体とする新規ベンザイン発生法の開発2016

    • Author(s)
      増田茂明、井川貴詞、中島大樹、赤井周司
    • Organizer
      第33回有機合成化学セミナー
    • Place of Presentation
      ニセコ
    • Year and Date
      2016-09-06
    • Related Report
      2016 Research-status Report
  • [Presentation] らせん分子の合成と最新の計算化学解析2016

    • Author(s)
      井川貴詞、村上智成、福元 豊、高木 晃、青山 浩、山本雄大、常盤広明、赤井周司
    • Organizer
      第20回生理活性をあまり意図しない自由な天然物合成勉強会
    • Place of Presentation
      大阪
    • Year and Date
      2016-08-27
    • Related Report
      2016 Research-status Report
  • [Presentation] ベンザインを用いるらせん分子の合成2016

    • Author(s)
      井川貴詞
    • Organizer
      第2回新学術領域研究『反応集積化が導く中分子戦略:高次生物機能分子の創製』若手シンポジウム
    • Place of Presentation
      鳥取
    • Year and Date
      2016-08-19
    • Related Report
      2016 Research-status Report
  • [Presentation] マイクロフロー環境で発生させたベンザインの効率的フッ素化反応2016

    • Author(s)
      増田茂明,井川貴詞,赤井周司
    • Organizer
      日本プロセス化学会2016サマーシンポジウム
    • Place of Presentation
      名古屋
    • Year and Date
      2016-07-28
    • Related Report
      2016 Research-status Report
  • [Presentation] 1,3-Benzdiyne equivalent bearing traceless directing groups for regioselective synthesis of polycyclic angular heterocycles2016

    • Author(s)
      Ikawa, Takashi; Masuda, Shigeaki, Takagi, Akira; Akai, Shuji
    • Organizer
      The 7th Heron Island Conference on Reactive Intermediates and Unusual Molecules: Synthesis and Mechanism (Heron 7)
    • Place of Presentation
      Australia
    • Year and Date
      2016-07-09
    • Related Report
      2016 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] TRIFLUOROMETHANESULFONYLOXY-GROUP-DIRECTED REGIOSELECTIVE REACTIONS OF BENZYNES FOR THE SYNTHESIS OF BENZO-FUSED HETEROCYCLES2016

    • Author(s)
      Takashi Ikawa, Hideki Kaneko, Shigeaki Masuda, Shuji Akai
    • Organizer
      French-Japanese Symposium on Medicinal and Fine Chemistry (FJS 2016)
    • Place of Presentation
      Tokyo, Japan.
    • Year and Date
      2016-05-16
    • Related Report
      2016 Research-status Report
    • Int'l Joint Research
  • [Presentation] 2-ヒドロキシフェニルボロン酸を前駆体とするベンザイン発生法の開発2016

    • Author(s)
      高木 晃、井川貴詞、赤井周司
    • Organizer
      第66回日本薬学会近畿支部総会・大会
    • Place of Presentation
      大阪薬科大
    • Related Report
      2016 Research-status Report
  • [Presentation] ベンザインのマイクロフローフッ素化によるフルオロベンゼン誘導体合成法の開発2016

    • Author(s)
      増田茂明,井川貴詞,赤井周司
    • Organizer
      第36回有機合成若手セミナー「明日の有機合成を担う人のために」(京都薬科)
    • Place of Presentation
      京都薬科
    • Related Report
      2016 Research-status Report
  • [Presentation] 2-ヒドロキシフェニルボロン酸を前駆体とする新規ベンザイン発生法の開発2016

    • Author(s)
      高木 晃,井川貴詞,山本梨加、赤井周司
    • Organizer
      第36回有機合成若手セミナー「明日の有機合成を担う人のために」(京都薬科)
    • Place of Presentation
      京都薬科
    • Related Report
      2016 Research-status Report
  • [Presentation] ベンザインを実験化学と理論化学の両面から斬る!2016

    • Author(s)
      井川貴詞
    • Organizer
      第36回有機合成若手セミナー「明日の有機合成を担う人のために」(京都薬科)
    • Place of Presentation
      京都薬科
    • Related Report
      2016 Research-status Report
    • Invited
  • [Remarks] 大阪大学大学院薬学研究科 薬品製造化学分野 研究成果

    • URL

      http://handai-seizo.jp/publication.html

    • Related Report
      2018 Annual Research Report 2017 Research-status Report 2016 Research-status Report
  • [Remarks] 大阪大学大学院薬学研究科 薬品製造化学分野 学会発表・講演

    • URL

      http://handai-seizo.jp/presentations.html

    • Related Report
      2018 Annual Research Report
  • [Remarks] 大阪大学大学院薬学研究科 研究トピックス

    • URL

      http://www.phs.osaka-u.ac.jp/information/topics_detail.cgi?id=1481696603

    • Related Report
      2016 Research-status Report

URL: 

Published: 2016-04-21   Modified: 2020-03-30  

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