Development bond exchange reaction and optimization reaction conditions using Machine Learning

• Project Area: Digitalization-driven Transformative Organic Synthesis (Digi-TOS)
• Project/Area Number: 21H05213
• Research Category: Grant-in-Aid for Transformative Research Areas (A)
• Allocation Type: Single-year Grants
• Review Section: Transformative Research Areas, Section (II)
• Research Institution: Waseda University
• Principal Investigator: 山口 潤一郎 早稲田大学, 理工学術院, 教授 (00529026)
• Project Period (FY): 2021-09-10 – 2026-03-31
• Project Status: Granted (Fiscal Year 2025)
• Budget Amount: ¥38,870,000 (Direct Cost: ¥29,900,000、Indirect Cost: ¥8,970,000); Fiscal Year 2025: ¥7,410,000 (Direct Cost: ¥5,700,000、Indirect Cost: ¥1,710,000); Fiscal Year 2024: ¥7,020,000 (Direct Cost: ¥5,400,000、Indirect Cost: ¥1,620,000); Fiscal Year 2023: ¥7,280,000 (Direct Cost: ¥5,600,000、Indirect Cost: ¥1,680,000); Fiscal Year 2022: ¥7,280,000 (Direct Cost: ¥5,600,000、Indirect Cost: ¥1,680,000); Fiscal Year 2021: ¥9,880,000 (Direct Cost: ¥7,600,000、Indirect Cost: ¥2,280,000)
• Keywords: ヘテロ環 / 機械学習 / 交換反応 / 分子編集 / 芳香族ケトン / 結合交換 / エステル / ニッケル / パラジウム / 芳香族ニトロ化合物 / 結合交換反応 / 金属触媒 / 芳香族化合物 / 官能基 / 芳香環交換反応 / クロスカップリング / ニトリル / スルフィド / アリール交換

Outline of Research at the Start

本研究は、申請者らが見いだした異種結合交換反応（アリール交換反応）に適用可能な芳香環の拡大、さらに多種な結合交換が可能な触媒開発に着手する。具体的には、エステル・ニトロ基・ケトン・エーテル・ニトリルなどの不活性結合を同時に活性化可能な触媒を用いた結合交換反応により安価で入手容易な化合物から高付加価値の化合物を合成する。さらに、最も高反応性官能基であるハロゲンを残したまま不活性結合を活性化し得る反応系の探索に挑戦する。触媒設計と適用できる化合物群の選定は結合解離エネルギーと触媒構造の適切なパラメータ化を用いて機械学習によって得られた知見を最短の最適化法として駆使する。

Outline of Annual Research Achievements

本研究は、申請者らが見いだした異種結合交換反応（アリール交換反応）に適用可能な芳香環の拡大、さらに多種な結合交換が可能な触媒開発に着手する。。具体的には、エステル・ニトロ基・ケトン・エーテル・ニトリルなどの不活性結合を同時に活性化可能な触媒を用いた結合交換反応により安価で入手容易な化合物から高付加価値の化合物を合成する。
これらの反応を進行させるためには、２種類の不活性結合の活性化が必要となる。それらを探索中に、芳香族ニトロ化合物のニトロ化反応、多様な芳香族化合物のチオメチル化反応を見出すことができた。関連研究として、芳香族ケトンの脱アシル型カップリング反応（結合交換反応を含む）、脱酸素型カップリング反応を開発した。その他、脱芳香族的官能基化反応として、アザアレーンの開環型ジフルオロ化反応や分子内環化/脱芳香族化反応（すぐに芳香環化する）を見出した。

Current Status of Research Progress

2: Research has progressed on the whole more than it was originally planned.

Reason

結合交換反応に関しては、今年度多くの進展はなかったが、その他の関連反応探索が順調であり、機械学習に関しても研究をすすめているため、おおむね順調に進呈しているとした。

Strategy for Future Research Activity

引き続き結合交換反応を探索する。現在見出している関連した反応に関しても論文としてまとめ公開する

Research Products

• [Journal Article] Ring‐opening Fluorination of Carbo/Heterocycles and Aromatics: Construction of Complex and Diverse Fluorine‐containing Molecules (2023)
  • Author(s): Komatsuda Masaaki、Yamaguchi Junichiro
  • Journal Title: The Chemical Record Volume: － Issue: 9
  • DOI: 10.1002/tcr.202200281
  • Peer Reviewed
• [Journal Article] Activation of Alkyl Chlorides Enabled by Zirconocene and Photoredox Catalysis (2023)
  • Author(s): Okita Toshimasa、Aida Kazuhiro、Tanaka Keisuke、Ota Eisuke、Yamaguchi Junichiro
  • Journal Title: Precis. Chem. Volume: 1 Pages: 112-118
  • DOI: 10.26434/chemrxiv-2022-5n811
• [Journal Article] Pd-Catalyzed Denitriative Intramolecular Mizoroki?Heck Reaction (2023)
  • Author(s): Asahara Kitty K.、Muto Kei、Yamaguchi Junichiro
  • Journal Title: Chemistry Letters Volume: － Issue: 4 Pages: 299-302
  • DOI: 10.1246/cl.230056
  • Peer Reviewed
• [Journal Article] Chloroacetyl boronate <i>N</i>-tosylhydrazone as a versatile synthetic building block (2023)
  • Author(s): Miyazaki Ryuya、Muto Kei、Yamaguchi Junichiro
  • Journal Title: Chemical Communications Volume: 59 Issue: 48 Pages: 7419-7422
  • DOI: 10.1039/d3cc02086j
  • Peer Reviewed
• [Journal Article] Repurposing carboxylic acids and alcohols/amines to create α-hydroxy/amino ketones (2023)
  • Author(s): Ishihara Yoshihiro、Yamaguchi Junichiro
  • Journal Title: Chem Volume: 9 Issue: 7 Pages: 1630-1632
  • DOI: 10.1016/j.chempr.2023.06.004
• [Journal Article] Concise synthesis of (±)-fortuneicyclidins and (±)-cephalotine B enabled by Pd-catalyzed dearomative spirocyclization (2023)
  • Author(s): Uwabe Yota、Muto Kei、Yamaguchi Junichiro
  • Journal Title: Chem. E. J. Volume: 29
  • DOI: 10.26434/chemrxiv-2023-jx26c-v2
• [Journal Article] Catalytic reductive ring opening of epoxides enabled by zirconocene and photoredox catalysis (2022)
  • Author(s): Aida Kazuhiro、Hirao Marina、Funabashi Aiko、Sugimura Natsuhiko、Ota Eisuke、Yamaguchi Junichiro
  • Journal Title: Chem Volume: 8 Issue: 6 Pages: 1762-1774
  • DOI: 10.1016/j.chempr.2022.04.010
  • Peer Reviewed / Open Access
• [Journal Article] Decarbonylative Reductive Coupling of Aromatic Esters by Nickel and Palladium Catalyst (2022)
  • Author(s): Peng Yunfei、Isshiki Ryota、Muto Kei、Yamaguchi Junichiro
  • Journal Title: Chemistry Letters Volume: 51 Issue: 7 Pages: 749-753
  • DOI: 10.1246/cl.220214
  • Peer Reviewed
• [Journal Article] Palladium-Catalyzed Tandem Ester Dance/Decarbonylative Coupling Reactions (2022)
  • Author(s): Kubo Masayuki、Inayama Naomi、Ota Eisuke、Yamaguchi Junichiro
  • Journal Title: Organic Letters Volume: 24 Issue: 21 Pages: 3855-3860
  • DOI: 10.1021/acs.orglett.2c01432
  • Peer Reviewed
• [Journal Article] Pd-Catalyzed 1,4-Carboamination of Bicyclic Bromoarenes with Diazo Compounds and Amines (2022)
  • Author(s): Wu Qikun、Muto Kei、Yamaguchi Junichiro
  • Journal Title: Organic Letters Volume: 24 Issue: 23 Pages: 4129-4134
  • DOI: 10.1021/acs.orglett.2c01233
  • Peer Reviewed
• [Journal Article] Chemical biology to dissect molecular mechanisms underlying plant circadian clocks (2022)
  • Author(s): Nakamichi Norihito、Yamaguchi Junichiro、Sato Ayato、Fujimoto Kazuhiro J.、Ota Eisuke
  • Journal Title: New Phytologist Volume: 235 Issue: 4 Pages: 1336-1343
  • DOI: 10.1111/nph.18298
  • Peer Reviewed / Open Access
• [Journal Article] Identification of α-Synuclein Proaggregator: Rapid Synthesis and Streamlining RT-QuIC Assays in Parkinson’s Disease (2022)
  • Author(s): Takada Fumito、Kasahara Takahito、Otake Kentaro、Maru Takamitsu、Miwa Masanori、Muto Kei、Sasaki Minoru、Hirozane Yoshihiko、Yoshikawa Masato、Yamaguchi Junichiro
  • Journal Title: ACS Medicinal Chemistry Letters Volume: 13 Issue: 9 Pages: 1421-1426
  • DOI: 10.1021/acsmedchemlett.2c00138
  • Peer Reviewed / Open Access
• [Journal Article] Unified synthesis of multiply arylated alkanes by catalytic deoxygenative transformation of diarylketones (2022)
  • Author(s): Kurosawa Miki B.、Kato Kenta、Muto Kei、Yamaguchi Junichiro
  • Journal Title: Chemical Science Volume: 13 Issue: 36 Pages: 10743-10751
  • DOI: 10.1039/d2sc03720c
  • Peer Reviewed / Open Access
• [Journal Article] Synthesis and Properties of Pyridine-Fused Triazolylidene?Palladium: Catalyst for Cross-Coupling Using Chloroarenes and Nitroarenes (2022)
  • Author(s): Iizumi Keiichiro、Nakayama Keito P.、Kato Kenta、Muto Kei、Yamaguchi Junichiro
  • Journal Title: The Journal of Organic Chemistry Volume: 87 Issue: 17 Pages: 11909-11918
  • DOI: 10.1021/acs.joc.2c01562
  • Peer Reviewed
• [Journal Article] Structure?Function Study of a Novel Inhibitor of Cyclin-Dependent Kinase C in Arabidopsis (2022)
  • Author(s): Saito Ami N、Maeda Akari E、Takahara Tomoaki T、Matsuo Hiromi、Nishina Michiya、Ono Azusa、Shiratake Katsuhiro、Notaguchi Michitaka、Yanai Takeshi、Kinoshita Toshinori、Ota Eisuke、Fujimoto Kazuhiro J、Yamaguchi Junichiro、Nakamichi Norihito
  • Journal Title: Plant and Cell Physiology Volume: 63 Issue: 11 Pages: 1720-1728
  • DOI: 10.1093/pcp/pcac127
  • Peer Reviewed / Open Access
• [Journal Article] Aryl Dance Reaction of Arylbenzoheteroles (2022)
  • Author(s): Nakahara Hikaru、Yamaguchi Junichiro
  • Journal Title: Organic Letters Volume: 24 Issue: 43 Pages: 8083-8087
  • DOI: 10.1021/acs.orglett.2c03442
  • Peer Reviewed
• [Journal Article] Ring-opening fluorination of bicyclic azaarenes (2022)
  • Author(s): Komatsuda Masaaki、Suto Ayane、Kondo Hiroki、Takada Hiroyuki、Kato Kenta、Saito Bunnai、Yamaguchi Junichiro
  • Journal Title: Chemical Science Volume: 13 Issue: 3 Pages: 665-670
  • DOI: 10.1039/d1sc06273e
  • Peer Reviewed / Open Access
• [Journal Article] Pd-Catalyzed Asymmetric Dearomative Arylation of Indoles via a Desymmetrization Strategy (2022)
  • Author(s): Nie Yu-Han、Komatsuda Masaaki、Yang Ping、Zheng Chao、Yamaguchi Junichiro、You Shu-Li
  • Journal Title: Organic Letters Volume: 24 Issue: 7 Pages: 1481-1485
  • DOI: 10.1021/acs.orglett.2c00129
  • Peer Reviewed
• [Journal Article] Formal Syntheses of Dictyodendrins B, C, and E by a Multi-substituted Indole Synthesis (2022)
  • Author(s): Kabuki Akira、Yamaguchi Junichiro
  • Journal Title: Synthesis Volume: － Issue: 22 Pages: 4963-4970
  • DOI: 10.1055/a-1786-9881
  • Peer Reviewed
• [Journal Article] Ring-Opening Fluorination of Isoxazoles (2022)
  • Author(s): Komatsuda Masaaki、Ohki Hugo、Kondo Hiroki、Suto Ayane、Yamaguchi Junichiro
  • Journal Title: Organic Letters Volume: 24 Issue: 17 Pages: 3270-3274
  • DOI: 10.1021/acs.orglett.2c01149
  • Peer Reviewed
• [Journal Article] Fluorination -A Decade of Progress (2010-2020) (2021)
  • Author(s): Suto Ayane、Yamaguchi Junichiro
  • Journal Title: Journal of Synthetic Organic Chemistry, Japan Volume: 79 Issue: 10 Pages: 910-967
  • DOI: 10.5059/yukigoseikyokaishi.79.910
  • NAID: 130008102165
  • ISSN: 0037-9980, 1883-6526
  • Year and Date: 2021-10-01
  • Peer Reviewed
• [Journal Article] Development of Pd-Catalyzed Denitrative Couplings (2021)
  • Author(s): 淺原光太郎, 柏原美勇斗, 武藤慶, 中尾佳亮, 山口潤一郎
  • Journal Title: Journal of Synthetic Organic Chemistry, Japan Volume: 79 Issue: 1 Pages: 11-21
  • DOI: 10.5059/yukigoseikyokaishi.79.11
  • NAID: 130007966738
  • ISSN: 0037-9980, 1883-6526
  • Year and Date: 2021-01-01
  • Peer Reviewed
• [Journal Article] Decarbonylative Synthesis of Aryl Nitriles from Aromatic Esters and Organocyanides by a Nickel Catalyst (2021)
  • Author(s): Yamaguchi Junichiro、Iizumi Keiichiro、Kurosawa Miki B.、Isshiki Ryota、Muto Kei
  • Journal Title: Synlett Volume: 32 Issue: 15 Pages: 1555-1559
  • DOI: 10.1055/s-0040-1705943
  • Peer Reviewed
• [Journal Article] Ni-Catalyzed Aryl Sulfide Synthesis through an Aryl Exchange Reaction (2021)
  • Author(s): Isshiki Ryota、Kurosawa Miki B.、Muto Kei、Yamaguchi Junichiro
  • Journal Title: Journal of the American Chemical Society Volume: 143 Issue: 27 Pages: 10333-10340
  • DOI: 10.1021/jacs.1c04215
  • Peer Reviewed / Open Access
• [Journal Article] Convergent Azaspirocyclization of Bromoarenes with <i>N</i>-Tosylhydrazones by a Palladium Catalyst (2021)
  • Author(s): Yanagimoto Aika、Uwabe Yota、Wu Qikun、Muto Kei、Yamaguchi Junichiro
  • Journal Title: ACS Catalysis Volume: 11 Issue: 16 Pages: 10429-10435
  • DOI: 10.1021/acscatal.1c02627
  • Peer Reviewed
• [Presentation] 開環型フッ素化反応と脱フッ素化反応 (2023)
  • Author(s): 山口潤一郎
  • Organizer: 京都大学講演会
  • Invited
• [Presentation] Unconventional Recipes for Aromatic Carbonyls Transformations (2023)
  • Author(s): Junichiro Yamaguchi
  • Organizer: 北京大学講演会
  • Int'l Joint Research / Invited
• [Presentation] Unconventional Recipes for Aromatic Carbonyls Transformations (2023)
  • Author(s): Junichiro Yamaguchi
  • Organizer: 西安交通大学講演会
• [Presentation] 有機合成化学の新潮流をつくる (2023)
  • Author(s): 山口潤一郎
  • Organizer: 先進研究講演会
  • Invited
• [Presentation] 開環型フッ素化反応と脱フッ素化反応 (2023)
  • Author(s): 山口潤一郎
  • Organizer: 大阪大学講演会
  • Invited
• [Presentation] Breaking C-F Bonds: Novel Strategies Using Polar and Radical Reactions (2023)
  • Author(s): Junichiro Yamaguchi
  • Organizer: 7th Gratama Workshop 2023
  • Int'l Joint Research / Invited
• [Presentation] 開環型フッ素化反応と脱フッ素化反応 (2023)
  • Author(s): 山口潤一郎
  • Organizer: 日本フッ素化学会第10回産学連携部会
  • Invited
• [Presentation] 応用化学科の現状と分子レベルのものづくり研究 (2023)
  • Author(s): 山口潤一郎
  • Organizer: 早稲田応用化学会中部支部
• [Presentation] 高難度有機反応の開発と医農薬関連企業との共同研究 (2021)
  • Author(s): 山口潤一郎
  • Organizer: 第31回万有福岡シンポジウム 有機合成化学の変革～未踏の森に飛び込もう～
  • Invited