共役イミンへの多段階反応の系統的制御を基盤とする反応の集積化

• Project Area: Organic Synthesis based on Integration of Chemical Reactions. New Methodologies and New Materials
• Project/Area Number: 24106715
• Research Category: Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)
• Allocation Type: Single-year Grants
• Review Section: Science and Engineering
• Research Institution: Mie University
• Principal Investigator: 清水 真 三重大学, 工学(系)研究科(研究院), 教授 (30162712)
• Project Period (FY): 2012-04-01 – 2014-03-31
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥6,760,000 (Direct Cost: ¥5,200,000、Indirect Cost: ¥1,560,000); Fiscal Year 2013: ¥3,380,000 (Direct Cost: ¥2,600,000、Indirect Cost: ¥780,000); Fiscal Year 2012: ¥3,380,000 (Direct Cost: ¥2,600,000、Indirect Cost: ¥780,000)
• Keywords: フロー合成 / β,γ-アルキニルα-イミノエステル / N-アルキルα-アシル化 / N,C-二重求核付加反応 / α-アシロキシイミノエステル / α-アミノエステル / N,N-ジアルキル化 / N,N,C-トリアルキル化 / α-イミノエステル / 極性転換反応 / 三成分カップリング反応 / イミニウム塩

Research Abstract

β,γ-アルキニルα-イミノエステルに対し、THF溶媒中、Grignard反応剤と種々の酸クロライドを順に滴下し、-78 ℃から室温まで30分反応させることにより、N-アルキルα-アシル化体が良好な収率で得られることを見出した。さらにルイス酸を加える事によってアシル化の位置選択性がかわりγ-アシル化体を選択的に得る事ができた。また、N-アルキル化後、エノラートをイミニウム塩に酸化し、第二の求核剤を作用させることにより、N,C-二重求核付加反応も進行することを見出した。
次にα-アシロキシイミノエステルに対して、求核剤として様々なGrignard反応剤を連続的に作用させることで、窒素原子上へ異なる置換基を導入することができ、それぞれ対応するα-アミノエステルが得られることを見出した。また、N,N-ジアルキル化進行後に酸化を行った後、もう一分子のGrignard反応剤で求核付加反応を行うことで、全て異なる置換基を有するN,N,C-トリアルキル化体が得られることを見出した。
このように、β,γ-アルキニル　α-イミノエステルへのGrignard反応剤によるN-アルキル後反応条件を選ぶことにより、α-アシル化およびγ-アシル化が位置選択的に良好な収率で進行することを見出した。これらの知見を活かし、β,γ-アルケニル　α-イミノエステルへの展開をはかっている。また、α-アシロキシイミノエステルを用いる反応は，全て異なる求核剤によるN,N,C-トリアルキル化反応が可能であり、そのフロー合成への展開をさらに推進している。

Current Status of Research Progress

Reason

25年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

25年度が最終年度であるため、記入しない。

Research Products

• [Journal Article] Tandem N-Alkylation/Vinylogous Aldol Reaction of β,γ-Alkenyl α-Imino Ester (2014)
  • Author(s): Tanaka, H.; Mizota, I.; Shimizu, M.
  • Journal Title: Org. Lett. Volume: 16 Issue: 8 Pages: 2276-2279
  • DOI: 10.1021/ol5007983
  • Peer Reviewed
• [Journal Article] 2-Aryl-4-quinolone Synthesis Using the Thermal Rearrangement of Iminocyclobutenones (2014)
  • Author(s): Hachiya, I.; Yokoyama, K.; Ito, A.; Shimizu, M.
  • Journal Title: Heterocycles Volume: 90 Issue: 1 Pages: 97-103
  • DOI: 10.3987/com-14-s(k)13
  • Peer Reviewed
• [Journal Article] Chemoselective Reductions and Iodinations Using Titanium Tetraiodide (2014)
  • Author(s): Hachiya, I.; Shimizu, M.
  • Journal Title: Tetrahedron Lett. Volume: 55 Issue: 17 Pages: 2781-2788
  • DOI: 10.1016/j.tetlet.2014.03.052
  • Peer Reviewed / Open Access
• [Journal Article] Integrated Reactions Based on the Sequential Addition to α-Imino Esters (2014)
  • Author(s): Koyama, K.; Mizota, I.; Shimizu, M.
  • Journal Title: Pure Appl. Chem. Volume: 86 Issue: 5 Pages: 755-764
  • DOI: 10.1515/pac-2013-1105
  • Peer Reviewed
• [Journal Article] Titanium Tetraiodide Mediated Organic Reactions (2014)
  • Author(s): Haneishi, T.; Hachiya, I.; Shimizu, M.
  • Journal Title: Arabian J. Sci. Eng. Volume: 39
  • Peer Reviewed
• [Journal Article] Chiral β-Lactam Synthesis Using Enantioselective Reduction of Iminocyclobutenones and Thermal Rearrangement of Aminocyclobutenones (2014)
  • Author(s): Hachiya, I.; Ito, A.; Shimizu, M.
  • Journal Title: Asian J. Org. Chem. Volume: 3
  • Peer Reviewed
• [Journal Article] Two-Step Synthesis of 3,4-Ethylenedioxythiophene (EDOT) from 2,3-Butanedione (2014)
  • Author(s): Hachiya, I.; Yamamoto, T.; Inagaki, T.; Matsumoto, T.; Takahashi, A.; Mizota, I.; Shimizu, M.
  • Journal Title: Heterocycles Volume: 88 Issue: 1 Pages: 607-612
  • DOI: 10.3987/com-13-s(s)8
  • Peer Reviewed
• [Journal Article] Diastereoselective Iodo Aldol Reaction of γ-Alkoxy α,β-Alkynyl Ketone Derivatives Promoted by Titanium Tetraiodide (2013)
  • Author(s): Hachiya, I.; Ito, S.; Kayaki, S.; Shimizu, M.
  • Journal Title: Asian J. Org. Chem. Volume: 2 Issue: 11 Pages: 931-934
  • DOI: 10.1002/ajoc.201300165
  • Peer Reviewed
• [Journal Article] Regioselective Tandem N-Alkylation/C-Acylation of β,γ-Alkynyl α-Imino Esters (2013)
  • Author(s): Mizota, I.; Matsuda, Y.; Kamimura, S.; Tanaka, H.; Shimizu, M.
  • Journal Title: Org. Lett. Volume: 15 Issue: 16 Pages: 4206-4209
  • DOI: 10.1021/ol401934x
  • Peer Reviewed
• [Journal Article] Synthesis of Azulene Derivatives Having an Azathiacrown Ether Moiety and Their Selective Color Reaction toward Silver Ion (2013)
  • Author(s): Wakabayashi, S.; Uchida, M.; Tanaka, R.; Shimizu, M.
  • Journal Title: Asian J. Org. Chem. Volume: 2 Issue: 9 Pages: 786-791
  • DOI: 10.1002/ajoc.201300131
  • Peer Reviewed
• [Journal Article] Tandem N-Alkylation-Addition Reaction of α-Imino Esters and Application to a New Flow System (2013)
  • Author(s): Sano, T.; Mizota, I.; Shimizu, M.
  • Journal Title: Chem. Lett. Volume: 42 Issue: 9 Pages: 995-997
  • DOI: 10.1246/cl.130396
  • NAID: 10031194318
  • Peer Reviewed
• [Journal Article] Highly Diastereoselective Tandem N-Alkylation-Mannich Reaction of α-Imino Esters (2013)
  • Author(s): Shimizu, M.
  • Journal Title: Asian. J. Org. Chem. Volume: 2 Issue: 3 Pages: 208-211
  • DOI: 10.1002/ajoc.201300010
  • Peer Reviewed
• [Journal Article] A New Single-ion Polymer Electrolyte Based on Polyvinyl Alcohol for Lithium Ion Batteries (2013)
  • Author(s): Zhu, Y. S.
  • Journal Title: Electrochimica Acta Volume: 87 Pages: 113-118
  • DOI: 10.1016/j.electacta.2012.08.114
  • Peer Reviewed
• [Journal Article] Synthesis of Indolin-3-ones and Tetrahydro-4-quinolones Using α-Imino Esters (2013)
  • Author(s): Shimizu, M.
  • Journal Title: Asian. J. Org. Chem. Volume: 2 Issue: 2 Pages: 130-134
  • DOI: 10.1002/ajoc.201200174
  • Peer Reviewed
• [Journal Article] Synthesis of α-Amino Ketones and O-Alkyloximes by Titanium Tetrahalide Promoted Ring-Opening Reaction of 2-Mono-Substituted Azetidin-3-ones and Their O-Alkyloximes (2012)
  • Author(s): Shizuka Ariga, Shingo Hata, Daisuke Fukuda, Takafumi Nishi, Iwao Hachiya, Makoto Shimizu
  • Journal Title: Heterocycles Volume: 86(2) Issue: 2 Pages: 1187-1210
  • DOI: 10.3987/com-12-s(n)74
  • Peer Reviewed
• [Journal Article] <i>N</i>,<i>N</i>-Di- and <i>N</i>,<i>N</i>,<i>C</i>-Trialkylation of &alpha;-Sulfoximino Esters (2012)
  • Author(s): Hata, S.
  • Journal Title: Bulletin of the Chemical Society of Japan Volume: 85 Issue: 11 Pages: 1203-1205
  • DOI: 10.1246/bcsj.20120195
  • NAID: 130004153004
  • ISSN: 0009-2673, 1348-0634
  • Peer Reviewed
• [Journal Article] Sulfur-Containing Pyridylazulenes: Synthesis and Chromogenic Behaviors for Heavy Metal Ions (2012)
  • Author(s): Wakabayashi, S.
  • Journal Title: Heterocycles Volume: 85 Issue: 9 Pages: 2251-2258
  • DOI: 10.3987/com-12-12536
  • Peer Reviewed
• [Journal Article] Integrated Reactions Using Addition to Conjugated Imines and Iminium Salts (2012)
  • Author(s): Nishi, T.
  • Journal Title: Pure Appl. Chem. Volume: 84 Issue: 12 Pages: 2609-2617
  • DOI: 10.1351/pac-con-12-01-03
  • Peer Reviewed
• [Presentation] 共役イミン誘導体を活用する新規合成反応 (2013)
  • Author(s): 清水 真
  • Organizer: 有機合成化学協会東海支部総合講演会
  • Place of Presentation: 岐阜薬科大学, 岐阜市
  • Invited
• [Presentation] Tandem N-Alkylation-Addition Reaction of α-Aldimino Esters and Application to a New Flow System (2013)
  • Author(s): Sano, T.; Mizota, I.; Shimizu, M.
  • Organizer: The 8th International Symposium on Integrated Synthesis (ISIS-8)
  • Place of Presentation: Nara, Japan,
• [Presentation] Integrated Reactions Based on the Sequential Addition to Conjugated Imines (2013)
  • Author(s): Shimizu, M.
  • Organizer: The 23rd International Symposium on Fine Chemistry and Functional Polymers & IUPAC 9th International Conference on Novel Materials and Their Synthesis
  • Place of Presentation: Shanghai, China
  • Invited
• [Presentation] Umpoled Tandem Reaction of α-Imino Esters (2013)
  • Author(s): Shimizu, M.
  • Organizer: The 15th Asian Chemical Congress (ACC15)
  • Place of Presentation: Singapore
  • Invited
• [Presentation] Unsaturated Imino Compounds as Acceptors for Multiple Nucleophiles (2013)
  • Author(s): Shimizu, M.
  • Organizer: 1st International Symposium on Nature Product, Biotechnology and Catalysis,
  • Place of Presentation: Hohhot, China
  • Invited
• [Presentation] Stereodivergent Synthesis of β-Lactams Using Thermal Rearrangement of Aminocyclobutenones (2012)
  • Author(s): Hachiya, I.
  • Organizer: The 12th International Kyoto Conference on New Aspects of Organic Chemistry
  • Place of Presentation: Kyoto, Japan
  • Year and Date: 2012-11-12
• [Presentation] 共役イミン誘導体―ハイブリッド合成素子 (2012)
  • Author(s): 清水 真
  • Organizer: 第43回中部化学関係学協会支部連合秋期大会
  • Place of Presentation: 名古屋工業大学、愛知
  • Year and Date: 2012-11-10
  • Invited
• [Presentation] α-Imino Esters as Versatile Building Blocks in Organic Synthesis (2012)
  • Author(s): Shimizu, M.
  • Organizer: The 22nd International Symposium on Fine Chemistry and Functional Polymers IUPAC 8th International Conference on Novel Materials and Their Synthesis
  • Place of Presentation: Xi’An, China
  • Year and Date: 2012-10-14
  • Invited
• [Presentation] Claisen Rearrangement of α-Imino Allyl Ester Using an Umpolung Reaction (2012)
  • Author(s): Mizota. I.
  • Organizer: The 22nd International Symposium on Fine Chemistry and Functional Polymers IUPAC 8th International Conference on Novel Materials and Their Synthesis
  • Place of Presentation: Xi’An, China
  • Year and Date: 2012-10-14
• [Presentation] Nucleophilic Addition to Conjugated Imines Leading to the Synthesis of HeterocyclesUmpoled Tandem Reaction of α-Imino Esters (2012)
  • Author(s): Shimizu, M.
  • Organizer: 4th Congress of the European Association for Chemical and Molecular Sciences
  • Place of Presentation: Prague, Czech Republic
  • Year and Date: 2012-08-16
  • Invited
• [Book] Samarium(II) Iodide and Titanium(IV) Iodide In Iodine: Chemistry and Application; (2014)
  • Author(s): Inanaga, J.; Shimizu, M.; Hachiya, I.
  • Total Pages: 14
  • Publisher: John Wiley & Sons
• [Patent(Industrial Property Rights)] 電解コンデンサの駆動用電解液およびそれを用いた電解コンデンサ (2013)
  • Inventor(s): 清水 真
  • Industrial Property Rights Holder: 清水 真
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2013-162112
  • Filing Date: 2013-08-05
• [Patent(Industrial Property Rights)] 電解コンデンサの駆動用電解液およびそれを用いた電解コンデンサ (2013)
  • Inventor(s): 清水 真
  • Industrial Property Rights Holder: 清水 真
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2013-146611
  • Filing Date: 2013-07-12