Palladium-catalyzed $α$-arylation for the addition of small rings to aromatic compounds
Abstract
Small, strained rings have rigid, defined conformations and unique electronic properties. For these reasons, many groups seek to use these subunits to form biologically active molecules. We report a generally applicable approach to attach small rings to a wide range of aromatic compounds by palladium-catalyzed α-arylation of cyclopropyl, cyclobutyl and azetidinyl esters. The direct α-arylation of cyclopropyl esters and cyclobutyl esters is achieved in high yield by ensuring that the rate of coupling exceeds the rate of Claisen condensation. The $α$-arylation of azetidines is achieved without ring opening of the strained saturated heterocycle by conducting the reactions with an azetidine derivative bearing a benzyl protecting group on nitrogen. Mechanistic studies show that the α-arylation of small rings is challenging because of the weak acidity of α C-H bond (cyclopropanes), strong sensitivity of the strained esters to Claisen condensation (cyclobutatanes), or facile decomposition of the enolates (azetidinyl esters).
- Publication Date:
- Research Org.:
- Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
- Sponsoring Org.:
- USDOE Office of Science (SC)
- OSTI Identifier:
- 1572052
- Grant/Contract Number:
- AC02-05CH11231
- Resource Type:
- Accepted Manuscript
- Journal Name:
- Nature Communications
- Additional Journal Information:
- Journal Volume: 10; Journal Issue: 1; Journal ID: ISSN 2041-1723
- Publisher:
- Nature Publishing Group
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY
Citation Formats
He, Zhi-Tao, and Hartwig, John F. Palladium-catalyzed $α$-arylation for the addition of small rings to aromatic compounds. United States: N. p., 2019.
Web. doi:10.1038/s41467-019-12090-z.
He, Zhi-Tao, & Hartwig, John F. Palladium-catalyzed $α$-arylation for the addition of small rings to aromatic compounds. United States. doi:10.1038/s41467-019-12090-z.
He, Zhi-Tao, and Hartwig, John F. Mon .
"Palladium-catalyzed $α$-arylation for the addition of small rings to aromatic compounds". United States. doi:10.1038/s41467-019-12090-z. https://www.osti.gov/servlets/purl/1572052.
@article{osti_1572052,
title = {Palladium-catalyzed $α$-arylation for the addition of small rings to aromatic compounds},
author = {He, Zhi-Tao and Hartwig, John F.},
abstractNote = {Small, strained rings have rigid, defined conformations and unique electronic properties. For these reasons, many groups seek to use these subunits to form biologically active molecules. We report a generally applicable approach to attach small rings to a wide range of aromatic compounds by palladium-catalyzed α-arylation of cyclopropyl, cyclobutyl and azetidinyl esters. The direct α-arylation of cyclopropyl esters and cyclobutyl esters is achieved in high yield by ensuring that the rate of coupling exceeds the rate of Claisen condensation. The $α$-arylation of azetidines is achieved without ring opening of the strained saturated heterocycle by conducting the reactions with an azetidine derivative bearing a benzyl protecting group on nitrogen. Mechanistic studies show that the α-arylation of small rings is challenging because of the weak acidity of α C-H bond (cyclopropanes), strong sensitivity of the strained esters to Claisen condensation (cyclobutatanes), or facile decomposition of the enolates (azetidinyl esters).},
doi = {10.1038/s41467-019-12090-z},
journal = {Nature Communications},
number = 1,
volume = 10,
place = {United States},
year = {2019},
month = {9}
}
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Works referenced in this record:
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journal, January 2018
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Palladium-Catalyzed Regioselective Mono- and Diarylation Reactions of 2-Phenylphenols and Naphthols with Aryl Halides
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Design of a Versatile and Improved Precatalyst Scaffold for Palladium-Catalyzed Cross-Coupling: (η 3 -1- t Bu-indenyl) 2 (μ-Cl) 2 Pd 2
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Designing Pd and Ni Catalysts for Cross-Coupling Reactions by Minimizing Off-Cycle Species
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Catalytic Enantioselective Intermolecular Desymmetrization of Azetidines
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Stereoselective Synthesis of a Dipyridyl Transient Receptor Potential Vanilloid-3 (TRPV3) Antagonist
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Metal-Catalyzed α-Arylation of Carbonyl and Related Molecules: Novel Trends in CC Bond Formation by CH Bond Functionalization
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“Cationic” Suzuki–Miyaura Coupling with Acutely Base-Sensitive Boronic Acids
journal, September 2017
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- Journal of the American Chemical Society, Vol. 139, Issue 36
New indole amide derivatives as potent CRTH2 receptor antagonists
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Synthesis of Substituted Cyclopropanecarboxylates via Room Temperature Palladium-Catalyzed α-Arylation of Reformatsky Reagents
journal, May 2017
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Synthesis of Conformationally Constrained Esters and Amines by Pd-Catalyzed α-Arylation of Hindered Substrates
journal, May 2016
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Development of a Palladium-Catalyzed α-Arylation of Cyclopropyl Nitriles
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Palladium-Catalyzed α-Arylation of Ketones
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Synthesis and insecticidal properties of ether analogues of DDT-pyrethroids
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Rings in Drugs: Miniperspective
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Palladium-Catalyzed α-Arylation of Carbonyl Compounds and Nitriles
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Palladium-Catalyzed Intramolecular α-Arylation of α-Amino Acid Esters
journal, January 2002
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Transition Metal-Catalyzed Direct Arylation of Substrates with Activated sp 3 -Hybridized C−H Bonds and Some of Their Synthetic Equivalents with Aryl Halides and Pseudohalides
journal, February 2010
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Palladium-Catalyzed Direct α-Arylation of Ketones. Rate Acceleration by Sterically Hindered Chelating Ligands and Reductive Elimination from a Transition Metal Enolate Complex
journal, December 1997
- Hamann, Blake C.; Hartwig, John F.
- Journal of the American Chemical Society, Vol. 119, Issue 50
On the Mechanism of the Palladium-Catalyzed β-Arylation of Ester Enolates
journal, January 2012
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- Chemistry - A European Journal, Vol. 18, Issue 7
Synthesis and pharmacological characterization of constrained analogues of Vestipitant as in vitro potent and orally active NK1 receptor antagonists
journal, January 2010
- Sabbatini, Fabio M.; Fabio, Romano Di; Griffante, Cristiana
- Bioorganic & Medicinal Chemistry Letters, Vol. 20, Issue 2
Highly Stereoselective Carbon–Carbon Bond-forming Reactions on Cyclopropane Rings Using 1-(Methoxycarbonyl)cyclopropylzinc Bromides
journal, June 2015
- Sakuma, Daichi; Yamada, Kenta; Sasazawa, Kazuya
- Chemistry Letters, Vol. 44, Issue 6
Efficient Synthesis of α-Aryl Esters by Room-Temperature Palladium-Catalyzed Coupling of Aryl Halides with Ester Enolates
journal, October 2002
- Jørgensen, Morten; Lee, Sunwoo; Liu, Xiaoxiang
- Journal of the American Chemical Society, Vol. 124, Issue 42
Palladium-Catalyzed α-Arylation of Esters and Protected Amino Acids
journal, August 2001
- Lee, Sunwoo; Beare, Neil A.; Hartwig, John F.
- Journal of the American Chemical Society, Vol. 123, Issue 34
Correction of the F508del-CFTR protein processing defect in vitro by the investigational drug VX-809
journal, October 2011
- Van Goor, F.; Hadida, S.; Grootenhuis, P. D. J.
- Proceedings of the National Academy of Sciences, Vol. 108, Issue 46
Efficient and chemoselective alkylation of amines/amino acids using alcohols as alkylating reagents under mild conditions
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Synthesis and Biological Activity of Conformationally Restricted Analogues of Milnacipran: (1 S ,2 R )-1-Phenyl-2-[( R )-1-amino-2-propynyl] -N,N- diethylcyclopropanecarboxamide Is a Novel Class of NMDA Receptor Channel Blocker
journal, August 1998
- Shuto, Satoshi; Ono, Shizuka; Imoto, Hiroaki
- Journal of Medicinal Chemistry, Vol. 41, Issue 18
Oral Morphine Versus Injected Meperidine (Demerol) for Pain Relief in Children After Orthopedic Surgery
journal, January 1987
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- Journal of Pediatric Orthopaedics, Vol. 7, Issue 1
C−C Bond-Forming Reductive Elimination of Ketones, Esters, and Amides from Isolated Arylpalladium(II) Enolates
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- Journal of the American Chemical Society, Vol. 123, Issue 24
Cyclobutanes in Catalysis
journal, July 2011
- Seiser, Tobias; Saget, Tanguy; Tran, Duc N.
- Angewandte Chemie International Edition, Vol. 50, Issue 34
Highly Diastereoselective α-Arylation of Cyclic Nitriles
journal, June 2017
- Dalziel, Michael E.; Chen, Penghao; Carrera, Diane E.
- Organic Letters, Vol. 19, Issue 13
The “Cyclopropyl Fragment” is a Versatile Player that Frequently Appears in Preclinical/Clinical Drug Molecules
journal, June 2016
- Talele, Tanaji T.
- Journal of Medicinal Chemistry, Vol. 59, Issue 19
Surprising Reactivity in NiXantphos/Palladium-Catalyzed α-Arylation of Substituted Cyclopropyl Nitriles
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Arylcyclopropanes: Properties, Synthesis and Use in Medicinal Chemistry
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- Gagnon, Alexandre; Duplessis, Martin; Fader, Lee
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α-Arylation of Esters Catalyzed by the Pd(I) Dimer {[P( t- Bu) 3 ]PdBr} 2
journal, April 2008
- Hama, Takuo; Hartwig, John F.
- Organic Letters, Vol. 10, Issue 8
Diastereoselective Palladium-Catalyzed α-Arylation of 4-Substituted Cyclohexyl Esters
journal, November 2008
- Bercot, Eric A.; Caille, Seb; Bostick, Tracy M.
- Organic Letters, Vol. 10, Issue 22
Works referencing / citing this record:
Palladium-Catalyzed Regioselective Mono- and Diarylation Reactions of 2-Phenylphenols and Naphthols with Aryl Halides
journal, September 1997
- Satoh, Tetsuya; Kawamura, Yuichiro; Miura, Masahiro
- Angewandte Chemie International Edition in English, Vol. 36, Issue 16
Metal-Catalyzed α-Arylation of Carbonyl and Related Molecules: Novel Trends in CC Bond Formation by CH Bond Functionalization
journal, January 2010
- Johansson, Carin C. C.; Colacot, Thomas J.
- Angewandte Chemie International Edition, Vol. 49, Issue 4
Cyclobutanes in Catalysis
journal, July 2011
- Seiser, Tobias; Saget, Tanguy; Tran, Duc N.
- Angewandte Chemie International Edition, Vol. 50, Issue 34
On the Mechanism of the Palladium-Catalyzed β-Arylation of Ester Enolates
journal, January 2012
- Larini, Paolo; Kefalidis, Christos E.; Jazzar, Rodolphe
- Chemistry - A European Journal, Vol. 18, Issue 7
Synthesis and insecticidal properties of ether analogues of DDT-pyrethroids
journal, December 1986
- Holan, George; Johnson, Wynona M. P.; Jarvis, Karen E.
- Pesticide Science, Vol. 17, Issue 6
Synthesis and pharmacological characterization of constrained analogues of Vestipitant as in vitro potent and orally active NK1 receptor antagonists
journal, January 2010
- Sabbatini, Fabio M.; Fabio, Romano Di; Griffante, Cristiana
- Bioorganic & Medicinal Chemistry Letters, Vol. 20, Issue 2
New indole amide derivatives as potent CRTH2 receptor antagonists
journal, June 2011
- Zaghdane, Helmi; Boyd, Michael; Colucci, John
- Bioorganic & Medicinal Chemistry Letters, Vol. 21, Issue 11
The “Cyclopropyl Fragment” is a Versatile Player that Frequently Appears in Preclinical/Clinical Drug Molecules
journal, June 2016
- Talele, Tanaji T.
- Journal of Medicinal Chemistry, Vol. 59, Issue 19
Stereoselective Synthesis of a Dipyridyl Transient Receptor Potential Vanilloid-3 (TRPV3) Antagonist
journal, November 2016
- Voight, Eric A.; Daanen, Jerome F.; Schmidt, Robert G.
- The Journal of Organic Chemistry, Vol. 81, Issue 23
Surprising Reactivity in NiXantphos/Palladium-Catalyzed α-Arylation of Substituted Cyclopropyl Nitriles
journal, November 2018
- Wright, Brandon A.; Ardolino, Michael J.
- The Journal of Organic Chemistry, Vol. 84, Issue 8
Synthesis of Substituted Cyclopropanecarboxylates via Room Temperature Palladium-Catalyzed α-Arylation of Reformatsky Reagents
journal, May 2017
- Greszler, Stephen N.; Halvorsen, Geoff T.; Voight, Eric A.
- Organic Letters, Vol. 19, Issue 10
Highly Diastereoselective α-Arylation of Cyclic Nitriles
journal, June 2017
- Dalziel, Michael E.; Chen, Penghao; Carrera, Diane E.
- Organic Letters, Vol. 19, Issue 13
Design of a Versatile and Improved Precatalyst Scaffold for Palladium-Catalyzed Cross-Coupling: (η 3 -1- t Bu-indenyl) 2 (μ-Cl) 2 Pd 2
journal, May 2015
- Melvin, Patrick R.; Nova, Ainara; Balcells, David
- ACS Catalysis, Vol. 5, Issue 6
Synthesis of Conformationally Constrained Esters and Amines by Pd-Catalyzed α-Arylation of Hindered Substrates
journal, May 2016
- Martin, Anthony; Vors, Jean-Pierre; Baudoin, Olivier
- ACS Catalysis, Vol. 6, Issue 6
Designing Pd and Ni Catalysts for Cross-Coupling Reactions by Minimizing Off-Cycle Species
journal, March 2018
- Balcells, David; Nova, Ainara
- ACS Catalysis, Vol. 8, Issue 4
Discovery of 3,3′-Spiro[Azetidine]-2-oxo-indoline Derivatives as Fusion Inhibitors for Treatment of RSV Infection
journal, January 2018
- Shi, Weihua; Jiang, Zhigan; He, Haiying
- ACS Medicinal Chemistry Letters, Vol. 9, Issue 2
Palladium-Catalyzed α-Arylation of Carbonyl Compounds and Nitriles
journal, April 2003
- Culkin, Darcy A.; Hartwig, John F.
- Accounts of Chemical Research, Vol. 36, Issue 4
Transition Metal-Catalyzed Direct Arylation of Substrates with Activated sp 3 -Hybridized C−H Bonds and Some of Their Synthetic Equivalents with Aryl Halides and Pseudohalides
journal, February 2010
- Bellina, Fabio; Rossi, Renzo
- Chemical Reviews, Vol. 110, Issue 2
C−C Bond-Forming Reductive Elimination of Ketones, Esters, and Amides from Isolated Arylpalladium(II) Enolates
journal, June 2001
- Culkin, Darcy A.; Hartwig, John F.
- Journal of the American Chemical Society, Vol. 123, Issue 24
Palladium-Catalyzed α-Arylation of Esters and Protected Amino Acids
journal, August 2001
- Lee, Sunwoo; Beare, Neil A.; Hartwig, John F.
- Journal of the American Chemical Society, Vol. 123, Issue 34
Efficient Synthesis of α-Aryl Esters by Room-Temperature Palladium-Catalyzed Coupling of Aryl Halides with Ester Enolates
journal, October 2002
- Jørgensen, Morten; Lee, Sunwoo; Liu, Xiaoxiang
- Journal of the American Chemical Society, Vol. 124, Issue 42
Palladium-Catalyzed α-Arylation of Ketones
journal, November 1997
- Palucki, Michael; Buchwald, Stephen L.
- Journal of the American Chemical Society, Vol. 119, Issue 45
Palladium-Catalyzed Direct α-Arylation of Ketones. Rate Acceleration by Sterically Hindered Chelating Ligands and Reductive Elimination from a Transition Metal Enolate Complex
journal, December 1997
- Hamann, Blake C.; Hartwig, John F.
- Journal of the American Chemical Society, Vol. 119, Issue 50
Catalytic Enantioselective Intermolecular Desymmetrization of Azetidines
journal, May 2015
- Wang, Zhaobin; Sheong, Fu Kit; Sung, Herman H. Y.
- Journal of the American Chemical Society, Vol. 137, Issue 18
“Cationic” Suzuki–Miyaura Coupling with Acutely Base-Sensitive Boronic Acids
journal, September 2017
- Chen, Liye; Sanchez, Daniel R.; Zhang, Bufan
- Journal of the American Chemical Society, Vol. 139, Issue 36
Rings in Drugs: Miniperspective
journal, February 2014
- Taylor, Richard D.; MacCoss, Malcolm; Lawson, Alastair D. G.
- Journal of Medicinal Chemistry, Vol. 57, Issue 14
Synthesis and Biological Activity of Conformationally Restricted Analogues of Milnacipran: (1 S ,2 R )-1-Phenyl-2-[( R )-1-amino-2-propynyl] -N,N- diethylcyclopropanecarboxamide Is a Novel Class of NMDA Receptor Channel Blocker
journal, August 1998
- Shuto, Satoshi; Ono, Shizuka; Imoto, Hiroaki
- Journal of Medicinal Chemistry, Vol. 41, Issue 18
Palladium-Catalyzed Intramolecular α-Arylation of α-Amino Acid Esters
journal, January 2002
- Gaertzen, Oliver; Buchwald, Stephen L.
- The Journal of Organic Chemistry, Vol. 67, Issue 2
Development of a Palladium-Catalyzed α-Arylation of Cyclopropyl Nitriles
journal, December 2014
- McCabe Dunn, Jamie M.; Kuethe, Jeffrey T.; Orr, Robert K.
- Organic Letters, Vol. 16, Issue 24
α-Arylation of Esters Catalyzed by the Pd(I) Dimer {[P( t- Bu) 3 ]PdBr} 2
journal, April 2008
- Hama, Takuo; Hartwig, John F.
- Organic Letters, Vol. 10, Issue 8
Diastereoselective Palladium-Catalyzed α-Arylation of 4-Substituted Cyclohexyl Esters
journal, November 2008
- Bercot, Eric A.; Caille, Seb; Bostick, Tracy M.
- Organic Letters, Vol. 10, Issue 22
Efficient and chemoselective alkylation of amines/amino acids using alcohols as alkylating reagents under mild conditions
journal, January 2010
- Xu, Chu-Pei; Xiao, Zhen-Hua; Zhuo, Bi-Qin
- Chemical Communications, Vol. 46, Issue 41
Correction of the F508del-CFTR protein processing defect in vitro by the investigational drug VX-809
journal, October 2011
- Van Goor, F.; Hadida, S.; Grootenhuis, P. D. J.
- Proceedings of the National Academy of Sciences, Vol. 108, Issue 46
Arylcyclopropanes: Properties, Synthesis and Use in Medicinal Chemistry
journal, February 2010
- Gagnon, Alexandre; Duplessis, Martin; Fader, Lee
- Organic Preparations and Procedures International, Vol. 42, Issue 1
Oral Morphine Versus Injected Meperidine (Demerol) for Pain Relief in Children After Orthopedic Surgery
journal, January 1987
- OʼHara, Murielle; McGrath, Patrick J.; DʼAstous, Jacqucs
- Journal of Pediatric Orthopaedics, Vol. 7, Issue 1
Highly Stereoselective Carbon–Carbon Bond-forming Reactions on Cyclopropane Rings Using 1-(Methoxycarbonyl)cyclopropylzinc Bromides
journal, June 2015
- Sakuma, Daichi; Yamada, Kenta; Sasazawa, Kazuya
- Chemistry Letters, Vol. 44, Issue 6