Chemistry › Organic Chemistry

Synthesis and Catalytic Reactions

Works Count: 35970

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This cluster of papers focuses on the catalytic C-H amination reactions, including nitrene transfer methods, enantioselective synthesis of aziridines, and the use of sulfoximines in medicinal chemistry. The research covers various metal-catalyzed approaches and their applications in the synthesis of biologically relevant compounds.

Keywords

Catalytic; Amination; C-H Bonds; Nitrene Transfer; Aziridines; Metal-Catalyzed; Enantioselective; Synthesis; Sulfoximines; Medicinal Chemistry

Potent and specific inhibition of glutathione synthesis by buthionine sulfoximine (S-n-butyl homocysteine sulfoximine).

1979-08-01

Owen W. Griffith , A Meister

Buthionine sulfoximine (S-n-butyl homocysteine sulfoximine), the most potent of a series of analogs of methionine sulfoximine thus far studied (Griffith, O.W., Anderson, M.E., and Meister, A. (1979) J. Biol. Chem. … Buthionine sulfoximine (S-n-butyl homocysteine sulfoximine), the most potent of a series of analogs of methionine sulfoximine thus far studied (Griffith, O.W., Anderson, M.E., and Meister, A. (1979) J. Biol. Chem. 254, 1205-1210), inhibited gamma-glutamylcysteine synthetase about 20 times more effectively than did prothionine sulfoximine and at least 100 times more effectively than methionine sulfoximine. The findings support the conclusion that the S-alkyl moiety of the sulfoximine binds at the enzyme site that normally binds the acceptor amino acid. Thus, the affinity of the enzyme for the S-ethyl, S-n-propyl, and S-n-butyl sulfoximines increases in a manner which is parallel to those of the corresponding isosteric acceptor amino acid substrates, i.e. glycine, alanine, and alpha-aminobutyrate. Buthionine sulfoximine did not inhibit glutamine synthetase detectably, nor did it produce convulsions when injected into mice. Injection of buthionine sulfoximine into mice decreased the level of glutathione in the kidney to a greater extent (less than 20% of the control level) than found previously after giving prothionine sulfoximine. alpha-Methyl buthionine sulfoximine was also prepared and found to be almost as effective as buthionine sulfoximine; this compound would not be expected to undergo substantial degradative metabolism. Buthionine sulfoximine and alpha-methyl buthionine sulfoximine may be useful agents for inhibition of glutathione synthesis in various experimental systems.

Bis(oxazoline)-copper complexes as chiral catalysts for the enantioselective aziridination of olefins

1993-06-01

David A. Evans , Margaret M. Faul , Mark T. Bilodeau +2 more

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTBis(oxazoline)-copper complexes as chiral catalysts for the enantioselective aziridination of olefinsDavid A. Evans, Margaret M. Faul, Mark T. Bilodeau, Benjamin A. Anderson, and David M. BarnesCite this: … ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTBis(oxazoline)-copper complexes as chiral catalysts for the enantioselective aziridination of olefinsDavid A. Evans, Margaret M. Faul, Mark T. Bilodeau, Benjamin A. Anderson, and David M. BarnesCite this: J. Am. Chem. Soc. 1993, 115, 12, 5328–5329Publication Date (Print):June 1, 1993Publication History Published online1 May 2002Published inissue 1 June 1993https://pubs.acs.org/doi/10.1021/ja00065a068https://doi.org/10.1021/ja00065a068research-articleACS PublicationsRequest reuse permissionsArticle Views4109Altmetric-Citations498LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-AlertscloseSupporting Info (2)»Supporting Information Supporting Information Get e-Alerts

Development of Cascade Reactions for the Concise Construction of Diverse Heterocyclic Architectures

2012-05-11

Liang‐Qiu Lu , Jia‐Rong Chen , Wen‐Jing Xiao

Heterocyclic structural architectures occur in many bioactive natural products and synthetic drugs, and these structural units serve as important intermediates in organic synthesis. This Account documents our recent progress in … Heterocyclic structural architectures occur in many bioactive natural products and synthetic drugs, and these structural units serve as important intermediates in organic synthesis. This Account documents our recent progress in the development of cascade reactions to construct complex carbocycles and heterocycles. We describe the rational design of cascade reactions and in-depth investigations of their mechanism as well as their applications in the synthesis of drugs, natural products, and related molecular analogs.Relying on knowledge about the dipole-type reactivity of sulfur ylides, we have developed three different types of cascade reactions: a [4 + 1] annulation/rearrangement cascade, a [4 + 1]/[3 + 2] cycloaddition cascade, and a Michael addition/N-alkylation cascade. Using these processes, we can generate oxazolidinones, fused heterocycles, and pyrrolines starting with simple and readily available substances such as nitroolefins and unsaturated imines. We have also developed corresponding enantioselective reactions, which are guided by axial chirality and asymmetric H-bonding control. In addition, by relying on the reactivity characteristics of newly designed acrylate-linked nitroolefins, we have disclosed an asymmetric Michael/Michael/retro-Michael addition cascade using the combination of a protected hydroxylamine and a bifunctional organocatalyst. Using this methodology, we prepared chiral chromenes in good yields and with high enantioselectivities. Moreover, a series of double Michael addition cascade reactions with anilines, thiophenols, and benzotriazoles generated highly functionalized chromanes. Via mechanistically distinct cascade processes that start with vinyl-linked indoles, we have synthesized polycyclic indoles. Intermolecular cross-metathesis/intramolecular Friedel–Crafts alkylation cascades, promoted by either a single ruthenium alkylidene catalyst or a sequence involving Grubbs' ruthenium catalyst and MacMillan's imidazolidinone catalyst, converted ω-indolyl alkenes into tetrahydrocarbazoles, tetrahydropyranoindoles, and tetrahydrocarbolines. In addition, we constructed tetrahydrocarbazoles and tetrahydroquinones using organocatalytic Friedel–Crafts alkylation/Michael addition cascades that used 2-vinyl indoles as common starting materials.Most green plants carry out photosynthesis to produce organic substances relying on readily available and renewable solar energy. In a related manner, we have also developed two cascade reactions that merge visible light-induced aerobic oxidation with either [3 + 2] cycloaddition/oxidative aromatization or intramolecular cyclization. These processes lead to the formation of pyrrolo[2,1-a]isoquinolines and enantiopure tetrahydroimidazoles, respectively.

Synopsis of Some Recent Tactical Application of Bioisosteres in Drug Design

2011-03-17

Nicholas A. Meanwell

ADVERTISEMENT RETURN TO ISSUEPerspectiveNEXTSynopsis of Some Recent Tactical Application of Bioisosteres in Drug DesignNicholas A. Meanwell*View Author Information Department of Medicinal Chemistry, Bristol-Myers Squibb Pharmaceutical Research and Development, 5 Research … ADVERTISEMENT RETURN TO ISSUEPerspectiveNEXTSynopsis of Some Recent Tactical Application of Bioisosteres in Drug DesignNicholas A. Meanwell*View Author Information Department of Medicinal Chemistry, Bristol-Myers Squibb Pharmaceutical Research and Development, 5 Research Parkway, Wallingford, Connecticut 06492, United StatesContact information. Phone: 203-677-6679. Fax: 203-677-7884. E-mail: [email protected]Cite this: J. Med. Chem. 2011, 54, 8, 2529–2591Publication Date (Web):March 17, 2011Publication History Received20 October 2010Published online17 March 2011Published inissue 28 April 2011https://pubs.acs.org/doi/10.1021/jm1013693https://doi.org/10.1021/jm1013693review-articleACS PublicationsCopyright © 2011 American Chemical SocietyRequest reuse permissionsArticle Views91020Altmetric-Citations2203LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose SUBJECTS:Antagonists,Heterocyclic compounds,Inhibitors,Molecules,Peptides and proteins Get e-Alerts

Catalytic C–H functionalization by metalloporphyrins: recent developments and future directions

2010-11-19

Hongjian Lu , X. Peter Zhang

Metalloporphyrins are a class of versatile catalysts with the capability to functionalize saturated C-H bonds via several well-defined atom/group transfer processes, including oxene, nitrene, and carbene C-H insertions. The corresponding … Metalloporphyrins are a class of versatile catalysts with the capability to functionalize saturated C-H bonds via several well-defined atom/group transfer processes, including oxene, nitrene, and carbene C-H insertions. The corresponding hydroxylation, amination, and alkylation reactions provide direct approaches for the catalytic conversion of abundant hydrocarbons into value-added functional molecules through C-O, C-N, and C-C bond formations, respectively. This tutorial review describes metalloporphyrin-based catalytic systems for the functionalization of different types of sp(3) C-H bonds, both inter- and intramolecularly, including challenging primary C-H bonds. Additional features of metalloporphyrin-catalyzed C-H functionalization include unusual selectivities and high turnover numbers.

Asymmetric Synthesis of Tertiary Alcohols and α-Tertiary Amines via Cu-Catalyzed C−C Bond Formation to Ketones and Ketimines

2008-06-21

Masakatsu Shibasaki , Motomu Kanai

ADVERTISEMENT RETURN TO ISSUEPREVReviewNEXTAsymmetric Synthesis of Tertiary Alcohols and α-Tertiary Amines via Cu-Catalyzed C−C Bond Formation to Ketones and KetiminesMasakatsu Shibasaki* and Motomu KanaiView Author Information Graduate School of Pharmaceutical … ADVERTISEMENT RETURN TO ISSUEPREVReviewNEXTAsymmetric Synthesis of Tertiary Alcohols and α-Tertiary Amines via Cu-Catalyzed C−C Bond Formation to Ketones and KetiminesMasakatsu Shibasaki* and Motomu KanaiView Author Information Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan* To whom correspondence should be addressed. Tel.: +81-3-5940-2830. Fax: +81-3-5684-5206. E-mail: [email protected]Cite this: Chem. Rev. 2008, 108, 8, 2853–2873Publication Date (Web):June 21, 2008Publication History Received29 November 2007Published online21 June 2008Published inissue 1 August 2008https://pubs.acs.org/doi/10.1021/cr078340rhttps://doi.org/10.1021/cr078340rreview-articleACS PublicationsCopyright © 2008 American Chemical SocietyRequest reuse permissionsArticle Views14614Altmetric-Citations525LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose SUBJECTS:Aldol reactions,Catalysts,Copper,Ketones,Stereoselectivity Get e-Alerts

Catalytic asymmetric oxidations using optically active (salen)manganese(III) complexes as catalysts

1995-03-01

Tsutomu Katsuki

Calichemicins, a novel family of antitumor antibiotics. 2. Chemistry and structure of calichemicin .gamma.1I

1987-05-01

May D. Lee , T. S. DUNNE , Conway C. Chang +5 more

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTCalichemicins, a novel family of antitumor antibiotics. 2. Chemistry and structure of calichemicin .gamma.1IMay D. Lee, Theresa S. Dunne, Conway C. Chang, George A. Ellestad, Marshall M. … ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTCalichemicins, a novel family of antitumor antibiotics. 2. Chemistry and structure of calichemicin .gamma.1IMay D. Lee, Theresa S. Dunne, Conway C. Chang, George A. Ellestad, Marshall M. Siegel, George O. Morton, William J. McGahren, and Donald B. BordersCite this: J. Am. Chem. Soc. 1987, 109, 11, 3466–3468Publication Date (Print):May 1, 1987Publication History Published online1 May 2002Published inissue 1 May 1987https://pubs.acs.org/doi/10.1021/ja00245a051https://doi.org/10.1021/ja00245a051research-articleACS PublicationsRequest reuse permissionsArticle Views742Altmetric-Citations350LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-AlertscloseSupporting Info (1)»Supporting Information Supporting Information Get e-Alerts

Catalytic C–H amination: recent progress and future directions

2009-01-01

Florence Collet , Robert H. Dodd , Philippe Dauban

Recent developments in catalytic C–H amination are discussed in this feature article. The careful design of reagents and catalysts now provides efficient conditions for exquisitely selective intramolecular as well as … Recent developments in catalytic C–H amination are discussed in this feature article. The careful design of reagents and catalysts now provides efficient conditions for exquisitely selective intramolecular as well as intermolecular nitrene C–H insertion. The parallel emergence of C–H activation/amination reactions opens new opportunities complementary to those offered by nitrenes.

Recent Advances in the Baylis−Hillman Reaction and Applications

2003-02-27

Deevi Basavaiah , Anumolu Jaganmohan Rao , Tummanapalli Satyanarayana

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTRecent Advances in the Baylis−Hillman Reaction and ApplicationsDeevi Basavaiah, Anumolu Jaganmohan Rao, and Tummanapalli SatyanarayanaView Author Information School of Chemistry, University of Hyderabad, Hyderabad, 500 046 India … ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTRecent Advances in the Baylis−Hillman Reaction and ApplicationsDeevi Basavaiah, Anumolu Jaganmohan Rao, and Tummanapalli SatyanarayanaView Author Information School of Chemistry, University of Hyderabad, Hyderabad, 500 046 India Cite this: Chem. Rev. 2003, 103, 3, 811–892Publication Date (Web):February 27, 2003Publication History Received11 October 2002Published online27 February 2003Published inissue 1 March 2003https://pubs.acs.org/doi/10.1021/cr010043dhttps://doi.org/10.1021/cr010043dresearch-articleACS PublicationsCopyright © 2003 American Chemical SocietyRequest reuse permissionsArticle Views20389Altmetric-Citations1495LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose SUBJECTS:Adducts,Aldehydes,Alkyls,Hydrocarbons,Organic compounds Get e-Alerts

Transition Metal-Mediated Cycloaddition Reactions

1996-01-01

Mark Lautens , Wolfgang Klute , William Tam

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTTransition Metal-Mediated Cycloaddition ReactionsMark Lautens, Wolfgang Klute, and William TamView Author Information Department of Chemistry, University of Toronto, Toronto, Ontario Canada M5S 1A1 Cite this: Chem. Rev. … ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTTransition Metal-Mediated Cycloaddition ReactionsMark Lautens, Wolfgang Klute, and William TamView Author Information Department of Chemistry, University of Toronto, Toronto, Ontario Canada M5S 1A1 Cite this: Chem. Rev. 1996, 96, 1, 49–92Publication Date (Web):February 1, 1996Publication History Received29 June 1995Revised13 October 1995Published online1 February 1996Published inissue 1 January 1996https://pubs.acs.org/doi/10.1021/cr950016lhttps://doi.org/10.1021/cr950016lresearch-articleACS PublicationsCopyright © 1996 American Chemical SocietyRequest reuse permissionsArticle Views14246Altmetric-Citations1635LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose SUBJECTS:Addition reactions,Catalysts,Cyclization,Hydrocarbons,Metals Get e-Alerts

Construction of Enantiopure Pyrrolidine Ring System via Asymmetric [3+2]-Cycloaddition of Azomethine Ylides

2006-10-25

Ganesh Pandey , Prabal Banerjee , Smita R. Gadre

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTConstruction of Enantiopure Pyrrolidine Ring System via Asymmetric [3+2]-Cycloaddition of Azomethine YlidesGanesh Pandey, Prabal Banerjee, and Smita R. GadreView Author Information Division of Organic Chemistry (Synthesis), National … ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTConstruction of Enantiopure Pyrrolidine Ring System via Asymmetric [3+2]-Cycloaddition of Azomethine YlidesGanesh Pandey, Prabal Banerjee, and Smita R. GadreView Author Information Division of Organic Chemistry (Synthesis), National Chemical Laboratory, Pune 411 008, India Cite this: Chem. Rev. 2006, 106, 11, 4484–4517Publication Date (Web):October 25, 2006Publication History Received26 September 2005Published online25 October 2006Published inissue 1 November 2006https://pubs.acs.org/doi/10.1021/cr050011ghttps://doi.org/10.1021/cr050011gresearch-articleACS PublicationsCopyright © 2006 American Chemical SocietyRequest reuse permissionsArticle Views10391Altmetric-Citations882LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose SUBJECTS:Addition reactions,Azomethine,Cyclization,Molecular structure,Stereoselectivity Get e-Alerts

Asymmetric alkene aziridination with readily available chiral diimine-based catalysts

1993-06-01

Zhen Li , Kathryn Rose Conser , Eric N. Jacobsen

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTAsymmetric alkene aziridination with readily available chiral diimine-based catalystsZhen Li, Kathryn R. Conser, and Eric N. JacobsenCite this: J. Am. Chem. Soc. 1993, 115, 12, 5326–5327Publication Date … ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTAsymmetric alkene aziridination with readily available chiral diimine-based catalystsZhen Li, Kathryn R. Conser, and Eric N. JacobsenCite this: J. Am. Chem. Soc. 1993, 115, 12, 5326–5327Publication Date (Print):June 1, 1993Publication History Published online1 May 2002Published inissue 1 June 1993https://pubs.acs.org/doi/10.1021/ja00065a067https://doi.org/10.1021/ja00065a067research-articleACS PublicationsRequest reuse permissionsArticle Views4421Altmetric-Citations491LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-AlertscloseSupporting Info (2)»Supporting Information Supporting Information Get e-Alerts

The chemistry of 2-oxazolines (1985–present)

1994-02-01

Thomas G. Gant , A. I. Meyers

Intermolecular Amidation of Unactivated sp2 and sp3 C−H Bonds via Palladium-Catalyzed Cascade C−H Activation/Nitrene Insertion

2006-06-27

Hung‐Yat Thu , Wing‐Yiu Yu , Chi‐Ming Che

This communication describes the Pd(OAc)2-catalyzed intermolecular amidation reactions of unactivated sp2 and sp3 C−H bonds using primary amides and potassium persulfate. The substrates containing a pendent oxime or pyridine group … This communication describes the Pd(OAc)2-catalyzed intermolecular amidation reactions of unactivated sp2 and sp3 C−H bonds using primary amides and potassium persulfate. The substrates containing a pendent oxime or pyridine group were amidated with excellent chemo- and regioselectivities. It is noteworthy that reactive C−X bonds were well-tolerated and a variety of primary amides can be effective nucleophiles for the Pd-catalyzed C−H amidation reactions. For the reaction of unactivated sp3 C−H bonds, β-amidation of 1° sp3 C−H bonds versus 2° C−H bonds is preferred. The catalytic reaction is initiated by chelation-assisted cyclopalladation involving C−H bond activation. Preliminary mechanistic study suggested that the persulfate oxidation of primary amides should generate reactive nitrene species, which then reacted with the cyclopalladated complex.

Complex N-Heterocycle Synthesis via Iron-Catalyzed, Direct C–H Bond Amination

2013-05-02

Elisabeth T. Hennessy , Theodore A. Betley

The manipulation of traditionally unreactive functional groups is of paramount importance in modern chemical synthesis. We have developed an iron-dipyrrinato catalyst that leverages the reactivity of iron-borne metal-ligand multiple bonds … The manipulation of traditionally unreactive functional groups is of paramount importance in modern chemical synthesis. We have developed an iron-dipyrrinato catalyst that leverages the reactivity of iron-borne metal-ligand multiple bonds to promote the direct amination of aliphatic C-H bonds. Exposure of organic azides to the iron dipyrrinato catalyst furnishes saturated, cyclic amine products (N-heterocycles) bearing complex core-substitution patterns. This study highlights the development of C-H bond functionalization chemistry for the formation of saturated, cyclic amine products and should find broad application in the context of both pharmaceuticals and natural product synthesis.

Palladium-Catalyzed Amination of Aromatic C−H Bonds with Oxime Esters

2010-02-26

Yichen Tan , John F. Hartwig

We report a conceptually new approach to the direct amination of aromatic C−H bonds. In this process, an oxime ester function reacts with an aromatic C−H bond under redox-neutral conditions … We report a conceptually new approach to the direct amination of aromatic C−H bonds. In this process, an oxime ester function reacts with an aromatic C−H bond under redox-neutral conditions to form, in the case studied, an indole product. These reactions occur with relatively low catalyst loading (1 mol %) by a mechanism that appears to involve an unusual initial oxidative addition of an N−O bond to a Pd(0) species. The Pd(II) complex from oxidative addition of the N−X bond has been isolated for the first time, and evidence for the intermediacy of such oxidative addition products in the catalytic reaction has been gained.

An overview of the key routes to the best selling 5-membered ring heterocyclic pharmaceuticals

2011-04-18

Marcus Baumann , Ian R. Baxendale , Steven V. Ley +1 more

This review presents a comprehensive overview on selected synthetic routes towards commercial drug compounds as published in both journal and patent literature. Owing to the vast number of potential structures, … This review presents a comprehensive overview on selected synthetic routes towards commercial drug compounds as published in both journal and patent literature. Owing to the vast number of potential structures, we have concentrated only on those drugs containing five-membered heterocycles and focused principally on the assembly of the heterocyclic core. In order to target the most representative chemical entities the examples discussed have been selected from the top 200 best selling drugs of recent years.

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Organocatalysis Mediated by (Thio)urea Derivatives

2006-03-03

Stephen J. Connon

Over the last decade the potential for N,N-dialkyl(thio)urea derivatives to serve as active metal-free organocatalysts for a wide range of synthetically useful reactions susceptible to the influence of general acid … Over the last decade the potential for N,N-dialkyl(thio)urea derivatives to serve as active metal-free organocatalysts for a wide range of synthetically useful reactions susceptible to the influence of general acid catalysis has begun to be realised. This article charts the development of these catalysts (with emphasis on the design principles involved), from early "proof-of-concept" materials to contemporary active chiral (bifunctional) promoters of highly selective asymmetric transformations.

A Predictably Selective Aliphatic C–H Oxidation Reaction for Complex Molecule Synthesis

2007-11-01

Mark S. Chen , M. Christina White

Realizing the extraordinary potential of unactivated sp3 C-H bond oxidation in organic synthesis requires the discovery of catalysts that are both highly reactive and predictably selective. We report an iron … Realizing the extraordinary potential of unactivated sp3 C-H bond oxidation in organic synthesis requires the discovery of catalysts that are both highly reactive and predictably selective. We report an iron (Fe)-based small molecule catalyst that uses hydrogen peroxide (H2O2) to oxidize a broad range of substrates. Predictable selectivity is achieved solely on the basis of the electronic and steric properties of the C-H bonds, without the need for directing groups. Additionally, carboxylate directing groups may be used to furnish five-membered ring lactone products. We demonstrate that these three modes of selectivity enable the predictable oxidation of complex natural products and their derivatives at specific C-H bonds with preparatively useful yields. This type of general and predictable reactivity stands to enable aliphatic C-H oxidation as a method for streamlining complex molecule synthesis.

Some recent applications of α-amino nitrile chemistry

2000-01-01

Dieter Enders , John P. Shilvock

Bifunctional α-amino nitriles are not only versatile intermediates in organic synthesis but also exhibit a valuable dual reactivity, which has been utilized in a broad range of synthetic applications. This … Bifunctional α-amino nitriles are not only versatile intermediates in organic synthesis but also exhibit a valuable dual reactivity, which has been utilized in a broad range of synthetic applications. This review highlights recent developments in the chemistry of α-amino nitriles, including asymmetric synthesis of α-amino acids via Strecker reactions using chiral auxiliaries and catalysts, α-amino nitriles as masked iminium ion equivalents in cationic reactions and the synthesis of natural products and heterocycles, and α-metallation to provide nucleophilic acyl anion equivalents and applications to asymmetric Umpolung reactions.

Enantioselective Catalytic Aziridinations and Asymmetric Nitrene Insertions into CH Bonds

2003-06-26

Paul Müller , Corinne Fruit

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTEnantioselective Catalytic Aziridinations and Asymmetric Nitrene Insertions into CH BondsPaul Müller and Corinne FruitView Author Information Department of Organic Chemistry, University of Geneva, 30, Quai Ernest Ansermet, … ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTEnantioselective Catalytic Aziridinations and Asymmetric Nitrene Insertions into CH BondsPaul Müller and Corinne FruitView Author Information Department of Organic Chemistry, University of Geneva, 30, Quai Ernest Ansermet, CH-1211 Geneva 4, Switzerland Cite this: Chem. Rev. 2003, 103, 8, 2905–2920Publication Date (Web):June 26, 2003Publication History Received21 January 2003Published online26 June 2003Published inissue 1 August 2003https://pubs.acs.org/doi/10.1021/cr020043thttps://doi.org/10.1021/cr020043tresearch-articleACS PublicationsCopyright © 2003 American Chemical SocietyRequest reuse permissionsArticle Views13869Altmetric-Citations1030LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose SUBJECTS:Aziridines,Catalysts,Hydrocarbons,Ligands,Stereoselectivity Get e-Alerts

Hypervalent Iodine Chemistry in Synthesis: Scope and New Directions

2005-04-12

Thomas Wirth

The impressive development of hypervalent iodine chemistry in recent years is reflected by the number of publications in this area. Although the synthesis of the first hypervalent iodine compound dates … The impressive development of hypervalent iodine chemistry in recent years is reflected by the number of publications in this area. Although the synthesis of the first hypervalent iodine compound dates back more than 100 years, the investigation of the reactivities of these compounds and their efficient use as metal-free reagents in organic synthesis is still ongoing. This contribution summarizes recent achievements and highlights key findings and developments that will influence future research and lead to novel applications of hypervalent iodine reagents in synthesis.

Development of the Copper-Catalyzed Olefin Aziridination Reaction

1994-04-01

David A. Evans , Mark T. Bilodeau , Margaret M. Faul

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTDevelopment of the Copper-Catalyzed Olefin Aziridination ReactionDavid A. Evans, Mark T. Bilodeau, and Margaret M. FaulCite this: J. Am. Chem. Soc. 1994, 116, 7, 2742–2753Publication Date (Print):April … ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTDevelopment of the Copper-Catalyzed Olefin Aziridination ReactionDavid A. Evans, Mark T. Bilodeau, and Margaret M. FaulCite this: J. Am. Chem. Soc. 1994, 116, 7, 2742–2753Publication Date (Print):April 1, 1994Publication History Published online1 May 2002Published inissue 1 April 1994https://pubs.acs.org/doi/10.1021/ja00086a007https://doi.org/10.1021/ja00086a007research-articleACS PublicationsRequest reuse permissionsArticle Views6861Altmetric-Citations566LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose Get e-Alerts

Expanding the Scope of C−H Amination through Catalyst Design

2004-11-09

Christine G. Espino , Kristin Williams Fiori , Mihyong Kim +1 more

Analysis of the mechanism for Rh-mediated C-H amination has led to the development of a remarkably effective dinuclear Rh catalyst derived from 1,3-benzenedipropionic acid. This unique complex, Rh2(esp)2, is capable … Analysis of the mechanism for Rh-mediated C-H amination has led to the development of a remarkably effective dinuclear Rh catalyst derived from 1,3-benzenedipropionic acid. This unique complex, Rh2(esp)2, is capable of promoting both intra- and intermolecular C-H oxidation reactions, and in all cases is superior to Rh2(O2CtBu)4. For the first time, C-H insertion is described with urea and sulfamide substrates to give 1,2- and 1,3-diamine derivatives, respectively. In addition, intermolecular amination of benzylic and secondary C-H bonds is shown to proceed efficiently even under conditions in which the starting alkane is employed as the limiting reagent.

The Synthesis of Vicinal Amino Alcohols

2000-04-01

Stephen C. Bergmeier

Asymmetric hydroxylation of enolates with N-sulfonyloxaziridines

1992-07-01

Franklin A. Davis , Bang Chi Chen

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTAsymmetric hydroxylation of enolates with N-sulfonyloxaziridinesFranklin A. Davis and Bang Chi ChenCite this: Chem. Rev. 1992, 92, 5, 919–934Publication Date (Print):July 1, 1992Publication History Published online1 May … ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTAsymmetric hydroxylation of enolates with N-sulfonyloxaziridinesFranklin A. Davis and Bang Chi ChenCite this: Chem. Rev. 1992, 92, 5, 919–934Publication Date (Print):July 1, 1992Publication History Published online1 May 2002Published inissue 1 July 1992https://pubs.acs.org/doi/10.1021/cr00013a008https://doi.org/10.1021/cr00013a008research-articleACS PublicationsRequest reuse permissionsArticle Views7158Altmetric-Citations574LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose Get e-Alerts

An overview of the synthetic routes to the best selling drugs containing 6-membered heterocycles

2013-10-30

Marcus Baumann , Ian R. Baxendale

This review which is the second in this series summarises the most common synthetic routes as applied to the preparation of many modern pharmaceutical compounds categorised as containing a six-membered … This review which is the second in this series summarises the most common synthetic routes as applied to the preparation of many modern pharmaceutical compounds categorised as containing a six-membered heterocyclic ring. The reported examples are based on the top retailing drug molecules combining synthetic information from both scientific journals and the wider patent literature. It is hoped that this compilation, in combination with the previously published review on five-membered rings, will form a comprehensive foundation and reference source for individuals interested in medicinal, synthetic and preparative chemistry.

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A Sulfoxide-Promoted, Catalytic Method for the Regioselective Synthesis of Allylic Acetates from Monosubstituted Olefins via C−H Oxidation

2004-01-15

Mark S. Chen , M. Christina White

Sulfoxide ligation to Pd(II) salts is shown to selectively promote C-H oxidation versus Wacker oxidation chemistry and to control the regioselectivity in the C-H oxidation products. A catalytic method for … Sulfoxide ligation to Pd(II) salts is shown to selectively promote C-H oxidation versus Wacker oxidation chemistry and to control the regioselectivity in the C-H oxidation products. A catalytic method for the direct C-H oxidation of monosubstituted olefins to linear (E)-allylic acetates in high regio- and stereoselectivities and preparatively useful yields is described. The method using benzoquinone as the stoichiometric oxidant and 10 mol % of Pd(OAc)2 or Pd(O2CCF3)2 as the catalyst in a DMSO/AcOH (1:1) solution was found to be compatible with a wide range of functionality (e.g., amides, carbamates, esters, and ethers, see Table 2). Addition of DMSO was found to be critical for promoting the C-H oxidation pathway, with AcOH alone or in combination with a diverse range of dielectric media, leading to mixtures favoring Wacker-type oxidation products (Tables 1, S3). To explore the role of DMSO as a ligand, the bis-sulfoxide Pd(OAc)2 complex 1 was formed and found to be an effective C-H oxidation catalyst in the absence of DMSO (eqs 2, 3). Moreover, catalyst 1 effects a reversal of regioselectivity, favoring the formation of branched allylic acetates.

Construction of Nitrogen‐Containing Heterocycles by CH Bond Functionalization

2009-05-13

Praew Thansandote , Mark Lautens

Nitrogen heterocycles are abundant in natural products and pharmaceuticals. An emerging interest among synthetic chemists is to use C-H functionalization to construct the nitrogen-containing core of these heterocycles. The following … Nitrogen heterocycles are abundant in natural products and pharmaceuticals. An emerging interest among synthetic chemists is to use C-H functionalization to construct the nitrogen-containing core of these heterocycles. The following article will provide a brief overview of this concept with respect to the type of C-H bond functionalized.

Metal–Salen Schiff base complexes in catalysis: practical aspects

2004-01-01

Pier Giorgio Cozzi

Schiff base ligands are considered “privileged ligands” because they are easily prepared by the condensation between aldehydes and imines. Stereogenic centres or other elements of chirality (planes, axes) can be … Schiff base ligands are considered “privileged ligands” because they are easily prepared by the condensation between aldehydes and imines. Stereogenic centres or other elements of chirality (planes, axes) can be introduced in the synthetic design. Schiff base ligands are able to coordinate many different metals, and to stabilize them in various oxidation states, enabling the use of Schiff base metal complexes for a large variety of useful catalytic transformations. Practical guidelines for the preparation and use of different Schiff base metal complexes in the field of catalytic transformations are discussed in this tutorial review.

Catalytic C–H amination: the stereoselectivity issue

2011-01-01

Florence Collet , Camille Lescot , Philippe Dauban

Catalytic C–H amination has recently emerged as a unique tool for the synthesis of amines. This tutorial review highlights the existing protocols catalyzed by metal complexes (rhodium, copper, ruthenium, manganese … Catalytic C–H amination has recently emerged as a unique tool for the synthesis of amines. This tutorial review highlights the existing protocols catalyzed by metal complexes (rhodium, copper, ruthenium, manganese and palladium) allowing diastereo- and enantioselective C–H amination. Substrate-, catalyst- and reagent-controlled methodologies are detailed. They involve either catalytic nitrene C–H insertion or C–H activation.

Sulfoximines: A Neglected Opportunity in Medicinal Chemistry

2013-08-09

Ulrich Lücking

Abstract Innovation has frequently been described as the key to drug discovery. However, in the daily routine, medicinal chemists often tend to stick to the functional groups and structural elements … Abstract Innovation has frequently been described as the key to drug discovery. However, in the daily routine, medicinal chemists often tend to stick to the functional groups and structural elements they know and love. Blockbuster cancer drug Velcade (bortezomib), for example, was rejected by more than 50 companies, supposedly because of its unusual boronic acid function (as often repeated: “only a moron would put boron in a drug!”). Similarly, in the discovery process of the pan‐CDK inhibitor BAY 1000394, the unconventional proposal to introduce a sulfoximine group into the lead series also led to sneers and raised eyebrows, since sulfoximines have seldom been used in medicinal chemistry. However, it was the introduction of the sulfoximine group that finally allowed the fundamental issues of the project to be overcome, culminating in the identification of the clinical sulfoximine pan‐CDK inhibitor BAY 1000394. This Minireview provides an overview of a widely neglected opportunity in medicinal chemistry—the sulfoximine group.

Chiral Aziridines—Their Synthesis and Use in Stereoselective Transformations

1994-03-31

David Tanner

Abstract The preparation of enantiomerically pure compounds is one of the major areas of organic chemistry. Much emphasis is placed on the elaboration of naturally occurring starting materials and on … Abstract The preparation of enantiomerically pure compounds is one of the major areas of organic chemistry. Much emphasis is placed on the elaboration of naturally occurring starting materials and on the development of techniques for enantio‐selective transformations of achiral substrates. In this field, chiral aziridines form an attractive class of compounds, since they are available in enantiomerically pure (or highly enriched) form by a variety of procedures and can be used for asymmetric synthesis in a number of different ways. The chemistry of aziridines is dominated by ring‐opening reactions, the driving force for which is relief of ring strain. By suitable choice of sub‐stituents on the carbon and nitrogen atoms, excellent stereo‐ and regiocontrol can be attained in ring‐opening reactions with a wide variety of nucleophiles, including organometallic reagents; this makes chiral aziridines useful as substrates for the synthesis of important biologically active species including alkaloids, amino acids, and /Mactam antibiotics. Substrate‐controlled diastereo‐selective synthesis is also possible by use of aziridines as removable chiral auxiliaries , while metalation at a ring carbon atom allows aziridines to be used as chiral reagents for asymmetric synthesis. Chiral bisaziridines can act as ligands for transition metals, and applications in the challenging field of enantioselective catalysis can be envisioned. Today, the exclusion of three‐membered carbo‐ and heterocycles from the arsenal of the organic chemist is inconceivable . H. Heimgartner, Angew. Chem. 1991 , 103 , 271; Angew. Chem. Int. Ed. Engl. 1991 , 30 , 238.

Aziridines: epoxides’ ugly cousins?

2002-01-01

J. B. Sweeney

Aziridines, the nitrogenous analogues of epoxides, have until recently excited far less interest amongst synthetic organic chemists than their oxygenated counterparts, with some justification. A range of reviews concerned with … Aziridines, the nitrogenous analogues of epoxides, have until recently excited far less interest amongst synthetic organic chemists than their oxygenated counterparts, with some justification. A range of reviews concerned with the physical properties, synthesis (asymmetric and otherwise), reactions and utility of aziridines exists; this review briefly summarizes the similarities and differences between oxiranes and their nitrogenated analogues, concentrating on the underlying properties of aziridines and recent developments in their chemistry. In addition to descriptions of the physical nature of aziridines, especially those features which underpin their utility as synthetic intermediates, the sections beneath describe reactions involving alkylative ring-opening and synthesis of aziridines.

Hydrogen‐Bond‐Mediated Asymmetric Catalysis

2008-02-19

Xinhong Yu , Wei Wang

The utilization of hydrogen bonding as an activation force has become a powerful tool in asymmetric organocatalysis. Significant advances have been made in the recent past in this emerging field. … The utilization of hydrogen bonding as an activation force has become a powerful tool in asymmetric organocatalysis. Significant advances have been made in the recent past in this emerging field. Due to space constraints, this Focus Review summarizes only the key aspects with an emphasis on catalysis based on chiral ureas and thioureas, diols, and phosphoric acids. The examples provided neatly demonstrate that chiral ureas and thioureas, diols, and phosphoric acids display effective and unique activation modes of catalysis for a broad spectrum of asymmetric organic transformations, including single-step and multiple-step cascade reactions. These functionalities, which have the ability to afford efficient H-bond activation of electrophiles including CO, CN, aziridines, and epoxides, have established their status as "privileged" functional groups in the design of organocatalysts.

“On Water”: Unique Reactivity of Organic Compounds in Aqueous Suspension

2005-04-21

Sridhar Narayan , John Muldoon , M. G. Finn +3 more

Water, the medium of choice: Many reactions, such as Claisen rearrangements (see scheme), are dramatically accelerated when performed in aqueous suspension (“on water”) relative to organic solvents or even neat … Water, the medium of choice: Many reactions, such as Claisen rearrangements (see scheme), are dramatically accelerated when performed in aqueous suspension (“on water”) relative to organic solvents or even neat conditions. Low miscibility of organic compounds with water is not detrimental: in fact, it facilitates the isolation of products. Water is a desirable solvent for chemical reactions for reasons of cost, safety, and environmental concerns, and the study of organic reactions in aqueous solvents has an intriguing history.1 Most notably, certain pericyclic reactions such as Diels–Alder cycloadditions2 and Claisen rearrangements3 of hydrophobic compounds have been found to be accelerated in dilute aqueous solution. Yet, either organic co-solvents and/or substrate modifications are almost always employed in preparative-scale reactions performed in water,1 as it is assumed that solubility is required for efficient reaction. Not only do these strategies detract from the simplicity and advantages sought from the use of water in the first place, but, as we report here, the venerable assumption “corpora non agunt nisi soluta” (substances do not interact unless dissolved) can be distinctly counterproductive. In recent years, we have focused on modular synthetic techniques that rely on a few nearly perfect reaction types.4 In the course of this work, we have noticed that many such reactions often proceed optimally in pure water,5 and particularly when the organic reactants are insoluble in the aqueous phase.6 We present here several examples that illustrate a remarkable phenomenon: substantial rate acceleration when insoluble reactants are stirred in aqueous suspension, denoted here as “on water” conditions. Even when the rate acceleration is negligible, the use of water as the only supporting medium has other advantages including ease of product isolation and above all, safety, thanks to its high heat capacity7 and unique redox stability. In connection with our studies on the reactivity of strained olefins, we explored the preparation of 1,2-diazetidines from quadricyclane (1) by the 2σ+2σ+2π cycloaddition with azodicarboxylates, discovered by Lemal and co-workers.8 The typical reaction conditions involve heating 1 with dimethyl azodicarboxylate (DMAD, 2) in toluene or benzene at 80 °C for 24 h or longer.8, 9 In contrast, when a mixture of DMAD and quadricyclane is vigorously stirred “on water”, the reaction is complete within a few minutes at ambient temperature. The corresponding neat (solvent-free) reaction of these two liquids takes nearly two days to reach completion, which shows that the rate acceleration is not the sole consequence of an increase in the effective concentration of reagents (Table 1). Solvent Conc. [M] T [°C] t Yield [%][a] neat 4.53[b] 0 2 h 0[c] neat 4.53[b] 23 48 h 85 toluene 1 80 24 h 74 on H2O 4.53[d] 0 1.5 h 93 on H2O 4.53[d] 23 10 min 82 As the cycloaddition of DMAD with quadricyclane demonstrates, the “on water” method consists simply of stirring the reactant(s) with water to generate an aqueous suspension. Nonpolar liquids that separate from water into a clear organic phase are ideal candidates for these reactions. Solid reactants can also be utilized, provided one reaction partner is a liquid and adequate mixing is ensured. Vigorous stirring promotes the reaction, most likely by increasing the area of surface contact between the organic and aqueous phases. The observed rate acceleration does not depend on the amount of water used, as long as sufficient water is present for clear phase separation to occur.10 The product is isolated simply by phase separation or filtration. In cases where clear phase separation does not occur, such as in small-scale reactions, liquid–liquid extraction may be necessary. Seeking insight into the origin of rate acceleration in the DMAD–quadricyclane cycloaddition, the reaction between 1 and 2 was carried out under a variety of conditions and the time to completion was monitored (Table 2). Under homogenous conditions, polar protic solvents accelerate the reaction, with observed reaction rates in the following order: MeOH/H2O (3:1)>MeOH>DMSO>CH3CN≈CH2Cl2>EtOAc≈toluene.11 This trend suggests that hydrogen bonding, charge stabilization, and dipolar effects may each be important for rate acceleration.12 While water contributes to such properties in homogeneous mixtures, heterogeneity was crucial for observing large rate accelerations. Thus, the presence or absence of methanol in a heterogeneous reaction made little difference, but the rate slowed considerably when enough methanol was used to make the reaction homogeneous. However, heterogeneity in itself is not responsible for rate acceleration as the reaction “on” perfluorohexane was only slightly faster than the neat reaction. Interestingly, a significant solvent isotope effect was also observed: the reaction slowed noticeably when D2O was used in place of water. Solvent Conc. [M][b] Time to completion toluene 2 >120 h EtOAc 2 >120 h CH3CN 2 84 h CH2Cl2 2 72 h DMSO 2 36 h MeOH 2 18 h neat 4.53 48 h on D2O 4.53 45 min on C6F14 4.53 36 h on H2O 4.53 10 min MeOH/H2O (3:1, homogeneous) 2 4 h MeOH/H2O (1:1, heterogeneous) 4.53 10 min MeOH/H2O (1:3, heterogeneous) 4.53 10 min Acceleration of reactions “on water” is evident even when a nonpolar solvent comprises a part or most of the organic phase as shown in Table 3. Thus, the reaction of quadricyclane (1) with diethyl azodicarboxylate (DEAD, 4), carried out simply by stirring a toluene solution of DEAD with 1 “on water”, proceeds at a considerably higher rate than when the reaction is carried out in toluene alone. t [h] Conversion [%][b] toluene[c] toluene on H2O[d] 3 4 42 6 8 56 17 18 69 We have found that the high reactivity of azodicarboxylates “on water” is not limited to their cycloaddition reactions: the ene reactions of these compounds respond similarly to conditions of aqueous suspension relative to organic solution. Leblanc et al. have used the ene reaction of bis(trichloroethyl) azodicarboxylate (7) to achieve the allylic amination of olefins under thermal conditions.13 In nonpolar solvents such as benzene, prolonged heating at 80 °C was reportedly required to attain useful levels of reactivity with simple olefins such as cyclohexene (6). In the absence of solvent, the reaction of liquid 6 and solid 7 was found to proceed at 50 °C, but still required 36 h for completion as well as the presence of excess cyclohexene. In contrast, the reaction performed “on water” was complete within eight hours at 50 °C and afforded the product in 91 % yield (see Table 4). The neat reaction between 6 and 7 not only appeared to be slower, but the reaction mixture was also considerably harder to mix uniformly. In contrast, when heated to 50 °C “on water” the reaction mixture initially formed a molten organic phase, which gave way to the product as a white precipitate. In practical terms, reactions of solid components in aqueous suspension are more reproducible and convenient than in the absence of solvent, as water provides for efficient “mixing” of the reactants without the dilution cost of a true solvent. Furthermore, the effective melting point of solid reaction mixtures is noticeably lowered in the presence of water, such that a fused organic phase is often formed. Solvent T [°C] t [h] Yield [%] benzene 80 24 70[a] neat 50 36[b] 62 on H2O 50 8 91 The notion of the special nature of water as a solvent for organic reactions began with examples of Diels–Alder reactions more than fifty years ago.14 The first quantitative data were reported by Rideout and Breslow, who showed that Diels–Alder reactions between nonpolar compounds proceeded at much higher rates in water (dilute homogeneous solution) than in organic solvents.15 Rate accelerations as high as 200-fold were noted in certain cases. Breslow et al. also noted the high endo selectivity of certain Diels–Alder reactions carried out in water, under both homogeneous and heterogeneous conditions.16 Although rate acceleration and selectivity were ascribed primarily to hydrophobic effects, it has since been appreciated that hydrogen bonding plays an important role.17 Ironically, much of the careful quantitative work on the process does not directly apply to synthetic chemistry, as the experiments reported by Breslow, Engberts, and others were conducted at low concentrations (mM or less) to maintain homogeneity in water, while preparative reactions usually require much higher concentrations. In a rare example of a heterogeneous process, Grieco et al. reported the Diels–Alder reaction of an acyclic diene bearing a carboxylic acid group to occur in aqueous suspension faster than in organic solution.18 The best results were obtained in the reactions of diene carboxylate salts with various dienophiles in water, and the rate accelerations due to water were ascribed to micellar catalysis.19 As some of these reactions were carried out under conditions similar to ours, we evaluated the effectiveness of the “on water” protocol for Diels–Alder reactions. We performed the cycloaddition of the water-insoluble trans, trans-2,4-hexadienyl acetate (9) and N-propylmaleimide (10) under various conditions (Table 5). As before, a protic solvent (methanol) was better than nonprotic solvents, and the reaction in aqueous suspension showed substantial rate acceleration over homogeneous solution. Consistent with the results of Grieco et al.18 and in contrast to the reaction of 1+2 described above, the neat Diels–Alder addition of 9 to 10 (both liquids) was approximately as fast as in water suspension.20 Solvent Conc. [M] Time to completion [h] Yield [%] toluene 1 144 79 CH3CN 1 >144 43[a] MeOH 1 48 82 neat 3.69[b] 10 82 H2O 3.69[b] 8 81 Claisen rearrangements are another significant class of reactions for which the accelerating effect of water is well-recognized.21 The initial discovery appears to have been made during mechanistic studies of the chorismate–prephenate rearrangement, a key step in the biosynthesis of shikimic acid.22 Brandes, Grieco, and Gajewski then performed a kinetic study on the rearrangement of an allyl vinyl ether substrate with an attached carboxylate functionality.23 The rate of rearrangement of the carboxylate salt in water was found to be about two orders of magnitude higher than that of the methyl ester in nonpolar solvents.24 These findings were exploited further by Grieco et al., who used the accelerating influence of water to promote difficult rearrangements.25 In contrast to the aliphatic Claisen rearrangements, the effect of water on the analogous aromatic Claisen rearrangement is little known.26 We have made preliminary measurements on naphthyl ether 12, which undergoes rearrangement at an appreciable rate even at room temperature. Table 6 shows the effect of various solvents on this process. After five days at 23 °C, the sample of 12 in aqueous suspension had completely rearranged to 13, while the rearrangement was considerably slower in organic solvents. The neat reaction was again closest in rate to water and required one further day to reach completion. As with Diels–Alder reactions, the “on water” protocol provides the best set of conditions in terms of efficiency, convenience, and safety, even when rate accelerations are not large. Solvent Yield [%][b] toluene 16 DMF 21 CH3CN 27 MeOH 56[c] neat 73 on H2O 100 Non-pericyclic reactions such as the opening of epoxides and aziridines with heteroatom nucleophiles also derive unique benefits from the “on water” environment. Hydrogen bonding is crucial for the activation of such electrophiles, making these ring-opening processes autocatalytic and difficult to control under neat conditions. Instead, protic solvents such as alcohols and especially alcohol/water mixtures provide good homogeneous media for these transformations.4 Here too, we find that water alone is the medium of choice. The reactions are completed in shorter times than in other protic solvents, and the pure product often precipitates, to be isolated by simple filtration. The reaction of cyclohexadiene monoepoxide (14) with N-(3-chlorophenyl)piperazine (15) is illustrative (Table 7). When heated at 50 °C, the reaction “on water” was completed overnight, while the reactions in solution in ethanol or without solvent required approximately three days to reach completion. In toluene, less than 10 % conversion occurred after five days at the same temperature. Thus, taking into account the concentrations of the reagents, the rates of reactions “on water” and in ethanol appeared to be approximately the same, and greater than that for the reaction performed in the absence of solvent. Solvent Conc. [M] t [h] Yield [%] toluene 1 120 <10[a] neat 3.88[b] 72 76 EtOH 1 60 89 on H2O 3.88[b] 12 88 Thus, a variety of reactions can be efficiently carried out in aqueous suspension, with the most dramatic effects observed for the addition of azodicarboxylates to unsaturated hydrocarbons. To the best of our knowledge, these examples represent some of the largest rate accelerations due to water observed under preparative conditions, that is, at molar concentrations. A central theme in the field of aqueous organic chemistry has been the need to promote solubility in these reactions. Clearly, solubility is not essential. Although the reactivity phenomenon described here has immediate practical implications, its origins are presently unclear; nevertheless, a few preliminary remarks are in order. For example, it is possible that reactions “on water” actually proceed through small amounts of dissolved solutes. Rate acceleration in homogeneous aqueous solution has been attributed to a variety of effects such as hydrophobic aggregation,2, 15 cohesive energy density,27 or ground-state destabilization.28, 29 Breslow et al. have invoked solution-phase hydrophobic effects to explain the high endo selectivity of certain Diels–Alder reactions in aqueous suspension and solution.2a, 16 Engberts and co-workers made a fundamental point by providing evidence that, in cycloaddition reactions, hydrophobic destabilization will have a considerably greater impact on the ground state than on the transition state.29, 30 The importance of hydrogen bonding in the acceleration of Diels–Alder reactions in aqueous solution is supported by both experimental31 and theoretical32 studies. However, it seems that many of the reactions described above are simply too fast for the acceleration to be solely due to solution-phase phenomena. In this regard, the observed requirement for heterogeneity and the finding that the rates of reactions “on water” often exceed those of the same reactions performed in the absence of solvent demand attention. Perhaps the unique properties of molecules at the macroscopic phase boundary between water and insoluble hydrophobic oils play a role.33 The same principles that contribute to solution-phase effects may be amplified at such phase boundaries, but other factors, such as the redistribution of surface species driven by surface-tension energetics,34 may also be relevant. We plan to keep exploring the “on water” phenomenon both for practical applications and mechanistic understanding. Supporting information for this article is available on the WWW under http://www.wiley-vch.de/contents/jc_2002/2005/z462883_s.pdf or from the author. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

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Oxidative C–H amination reactions

2013-11-11

Marie‐Laure Louillat , Frédéric W. Patureau

Towards "Oxidative-Ullmann-Goldberg" and "Oxidative-Buchwald-Hartwig" type amination reactions. This review focuses on the newly developed oxidative C-N bond formation techniques, applicable in the field of organic synthesis. Particular emphasis is given … Towards "Oxidative-Ullmann-Goldberg" and "Oxidative-Buchwald-Hartwig" type amination reactions. This review focuses on the newly developed oxidative C-N bond formation techniques, applicable in the field of organic synthesis. Particular emphasis is given to those which are classified as cross-dehydrogenative-couplings, through dual C-H and N-H activation, thus formally extruding "H2" as a by-product.

Site-selective arene C-H amination via photoredox catalysis

2015-09-18

Nathan A. Romero , Kaila A. Margrey , Nicholas E. S. Tay +1 more

Over the past several decades, organometallic cross-coupling chemistry has developed into one of the most reliable approaches to assemble complex aromatic compounds from preoxidized starting materials. More recently, transition metal-catalyzed … Over the past several decades, organometallic cross-coupling chemistry has developed into one of the most reliable approaches to assemble complex aromatic compounds from preoxidized starting materials. More recently, transition metal-catalyzed carbon-hydrogen activation has circumvented the need for preoxidized starting materials, but this approach is limited by a lack of practical amination protocols. Here, we present a blueprint for aromatic carbon-hydrogen functionalization via photoredox catalysis and describe the utility of this strategy for arene amination. An organic photoredox-based catalyst system, consisting of an acridinium photooxidant and a nitroxyl radical, promotes site-selective amination of a variety of simple and complex aromatics with heteroaromatic azoles of interest in pharmaceutical research. We also describe the atom-economical use of ammonia to form anilines, without the need for prefunctionalization of the aromatic component.

Highly Efficient Syntheses of Azetidines, Pyrrolidines, and Indolines via Palladium Catalyzed Intramolecular Amination of C(sp3)–H and C(sp2)–H Bonds at γ and δ Positions

2011-12-21

Gang He , Yingsheng Zhao , Shu‐Yu Zhang +2 more

Efficient methods have been developed to synthesize azetidine, pyrrolidine, and indoline compounds via palladium-catalyzed intramolecular amination of C-H bonds at the γ and δ positions of picolinamide (PA) protected amine … Efficient methods have been developed to synthesize azetidine, pyrrolidine, and indoline compounds via palladium-catalyzed intramolecular amination of C-H bonds at the γ and δ positions of picolinamide (PA) protected amine substrates. These methods feature relatively a low catalyst loading, use of inexpensive reagents, and convenient operating conditions. Their selectivities are predictable. These methods highlight the use of unactivated C-H bond, especially the C(sp(3))-H bond of methyl groups, as functional groups in organic synthesis.

Metal-Catalyzed Nitrogen-Atom Transfer Methods for the Oxidation of Aliphatic C–H Bonds

2012-04-30

Jennifer L. Roizen , Mark Edwin Harvey , J. Du Bois

For more than a century, chemists have endeavored to discover and develop reaction processes that enable the selective oxidation of hydrocarbons. In the 1970s, Abramovitch and Yamada described the synthesis … For more than a century, chemists have endeavored to discover and develop reaction processes that enable the selective oxidation of hydrocarbons. In the 1970s, Abramovitch and Yamada described the synthesis and electrophilic reactivity of sulfonyliminoiodinanes (RSO2N═IPh), demonstrating the utility of this new class of reagents to function as nitrene equivalents. Subsequent investigations by Breslow, Mansuy, and Müller would show such oxidants to be competent for alkene and saturated hydrocarbon functionalization when combined with transition metal salts or metal complexes, namely those of Mn, Fe, and Rh. Here, we trace our own studies to develop N-atom transfer technologies for C–H and π-bond oxidation. This Account discusses advances in both intra- and intermolecular amination processes mediated by dirhodium and diruthenium complexes, as well as the mechanistic foundations of catalyst reactivity and arrest. Explicit reference is given to questions that remain unanswered and to problem areas that are rich for discovery.A fundamental advance in amination technology has been the recognition that iminoiodinane oxidants can be generated in situ in the presence of a metal catalyst that elicits subsequent N-atom transfer. Under these conditions, both dirhodium and diruthenium lantern complexes function as competent catalysts for C–H bond oxidation with a range of nitrogen sources (e.g., carbamates, sulfamates, sulfamides, etc.), many of which will not form isolable iminoiodinane equivalents. Practical synthetic methods and applications thereof have evolved in parallel with inquiries into the operative reaction mechanism(s). For the intramolecular dirhodium-catalyzed process, the body of experimental and computational data is consistent with a concerted asynchronous C–H insertion pathway, analogous to the consensus mechanism for Rh-carbene transfer. Other studies reveal that the bridging tetracarboxylate ligand groups, which shroud the dirhodium core, are labile to exchange under standard reaction conditions. This information has led to the generation of chelating dicarboxylate dinuclear rhodium complexes, exemplified by Rh2(esp)2. The performance of this catalyst system is unmatched by other dirhodium complexes in both intra- and intermolecular C–H amination reactions.Tetra-bridged, mixed-valent diruthenium complexes function as effective promoters of sulfamate ester oxidative cyclization. These catalysts can be crafted with ligand sets other than carboxylates and are more resistant to oxidation than their dirhodium counterparts. A range of experimental and computational mechanistic data amassed with the tetra-2-oxypyridinate diruthenium chloride complex, [Ru2(hp)4Cl], has established the insertion event as a stepwise pathway involving a discrete radical intermediate. These data contrast dirhodium-catalyzed C–H amination and offer a cogent model for understanding the divergent chemoselectivity trends observed between the two catalyst types. This work constitutes an important step toward the ultimate goal of achieving predictable, reagent-level control over product selectivity.

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The Chemistry of Transition Metals with Three-Membered Ring Heterocycles

2014-05-28

Chung‐Yang Huang , Abigail G. Doyle

ADVERTISEMENT RETURN TO ISSUEPREVReviewNEXTThe Chemistry of Transition Metals with Three-Membered Ring HeterocyclesChung-Yang (Dennis) Huang and Abigail G. Doyle*View Author Information Department of Chemistry, Princeton University, Princeton, New Jersey 08544, United … ADVERTISEMENT RETURN TO ISSUEPREVReviewNEXTThe Chemistry of Transition Metals with Three-Membered Ring HeterocyclesChung-Yang (Dennis) Huang and Abigail G. Doyle*View Author Information Department of Chemistry, Princeton University, Princeton, New Jersey 08544, United States*E-mail: [email protected]Cite this: Chem. Rev. 2014, 114, 16, 8153–8198Publication Date (Web):May 28, 2014Publication History Received21 January 2014Published online28 May 2014Published inissue 27 August 2014https://pubs.acs.org/doi/10.1021/cr500036thttps://doi.org/10.1021/cr500036treview-articleACS PublicationsCopyright © 2014 American Chemical SocietyRequest reuse permissionsArticle Views15263Altmetric-Citations424LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose SUBJECTS:Aziridines,Catalysts,Ethers,Hydrocarbons,Metals Get e-Alerts

Modern advances in heterocyclic chemistry in drug discovery

2016-01-01

A. Taylor , Ralph P. Robinson , Yvette M. Fobian +3 more

New advances in functionalized heterocyclic chemistry are of critical importance to the medicinal chemist as it provides the ability to expand the available drug-like chemical space and drive more efficient … New advances in functionalized heterocyclic chemistry are of critical importance to the medicinal chemist as it provides the ability to expand the available drug-like chemical space and drive more efficient delivery of drug discovery programs.

Aziridines and Epoxides in Organic Synthesis

2006-01-09

Transition Metal-Catalyzed C–H Amination: Scope, Mechanism, and Applications

2017-01-04

Yoonsu Park , Youyoung Kim , Sukbok Chang

Catalytic transformation of ubiquitous C-H bonds into valuable C-N bonds offers an efficient synthetic approach to construct N-functionalized molecules. Over the last few decades, transition metal catalysis has been repeatedly … Catalytic transformation of ubiquitous C-H bonds into valuable C-N bonds offers an efficient synthetic approach to construct N-functionalized molecules. Over the last few decades, transition metal catalysis has been repeatedly proven to be a powerful tool for the direct conversion of cheap hydrocarbons to synthetically versatile amino-containing compounds. This Review comprehensively highlights recent advances in intra- and intermolecular C-H amination reactions utilizing late transition metal-based catalysts. Initial discovery, mechanistic study, and additional applications were categorized on the basis of the mechanistic scaffolds and types of reactions. Reactivity and selectivity of novel systems are discussed in three sections, with each being defined by a proposed working mode.

Nucleophilic ring opening of aziridines

2004-02-17

Xiaoyan Hu

Synthesis of 1,3-Difunctionalized Amine Derivatives through Selective C−H Bond Oxidation

2001-06-22

Christine G. Espino , Paul M. Wehn , Jessica Chow +1 more

ADVERTISEMENT RETURN TO ISSUEPREVCommunicationNEXTSynthesis of 1,3-Difunctionalized Amine Derivatives through Selective C−H Bond OxidationChristine G. Espino, Paul M. Wehn, Jessica Chow, and J. Du BoisView Author Information Department of Chemistry, Stanford … ADVERTISEMENT RETURN TO ISSUEPREVCommunicationNEXTSynthesis of 1,3-Difunctionalized Amine Derivatives through Selective C−H Bond OxidationChristine G. Espino, Paul M. Wehn, Jessica Chow, and J. Du BoisView Author Information Department of Chemistry, Stanford University Stanford, California 94305 Cite this: J. Am. Chem. Soc. 2001, 123, 28, 6935–6936Publication Date (Web):June 22, 2001Publication History Received24 April 2001Published online22 June 2001Published inissue 1 July 2001https://pubs.acs.org/doi/10.1021/ja011033xhttps://doi.org/10.1021/ja011033xrapid-communicationACS PublicationsCopyright © 2001 American Chemical SocietyRequest reuse permissionsArticle Views12982Altmetric-Citations471LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-AlertscloseSupporting Info (1)»Supporting Information Supporting Information SUBJECTS:Alcohols,Amines,Heterocyclic compounds,Organic compounds,Organic reactions Get e-Alerts

Recent Synthetic Applications of Chiral Aziridines

2000-01-01

William McCoull , Franklin A. Davis

Due to their ready availability in chiral form, and propensity to undergo regio- and stereoselective ring opening, aziridines have found widespread use in asymmetric synthesis. This review attempts to summarise … Due to their ready availability in chiral form, and propensity to undergo regio- and stereoselective ring opening, aziridines have found widespread use in asymmetric synthesis. This review attempts to summarise the breadth of use of chiral aziridines in synthesis that has recently been reported. Particular emphasis is put on the effect of substituents on ring openings, rearrangements and use as chiral ligands and auxiliaries.

Allylic Amination

1998-05-15

Mogens Johannsen , Karl Anker Jørgensen

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTAllylic AminationMogens Johannsen and Karl Anker JørgensenView Author Information Center for Metal Catalyzed Reactions, Department of Chemistry, Aarhus University, DK-8000 Aarhus C, Denmark Cite this: Chem. Rev. … ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTAllylic AminationMogens Johannsen and Karl Anker JørgensenView Author Information Center for Metal Catalyzed Reactions, Department of Chemistry, Aarhus University, DK-8000 Aarhus C, Denmark Cite this: Chem. Rev. 1998, 98, 4, 1689–1708Publication Date (Web):May 15, 1998Publication History Received12 January 1998Revised16 March 1998Published online15 May 1998Published inissue 1 June 1998https://pubs.acs.org/doi/10.1021/cr970343ohttps://doi.org/10.1021/cr970343oresearch-articleACS PublicationsCopyright © 1998 American Chemical SocietyRequest reuse permissionsArticle Views10174Altmetric-Citations718LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose SUBJECTS:Chemical reactions,Hydrocarbons,Organic reactions,Rearrangement,Substitution reactions Get e-Alerts

Modern Amination Methods

2000-07-13

Alfredo Ricci

Modern Allylic Amination Methods (K. Jorgensen) Eletrophilic Amination Routes from Alkenes (E. Fernandez & J. Brown) Stereoselective Electrophilic Amination with Sulfonyloxycarbamates and Azodicarboxylates (J.-P. Genet, et al.) Glycosylamines as Auxiliaries … Modern Allylic Amination Methods (K. Jorgensen) Eletrophilic Amination Routes from Alkenes (E. Fernandez & J. Brown) Stereoselective Electrophilic Amination with Sulfonyloxycarbamates and Azodicarboxylates (J.-P. Genet, et al.) Glycosylamines as Auxiliaries in Stereoselective Syntheses of Chiral Amino Compounds (H. Tietgen, et al.) Syntheses of Transition Metal Nitride Complexes (C. Tomooka, et al.) Asymmetric Nitrogen Transfer with Nitridomanganese Complexes (S. Minakata & M. Komatsu) Palladium-Catalyzed Amination of Aryl Halides and Sulfonates (J. Hartwig) Index.

Chemoselective Synthesis of α‐Chloro and α,α‐Dichloro Acetamidines via the Carbenoids Addition to Inherently Low Electrophilic Carbodiimides

2025-06-25

Davide Castiglione , Margherita Miele , Annalisa Nardi +2 more | Advanced Synthesis & Catalysis

The hitherto few explored α‐halomethyl amidine motif has been assembled through the addition of a lithiated (di)‐halomethane (i.e., carbenoid) to easily accessible N,N’‐diaryl‐substituted carbodiimides. Despite the inherent low electrophilicity of … The hitherto few explored α‐halomethyl amidine motif has been assembled through the addition of a lithiated (di)‐halomethane (i.e., carbenoid) to easily accessible N,N’‐diaryl‐substituted carbodiimides. Despite the inherent low electrophilicity of these heterocumulenes—as quantitatively determined in Mayr's previous studies—their sp‐hybridized carbon atom acts as a competent site of attack for these tamed nucleophiles. The overall high‐yielding transformation featuring a genuine chemoselective profile—as documented by using variously functionalized materials—is adaptable to the addition of dihalogenated carbenoids. Reaction products could be advantageously used in nucleophilic substitution sequences as well as in further functionalization of the nitrogen atoms due to the constitutive heteroallyl‐type skeleton.

One-Pot Synthesis of Alpha-Diimines from Alkylammonium Salts

2025-06-25

Emily K. Burke , Shay Heans Moreyra , Erin N. Welsh +3 more | Canadian Journal of Chemistry

A one-pot synthesis of alkyl-containing diazabutadienes from primary alkylamine HCl salts is presented. This synthesis substitutes halogenated solvents with isopropyl acetate (a recommended solvent from an environmental and hazard perspective), … A one-pot synthesis of alkyl-containing diazabutadienes from primary alkylamine HCl salts is presented. This synthesis substitutes halogenated solvents with isopropyl acetate (a recommended solvent from an environmental and hazard perspective), toluene or heptane, and avoids the need for a separate step for generating the free base amine when starting with amines in their HCl salt form. The amine HCl salts, whether commercially available or synthesized are conveniently handled and stored. The diazabutadienes have comparable or superior purity to examples prepared with halogenated solvents, ascertained by NMR spectroscopy. Since diazabutadienes are commonly used as either ligands, or precursors for heterocycles including N-heterocyclic carbenes and diazaphospholenes, this route will be of convenience to many researchers in multiple areas of catalysis.

Enantioselective Synthesis of 2,3-Disubstituted Azetidines via Copper-Catalyzed Boryl Allylation of Azetines

2025-06-24

Minghui Zhu , Jianwei Sun | Journal of the American Chemical Society

Disclosed here is a highly enantioselective difunctionalization of azetines for convenient access to chiral 2,3-disubstituted azetidines, a family of important scaffolds previously lacking general access. With Cu/bisphosphine as a catalyst, … Disclosed here is a highly enantioselective difunctionalization of azetines for convenient access to chiral 2,3-disubstituted azetidines, a family of important scaffolds previously lacking general access. With Cu/bisphosphine as a catalyst, two versatile functionalities (boryl and allyl) were installed on azetine with concomitant construction of two new stereogenic centers. This represents a rare demonstration of Cu-catalyzed asymmetric boryl alkylation of electron-rich olefins and C═C bonds in strained heterocycles. The use of allyl phosphates proved critical not only to overcome the low reactivity of the borylated alkylcuprate intermediate toward alkylation but also to avoid competing side reactions. Remarkably, in almost all cases, single isomers were obtained with complete regio-, enantio-, and diastereoselectivies on the azetidine motif as well as excellent control on the double bond configuration. The mild conditions exhibited outstanding functional group compatibility and chemoselectivity. The versatile boryl and allyl functionalities allowed for easy transformations of the products to other useful chiral azetidines previously lacking straightforward access. Control experiments and kinetic studies indicated that the reaction proceeds by a fast boryl cupration of azetine followed by rate-determining allylation via an intrinsically controlled SN2' pathway.

A Multicomponent Reaction to Access Functionalized Azetidine Derivatives

2025-06-23

| Synfacts

Titanium-Catalyzed Radical Kinetic Resolution of Aziridines Using Water as Hydrogen Atom Donor

2025-06-23

| Synfacts

Synthesis of Alkyl Azetidines via Batch and Flow Photochemistry

2025-06-23

| Synfacts

Catalytic, Enantioselective Aziridine Desymmetrization with Pyrroles

2025-06-23

Dustin Mauldin , Nguyen Thi Hoang Ha , Ernest Brubaker +4 more | The Journal of Organic Chemistry

Ring-opening reactions of meso-aziridines with carbon nucleophiles lead to complex, enantioenriched chiral amine derivatives through enantioselective catalysis. We report that a diphosphine-palladium(II) catalyst enables the highly enantioselective desymmetrization of N-acylaziridines … Ring-opening reactions of meso-aziridines with carbon nucleophiles lead to complex, enantioenriched chiral amine derivatives through enantioselective catalysis. We report that a diphosphine-palladium(II) catalyst enables the highly enantioselective desymmetrization of N-acylaziridines with pyrroles. The β-pyrrole amine products are isolated with excellent enantioselectivity and varying yields across a range of pyrrole and aziridine substitution patterns. The synthetic utility of the pyrrole products is demonstrated by conversion to a novel saturated pyrrolopyridine core.

Difunctionalization of Sulfamate-Derived Cyclic Imines through Phosphine Catalysis

2025-06-22

Yaping Wang , Bing Zheng , Jiawei Liu +4 more | Organic Letters

With the use of alkynyl 1,2-diones as phosphine acceptors and H2O as a reaction partner, an unprecedented phosphine-catalyzed three-component difunctionalization of sulfamate-derived cyclic imines was achieved, providing a wide range … With the use of alkynyl 1,2-diones as phosphine acceptors and H2O as a reaction partner, an unprecedented phosphine-catalyzed three-component difunctionalization of sulfamate-derived cyclic imines was achieved, providing a wide range of highly functionalized cyclic sulfonamide products in moderate to good yields. This protocol features a broad substrate scope and mild reaction conditions. It also represents a rare example of H2O serving as a substrate to participate in phosphine-catalyzed reactions. The reaction mechanism involves a tandem acyloxylation/cinnamoylation reaction.

Photoelectrochemical Iron–Nickel Synergistic Catalysis for C(sp3)-H and Dehydroxymethylative Acylation

2025-06-20

Xiao Zhou , Ping‐Fu Zhong , Zhuohua Li +6 more | Organic Letters

We developed an iron-nickel dual-catalytic system for efficient C(sp3)-H activation acylation of hydrocarbons and carboxylic acids under photoelectrochemical conditions. This system is based on ligand-to-metal charge transfer-mediated direct hydrogen atom … We developed an iron-nickel dual-catalytic system for efficient C(sp3)-H activation acylation of hydrocarbons and carboxylic acids under photoelectrochemical conditions. This system is based on ligand-to-metal charge transfer-mediated direct hydrogen atom transfer and is applicable to inert C(sp3)-H-containing compounds. It also enables dehydroxymethylative acylation of alcohols, both these two reactions demonstrating broad substrate scope and unconventional chemoselectivity. Gram-scale synthesis, flow chemistry, and mechanistic studies highlight its potential in sustainable C(acyl)-C bond formation.

Asymmetric C–H Amination via Fe(III)-Metalloradical Catalysis Featuring α-Fe(IV)-Aminyl Radicals as Key Intermediates

2025-06-19

Wan‐Chen Cindy Lee , Duo‐Sheng Wang , Arghya Deb +2 more | Journal of the American Chemical Society

Metalloradical catalysis (MRC) offers a general mechanistic platform for controlling the reactivity and selectivity of homolytic radical reactions. While Co(II)-based d7-metalloradical catalysts have dominated the field, we introduce here an … Metalloradical catalysis (MRC) offers a general mechanistic platform for controlling the reactivity and selectivity of homolytic radical reactions. While Co(II)-based d7-metalloradical catalysts have dominated the field, we introduce here an Fe(III)-based d5-metalloradical system that is highly effective for asymmetric C-H amination. In particular, we reveal that five-coordinate Fe(III) complexes of porphyrins with an axial ligand, a family of stable 15e-metalloradicals, are potent metalloradical catalysts for 1,5-C(sp3)-H amination of aryl azides. Leveraging a specially designed D2-symmetric chiral amidoporphyrin ligand, this Fe(III)-based metalloradical system enables the homolytic activation of various aryl azides for the intramolecular amination of diverse C(sp3)-H bonds, allowing for the high-yielding construction of chiral indolines with excellent enantioselective control. Notably, this process operates without light or additional additives and generates N2 as the sole byproduct. Through comprehensive experimental investigations and detailed computational studies, we provide compelling evidence in support of the underlying stepwise radical mechanism. The catalytic pathway involves key steps of hydrogen atom abstraction (HAA) and radical substitution (RS), mediated by the initially generated α-Fe(IV)-aminyl radicals and the subsequently formed ε-Fe(IV)-alkyl radicals, respectively.

Borane‐Catalyzed Chemo‐ and Regioselective Ring Opening of 2‐Substituted Aziridines with Phenols for Direct Synthesis of β‐Arylethylamines

2025-06-18

Sanjukta Saha , Debraj Ghosh , Devendra K. Dhaked +1 more | Advanced Synthesis & Catalysis

A metal‐free chemo‐ and regioselective nucleophilic ring opening of 2‐substituted aziridines with ortho ‐C(sp 2 ) atom of phenols enables facile access to medicinally relevant β ‐arylethylamine derivatives. In this … A metal‐free chemo‐ and regioselective nucleophilic ring opening of 2‐substituted aziridines with ortho ‐C(sp 2 ) atom of phenols enables facile access to medicinally relevant β ‐arylethylamine derivatives. In this approach, phenols act as aryl nucleophiles that favor CC bond formation selectively at the ortho ‐C(sp 2 ) position with the more substituted carbon of aziridines to generate branched, selective arylated products. Despite the significant advancement of transition‐metal‐catalyzed cross‐coupling and nucleophilic ring opening of 2‐substituted azirines, only linear arylated products are widely demonstrated. The first metal‐free branched selective nucleophilic ring opening of 2‐alkyl and 2‐aryl aziridines with phenols is reported to address this challenge. Furthermore, the diversity of the substrate scope by using N‐heterocycles as nucleophiles empowers the generation of β ‐heteroarylethylamine derivatives. A combination of computational and experimental investigation reveals that the reaction proceeds via a borane‐promoted proton transfer, followed by aziridine ring opening and Fridel–Crafts alkylation involving a π ‐complex of carbocation‐anion ion pair. This protocol is further applicable for the synthesis of pharmaceutically relevant compounds like serotonin and tryptamine.

Monocyclic Azetidines via a Visible-Light-Mediated Aza Paternò-Büchi Reaction of Ketone-Derived Sulfonylimines

2025-06-17

Cody Ng , Emily R. Wearing , Dominique E. Blackmun +7 more | Journal of the American Chemical Society

The recent rise in popularity of azetidines in pharmaceutical chemistry has inspired the development of visible-light-mediated aza Paternò-Büchi reactions as direct transformations to form these desirable products. Despite these advancements, … The recent rise in popularity of azetidines in pharmaceutical chemistry has inspired the development of visible-light-mediated aza Paternò-Büchi reactions as direct transformations to form these desirable products. Despite these advancements, successful reports of accessing monocyclic azetidines from acyclic imines remain scarce. Here, we report a visible-light-mediated aza Paternò-Büchi reaction of acyclic ketone-derived sulfonylimines, which are previously unexplored substrates in this transformation, with activated alkenes (i.e., styrenes and dienes) to form 2,2-disubstituted monocyclic azetidines that can be further modified to reveal free N-H azetidines. Computational and experimental mechanistic studies reveal that in contrast to aldehyde-derived oximes, the use of ketone-derived sulfonylimines enables tuning of the reaction mechanism to favor initial formation of the C-N rather than C-C bond, thus enabling access to 2,2-disubstituted monocyclic azetidine scaffolds.

Direct, Asymmetric, and Stereodivergent Reactions of N-Azidoacetyl Thioimides with Aromatic Acetals Catalyzed by Chiral Nickel(II) Complexes. An Approach to the Synthesis of syn- and anti-β-Alkoxy-α-amino Acids

2025-06-17

Miguel Mellado‐Hidalgo , Joan Conejos-Jalencas , Saúl F. Teloxa +7 more | The Journal of Organic Chemistry

A new approach to the synthesis of all of the potential stereoisomers of β-alkoxy-α-amino acids derived from phenylalanine, tyrosine, tryptophan, and other β-aryl counterparts is reported. Such a method hinges … A new approach to the synthesis of all of the potential stereoisomers of β-alkoxy-α-amino acids derived from phenylalanine, tyrosine, tryptophan, and other β-aryl counterparts is reported. Such a method hinges on direct and asymmetric Lewis acid-mediated aldol-like reactions of N-azidoacetyl thioimides with dialkyl acetals from aromatic aldehydes catalyzed by chiral nickel(II) complexes. This produces at will both the corresponding syn and anti adducts, which can be smoothly converted into enantiomerically pure intermediates such as dipeptide fragments. In turn, computational calculations have unveiled clues for a better understanding of such a stereocontrolled carbon-carbon bond-forming transformation.

Ligand-Free Silver Fluoride-Promoted (3 + 2) Annulation of Oxaziridines and α-Isocyanoacetates: A Diastereoselective Route to cis-Imidazolines

2025-06-17

Jubao Zhou , Siyun Wang , Hu Shi +2 more | The Journal of Organic Chemistry

A ligand-free silver fluoride-promoted diastereoselective (3 + 2) annulation reaction between oxaziridines and isocyanoacetates was developed, enabling the efficient synthesis of cis-2-imidazolines under mild conditions (room temperature within 10 min) … A ligand-free silver fluoride-promoted diastereoselective (3 + 2) annulation reaction between oxaziridines and isocyanoacetates was developed, enabling the efficient synthesis of cis-2-imidazolines under mild conditions (room temperature within 10 min) with up to 90% yield. The resulting cis-imidazolines are readily hydrolyzed to anti-α,β-diamino acid derivatives while maintaining the stereochemical integrity. Additionally, the cis-imidazolines can be efficiently converted to their trans epimers in high yields, providing stereodivergent access to the syn-α,β-diamino acid derivatives.

Photo‐induced Thiocyanation of Alkenes Catalyzed by Non‐heme Iron Complexes: Synthetic Methodology and Mechanistic Insights

2025-06-17

Cece Wang , Yingji Liu , Haozhe Dong +1 more | Chinese Journal of Chemistry

Comprehensive Summary High valent iron complexes Fe‐X have been known to transfer their X group toward carbon radical species to form R–X bond. To utilize this capability of iron catalyst, … Comprehensive Summary High valent iron complexes Fe‐X have been known to transfer their X group toward carbon radical species to form R–X bond. To utilize this capability of iron catalyst, novel photo‐induced iron catalysis system had been developed in the difunctionalization of alkenes in the presence of radical initiator. However, the details of the reaction mechanism are still unclear, especially the transformations of the photocatalyst and the iron catalyst during the catalytic turnover. Herein, we expanded the photo‐driven non‐heme iron complex catalyzed thiocyanation of styrene substrate. This protocol exhibited broad substrate scope and high efficiency. Detailed mechanistic studies using various spectroscopies, such as UV‐vis, mass spectrometry, transient absorption spectroscopy and X‐ray absorption spectroscopy, revealed the transformations of photocatalyst [Ir III (ppy) 3 ] and group transfer catalyst [Fe II (bpmen)] 2+ . Real‐time spectroscopies combined with mechanistic experiments demonstrated that [Ir IV (ppy) 3 ] + and [Fe III (bpmen)] 3+ were the key intermediates involved in the reaction cycle.

Correction to “ortho-C–H Amidation of Phenols through Intramolecular Rearrangement of N-Phenoxyarylamides”

2025-06-15

Guodong Zhang , Songlin Zhuang , H. R. Nan +7 more | Organic Letters

Stereoselective Synthesis of Delgocitinib and Its Diastereomer Using Organocatalyzed Michael Addition

2025-06-14

K. Morita , Nariyoshi Umekubo , Haruo Matsuzaki +2 more | Organic Letters

Herein, we describe the stereoselective synthesis of delgocitinib and its diastereomer. Delgocitinib, a Janus kinase (JAK) inhibitor, is characterized by a diaza-spirocyclic structure consisting of pyrrolidine and azetidine rings. The … Herein, we describe the stereoselective synthesis of delgocitinib and its diastereomer. Delgocitinib, a Janus kinase (JAK) inhibitor, is characterized by a diaza-spirocyclic structure consisting of pyrrolidine and azetidine rings. The organocatalyzed Michael addition of propanal with fumarate or maleimide facilitated the formation of contiguous tertiary stereogenic centers, leading to the stereoselective production of each diastereomer. Intramolecular C-H amination reactions introduced a nitrogen atom on one of the tertiary carbons, and subsequent azetidine formation constructed the spirocyclic system.

Nucleophilic Aliphatic Substitution 2021

2025-06-13

J. G. Moloney , Mark G. Moloney | Organic Reaction Mechanisms/Organic reaction mechanisms

Proton Relay Catalysis Enables the Synthesis of 2-Oxa- and 2-Azabicyclo[2.2.1]heptanes

2025-06-12

Chenyang Chang , Stephanie G. E. Amos , J. Benet‐Buchholz +1 more | Organic Letters

An effective binary catalytic system enables the synthesis of oxa- and aza-bicyclo[2.2.1]heptanes from cyclic γ-epoxy-alcohols. A combination of an aminotriphenolate Al(III) complex and a bromide salt delivers a wide variety … An effective binary catalytic system enables the synthesis of oxa- and aza-bicyclo[2.2.1]heptanes from cyclic γ-epoxy-alcohols. A combination of an aminotriphenolate Al(III) complex and a bromide salt delivers a wide variety of target compounds in good to excellent yields, with high diastereo-control. The mechanism includes a double-nucleophilic displacement at a carbon center via a proton-relay step involving the Al(III) complex phenolate, as supported by control experiments. Med-chem inspired synthons could successfully be obtained with the aza-bicyclo[2.2.1]heptanes.

Dual Role of C,N-Cyclic Azomethine Imine as a Dipole and an Oxidant in the Synthesis of Pyrazolidine-Fused Tetrahydroquinolines and C3-Functionalized Quinolines

2025-06-12

SoJin Shin , Subin Lee , Seewon Joung | The Journal of Organic Chemistry

A selective synthesis of pyrazolidine-fused tetrahydroquinoline and C3-functionalized quinoline from N-silyl enamine and C,N-cyclic azomethine imine is presented, using [3 + 2] cycloaddition with varying reagent ratios. In this study, … A selective synthesis of pyrazolidine-fused tetrahydroquinoline and C3-functionalized quinoline from N-silyl enamine and C,N-cyclic azomethine imine is presented, using [3 + 2] cycloaddition with varying reagent ratios. In this study, the C,N-cyclic azomethine imine serves dual roles as both dipole and oxidant, with the latter being unprecedented. The dual role of C,N-cyclic azomethine imine was confirmed through stepwise control reactions and deuterium-labeling studies.

Chemoselective Electrochemical Coupling of Thioethers and Primary Amines for Accessing Sulfilimines and Sulfoximines

2025-06-12

Sukwoo Lee , Jonas Rein , Evan A. Weingarten +1 more | Journal of the American Chemical Society

We report the electrooxidative coupling of thioethers with primary alkylamines, furnishing structurally diverse sulfilimines and sulfoximines including unconventional isopeptides. Cyclic voltammetry and control experiments revealed that modulating the protonation states … We report the electrooxidative coupling of thioethers with primary alkylamines, furnishing structurally diverse sulfilimines and sulfoximines including unconventional isopeptides. Cyclic voltammetry and control experiments revealed that modulating the protonation states of reactants and products is key to achieving chemoselective oxidation.

Asymmetric Synthesis of Biaryl Sulfilimines Bearing Multiple Chiral Elements Involving Cyclic Diaryliodoniums

2025-06-11

Xiangyu Liu , Zenghui Ye , Jici Liu +2 more | Organic Letters

The enantio- and diastereoselective synthesis of biaryl atropisomers with a sulfur stereogenic center is a significant challenge for current chemical synthesis due to the lack of effective synthetic strategies. Herein, … The enantio- and diastereoselective synthesis of biaryl atropisomers with a sulfur stereogenic center is a significant challenge for current chemical synthesis due to the lack of effective synthetic strategies. Herein, we report an efficient method for the construction of chiral biaryl sulfilimines possessing both axial and sulfur central chiralities via copper/chiral cobalt anion-catalyzed sulfuration of cyclic diaryliodoniums under mild conditions. Various axial chiral biaryl sulfilimines were efficiently prepared in high yields (up to 99%) and enantioselectivities (up to 98% ee), which can be easily transformed into a wide range of valuable chiral biaryl sulfoximines and their derivatives.

Catalytic Aerobic Cross‐Coupling of Indoles and Urazoles

2025-06-10

L. Du , Yingying Xu , Kai Xu +1 more | Chinese Journal of Chemistry

Comprehensive Summary TAD‐indole adducts, serving as stable surrogates for reactive triazolinediones (TADs), are pivotal in bioconjugation and polymer chemistry but remain limited by cumbersome synthesis. Current methods rely on preformed … Comprehensive Summary TAD‐indole adducts, serving as stable surrogates for reactive triazolinediones (TADs), are pivotal in bioconjugation and polymer chemistry but remain limited by cumbersome synthesis. Current methods rely on preformed TADs or stoichiometric oxidants, posing practical and environmental challenges. Herein, we report a sustainable catalytic cross‐coupling protocol to directly synthesize TAD‐indole adducts from indoles and urazoles via Ma's oxidation. This one‐step method employs the Fe(NO₃)₃·9H₂O/TEMPO/NaCl system with air as the terminal oxidant, achieving high efficiency (up to 86% yield), broad substrate scope (electron‐rich/‐deficient indoles/urazoles), and mild conditions. The protocol's practicality is demonstrated through gram‐scale synthesis and the preparation of blocked TAD cross‐linkers for temperature‐controlled polymer networks. By circumventing traditional TAD‐handling limitations and eliminating excess oxidants, this strategy establishes a green, scalable platform for advancing TAD chemistry in materials and bioconjugation.

Probing Unspecific Peroxygenases for Non‐Natural Nitrene Chemistry

2025-06-06

Pascal Püllmann , Dominik Homann , Lewis R. Thomas‐Hargreaves | ChemBioChem

Unspecific peroxygenases (UPOs) perform challenging oxyfunctionalization chemistry with high catalytic efficiency and reaction stability.[1‐5] In this report, we add nitrene chemistry to the current repertoire of UPO chemistry, utilizing the … Unspecific peroxygenases (UPOs) perform challenging oxyfunctionalization chemistry with high catalytic efficiency and reaction stability.[1‐5] In this report, we add nitrene chemistry to the current repertoire of UPO chemistry, utilizing the inexpensive commodity chemical hydroxylamine as co‐substrate. 1,2,3,4‐tetrahydronaphthalene was investigated as model substrate employing a diverse panel of UPOs, reaching turnover numbers up to 745 and enantiomeric excess values up to 62 %. Overall, we report the first account of UPO activity regarding non‐natural reactivities.

Intramolecular N–O Bond Formation for the Synthesis of N-Alkyl and N-Aryl Isoxazolidines

2025-06-05

Margaret Solecki , David Crich | Journal of the American Chemical Society

We describe the synthesis of a series of readily assembled, variously substituted 3-(4-trifluoromethyl-2-nitrobenzenesulfonamido)alkyl silylperoxides and their conversion to the corresponding isoxazolidines in moderate to high yield by intramolecular N-O bond … We describe the synthesis of a series of readily assembled, variously substituted 3-(4-trifluoromethyl-2-nitrobenzenesulfonamido)alkyl silylperoxides and their conversion to the corresponding isoxazolidines in moderate to high yield by intramolecular N-O bond formation on removal of the sulfonamide protecting group. Cyclization with N-O bond formation was dependent on steric hindrance of the electrophilic silylperoxides, with primary systems cyclizing directly during the course of sulfonamide cleavage with thiolate anions. Secondary silyl peroxides, on the other hand, were best cyclized by warming in the presence of hexafluoroisopropanol after desulfonylation, while tertiary silylperoxides required deprotonation of the intermediate amine. Tertiary benzylic peroxides underwent cyclization by a novel mechanism, with the formation of intermediate trifluoromethylnitrophenyl peroxides, during the course of fluoride-mediated desilylation. The cyclization was extended to include the formation of a simple oxazine, but extrapolation to the formation of an oxazepine was foiled by competing Kornblum DeLaMare fragmentation at the level of the intermediate aminoperoxide.