Enamine-Based Organocatalysis with Proline And
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Part I: Carbonyl-Olefin Metathesis of Norbornene
Part I: Carbonyl-Olefin Metathesis of Norbornene Part II: Cyclopropenimine-Catalyzed Asymmetric Michael Reactions Zara Maxine Seibel Submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Graduate School of Arts and Sciences COLUMBIA UNIVERSITY 2016 1 © 2016 Zara Maxine Seibel All Rights Reserved 2 ABSTRACT Part I: Carbonyl-Olefin Metathesis of Norbornene Part II: Cyclopropenimine-Catalyzed Asymmetric Michael Reactions Zara Maxine Seibel This thesis details progress towards the development of an organocatalytic carbonyl- olefin metathesis of norbornene. This transformation has not previously been done catalytically and has not been done in practical manner with stepwise or stoichiometric processes. Building on the previous work of the Lambert lab on the metathesis of cyclopropene and an aldehyde using a hydrazine catalyst, this work discusses efforts to expand to the less stained norbornene. Computational and experimental studies on the catalytic cycle are discussed, including detailed experimental work on how various factors affect the difficult cycloreversion step. The second portion of this thesis details the use of chiral cyclopropenimine bases as catalysts for asymmetric Michael reactions. The Lambert lab has previously developed chiral cyclopropenimine bases for glycine imine nucleophiles. The scope of these catalysts was expanded to include glycine imine derivatives in which the nitrogen atom was replaced with a carbon atom, and to include imines derived from other amino acids. i Table of Contents List of Abbreviations…………………………………………………………………………..iv Part I: Carbonyl-Olefin Metathesis…………………………………………………………… 1 Chapter 1 – Metathesis Reactions of Double Bonds………………………………………….. 1 Introduction………………………………………………………………………………. 1 Olefin Metathesis………………………………………………………………………… 2 Wittig Reaction…………………………………………………………………………... 6 Tebbe Olefination………………………………………………………………………... 9 Carbonyl-Olefin Metathesis……………………………………………………………. -
Thiourea Derivatives of Tröger's Base
General Papers ARKIVOC 2009 (xiv) 124-134 Thiourea derivatives of Tröger’s base: synthesis, enantioseparation and evaluation in organocatalysis of Michael addition to nitroolefins Delphine Didiera and Sergey Sergeyeva,b* a Université Libre de Bruxelles (ULB), Laboratoire de Chimie des Polymères, CP 206/01, Boulevard du Triomphe, 1050 Brussels, Belgium b University of Antwerp, Department of Chemistry, Groenenborgerlaan 171, 2020 Antwerp, Belgium E-mail: [email protected] Abstract The catalytic activity of racemic thiourea derivatives of Tröger’s base (±)-2–4 in Michael additions of malonate derivatives to trans-β-nitrostyrene was studied. Due to the low basicity of Tröger’s base, the outcome of the addition reactions was strongly dependent on the pKa of the nucleophile. Thiourea catalysts (±)-2, 3 were resolved on the chiral stationary phase Whelk O1. Unfortunately, enantiopure catalysts 2 and 3 showed no stereoselectivity in the Michael addition. Keywords: Tröger’s base, thiourea, Michael addition, catalysis, WhelkO1 Introduction In the recent years, asymmetric organocatalysis has emerged as a competitive, environment- friendlier alternative to catalysis with transition metal complexes. While simple molecules such as derivatives of proline have been receiving a great deal of attention due to their availability, considerable effort has been directed towards searching for novel chiral scaffolds for asymmetric organocatalysis.1 Tröger’s base 1 is a chiral diamine bearing two stereogenic bridge-head nitrogen atoms (Figure 1). The two aromatic rings fused to the central bicyclic framework are almost perpendicular to each other, creating a rigid, V-shaped C2-symmetrical molecular scaffold with a distance of ca. 1nm between the two extremities.2 Due to its chirality and relatively rigid geometry, one would intuitively expect a considerable interest for analogues of Tröger’s base in the field of asymmetric synthesis and catalysis. -
Alkylation by Enamines for Synthesis of Some Heterocyclic Compounds ﻴﺩ
------J. Raf. Sci., Vol. 20, No.2, pp 92- 101, 2009 ------ Alkylation by Enamines for Synthesis of some Heterocyclic Compounds Jasim A. Abdullah Department of Chemistry College of Education Mosul University (Received 25/ 9/ 2008 ; Accepted 13 / 4 / 2009) ABSTRACT Compounds of 4-phenyl-3-butene-2-one (1) and 4-(4-chlorophenyl)-3-butene-2-one (2) were prepared by reaction of benzaldehyde or 4-chlorobenzaldehyde with acetone. Also 1,3-diphenyl-2-chloropropene-1-one (3) was synthesized from the reaction of benzaldehyde with 2-chloroacetophenone through Claisen-Shmidt condensation. The substituted ∆1(9)- octalone-2 (4,5) was prepared by reaction of the compounds (1and2) with cyclohexanone through Michael addition followed by aldol condensation. Compounds (4,5) were reacted with alkyl halide, as 2-chloroacetophenone or 1,3-diphenyl-2-chloropropene-1-one (3), via enamines formation which then hydrolyzed to give compounds (6-9). Compounds (6,7) were reacted with hydrazine , urea and thiourea to afford compounds (10-15) . The structures of all synthesized compounds were confirmed by available physical and spectral means . Keywords : Enamines , Heterocyclic compounds. ــــــــــــــــــــــــــــــــــــــــــــــــــ ﺍﻻﻟﻜﻠﺔ ﺒﻭﺍﺴﻁﺔ ﺍﻷﻴﻨﺎﻤﻴﻨﺎﺕ ﻟﺘﺸﻴﻴﺩ ﺒﻌﺽ ﺍﻟﻤﺭﻜﺒﺎﺕ ﺍﻟﺤﻠﻘﻴﺔ ﻏﻴﺭ ﺍﻟﻤﺘﺠﺎﻨﺴﺔ ﺍﻟﻤﻠﺨﺹ ﺘﻡ ﺘﺤﻀﻴﺭ ﺍﻟﻤﺭﻜﺒﺎﺕ 4-ﻓﻨﻴل-3-ﺒﻴﻭﺘﻴﻥ-2-ﺍﻭﻥ (1) ﻭ4-(4-ﻜﻠﻭﺭﻭﻓﻨﻴل)-3-ﺒﻴﻭﺘﻴﻥ-2-ﺍﻭﻥ (2) ﻤﻥ ﺘﻔﺎﻋل ﺍﻟﺒﻨﺯﺍﻟﺩﻴﻬﻴﺩ ﺃﻭ 4-ﻜﻠﻭﺭﻭﺍﻟﺒﻨﺯﺍﻟﺩﻴﻬﻴﺩ ﻤﻊ ﺍﻻﺴﻴﺘﻭﻥ . ﺤﻀﺭ ﺍﻟﻤﺭﻜﺏ 3,1-ﺜﻨﺎﺌﻲ ﻓﻨﻴل -2-ﻜﻠـﻭﺭﻭﺒﺭﻭﺒﻴﻥ -1-ﺍﻭﻥ (3) ﻤـﻥ ﺘﻔﺎﻋـل ﺍﻟﺒﻨﺯﺍﻟﺩﻴﻬﻴـﺩ ﻤـﻊ -2 9 1 ﻜﻠﻭﺭﻭﺍﺴﻴﺘﻭﻓﻴﻨﻭﻥ ﺒﻭﺴﺎﻁﺔ ﺘﻜﺎﺜﻑ (ﻜﻠﻴﺯﻥ-ﺸﻤﺩﺕ).ﺤﻀﺭﺕ ﻤﻌﻭﻀﺎﺕ ∆ ( ) –ﺍﻭﻜﺘﺎﻟﻭﻥ-2 ﻤﻥ ﺨﻼل ﺘﻔﺎﻋل ﺍﻟﻤﺭﻜﺒﻴﻥ (2,1) ﻤﻊ ﺍﻟﻬﻜﺴﺎﻨﻭﻥ ﺍﻟﺤﻠﻘﻲ ﺒﻭﺴﺎﻁﺔ ﺍﻀﺎﻓﺔ ﻤﺎﻴﻜل ﺍﻟﺘﻲ ﻴﺘﺒﻌﻬﺎ ﺘﻜﺎﺜﻑ ﺍﻻﻟﺩﻭل . -
Catalytic Direct Asymmetric Michael Reactions
ORGANIC LETTERS 2001 Catalytic Direct Asymmetric Michael Vol. 3, No. 23 Reactions: Taming Naked Aldehyde 3737-3740 Donors Juan M. Betancort and Carlos F. Barbas III* The Skaggs Institute for Chemical Biology and the Department of Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037 [email protected] Received September 5, 2001 ABSTRACT Direct catalytic enantio- and diastereoselective Michael addition reactions of unmodified aldehydes to nitro olefins using (S)-2-(morpholinomethyl)- pyrrolidine as a catalyst are described. The reactions proceed in good yield (up to 96%) in a highly syn-selective manner (up to 98:2) with enantioselectivities approaching 80%. The resulting γ-formyl nitro compounds are readily converted to chiral, nonracemic 3,4-disubstituted pyrrolidines. The Michael reaction is generally regarded as one of the Typically, carbon nucleophiles that contain an active most efficient carbon-carbon bond forming reactions, and methylene center such as malonic acid esters, â-keto esters, studies concerning this reaction have played an important nitroalkanes, etc. have been studied in the Michael reaction. role in the development of modern synthetic organic Carbonyl compounds, and ketones in particular, have gener- chemistry.1 As the demand for optically active compounds ally only been used as donors following their preactivation has soared in recent years, much progress has been made in by conversion into a more reactive species such as enol or the development of asymmetric variants of this reaction, enamine equivalents.5,6 In these cases, additional synthetic providing for the preparation of Michael adducts with high enantiomeric purity.2 Though remarkable advances have been (3) (a) Chataigner, I.; Gennari, C.; Ongeri, S.; Piarulli, U.; Ceccarelli, S. -
Part I Principles of Enzyme Catalysis
j1 Part I Principles of Enzyme Catalysis Enzyme Catalysis in Organic Synthesis, Third Edition. Edited by Karlheinz Drauz, Harald Groger,€ and Oliver May. Ó 2012 Wiley-VCH Verlag GmbH & Co. KGaA. Published 2012 by Wiley-VCH Verlag GmbH & Co. KGaA. j3 1 Introduction – Principles and Historical Landmarks of Enzyme Catalysis in Organic Synthesis Harald Gr€oger and Yasuhisa Asano 1.1 General Remarks Enzyme catalysis in organic synthesis – behind this term stands a technology that today is widely recognized as a first choice opportunity in the preparation of a wide range of chemical compounds. Notably, this is true not only for academic syntheses but also for industrial-scale applications [1]. For numerous molecules the synthetic routes based on enzyme catalysis have turned out to be competitive (and often superior!) compared with classic chemicalaswellaschemocatalyticsynthetic approaches. Thus, enzymatic catalysis is increasingly recognized by organic chemists in both academia and industry as an attractive synthetic tool besides the traditional organic disciplines such as classic synthesis, metal catalysis, and organocatalysis [2]. By means of enzymes a broad range of transformations relevant in organic chemistry can be catalyzed, including, for example, redox reactions, carbon–carbon bond forming reactions, and hydrolytic reactions. Nonetheless, for a long time enzyme catalysis was not realized as a first choice option in organic synthesis. Organic chemists did not use enzymes as catalysts for their envisioned syntheses because of observed (or assumed) disadvantages such as narrow substrate range, limited stability of enzymes under organic reaction conditions, low efficiency when using wild-type strains, and diluted substrate and product solutions, thus leading to non-satisfactory volumetric productivities. -
Amide Activation: an Emerging Tool for Chemoselective Synthesis
Featuring work from the research group of Professor As featured in: Nuno Maulide, University of Vienna, Vienna, Austria Amide activation: an emerging tool for chemoselective synthesis Let them stand out of the crowd – Amide activation enables the chemoselective modification of a large variety of molecules while leaving many other functional groups untouched, making it attractive for the synthesis of sophisticated targets. This issue features a review on this emerging field and its application in total synthesis. See Nuno Maulide et al., Chem. Soc. Rev., 2018, 47, 7899. rsc.li/chem-soc-rev Registered charity number: 207890 Chem Soc Rev View Article Online REVIEW ARTICLE View Journal | View Issue Amide activation: an emerging tool for chemoselective synthesis Cite this: Chem. Soc. Rev., 2018, 47,7899 Daniel Kaiser, Adriano Bauer, Miran Lemmerer and Nuno Maulide * It is textbook knowledge that carboxamides benefit from increased stabilisation of the electrophilic carbonyl carbon when compared to other carbonyl and carboxyl derivatives. This results in a considerably reduced reactivity towards nucleophiles. Accordingly, a perception has been developed of amides as significantly less useful functional handles than their ester and acid chloride counterparts. Received 27th April 2018 However, a significant body of research on the selective activation of amides to achieve powerful DOI: 10.1039/c8cs00335a transformations under mild conditions has emerged over the past decades. This review article aims at placing electrophilic amide activation in both a historical context and in that of natural product rsc.li/chem-soc-rev synthesis, highlighting the synthetic applications and the potential of this approach. Creative Commons Attribution 3.0 Unported Licence. -
S41467-018-07534-X.Pdf
ARTICLE DOI: 10.1038/s41467-018-07534-x OPEN Differentiation between enamines and tautomerizable imines in the oxidation reaction with TEMPO Xiaoming Jie1, Yaping Shang1, Zhe-Ning Chen 1, Xiaofeng Zhang1, Wei Zhuang1 & Weiping Su1 Enamine and imine represent two of the most common reaction intermediates in syntheses, and the imine intermediates containing α-hydrogen often exhibit the similar reactivity to 1234567890():,; enamines due to their rapid tautomerization to enamine tautomers. Herein, we report that the minor structural difference between the enamine and the enamine tautomer derived from imine tautomerization results in the different chemo- and regioselectivity in the reaction of cyclohexanones, amines and TEMPO: the reaction of primary amines furnishes the formal oxygen 1,2-migration product, α-amino-enones, while the reaction of secondary amines under similar conditions generates exclusively arylamines via consecutive dehydrogenation on the cyclohexyl rings. The 18O-labeling experiment for α-amino-enone formation revealed that TEMPO served as oxygen transfer reagent. Experimental and computational studies of reaction mechanisms revealed that the difference in chemo- and regioselectivity could be ascribed to the flexible imine-enamine tautomerization of the imine intermediate con- taining an α-hydrogen. 1 State Key Laboratory of Structural Chemistry, Center for Excellence in Molecular Synthesis, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, 155 Yangqiao Road West, Fuzhou 350002, China. -
Organocatalytic Cyclopropanation of (E)-Dec-2-Enal: Synthesis, Spectral Analysis and Mechanistic Understanding
Organocatalytic Cyclopropanation of (E)-Dec-2-enal: Synthesis, Spectral Analysis and Mechanistic Understanding. Marta Meazza, Agnieszka Kowalczuk, Sarah Watkins, Simon Holland, Thomas A. 5 Logothetis, Ramon Rios Faculty of Natural & Environmental Sciences, Department of Chemistry, University of Southampton, Highfield Campus, Southampton, SO17 1BJ, United Kingdom In memoriam Klaus Burger ABSTRACT 10 An undergraduate experiment combining synthesis, NMR analysis and mechanistic understanding is reported. The students perform an organocatalyzed cyclopropanation reaction of (E)-dec-2-enal and are then required to determine the diastereoselectivity and assign the relative configuration of each product using NMR spectroscopy. 15 ABSTRACT GRAPHIC Journal of Chemical Education 8/20/18 Page 1 of 21 KEYWORDS Upper Division Undergraduate, Organic Chemistry, Hands-On Learning/Manipulatives, Inquiry-Based/Discovery Learning, Asymmetric Synthesis, 20 NMR Spectroscopy, Diastereomers. BACKGROUND In recent years, catalysis has had a huge impact on the nature of organic synthesis. With the increasing emphasis on green chemistry and sustainable processes, the development of new, highly enantioselective methodologies for the 25 synthesis of new, 3D scaffolds has become of paramount importance for organic chemists. A clear example is the 2001 Nobel Prize awarded to K. B. Sharpless, R. Noyori and W. S. Knowles for their contributions to this field. A further step towards the development of greener methodologies was made in 2000 with the “renaissance” of organocatalysis by the pioneering works of B. List1 and D.W.C. 30 MacMillan.2 List et al.1 developed the first intermolecular enantioselective aldol reaction catalyzed by proline through enamine activation, while MacMillan and coworkers2 developed the first organocatalyzed enantioselective Diels-Alder reaction through iminium activation. -
Detection of Phenethylamine, Amphetamine, and Tryptamine Imine By-Products from an Acetone Extraction
Detection of Phenethylamine, Amphetamine, and Tryptamine Imine By-Products from an Acetone Extraction Mary A. Yohannan* and Arthur Berrier U.S. Department of Justice Drug Enforcement Administration Special Testing and Research Laboratory 22624 Dulles Summit Court Dulles, VA 20166 [email: mary.a.yohannan -at- usdoj.gov] ABSTRACT: The formation of imine by-products from phenethylamines, amphetamines, and tryptamines upon an acetone extraction is presented. These imine by-products were characterized using GC/MSD and exhibited preferential cleavage at the α-carbon of the alkyl chain. Further characterization of the imine by-products of phenethylamine and tryptamine was done using IR and NMR. KEYWORDS: phenethylamine, tryptamine, imine, acetone, schiff base, drug chemistry, forensic chemistry In most forensic laboratories, the solvents used to extract at the α-carbon on the alkyl chain. In addition to GC/MS, the drugs are chosen based upon their solubility properties and their imines formed from phenethylamine base and tryptamine base ability to not interact with the drug. In fact, there are very few were characterized by Fourier transform-infrared spectroscopy publications where a solvent used to extract a drug reacts with (FTIR) and nuclear magnetic resonance (NMR) spectroscopy. the drug and forms by-products [1-3]. This laboratory recently discovered that an additional Experimental component was formed when acetone was used to extract a Solvents, Chemicals, and Materials sample containing a known tryptamine. Analysis by gas Acetone was ACS/HPLC grade from Burdick and Jackson chromatography/mass spectroscopy (GC/MS) of the acetone Laboratories (Muskegon, MI). Phenethylamine base and extract yielded an extra peak in the total ion chromatogram that tryptamine base were obtained from Sigma-Aldrich Chemicals was approximately half the abundance of the known tryptamine (Milwaukee, WI). -
The Carcinogenicity of the O-Methoxy Derivatives of N-2-Fluorenylacetamide and of Related Compounds in the Rat
[CANCER RESEARCH 28, 234-244, February 1968] The Carcinogenicity of the o-Methoxy Derivatives of N-2-Fluorenylacetamide and of Related Compounds in the Rat H. R. Gutmann, S. B. Galitski, and W. A. Foley Laboratory ]or Cancer Research, Veterans Administration Hospital, and Department o] Biochemistry, University o] Minnesota, Minneapolis, Minnesota 55417 SUMMARY acetamide by the sequential reactions of deacetylation and oxidation. In order to test the idea that the lack of carcinogenicity of the o-amidofluorenols, N- (1-hydroxy-2-fluorenyl) acetamide and INTRODUCTION N-(3-hydroxy-2-fluorenyl)acetamide, is due to the hydrophilic phenolic hydroxyl group, the methylated derivatives, N-(1- Several model studies from this laboratory have shown that methoxy-2-fluorenyl)acetamide and N-(3-methoxy-2-fluorenyl) the o-quinone imines, 2-imino-l,2-fluorenoquinone and 2-imino- acetamide as well as the hydrochlorides of 1-methoxy-2-fluo- 2,3-fluorenoquinone, which are derived from the carcinogen renamine and 3-methoxy-2-fiuorenamine, were prepared, and N-2-fluorenylacetamide by the sequential enzymatic reactions their carcinogenicity was evaluated in the rat. N-(1-Methoxy- of hydroxylation, deacetylation, and oxidation (6, 10, 12, 27, 2-fluorenyl)acetamide and 1-methoxy-2-fluorenamine hydro- 34, 35), form stable adducts with a variety of proteins (17, 18). chloride, when administered orally to male rats for 5 months, However, the relevance of the binding of these o-quinone imines gave a tumor incidence of 27 and 50%, respectively. Approxi- to chemical carcinogenesis has remained obscure largely be- mately one-half of the lesions produced by either com- cause the o-amidofluorenols, 1-OH-AAF 2 and 3-OH-AAF pound were adenocarcinomas of the small intestine. -
Asymmetric Organocatalysis Revisited: Taming Hydrindanes with Jørgensen–Hayashi Catalyst
SYNTHESIS0039-78811437-210X Georg Thieme Verlag Stuttgart · New York 2019, 51, 1123–1134 feature 1123 en Syn thesis Y. Stöckl et al. Feature Asymmetric Organocatalysis Revisited: Taming Hydrindanes with Jørgensen–Hayashi Catalyst Yannick Stöckl O Michael addition Wolfgang Frey O Aldol [4+2] cat. 1 H H H Johannes Lang N R H Birgit Claasen + H Angelika Baro O O O O O H H Sabine Laschat* 0000-0002-1488-3903 R R O R O O Institut für Organische Chemie, Universität Stuttgart, Pfaffenwaldring 55, 70569 Stuttgart, Germany [email protected] Published as part of the 50 Years SYNTHESIS – Golden Anniversary Issue Received: 12.11.2018 amples are amaminol A (2),9 the tricyclic unit of Accepted: 15.11.2018 ikarugamycin (3),10 or the CD ring unit of deoxycholic acid Published online: 14.12.2018 11 DOI: 10.1055/s-0037-1610409; Art ID: ss-2018-z0760-fa (4) (Figure 1). License terms: H Abstract The organocatalytic Michael reaction of easily available 1-cy- clopentene-1-carbaldehyde and 1,3-dicarbonyl compounds led to cy- H clopentanecarbaldehydes on a gram scale with low catalyst loading (2 1 (hydrindane) mol%) and high enantioselectivity. The synthetic potential of 4-acyl- H2N hexahydroindenones from intramolecular aldol condensation was OH demonstrated by Diels–Alder reaction to a tetracyclic derivative with seven stereogenic centers. The diastereofacial preference of the tetra- 2 (amaminol A) H H cyclic product was confirmed by DFT calculations. The described reac- R1 tion sequence is characterized by few redox-economic steps and high degree of molecular complexity. -
Synthesis and Characterization of Novel Imine-Linked Covalent Organic Frameworks
Synthesis and Characterization of Novel Imine-Linked Covalent Organic Frameworks THESIS Presented in Partial Fulfillment of the Requirements for the Degree Master of Science in the Graduate School of The Ohio State University By Toni Beirl Graduate Program in Chemistry The Ohio State University 2015 Master's Examination Master's Examination Committee: Professor Psaras McGrier, Advisor Professor Jovica D. Badjic Copyrighted by Toni M.Beirl 2015 Abstract Covalent organic frameworks (COFs) are a class of porous crystalline materials composed of light elements (such as H, B, C, N, and O) that are linked by covalent bonds. The modular nature of COFs permits the integration of various π-conjugated molecular building blocks into highly ordered polymeric structures with low densities and high thermal stabilities making them suitable for applications related to energy storage and conversion, catalysis, and gas storage. Since a majority of the early examples of COFs contained boroxine or boronate esters linkages, many of these materials were often susceptible to hydrolysis when exposed to aqueous conditions resulting in decomposition of the framework. The recent discovery of imine-linked COFs has sparked the creation of COFs with superior chemical stability on account of an intramolecular hydrogen bond between the hydroxyl and imine functional groups, which enhances their stability in aqueous and acidic environments. Utilizing this feature, this thesis examines the synthesis and gas adsorption properties of novel imine-linked COFs that contain 1,3,5-tris(styryl)benzene and 1,3,5– tris(arylethynyl)benzene π-conjugated units. By creating analogs which were fluorescent in both solution and solid-state, studies were conducted to determine their ability to serve as chemical sensors for explosives.