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Jan Szymoniak - One of the best experts on this subject based on the ideXlab platform.
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Preparation and Some Synthetic Applications of 2-Hydroxyethyl-Substituted Cyclopropylamines
Synlett, 2008Co-Authors: Antoine Joosten, Philippe Bertus, Jean-luc Vasse, Jan SzymoniakAbstract:Primary Cyclopropylamines bearing hydroxy side chains were obtained by Ti-mediated coupling of nitriles and homoallylic alcohols. Their usefulness as synthetic intermediates was demonstrated by the preparation of a constrained glutamic acid derivative and pyrrolizidine analogues.
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Titanium-Mediated Synthesis of Primary Cyclopropylamines from Nitriles and Grignard Reagents
Synlett, 2007Co-Authors: Philippe Bertus, Jan SzymoniakAbstract:This account presents studies on the development of a new method for the preparation of primary Cyclopropylamines. The established procedure is simple and the reaction appears to be quite general. A wide range of nitriles and organomagnesium reagents can react to afford diversely substituted Cyclopropylamines. Furthermore, bicyclic Cyclopropylamines can be obtained via an intramolecular coupling from unsaturated nitriles. The reaction allows an easy preparation of 1-aminocyclopropanecarboxylic acids and 1-azaspirocyclic compounds bearing a cyclopropane ring. The reaction can also be applied to the preparation ofpolyfunctional and more complex organic molecules as exemplified with the synthesis of carbohydrates bearing aminocyclopropyl moieties and spirocyclopropyl pyrrolidines. During study of the title reaction, an unusual [4+1] cycloaddition reaction to afford cyclopentenylamines or cyclopentenones has been discovered and is described. 1 Introduction 2 Direct Synthesis of Cyclopropylamines from Nitriles and Grignard Reagents 3 Synthesis of Cyclopropylamines via Ligand Exchange 4 Attempt to Prepare 2-Alkenyl Cyclopropylamines from 1,3-Dienes and Nitriles: An Unusual [4+1] Assembly Reaction 5 Summary and Outlook.
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Titanium-mediated synthesis of bicyclic Cyclopropylamines from unsaturated nitriles
Tetrahedron Letters, 2003Co-Authors: Christophe R. Laroche, Philippe Bertus, Jan SzymoniakAbstract:Here we report an easy synthesis of bicyclic primary Cyclopropylamines directly from unsaturated nitriles. The described reaction involves Ti(II)-mediated intramolecular coupling of alkene and nitrile moieties.
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New and easy route to primary Cyclopropylamines from nitriles
Chemical communications (Cambridge England), 2001Co-Authors: Philippe Bertus, Jan SzymoniakAbstract:Starting from readily available substrates, we have developed a new synthesis of primary Cyclopropylamines. The reaction involves a cooperative Ti(II)- and Lewis acid-mediated coupling of alkanenitriles with Grignard reagents.
Armin De Meijere - One of the best experts on this subject based on the ideXlab platform.
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Scalable synthesis of (1-cyclopropyl)Cyclopropylamine hydrochloride.
Beilstein journal of organic chemistry, 2011Co-Authors: Sergei I. Kozhushkov, Alexander F. Khlebnikov, Rafael R. Kostikov, Dmitrii S. Yufit, Armin De MeijereAbstract:1-Cyclopropylcyclopropanecarboxylic acid (2), which is accessible on a large scale (900 mmol) from 1-bromo-1-cyclopropylcyclopropane (1) in 64% yield (89% on a 12.4 mmol scale), has been subjected to a Curtius degradation employing the Weinstock protocol to furnish the N-Boc-protected (1-cyclopropyl)Cyclopropylamine 3 (76%). Deprotection of 3 with hydrogen chloride in diethyl ether gave the (1-cyclopropyl)Cyclopropylamine hydrochloride (4·HCl) in 87% yield.
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Cyclopropylamines from N,N-Dialkylcarboxamides and Grignard Reagents in the Presence of Titanium Tetraisopropoxide or Methyltitanium Triisopropoxide.
ChemInform, 2011Co-Authors: Armin De Meijere, Vladimir Chaplinski, Harald Winsel, Markus Kordes, Bjoern Stecker, Vesta Gazizova, Andrei I. Savchenko, Roland Boese, Farina SchillAbstract:Cyclopropylamines are successfully synthesized by the reaction of different substituted carboxamides with Grignard reagents in the presence of stoichiometric amounts of Me-Ti(O-iPr)3.
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Cyclopropylamines from N,N‐Dialkylcarboxamides and Grignard Reagents in the Presence of Titanium Tetraisopropoxide or Methyltitanium Triisopropoxide
Chemistry (Weinheim an der Bergstrasse Germany), 2010Co-Authors: Armin De Meijere, Vladimir Chaplinski, Harald Winsel, Markus Kordes, Bjoern Stecker, Vesta Gazizova, Andrei I. Savchenko, Roland Boese, Farina SchillAbstract:Thirty-three different N,N-dialkyl- and N-alkyl-N-phosphorylalkyl-substituted carboxamides 9-17 were treated with unsubstituted as well as with 2-alkyl-, 2,2-dialkyl-, and 3-alkenyl-substituted ethylmagnesium bromides 6 in the presence of stoichiometric amounts of titanium tetraisopropoxide or methyltitanium triisopropoxide to furnish substituted Cyclopropylamines 20-25 in 20-98% yield, depending on the substituents with no (1:1) to excellent (>25:1) diastereoselectivities. Generally higher yields (up to 98%) of the Cyclopropylamines 20-28 without loss of the diastereoselectivity were obtained with methyltitanium triisopropoxide as the titanium mediator. Under these conditions, even dioxolane-protected ketones and halogen-substituted and chiral as well as achiral alkyloxyalkyl-substituted carboxamides could be converted to the correspondingly substituted Cyclopropylamines with unsubstituted as well as phenyl- and a variety of alkyl-substituted ethylmagnesium bromides in addition to numerous heteroatom-containing (e.g., halogen-, trityloxy-, tetrahydropyranyloxy-substituted) Grignard reagents (62 examples altogether). The transformation of N,N-diformylalkylamines 54 with ethylmagnesium bromide in the presence of methyltitanium triisopropoxide to N,N-dicyclopropyl-N-alkylamines 55 can be brought about in up to 82% yield (6 examples). An asymmetric variant of the titanium-mediated cyclopropanation of N,N-dialkylcarboxamides has been developed by applying chiral titanium mediators generated from stoichiometric amounts of titanium tetraisopropoxide and chiral diamino or diol ligands, respectively. The most efficient chiral mediators turned out to be titanium bistaddolates that provided the corresponding Cyclopropylamines with enantiomeric excesses (ee) of up to 84%. Evaluation of several silyl-based additives revealed that the reaction can also efficiently be carried out with substoichiometric amounts (down to 25 mol%) of the titanium reagent, as long as 2-aryl- or 2-ethenyl-substituted ethylmagnesium halides are used and a concomitant slight decrease in yields is accepted. The newly developed methodology was successfully applied for the preparation of analogues with Cyclopropylamine moieties of known drugs and natural products such as the nicotine metabolite (S)-Cotinine as well as the insecticides Dinotefuran and Imidacloprid.
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Titanium-mediated syntheses of Cyclopropylamines
Journal of Organometallic Chemistry, 2004Co-Authors: Armin De Meijere, Sergei I. Kozhushkov, Andrei I. SavchenkoAbstract:Abstract The transformations of N , N -dialkylcarboxamides and nitriles with 1,2-dicarbanionic organometallics in situ generated from organomagnesium (Grignard) as well as organozinc reagents in the presence of stoichiometric or substoichiometric (semi-catalytic) quantities of a titanium alkoxide derivative of type XTi(OR) 3 with X=OR, Cl, Me and OR=O i Pr, OEt are described. The key step in the transformation of a monocarbanionic into a 1,2-dicarbanionic organotitanium species is a disproportionation of a dialkyltitanium intermediate to form an alkane and a titanium alkene complex which has the reactivity of a titanacyclopropane derivative. The latter are able to undergo insertion of the carbonyl group of an N , N -dialkylcarboxamide or a cyano group to furnish, after ring contraction and hydrolysis, dialkylCyclopropylamines or Cyclopropylamines, respectively. The titanium alkene complexes can also undergo ligand exchange with alkenes to afford new titanacyclopropanes, which subsequently react as 1,2-dicarbanionic equivalents. In many cases, these titanium-mediated formations of a wide range of synthetically and/or pharmacologically important Cyclopropylamines proceed in good to very good yields (from 20% to 98% for dialkylCyclopropylamines from N , N -dialkylcarboxamides and from 27% to 73% for primary Cyclopropylamines from nitriles) and with high chemo- and stereoselectivity. These circumstances in conjunction with the simplicity of the experimental handling and inexpensiveness of the reagents favor these reactions for an ever increasing range of applications in organic synthesis.
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Easy access to various substituted 4-aminocyclopentenes by rearrangement of 2-ethenyl-substituted Cyclopropylamines
Journal of the Chemical Society Perkin Transactions 1, 1998Co-Authors: Craig M. Williams, Armin De MeijereAbstract:A variety of 2-ethenyl-substituted Cyclopropylamines upon flash vacuum pyrolysis or under silver nitrate catalysis cleanly undergo ring enlargement and afford high yields (up to 95%) of 4-aminocyclopent-1-enes, some of which have unprecedented substitution patterns.
Philippe Bertus - One of the best experts on this subject based on the ideXlab platform.
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Preparation and Some Synthetic Applications of 2-Hydroxyethyl-Substituted Cyclopropylamines
Synlett, 2008Co-Authors: Antoine Joosten, Philippe Bertus, Jean-luc Vasse, Jan SzymoniakAbstract:Primary Cyclopropylamines bearing hydroxy side chains were obtained by Ti-mediated coupling of nitriles and homoallylic alcohols. Their usefulness as synthetic intermediates was demonstrated by the preparation of a constrained glutamic acid derivative and pyrrolizidine analogues.
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Titanium-Mediated Synthesis of Primary Cyclopropylamines from Nitriles and Grignard Reagents
Synlett, 2007Co-Authors: Philippe Bertus, Jan SzymoniakAbstract:This account presents studies on the development of a new method for the preparation of primary Cyclopropylamines. The established procedure is simple and the reaction appears to be quite general. A wide range of nitriles and organomagnesium reagents can react to afford diversely substituted Cyclopropylamines. Furthermore, bicyclic Cyclopropylamines can be obtained via an intramolecular coupling from unsaturated nitriles. The reaction allows an easy preparation of 1-aminocyclopropanecarboxylic acids and 1-azaspirocyclic compounds bearing a cyclopropane ring. The reaction can also be applied to the preparation ofpolyfunctional and more complex organic molecules as exemplified with the synthesis of carbohydrates bearing aminocyclopropyl moieties and spirocyclopropyl pyrrolidines. During study of the title reaction, an unusual [4+1] cycloaddition reaction to afford cyclopentenylamines or cyclopentenones has been discovered and is described. 1 Introduction 2 Direct Synthesis of Cyclopropylamines from Nitriles and Grignard Reagents 3 Synthesis of Cyclopropylamines via Ligand Exchange 4 Attempt to Prepare 2-Alkenyl Cyclopropylamines from 1,3-Dienes and Nitriles: An Unusual [4+1] Assembly Reaction 5 Summary and Outlook.
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Titanium-mediated synthesis of bicyclic Cyclopropylamines from unsaturated nitriles
Tetrahedron Letters, 2003Co-Authors: Christophe R. Laroche, Philippe Bertus, Jan SzymoniakAbstract:Here we report an easy synthesis of bicyclic primary Cyclopropylamines directly from unsaturated nitriles. The described reaction involves Ti(II)-mediated intramolecular coupling of alkene and nitrile moieties.
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New and easy route to primary Cyclopropylamines from nitriles
Chemical communications (Cambridge England), 2001Co-Authors: Philippe Bertus, Jan SzymoniakAbstract:Starting from readily available substrates, we have developed a new synthesis of primary Cyclopropylamines. The reaction involves a cooperative Ti(II)- and Lewis acid-mediated coupling of alkanenitriles with Grignard reagents.
Mark Stradiotto - One of the best experts on this subject based on the ideXlab platform.
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Nickel-Catalyzed N-Arylation of Cyclopropylamine and Related Ammonium Salts with (Hetero)aryl (Pseudo)halides at Room Temperature
ACS Catalysis, 2017Co-Authors: Joseph P. Tassone, Preston M. Macqueen, Christopher M. Lavoie, Michael J. Ferguson, Robert Mcdonald, Mark StradiottoAbstract:Whereas the metal-catalyzed C(sp2)–N cross-coupling of Cyclopropylamine with aryl electrophiles represents an attractive route to pharmaceutically relevant N-arylCyclopropylamines, few catalysts that are capable of effecting such transformations have been identified. Herein, the nickel-catalyzed C(sp2)–N cross-coupling of Cyclopropylamine and related nucleophiles, including ammonium salts, with (hetero)aryl (pseudo)halides is reported for the first time, with the demonstrated scope of reactivity exceeding that displayed by all previously reported catalysts (Pd, Cu, or other). Our preliminary efforts to effect the N-arylation of Cyclopropylamine with (hetero)aryl chlorides at room temperature by use of (L)NiCl(o-tolyl) precatalysts (L = PAd-DalPhos, C1; L = JosiPhos CyPF-Cy, C2) were unsuccessful, despite the established efficacy of C1 and C2 in transformations of other primary alkylamines. However, systematic modification of the ancillary ligand (L) structure enabled success in such transformations, with ...
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Nickel-Catalyzed N‑Arylation of Cyclopropylamine and Related Ammonium Salts with (Hetero)aryl (Pseudo)halides at Room Temperature
2017Co-Authors: Joseph P. Tassone, Preston M. Macqueen, Christopher M. Lavoie, Michael J. Ferguson, Robert Mcdonald, Mark StradiottoAbstract:Whereas the metal-catalyzed C(sp2)–N cross-coupling of Cyclopropylamine with aryl electrophiles represents an attractive route to pharmaceutically relevant N-arylCyclopropylamines, few catalysts that are capable of effecting such transformations have been identified. Herein, the nickel-catalyzed C(sp2)–N cross-coupling of Cyclopropylamine and related nucleophiles, including ammonium salts, with (hetero)aryl (pseudo)halides is reported for the first time, with the demonstrated scope of reactivity exceeding that displayed by all previously reported catalysts (Pd, Cu, or other). Our preliminary efforts to effect the N-arylation of Cyclopropylamine with (hetero)aryl chlorides at room temperature by use of (L)NiCl(o-tolyl) precatalysts (L = PAd-DalPhos, C1; L = JosiPhos CyPF-Cy, C2) were unsuccessful, despite the established efficacy of C1 and C2 in transformations of other primary alkylamines. However, systematic modification of the ancillary ligand (L) structure enabled success in such transformations, with crystallographically characterized (L)NiCl(o-tolyl) precatalysts incorporating o-phenylene-bridged bisphosphines featuring phosphatrioxaadamantane and PCy2 (L = L3, CyPAd-DalPhos; C3), P(o-tolyl)2 and P(t-Bu)2 (L = L4; C4), or PCy2 and P(t-Bu)2 (L = L5; C5) donor pairings proving to be particularly effective. In employing the air-stable precatalyst C3 in cross-couplings of Cyclopropylamine, substituted electrophiles encompassing an unprecedentedly broad range of heteroaryl (pyridine, isoquinoline, quinoline, quinoxaline, pyrimidine, purine, benzothiophene, and benzothiazole) and (pseudo)halide (chloride, bromide, mesylate, tosylate, triflate, sulfamate, and carbamate) structures were employed successfully, in the majority of cases under mild conditions (3 mol % of Ni, 25 °C). Preliminary studies also confirmed the ability of C3 to effect the N-arylation of cyclopropanemethylamine hydrochloride and cyclobutylamine hydrochloride under similar conditions. A notable exception in this chemistry was observed specifically in the case of electron-rich aryl chlorides, where the use of C4 in place of C3 proved more effective. In keeping with this observation, catalyst inhibition by 4-chloroanisole was observed in the otherwise efficient cross-coupling of Cyclopropylamine and 3-chloropyridine when using C3. Competition studies involving C3 revealed a (pseudo)halide reactivity preference (Cl > Br, OTs)
Timothy L Macdonald - One of the best experts on this subject based on the ideXlab platform.
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in vitro metabolism of a model Cyclopropylamine to reactive intermediate insights into trovafloxacin induced hepatotoxicity
Chemical Research in Toxicology, 2008Co-Authors: Qin Sun, Ran Zhu, Frank W Foss, Timothy L MacdonaldAbstract:Trovafloxacin (Trovan) is a fluoroquinolone antibiotic drug with a long half-life and broad-spectrum activity. Since its entry into the market in 1998, trovafloxacin has been associated with numerous cases of hepatotoxicity, which has limited its clinical usefulness. Trovafloxacin possesses two substructural elements that have the potential to generate reactive intermediates: a Cyclopropylamine moiety and a difluoroanilino system. The results presented here describe the in vitro metabolic activation of a synthetic drug model (DM) of trovafloxacin that contains the Cyclopropylamine moiety. Cyclopropylamine can be oxidized to reactive ring-opened products—a carbon-centered radical and a subsequently oxidized α,β-unsaturated aldehyde. Experiments with monoamine oxygenases, horseradish peroxidase, flavin monooxygenase 3, and cDNA-expressed P450 isoenzymes revealed that P450 1A2 oxidizes DM to a reactive α,β-unsaturated aldehyde, M1. Furthermore, myeloperoxidase (MPO) was also demonstrated to oxidize DM in the...
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Mechanisms of trovafloxacin hepatotoxicity: studies of a model Cyclopropylamine-containing system.
Bioorganic & medicinal chemistry letters, 2007Co-Authors: Qin Sun, Ran Zhu, Frank W Foss, Timothy L MacdonaldAbstract:The mechanism for the hepatotoxicity of trovafloxacin remains unresolved. Trovafloxacin contains a Cyclopropylamine moiety which has a potential to be oxidized to reactive intermediate(s) although other putative elements may exist. In this study, a drug model of trovafloxacin containing the Cyclopropylamine substructure was synthesized. Chemical oxidation of the drug model by K3Fe(CN)6 and NaClO revealed that both oxidants oxidize this drug model to a reactive α,β-unsaturated aldehyde, 11. The structure of 11 was fully elucidated by LC/MS/MS and NMR analysis. These results suggested that P450s with heme-iron center and myeloperoxidase generating hypochlorous acid in the presence of chloride ion are capable of bioactivating the Cyclopropylamine moiety of trovafloxacin. This deleterious metabolism may lead to eventual hepatotoxicity.
