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[3 + 2] Cycloaddition of Nonstabilized Azomethine Ylides. 8. † An Efficient Synthetic Strategy for Epiboxidine
... These reactions are synthetically very useful because of their high stereospecificity and stereoselectivity. [5][6][7] Several studies have reported on the effect of Lewis acid catalysts in these reactions. [8][9][10] The coordination of a Lewis acid to dipole or dipolarophile is of fundamental importance for asymmetric 1,3-dipolar cycloadditions, because the metal can catalyze the reaction. ...
Δ 4-Isoxazoline derivatives were synthesized in excellent yields via the titanium tetrachloride–catalyzed 1,3-dipolar cycloaddition reaction of nitrones with α,β-unsaturated compounds under neat conditions at room temperatures in very short reaction time.
This review aims to report recent advances on decarboxylative reactions of amino acids catalyzed by transition metals or non‐metals and the growing opportunities they present in the construction of complex chemical scaffolds for applications encompassing natural product synthesis, synthetic methodology development, and functional materials. Different decarboxylative reactions have been highlighted such as radical, photoredox and metal and metal‐free coupling reactions. etc. The review is divided into two main sections: one deals with reactions via radical pathways and the other via azomethine ylide pathways. The reactions have been discussed in more detail with particular emphasis on their useful applications and mechanistic illustrations.
Abbreviations: 1,3‐DCB: 1,3‐dicyanobenzene; 1,4‐DCB: 1,4‐dicyanobenzene; Acr: acridinium; BI: benziodoxolone; Boc: tert‐butoxycarbonyl; CB: conduction band; CBX: cyanobenziodoxolone; CFL: compact fluorescent lamp; DBU: 1,8‐diazabicyclo[5.4.0]undec‐7‐ene; DCA: 9,10‐dicyanoanthracene; DCB: 1,2‐dichlorobenzene; DCE: 1,2‐dichloroethane; DDDS: bis(4‐chlorophenyl) disulfide; DIPEA: diisopropylethylamine; DMA: N,N‐dimethylacetamide; DMF: N,N‐dimethylformamide; DMSO: dimethyl sulfoxide; DNA: deoxyribonucleic acid; dtbbpy: 4,4′‐di‐tert‐butyl‐2,2'‐bipyridine; DTBP: di‐tert‐butyl peroxide; equiv.: equivalent; ET: electron transfer; h: hour; HE: Hantzsch ester; LED: light‐emitting diode; min: minutes; mL: millilitre; MS: molecular sieves; MW: microwave; nm: nanometer; NS: nanosphere; Nu: nucleophile; ODCB: o‐dichlorobenzene; PA‐1: (±)‐1,1′‐binaphthyl‐2,2′‐diyl hydrogen phosphate; PC: photocatalyst; PET: photoinduced electron transfer; PEG: polyethylene glycol; PG: protecting group; Phen: phenanthrene; PTA: phosphotungstic acid 44‐hydrate; RNA: ribonucleic acid; r.t.: room temperature; SET: single‐electron transfer; TBAI: tetrabutylammonium iodide; TBHP: tert‐butyl hydroperoxide; TFA: trifluoroacetic acid; THF: tetrahydrofuran; TMEDA: N,N,N′,N′‐tetramethylethylenediamine; TS: transition state; UV: ultraviolet; VB: valence band; W: watt.
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This review covers the use of 2-azaallyl anions, 2-azaallyl cations, and 2-azaallyl radicals in organic synthesis up through June 2018. Particular attention is paid to both foundational studies and recent advances over the past decade involving semistabilized and nonstabilized 2-azaallyl anions as key intermediates in various carbon-carbon and carbon-heteroatom bond-forming processes. Both transition-metal-catalyzed and transition-metal-free transformations are covered. Azomethine ylides, which have received significant attention elsewhere, are discussed briefly with the primary focus on critical comparisons with 2-azaallyl anions in regard to generation and use.
The pyrrolidines are privileged substructures of numerous bioactive natural products and drugs. How to synthesize these important synthetic targets in a more efficient manner is a hot research topic. A plenty of novel strategies and methods have been developed in recent years. Among them, cycloaddition and annulation strategies are the most efficient ways for the construction of multisubstituted pyrrolidines in terms of atom economy, stereoselectivity, diversity of products, and especially, the potential for asymmetric synthesis. These advantages have been well demonstrated by their applications in the syntheses of pyrrolidine-containing alkaloids. In this review, we highlight both the reaction and strategy development and synthetic applications from 2008 to June of 2017. This review covers 1,3-dipolar cycloadditions, formal [3+2] cycloadditions/annulations, and other interesting cycloaddition or annulation strategies to illustrate a so-called “reaction-based” strategy for the total synthesis of related natural products.
Theoretical calculations were performed on the [3+2] cycloaddition (32CA) reaction of nitrile oxide and N-vinylpyrrole. The regiochemistry of the reaction has been studied based on potential energy surface analysis and global and local reactivity indices of the reactants. The global electron density transfer (GEDT) calculations at the possible transition states revealed that this cycloaddition has a nearly non-polar character. The ELF topological analyses of the selected structures involved in the intrinsic reaction coordinate (IRC) of TS1a suggests that this 32CA reaction takes place through a two-stage one-step mechanism.
Thermal Activation of Organic MoleculesPhotochemical ActivationElectrochemical ActivationChemical ActivationAccumulation of Reactive SpeciesContinuous Generation of Reactive Species in a Flow SystemInterconversion Between Reactive SpeciesConclusions
References
Non-stabilised azomethine ylides (AMY) which are represented as a zwitterionic form of a C-N-C unit having four electrons in three parallel atomic π orbitals perpendicular to the plane of the dipole, undergoes 1,3-dipolar cycloaddition to produce isolated as well as fused pyrrolidine ring system stereoselectively. Various new structural entities related to x-azatricyclo[m.n.0.0a,b]alkanes are constructed by the intramolecular 1,3-dipolar cycloaddition of nonstabilized cyclic azomethine ylides. The ylide is generated by the sequential double desilylation of N-alkyl α, α’-bis(trimethylsilyl)cyclic amines using Ag(I)F as a one-electron oxidant. Various alkaloids such as (±)-pancracine, (±)-brunsvigine, (±)-maritidine, (±)-crinine, (-)-vincodifformine and (+)-aspidospermidine have been synthesized employing AMY cycloaddition strategy.
Structural subunits containing Si-C-X or Si-C-EWG have been recognized as carbanion equivalents under Lewis base promotion. The resulting activated intermediates undergo addition reactions to various electrophiles in the presence of a suitable Lewis base. This chapter introduces the reactions of ß-ketosilanes with various electrophiles in the presence of Lewis base. Carbonyl compounds, such as aldehydes and ketones, react with ß-ketosilanes readily in the presence of catalytic or stoichiometric amounts of Lewis base. The reaction works well with aromatic aldehydes. Some reactive primary alkyl halides could react with ß-ketosilanes in the presence of Lewis base. Typically, the addition of acetonitrile to carbonyl compounds under the assistance of strong alkali metal base is the most straightforward way to prepare ß-hydroxynitriles. Carbanion equivalents are generated from allyl- or benzylsilanes that contain an a-oxygen substituent. Finally, the chapter provides examples of the chemistry of Sn-C-X and Sn-C-EWG substrates under conditions of Lewis base promotion.
An unprecedented Ag(i)-catalyzed ligand-controlled stereodivergent 1,3-dipolar cycloaddition of azomethine ylides with 3-methyl-4-nitro-5-styrylisoxazoles has been developed to afford heterocycles bearing both methylisoxazole and pyrrolidine moieties. The endo- and exo-cycloadducts were obtained in good yields with excellent stereoselectivities, assisted by (t)Bu-Phosferrox and phosphoramidite as chiral ligands, respectively.
This review is about the application of electroauxiliaries in electroorganic synthesis in recent years. The electroauxiliaries have two types. One is the organic group which contains silicon, tin, germanium and other element of IVA group, the other contains organothio group. The electroauxiliaries raised the energy of HOMO, accelerated the transfer of electron, and lowered the oxidation potential of the substrate. This enabled the rupture of special bond and combined with the desired nucleophile, reducing the chance for overoxidation and enhancing the selectivity of the reaction. The electroauxiliaries will be widely used in electroorganic synthesis.
Free radical reactions of organoselenium and tellurium compounds have been widely studied and exploited since the first two volumes of this series appeared. Alkyl aryl selenides and tellurides undergo alkyl C-Se or C-Te cleavage with stannanes or silanes to generate alkyl radicals that can be employed in reductions, allylations and both intermolecular and intramolecular additions to a large variety of unsaturated substrates, terminated by either hydrogen or arylchalcogen transfer. Selenoesters, telluroesters and related species generate acyl radicals that are useful in overall decarboxylations of carboxylic acids, and in addition and radical cyclization processes, including cascade reactions of polyenes to afford polycyclic products. Homolytic cleavage of diselenides and ditellurides produces selenyl and telluryl radicals that can be employed in additions to unsaturated acceptors, while the dichalcogenides themselves function as effective trapping agents for radicals produced in a variety of other ways, as from Barton thiohydroxamates. Selenols are efficient hydrogen donors that are of importance in kinetic studies of radical processes. When selenium and tellurium are joined to other heteroatoms, the resulting reagents effect radical 1,2-additions to unsaturated substrates, as in the case of selenosulfonation and azidoselenenylation reactions. Other radical processes include oxidations, SH2 substitutions, single electron transfers, extrusions and fragmentations, and reactions performed on solid supports. The synthetic utility of these processes, as well as mechanistic considerations are covered in this chapter.Keywords:reductions;oxidations;radical additions;radical cyclizations;radical trapping;hydrogen transfer;SH2 reactions
[127-06-0] C3H7NO (MW 73.09) InChI = 1S/C3H7NO/c1-3(2)4-5/h5H,1-2H3InChIKey = PXAJQJMDEXJWFB-UHFFFAOYSA-N(a useful reagent for synthesis of isoxazoles and isoxazolidines; useful as an acetone equivalent for regiospecific C-alkylations)Alternate Names: propan-2-one oxime, acetoxime.Physical Data: mp 60–63 °C.Solubility: soluble in most commonly used organic solvents.Form Supplied in: white crystalline solid, widely available.Preparative Method: most commonly synthesized by condensation of acetone with hydroxylamine hydrochloride.Purification: 1 solid can be recrystallized from petroleum ether, hexane, or can be sublimed.Handling, Storage, and Precautions: sensitive to moisture; toxic by inhalation, in contact with skin, and if swallowed; may cause eye irritation.
Facile synthesis of N-(methyl and phenyl)-Δ4-isoxazolines via the reaction of (Z)-N-(methyl and phenyl)-C-arylnitrones with dimethyl acethylenedicarboxylate, DMAD, in ionic liquid is described. (Z)-N-methyl-C-arylnitrones afforded the high yield of N-methyl-Δ4-isoxazolines 4a, 4b, 4c, 4d, 4e in ionic liquid, [bmim]BF4, at room temperature. However, the reaction of (Z)-N-phenyl-C-arylnitrones with DMAD afforded the mixtures of cis and trans isomers of related N-phenyl-Δ4-isoxazolines (5a, 5b, 5c, 5d, 5e, 5f, 5g, 5h, 5i, 5j, 6a, 6b, 6c, 6d, 6e, 6f, 6g, 6h, 6i, 6j) under these conditions. J. Heterocyclic Chem., (2012).
[106018-85-3] C5H13ClO2SSi (MW 200.79)
Introduction Ammonium 1,3-Ylides 1,2-Ammonium Ylides Conclusion References
A series of novel spiro[acenaphthylene-1,2′-pyrrolidine] (4), spiro[acenaphthylene-1,2′-pyrrolizidine] (7), and spiro[indoline-3,2′-pyrrolidine] derivatives (9) containing cyano group were successfully synthesized via a three-component 1,3-dipolar cycloaddition reaction of acenaphthenequinone or isatin, sarcosine or proline, and Knoevenagel adducts in refluxing aqueous methanol. In this intermolecular three-component combinatorial process it is amazing that three stereogenic centers with one spiro carbon are controlled very well. The structure and relative stereo-chemistry of cycloadducts were carried out by single crystal X-ray diffraction, as well as by the help of 1H, 13C, and HMBC spectroscopy.
A facile synthesis of novel spiroindane-1,3-diones has been achieved via 1,3-dipolar cycloaddition of an azomethine ylide, generated in situ from ninhydrin and 1,2,3,4-tetrahydroisoquinoline, with the conjugated double bond of chalcone derivatives. The regiochemistry and structures of the cycloadducts were determined with spectroscopic data and by X-ray crystal structure analysis.
Starting from the enantiomerically pure 2H-azirin-3-amines (R,S)-4 and (S,S)-4, the enantiomeric, optically active 4-benzyl-4-methyl-2-phenyl-1,3-thiazole-5(4H)-thiones (R)-1 and (S)-1, respectively, have been prepared (Schemes 2 and 3). In each case, the reaction of 1 with N-(benzylidene)[(trimethylsilyl)methyl]amine (2) in HMPA in the presence of CsF and trimethylsilyl triflate gave a mixture of four optically active spirocyclic cycloadducts (Scheme 4). Separation by preparative HPLC yielded two pure diastereoisomers, e.g., (4R,5R,9S)-10 and (4R,5R,9R)-10. The regioisomeric compounds 11 were obtained as a mixture of diastereoisomers. The products were formed by a 1,3-dipolar cycloaddition of 1 with in situ generated azomethine ylide 3, which attacks 1 stereoselectively from the sterically less-hindered side, i.e., with (R)-1 the attack occurs from the re-side and in the case of (S)-1 from the si-side.
This report shows the synthesis and biological evaluation of two new conformationally restricted ABT-418 analogues. This restriction is introduced by the incorporation of the 7-azabicyclo[2.2.1]heptane skeleton. Furthermore, we report here a high-level quantum mechanical study of their conformations in the gas phase.
Various new structural entities related to X-azatricyclo[m.n.0.0. a,b]alkanes 15a-d are constructed employing the intramolecular [3+2]-dipolar cycloaddition of nonstabilized cyclic azomethine ylides. The ylides are generated by the sequential double desilylation of N-alkyl-α,α′-bis(trimethylsilyl)cyclic amines 14a-d using Ag(I)F as a one-electron oxidant. More rigid azatetracyclo compounds of type 23, in which benzene ring is attached as a tether unit in the N-alkyl chain moiety, are also synthesized by the cyclization of 22. These rigid azatricyclo compounds 15 and 23 possess structural resemblance to the rigid azatricyclo analogues 8-10, which are reported to exhibit selective and high binding affinity at dopamine transporter (DAT).
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The bromination (CuBr 2 , AcOEt/CHCI 3 ) plus Favorskii rearrangement (EtONa, EtOH) of N ‐carbethoxytropinone ( 4 ), readily available from tropinone ( 3 ), affords mixtures of exo ‐ and endo ‐isomers of 2,7‐dicarbethoxy‐7‐azabicyclo[2.2.1]heptane ( 1b ) in variable and moderate chemical yield (maximum 37%). The bromination (Br 2 , HBr/AcOH) reaction of compound 4 gives ethyl trans ‐2,4‐dibromo‐3‐oxo‐8‐azabicyclo[3.2.1]octane‐8‐carboxylate ( 5 ) in 99% yield, a product that on Favorskii rearrangement (EtONa/EtOH) affords ethyl 2,2‐diethoxy‐3‐oxo‐8‐azabicyclo[3.2.1]octane‐8‐carboxylate in moderate yield ( 6 ) (52%).
The unique core structure of the complex pentacyclic 5,11-methanomorphanthridine has been constructed stereospecifically in one step by an intramolecular [3+2] cycloaddition of a non-stabilized azomethine ylide (AMY), generated by the sequential double desilylation of 14 using AgIF as a one-electron oxidant. The formation of the single diastereomer in the key step is explained by the preferred transition state produced by endo attack of the AMY on the “Re” face of the dipolarophile. An asymmetric version of the cycloaddition using a chiral dipolarophile was applied to construct the core structure 68 with 63 % ee. This strategy was successfully applied to the formal synthesis of (±)-pancracine and the total synthesis of (±)-brunsvigine. An unprecedented and interesting skeletal rearrangement product 49 was observed during the attempted assembly of the E ring from 46 through Horner–Wadsworth–Emmons reactions. Mechanisms involving azetidinium salt formation or the Grob-type fragmentation are advanced to explain the observed rearrangement.
(Chemical Equation Presented) A series of isoxazolidine derivates (isomeric 2,3,5-trisubstitutedperhydropyrrolo[3,4-d]isoxazole-4,6-diones) used as anti-inflammatory, immunosuppressive, antibacterial agent, and inhibitor for some enzymes were synthesized. These compounds were prepared by 1,3-dipolar cycloaddition of N-methyl maleimide and N-phenyl maleimide with nitrones. Diastereomeric products obtained in this reaction were separated by column chromatography and recrystallized. All compounds synthesized were characterized by elemental analysis and spectroscopic methods (1H NMR, 13C NMR, and FTIR).
According to the CN(R,S) strategy, a general method for the synthesis of azabicyclo[n.2.1]alkanes of type 4 was described starting from the 2-cyano-5-oxazolopyrrolidine 5. A Mannich-type cyclization allowed an asymmetric access to potent nicotinic acetylcholine receptor agonists like epibatidine 1, ferruginine 2 and anatoxine-a 3. (© Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002)
Vicinal quaternary and tertiary stereocenters of the 5,10b-phenanthridine skeleton 1 are constructed simultaneously in one step by the [3+2]-cycloaddition of non-stabilized azomethine ylide 9, generated by sequential double desilylation of 10 utilizing silver(I) fluoride as a one-electron oxidant. The regio- as well as stereochemical origin of this cycloaddition reaction is explained through a favorable transition state 9″. The strategy is successfully applied for the total synthesis of the biologically active alkaloids (±)-maritidine (1a), (±)-crinine (1b), and their analogues (1d, 1e, and 1f).
A short and efficient synthesis of optically pure (+)-N-Boc-azabicyclo[2.2.1]hept-2-one (2), a precursor in the synthesis of natural (−)-epibatidine (1), is reported by the asymmetric desymmetrization of meso-N-methoxycarbonyl-2,3-bis(phenylsulfonyl)-7-azabicyclo[2.2.1]hept-2-ene (3).
The 1,3-dipolar cycloaddition reactions of α-2-methoxyaryl nitrones with nitrostyrenes and chalcones have been investigated. The regiochemistry and stereochemistry of the resultant cycloadducts have been determined with the help of NMR spectroscopy and X-ray analysis. β-Nitrostyrenes add to nitrones to give two geometrical isomers, while the β-methyl-β-nitrostyrene gives a single isomer in relatively low yield. The chalcones give a single cycloadduct upon 1,3-dipolar addition. Graphical Abstract
Theoretical study of Lewis acid catalyzed nitrone cycloadditions to α,β-unsaturated carbonyl compounds is reported. Ab initio calculation using the 6-31++G∗∗ basis set has been applied to the model reaction between the parent nitrone (CH2N(O)H) and acrolein (CH2CHCHO) in the presence of BH3 or BF3 catalyst. Although the nitrone/BH3 complex is predominantly formed at the early stage of the reaction, the acrolein/BH3 complex as minor contributor shows high rate acceleration, giving the electronically controlled endo-isoxazolidine-4-carbaldehyde complex as the major regio- and stereoisomeric cycloadduct. On the other hand, the nitrone cycloaddition reaction of acrolein in the presence of BF3 leads to the formation of the corresponding Michael adduct complex intermediate which then cyclizes to the isoxazolidine-4-carbaldehyde complex. These calculation studies indicate that the nitrone cycloadditions with electron-deficient alkenes may proceed through a stepwise mechanism when catalyzed by a strong Lewis acid.
The β-epimer of methyl (1S,2R,4R)-N-benzoyl-2-formyl-7-azabicyclo[2.2.1]heptane-1-carboxylate, (1S, 2S, 4R)-7, has been obtained by treatment of the exo-formyl derivative with triethylamine in methanol. The development of this epimerization procedure has further increased the already wide possibilities offered by our methodology and solves the problem of access to the endo derivatives that would result from the Diels–Alder reaction of Danishefsky's diene and the C-4 unsaturated E-oxazolones, whose preparation frequently proves to be problematic.
Sonification of N-benzyl-N-(methoxymethyl)-N-[(trimethylsilyl)methyl]amine in the presence of LiF led to the formation of a reactive azomethine ylide (I), which was intercepted by cyclic thioketones to give spirocyclic 1,3-thiazolidines, e.g., II. In the case of 2,2,4,4-tetramethylcyclobutane-1,3-dithione, the 1:1- (III) and 1:2-cycloadduct (IV) were formed as the major product, depending on the ratio of the starting materials. With 1,3-thiazole-5(4H)-thiones, I undergoes stereoselective [2+3]-cycloaddns. with the C:S group to yield spirocyclic 1:1-adducts. In the case of the 1,3-dipole generated from N-benzyl-N-(methoxymethyl)-N-[1-(trimethylsilyl)ethyl]amine, the [2+3]-cycloaddn. proceeded in a non-regioselective manner leading to a mixt. of regio- and diastereoisomers. [on SciFinder (R)]
The Lewis acid (LA) catalyzed 1,3-dipolar cycloaddition of N-benzylideneaniline N-oxide with acrolein has been studied using DFT calculations. Coordination of AlCl3 to the acrolem oxygen atom produces a drastic change in the mechanism along the more favorable meta reactive channel. The process is characterized by a strong nucleophile/electrophile interaction allowing the formation of a zwitterionic intermediate, a Michael-type addition. The subsequent ring closure constitutes the rate-determining step. The energies obtained with the inclusion of solvent effect by means of the polarizable continuum model are in good agreement with experimental findings. Analysis of the global and local electrophilicity allows to explain correctly the reactivity and regioselectivity of the LA catalyzed cycloaddition. (C) 2007 Elsevier Ltd. All rights reserved.
Racemic exo-epiboxidine 3, endo-epiboxidine 6, and the two unsaturated epiboxidine-related derivatives 7 and 8 were efficiently prepared taking advantage of a palladium-catalyzed Stille coupling as the key step in the reaction sequence. The target compounds were assayed for their binding affinity at neuronal alpha4beta2 and alpha7 nicotinic acetylcholine receptors. Epiboxidine 3 behaved as a high affinity alpha4beta2 ligand (K(i)=0.4 nM) and, interestingly, evidenced a relevant affinity also for the alpha7 subtype (K(i)=6 nM). Derivative 7, the closest analogue of 3 in this group, bound with lower affinity at both receptor subtypes (K(i)=50 nM for alpha4beta2 and K(i)=1.6 microM for alpha7) evidenced a gain in the alpha4beta2 versus alpha7 selectivity when compared with the model compound.
A method for sequential introduction of two organic groups on the same or the different α-carbons of nitrogen has been developed based on a combination of the concept of electroauxiliary and the cation pool method. Selective introduction of two carbon nucleophiles into 2,5- or 2,2-position of pyrrolidine has been accomplished via sequential electrochemical oxidation of pyrrolidine derivatives containing two silyl groups as the electroauxiliaries. Introduction of two carbon nucleophiles into 2,6-position of piperidine was also successful. The products having two olefinic groups were effectively converted to nitrogen-containing spiro compounds using ring closing metathesis, and an application to formal synthesis of cephalotaxine was also carried out. These results clearly illustrate the synthetic utility and potential of the present approach, and open a new aspect of the synthesis of nitrogen-containing compounds.
The selective electrochemical oxidation of heteroatom compounds having two different electroauxiliaries, i.e. silicon and tin, on the same α-carbon was examined. The oxidation potentials of such compounds were found to be similar to those of the corresponding compounds having only tin, indicating the predominant role of tin over that of silicon. The HOMO levels obtained by the molecular orbital calculations were consistent with the experimental results. The molecular orbital calculation of the cation radical suggests the selective cleavage of the CSn bond by the oxidation. Preparative electrochemical oxidation gave rise to selective cleavage of the CSn bond and the introduction of a nucleophile to the carbon. The CSi bond was not affected at all. The product can also be further oxidized using the silyl group as an electroauxiliary. The second oxidation proceeded smoothly to cleave the CSi bond and a second nucleophile was introduced on the same carbon. The present study indicates the feasibility of the redox potential based selective sequential transformation using electroauxiliaries.
Friedel-Crafts reactions of aromatic and heteroaromatic compounds with an N-acyliminium ion pool were studied. The reaction of 1,3,5-trimethylbenzene in a batch reactor gave rise to the selective formation of a monoalkylation product (69%). Presumably, the second alkylation is slower than the first alkylation because of the protonation of the monoalkylation product that decreases its reactivity. The reaction of 1,3,5-trimethoxybenzene, however, gave rise to the formation of both monoalkylation (37%) and dialkylation (32%) products. Disguised chemical selectivity due to faster reaction than mixing seems to be responsible for the lack of selectivity. The use of micromixing was found to be quite effective to solve this problem to increase the selectivity. The monoalkylation product was obtained in 92% yield together with a small amount of the dialkylation product (4%). The reaction with various aromatic and heteroaromatic compounds revealed that the low mono/dialkylation selectivity was observed only for highly reactive aromatics. In such cases, the use of micromixing was quite effective to improve the selectivity. On the basis of micromixing, the selective sequential dialkylation using two different N-acyliminium ions was achieved. CFD simulations using a laminar flow and finite-rate model are consistent with the experimental observations and clearly indicate the importance of mixing.
A straightforward synthesis of 4-amido-N(5)-acetyl-4-deoxyneuraminic acid, a key precursor to various 4-amidoneuraminic acid analogues, has been achieved using a highly regioselective and diastereoselective [3 + 2]-cycloaddition of d-mannose-derived nitrone with methyl acrylate. Advantages of this newly developed synthesis include the use of economically available materials and reagents, the ease of operations and the excellent control of stereochemistry, as well as the convenience in application to the C-4 modifications of sialic acids.
The challenging vicinal quaternary and tertiary stereocenters of the 5,10b-ethanophenanthridine skeleton are created in a single step utilizing intramolecular [3 + 2]-cycloaddition of nonstabilized azomethine ylide as the key step. The application of the chemistry is demonstrated by synthesizing (+/-)-maritidine.
Density functional (B3LYP) calculations using the 6-31++g basis set have been employed to study the title reaction between the cationic 1,3-dipolar 1-aza-2-azoniaallene ion (H2C=N(+)=NH) and ethene. Our calculations confirmed that [3 + 2] cycloaddition reaction takes place via a three-membered ring intermediate. In addition, solvent effects and substituent effects were also studied. For the reactions involving tetrachloroethene, there are two attacking sites. One is on the NH group in the 1-aza-2-azoniaallene ion, another is on its terminal CH2 group, and they are competitive for both approaching positions. Electron-releasing methyl substituents on ethene favor the reaction, and the potential energy surface is quite different from the previous one.
The core structure of the complex pentacyclic 5,11-methanomorphanthridine alkaloids is constructed stereospecifically in one step employing an intramolecular [3 + 2]-cycloaddition of nonstabilized azomethine ylide as the key step. The strategy is demonstrated by accomplishing the formal total synthesis of (+/-)-pancracine. [reaction: see text]
This feature article provides a brief outline of the concept of flash chemistry for conducting extremely fast reactions in organic synthesis using electrochemically generated highly reactive species and microsystems.
The syntheses of (+/-)-epibatidine and (+/-)-epiboxidine have been accomplished from commercial 2-methoxy-3,4-dihydro-2H-pyran. A recently developed aza-Prins-pinacol rearrangement was employed for the construction of the key 7-azabicyclo[2.2.1]heptane skeleton of these targets.
A "cation pool" of an N- acyliminium ion was found to serve as an effective initiator of cationic polymerization of vinyl ethers in a microflow system consisting of two micromixers (IMM micromixer) and two microtube reactors. The cationic polymerization of n-butyl vinyl ether in CH(2)Cl(2) at -78 degrees C led to very narrow molecular weight distribution (M(w)/M(n)=1.14). The molecular weight (M(n)) increased linearly with an increase in monomer/initiator ratio. The carbocationic polymer end was effectively trapped by allyltrimethylsilane. Additionally, the synthesis of block polymers was accomplished by the present microflow system controlled method. The polymerization was also conducted using commercially available trifluoromethanesulfonic acid (TfOH) as an initiator. A high level of molecular weight control was attained even at -25 degrees C. The TfOH-initiated polymerization could be conducted using a microflow system based on T-shaped micromixers, which serves as a practical tool for microflow system controlled carbocationic polymerization.
A review on the coinage metals as with Cu, Ag, and Au is given regarding its uses in the synthesis of heterocycles. In addition, a discussion with the mechanism of the C-C and C-X bond formation reactions will be provided so as to show the activation of substrates and possible reaction pathways. Then, a description on the use of coinage metals as a sole catalyst for the synthesis of heterocycles is also offered. However, only the reactions where a heterocyclic ring that is essentially generated will only be discussed. Specific topics to be discussed include: the cyclization of unsaturated C-C bonds with tethered nucleophiles; cycloaddition reactions; the cycloisomerization of enynes/diynes; the intramolecular friedel-crafts-type reactions; reactions of α-Diazocarbonyl compounds; aziridination of olefins; N/O-vinylation/arylation; and finally, the radical cyclization of haloalkenes and haloalkynes.
Epibatidine, an alkaloid isolated from skin of the poison frog, Epipedobates tricolor, has been shown to be a very potent analgesic with a non-opioid mechanism of action. We found that epibatidine was about 120 times more potent and has longer duration than nicotine in analgesia, which could be antagonized by pretreatment with mecamylamine. Furthermore, epibatidine competed with high affinity (IC50 = 70 pM, Ki = 43 pM) for [3H]cytisine binding in rat brain preparations. These results indicated that the analgesic activity of epibatidine is attributed to its unique property as the most potent nicotinic acetylcholine receptor agonist.
A nonopiate analgesic, epibatidine (1), isolated from the skin of the Ecuadoran poison frog was synthesized in racemic form starting from tropinone. Distinctly different from the previously published approaches, this synthesis features the novel synthesis of the 7-azabicyclo[2.2.1]heptane ring system by contraction of the tropinone skeleton viaFavorskii rearrangement. Five analogues of 1 were also prepared, and their analgesic activities were evaluated.
Several 7-aza-norbornadiene-derivatives have been synthesized. Their UV.- and NMR.-data are reported.
The racemic form, d, and l-enantiomers and the 7-N-methyl derivative of synthetic epibatidine are equally potent at 10 μg/kg in the tail-flick analgesic model without any enantioselectivity, whereas the endo- stereoisomer is not active at 1 mg/kg. The analgesic response is not antagonized by pretreatment with naloxone.
Thiohydroxamic-carboxylic mixed anhydrides can be decarboxylated in the presence of diaryl disulphides, diselenides and ditellurides to give sulphides, selenides and tellurides respectively in reasonable to good yield.
An effecient method of cyclic azomethine ylide generation and their application in synthesizing x-azabicyclo (m.2.1) alkanes has been described.
The aliphatic and alicyclic esters of N-hydroxypyridine-2-thione are readily reduced by tributylstannane in a radical chain reaction to furnish nor-alkanes.1 In the absence of the stannane a smooth decarboxylatlive rearrangement occurs to give 2-substituted thiopyridines.1 The radicals present in this reaction provoke with -butylthiol an efficient radical reaction with formation of nor-alkane and 2-pyridyl--butyl disulphide.1Similarly these carbon radicals can be captured by halogen atom transfer to give noralkyl chlorides, bromides and iodides. 2 With oxygen in the presence of t-butylthiol the corresponding noralkyl hydroperoxides are formed in another radical chain reaction.3
An efficient synthesis of Epibatidine and its analogues via [3+2] cycloaddition of non-stabilised azomethine ylide and substituted 6-chloro-3-vinyl pyridine.
UB-165 (5), a hybrid corresponding to natural anatoxin-a and epibatidine, has been synthesised and shows significant potency at the high affinity nicotine binding site in rat brain. Ent-(5) shows a much lower level of activity which parallels the sense of enantiospecificity associated with anatoxin-a.
Sequences of alpha'-lithiations and electrophilic substitutions of Boc-pyrrolidines, Boc-piperidines, and Boc-hexahydroazepines that provide compounds which are substituted adjacent to nitrogen are reported, and the pathways of the reactions are discussed. By this methodology monosubstituted 2 and disubstituted 2,4,2,6, and 2,5 Boc-piperidines are obtained as single or separable diastereoisomers consistent with equatorial lithiations and retentive electrophilic substitution in chair conformations. Both cis and trans 2,6-disubstituted diastereoisomers can be prepared, and control of diastereoselectivity is demonstrated by syntheses of solenopsin A, a 2,6-trans-disubstituted piperidine, and of Boc-dihydropinidine, a 2,6-cis-disubstituted piperidine. In the case of 3-methoxy-Boc-piperidine elimination of methoxide occurs upon lithiation, and with cis-2,4-disubstituted Boc-piperidines the electrophile is introduced with trans stereochemistry at C-6. These reactions are suggested to involve twist boat conformations consistent with an X-ray crystal structure of 2-methyl-6-(trimethylstannyl)-4-phenyl-N-Boc-piperidine. Boc-pyrrolidine lithiates more rapidly than Boc-piperidine, provides 2-substituted products with electrophiles, and on further lithiation-substitution gives 2,5-cis- and -trans-substituted products. Boc-perhydroazepine provides 2-substituted products by the sequence and on further lithiation-substitution gives 2,7-trans-disubstituted products.
The 60- and 100-Mc/sec nuclear magnetic resonance spectra of several bridged bicyclo[2.2.1]heptane derivatives have been analyzed in detail. These compounds possess the common structural feature of a 2,6 oxygenated bridge which may be either a lactone as in 5-exo-iodo-6-endo-hydroxybicyclo[2.2.1]heptane-2-endo-carboxylic acid lactone (1) and the 5-exo-bromo (2), 5-exo-acetoxy (3), 5-exo-tosyloxy (4), 2-exo-methyl-5-exo-iodo (5), 2-exo-methyl-5-exo-bromo (6) derivatives; or the 2,6 bridge may be an oxido unit as in 4-exo-tosyloxy-6-oxatricyclo[3.2.-1.13,8]nonane (7) and 4-exo-acetoxy-6-oxatricyclo[3.2.1.13,8]nonane (8). Chemical shifts for all the protons in these structures have been assigned, and the geminal and vicinal couplings measured. Aromatic solvent shifts observed for compounds 1, 5, and 7 are discussed in terms of solvent-solute collisional complexes of defined stereochemistry. Long-range couplings for the proton pairs: 1-4, 3-endo-7(a), 5-endo-7(b), 2-exo-6-exo, 1-3-exo, 2-exo-4, and 6-exo-4 in compound 1 were observed and most of these were confirmed using spin-decoupling techniques. For the C5-endo proton doublet in the lactone derivatives it is noteworthy that the principal coupling is with the C7(b) proton; this amounts to about 2.5 cps while the C5-endo-C6-exo vicinal coupling is negligibly small (0.3 cps) and the C5-endo-C4-vicinal ranges from 0.5 to 1.0 cps. The nmr spectra of the 5-keto and 7-keto derivatives in the 2,6 lactone series are discussed in relationship to the changes in chemical shifts relative to the precursor secondary alcohols. The alcohol-ketone pairs are 5-exo,6-endo-dihydroxybicyclo[2.2.1]heptane-2-endo-carboxylic acid lactone (9) and 5-keto,6-endo-hydroxybicyclo[2.2.1]heptane 2-endo-carboxylic acid lactone (10); 6-endo,7(b)-dihydroxybicyclo[2.2.1]-heptane-2-endo carboxylic acid lactone (11) and 7-keto,6-endo-hydroxybicyclo[2.2.1]heptane-2-endo-carboxylic acid lactone (12).
A potent non-opioid analgesic, epibatidine, has been isolated from skins of the Ecuadoran poison frog, Epipedobates tricolor, and its structure determined by MS, IR, and H-1 NMR analyses as exo-2-(6-chloro-3-pyridyl)-7-azabicyclo[2.2.1]heptane. It represents a unique new class of alkaloids.
Two optically pure epibatidine analogs, 4 and 5, which contain the 8-azabicyclo[3.2.1]octane ring system were synthesized from (−)-cocaine. The nicotinic receptor binding affinity and the stimulant activity of 4 and 5 were measured to be significantly lower than racemic epibatidine (±-1).
N-BOC-exo-2-(methoxycarbonyl)-7-azabicyclo[2.2.1]heptane, an important intermediate for the synthesis of epibatidine and its analogs was efficiently synthesized from N-BOC-exo-2-(methoxycarbonyl)-7-azabicyclo[2.2.1]hepta-2,5-diene (5) via hydrogenation followed by reductive dehalogenation or via hydrodehalogenation followed by epimerization. The diene 5 was obtained by Diels-Alder reaction.
Synthetic approaches are described leading to homoepibatidine and bis-homoepibatidine which are based, respectively, on the tropane (8-azabicyclo[3.2.1]octane) and homotropane (9-azabicyclo[4.2.1]nonane) ring systems. Epoxy- tropanes and -homotropanes (which are readily available from simple cyclic dienes) are convenient precursors for the azabicyclic alkenes needed for the key reductive coupling with pyridine derivatives.
A non-opioid analgesic, epibatidine (1), isolated from Ecuadoran poison frogs was synthesized in the racemic form starting from a readily available compound 2. A partial Curtius rearrangement product 5 of 2 was converted into 12c by way of the ketone 3 and its condensation product with the pyridine moiety 9c, and catalytic hydrogenation of 12c was specifically conducted in hydrochloric acid-containing 2-propanol for the preferential formation of an exo-product 15b. Conversion of the substituent from 15b to 15a in a single operation using the Vilsmeier reagent, followed by deprotection of the p-toluenesulfonyl group with hydrobromic acid completed an eight-step synthesis of (+/-)-1 from 2.
Synthetic (+/-)-epiboxidine (exo-2-(3-methyl-5-isoxazolyl)-7-azabicyclo[2.2.1]heptane) is a methylisoxazole analog of the alkaloid epibatidine, itself a potent nicotinic receptor agonist with antinociceptive activity. Epiboxidine contains a methylisoxazolyl ring replacing the chloropyridinyl ring of epibatidine. Thus, it is also an analog of another nicotinic receptor agonist, ABT 418 ((S)-3-methyl-5-(1-methyl-2-pyrrolidinyl)isoxazole), in which the pyridinyl ring of nicotine has been replaced by the methylisoxazolyl ring. Epiboxidine was about 10-fold less potent than epibatidine and about 17-fold more potent than ABT 418 in inhibiting [3H]nicotine binding to alpha 4 beta 2 nicotinic receptors in rat cerebral cortical membranes. In cultured cells with functional ion flux assays, epiboxidine was nearly equipotent to epibatidine and 200-fold more potent than ABT 418 at alpha 3 beta 4(5) nicotinic receptors in PC12 cells. Epiboxidine was about 5-fold less potent than epibatidine and about 30-fold more potent than ABT 418 in TE671 cells with alpha 1 beta 1 gamma delta nicotinic receptors. In a hot-plate antinociceptive assay with mice, epiboxidine was about 10-fold less potent than epibatidine. However, epiboxidine was also much less toxic than epibatidine in mice.
Epibatidine (1) is synthesized by employing a [3 + 2] cycloaddition strategy as a key step via nonstabilized azomethine ylide 10, generated by one-electron oxidative double desilylation of N-benzyl-2,5-bis(trimethylsilyl)pyrrolidine (12). Cycloaddition of 10 with trans-ethyl-3-(6-chloro-3-pyridyl)-2-propenoate (22a) gives 26 in which the 6-chloro-3-pyridyl moiety is endo-oriented. Decarboxylation followed by debenzylation gives unnatural epimer 30 of 1. The required cycloadduct 33, in which 6-chloro-3-pyridyl moiety is exo-oriented, is obtained stereoselectively utilizing cis-ethyl-(6-chloro-3-pyridyl)-2-propenoate (22b) as dipolarophile. 30 is also converted to 1 by epimerization reaction using KO(t)()Bu. An alternative route involving conjugate addition of 6-chloro-3-iodo pyridine (37) to 36, obtained by cycloaddition of 10 with ethyl propiolate, is also suggested for the stereoselective synthesis of 1. A number of substituted epibatidines (38, 39, 40, 41, and 42) are synthesized through this strategy using appropriate dipolarophiles. Formal synthesis of the N-methyl homoepibatidine 48 and its epimer 46 is suggested from the cycloaddition of homologous azomethine ylide 44, derived from 43, with 22a and 22b, respectively.