No full-text available
To read the full-text of this research,
you can request a copy directly from the authors.
ChemInform Abstract: Copper(I)-Catalyzed Three Component Reaction of Sulfonyl Azide, Alkyne, and Nitrone Cycloaddition/Rearrangement Cascades: A Novel One-Step Synthesis of Imidazolidin-4-ones.
Abstract
A novel one-pot azide-alkyne/ketenimine-nitrone cycloaddition sequence that is induced by copper(I) and allows the transformation of sulfonyl azides, alkynes, and nitrones to highly substituted imidazolidin-4-ones is described. The corresponding heterogeneous version utilizing Cu(I)-modified zeolites as recyclable heterogeneous catalysts shows marginally improved yield and diastereoselectivity.
... A very interesting approach explored by the group was the use of reactive N-sulfonylketenimine intermediates 3 to synthesize heterocycles with complex molecular architecture. These intermediates can be obtained via the [3 þ 2]-cycloaddition between sulfonyl azides 1 and terminal alkynes 2 catalyzed by a copper(I)-exchanged Y zeolite (Cu I -Y) followed by nitrogen elimination and then nucleophilic attack or cycloaddition reaction (Scheme 1a) [12]. ...
... Multicomponent reactions using Cu I -Y zeolites [12]. ...
Multicomponent reactions are processes in which three or more reactants are introduced concurrently to deliver a single product that contains the essential parts of the starting materials, and those have emerged in the last few years as an important tool for the development of more sustainable processes in modern synthetic organic chemistry. Still, considering the pronounced attention devoted to zeolites as efficient and selective catalysts for organic transformations, in this work we have reviewed the recent applications of zeolites as catalysts in multicomponent reactions; initially, zeolites modified with transition metals were discussed, followed by zeolites with alkaline metals and in the final section, zeolites in the protonic form.
... When sulfonyl azides, alkynes, and nitrones react though a one-pot azide-alkyne/ketenimine-nitrone cycloaddition sequence that is induced by Cu(I)-modified zeolites allows the formation of substituted imidazolidin-4-ones (Fig. 57). The heterogeneous Cu(I) catalysis version of the process shows marginally improved yield and diastereoselectivity [66]. The synthesis of iminocoumarin aryl methyl ethers from the coupling of ynals, phenols, and sulfonyl azides using CuIcatalysis at room temperature under air, proceeds through a cascade [3+2]-cycloaddition, ketemine rearrangement, 1,4conjugate addition, and aldol condensation, with good yields (57-79%) (Fig. 58). ...
The ketenimines represent an interesting class of organic intermediates which has undergone a regrowth as a consequence of recent extensions of copper catalyzed azide alkyne cycloaddition (CuAAC) to other synthetic fields. This review summarizes the most recent generation methods of ketinimines from CuAAC reaction, highlighting chemical properties focused to the synthesis of cyclic compounds among others, affording a general outlook towards the development of new biologically active compounds.
... These results prompted us to explore the implementation of this strategy to trigger reactions with heterodipoles such as nitrones or hydrazones. Only few examples of [3 + 2] cycloadditions between N-sulfonylketenimines (generated using copper catalysis) with heterodipoles such as, hydrazones [19] or nitrones [20] have been reported. ...
Under basic conditions, N‐arylketenimines were generated in situ from N‐Boc ynamides and reacted with various hydrazones. Under heating, an addition of the deprotonated hydrazone onto the central carbon of the ketenimines takes place giving rise to various acetimidohydrazides.
... [19,20] Overall, reports of 1,3-dipolar cycloaddition with a ketenimine as the dipolarophile remain rather scarce. [21][22][23][24][25] Moreover, [3 + 2] cycloadditions with non-or semi-stabilized azaallyl anions [26,27] were mostly developed with olefins as dipolarophiles. [28][29][30] This serendipitous discovery thus gave us the opportunity to explore some unprecedented annulation reactions towards nitrogenrich heterocycles. ...
Under basic conditions and heat, ynamides can serve as precursors to ketenimines, whose synthetic potential is often hampered by their difficulty of access. Herein, we report that they can undergo a [3+2] cycloaddition with 2‐azaallyl anions, obtained from benzylimines under the same reaction conditions. This reaction between two highly reactive intermediates, both generated in situ from bench stable starting materials, gives access to various nitrogen‐rich heterocycles. The reaction usually proceeds with excellent diastereoselectivity, in favor of the cis adduct. Deuteration experiments and DFT calculations helped rationalize the regio‐ and stereoselectivity of the process as well as the formation of side products.
image
... N-sulfonylketenimine as an appropriate dipolarophile reacted with nitrones 43 in one step sequence to secure various heavily substituted and stereodefined imidazolidin-4-ones 44 ( Table 4). The strategy offered excellent yields, mild reaction conditions and good diastereoselectivity [24]. ...
Background
Pericyclic reactions characterized by a cyclic transition state, have been established as a dominant approach for the synthesis of heterocyclic scaffolds owing to their tremendous efficacy, regioselectivity, and enantioselectivity. Pericyclic chemistry is a promising and creative route to various biologically significant five and six membered oxygen or nitrogen ring systems. Recognizing the reaction's potential, synthetic organic chemists have invested significant efforts in developing and applying a seemingly endless array of useful variations of pericyclic reactions.
Objective
The driving force of this review is to focus the character of perfection and beauty inherent in these powerful reaction pathways that lead to unique and densely functionalized heterocylic assemblies.
Conclusion
In this review, we have presented recent strategic applications of pericyclic reactions that provide quick access to molecular complexity with high efficiency. A summary of these illustrative examples will showcase the extensive role of pericyclic chemistry in the construction of synthetically intimidating structural motifs.
... In a more interesting approach, the same group was able to trap the N-sulfonylketenimines derived from 'click' adducts in [3+2] cycloadditions with nitrones (Scheme 28) [61]. However, the expected heterocycles proved unstable under the reaction conditions and rearranged to functionalized imidazolidin-4-ones in high yields. ...
Within the Green Chemistry context, one of the major challenges is the replacement of conventional homogeneous catalysts by heterogeneous catalysts, which are easy to handle and usually recyclable since they can be readily recovered. This paradigm change is becoming particularly significant with the development of zeolites, either in their native acidic form or modified by metal ions, as catalysts in organic chemistry. Due to the current burgeoning of this new field, the present review only covers some typical but representative aspects. Typical reactions of carbohydrates and other acid-sensitive organic compounds can be catalyzed by H-zeolites, advantageously replacing dangerous and toxic strong acids. Metal-doped zeolites can act as catalysts for various transformations. Some cycloadditions, including the well-known ‘click’ reaction, and coupling, specially Cu-catalyzed reactions. This new kind of heterogeneous catalysts can be recycled and reused, in sharp contrast to conventional homogeneous catalysts.
A convenient and applicable approach for constructing diverse functionalized 4′‐nitro‐2′,5′‐diphenyl spiro[indoline‐3,3′‐isoxazolidin]‐2‐one derivatives has been developed via a transition metal‐ and base‐free [3 + 2] cycloaddition reaction of isatin ketonitrone derivatives with β‐nitrostyrene. The structure of the compounds was confirmed by NMR and HRMS, while the structure of one specific compound, 11m, was definitively determined through single crystal X‐ray analysis. This method offers several advantages, including shorter reaction time, high yields, and a broad substrate scope. The synthesized compounds were evaluated for their in vitro antibacterial activities against two human pathogenic bacterial strains, Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus). Among all the tested compounds, 11c showed the highest potency, outperforming the standard antibiotic gentamicin, with a MIC value of 20 µg/mL. Structure‐activity relationship studies (SARs) revealed that compound 11c, having Cl‐substituted styrene, possesses the most significant antibacterial activity. These spiro isoxazolidine derivatives exhibit promising antibacterial properties and favorable pharmacokinetic profiles, indicating their potential as viable antibacterial agents. In silico ADME predictions suggested favorable pharmacokinetic properties, indicating the potential of these compounds as antibacterial drug candidates.
The iminopyrans were synthesized by the CuAAC‐MCR approach, the coupling of enaminones, phenyl acetylenes, and sulfonyl, under microwave treatment. The mechanism of the formation of iminopyrans along with amidine has been studied in detail. Experiments to minimize amidine formation were explored, and unfortunately, these experiments were unsuccessful. Molar equivalents of enaminones, phenyl acetylenes, and sulfonyl were optimized to increase the yield of iminopyran. Fluorescent properties of iminopyrans were characterized using Frontier molecular orbital analysis, UV absorption, and emission studies.
An unprecedent [4 + 3] cycloaddition of furoketenimines with furocarbenoids has been disclosed for the divergent and efficient synthesis of cycloheptafuran and cycloheptapyrrole scaffolds. Zinc chloride acted as promoters for both the formation of these two transient intermediates from isocyanides and ene-yne-ketones, and the subsequent construction of seven-membered ring. Three rings and five bonds were constructed successively in this three-component one-pot domino reaction.
Herein, we report a copper/amine catalyzed stereoselective addition of alkynes to ketenimine intermediates generated in situ from the sulfonyl azide-alkyne cycloaddition cascade for the stereoselective synthesis of (Z)-1,3-enynes. Significantly, for the first-time, enamine intermediates generated in the copper-catalyzed sulfonyl azide-alkyne cycloaddition reactions have been successfully trapped and isolated as the products. Density functional theory computations have also been performed and found to be consistent with the observed experimental stereoselectivity.
The highly efficient Fe2(SO4)3/KHSO4 promoted synthesis of N‐sulfonylimidates from amides, sulfonamides and ethyl diazoacetate is reported. This transformation is compatible with a wide range of substrates and exhibits good functional group tolerance. This multi‐component reaction can be useful for synthesizing a variety of drugs and bioactive molecules with satisfactory yields.
A single-step approach is reported for the preparation of nitrones from benzyl halides and nitrosoarenes via pyridinium ylides, utilizing 4-dimethylaminopyridine (DMAP) catalyst and mild reaction conditions (Li2CO3, dimethylacetamide, and room temperature). The reaction provides both keto- and aldonitrones in high yields with a wide scope for benzyl halides and nitrosoarenes. In the same reaction system, 2-methyl-2-nitrosopropane, which does not have an aryl group, also affords the corresponding N-tert-butyl nitrones from primary benzyl bromides that have an electron-withdrawing group. As an application of the reaction, methyl 2-bromo-2-phenylacetate was used to prepare the corresponding isoxazolidine by a sequential one-pot synthesis.
In this project, a moderately efficient approach to multisubstituted N-(isoquinolin-1-yl)sulfonamide derivatives was illustrated, utilizing ortho-alkynylbenzaldoximes and zwitterionic ketenimine salts in a tandem reaction catalyzed by silver oxide. The oxophilicity of Ag2O, along with its nature as Lewis acid, pave the way for a smooth [3 + 2] cycloaddition between isoquinoline N-oxides and ketenimine species, which is a key step in this reaction. DFT calculation suggests that 1,3-dipolar cycloaddition of nitrone and ketenimine proceeds through a selective stepwise mechanism.
The introduction of more facile and atom efficient methods for the synthesis of organic linear and cyclic compounds is the aim of various researchers worldwide. N-sulfonyl ketenimine is an interesting intermediate in modern organic synthesis. N-sulfonyl ketenimine is capable of selective production of various heteroatom containing compounds, based on the functional groups in the structure of this intermediate. Several linear and cyclic compounds are synthesized from this intermediate. In this review, the role of N-sulfonyl ketenimine is studied as an intermediate in several organic syntheses.
Ketenimines have been explored as useful building blocks for the synthesis of heteroatom containing cyclic compounds through the cycloaddition with polar multiple bonds. Herein we report the cycloaddition of difluoroketenimine with non-polar multiple bonds, namely the cycloaddition with alkenes or alkynes. The difluoroketenimine is generated from the coupling of tert-butylisocyanide and difluorocarbene, which is formed in situ from (bromodifluoromethyl)trimethylsilane. The difluoroketenimine then reacts in situ with alkenes or alkynes to afford fluorinated pyrrolidines or pyrroles. DFT study suggests that a fluorinated cyclic (alkyl)(amino)carbene is involved as the key intermediate in these reactions.
A copper-catalyzed three-component reaction of terminal alkynes, TsN3, and tertiary allylic amines is developed toward the one-pot synthesis of α-allylic amidines. The product was synthesized on gram scale under 1 mol % of catalyst loading. Transformations of products into alkenyl amine and other nitrogen-containing compounds are demonstrated without any loss of stereochemical information.
A pyrazolyl nitrone (2) underwent 1,3-dipolar cycloadditions to afford some N-substituted maleimides (3a–o). An atropisomeric character was introduced into the formed cycloadducts by using maleimides that have a restricted rotation around the C–N bond. Also, facial selectivity of both endo and exo cycloaddition was observed where the major atropisomer was one that is formed by attacking the nitrone from the less hindered face of the dipolarophile. On the other hand, maleimides with free rotation around the C–N bond led to endo and exo cycloadducts without atropisomerism. The presence of atropisomerism in the formed cycloadducts was confirmed by extensive NMR studies and DFT calculations.
Ketenimines are versatile synthetic intermediates capable of performing novel transformations in organic synthesis. They are normally generated in situ due to their inherent instability and high level of reactivity. Herein, we report pyridine stabilized ketenimine zwitterionic salts, which are prepared through click chemistry from readily accessible alkynes and sulfonyl azides. To demonstrate their synonymous reactivity to ketenimines, these salts have been utilized in a cascade sequence to access highly functionalized quinolines including the core structures of an antiprotozoal agent and the potent topoisomerase inhibitor Tas-103.
1,3‐Dipolar cycloaddition of a sugar‐based nitrone to differently N‐substituted maleimides afforded mixtures of isoxazolidine‐based cycloadducts. The obtained predominant cycloadducts displayed three new contiguous stereogenic centers placing the protons in syn and anti‐relationship, respectively at the fused bond, and for H5 and H6. This was explained by an endo approach of the maleimide derivatives to the Si‐face of the nitrone reacting in its Z‐form. The mCPBA‐mediated oxidative cleavage N−O bond of the isoxazolidine occurred almost quantitatively to afford unprecedented sugar nitrones. Their pyrolysis under thermal or microwave activation led to new 4‐ylidene (3 S)‐3‐hydroxy‐1‐aryl (alkyl)‐pyrrolidine‐2,5‐diones.
A terminal alkyne-assisted protocol for the one-pot formation of a diverse range of arylamidines from a novel cascade reaction of in situ generated nitrile oxides, sulfonyl azides, terminal alkynes and water by [3+2] cycloaddition and ring opening sequence was developed. The use of aryl oxime chlorides as the carbon source of amidine group and the addition of water proved to be critical for the reaction. Moreover, terminal alkynes, which can lead to high yields of products by employing less amount, may play a catalytic role in the reaction. A broader range of substrates was investigated.
High-valent cobalt carbene Co(OR) 2 (=CPh 2 ) (OR = OC t Bu 2 Ph) undergoes reaction with various isocyanides CNR′ (CNR′ = 2,6-dimethylphenyl isocyanide, 4-methoxyphenyl isocyanide, 2-chloro-6-methylphenyl isocyanide, adamantyl isocyanide) to yield the corresponding ketenimine. The reaction is accompanied by the formation of cobalt bis(alkoxide) bis(isocyanide) complexes Co(OR) 2 (CNR) 2 , which were independently synthesized and characterized. DFT calculations suggest the mechanism proceeds through isocyanide binding to Co, followed by intramolecular insertion into the Co-carbene bond to form the ketenimine. We have also conducted an investigation of the catalytic formation of ketenimines at room temperature using mixtures of diazoalkanes (diphenyldiazomethane, methyl diazo(phenyl)acetate, and ethyl diazoacetate) and isocyanides (2,6-dimethylphenyl isocyanide, 4-methoxyphenyl isocyanide, adamantyl isocyanide, cyclohexyl isocyanide, and benzyl isocyanide). While no catalytic reactivity was observed for diphenyldiazomethane, ester-substituted diazoalkanes (diazoesters) demonstrate catalytic turnover. Relatively high yields are observed for the reactions involving bulkier aliphatic substrates adamantyl and cyclohexyl isocyanides. Mechanistic studies suggest that the lack of catalytic reactivity involving diphenyldiazomethane results from the inability of Co(OR) 2 (CNR) 2 to undergo carbene formation upon reaction with N 2 CPh 2 . In contrast, facile reaction is observed between Co(OR) 2 (CNR) 2 and diazoesters, which enables the overall catalytic reactivity.
Multicomponent Reactions (MCRs) have emerged as an efficient and eco-safe approach in organic synthesis. The influential nature of this approach has been well established in the fields of drug discovery, catalysis, material science, pharmaceutical and combinatorial chemistry. Not surprisingly, the development of multicomponent reactions leading to 1,2/1,3-azoles has expanded rapidly over the last few years. Despite their myriad synthetic applications, there is yet no exclusive review on the MCRs concerning the synthesis of 1,2/1,3-azoles. Therefore, this critical review covers the journey of MCRs to 1,2/1,3-azoles, including the reaction conditions, scope, and rationale behind the choice of catalyst as well as the proposed mechanism.
We report the development of a chiral guanidine‐based copper(I) catalyst for the asymmetric azide‐alkyne cycloaddition/[2+2] cascade reaction. Optically active spiroazetidinimine oxindoles were constructed via trapping the ketenimine species under mild reaction conditions. High level of enantioinduction and excellent isolated yields were achieved in the three‐component reaction of various isatin‐derived ketimines, sulfonyl azides and terminal alkynes. Control experiments and X‐ray crystallography were used to probe into the interaction of chiral guanidinium salt with copper salt.
We report the development of a chiral guanidine‐based copper(I) catalyst for the asymmetric azide‐alkyne cycloaddition/[2+2] cascade reaction. Optically active spiroazetidinimine oxindoles were constructed via trapping the ketenimine species under mild reaction conditions. High level of enantioinduction and excellent isolated yields were achieved in the three‐component reaction of various isatin‐derived ketimines, sulfonyl azides and terminal alkynes. Control experiments and X‐ray crystallography were used to probe into the interaction of chiral guanidinium salt with copper salt.
An effective and facile method for the synthesis of highly substituted 1,2,3,5‐tetrahydrobenzo[ e ][1,2,4]‐oxadiazepines is described. A formal [4+3] cycloaddition of N ‐(2‐(chloromethyl) phenyl) amides with nitrones afforded benzo[ e ][1,2,4]‐oxadiazepine derivatives with high atom economy and excellent yields (up to 97%).
magnified image
The first intermolecular ring-expansion cascade of azirines with alkynes for the synthesis of pyridines, enabled by a copper/triethylamine catalytic system via simultaneous generation and utilization of yne-enamine and skipped-yne-imine intermediates, is reported. Experimental as well as computational mechanistic studies revealed that the role of triethylamine is crucial in deciding the reaction pathway toward the pyridine products. This process offers a novel, one-step, direct, and practical strategy for the rapid construction of highly substituted pyridines under exceedingly mild conditions, and an installed alkyne functionality.
Heterocyclic polymers have gained enormous attention for their unique functionalities and wide applications. In contrast with the well-studied polymer systems with five- or six-membered heterocycles, functional polymers with readily openable small-ring heterocycles have rarely been explored due to their large synthetic difficulty. Herein, a facile one-pot multicomponent polymerization to such polymers is developed. A series of functional polymers with multisubstituted and heteroatom-rich azetidine frameworks are efficiently generated at room temperature in high atom economy from handy monomers. The four-membered azetidine rings in the polymer skeletons can be easily transformed into amide and amidine moieties via a fast and efficient acid-mediated ring-opening reaction, producing brand-new polymeric materials with distinctive properties. All the as-prepared azetidine-containing polymers exhibit intrinsic visible luminescence in the solid state under long-wavelength UV irradiation even without conventionally conjugated structures. Such unconventional luminescence is attributed to the clusteroluminogens formed by through-space electronic interactions of heteroatoms and phenyl rings. All the obtained polymers show excellent optical transparency, high and tunable refractive indices, low optical dispersions and good photopatternability, which make them promising materials in various advanced electronic and optoelectronic devices. The ring-opened polymers can also function as a lysosome-specific fluorescent probe in biological imaging.
A concise account on the use of transition metals copper (Cu) and palladium (Pd), as their cations as well as nanoparticles exchanged/immobilized onto porous frameworks such as zeolites, metal organic frameworks (MOFs), covalent organic polymers (COPs) and hollow nanostructures, functioning as catalysts in organic synthesis is presented. This biomimetic account, “focusing on catalytic systems in confinement” within zero-dimensional microenvironments and second sphere coordination covers primarily results from our group on N-sulfonylketenimine mediated cycloaddition, hydrogenation and C−C bond forming reactions, thus providing an interesting insight into the versatility and utility of these Cu and Pd catalysts. Other significant advantages and green credentials of confinement such as stability, selectivity, reusability, promotion of multicomponent reactions, use of green solvents, atom economy, and use of ambient conditions are highlighted at appropriate places. In the final section, our views on the current achievements and the future prospects in this area are summarized.
A rapid and effective approach to 4‐tosyl‐4,5‐dihydropyrazolo[1,5‐ a ]pyrimidines via copper‐catalyzed one‐pot cascade transformation of N ‐propargylic sulfonylhydrazones with sulfonyl azides under mild conditions has been developed. This process relies on the copper‐catalyzed azide‐alkyne cycloaddition (CuAAC) and intramolecular [4+2] cycloaddition of α,β‐unsaturated hydrazone with the in situ generated ketenimine intermediate, affording the useful bicyclization products with high efficiency.
magnified image
A novel heterogeneous nanocatalyst was fabricated by depositing copper iodide and Fe3O4 nanoparticles on imidazolium-based ionic liquid-grafted cellulose and successfully characterized using Fourier transform infrared spectroscopy, thermogravimetric analysis, powder X-ray diffraction, scanning electron microscopy, energy-dispersive X-ray spectroscopy, vibrating sample magnetometry and flame atomic absorption spectrometry. It was employed to catalyse the reaction of terminal acetylenes with sulfonyl azides to afford highly reactive sulfonyl ketenimine intermediates which were subsequently trapped by secondary amines to give N-sulfonylamidines and N-sulfonylacrylamidines under solvent-free conditions at room temperature. Good to excellent yields, very short reaction times, eco-friendly processing, easy separation and reusability without significant loss of catalytic activity were found to be the notable features of this synthetic protocol.
An efficient copper(I)‐catalyzed one‐pot domino reaction for the ( Z )‐selective construction of diazabicyclo[5.3.0]decatriene derivatives under mild conditions has been developed. This protocol was initiated by a Cu(I)‐catalyzed azide‐alkyne cycloaddition (CuAAC), followed by a ring opening rearrangement and then subsequent higher‐order [8+2] cycloaddition of azaheptafulvene with ketenimine intermediates at the corresponding C‐2 and N‐3 sites, affording biologically active heterocycles in good to high yields.
magnified image
Direct α-amination of nitrones has been developed by using N-haloimide-DBU protocol. Reaction of nitrones with N-haloimide takes place readily in the presence of DBU in DCM, affording directly α-aminonitrones in moderate to excellent yields. N-Haloimide activated by DBU provides both a halogen cation and a nitrogen anion source. E- and Z-isomerization of α-aminonitrones was examined and found to be highly sensitive to acidic substances like silica gel and Brønsted acid. In addition to nitrones, quinoline N-oxides are also suitable substrates. Direct amination achieved by the protocol demonstrates new reactivity of nitrones and quinoline N-oxides.
N1-unsubstituted imidazolidin-4-ones of primaquine (PQ) can be stabilized by N1-alkylation under basic conditions. Here we report the development, with our conditions, of peptidomimetic derivatives of PQ with L-amino acid and alkyl derivatives. The new derivatives represent potential new therapeutics for use against protozoan parasites, through enzymatic protection of aminopeptidases.
An efficient one pot synthesis for the construction of novel naphtho[2,1-b]furan-2,5-diones and benzo[de]chromene-2,6-diones using copper(i)-Y zeolite catalyzed reaction of N-sulfonylketenimine with 2-hydroxy-1,4-naphthoquinone and 5-hydroxy-1,4-naphthoquinone followed by the elimination of p-toluenesulfonamide is reported. The intermediate N-sulfonylketenimine, generated by (3+2) cycloaddition/ring-opening reaction/retro-Wolff rearrangement, cascade, and annulation, promotes the reaction involving the inter- and intramolecular nucleophilic addition/dehydration followed by hydrolysis and elimination of p-toluenesulfonamide to afford the target products in good yield.
A copper-catalyzed dimethylzinc-promoted three-component cascade reaction of alkynes, sulfonyl azides, and simple aldehydes or ketones is described. Polysubstituted olefins were thus constructed expeditiously in a one-pot procedure under mild conditions.
Nitrone chemistry has been widely developed for a long time and many reviews have outlined its rich transformation chemistry. However, most of these reviews involve aldonitrones due to their easy preparation and high reactivity. In recent years, N-substituents α,β-unsaturated ketonitrones and N-vinyl nitrones have attracted much attention of synthetic chemists to develop novel methodologies for their preparation and transformation. Various properties and new transformations of these nitrones have been discovered and applied into the synthesis of important heterocycle scaffolds. This review describes some recent breakthroughs in the development of new transformation of these nitrones. These new reactions include novel strategies for preparation of N-substituents α,β-unsaturated ketonitrones or N-vinyl nitrones, new rearrangement of nitrones, and reaction of nitrones with dipolarophiles such as alkynes, allenes and isocyanates.
An elegant copper(I)-Y zeolite catalyzed tandem process, involving ketenimine based termolecular [2+2+2]/[NC+CC+NC] cycloaddition, using sulfonyl azide, alkyne and quinoline, to prepare pyrimido[1,6-a]quinolines is reported. In this straightforward, highly atom- and step-economical protocol, copper(I) promotes for azide-alkyne [3+2] cycloaddition which is followed by ring-rearrangement/ketenimine formation/regio- and stereoselective [2+2+2] termolecular cycloaddition and dehydrogenation cascade to yield selectively the E-isomer of pyrimido[1,6-a]quinoline.
The current requirements for clean, fast, efficient, and selective processes have increased the demand for cascade processes using transition metal salts or complexes as catalysts. Among transition metal catalysts, ruthenium, iron, iridium, rhodium, and copper have long been used widely and extensively as catalysts. It has been well demonstrated that transition metal catalysts are able to catalyze both intramolecular and intermolecular cascade reactions under mild conditions and often with high levels of chemo-, regio-, and stereoselectivities. Another essential advantage of these transition metals is that they allow consecutive metal-catalytic or metal-catalytic relaying cascade processes to combine different catalytic cycles with different metal catalysts for each step. Recent progress in cascade reactions catalyzed by these metals is discussed in this chapter. From the viewpoint of practical applications, iron and copper are the most abundant metals on Earth and, consequently, inexpensive and environmentally friendly.
Alkynes are highly versatile functionalities for multicomponent syntheses of heterocycles. Although they can be considered as electron-rich functionalities displaying σ- and π-nucleophilic reactivity as well as they can participate in many organometallic transformations, alkynes with electron-withdrawing substituents are excellent electro-, dipolaro-, and dienophiles in multicomponent reactions furnishing heterocycles. It is particularly interesting that acceptor-substituted alkynes, such as ynones, can be generated catalytically and they can be directly used in multicomponent reactions. Most recent contributions in the field of alkynes as reactants in multicomponent syntheses of heterocycles are discussed in this chapter.
Microwave-assisted copper-catalyzed four-component tandem synthesis of 3-N-sulfonylamidine coumarins has been described by the coupling of salicylaldehydes, propiolates, sulfonyl azides and secondary amines. This one-pot protocol affords an effective route for the construction of functionalized coumarin structural frameworks in single operation with moderate to high yields.
A simple way to stereoselective synthesis of pyrrolopyrrolo[2,1-a]isoquinoline derivatives has been developed with mild reaction condition and easily available substrate. A new kind of heterocycles, 10’, 14’-diazaspiro[pyrrolidine-3,11’-tetracyclo[8.6.0.02,7,012,16]hexadecane]-2’(7’),4’,6’,8’-tetraene-2,5,13’,15’-tetrone derivatives is disclosed.
Graphical Abstract
A simple way to stereoselective synthesis of pyrrolopyrrolo[2,1-a]isoquinoline derivatives has been developed with mild reaction condition and easily available substrate. A new kind of heterocycles, 10',14'-diazaspiro[pyrrolidine-3,11'-tetracyclo[8.6.0.02,7,012,16] hexadecane]-2'(7'),4',6',8'-tetraene-2,5,13',15'-tetrone derivatives is disclosed.
The first example of Rh(III)-catalyzed cyclization of arylnitrones to indolines under external oxidant-free conditions is presented. An intermolecular coupling of arylnitrones with internal alkynes is made possible by the dual role of Cp*Rh(III) catalyst mediating both the C-H bond activation and oxygen atom transfer. Synthetically important and pharmacologically privileged indoline derivatives were obtained in good yields with high diastereoselectivity.
An efficient, four-component reaction for the synthesis of hydrazono-sulfonamide adducts via in situ generated ketenimine was discovered. Highly porous copper benzenetricarboxylate [Cu(BTC)], a metal–organic framework (MOF), was used as a heterogeneous catalyst for the four-component coupling reaction involving aldehyde, alkyne, tosyl azide, and phenylhydrazine in a one pot process. For the first time, a copper(II) catalyst was utilized to generate a ketenimine intermediate. The Cu(BTC) catalyst was recycled and reused six times without any substantial loss in the yield. In addition, pyrene adduct (5r) shows remarkable aggregation induced emission enhancement (AIEE) properties, and was studied in detail using THF:water solvent mixtures. Adduct 5r is almost non-emissive in pure THF solution, however, it emits a greenish-yellow colour in the aggregated state. Formation of nano-aggregates was confirmed by TEM analysis. A theoretical DFT study supports the observed photophysical changes.
Die cis-Regel wird gebrochen: L-Prolin und nicht wie erwartet D-Prolin führte in einer kurzen Synthesefolge zu richtig konfiguriertem (−)-Amathaspiramid F (siehe das Retrosyntheseschema). Diese Synthese stellt eine Ausnahme vom Prinzip der Selbstregenerierung der Chiralität dar und bietet eine Strategie an, eine problematische Nef-Reaktion in Gegenwart dicht gepackter polarer Funktionalität zu umgehen.
Catalytic asymmetric methodologies provide versatile routes to many complex molecules through expedient and often elegant processes. This review summarises the work on the development and application of tandem and domino catalysed reactions within enantioselective organic synthesis. 1 Introduction 2 Transition-Metal-Catalysed Processes 2.1 Processes Involving Michael Additions 2.2 Hydroformylations 2.3 Heck Reactions 2.4 Allylic Substitutions 2.5 Processes Involving Pericyclic Reactions 2.6 Hydrogenations 2.7 Aldol Reactions 2.8 Metathesis Reactions 2.9 Processes Involving Epoxide Formation 2.10 Miscellaneous Transition-Metal-Catalysed Processes 3 Chiral Organocatalytic Reactions 3.1 Processes Involving Michael Additions 3.2 Aldol Reactions 3.3 Mannich Reactions 3.4 Processes Involving Pericyclic Reactions 3.5 Miscellaneous Organocatalytic Processes 4 Conclusions.
The development of highly efficient methodologies for constructing heterocyclic compounds is a major challenge in organic chemistry. This Account presents the recent progresses on cascade strategies for heterocyclic synthesis based on ketenimine intermediates. Three types of cascade reactions for the synthesis of a variety of heterocycles, involving nucleophilic addition to the central carbon of ketenimine, radical addition to the central carbon of ketenimine, and pericyclic reaction of ketenimine, are highlighted in this Account. A brief discussion on the mechanism of copper-catalyzed azide-alkyne cycloaddition (CuAAC) providing ketenimines is also included.
1 Introduction
2 Nucleophilic Addition to the Central Carbon of Ketenimines
3 Radical Addition to Ketenimines
4 Pericyclic Reactions of Ketenimines: Cycloaddition Reaction
4.1 Ketenimine-Imine [2+2] Cycloadditions
4.2 Ketenimine-Alkene [2+2] Cycloadditions
5 Pericyclic Reactions of Ketenimines: Electrocyclic Ring Closure
6 Pericyclic Reactions of Ketenimines: Sigmatropic Migration
7 Conclusions and Outlook
A high pressure promoted tandem [4 + 2]/[3 + 2] cycloaddition of β-nitrostyrene with a variety of enol ethers followed by a base catalysed rearrangement provided a novel class of di- and tricyclic N-oxy-β-lactam compounds.
Nickel nanoparticles are prepared in the interlamellar spaces of K10-Montmorillonite clay by chemical reduction at moderate temperatures. These clay entrapped nickel nanoparticles are characterized by UV–vis, powder XRD, EDX and HRTEM studies. The resultant ecofriendly supramolecular assembly with nickel content (2.84wt%) has good catalytic efficiency in hydrogenation of alkenes and alkynes with hydrazine as a reducing agent in ethanol medium. Advantages of the present study include absence of an external hydrogen source, catalyst reusability and a green medium.
2-Methoxybuta-1,3-diene reacts under high pressure conditions in a one-pot domino (4+2)/(4+2)/(3+2) cycloaddition reaction with a dienophile, β-nitrostyrene and a dipolarophile to give tri, tetra and pentacyclic nitroso acetals. In this novel domino reaction up to six bonds and up to eight stereogenic centers are created in one step in good yield and good stereoselectivity.
An efficient method for the incorporation of an imidazolidinone moiety into peptide sequences via an alkylidene bridge between two neighboring amide bonds is presented. A benzotriazole-mediated reaction of aldehydes with resin-bound peptides provides N-terminal 4-imidazolidinone-peptide derivatives. The generated five-membered ring, which will be expected to have similar properties to ‘pseudo-prolines’, can be acylated at the secondary amine to allow elongation of the peptide backbone. NMR studies of imidazolidinone-containing peptides show the existence of cis/trans isomerization, typical for proline-based peptides.
The interaction between CuCl and HY (Si/Al=20) zeolite under inert nitrogen gas atmosphere has been studied by TG/TGA, XRD, 27Al MAS NMR, and 29Si MAS NMR spectra. CuCl is easy to sublimate and disperse on the surface of the zeolite. But if CuCl was adsorbed on the cage of the zeolite, it was unlikely to be desorbed from the zeolite at over 800°C. The ion-exchange of CuI in solid CuCl with H+ in HY zeolite occurred at over 300°C and the maximum ion-exchange rate was reached at 340°C under a heating rate of 10°C/min, with the consequent release of HCl gas. And it was found that CuCl promotes the dealumination of framework aluminium of the HY zeolite and probably reacted with the extra framework aluminium to form (AlO)Cl. During the heating treatment, the unique structure of the Y zeolite was kept and CuCl crystalline phase was unlikely to disappear because the powder XRD pattern of CuCl crystalline phase was still observed when the CuCl/HY sample was treated at 350°C for 60h and 650°C for 5h. Over 100% ion-exchanged degree of the CuI with H+ in HY zeolite was obtained at high treatment temperature (650°C or over) due to the reaction between defect –Si–OH and CuCl to form –Si–OCu.
A one-pot synthesis of N-sulfonyl-2-alkylidene-1,2,3,4-tetrahydropyrimidines via a highly selective and copper-catalyzed multicomponent reaction of sulfonyl azides, terminal alkynes and α,β-unsaturated imines has been developed. The α,β-unsaturated imine substrates could be generated from amines and α,β-unsaturated aldehydes in a one-pot process. The procedure is concise, general and efficient.
The present review portrays a concise account of the isolation, bioactivity, and synthesis of bioactive quinazolinone-based natural products for the period 1983–2005 and the recent developments in the area of complex quinazolinone natural products with a special emphasis on new synthetic routes and strategies.
Treatment of o-propargylaryl nitrones with base provided 1,2-dihydro[c]benzazepin-3-ones in good yields. The straightforward transformation is explained on the basis of a multistep rearrangement involving conjugated allene−nitrones as precursors of a 1,7-dipolar electrocyclization process that is followed by further bond reorganizations.
Dipeptide esters (of glycylglycine, glycylalanine, alanylglycine) and aldehydes (isobutyraldehyde, pivalaldehyde, benzaldehyde) are condensed to (4-oxoimidazolidin-3-yl)acetates and -propionates (1-3). Lithium enolates of these derivatives are generated (deprotonation of the ring and/or side-chain α-carbonyl positions) with LDA, LDA/LiBr, or LHMDS and alkylated with high diastereoselectivity (products 4, 6, 7). Dipeptides of either R,R or S,S configuration can be prepared from the glycine-containing precursors. Surprising proton-transfer effects (Schemes VI-IX, XII) are interpreted as a consequence of "intimate complexation" among LDA, LiBr, lithium enolates, and diisopropylamine.
A highly efficient and enantioselective organocatalyst, imidazolidin-4-one, has been successfully immobilized on siliceous MCF and polymer-coated MCF. The resulting heterogenized catalyst demonstrated excellent catalytic performance and recyclability for Friedel–Crafts alkylation and Diels–Alder cycloaddition. The performance of the supported catalysts in relation to the surface environment of siliceous MCF was examined. It was found that partially pre-capping the MCF with TMS groups enabled us to attain well-dispersed catalysts on the siliceous support with optimal performance. We have also developed a polymer-coated MCF, which retained the porous structure of MCF without the surface silanol groups. High reactivity and excellent recyclability were achieved by the organocatalyst immobilized on polymer-coated MCF.
Die Entwicklung und Umsetzung von Kaskadenreaktionen hat zu beachtlichen neuartigen, eleganten und effizienten Synthesestrategien geführt. Als besonders anspruchsvoll erwies sich die Anwendung von Kaskadenreaktionen in der Naturstoffsynthese, doch gerade hier winken verblüffende und zugleich aufschlussreiche Ergebnisse als Belohnung. In diesem Aufsatz werden ausgewählte Kaskadenreaktionen in der Totalsynthese erläutert, wobei neuere Anwendungen besonders hervorgehoben werden. Die erörterten Beispiele sollen die Leistungsfähigkeit dieser Prozesse beim Aufbau von komplexen Molekülstrukturen veranschaulichen und ihr Potenzial für zukünftige chemische Synthesen verdeutlichen.
A copper-catalyzed one-pot synthesis of functionalized benzimidazoles has been developed. The procedure combines the copper-catalyzed three-component cascade reaction of sulfonyl azides, alkynes and 2-bromoaniline and the copper-catalyzed intramolecular N-arylation of sulfonamides in one sequence, which afforded the products in moderate to good yields.
4-(Alkoxycarbonyl)-pent-4-enimidates were regioselectively synthesized via a copper-catalyzed four-component reaction of Baylis–Hillman adducts with terminal alkynes, sulfonyl azides and alcohols. The procedure is concise, general and efficient. The resulting pentenimidates could be further transformed to 3-methylene-2,3-dihydroindene-1-imidates.
A versatile three-component coupling of aldehydes, alkynes and amines has been developed, catalyzed by Ni2+ exchanged Y-zeolite, which acts as all environmentally benign, recyclable, efficient and heterogeneous catalyst This three-component (A(3)) coupling (reported for the first time to proceed under nickel catalysis) is carried out under solvent-free conditions, and the corresponding propargylamines are obtained in good to excellent yields
Unter der asymmetrischen Mehrkomponenten-Reaktion versteht man die Synthese von chiralen Verbindungen aus drei oder mehr gleichzeitig zusammengegebenen Reaktionspartnern. Diese Art der Zugabe und Umsetzung hat gegenüber klassischen divergenten Strategien eine Reihe von Vorteilen, darunter ein geringerer Aufwand an Kosten, Zeit und Energie sowie eine bessere Umweltverträglichkeit. Dies und die hohe Stereoselektivität mancher Reaktionen werden diese neue Synthesestrategie für die chemische Industrie und für Hochschulen zunehmend wichtig machen. In diesem Aufsatz werden die Vorzüge, aber auch die Probleme asymmetrischer Mehrkomponenten-Reaktionen diskutiert.
In contrast to the very large number of special methods applicable to syntheses in the heterocyclic series, relatively few general methods are available. The 1,3-dipolar addition offers a remarkably wide range of utility in the synthesis of five-membered heterocycles. Here the “1,3-dipole”, which can only be represented by zwitterionic octet resonance structures, combines in a cycloaddition with a multiple bond system – the “dipolarophile” – to form an uncharged five-membered ring. Although numerous individual examples of this reaction were known, some even back in the nineteenth century, fruitful development of this synthetic principle has been achieved only in recent years.
A new type of Cu-catalyzed multicomponent reaction has been developed relying on the in situ generation of N-sulfonyl-or N-phosphorylketenimine intermediates, which are obtained from the cycloaddition of 1-alkynes and sul-fonyl-or phosphoryl azides followed by ring-opening rearrangement of the initially formed copper triazole species. This facile and versatile route to ketenimines has led to develop a range of highly efficient multicomponent reactions by em-ploying diverse nucleophiles such as amines, alcohols, water, pyrroles, and thiolates. Additionally, intramolecular version and cycloadditions of the ketenimines with imines or their derivatives have also been developed on the basis of the same strategy.
A novel and efficient route for the synthesis of 2-amino-H-pyrazolo[5,1-a]isoquinolines via a three-component reaction of N'-(2-alkynylbenzylidene)hydrazide, alkyne, and sulfonyl azide is described. This transformation, co-catalyzed by silver triflate and copper(I) bromide under mild conditions, proceeds efficiently to generate the 2-amino-H-pyrazolo[5,1-a]isoquinolines in good to excellent yields.
A cascade reaction of 2-ethynylaryl methylenecyclopropane with sulfonyl azide catalyzed by copper(I) iodide under mild conditions is described, which provides a novel and efficient route for the generation of fused indolines.
First syntheses of C6,7 and C7 enantiopure cocaine analogues were achieved from D-(-)-ribose via a trans-acetonide controlled endo-selective intramolecular nitrone-alkene cycloaddition (INAC) as the key step. This synthetic scheme allows practical preparation of cocaine analogues for bioevaluation as potential candidates for the treatment of cocaine addiction and as potential conjugates for immunotherapy.
A copper-catalyzed three-component reaction of 2-ethynylaniline, sulfonyl azide, and nitroolefin is reported. This reaction generates functionalized indoles in good yields and proceeds smoothly under mild conditions. Some hits as an HCT-116 inhibitor are found from the preliminary biological screening.
A three-component reaction of indoles, sulfonyl azides and terminal alkynes afforded 3-functionalized indoles in a single step via copper-cascade catalysis.
Reactions of α-keto esters with N-sulfonylketimines, prepared in situ from terminal alkynes and azide (III), proceeds via 2-iminooxetane intermediates such as (VII) which are transformed into maleimide derivatives or 5-iminopyrrolidinones.
Concise asymmetric total syntheses of vindoline (1) and vindorosine (2) are detailed based on a unique intramolecular [4 + 2]/[3 + 2] cycloaddition cascade of 1,3,4-oxadiazoles inspired by the natural product structures. A chiral substituent on the tether linking the dienophile and oxadiazole was used to control the facial selectivity of the initiating Diels-Alder reaction and set the absolute stereochemistry of the remaining six stereocenters in the cascade cycloadduct. This key reaction introduced three rings and four C-C bonds central to the pentacyclic ring system setting all six stereocenters and introducing essentially all the functionality found in the natural products in a single step. Implementation of the approach for the synthesis of 1 and 2 required the development of a ring expansion reaction to provide a 6-membered ring suitably functionalized for introduction of the Δ(6,7)-double bond found in the core structure of the natural products. Two unique approaches were developed that defined our use of a protected hydroxymethyl group as the substituent that controls the stereochemical course of the cycloaddition cascade. In the course of these studies, several analogues of vindoline were prepared containing deep-seated structural changes presently accessible only by total synthesis. These analogues, bearing key modifications at C6-C8, were incorporated into vinblastine analogues and used to probe the unusual importance (100-fold) and define the potential role of the vinblastine Δ(6,7)-double bond.
A series of 4-arylsulfonylimino-4,5-dihydrofurans (14 examples) were efficiently synthesized in good to excellent yields by using the copper-catalyzed three-component reaction between sulfonyl azides, phenylacetylene, and beta-ketoesters in tetrahydrofuran (THF) at 40 degrees C for 8 h in the presence of triethylamine (TEA). A plausible mechanism for this process is proposed.
A four-component, one-pot procedure gives access to alpha-functionalized imidates starting from readily available terminal alkynes, sulfonyl azides, alcohols and nitroalkenes using a copper catalyst and triethylamine as a base under mild conditions.
Gamma-nitro imidates were synthesized via a copper-catalyzed four-component cascade reaction of sulfonyl azides, alkynes, alcohols, and nitroolefins. This one-step procedure is general and efficient, and the reaction condition is mild.
The growing importance of cascade reactions reflects and imparts advances in the state of the art of organic synthesis and underscores the desire of synthetic chemists to achieve higher levels of elegance and efficiency. Besides their esthetic appeal, cascade processes offer economical and environmentally friendly means for generating molecular complexity. Because of their many advantages, these reactions have found numerous applications in the synthesis of complex molecules, both natural and designed. In this tutorial review, we highlight the design and execution of cascade reactions within the context of total synthesis as demonstrated with selected examples from these laboratories.
Benzyne-[2 + 2] cycloadditions with enamides are described. This effort led to the development of a highly stereoselective tandem [2 + 2] cycloaddition-pericyclic ring-opening-intramolecular-N-tethered-[4 + 2] cycloaddition for rapid assembly of nitrogen heterocycles.
The synthesis of polyhydroxylated indolizidines and pyrrolizidines belonging to the class of iminosugars, endowed with a vast and assorted biological activity, can be achieved in a straightforward manner by a general strategy consisting of a highly stereoselective 1,3-dipolar cycloaddition of polyhydroxylated pyrroline-N-oxides followed by simple transformations of the isoxazolidine adducts. The strategy allows the complete control of the relative and absolute stereochemistry of the numerous stereogenic centers decorating these compounds.
Rapid access: A gold(I)-catalyzed 1,3-dipolar cycloaddition of 2-(1-alkynyl)-2-alken-1-ones with nitrones provides a practical, regiospecific, and stereoselective access to highly substituted fused bicyclic furo[3,4-d][1,2] oxazines under mild conditions (see scheme). These fused heterobicyclic compounds can be readily converted into furans or 3,6-dihydro-2H-1,2-oxazines in a chemoselective fashion.
Multicomponent Reaction (MCR) Strategies which are far reaching and demonstrate a broad scope of applications with the variety of natural products has been demonstrated. MCR provide the shortest path possible to complex structural motifs by optimizing convergency at every possible step. MCR product was obtained via bicycle in excellent yield and with complete diastereoselectivity. The coupling of three of more suitable and compatible partners is the most suitable applications of transition metal catalysis in the design of MCR. The burgeoning of transition metal-catalyzed MCR will translate into new applications in natural product syntheses and will provide a potential solution to expanding the scope of mechanistic diversity. Natural product synthesis is the yardstick by which progress is often measured in organic synthesis.
A copper-aluminum hydrotalcite (Cu/Al-HT(3:1) as a new, environmentally benign, recyclable, efficient, and heterogeneous CuII catalyst system for the Huisgen [3+2] cycloaddition of azides and alkynes, was reported. (Cu/Al-HT(3:1) was prepared and characterized by powder x-ray diffraction (XRD). Reactions of benzyl azide with several aliphatic and aromatic terminal alkynes substituted by electron-donating as well as electron-withdrawing groups were carried out to evaluate the scope of this new CuII catalyzed process. Very good yields of a single regiosomer, namely 1,4-disubstituted 1,2,3-triazoles, were obtained. The energy barrier for the addition decreases considerably since the chance of having CuII ions in the HT framework was very high. It was observed that (Cu/Al-HT(3:1)) serves as a novel recyclable, efficient, and heterogeneous catalyst without any additives under aerobic conditions.
A fast and efficient route for diversity-oriented synthesis of 3- and 2,3-disubstituted piperidines, featuring an intramolecular nitrone cycloaddition with high regio- and diastereoselectivity, was achieved in six steps and 36-66% overall yield from commercially available gamma-butyrolactone or 1,4-butanediol. A new N-alkenyl nitrone enoate was used in this intramolecular nitrone cycloaddition, and the regioselectivity, diastereoselectivity, and reversibility of this cycloaddition were investigated.
Ammonium salts were found to be a convenient and inexpensive reagent in the Cu-catalyzed three-component reaction with terminal alkynes and sulfonyl or phosphoryl azides leading to N-unprotected amidines. Thus obtained amidines bearing 2-bromobenzenesulfonyl moiety were efficiently cyclized by the Cu-catalyzed intramolecular N-arylation to give an important pharmacophore skeleton of 2H-1,2,4-benzothiadiazine 1,1-dioxides. Conveniently, two tandem catalytic procedures could be readily operated in one pot.
Introduction Cationic domino reactions Anionic domino reactions Radical domino reactions Pericyclic domino reactions Photochemically induced domino processes Transition metal catalysis Domino reactions initiated by oxidation or reduction Enzymes in domino reactions Multicomponent reactions Special techniques in domino reactions
Breaking the cis rule: L-Proline and not as expected D-proline led to (−)-amathaspiramide F with the correct configuration in a short sequence of steps (see retrosynthetic scheme). This synthesis features an exception to the principle of self-regeneration of chirality and a strategy for circumventing a problematic Nef reaction in the presence of densely spaced polar functionality.
Cycloaddition reactions between a new homochiral imidazolone-derived nitrone afford cycloadducts in high yield and with high stereoselectivity. Subsequent cycloadduct elaboration affords the gamma-lactones of gamma-hydroxy-alpha-amino acids as well as the optically pure amino acids themselves.
Anhydrous magnesium iodide (MgI(2)) is shown to be an effective promoter of the "homo 3+2" dipolar cycloaddition of nitrones with 1,1-cyclopropane diesters. In almost all cases the products tetrahydro-1,2-oxazines are formed in excellent yields. The reactions are highly diastereoselective for a cis relationship between the substitutents at the 3- and 6-positions on the tetrahydrooxazine ring. As an alternative to using a preformed nitrone, the reaction may be performed in a 3-component sense by combining an aldehyde, an hydroxylamine, and the cyclopropane in the presence of catalytic MgI(2).
The first enantioselective organocatalytic hydride reduction has been accomplished. The use of iminium catalysis has provided a new organocatalytic strategy for the enantioselective reduction of beta,beta-substituted alpha,beta-unsaturated aldehydes to generate beta-stereogenic aldehydes. The use of imidazolidinone 2 as the asymmetric catalyst has been found to mediate the transfer of hydrogen to a large class of enal substrates from ethyl Hantzsch ester. The capacity of catalyst 2 to accelerate E-Z isomerization prior to selective E-olefin reduction allows the implementation of geometrically impure enals in this operationally simple protocol.
Imidazolidin-4-one derivatives of primaquine were synthesized as potential double prodrugs of the parent drug. The title compounds inhibit the development of the sporogonic cycle of Plasmodium berghei, affecting the appearance of oocysts in the midguts of the mosquitoes. The imidazolidin-4-ones are very stable, both in human plasma and in pH 7.4 buffer, indicating that they are active per se. Thus, imidazolidin-4-ones derived from 8-aminoquinolines represent a new entry in antimalarial structure-activity relationships.
A highly efficient, mild, practical, and catalytic multicomponent reaction for the synthesis of N-sulfonylamidines has been developed. This reaction has an extremely wide scope with regard to all three coupling components of alkyne, sulfonyl azide, and amine. Two plausible mechanistic pathways involving ketenimine or triazole intermediate are tentatively presented for the copper-catalyzed three-component coupling reactions.
Concurrent tandem catalysis (CTC) involves the cooperative action of two or more catalytic cycles in a single reactor. In CTC, each catalyst must be compatible with substrates, intermediates and other catalysts and must also exhibit reaction sequence selectivity. This review describes, in general terms, published CTC reaction schemes that have been reported through May 2004. First, a simple classification scheme for coupled catalytic cycles is proposed. Following this, specific examples, grouped by reaction classes, is presented with emphasis placed on methodologies utilized for the development of CTC. Finally, future prospects including developmental approaches related to tandem catalysis are outlined.
In this paper, we demonstrate the first examples of chiral Lewis acid catalysis in the formation of tetrahydro-1,2-oxazines with very high enantioselectivity starting with diactivated cyclopropanes and nitrones (>90% yields and ee). Reactions with racemic substituted cyclopropanes provide approximately 1:1 diastereomeric tetrahydro-1,2-oxazine products with high enantioselectivity. Mechanistic information for the formation of the tetrahydro-1,2-oxazines is also detailed.