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Strategies for Heterocyclic Synthesis via Cascade Reactions Based on Ketenimines
Abstract
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
... Their C=C=N cumulenic system can be represented by resonance structures 1a, 1b, and 1c ( Fig. 1). They contain a central sp-hybridized carbon atom (Cα) [3] that is electron-deficient and can be attacked by nucleophiles; a second carbon atom called Cβ and a nitrogen atom that could be attacked by electrophiles [4]. For this reason, ketemines have rich and diverse chemistry and are considered an important class of reactive species and useful synthetic intermediates or synthons. ...
... Ketemines were first described and prepared by Staudinger and Hauser in 1921, and its earlier chemistry was reviewed by Krow in 1971 [4] and by McHenry in 1980 [6]. However, in the last two decades, the availability of ketemines was rather limited, which significantly constrained their synthetic applications [5] because the corresponding methodologies required hardly accessible reagents and, therefore, these procedures have been rarely used in organic synthesis [7]. ...
... Ketemines are extensively involved in cascade reactions. They have attracted attention in recent years due to their easy formation from CuAAC reaction, relative reactivity, tolerance of procedure, and diversity of products [4]. There are mainly five groups of reactions known with ketemines: nucleophilic additions, radical additions, cycloadditions, electrocyclic ring-closure reactions, and σ-rearrangements [16]. ...
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.
... To date, the flourishing development of radical chemistry has provided attractive protocols to access heterocycles via cascade routes [7][8][9][10][11][12][13]. Utilizing radicals as functional reagents, the complicated heterocycles could be effectively obtained under mild conditions. ...
Due to the importance of SCN-containing heteroarenes, developing novel and green synthetic protocols for the synthesis of SCN-containing compounds has drawn much attention over the last decades. We reported here an electrochemical oxidative cyclization of ortho-vinyl aniline to access various SCN-containing benzoxazines. Mild conditions, an extra catalyst-free and oxidant-free system, and good tolerance for air highlight the application potential of this method.
... In the past few years, multi-component reactions such as three component coupling reactions have proven to be an important tool for the synthesis of industrially important compounds. [151][152][153][154][155] Among them, A 3 -coupling reactions of aldehydes, amines and alkynes have been increasingly developed in the last few years for the synthesis of diverse complex molecules like propargylamines. Propargylamines are essential building units in the synthesis of molecules such as β-lactams, allylamines, oxotremorine analogues, isosteres, oxazole which are biologically active as well as various therapeutics. ...
This review presents a brief discussion on the numerous synthetic techniques used to prepare metal nanoparticles supported on various two-dimensional (2D) materials. Special emphasis has been given to graphene and other 2D analogues such as g-C3N4, h-BN, MoS2, WS2 etc. supported metal nanoparticles. In addition to these, this review outlines the applications of the developed metal nanoparticles–2D composite materials for catalytic coupling reactions, which have recently emerged as a promising strategy in carbon–heteroatom or carbon–carbon bond formation. The effect of size and morphology of metal nanoparticles–2D composite materials on their catalytic performance toward different coupling reactions such as Suzuki, Heck, Sonogashira, etc. have been discussed in detail.
... In [3 + 2]-cycloaddition reactions between isoquinolinium-2ylamide 43 and keteneimine 57 [79], silver salt plays the usual role of a π-philic catalyst, whereas ketene imine 57 is generated by a well-known procedure involving a copper(I)-catalyzed azide-alkyne [3 + 2] cycloaddition (CuAAC) giving rise to 5-cuprated triazole intermediate 56 which, by subsequent ring opening and loss of nitrogen gas, smoothly resulted in ketenimine 57 [80]. The overall process proceeds efficiently to generate the 2-amino-H-pyrazolo [ have been previously described by Kerr and may proceed on the activated cyclopropane by a stepwise or concerted mechanism [81]. ...
Density functional theory (DFT) calculations with BP86-D3(BJ) functionals were employed to reveal the mechanism and stereoselectivity of chiral guanidine/copper(I) salt-catalyzed stereoselective three-component reaction among N-sulfonyl azide, terminal alkyne, and isatin-imine for spiroazetidinimines that was first reported by Feng and Liu (Angew. Chem. Int. Ed. 2018, 57, 16852-16856). For the noncatalytic cascade reaction, the denitrogenation to generate ketenimine species was the rate-determining step, with an activation barrier of 25.8-34.8 kcal mol-1. Chiral guanidine-amide promoted the deprotonation of phenylacetylene, generating guanidine-Cu(I) acetylide complexes as active species. In azide-alkyne cycloaddition, copper acetylene coordinated to the O atom of the amide moiety in guanidium, and TsN3 was activated by hydrogen bonding, affording the Cu(I)-ketenimine species with an energy barrier of 3.5∼9.4 kcal mol-1. The optically active spiroazetidinimine oxindole was constructed via a stepwise four-membered ring formation, followed by deprotonation of guanidium moieties for C-H bonding in a stereoselective way. The steric effect of the bulky CHPh2 group and chiral backbone in the guanidine, combined with the coordination between the Boc group in isatin-imine with a copper center, played important roles in controlling the stereoselectivity of the reaction. The major spiroazetidinimine oxindole product with an SS configuration was formed in a kinetically more favored way, which was consistent with the experimental observation.
Heterocyclic compounds play a very important role in both life and drug discovery, and in particular, a large number of synthetic molecules based on these structures have been reported with great potential in medicinal chemistry. Small polycyclic heterocycles are often found in pharmacophores and play an important role in drug discovery. Ketene aminals are multifunctional building blocks for the synthesis of all kinds of compounds. Bicyclic, tricyclic, and tetracyclic nitrogen-containing analogs with ketene aminal skeletons are widely available in natural and synthetic drugs. In recent years, significant progress has been made in the chemistry of ketene aminals. To understand and dominance the reaction properties of ketene aminals and the synthesis of other novel fused heterocycles, the investigation of ketene aminals is very important and necessary. This review covers relevant contributions with regard to the development and applications of ketene aminals, classified by reaction type and type of synthetic products.
We report herein the in situ generation of difluoromethoxylated ketenimines. This novel intermediate is readily obtained from the corresponding oxime through a Beckmann rearrangement. The reactivity potential of this species is demonstrated as it easily undergoes addition of various nucleophiles, with a great modularity of the starting oxime. The broad applicability of this transformation leads to a chemical library of original molecules bearing -OCHF2, an Emergent Fluorinated Group (EFG).
Background
In this paper, a novel catalyst is synthesized and characterized by immobilization of copper onto imidazolylpyridine modified super paramagnetic iron oxide nanoparticles (SPION).
Methods
The catalyst is characterized by several methods, including TEM, SEM, ICP, DLS, and VSM. The catalytic activity of the catalyst is evaluated in the synthesis of thiosolfunamide. The synthesized catalyst showed very good activity in the mentioned reaction and showed very good performance for the synthesis of the desired products in high isolated yields.
Results
For the synthesis of the products, sequential transformations enable the facile synthesis of complex target molecules from simple building blocks in a single preparative step.
Conclusion
Using terminal alkynes and sulfonyl azides as starting materials, the reaction can be performed with high yield using water and ethanol as the reaction green solvent. The reusability of the catalyst was tested and the results proved the high reusability of the catalyst.
The ability of [1,2,3]triazolobenzoxazinones to act as a source of "hidden" diazo group was discovered. These diazo precursors can be easily prepared by the intramolecular cyclization of 2-(5-iodo-1,2,3-triazolyl)benzoic acids. The Cu-catalyzed capture of the hidden diazo group allows for further functionalization through the denitrogenative pathway. The transformations proceed via the formation of either diazoimine or diazoamide intermediates. Novel routes to various anthranilamides as well as thiolated benzoxazinones were developed using the one-pot cyclization/diazo capture procedure.
A copper‐catalyzed/TsOH‐promoted one‐pot tandem annulation of 1,6‐allenynes with organic azides was reported, providing N‐allyl 1,2,3‐triazole‐fused structures in moderate to excellent yields under mild reaction conditions. Moreover, the late‐stage diversification of the N‐allyl products can be realized by chemoselectively reducing to the N‐alkyl counterparts.
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Diazo compounds and isocyanides are reactive functionalities and valuable building blocks commonly utilized in organic synthesis. Their cross-coupling for the synthesis of useful isolable ketenimines remains an unsolved challenge in synthetic chemistry. Herein, we report a general method for the preparation of ketenimines via a palladium-catalyzed cross-coupling of easily accessible diazo compounds with isocyanides. The reaction benefits from the use of readily available starting materials, a wide substrate scope, high functional group tolerance, and a high yield in products, and the resultant ketenimines are amenable to further functionalization. Experimental findings and DFT calculations unambiguously corroborate the initial formation of a Pd(II)-isocyanide complex as the active catalytic species, which enables the cross-coupling reaction via a migratory insertion of Pd(II)-carbene into isocyanide, with evidence suggesting that the oxidation state of Pd(II) remains unchanged during the reaction.
An efficient strategy for facilitating the cross-coupling of two radicals has been established via the coordination of a radical with a metal catalyst. This strategy provides a remarkable ability to harness the reactivity of nitrile-containing azoalkanes and enables a novel cascade reaction with nitrile-containing azoalkanes and propargylic alcohols to be established. By using this reaction, a range of acetylenic and allenic amides were obtained that provides a versatile platform for further derivatizations.
Herein, we describe the first synthesis of anionic silaketenimines as well as the coupling product with an isocyanide. Treatment of boryl silanorcaradienyllithium [CH2(L)N]2BSiLi (where L = B[N(Ar)CH]2 and Ar = 2,6-iPr2C6H3) with isocyanides afforded novel silaketenimine anions [CH2(R)N]2BSi(Li)=C=NR featuring a Si=C=N allenic structure. X-ray diffraction studies and density functional theory calculations strongly support the presence of an anionic silicon atom and a strong bond between the silicon and carbon atoms. One of the silaketenimine anions underwent a formal [2 + 2] cycloaddition reaction with a second molecule of isocyanide to give a novel silacyclopropyl anion with a delocal-ized anionic N C Si C N skeleton. These reactions demon-strated that the bonding nature of the boryl lithiosilylene was distinct from that of common silylenes.
This study reports the synthesis and characterization of a highly active catalyst based on chelated copper iodide on magnetic chitosan-salicylaldehyde Schiff base. This catalyst was successfully used for the three-component reaction of N-propargylphthalimide, tosylazide, and NH or OH containing nucleophiles to access new classes of N-sulfonylamidine or N-sulfonylimidate derivatives. The products, which were constructed via an in situ generated sulfonyl keteneimine intermediate, were obtained in good to excellent yields. Short reaction times, easy separation and reusability without significant loss of catalyst activity were found to be the notable features of this synthetic protocol.
A novel and efficient synthesis of 4-iminotetrahydropyrimidin-2-one derivatives was developed through a Cu(I)-catalyzed three-component tandem reaction employing propargylamines, isocyanates and sulfonyl azides as starting materials. A wide range of polysubstituted 4-sulfonyliminotetrahydropyrimidin-2-ones, which might be useful in biological chemistry and medicinal science, were conveniently and efficiently assembled in one pot.
A rhodium-catalyzed highly regio- and stereoselective intermolecular hydrosilylation of internal ynamides has been developed. With the neutral rhodium complex [Rh(CO)2Cl]2 as catalyst and the bulky silanes as reactants, various ynamides underwent hydrosilylation smoothly at room temperature with excellent β regioselectivity and anti stereoselectivity. The synthetically versatile β-silyl (Z)-enamide products could be further transformed to diverse useful building blocks. Several possible mechanisms are proposed to rationalize this unique formal trans-addition-type selectivity.
Manganese-catalyzed C2–H enaminylation of 1-(pyrimidin-2-yl)-1H-indoles with ketenimines is reported. The reaction provided 2-enaminylated indole derivatives in moderate to excellent yields with a broad substrate scope. A migration of the directing group pyrimidinyl occurred during this process. The synthesized 2-enaminyl indoles could be conveniently converted into 5-aryl-7H-benzo[c]carbazol-6-amines.
A general, stereospecific, and straightforward method for the rapid preparation of functionalized (E)-monofluoroenamines is reported. Rather than transition metals (Rh, Ni, Pd, Cu, Ag, etc.), Et2O·BF3 was employed to promote the formation of α-diazoimine through the Dimroth equilibrium of common 1-sulfonyl-1,2,3-triazole for the first time. An overall migration of fluoride from boron to the diazo-linked carbon of α-diazoimine was achieved. Derivations and late-stage modification of bioactive molecule were conducted. A plausible mechanism was also proposed.
A new approach for the formation of ketenimines via a decarboxylative allylic rearrangement pathway that does not require strong stabilizing or protecting groups has been developed. The products can be readily hydrolyzed into their corresponding secondary amides or reacted with sulfur ylides to perform an additional [2,3]-Wittig process. Mechanistic studies suggest an outer-sphere process in which reductive alkylation is rate-limiting.
Tetrazolo[1,5-a]pyrimidines are well recognized and valuable scaffolds in drug discovery. In the current manuscript, we demonstrated AlCl3 catalyzed synthesis of series of dihydrotetrazolo[1,5-a]pyrimidines and tetrahydrotetrazolo[1,5-a]quinazolinones via a modified Biginelli type multi-component reaction of 5-aminotetrazole, aldehyde and diverse active methylene components such as acetophenone/alkylacetoacetates/dimedone. This provides an efficient route to construct highly functionalized dihydrotetrazolo[1,5-a]pyrimidines and tetrahydrotetrazolo[1,5-a]quinazolinones directly from readily available starting materials.
A cyanide-free one-pot procedure was developed to access 2-amino-3-hydroxy-3H-indoles, which involved: 1) in situ formation of ketenimines by the reaction of N'-(1-(2-aminophenyl)ethylidene)-p-tosylhydrazones with isonitriles; 2) the intra-molecular nucleophillic attack of ketenimines by the amino in phenyl furnishing the ring closure leading to 2-aminoindoles; 3) the oxidation of 2-aminoindoles by O2 leading to 2-amino-3-hydroxy-3H-indoles. This strategy represents not only a key compliment to the sporadic synthetic methods towards 2-amino-3-hydroxy-3H-indoles but also a progress in N-tosylhydrazone, isonitrile and ketenimine chemistry.
A series of novel 1,2,3-triazole allyl acetates were prepared by CuTC-catalyzed azide-alkyne cycloaddition (CuAAC) from 3-acyloxy-1,4-enynes and sulfonyl azides. The 1,2,3-triazole allyl acetates could be further transformed to pyridine derivatives through 6π-azaelectrocyclization followed by elimination.
An efficient and highly regioselective synthesis of 1-allenyl-5-aryl-1,2,3-triazoles from 1-sulfonyl-4-aryl-1,2,3-triazoles is disclosed. 1-Sulfonyl-4-aryl-1,2,3-triazoles reacted with propargylic alcohols in the presence of trifluoroboron etherate to furnish 1-allenyl-5-aryl-1,2,3-triazoles. When secondary alcohols were used as substrate, the outcome of the reaction was 1-alkyl-5-aryl-1,2,3-triazoles.
Rhodium-catalyzed C-H activation/annulation reactions of ketenimines with N-methoxybenzamides are reported. The outcome of reactions is dependent on the structure of ketenimines. The β-alkyl-substituted ketenimines furnish 3-iminoisoquinolin-1(2H)-ones through a formal [4+2] annulation manner, while the β-ester substituted ketenimines afford 3-aminoisoindolin-1-ones through a formal [4+1] annulation manner. The synthesized [4+2] products undergo an intramolecular Cu-catalyzed C-N coupling to be converted to benzo[4,5]imidazo[1,2-b]isoquinolin-11-ones, which can be directly prepared from ketenimines and N-methoxybenzamides by a one-pot Rh-catalyzed annulation /Cu-catalyzed C-N coupling sequence.
In this work, we have designed an efficient and convenient method for the synthesis of novel spiro[indene-2,2'-[1,3,5]oxathiazine]-1,3-diones by the one-pot, three component condensation of tetramethyl guanidine, ninhydrin, and isothiocyanates in water. Easy purification, green reaction conditions, easy performance and good yields are some advantages of this procedure.
A new way of developing novel synthesis strategies for the construction of monocyclic rings found in organic molecules is presented. The method is based on the visual application of integer partitioning to chemical structures. Two problems are addressed: (1) the determination of the total number of possible ways to construct a given ring by 2-, 3-, and 4-component couplings; and (2) the systematic enumeration of those possibilities. The results of the method are illustrated using cyclohexanone, pyrazole, and the Biginelli adduct as target ring systems with a view to discover new and greener strategies for their construction using multicomponent reactions. The application of the method is also extended to various heterocycles found in many natural products and pharmaceuticals.
Over the past few decades, the development of versatile methodologies to employ azides as aminating agents for the formation of nitrogen-containing compounds has attracted significant attention in synthetic chemistry. This review examines recent developments in the tandem reaction of azides with alkynes and alkynols, which have not been solely discussed before. The formation of diverse nitrogen-containing compounds is classified in this review according to the types of reactions.
A rapid practical microwave-assisted new synthesis of sulfonylidene–sulfonamide was developed via the one-pot, three-component reaction of sulfonyl azides, terminal alkynes, and sodium arylsulfinates catalyzed by copper(I) iodide in DMF in moderate to good yields.
An efficient, green and environmentally procedure for the synthesis of spirooxindole derivatives has been developed by a one-pot three-component reaction of isatin derivatives, activated methylene, and 1,3-dicarbonyl compounds in the presence of Fe3O4@SiO2-imid-PMA? magnetic nanocatalyst under conventional heating conditions in water or microwave irradiation under solvent-free conditions. The reactions under conventional heating conditions were compared with the microwave-assisted reactions. The suggested method offers several advantages such as excellent yields, short reaction times, operational simplicity, a cleaner reaction, absence of any tedious workup or purification and ease of recovery and reusability of the catalyst by a magnetic field. In addition, the excellent catalytic performance in a water medium and the easy preparation, thermal stability and separation of the catalyst make it a good heterogeneous system and a useful alternative to other heterogeneous catalysts. The catalyst can be easily recovered by a magnetic field and reused for six consecutive reaction cycles without significant loss of activity. Also, the morphology of Fe3O4@SiO2-imid-PMA?, particle size distribution and leaching of nano H3PMo12O40 (PMA?) after reaction cycles were investigated by scanning electron microscopy (SEM), dynamic light scattering (DLS), and inductively coupled plasma (ICP) analyzer.
A cobalt(III)-catalyzed cross-coupling reaction of 1-(pyrimidin-2-yl)-1H-indoles with ketenimines is reported. The reaction provided 2-enaminylated indole derivatives in moderate to excellent yields with a broad substrate scope. The prepared 2-enaminylated indoles could be conveniently converted into pyrrolo[1,2-a]indoles, which are an important class of compounds in medicinal chemistry.
Cyclopenta[ b ]quinolines and cyclohexa[ b ]quinolines were prepared via the reactions of α‐diazo ketones with N ‐(2‐cyclopropylidenemethylphenyl)phosphanimines and N ‐(2‐cyclobutylidenemethylphenyl) phosphanimine, respectively. The reaction proceeds in a cascade involving ketenimine formation, 6 π‐electron ring closure, and 1,3‐alkyl shift. A similar approach was developed for the synthesis of dihydropyrrolo‐[2,3‐ b ]quinolines from N ‐(2‐cyclopropylidenemethylphenyl)phosphanimines and isocyanates.
An efficient method for the synthesis of C-phosphonoketenimines through palladium-catalyzed migratory insertion of isocyanides has been developed for the first time. This procedure tolerates wide functional-groups and has a good atom economy. Further transformations of the products which are useful building blocks for the β-aminophosphonates, β-aminovinylphosphonates and C-phosphorylated tetrazoles indicate potential synthetic utility.
The reaction of aromatic aldehydes, dimedone, and malononitrile in the presence of ammonium acetate has afforded tetrahydrobenzo[b]pyrans instead of polyhydroquinolines under both grinding and reflux conditions; thus ammonium acetate acts as a catalyst for this transformation instead of a reactant. Polyhydroquinoline derivatives were also synthesized via a one-pot condensation of aromatic aldehydes, malononitrile and an enaminone, which was prepared by the reaction of dimedone and ammonium acetate, in refluxing ethanol in high yields.
Graphical abstract
This review focuses on new developments in [2+2] cycloadditions leading to four-membered heterocycles (β-lactams, β-lactones, β-sultams, azetidines, etc.) which appeared between 1992 and 2011. A special attention is drawn to the mechanistic aspects of the reactions and their consequences on the stereochemical outcome of the cycloaddition processes. Accordingly, the subdivision in sections reflects this point of view: the entries are related to reactions of various reagents (ketenes, enolates, ynolates, isocyanates, etc.) with C. X bonds instead of a list of types of heterocycles. The accent is also put on asymmetric catalysis, which is of particular interest for the enantioselective synthesis of biologically active compounds or their precursors.
A facile synthetic method to access 3-substituted isoquinoline or dihydroisoquinoline derivatives has been developed via a novel cyclization reaction of N-sulfonyl-1,2,3-triazole derivatives by thermally induced rearrangement.
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.
Acrylamidines were synthesized via the copper-catalyzed three-component reaction of propargyl acetates, sulfonyl azides and amines, which are readily accessible materials. The synthesized N,N'-bis(aryl)amidines could be converted into 2-styrylbenzoimidazoles by the iodobenzene-catalyzed oxidative C-H amination using mCPBA as terminal oxidant.
From readily available propargylic amines, 1,2,5-trisubstituted imidazoles are efficiently obtained through a cascade reaction catalyzed by AgOTf or promoted by molecular iodine. The AgOTf-catalyzed reaction involves nucleophilic addition of propargylic amine to ketenimine, a silver-catalyzed electrophilic cyclization reaction of alkyne, and a tautomerism/isomerism/metal-H exchange cascade. The iodine-mediated counterpart yields 5-formyl-1,2-disubtituted imidazoles, which presumably includes a cascade hydrolysis/oxidation reaction. Furthermore, the presented protocol can be scaled up and the resultant 1,2,5-trisubstituted imidazole can be converted into fused indeno[1,2-d]imidazole.
A mild three-component synthetic approach to versatile 2-amino-1,4-dihydropyridines from terminal alkynes, sulfonyl azides, and N-sulfonyl-1-aza-1,3-butadienes was successfully developed and relied on the in situ generation of metalated ynamide intermediates Ib to achieve a formal inverse electron-demand hetero-Diels-Alder reaction. Experimental results suggest that alkali metal cations (Li(+) and Cs(+) ions) might play a critical role to achieve the cycloaddition process.
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.
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 catalyst free multicomponent reaction (MCR) capable of affording a wide range of novel 3,4-dihydro-2H-naphtho[2,3-e][1,3]oxazine-5,10-dione derivatives via one pot three component condensation of 2-hydroxy-1,4-naphthoquinone, aromatic amine and formaldehyde in ionic liquid [bmim]BF4 is reported. Mild reaction conditions, high yields, short reaction time, and easy separation are some of the salient features of the present protocol.
3-Amino-2-carbamimidoylacrylamides were efficiently prepared via a copper (I)-catalyzed three-component reaction of sulfonylazides, propriolamides, and amidines. These compounds provided three kinds crystalline structures based on the position of halogen. Two of them presented channel-type inclusion complexes with ethyl acetate through the weak intermolecular C-H…pi, and van der Waals forces.
A new and environmentally benign multi-component synthesis of tetra substituted 4H-pyran derivatives is developed via the one-pot reaction of an aromatic aldehyde, malononitrile, and 1,3-diketone in the presence of NaOH with water as the solvent at RT. The reaction is efficient and affords excellent yields of the products.
Nanorod vanadatesulfuric acid (VSA NRs), as a novel, recyclable and eco-benign catalyst, was used for an efficient synthesis of hexahydroacridine-1,8-diones using 1,3-cyclohexanedione derivatives, aldehydes and ammonium acetate or aniline under solvent-free conditions. VSA was prepared by the reaction of high-purity chlorosulfonic acid and sodium metavanadate. The present method offers some advantages over conventional ones, such as simple procedure and work-up, short reaction times, high yields, stability and reusability of the catalyst and simple purification of the products. Also, some greenness aspects of this method were investigated and compared with data from previous reports.
The synthesis of a novel class of N-(1H-benzo[d]imidazol-2-yl)-2-alkyl-N′-sulfonylacetamidines via a copper-catalyzed, three-component coupling reaction of 1H-benzo[d]imidazol-2-amine, sulfonyl azides, and terminal alkynes is described.
This brief review describes the syntheses of different five- and six-membered heterocyclic rings in various compounds by radical cyclization.
A synthetic route for N-(tosyl)azetidin-2-imines , a novel class of derivatives of β-lactams, has been developed. The procedure is applicable to the synthesis of azetidin-2-imines related to penicillins and cephalosporins.
A domino approach to 2-imino-1,2-dihydroquinolines and 2-imino-thiochromenes from sulfonyl azides, alkynes, and 2-acyl anilines or the potassium salt of 2-mercapto-benzaldehyde has been developed. This one-pot method is efficient and versatile.
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 principle of orbital control of pericyclic reactions has deepened our understanding of reaction phenomena and provided an excellent classification of these one-step processes. The electrocyclic reaction of the pentadienyl anion ⇌ cyclopentenyl anion type is relatively unimportant in all-carbon systems and has not even been verified in the case of the parent compound. In the heterocyclic series, however, where up to five C-atoms of the pentadienyl anion are replaced by heteroatoms, a multitude of ring closures and ring openings find their ordering principle in the mentioned electrocyclic reaction. The replacement of the carbon atoms by heteroatoms can take place isoinically, i. e., with retention of the anionic character, or isoelectronically. An isoelectronic replacement of CR2 in position 1 by NR2 OR, and or CR in position 3 by NR or O leads to a charge-free resonance structure for the open-chain species; the migration of the charge during the electrocyclization results in a correlation with a cyclic zwitterion. Conversely, isoelectronic exchange of CR in position 2 by NR or O produces a conjugated 1,3-dipole, which cyclizes to a charge-free unsaturated five-membered ring. Twofold isoelectronic exchange allows the whole process to take place in a cation. Selected examples are to shed light on the classification and the thermodynamics of this electrocyclic reaction.
α-Iminocarbenes(1)—now readily accessible by a new route—have been observed to undergo novel rearrangement to the hitherto unknown aminoketenimines (2). The latter compounds react with methanol to give (3). A certain proportion of (1) undergoes “normal” stabilization via addition of methanol (RC6H5).
Ketenimines R1R2CCNR3 were first reported in 1919, but the development of the chemistry of these compounds is of relatively recent origin. These heterocumulenes are becoming of increasing interest as a dehydrating agent for peptide syntheses, as a coreagent in dimethyl sulfoxide oxidations, and as a substrate in the synthesis of heterocycles by condensation with polar multiple bonds and dipolar systems. The cycloadditions are of special interest from the viewpoint of orbital symmetry considerations. Some unusual organometallic complexes of ketenimines have also been synthesized. Recently some triaryl ketenimines have been found to have insecticidal and miticidal activity. Polymeric ketenimines have been implicated as molecular precursors of life.
Intramolecular ketenimine-imine [2+2] cycloadditions leading to 1,2-dihydroazeto[2,1-b]quinazolines occur in a notably stereocontrolled manner along the newly formed C-C single bond when prochiral ketenimine and imine fragments are combined. Computational studies support stepwise mechanisms for these reactions. In sharp contrast with other well-known [2+2] cycloadditions, the first step of the reaction determines its stereochemical outcome, thereby surpassing the low stereocontrol induced by torquoelectronic effects.
Cu-I-catalyzed alkyne-azide cycloaddition provides 1,4-disubstituted 1,2,3-triazoles with such efficiency and scope that the transformation has been described as "click" chemistry. An overview of the mechanism of this remarkable reaction is presented as a means to explain the myriad of experimental results, particularly the various methods of catalyst generation, solvent and substrate effects, and choice of base or ligand. Both solution-phase and solid-phase results are comprehensively examined. ((c) Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2006).
ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.
A one-pot synthesis of substituted pyridines via a cascade reaction of 2-azido-2,4-dienoates with alpha-diazocarbonyl compounds and triphenylphosphine is reported. The process involves a Staudinger-Meyer reaction, a Wolff rearrangement, an aza-Wittig reaction, and an electrocyclic ring-closure. The procedure is general and efficient. The substrates are readily available.
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.
The cycloaddition of azides to alkynes is one of the most important synthetic routes to 1H-[1,2,3]-triazoles. Here a novel regiospecific copper(I)-catalyzed 1,3-dipolar cycloaddition of terminal alkynes to azides on solid-phase is reported. Primary, secondary, and tertiary alkyl azides, aryl azides, and an azido sugar were used successfully in the copper(I)-catalyzed cycloaddition producing diversely 1,4-substituted [1,2,3]-triazoles in peptide backbones or side chains. The reaction conditions were fully compatible with solid-phase peptide synthesis on polar supports. The copper(I) catalysis is mild and efficient (>95% conversion and purity in most cases) and furthermore, the X-ray structure of 2-azido-2-methylpropanoic acid has been solved, to yield structural information on the 1,3-dipoles entering the reaction. Novel Fmoc-protected amino azides derived from Fmoc-amino alcohols were prepared by the Mitsunobu reaction.
The acid-catalyzed condensation chemistry of simple amides and aldehydes provides a highly prolific source of diverse reactants for irreversible follow-up reactions. Amide–aldehyde mixtures have been successfully employed in multicomponent syntheses of N-acyl α-amino acids (via palladium-catalyzed amidocarbonylation) and various cyclohexene, cyclohexadiene, and benzene derivatives (via the amide–aldehyde–dienophile (AAD) reaction). Die säurekatalysierte Kondensationschemie von einfachen Amiden und Aldehyden generiert einen reichhaltigen Pool an diversen Reaktanden für irreversible Folgereaktionen. Amid-Aldehyd-Mischungen wurden erfolgreich in Multikomponentenreaktionen zur Synthese von N-Acyl-α-aminosäuren (Palladiumkatalysierte Amidocarbonylierung) sowie vielfältiger Cyclohexen-, Cyclohexadien- und Benzol-Derivate (Amid-Aldehyd-Dienophil-Reaktion, AAD) eingesetzt.
Click chemistry is a modular approach that uses only the most practical and reliable chemical transformations. Its applications are increasingly found in all aspects of drug discovery, ranging from lead finding through combinatorial chemistry and target-templated in situ chemistry, to proteomics and DNA research, using bioconjugation reactions. The copper-(I)-catalyzed 1,2,3-triazole formation from azides and terminal acetylenes is a particularly powerful linking reaction, due to its high degree of dependability, complete specificity, and the bio-compatibility of the reactants. The triazole products are more than just passive linkers; they readily associate with biological targets, through hydrogen bonding and dipole interactions.
The inter- and intramolecular addition of free radicals onto ketenimines is studied. All the attempts to add intermolecularly several silicon, oxygen or carbon centered radicals to N-(4-methylphenyl)-C,C-diphenyl ketenimine were unsuccessful. In contrast, the intramolecular addition of benzylic radicals, generated from xanthates, onto the central carbon of a ketenimine function with its N atom linked to the ortho position of the aromatic ring occurred under a variety of reaction conditions. These intramolecular cyclizations provide a novel radical-mediated synthesis of 2-alkylindoles.
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.
Asymmetric multicomponent reactions involve the preparation of chiral compounds by the reaction of three or more reagents added simultaneously. This kind of addition and reaction has some advantages over classic divergent reaction strategies, such as lower costs, time, and energy, as well as environmentally friendlier aspects. All these advantages, together with the high level of stereoselectivity attained in some of these reactions, will force chemists in industry as in academia to adopt this new strategy of synthesis, or at least to consider it as a viable option. The positive aspects as well as the drawbacks of this strategy are discussed in this Review.
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.
[reaction: see text] N-[2-(Alkyl- or arylthio)carbonyl]phenyl ketenimines undergo cyclization under mild thermal conditions to afford 2-alkyl(aryl)thio-3H-quinolin-4-ones by means of the 1,5-migration of the alkyl(aryl)thio group from the carbonyl carbon to the central carbon atom of the ketenimine fragment followed by the 6pi-electrocyclization of the resulting vinyliminoketene. These 1,5-migration and electrocyclization processes occur via transition states whose pseudopericyclic characteristics have been established on the basis of their magnetic properties, geometries, and NBO analyses.
It is shown for the first time that N-sulfonyl amides can be efficiently prepared by an unconventional approach of the hydrative reaction between terminal alkynes, sulfonyl azides, and water in the presence of copper catalyst and amine base under very mild conditions. The present route is quite general, and a wide range of alkynes and sulfonyl azides are readily coupled catalytically with water to furnish amides in high yields. A variety of labile functional groups are tolerated under the conditions, and the reaction is regioselective in that only terminal alkynes react while double or internal triple bonds are intact. The reaction can be readily scaled up and is also adaptable to a solid-phase procedure with high efficiency.
[reaction: see text] It is shown that N-sulfonylimidates can be efficiently prepared by a three-component coupling of terminal alkynes, sulfonyl azides, and alcohols with use of a copper catalyst and an amine base. The reaction is characterized by mild conditions, high selectivity, and tolerance with various functional groups. Facile transformation of imidates to amidines was also achieved by sodium cyanide. Additionally, a protocol for the extremely efficient Pd-catalyzed [3,3]-sigmatropic rearrangement of allylic sulfonimidates to N-allylic sulfonamides has been developed.
ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.
ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.
A variety of substituted iminocoumarins are prepared in good to excellent yields via a copper-catalyzed multicomponenet reaction of sulfonyl azides, terminal alkynes, and salicylaldehydes or o-hydroxylacetophenones. The method is general, mild, versatile, and efficient. A plausible mechanism for the domino process is proposed.
N-(2-X-Carbonyl)phenyl ketenimines undergo, under mild thermal conditions, [1,5]-migration of the X group from the carbonyl carbon to the electron-deficient central carbon atom of the ketenimine fragment, followed by a 6pi-electrocyclic ring closure of the resulting ketene to provide 2-X-substituted quinolin-4(3H)-ones in a sequential one-pot manner. The X groups tested are electron-donor groups, such as alkylthio, arylthio, arylseleno, aryloxy, and amino. When involving alkylthio, arylthio, and arylseleno groups, the complete transformation takes place in refluxing toluene, whereas for aryloxy and amino groups the starting ketenimines must be heated at 230 degrees C in a sealed tube in the absence of solvent. The mechanism for the conversion of these ketenimines into quinolin-4(3H)-ones has been studied by ab initio and DFT calculations, using as model compounds N-(2-X-carbonyl)vinyl ketenimines bearing different X groups (X = F, Cl, OH, SH, NH(2), and PH(2)) converting into 4(3H)-pyridones. This computational study afforded two general reaction pathways for the first step of the sequence, the [1,5]-X shift, depending on the nature of X. When X is F, Cl, OH, or SH, the migration occurs in a concerted mode, whereas when X is NH(2) or PH(2), it involves a two-step sequence. The order of migratory aptitudes of the X substituents at the acyl group is predicted to be PH(2) > Cl > SH > NH(2) > F> OH. The second step of the full transformation, the 6pi-electrocyclic ring closure, is calculated to be concerted and with low energy barriers in all the cases. We have included in the calculations an alternative mode of cyclization of the N-(2-X-carbonyl)vinyl ketenimines, the 6pi-electrocyclic ring closure leading to 1,3-oxazines that involves its 1-oxo-5-aza-1,3,5-hexatrienic system. Additionally, the pseudopericyclic topology of the transition states for some of the [1,5]-X migrations (X = F, Cl, OH, SH), for the 6pi-electrocyclization of the ketene intermediates to the 4(3H)-pyridones, and for the 6pi-electrocyclization of the starting ketenimines into 1,3-oxazines could be established on the basis of their geometries, natural bond orbital analyses, and magnetic properties. The calculations predict that the 4(3H)-pyridones are the thermodynamically controlled products and that the 1,3-oxazines should be the kinetically controlled ones.
2-monosubstituted 1,3-dioxolanes and dithiolanes act as hydride-releasing fragments, transferring intramolecularly their acetalic H atom to the central carbon of ketenimine functions. The presumed products of these migrations, o-quinomethanimines, undergo in situ 6pi-electrocyclization. A computational study supports this mechanism and the hydride-shift character of the first step. Carbodiimides were also suitable substrates, although less reactive. [reaction: see text].
Multicomponent reactions (MCRs) designated as ABB' are defined as those reactions that introduce into the final product one molecule of component A and two molecules of component B in a chemo-differentiating manner. This ability to discriminate the incorporation of component B ensures that these processes maintain the advantages of using multicomponent reactions in diversity-oriented molecular construction. Furthermore, they benefit from the fact that only two reagents need to be mixed together. Component B can be therefore considered to be a privileged building block, and the reactions in which it participates, chemo-differentiating multicomponent reactions. Among the reduced set of compounds capable of acting as such building blocks, we discuss the use of ketenes, terminal conjugated alkynoates, enolisable carbonyl compounds, cyclic enol ethers and cyclic enamines.
[reaction: see text] Under very mild conditions, functionalized 2-(sulfonylimino)-4-(alkylimino)azetidine derivatives were prepared in good to excellent yields via a copper-catalyzed multicomponent reaction of readily available terminal alkynes, sulfonyl azides, and carbodiimides without the assistance of a base. The mechanism may be through a [2 + 2] cycloaddition.
ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.
Bis(ketenimines), in which the two heterocumulenic functions are placed in close proximity on a carbon skeleton to allow their mutual interaction, show a rich and not easily predictable chemistry. Intramolecular [2 + 2] or [4 + 2] cycloadditions are, respectively, observed when both ketenimine functions are supported on either ortho-benzylic or 2,2'-biphenylenic scaffolds. In addition, nitrogen-to-carbon [1,3] and [1,5] shifts of arylmethyl groups in N-arylmethyl-C,C-diphenyl ketenimines are also disclosed.
Phosphoryl azide was successfully employed as an efficient reacting partner in the Cu-catalyzed three-component reaction with 1-alkynes and amines to produce the corresponding phosphoryl amidines in high yields. A range of fruitful applicability of the produced amidines was also demonstrated such as an alkoxide exchange and asymmetric alpha-alkylation of optically active BINOL-derived amidines.
The synthesis of a novel class of 2-imino-5-arylidene-3-pyrrolines via a copper-catalyzed multicomponent reaction of sulfonyl azides with alkynes and aziridines is described. The protocol is efficient and general.
Copper-catalyzed multicomponent reactions with sugar alkynes, sulfonyl azides, and amines to furnish glycosylated N-sulfonylamidines are reported. The reaction is established to be general in terms of different combinations of sugar alkyne, sulfonyl azide, and amines.
(Chemical Equation Presented) Making rings: A new Cu-catalyzed three-component coupling reaction between 1-alkynes, sulfonyl azides, and pyrrole derivatives has been developed for making 2-functionalized pyrrole rings (see scheme). This C-C bond formation offers high efficiency and selectivity, mild reaction conditions, and a wide substrate scope.
A one-pot cascade approach to 4-alkylidene-beta-lactams and N, N'-diarylamidines from aryl azides and aryloxyacetyl chlorides has been developed. The chemical outcome of the reaction can be controlled selectively by an appropriate choice of the stoichiometric ratio of different substrates and reagents. The products should find use in pharmaceutical discovery, especially in the development of new antimicrobial agents against multidrug-resistant pathogens.
2-Azido-3-arylacrylates react with alpha-diazocarbonyl compounds and triphenylphosphine to furnish isoquinolines in 60-92% yields. The tandem process involves a Wolff rearrangement, an aza-Wittig reaction, and an electrocyclic ring closure. The procedure is efficient, rapid, and general, and the substrates are readily available.
Combined analyses of experimental and computational studies on the Cu-catalyzed three-component reactions of sulfonyl azides, terminal alkynes and amines, alcohols, or water are described. A range of experimental data including product distribution ratio and trapping of key intermediates support the validity of a common pathway in the reaction of 1-alkynes and two distinct types of azides substituted with sulfonyl and aryl(alkyl) groups. The proposal that bimolecular cycloaddition reactions take place initially between triple bonds and sulfonyl azides to give N-sulfonyl triazolyl copper intermediates was verified by a trapping experiment. The main reason for the different outcome from reactions between sulfonyl and aryl(alkyl) azides is attributed to the lability of the N-sulfonyl triazolyl copper intermediates. These species are readily rearranged to another key intermediate, ketenimine, into which various nucleophiles such as amines, alcohols, or water add to afford the three-component coupled products: amidines, imidates, or amides, respectively. In addition, the proposed mechanistic framework is in good agreement with the obtained kinetics and competition studies. A computational study (B3LYP/LACV3P*+) was also performed confirming the proposed mechanistic pathway that the triazolyl copper intermediate plays as a branching point to dictate the product distribution.