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ChemInform Abstract: Palladium-Catalyzed Synthesis of 4-Aminophthalazin-1(2H)-ones by Isocyanide Insertion.
Abstract
Palladium-catalyzed cross-coupling of a wide range of substituted o-(pseudo)halobenzoates and hydrazines with isocyanide insertion followed by lactamization efficiently affords 4-aminophthalazin-1(2H)-ones that are difficult to obtain regioselectively by classical methods.
... Based on previous work, [93][94] the authors propose a plausible mechanism for a three-component reaction ( Figure 9): Firstly, Pd (0) was generated from the in situ Pd (II) catalyst by oxidizing the CÀ X bond of 2-bromobenzoic acid methyl ester to incorporate Pd (0) to obtain I. Next, polyformaldehyde migration was inserted into the ArÀ Pd bridge to obtain II, and then β- Figure 8. Proposed reaction mechanism. Reproduced with permission. ...
Recently, polyformaldehyde (PFA) has been used as C1 source to synthesize a series of value‐added compounds due to its low price, stability, low level of toxicity and easy operation. Exploiting paraformaldehyde as C1 source, rather than using traditional methylation reagent to develop benign N‐methylation reactions, can be more environment‐friendly and make the chemical industry more sustainable. In this paper, the chemical transformation of polyformaldehyde and a new strategy of methylating polyformaldehyde with amine compound to methylamine compound are reviewed. These methods will provide a reference for researchers to synthesize a large number of methylamine compounds in a short reaction by using paraformaldehyde as a single carbon source.
... The reaction of ortho-(pseudo) halobenzoate 193 with hydrazine and isocyanide under microwave heating for 5 min progressed by isocyanide insertion to the ortho-halogen-carbon bond followed by amine attachment and lactomization to 4-aminophthalzin-1(2H)-ones 194 with the high yield up to 99%. 126 Another palladium-catalyzed reaction of ortho-bromobenzaldehyde with arylhydrazines yielded Narylphthalazinone 195. In the reaction, Mo(CO)6 was employed (avoided use of toxic carbon monoxide), which furnished appreciable yields up to 75% with microwave heating at 140 °C for 60 min (Scheme 55). ...
The dominance of N-Heterocycles' in chemical sciences, especially in drugs and pharmacological agents, makes them fascinating to advance their sustainable chemistry. Besides, the microwave technique enables functioning at higher temperatures beyond the boiling point of the reaction medium to offer adequate chemical transformations, which tend to be hassled with the classical approach. Herein, we have discussed microwave-assisted chemical transformations of paramount N-heterocycles (five- and six-membered) from the past decade. The role of microwave technique and its benefits has been emphasized in terms of reaction time, product yields, neat and clean reaction products, chemo/regio/enantioselectivity, and mild reaction conditions to achieve efficient transformations.
... In addition to aryl bromides, aryl iodides and triflates provided products 4a-f in moderate to good yields after 5 min of microwave irradiation (Scheme 1). 21 In the following year, Beller's group elegantly described the Pd-catalyzed synthesis of phthalazinones 8 via carbonylative coupling of 2-bromobenzaldehyde with methylhydrazine under CO (10 bar) in the presence of DBU (1 mmol). The investigation of different ligands and solvents demonstrated that dppf ligand (2 mol%) and DMSO were the most effective for the carbonylation reaction, providing product 8a in 52% yield. ...
Phthalazinones and their higher congeners are commonly prevalent structural motifs that occur in natural products, bioactive molecules, and pharmaceuticals. In the past few decades, transition-metal-catalyzed reactions have received an overwhelming response from organic chemists as challenging organics and heterocycles could be built with ease. Currently, the synthesis of phthalazinones largely depends on transition-metal catalysis, especially by palladium-catalyzed carbonylation. Further, the dominance of transition-metal catalysts was realized from the phthalazinones viewpoint, as nitrogen and oxygen atoms endowed upon them act as directing groups to facilitate diverse C-H activation/functionalization/annulation reactions. This highlight describes the various synthetic methods used to access phthalazinones and functionalize them by reacting with various coupling partners via chelation assistance strategy involving C(sp2)-H/N-H bond activation in the presence of transition-metal (Rh, Ru, Pd, and Ir) catalysts. The mechanisms of sulfonylation, halogenation, acylmethylation, alkylation, and annulation reactions are discussed.
... In the literature, the number of reported synthetic methods for 4-aminophthalazin-1(2H)-ones is limited to a few examples and they usually involve two main approaches: 1) the application of multicomponent reactions starting from, e.g., the available o-bromobenzoate via palladium-catalyzed isocyanide insertion [32,33] (a method that is limited to tertiary-substituted isocyanides) or 2) the palladium or copper-catalyzed coupling of bromolactams with amines (a method that requires the usually lengthy synthesis of the bromoprecursors) [19,34]. ...
Amino- and polyaminophthalazinones were synthesized by the palladium‐catalyzed amination (alkyl- and arylamines, polyamines) of 4-bromophthalazinones in good yields. The coordinating properties of selected aminophthalazinones towards Cu(II) ions were investigated and the participation of the nitrogen atoms in the complexation of the metal ion was shown. A biological screening of the potential cytotoxicity of selected synthesized compounds on HT-29 and PC-3 cell lines, as well as on the L-929 cell line, proved that some amino derivatives of phthalazinone show interesting anticancer activities. The detailed synthesis, spectroscopic data, and biological assays are reported.
... In this regard, many synthetic methods have been introduced, including copper-catalyzed reactions of aryl halides and isocyanides in DMSO (Yavari et al., 2014). A palladiumcatalyzed reaction was developed for amidation of aryl halides (Jiang et al., 2011), as well as the synthesis of 4aminophthalazin-1(2H)-ones in a palladium-catalyzed reaction with isocyanide insertion in a multi-component reaction, which is difficult to achieve via a classical route (Vlaar et al., 2011). Palladium-catalyzed isocyanide insertion was applied to a carboxamidation/hydroamidation reaction to synthesize isoindolin-1-one derivatives (Pathare et al., 2016). ...
A palladium-catalyzed three-component reaction between 5-(2-chloroquinolin-3-yl) oxazoles, isocyanides, and water to yield 3-(oxazol-5-yl)quinoline-2-carboxamides is described. Interestingly, sulfonylation occurred when the same reaction was performed with toluenesulfonylmethyl isocyanide (TosMIC) as an isocyanide source. The reaction with 5-(2-chloroquinolin-3-yl)oxazoles and TosMIC in the presence of Cs2CO3 in DMSO afforded 5-(2-Tosylquinolin-3-yl)oxazoles. In basic media, TosMIC probably decomposed to generate Ts⁻ species, which were replaced with Cl⁻. Tandem oxazole formation with subsequent sulfonylation of 2-chloroquinoline-3-carbaldehydes to form directly 5-(2-tosylquinolin-3-yl)oxazoles was also investigated.
... The replacement of one of the ortho methyl groups on the isocyanide substrate with a chloro or ethyl group was also well tolerated, with the C-H bond of the remaining methyl group reacting selectively to give the desired corresponding indoles 40l and m as single products. The use of an isocyanide substrate bearing only one ortho substituent (i.e., 2,4-dimethylphenyl isocyanide) failed to afford any of the desired product 40n, most likely because of the poor stability of the less hindered isocyanide 93,94) and the flexible conformation of the reaction intermediate. ...
C–H functionalization reactions involve the activation of otherwise unreactive C–H bonds, and represent atom economical methods for the direct transformation of simple substrates to complex molecules. While transition metal-catalyzed C(sp²)–H functionalization reactions are regularly used in synthesis, C(sp³)–H functionalization is rarely applied to the synthesis of complex natural products because of the difficulties associated with controlling selectivity. With this in mind, we focused on the development of new palladium (Pd)(0)-catalyzed C(sp³)–H functionalization reactions for the synthesis of complex molecules, resulting in several new methods capable of solving these problems. We initially developed a concise synthetic method for the facile construction of oxindoles and spirooxindoles via a Pd-catalyzed benzylic C(sp³)–H functionalization reaction. This method was subsequently extended to the synthesis of various heterocycles, including 2-arylindoles, benzocarbazole, indolocarbazole, indoloquinazolinone, and indoloquinazolinedione, as well as the total synthesis of several pyrrolophenanthridine alkaloids without the need for any protecting groups. This method was also successfully applied to the synthesis of the right-hand fragment of benzohopane from tetrahydro-2H-fluorene, which was constructed by a Pd-catalyzed benzylic C(sp³)–H functionalization. In this review, we provide a detailed discussion of our most recent investigations pertaining to Pd(0)-catalyzed benzylic C(sp³)–H functionalization.
... Due to the extraordinary function of isocyanide derivatives, isocyanide-based MCRs are frequently exploited, and some examples of the MCRs using isocyanide as a component have been reported in recent years [8][9][10]. For example, Sagirli and co-workers synthesized polysubstituted cyclopentenes by the reaction between b-nitrostyrene, 2-morpholinoethyl isocyanide and benzylidenemalononitriles in dry tetrahydrofuran (THF) for 36-48 h under catalyst-free condition (depicted in Scheme 1) [11]. ...
In this study, the reaction mechanisms of isocyanide-based three-component synthesis of polysubstituted cyclopentenes have been firstly investigated using density functional theory (OFT). Three possible reaction channels (including channels I, 2, and 3) have been suggested and investigated in detail. For channels 1 and 2, the reaction is initiated by the nucleophilic attack of 2-morpholinoethyl isocyanide (R1) on 2-benzylidenemalononitrile (R2). While for channel 3, the reaction is initiated by the nucleophilic attack of reactant R1 on the reactant (E)-(2-nitrovinyl)benzene (R3). Our calculated results indicate that reaction channel 2 is the most energetically favorable channel. The computational results reveal that channel 2 contains three reaction steps. Firstly, it is the nucleophilic attack on R2 by RI. The second step is the formation of five-membered ring through a [3 + 2] cycloaddition process. The last step is a bimolecular proton transfer process. The 16.21 kcal/mol energy barrier for channel 2 demonstrates that the reaction can occur easily at the room temperature, which is in good agreement with the experiment. Moreover, the substituent effects have been considered by constructing four different model systems based on the experiments. The detailed reaction mechanisms should be helpful for people to understand the reaction at molecular level, and the suggested novel bimolecular proton transfer process provides some valuable insights on rational design of the suitable Bronsted acid/base catalysts for this type of reaction.
Nitrogen based heterocycles bearing trisubstituted alkenes are prodigious and indispensable motifs in pharmaceuticals, clinical candidates and functional materials. Herein, we developed tandem one-pot ruthenium-catalyzed multicomponent reaction to access phthalazinones bearing...
Visible‐light photoredox‐catalyzed metal‐free one‐pot tandem regioselective synthesis of C4‐phosphorylated phthalazin‐1(2H)‐ones from arylhydrazines, 2‐formylbenzoic acids with diarylphosphine oxides is described. This three‐component transformation occurs smoothly under mild conditions, providing regiospecific access to various phosphorylated products in 73–91% yield. The efficacy of the current catalysis arises from the use of organic 1,2,3,5‐tetrakis(carbazol‐9‐yl)‐4,6‐dicyanobenzene (4CzIPN) as the photocatalyst and cheap K2S2O8 as the oxidant.
This chapter is an update to the earlier Science of Synthesis contribution (Section 16.10) concerning the synthesis and reactions of phthalazines. Literature from 2004 to early 2014 has been considered. The major focus since the initial publication involves phthalazine substituent modification rather than the synthesis of phthalazine rings.
Tandem one‐pot regioselective synthesis of C4‐difluoroalkylated phthalazin‐1(2H)‐ones from readily available hydrazines, 2‐formylbenzoic acids and bromodifluoroacetate derivatives under visible‐light photocatalysis is reported. This mild protocol provides straightforward access to various C4‐difluoroalkylated phthalazin‐1(2H)‐ones, and displays broad substrate scope and wide functional group tolerance. Moreover, this process is also suitable for the synthesis of C4‐trifluoromethylated and perfluorobutylated phthalazin‐1(2H)‐ones. The use of fac‐[Ir(ppy)3] photocatalyst and the introduction of an organic base additive are pivotal to catalysis.
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The historical background and chemistry development of pyridazine and its derivatives prior to 2008 have been covered extensively in CHEC-II and CHEC-III. This article covers the recent developments in this realm during the past decade.
A new method for synthesizing phenanthridines by photocyclization has been established. This method does not require inert gas protection, does not require transition metal catalysts and is environmentally friendly, efficient and convenient. It is proposed to use (E)-N,1-diphenylformimines as substrates to synthesize phenanthridine and its derivatives by ultraviolet light, which provides a new synthesis route for further research on the synthesis of phenanthridines by photocyclization. Eight new phenanthridine compounds were synthesized. The confirmation of their structures provides a material basis for further study of their properties and tapping of their potential for applications. The establishment of this method further broadens the synthetic pathways of phenanthridine compounds.
An efficient, ligand-free, and Pd-catalyzed method for the synthesis of imidazoisoindole imine scaffolds with satisfactory yields via C-C and C-N bond formation has been developed. The synthesized scaffolds have unique potential for selective MeOH detection from other solvents, especially EtOH. The appealing features of this transformation are phosphinic ligand-free conditions, the use of a small amount of Pd(OAc)2, and a practical procedure for the synthesis of imidazoisoindole imine scaffolds.
The first palladium-catalyzed, ligand-controlled chemoselective synthesis of imides has been achieved. An orthogonal set of conditions has been developed for multicomponent reaction of various olefin-tethered aryl iodides, isocyanides, and carboxylic acids. Alkylimides ("cyclization on" products) via arylimidation of tethered unactivated alkenes and aryl imides ("cyclization off" products) via direct imidation of aryl iodides were obtained in good to excellent yields with good to excellent selectivity. Computational studies were performed to gain insight into the origin of the high levels of chemoselectivity observed.
The first example of dearomative palladium-catalysed isocyanide insertion reaction has been developed using functionalized isocyanides as the reaction partner of N-(2-bromobenzoyl)indoles. The imidoyl-palladium intermediate generated by tandem indole double bond/isocyanide insertion reactions could be trapped by intramolecular functional groups such as C(sp2)-H bond and alkenes, affording diversified indoline derivatives bearing C3 imine-containing heterocycles. The dearomative aryl/cycloimidoylation of indoles proceed smoothly in good to excellent yields with wide functional group tolerance.
Catalysis Changes the Scenario
Phenyl hydrazine was the first hydrazine derivative prepared by Emil Fisher in 1875 for the characterization of sugars via hydrazones formation. Since then, various chemical applications have been demonstrated for hydrazines such as the synthesis of heterocyclic molecules like Fischer indole synthesis and hydrazone formation, among others. In the recent scenario, the catalytic decomposition of phenyl hydrazines and structurally similar phenylsulfonyl hydrazides has enabled unique reactivity properties and emerged as stable and readily available sources for diverse functionalizations by extruding small fragments like N2, SO2, and H2 gases in situ. Under mild oxidative conditions arylhydrazines leads to aryl radicals via the intermediate formation of instable diazenes. Due to these salient features, arylated hydrazines have gained considerable attention and serve as the building block for various important direct catalytic functionalizations such as Heck-type reactions, conjugate additions, C-H bond arylations, etc. Numerous catalytic methods have been developed utilizing arylated hydrazine; therefore, a focused anthology along with mechanistic insight will help in futuristic developments in direct functionalizations. Herein, we describe a focused compilation on the subject based on recent research in this direction. We have included recent articles (last 10 years) in this specific area describing applications and mechanistic aspects of the catalytic methodologies.
Imidazo[1,2‐a]pyridine is a well‐known scaffold in many marketed drugs, such as Zolpidem, Minodronic acid, Miroprofen and DS‐1 and it also serves as a broadly applied pharmacophore in drug discovery. The scaffold revoked a wave of interest when Groebke, Blackburn and Bienaymé reported independently a new three component reaction resulting in compounds with the imidazo[1,2‐a]‐heterocycles as a core structure. During the course of two decades the Groebke Blackburn Bienaymé (GBB‐3CR) reaction has emerged as a very important multicomponent reaction (MCR), resulting in over a hundred patents and a great number of publications in various fields of interest. Now two compounds derived from GBB‐3CR chemistry received FDA approval. To celebrate the first 20 years of GBB‐chemistry, we present an overview of the chemistry of the GBB‐3CR, including an analysis of each of the three starting material classes, solvents and catalysts. Additionally, a list of patents and their applications and a more in‐depth summary of the biological targets that were addressed, including structural biology analysis, is given.
Herein a simple, catalyst- and solvent-free system for highly atom-economic synthesis of phthalazinones has been developed using phthalaldehydic acid, 2-acyl-benzoic acid and substituted hydrazine as simple substrates. The reaction time was shortened to 20-60 minutes. Structurally diverse phthalaldehydic acids, 2-acyl-benzoic acids and hydrazines were transformed into phthalazinones nearly 100% yield regardless of the aggregate state and electronic nature of the substituents. The transformation was demonstrated to be amenable for scale-up with multiple liquid and solid materials. In addition, isolation and purification of the crude products can be simply done with only crystallization. The heavy metal pollution was also eliminated from the source.
A domino one‐pot strategy for the diversified synthesis of phthalazines, phthalazinones and benzooxazinones, was presented. This strategy proceeds via [Pd]‐catalyzed acylation and nucleophilic cyclocondensation with dinucleophilic reagents. Simple bench‐top aldehydes and nitrogen nucleophiles were utilized, as non‐toxic agents. This process was based on direct coupling with aldehydes, without the assistance of directing group and without activating the carbonyl group. Significantly, the strategy was applied to one‐pot synthesis of PDE‐4 inhibitor.
A highly efficient synthesis of planar chiral pyrido[3,4-b] ferrocenes by a palladium-catalyzed enantioselective isocyanide insertion/desymmetric C(sp²)–H bond activation reaction was developed. Various planar chiral pyridoferrocenes were obtained in high yields with good to excellent enantioselectivity under mild conditions (up to 99% yield, 99% ee), enabled by a unique SPINOL-derived phosphoramidite ligand.
A palladium‐catalyzed isocyanides insertion into 2‐halophenoxy acrylates leading to an unparalleled synthesis of dihydrobenzofurans (DHBs) having two exocyclic double bonds have been achieved. While the iodo substrates gave products having an exocyclic imine bond, its bromo analogue yielded reduced secondary amines as the product. An acid hydrolysis of the exocyclic imine bond in DHBs produces various aurone esters.
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The Hofmann carbylamines reaction is a very attractive route for preparing isocyanides directly from primary amines. However, its environmentally friendly potential is depressed by the use of hazardous chloroform in...
Water was found to be an excellent solvent for the one-pot synthesis of tetrasubstituted pyrrole derivatives under ultrasound involving the standard Knoevenagel condensation followed by the Michael type reaction. A new catalyst free system, excellent atom economy, ultrasound in water medium, short reaction times, good yields (88–93%), and ease of workup make this protocol more attractive and economically viable. The resulting substituted pyrroles are characterized by ¹H and ¹³C NMR, elemental analysis, and mass spectral data.
An unprecedented chemoselective double annulation of α-trifluoromethylated isocyanides with o-acylaryl isocyanides has been developed. This new reaction provides a rapid, efficient, and complete atom-economic strategy for the synthesis of trifluoromethylated oxadiazino[3,2-a]indoles in a single operation from readily available starting materials. Isocyanide insertion into C═O double bonds is disclosed for the first time as indicated by the results of ¹⁸O-labeling experiment. A mechanism for this domino reaction is proposed involving chemoselective heterodimerization of two different isocyanides, followed by indole-2,3-epoxide formation and rearrangement.
A novel and efficient strategy for the synthesis of 2-hydroxy-6-oxocyclohex-1-enecarboxamides through a Rh2(OAc)4-catalyzed direct carboxamidation of cyclic 2-diazo-1,3-diketones has been developed. The method features readily available starting materials, easy scalability,...
An efficient synthesis of N-acyl enamine amides via palladium-catalyzed alkene C–H activation and isocyanide insertion has been developed. The reaction was realized with good regioselectivity through directing-group-assisted alkenyl C(sp2)–H bond carboxamidation under mild conditions. A facile pathway to β-amino amides was achieved via reduction of the synthesized N-acyl enamine amides.
A redox-neutral palladium-catalyzed N-O/C(sp(3))-H functionalization of aryl oximes with isocyanides has been developed. Various pyrrole derivatives were prepared in good to excellent yields through oxime carbamate as a key intermediate and internal oxidant in this process. Furthermore, this transformation also features readily available starting materials, good functional group tolerance, and excellent regioselectivity.
In the presence of a catalytic amount of Pd(OAc)2 and a stoichiometric amount of tert-butylamine, the reaction of propargyl carbonates, isocyanides, and alcohols afforded polysubstituted aminopyrroles in good yields. Using water as a nucleophile instead of alcohol, the same reaction provided 1,4-dihydro-6H-furo[3,4-b]pyrrol-6-imines. A triple isocyanide insertion to the hypothetic (σ-allenyl)palladium(II) intermediate was involved in these ABC3-type multicomponent reactions. The key role of tert-butylamine was accounted for by its reaction with in situ generated carbon dioxide to form the carbamic acid, which in turn served as a nucleophile to trap the nitrilium intermediate.
A palladium-catalyzed multicomponent reaction (MCR) of propargylic carbonates with isocyanides is reported. Remarkably, the orderly insertion of isocyanides affords two types of valuable N-heterocyclic products (Z)-6-imino-4,6-dihydro-1H-furo[3,4-b]pyrrol-2-amines and (E)-5-iminopyrrolones in high yields. Systematic analysis of the reaction conditions indicates that the selectivity of these N-heterocyclic products can be controlled by ligands and temperature.
The synthesis of a series of new alkylsulfanyl phthalazinone and phthalazine derivatives is described. The target compounds were efficiently synthesized in a four step sequence, consisting of (1) cyclization of 2-formylbenzoic acid with hydrazine hydrate to form phthalazinone, (2) the direct bromination of phthalazinone core with KBr3, (3) alkylation of the obtained 4-bromolactam (Mitsunobu procedure) to make N- and also O-alkyl derivatives and finally (4) palladium-catalyzed coupling reactions of 2-alkyl-4-bromophthalazinone and 1-alkyloxy-4-bromophthalazine derivatives with aliphatic mercaptanes. Furthermore, the synthesis of 2-methyl-8-(propan-2-yl)sulfanyl-pyrido[3,4-d]pyridazin-1(2H)-one from 2-methyl-pyrido[3,4-d]pyridazin-1(2H)-one via bromination reaction with KBr3 and subsequent sulfanylation by isopropyl mercaptan under catalyzed coupling reaction conditions is also described.
Kinetic, spectroscopic and computational studies examining a palladium-catalyzed imidoylative coupling highlight the dual role of isocyanides as both substrates and ligands for this class of transformations. The synthesis of secondary amides from aryl halides and water is presented as a case study. The kinetics of the oxidative addition of ArI with RNC-ligated Pd(0) species have been studied and the resulting imidoyl complex [(ArC=NR)Pd(CNR)2 I] (Ar=4-F-C6 H4 , R=tBu) has been isolated and characterized by X-ray diffraction. The unprecedented ability of this RNC-ligated imidoyl-Pd complex to undergo reductive elimination at room temperature to give the amide in the presence of water and an F(-) /HF buffer is demonstrated. Its behavior in solution has also been characterized, revealing an unexpected strong tendency to give cationic complexes, and notably [(ArC=NR)Pd(CNR)3 ](+) with excess isocyanide and [(ArC=NR)Pd(PP^ )(CNR)](+) with bidentate phosphines (PP^ ). These species may be responsible for catalyst deactivation and side-reactions. Ab initio calculations performed at the DFT level allowed us to rationalize the multiple roles of RNC in the different steps of the catalytic cycle.
An unusual oxidative coupling reaction of isocyanide and toluene derivatives using tetrabutylammonium iodide (TBAI) as a catalyst is disclosed. The experimental results and mechanistic study show that the isocyano group acts formally as an N1 synthon during the transformation, thus expanding the reactivity profile of isocyanide.
Efficient access to five- to seven-membered cyclic ketoimines, through palladium-catalyzed intramolecular imidoylative Heck reaction of alkene-containing isocyanides, has been developed. Consecutive isocyanide and alkene insertion into aryl or alkyl Pd(II) intermediates takes place in this process. No byproduct derived from monoinsertion or reversed sequence is detected.
Katrin Groebke, Christopher Blackburn, and Hugues Bienaymd have individually reported a three-component-reaction (3CR) among 2-aminopyridine, aldehyde, and isocyanide to afford imid-azo[1,2-a]pyridine in 1998. This multicomponent reaction was so-called as Groebke-Blackburn-Bienaymd reaction (abbreviated as Groebke 3CR). The Groebke 3CR led to a convenient way for accessing to a great abroad of imidazo[1,2-a]-contained N-heterocycles, which were believed to be anticancer, antibacterial, and antimalarial drugs or to be inhibitors for epoxide hydrolase, 5-lipoxygenase, and non-nucleoside reverse transcriptase, etc. The potent applications of the imidazo[1,2-a]-contained N-heterocycles triggered the research enthusiasm on the Groebke 3CR, including the expanding of the substrates, the changing of the substrates, and the exploring of the catalytic process. In particular, other substrates instead of 2-aminopyridine were employed in the Groebke 3CR, leading to the formation of different N-heterocycles for screening pharmacological activities. Taken collectively, more details of the Groebke 3CR should be revealed in the following researches in order to produce much more N-polyheterocyclic candidates for finding novel drugs.
The rhodium-catalyzed cycloisomerization reaction of 2-alkynyl-N'-arylidenebenzohydrazides is reported. The reaction provides 4-alkenylphthalazin-1(2H)-ones through an intramolecular exo-carboamination.
A valuable palladium-catalyzed three-component coupling reaction for the synthesis of amidines has been developed. Using arylboronic acids, isocyanides and anilines as the reactants under oxidative conditions, various amidines were isolated in good yields with good functional group tolerances.
A novel strategy to furnish selective double insertion of isocyanides with the aid of potassium tetrachloroaurate(III) has been disclosed. This strategy provides quick access to approach a complex polycyclic skeleton in an efficient manner. Unexpected oxygen migration was also observed when the reaction was conducted at a lower temperature.
Multicomponent reactions (MCRs) are increasingly appreciated as efficient synthesis tools to rapidly access complex products. Syntheses involving MCRs save time and energy (step efficiency) and proceed with high convergence (process efficiency). In addition, MCRs are ideally suited for combinatorial chemistry and library design, and are of great utility in medicinal chemistry, materials science, recognition (host–guest) chemistry, and catalyst design. Especially, MCRs are believed to be crucial in exploiting the full potential of “diversity-oriented synthesis” (DOS) and “biology-oriented synthesis” (BIOS) design strategies for effective and functional library synthesis uncovering virgin areas of biologically relevant chemical space. This chapter describes the ways to discover new MCRs. It first discusses a couple of design strategies, after that it touches on some recent developments including application of biocatalysis and green chemistry principles.
A novel Cu-mediated rearrangement reaction based on bisamides containing a thiazolidine substructure opens the possibility for diastereoselective synthesis toward a tricyclic annulated and bridged heterocyclic system. The required precursors are easily synthesizable by a two-step synthetic pathway using the concept of sequential multicomponent reactions, i.e. the Asinger and Ugi reactions. Due to this synthesis strategy, a number of unique tricyclic heterocycles, characterized by high diversity, are synthesized in an effective manner.
Transition-metal-mediated multicomponent reactions constitute an intensive area of research directed toward the development of new single-step methodologies for the preparation of relevant or complex molecules. In this Chapter, we present an overview of recent literature regarding this topic with the aim of illustrating progress in a large variety of catalyzed multicomponent reactions since 2005.
A novel and robust route for the synthesis of diversely substituted isoindoline skeletons through a ligand-free Pd-catalyzed cascade consisting of isocyanide insertion into Ugi-tetrazole has been developed. The tetrazole precursor is prepared in one step by the Ugi-four component reaction. The reaction proceeds smoothly under mild conditions with high efficiency. This chemistry is simple, economical, and is believed to be the key step during the synthesis of significant pharmaceuticals.
An unusual multiple isocyanide insertion reaction with methyleneindolinone using indium(III) chloride as the catalyst has been disclosed. This strategy allows for the rapid construction of structurally complex spirooxindole in an efficient manner. The present protocol features mild conditions, atom economy, and broad substrate scope.
A novel and efficient method for the construction of pyrazolo[5,1-a]isoindole scaffold via a one-pot three-component cascade reaction of 1-(2-bromophenyl)buta-2,3-dien- 1-one with hydrazine and isocyanide promoted by Pd catalyst is described. This cascade process proceeds through an initial condensation of allenic ketone with hydrazine followed by a Pd-catalyzed C-Br bond isocyanide insertion and an intramolecular C-N bond formation. Interestingly, when acetohydrazide was used in place of hydrazine, a more sophisticated procedure involving condensation, C-H and C-Br bonds isocyanide insertion, deacetylation, as well as C-C, C-O, and C-N bonds formation occurred to afford pyrazolo[5,1-a]isoindole-3-carboxamides with good efficiency.
A practical method for a convenient access to isonitriles by using inexpensive and readily available reagents of low toxicity is presented.
The combination of Co(acac)2 and AgOTf enables the bimetallic relay catalysis reaction of 2-ethynylanilines and isocyanides, allowing an easy and low-cost access to deliver new densely functionalized pyrrolo[2,3-b]indoles. The reaction pathway involves a Co(acac)2-catalyzed double isocyanide insertion and a followed silver-enabled 1,3-dipolar cycloaddition. The synthetic utility of these bicycloaddtion reactions results in subsequent C−C and C−N bond-forming events to rapidly build up molecular complexity.
A palladium-catalyzed isocyanide insertion-cyclization using low-cost and readily accessible 2-haloanilines, 2-iodophenylethanones, and isocyanides for efficient synthesis of 3-iminoindol-2-amine and cyclic enaminone derivatives has been developed. The method features low-cost and readily accessible starting materials, reliable scalability, and bond-forming efficiency as well as simple one-pot operation, which makes this strategy highly attractive. Reasonable mechanism for forming 3-iminoindol-2-amine involved double isocyanide insertion/cyclization process is proposed.
A novel and efficient palladium-catalyzed strategy via tert-butyl isocyanide insertion from N-(2-bromophenyl)benzamides has been developed. Treatment of the same imine intermediates with FeCl3 gives 4H-benzo[d][1,3]oxazin-4-ones, whereas with AlCl3 delivers N-(2-cyanophenyl)benzamides.
Multicomponent reactions (MCRs) are fundamentally different from two-component reactions in several aspects. Among the MCRs, those with isocyanides have developed into popular organic-chemical reactions in the pharmaceutical industry for the preparation of compound libraries of low-molecular druglike compounds. With a small set of starting materials, very large libraries can be built up within a short time, which can then be used for research on medicinal substances. Due to the intensive research of the last few years, many new backbone types have become accessible. MCRs are also increasingly being employed in the total synthesis of natural products. MCRs and especially MCRs with isocyanides offer many opportunities to attain new reactions and basic structures. However, this requires that the chemist learns the “language” of MCRs, something that this review wishes to stimulate.
Palladium catalyzed reactions of ternary systems involving bromobenzene, t-butyl isocyanide, and organotin compounds were found to occur giving the corresponding imines, although the catalytic efficiencies were rather low.
A novel three-component, one-pot condensation yielding 3-amino-substituted imidazo[1,2-a]pyridines, imidazo[1,2-a]pyrazines and imidazo[1,2-a]pyrimidines from aldehydes, isonitriles and 2-amino-pyridine, 2-amino-pyrazine or 2-amino-pyrimidine is described.
Palladium-catalysed coupling between aryl- or heteroaryl-bromides, alkoxides, aryloxides or thioalkoxides, and isocyanides gives aryl-imidates and -thioimidates in high yield. Amidines can be synthesised in a one-pot procedure via imidates.
A three-component condensation reaction between 2-aminopyridine, an aldehyde and an isonitrile catalyzed by scandium triflate affords derivatives of 3-aminoimidazo[1,2-a]pyridine; aminopyrazine reacts similarly. A library of heterocycles, prepared in high yield by parallel synthesis and purification on an ion-exchange resin, was subjected to further reactions at the amino group.
D-ring substituted 5-methyl-5H-indolo[2,3-c]quinolines (4) have been synthesized in three steps starting from commercially available 3-bromoquinoline (5) and 2-bromoanilines (6). The methodology consists of two consecutive palladium-catalyzed reactions: a selective Buchwald–Hartwig amination followed by a regioselective intramolecular Heck-type reaction. The latter step has been investigated under microwave irradiation. Heating at 180°C allows to seriously reduce the catalyst loading and get a full conversion to reaction product in 10min. In addition, the former simplifies the purification.
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Palladium-catalysed three component coupling of an alkenylbromide, isonitrile and an amine or alkoxide/phenoxide affords α,β-unsaturated-amidines and -imidates.
The three-component condensation between a 2-aminoazine, an aldehyde and an isonitrile catalyzed by scandium triflate was conducted on a solid support with any of the three reacting functional groups tethered to Rink amide resin via an appropriate bifunctional carboxylic acid. The resulting resin-bound 3-aminoimidaz[1,2-a]azines could be efficiently acylated prior to cleavage.
When general and reliable, multicomponent reactions are among the most powerful tools in modern drug discovery. The principle of chemical ligation of reactive partners (see reaction scheme) has been employed to find a new, highly efficient synthesis of fused 3-aminoimidazoles.
The importance of palladium-catalyzed cross coupling reactions in contemporary organic synthesis is undisputed and underlined by the Nobel Prize for Chemistry in 2010. In addition to the highly efficient cross coupling reactions for single CC bond construction, palladium-catalyzed cascade processes involving multiple bond formations have emerged in recent years as valuable tools for the rapid synthesis of complex molecular scaffolds. This review presents an overview of the most relevant developments in this field, with a focus on the generation of diverse poly- and heterocyclic scaffolds. The generally well understood reactivity of palladium has allowed the discovery of many intriguing novel cascade processes, and the creativity of the synthetic community will undoubtedly lead to many more discoveries in the future.
Compared with the widespread use of carbonylative Pd-catalyzed cross-coupling reactions, similar reactions involving isocyanide insertion are almost virgin territory. We investigated the intramolecular imidoylative cross-coupling of N-(2-bromoaryl)amidines, leading to 4-aminoquinazolines. After thorough optimization of the reaction with respect to palladium source and loading, ligand, base, temperature, and solvent, a small library of 4-aminoquinazolines was prepared to determine the scope of this method. Various substituents are tolerated on the amidine and the isocyanide, providing efficient access to a broad range of diversely substituted 4-aminoquinazolines of significant pharmaceutical interest.
An efficient method for the synthesis of 4-amino-2-aryl(alkyl)quinazolines from readily available N-arylamidines and isonitriles via palladium-catalyzed intramolecular aryl C-H amidination by isonitrile insertion has been developed.
Multicomponent reactions have become increasingly popular as tools for the rapid generation of small-molecule libraries. However, to ensure sufficient molecular diversity and complexity, there is a continuous need for novel reactions. Although serendipity has always played an important role in the discovery of novel (multicomponent) reactions, rational design strategies have become much more important over the past decade. In this Review, we present an overview of general strategies that allow the design of novel multicomponent reactions. The challenges and opportunities for the future will be discussed.
Umzingelt: Peptidamphiphile und entgegengesetzt geladene Polymere aggregieren unter Bildung hoch organisierter Membranen (siehe Bild) an der Grenzfläche zweier wässriger Lösungen. Tropfen einer Biopolymerlösung, die mithilfe einer Zerstäubungstechnik in eine Lösung des Peptidamphiphils geprüht werden, wirken als Templat beim Aufbau der Mikrokapseln. Diese enthalten die Biopolymerlösung in ihrem Inneren und tragen Nanofasern an ihrer Oberfläche.
Following a molecular simplification approach, we have identified the 2-phenylphthalazin-1(2H)-one (PHTZ) ring system as a new decorable core skeleton for the design of novel hA(3) adenosine receptor (AR) antagonists. Interest for this new series was driven by the structural similarity between the PHTZ skeleton and both the 2-aryl-1,2,4-triazolo[4,3-a]quinoxalin-1-one (TQX) and the 4-carboxamido-quinazoline (QZ) scaffolds extensively investigated in our previously reported studies. Our attention was focused at position 4 of the phthalazine nucleus where different amido and ureido moieties were introduced (compounds 2-20). Some of the new PHTZ compounds showed high hA(3) AR affinity and selectivity, the 2,5-dimethoxyphenylphthalazin-1(2H)-one 18 being the most potent and selective hA(3) AR antagonist among this series (K(i) = 0.776 nM; hA(1)/hA(3) and hA(2A)/hA(3) > 12000). Molecular docking studies on the PHTZ derivatives revealed for these compounds a binding mode similar to that of the previously reported TQX and QZ series, as was expected from the simplification approach.
1,2,3-Benzotriazin-4(3H)-ones and 1,2,3,4-benzothiatriazine 1,1(2H)-dioxide reacted with isocyanides in the presence of a palladium catalyst to give 3-(imino)isoindolin-1-ones and 3-(imino)thiaisoindoline 1,1-dioxides, respectively, in high yield. An intermediate azapalladacycle was generated through denitrogenation of the triazine moiety, and an isocyanide was incorporated therein.
A new and efficient method for the synthesis of amides via palladium-catalyzed C-C coupling of aryl halides with isocyanides is reported, by which a series of amides were formed from readily available starting materials under mild conditions. This transformation could extend its use to the synthesis of natural products and significant pharmaceuticals.
The inhibition of Aurora kinases in order to arrest mitosis and subsequently inhibit tumor growth via apoptosis of proliferating cells has generated significant discussion within the literature. We report a novel class of Aurora kinase inhibitors based upon a phthalazinone pyrazole scaffold. The development of the phthalazinone template resulted in a potent Aurora-A selective series of compounds (typically >1000-fold selectivity over Aurora-B) that display good pharmacological profiles with significantly improved oral bioavailability compared to the well studied Aurora inhibitor VX-680.
In the very first book on this hot topic, the expert editors and authors present a comprehensive overview of these elegant reactions. From the contents: Organoboron compounds. Free-radical mediated multicomponent coupling reactions. Applications in drug discovery. Metal catalyzed reactions. Total synthesis of natural products. Asymmetric isocyanide-based reactions. The Biginelli reaction. Asymmetric isocyanide-based reactions. The Domino-Knoevenagel-Hetero-Diels-Alder Reaction and related transformations. Catalytic asymmetric reactions. Algorithm based methods for discovering novel reactions. Post-condensation modifications of the Passerini and Ugi reactions. An essential reference for organic and catalytic chemists, and those working in organometallics both in academia and industry.
Optimized reaction conditions are developed.
With the development of a novel microwave-assisted one-pot tandem de-tert-butylation of tert-butyl amine in an Ugi-type multicomponent reaction product, tert-butyl isocyanide as a useful convertible isonitrile has been explored for the first time affording access to molecular diversity of pharmaceutically-important polycyclic N-fused imidazo-heterocycles.
To demonstrate the utility of isocyanides in catalytic C-H bond functionalization reactions, a palladium-catalyzed cyclocoupling reaction of 2-halobiaryls with isocyanides was developed. The reaction afforded an array of fluorenone imine derivatives via the cleavage of a C-H bond at the 2'-position of 2-halobiaryls. The use of 2,6-disubstituted phenyl isocyanide was crucial for this catalytic cyclocoupling reaction to proceed. The reaction was applicable to heterocyclic and vinylic substrates, allowing the construction of a wide range of ring system. The large kinetic isotope effect observed (k(H)/k(D) = 5.3) indicates that C-H bond activation was the turnover-limiting step in this catalysis.
A CO group richer : (Hetero)arenes are vital intermediates in the manufacture of agrochemicals, dyes, pharmaceuticals, and other industrial products. In the past decades transition‐metal‐catalyzed coupling reactions of aryl halides with all types of nucleophiles have been developed. This Review summarizes recent work in the area of palladium‐catalyzed carbonylation reactions of aryl halides and related compounds (see scheme). magnified image
Palladium‐catalyzed carbonylation reactions of aromatic halides in the presence of various nucleophiles have undergone rapid development since the pioneering work of Heck and co‐workers in 1974, such that nowadays a plethora of palladium catalysts are available for different carbonylative transformations. The carboxylic acid derivatives, aldehydes, and ketones prepared in this way are important intermediates in the manufacture of dyes, pharmaceuticals, agrochemicals, and other industrial products. In this Review, the recent academic developments in this area and the first industrial processes are summarized.
With the recent emergence of combinatorial chemistry and high-speed parallel synthesis for drug discovery applications, the multi-component reaction (MCR) has seen a resurgence of interest. Easily automated one-pot reactions, such as the Ugi and Passerini reactions, are powerful tools for producing diverse arrays of compounds, often in one step and high yield. Despite this synthetic potential, the Ugi reaction is limited by producing products that are flexible and peptide-like, often being classified as 'non drug-like'. This review details developments of new, highly atom-economic MCR derived chemical methods, which enable the fast and efficient production of chemical libraries comprised of a variety of biologically relevant templates. Representative examples will also be given demonstrating the successful impact of MCR combinatorial methods at different stages of the lead discovery, lead optimization and pre-clinical process development arenas. This will include applications spanning biological tools, natural products and natural product-like diversity, traditional small molecule and 'biotech' therapeutics respectively. In particular, this review will focus on applications of isocyanide based MCR (IMCR) reactions.
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The licensing of bevacizumab in patients with metastatic colorectal cancer has fueled research in angiogenesis. Vatalanib (PTK787/ZK 222584), a potent oral tyrosine kinase inhibitor with a selective range of molecular targets, has been extensively investigated and has shown promising results in patients with colorectal cancer in early trials. Dynamic contrast-enhanced MRI has been useful as a pharmacodynamic tool to define the dose that has a biological effect. The primary objectives of the Phase III CONFIRM (Colorectal Oral Novel Therapy for the Inhibition of Angiogenesis and Retarding of Metastases in First-line) studies were not met. However, an interesting pre-planned subset analysis in both studies showed that patients with high lactate dehydrogenase derived clinical benefit. Although this type of analysis should always be considered with caution, the Phase III clinical programme of vatalanib is continuing with further innovative studies looking at other indications and schedules for vatalanib.
This review describes recent advances in the application of isocyanide-based multicomponent reactions (IMCRs) in drug discovery and summarizes the various chemotypes used to probe biological targets. In the past couple of years, IMCR-derived ligands have been used to develop agents against infectious diseases and to interfere with protein-protein interactions. Additionally, they were active against a variety of targets such as enzymes, GPCRs and ion channels. The rational for the chemical biologist to apply such diversity generating chemistries is also discussed.
- Saluste C. G.
- Orru R. V. A.