No full-text available
To read the full-text of this research,
you can request a copy directly from the authors.
ChemInform Abstract: Sustainable Synthesis of Diverse Privileged Heterocycles by Palladium-Catalyzed Aerobic Oxidative Isocyanide Insertion.
Angewandte Chemie International Edition
Abstract
Heterocycles containing a guanidine moiety are of great importance in medicinal chemistry (Scheme 1).[1] As a result, several methods for the synthesis of these "privileged scaffolds" have been reported.[2, 3] Classical approaches, such as the addition of diamines to isothiocyanates followed by condensation and the coupling of diamines with cyanogen bromide,[2, 4] have some clear limitations, such as the availability and toxicity of reagents. Moreover, these procedures suffer from poor atom and/or step efficiency, thus making them unattractive from a sustainability point of view.
... The direct formation of pyrrolo [2,3-β]indoles via catalyzed bicycloaddition reactions is a very attractive yet challenging process. Isocyanides can be inserted either with a Lewis acid [33] or via transition metal catalysis, undoubtedly with palladium as the most popular choice [34][35][36]. In contrast, in 2015, Gao and coworkers explored the preparation of pyrrolo [2,3-β]indoles using an inexpensive Co(II)-enabled process (Scheme 6) [37]. ...
... In 2017, Mu and coworkers reported a new and efficient protocol for the preparation of chlorine-containing 1,2,4-triazolo [1,5-b]pyridazine scaffolds (Scheme 9) [40]. The authors developed a one-pot oxidative cycloaddition reaction of 3-aminopyridazine derivatives (34) and nitriles (35) involving cooperative Cu(I) and Zn(II)-catalyzed tandem C-N Scheme 7. General conditions and a plausible mechanism for the preparation of furo [3,4-β]indoles using a Ag(I)/Bi(III)/Pd(II)-catalyzed trimetallic approach. ...
... In 2017, Mu and coworkers reported a new and efficient protocol for the preparation of chlorine-containing 1,2,4-triazolo [1,5-b]pyridazine scaffolds (Scheme 9) [40]. The authors developed a one-pot oxidative cycloaddition reaction of 3-aminopyridazine derivatives (34) and nitriles (35) involving cooperative Cu(I) and Zn(II)-catalyzed tandem C-N Scheme 8. General conditions and a plausible mechanism for the preparation of 1,3-di-and 1,3,4trisubstituted β-carbolines using a Ag(I)/Bi(III)/Pd(II)-catalyzed trimetallic approach. ...
Bimetallic (or multimetallic) catalysis has emerged as a powerful tool in modern chemical synthesis, offering improved reaction control and versatility. This review focuses on the recent developments in bimetallic sequential catalysis for the synthesis of nitrogen heterocycles, which are essential building blocks in pharmaceuticals and fine chemicals. The cooperative action of two (sometimes more) different metal catalysts enables intricate control over reaction pathways, enhancing the selectivity and efficiency of the synthesis of N-heterocyclic compounds. By activating less reactive substrates, this multimetal catalytic strategy opens new synthetic possibilities for challenging compounds. The use of catalytic materials in bimetallic systems reduces waste and improves atom efficiency, aligning with green chemistry principles. With a diverse range of metal combinations and reaction conditions, bimetallic catalysis provides access to a broad array of N-heterocyclic compounds with various functionalities. This paper highlights the significant progress made in the past decade in this topic, emphasizing the promising potential of bimetallic catalysis in drug discovery and the fine chemical industries.
... 55 This compound was synthesized according to modified literature procedures. 55 56 56 This compound was synthesized according to modified literature procedures. 56 In a 300 mL round-bottom flask under an argon atmosphere, 45 mL 90% H2SO4 ...
... 55 This compound was synthesized according to modified literature procedures. 55 56 56 This compound was synthesized according to modified literature procedures. 56 In a 300 mL round-bottom flask under an argon atmosphere, 45 mL 90% H2SO4 ...
... 55 56 56 This compound was synthesized according to modified literature procedures. 56 In a 300 mL round-bottom flask under an argon atmosphere, 45 mL 90% H2SO4 ...
Organohydrides are an important class of organic compounds that can provide hydride anions for chemical and biochemical reactions, as demonstrated by reduced nicotinamide adenine dinucleotide serving as an important natural redox cofactor. The coupling of hydride transfer from the organohydride to the substrate and subsequent regeneration of the organohydride from its oxidized form can realize organohydride-catalyzed reduction reactions. Depending on the structure of the organohydride, its hydridicity and ease of regeneration vary. Benzimidazoline (BIH) is one of the strongest synthetic C–H hydride donors; however, its reductive regeneration requires highly reducing conditions. In this study, we synthesized various oxidized and reduced forms of BIH derivatives with aryl groups at the 2-position and investigated their photophysical and electrochemical properties. 4-(Dimethylamino)phenyl-substituted BIH exhibited salient red-shifted absorption compared to other synthesized BIH derivatives, and visible-light-driven regeneration without using an external photosensitizer was achieved. This knowledge has significant implications for the future development of solar-energy-based catalytic photoreduction technologies that utilize organohydride regeneration strategies.
... Exploration of catalytic performance 2-Aminobenzoxazole (3a) could be synthesized by Pd(OAc) 2 -catalyzed oxidative cyclization of o-aminophenol (1a) with isocyanide (2a), which was chosen to investigate the catalytic performance of d-MOFs-based Pd catalysts 64,65 . When the reaction was catalyzed by Pd-UiO-67(N) 0 without defects, the corresponding product 3a was obtained in only 33% yield ( Table 1, entry 2). ...
... Additionally, by comparing the binding energies of the three catalysts, the These findings indicate that in the context of d-MOF-catalyzed systems, the efficiency of catalysis is influenced by the electron cloud density surrounding the Pd(II) center. The electron-deficient Pd may facilitate the activation of o-aminophenols and isocyanides, thereby enhancing the catalytic efficiency 64,65 . Furthermore, when tert-butyl isocyanate (3ab) was used instead of tert-butyl isocyanide, a substantial amount of 1a remained, and no 3a was detected, a result that precludes the possibility of an oxidation pathway where isocyanide is converted to isocyanate, followed by a cyclization reaction with 1a (Fig. 6a). ...
Recently, defective sites in MOFs have become an important tool for tuning the catalytic performance of MOFs. Herein, we report a heterogeneous catalyst “Pd-UiO-67(N)x” by utilizing the active site of defective MOF to modulate the electronic state of Pd, which demonstrates excellent catalytic performances in the oxidative cyclization reaction of isocyanides with o-aminophenols benefiting from the electron-deficient nature of the Pd species. When the Pd loading in defective Pd-UiO-67(N)x system was decreased to 0.37 mol %, the catalytic efficiency was significantly enhanced and the Pd turnover number (TON) increased to 232, which was 27 and 2.6 times higher than that of homogeneous Pd catalysts and defect-free Pd-UiO-67(N)0, respectively. The open pore structure of d-MOFs supports the adsorption of o-aminophenols. Additionally, the domain-limiting effect of the framework restricts the aggregation of Pd, resulting in good stability of the Pd species, which without significant loss of its activity in five consecutive reaction cycles. This work provides an insight into the improvement of stereoelectronic properties of organometallic catalysts through defect-engineered MOFs.
... For example, Orru and coworkers demonstrated a palladium-catalyzed aerobic oxidative isocyanide insertion for the synthesis of guanidine-containing heterocycles employing molecular oxygen as oxidant. [18] Ji's group reported Co(acac) 2 /O 2 -mediated oxidative synthesis of 6amino phenanthridine derivatives. [19] Hoover's group reported a cobalt-catalyzed aerobic oxidative cyclization for the synthesis of 2-aminobenzoxazoles and 2-aminobenzimidazoles. ...
... Other solvent including toluene, CHCl 3 , DCE, and THF did not improve the reaction efficiencies (entries [14][15][16][17]. Furthermore, the reaction yield was not increased when screening of other oxidants such as Cu(TFA) 2 , Cu(OAc) 2 , Cu(OTf) 2 , TBHP and K 2 S 2 O 8 (entry [18][19][20][21][22][23]. Finally, temperature and catalyst loading studies revealed that 10 mol% Pd(OAc) 2 and 70°C led to the best results (entries [24][25][26][27]. ...
We describe a highly efficient cyclization of substituted 2‐(1H‐pyrrol‐1‐yl)anilines with isocyanides. Various pyrrolo[1,2‐a]quinoxalines and 4‐aminopyrrolo[1,2‐a]quinoxalines were obtained by Lewis acid (TMSCl) or transition‐metal (palladium) catalyzed isocyanide insertion in good to high yields. The notable feature of this protocol includes its mild reaction condition, diverse products and broad functional group tolerance.
... This reaction was only tried with tert-butyl and cyclohexyl isocyanides, and proceeds rapidly, using air as the (re)oxidant. An equivalent of amine is formed by the known [122] oxidation of isocyanide to isocyanate, and its subsequent hydrolysis, effectively using the isocyanide as a dual reactant. Additionally, an oxidative aminoiminoylation of primary amides 274 affords the substituted Nacylguanidines 275 (Scheme 72) [121]. ...
... This reaction was only tried with tert-butyl and cyclohexyl isocyanides, and proceeds rapidly, using air as the (re)oxidant. An equivalent of amine is formed by the known [122] oxidation of isocyanide to isocyanate, and its subsequent hydrolysis, effectively using the isocyanide as a dual reactant. ...
Isocyanides have long been known as versatile chemical reagents in organic synthesis. Their ambivalent nature also allows them to function as a CO-substitute in palladium-catalyzed cross couplings. Over the past decades, isocyanides have emerged as practical and versatile C1 building blocks, whose inherent N-substitution allows for the rapid incorporation of nitrogeneous fragments in a wide variety of products. Recent developments in palladium catalyzed isocyanide insertion reactions have significantly expanded the scope and applicability of these imidoylative cross-couplings. This review highlights the advances made in this field over the past eight years.
... [120] Among the reported synthetic methodologies, the [3 + 2] cycloaddition between carbodiimides and aziridines is a good approach. [121] However, the reported methods always afforded N 2 -protected cyclic guanidines. To solve this issue, the Chen group reported a new annulation of 2-substituted aziridines and N-tosyl cyanamides to provide N 2 -unprotected cyclic guanidines with good yields (Scheme 79). ...
3+2] Annulations are a powerful method for the synthesis of five‐membered heterocyclic compounds. The annulations have concerted cycloaddition and formal (stepwise) cycloaddition reaction pathways. In addition to the well‐established O‐centered and N‐centered ylides, epoxides and aziridines could serve as synthetic equivalent of 1,3‐dipoles for [3+2] annulation with dipolarophiles for making functionalized tetrahydrofuran, pyrrolidine, and associated compounds. This review article covers recent development on epoxide‐ and aziridine‐based [3+2] annulation reactions. The reactions are classified based on the ring opening conditions, including acid/base catalysis, organocatalysis, and transitional‐metal catalysis.
... The direct formation of pyrrolo[2,3-b]indoles via catalyzed bicycloaddition reactions is a very attractive yet challenging process. Isocyanides happen to be a simple group and, taking advantage of their electrophilicity, can be inserted either by Lewis acid [32], or transition metal catalysis, undoubtedly with palladium as the most popular choice [33][34][35]. In contrast, Gao and co-workers, in 2015, explored the preparation of pyrrolo [2,3-b]indoles by an inexpensive Co(II)-enabled process (Scheme 6) [36]. ...
Bimetallic (or multimetallic) catalysis has emerged as a powerful tool in modern chemical synthesis, offering improved reaction control and versatility. This review focuses on the recent de-velopments in bimetallic sequential catalysis for the synthesis of nitrogen heterocycles, essential building blocks in pharmaceuticals and fine chemicals. The cooperative action of two (and sometimes more) different metal catalysts enables intricate control over reaction pathways, enhancing selectivity and efficiency of N-heterocyclic compounds synthesis. By activating less reactive substrates, this multimetal catalytic strategy opens new synthetic possibilities for challenging compounds. The use of catalytic materials in bimetallic systems reduces waste and improves atom efficiency, aligning with green chemistry principles. With a diverse range of metal combinations and reaction conditions, bimetallic catalysis provides access to a broad array of N-heterocyclic compounds with various functionalities. This paper highlights the significant progress made in the past decade in this topic, emphasizing the promising potential of bimetallic catalysis in drug discovery and the fine chemical industries.
... Such a high homo-insertion reactivity implies that a selective cross-reaction is difficult to control. The current methods are mostly done indirectly by an in situ generated imidoyl-M species (i.e., a two-steps process) 4,8 , either through a 1,1-insertion of isocyanide to the M-R (Type 1: σ-bond insertion, Fig. 1f), such as L n Ni-R and L n Pd-R from an alkene or by a nucleophilic attack on the electrophilic isocyanide for a subsequent an alkene insertion (Type 2: nucleophilic insertion, Fig. 1g) [9][10][11][12][13][14][15][16][17] . There are only handful of examples that can join them together directly. ...
Isocyanides are common compounds in fine and bulk chemical syntheses. However, the direct addition of isocyanide to simple unactivated cyclopropene via transition metal catalysis is challenging. Most of the current approaches focus on 1,1-insertion of isocyanide to M-R or nucleophilc insertion. That is often complicated by the competitive homo-oligomerization reactivity occurring at room temperature, such as isocyanide 1,1-insertion by Ni(II). Here we show a (N-heterocyclic carbene)Ni(II) catalyst that enables cyclopropene-isocyanide [5 + 1] benzannulation. As shown in the broad substrate scope and a [trans-(N-heterocyclic carbene)Ni(isocyanide)Br2] crystal structure, the desired cross-reactivity is cooperatively controlled by the high reactivity of the cyclopropene, the sterically bulky N-heterocyclic carbene, and the strong coordination ability of the isocyanide. This direct addition strategy offers aromatic amine derivatives and complements the Dötz benzannulation and Semmelhack/Wulff 1,4-hydroquinone synthesis. Several sterically bulky, fused, and multi-substituted anilines and unsymmetric functionalized spiro-ring structures are prepared from those easily accessible starting materials expediently. The direct addition of isocyanides to cyclopropenes is challenging. Here, the authors report a catalytic cyclopropene-isocyanide [5 + 1] benzannulation catalyzed by an (N-heterocyclic carbene)Ni(II) complex; this method enables the preparation of fused and multi-substituted anilines and unsymmetrically functionalized spiro-ring structures.
... Ruijter and co-workers studied a novel aerobic oxidative coupling of diamines as bisnucleophiles and isocyanides using palladium catalysis to access to a wide range of guanidinecontaining heterocycles. 299 Aiming to improve on the previously reported multistage synthesis of astemizol, 300 the authors developed a new synthetic route using this novel palladiumcatalyzed oxidation reaction (Scheme 63). ...
Over the last 100-120 years, due to the ever-increasing importance of fluorine-containing compounds in modern technology and daily life, the explosive development of the fluorochemical industry led to an enormous increase of emission of fluoride ions into the biosphere. This made it more and more important to understand the biological activities, metabolism, degradation, and possible environmental hazards of such substances. This comprehensive and critical review focuses on the effects of fluoride ions and organofluorine compounds (mainly pharmaceuticals and agrochemicals) on human health and the environment. To give a better overview, various connected topics are also discussed: reasons and trends of the advance of fluorine-containing pharmaceuticals and agrochemicals, metabolism of fluorinated drugs, withdrawn fluorinated drugs, natural sources of organic and inorganic fluorine compounds in the environment (including the biosphere), sources of fluoride intake, and finally biomarkers of fluoride exposure.
... 11 In this context, the classical four-component Ugi and three-component Passerini reaction have found applications in many fields such as asymmetric synthesis and total synthesis of natural products. [12][13] Furthermore, isocyanide-based insertion reactions [14][15][16][17] and related radical processes have also received considerable attention. [18][19] Recently, investigation on isocyanide-involving C-H functionalizations with tandem cyclization reactions had been employed in the construction of various hetero-and carbocyclic compounds (Scheme 1, eq 1). ...
... [52] This group also proposed a synthesis of diverse heterocycles 41 by palladium-catalyzed aerobic oxidative isocyanide insertion (Scheme 16). [53] 1,4-Benzoxazepines have been further synthesized by Cai et al. via a palladium-catalyzed MCR reaction of N-tosylaziridines, isocyanides, and 2-iodophenols. Ring opening of aziridine moiety followed by a Pd-catalyzed isocyanide insertion with 2-iodophenols affords the desired product in moderate to high yields (Scheme 17). ...
Heterocyclic compounds have a wide range of applications: they are predominant among the type of compounds used as pharmaceuticals, agrochemicals, fine chemicals, electronic components, polymers, and veterinary products. There is a vast scope to develop new heterocyclic compounds considering the high yield, low waste, and green synthesis. In this review, we have described the synthesis of heterocycles via insertion and cyclization which is achieved in recent years with the ideas, challenges, and milestone reactions.
Catalytic systems based on transition metal ions, especially palladium and nickel ions, have gained great interest, due to the variety of their structures, their ability to bind with other molecules and to stabilize active centers to form catalysts.
A novel and concise approach to rare 2,3,5‐triamino‐imidazole scaffolds via Ni‐catalyzed coupling of alkylisocyanides and N,N′‐diarylguanidines has been developed. This reaction features include mild conditions (thermal or visible light activation), a wide substrate scope, and high efficiency. The coupling proceeds through a NiII/NiIV catalytic cycle, involving two‐electron aerobic oxidation and the sequential insertion of two isocyanide units into Ni−N bonds.Testing these compounds against pathogens of the ESKAPE panel showed their high activity with a minimum inhibitory concentration down to 0.38 μg/mL.
Elemental selenium promoted method has been developed for the synthesis 2‐amino benzazoles through cyclization reaction of ortho‐substituted anilines with isocyanides under transition metal or external chemical oxidants free conditions. This protocol offers a mild and efficient approach to construct a variety of 2‐amino benzooxa/(thia)zoles and benzimidazoles in good to excellent yields with favorable functional group tolerance. image
A convenient and straight-forward entry to pyrrole[2,3- b ]indoles and ureas via ligand-controlled palladium-catalyzed chemoselective tandem reaction of 2-ethynylanilines and isocyanides has been established.
A palladium‐catalyzed domino reaction of 2‐azidosulfonamides and isocyanides enables the synthesis of 3‐amino‐substituted 1,2,4‐benzothiadiazine 1,1‐dioxides at room temperature. By applying commercially available Pd(dba)2 in catalyst loadings as low as 1.0 mol%, a variety of 21 differently substituted 2H‐1,2,4‐benzothiadiazine 1,1‐dioxides can be prepared within 2 h. Moreover, the developed protocol gives access to the related 4H heterocycles.
Organohydrides are an important class of organic compounds that can provide hydride anions for chemical and biochemical reactions, as demonstrated by reduced nicotinamide adenine dinucleotides serving as important natural redox cofactors. The coupling of hydride transfer from the organohydride to the substrate and subsequent regeneration of the organohydride from its oxidized form can realize organohydride-catalyzed reduction reactions. Depending on the structure of the organohydride, its hydridicity and ease of regeneration vary. Benzimidazoline (BIH) is one of the strongest synthetic C-H hydride donors; however, its reductive regeneration requires highly reducing conditions. In this study, we synthesized various oxidized and reduced forms of BIH derivatives with aryl groups at the 2-position and investigated their photophysical and electrochemical properties. 4-(Dimethylamino)phenyl-substituted BIH exhibited salient red-shifted absorption compared with other synthesized BIH derivatives, and visible-light-driven regeneration without using an external photosensitizer was achieved. This knowledge has significant implications for the future development of solar-energy-based catalytic photoreduction technologies that utilize organohydride regeneration strategies.
A Pd-catalyzed cyclization reaction of 2-(2-vinylarene)acetonitriles and isocyanides has been documented. Various naphthalen-2-amines were obtained in moderate to good yields under mild conditions. The in vitro cytotoxicity of all products was evaluated by MTT assay against seven human cancer cell lines. The results indicated that compounds 3ea, 3ma, and 3ob exhibited effective anticancer activities against the tested cancer cells.
A variety of 3-amino-substituted benzothiadiazine oxides were synthesised in a single-step by applying a palladium-catalysed cascade reaction of 2-azido sulfoximines with isonitriles. The desired heterocycles were observed in good to...
BACKGROUND
Palladium metal has been extensively used in the synthesis of organic molecules for the last few decades. Heterocyclic ring synthesis being a significant part of organic synthesis, transition metal catalysis, especially catalysis by palladium, has been actively employed in heterocyclic synthesis. However, since palladium is an expensive metal, there has always been an urge to reuse or recycle the palladium catalyst to make the process economically viable. Modern synthetic chemists are also in constant search for newer sustainable strategies for molecular synthesis, which will lead to eco-friendly synthetic protocols. Thus, in the last few years, palladium catalysed green synthesis of heterocycles has gained importance as these aim to make the synthetic organic chemical world slightly more sustainable.
METHODS
This review comprises palladium catalysed synthetic strategies that proceed in a sustainable fashion. A few protocols included here involve either organic solvent-free or greener solvents as reaction medium, which is one of the modes adopted towards sustainability. Other modes of sustainability included in this review are recyclability of the palladium catalyst, one pot tandem reaction strategy, use of air as oxidant, etc. All these modes aim at achieving one or the other green chemistry principles like reduction of waste and by-products, increasing atom economy, reduction of cost and use of safer solvents.
RESULTS
The review aims to reflect the scope of sustainability in palladium catalysed synthesis of heterocycles so that economically and environmentally viable synthetic methodologies may be selectively identified and applied in academia and industries.
CONCLUSION
Keeping the principles of green chemistry in mind, in this review, we aim to compile the recent advancements in palladium catalysed sustainable synthesis of heterocycles in a single platter that may serve as a piece of reliable literature for further research in this area.
By employing a simple strategy of reacting SO 2 gas with easily attainable hydride donors such as 2-substituted-1,3-dimethyl-2,3-dihydro-1H-benzo-[d]imidazole, benzimidazoline and SO 2 were converted into benzimidazolium bisulfate at room temperature and atmospheric pressure. Bisulfate originated from SO 2 and hydride from benzimidazoline and aerial oxygen. Metastable dimers of bisulfate anions were observed in the solid state and in solution where the anions are not stabilized by encapsulation in cages but through hydrogen bonding from benzimidazolium cations. All three benzimidazolines and resulted benzimidazolium bisulfates have been characterized using 1 H and 13 C NMR spectroscopy, high-resolution electrospray ionization mass spectrometry, and single crystal X-ray diffraction techniques.
The reaction media typically constitute the largest part of the reaction mixture. In attempts to develop more sustainable methods for heterocyclic synthesis, bio‐based reaction media are becoming a viable alternative replacing conventional fossil‐derived organic solvents. A variety of bio‐based media produced from renewable sources, often from biomass generated as waste by industries, allow the selection of a medium with specific properties satisfying reaction requirements. This chapter illustrates applications of several relatively more established bio‐based media such as glycerol, lactic acid, γ‐valerolactone, and 2‐methyltetrahydrofuran and emerging bio‐based solvents like Cyrene, limonene, eucalyptol, and p ‐cymene for the synthesis of heterocycles.
o-Phenylene N-substituted iminocarbonates have been obtained by aerobic Ni-catalyzed reaction of readily available catechols and isocyanides. The choice of oxidant and absence of base proved crucial to avoid competitive catechol oxidation into (semi)quinone, leading to degradation. The developed protocol is generally applicable on other oxidation-sensitive aromatic 1,2-bis-nucleophiles, generating a variety of important bicyclic heterocycles from readily available building blocks, hitherto only accessible via aerobic noble metal catalysis. Experimental studies suggest involvement of a Ni(II)-catecholate complex, which has been supported by density functional theory of the catalytic cycle. o-Phenylene N-substituted iminocarbonates demonstrated to be interesting platform molecules providing access to dialkyl N-substituted iminocarbonates, dialkyl N-substituted dithioiminocarbonates, and N,N′,N″-trialkyl guanidines via reaction with respectively alcohols, thiols, and amines. The catechol, which is concomitantly produced as a byproduct in these substitution reactions, can be recycled. When 4-propylcatechol, accessible from pine and clove tree feedstock, is applied, the leaving group is also biorenewable.
A novel and efficient [3+2] annulation of 2-substituted aziridines and N-tosyl cyanamides via domino regioselective ring-opening/5-exo-dig cyclization procedure has been developed, allowing the direct preparation for N2-unprotected five-membered cyclic guanidines...
Charge‐transfer emitters are attractive due to their color tunability and potentially high photoluminescence quantum yields (PLQYs). We herein present tetraaminospirenes as donor moieties, which, in combination with a variety of acceptors, furnished 12 charge‐transfer emitters with a range of emission colors and PLQYs of up to 99 %. The spatial separation of their frontier molecular orbitals was obtained through careful structural design, and two DA structures were confirmed by X‐ray crystallography. A range of photophysical measurements supported by DFT calculations shed light on the optoelectronic properties of this new family of spiro‐NN‐donor‐acceptor dyes.
The possibility to harness aromatic isocyanides as visible-light photocatalysts in the α-amino C(sp³)–H functionalization is herein presented. Actually, the three-component cross-dehydrogenative coupling of aromatic tertiary amines with isocyanides and water leads to amide products under very mild conditions in high yields and with a good substrate scope. While the reaction with aromatic isocyanides proceeds upon direct photoexcitation, aliphatic isocyanides are able to form a photoactive electron–donor–acceptor complex with aromatic amines. Moreover, the use of a catalytic loading of an aromatic isocyanide promotes the oxidative coupling of N-phenyl-1,2,3,4-tetrahydroisoquinoline with an array of different (pro)nucleophiles in good to excellent yields, thus providing the proof-of-concept for the development of a new highly tunable class of organic visible-light photocatalysts.
The 6-membered aza-heterocycles, 1,2,4-oxadiazines and 1,2,4-thiadiazines, are valuable scaffolds due to the vast spectrum of medicinal properties they possess. These scaffolds exist in several drugs or drug-leads such as MK-8428, mS-11, BPDZ44, and IDRA21. These can be classified as 2H-, 4H- or 6H-isomers depending upon the position of double bonds in the ring. The sulfur in thiadiazines exists in different oxidation states, namely, SII, SIV and SVI, of which SVI (1,2,4-benzothiadiazine-1,1-dioxide) is the most common oxidation state. This article discusses various methods such as cycloaddition, rearrangement and CH functionalization for the synthesis of 1,2,4-oxadiazines and 1,2,4-thiadiazines and their biological properties.
N‐heterocycles are key structures for many pharmaceutical intermediates. The synthesis of such units normally is conducted under homogeneous catalytic conditions. Among all methods, aerobic oxidative aromatization is one of the most effective. However, in homogeneous conditions, catalysts are difficult to be recycled. Herein, we report a heterogeneous catalytic strategy with a mesoporous cobalt oxide as catalyst. The developed protocol shows a broad applicability for the synthesis of N‐heterocycles (32 examples, up to 99 % yield), and the catalyst presents high turnover numbers (7.41) in the absence of any additives. Such a heterogenous approach can be easily scaled up. Furthermore, the catalyst can be recycled by simply filtration and be reused for at least six times without obvious deactivation. Comparative studies reveal that the high surface area of mesoporous cobalt oxide plays an important role on the catalytic reactivity. The outstanding recycling capacity makes the catalyst industrially practical and sustainable for the synthesis of diverse N‐heterocycles.
Palladium-catalyzed aerobic oxidative cyclizations of substituted 2-(1H-pyrrol-1-yl)phenols with isocyanides via O-H/C-H insertion cascade have been developed. This strategy provides a facile access to pyrrolo[2,1-c][1,4]benzoxazine derivatives in good to excellent yields...
Isocyanide is well known for its multi-component reactions (MCR), such as Passerini reaction and Ugi reaction, with diverse molecular skeletons, high functional group compatibility, and good atom economy. With the...
The first nickel-promoted oxidative Csp3-H/N-H double isocyanide insertion reaction of acetamides with isocyanides has been developed for the synthesis of pyrrolin-2-one derivatives. A wide range of acetamides bearing various functional...
This review summarizes recent advances of indium trichloride catalyzed synthesis of different organic compounds. It is obvious that InCl3 co‐ordinates with C−C and/or C‐heteroatom multiple bonds and thereby makes them very prone to nucleophilic attack to form a new bond. This Lewis acid catalyst also activates oxiranes to produce aldehydes. Multicomponent synthesis including C−C bond formation reaction and construction of N, O and S‐containing heterocycles are discussed in organic solvents as well as in water. This article highlights recent developments and application of indium(III) chloride as a catalyst in organic synthesis from 2015 to 2020. The mechanism of few important reactions is discussed in detail which will be very useful for the readers.
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.
This chapter introduces plant-derived solvents production and purification methods. The plant-derived solvents are classified as sustainable, bio-based, green solvents. Therefore, at first, the importance and classification of green solvents are presented. Then some of the sustainable solvents that are renewable and environmentally friendly, which called bio-based solvents are introduced. Next, the details of the most important bio-based solvents derived from plants, such as their sources, chemical structure, and the uses are reviewed. Finally, the purification methods for the plant-derived solvents are extensively discussed.
This chapter provides an overview of the main applications of 2-methyltetrahydrofuran, a sustainable solvent obtained from lignocellulose biomass, whose physicochemical properties make them a suitable solvent in different application fields. It has been proposed as a more benign, environmentally friendly, biodegradable, and versatile alternative solvent to n-hexane, a fossil fuel-derived solvent, largely used in many organic processes. In this sense, 2-methyltetrahydrofuran (2-MeTHF) is revealed as a suitable green solvent for the extraction of natural products from plants (carotenoids and lipids, among others), for organometallic reactions and biotransformations mediated by enzymes or cells (biocatalysis), besides its potential use as biofuels. Some examples of the processes mentioned above, where 2-MeTHF has been used, will be provided, in which its potential for replacing other conventional solvents derived from a fossil-derived raw materials solvent is demonstrated.
Azadirachta indica is native to the Indian subcontinent. Neem oil is a golden to dark-brown liquid with a strongly unpleasant and offensive odor and is obtained from fruits, seeds, and flowers of the neem tree. It contains fatty acids, limonoids, vitamin E, triglycerides, antioxidants, and calcium. This plant is very important in many sectors including agriculture and medicine. Pusa neem golden urea is an agrochemical which is a mixture of neem oil and urea, and is used for inhibiting nitrification. Neem oil can be used as a green solvent because it is eco-friendly and its residues degrade quickly in the environment. The neem seed contains up to 40% oil and has high potential for production of biodiesel. There are many methods for extracting neem oil but the most commonly used method is solvent extraction because it extracts clear oil with high yield as compared to other methods. Considering its importance, the United Nations declared the neem tree as the tree of the 21st century. Extensive research is being carried out around the world to reveal the benefits of this divine tree.
An efficient metal‐free approach has been devised towards the synthesis of azoles via C−H insertion protocol. Various isocyanides were examined as effective C1‐synthons. The HFIP plays crucial role as hydrogen source and promoter of the reaction in order to reveal the maximum efficacies to accomplish the transformation in high yields of the products with excellent functional group tolerance. The control experiment affirmed 83% of deuterium incorporation, when the reaction was performed using HFIP‐d2.
A highly efficient TMSCl-mediated addition of N-nucleophiles to isocyanides has been achieved.
A convenient and efficient palladium-catalyzed approach has been developed for the synthesis of 5-amino-1,2,4-oxadiazoles from amidoximes and isocyanides. Various 5-amino-1,2,4-oxadiazoles were obtained in moderate to high yields under mild conditions....
A facile synthesis of imidazoles and tetrazoles via [3+1+1] type cyclization of ClCF2COONa is developed. A diverse array of imidazoles and tetrazoles were obtained in decent yields via isocyanide intermediates....
This work discloses an electrochemical oxidative cross-coupling of amines with aryl and aliphatic isocyanides. In an undivided cell, the reaction proceeds without involving any transition-metal catalyst, oxidant, or toxic reagents providing carbodiimides in good yields, thereby circumventing stoichiometric chemical oxidants, with H2 as the only byproduct. Moreover, carbodiimides were in situ converted into unsymmetrical ureas in moderate to good yields using an electricity ON-OFF strategy.
Charge-transfer-based materials with intramolecular donor–acceptor structure are widely used in technological applications. A separation of donor and acceptor through a tetrahedral spiro center leads to a rigid orthogonal arrangement. Furthermore, spiroconjugation can enhance efficient charge transfer. We herein present the syntheses, structural, electrochemical and optical properties of spiro-based CT compounds with diamine donors and diketone acceptors supported by TDDFT calculations. All compounds showed strong charge transfer in their absorbance spectra. Extending the acceptor or donor part of these compounds led to materials with emissions from the CT states. These results can aid the future design of spiro-DA-compounds towards achieving the desired optical properties.
Benzimidazoles are common in nature, medicines, and materials. Numerous strategies for preparing 2-arylbenzimidazoles exist. In this work, 1,2-disubstituted benzimidazoles were prepared from various mono- and di-substituted ortho-phenylenediamines (OPD) by iron-catalyzed oxidative coupling. Specifically, O2 and FeCl3●6H2O catalyzed the cross dehydrogenative coupling and aromatization of diarylmethyl- and dialkyl- benzimidazole precursors. N,N’-disubstituted-OPD substrates were significantly more reactive than their N,N-disubstituted isomers, which appears to be relative to their propensity for complexation and charge transfer with Fe³⁺. The reaction also converted N-monosubstituted OPD substrates to 2-substituted-benzimidazoles; however, electron-poor substrates produce 1,2-disubstituted benzimidazoles by intermolecular imino-transfer. Kinetic, reagent, and spectroscopic (UV-Vis and EPR) studies suggest a mechanism involving metal-substrate complexation, charge transfer, and aerobic turn over, involving high-valent Fe(IV) intermediates. Overall, comparative strategies for the relatively sustainable and efficient synthesis of 1,2-disubstituted benzimidazoles are demonstrated.
A highly efficient 2‐chloroquinazolin‐4(3H)‐one rearrangement was developed that predictably generates either twisted‐cyclic or ring‐fused guanidines in a single operation, depending on the presence of a primary versus secondary amine in the accompanying diamine reagent. Exclusive formation of twisted‐cyclic guanidines results from pairing 2‐chloroquinazolinones with secondary diamines. Use of primary amine‐containing diamines permits a domino quinazolinone rearrangement/intramolecular cyclization, gated through (E)‐twisted‐cyclic guanidines, to afford ring‐fused N‐acylguanidines. This scalable, structurally tolerant transformation generated 55 guanidines and delivered twisted‐cyclic guanidines with robust plasma stability and an abbreviated total synthesis of an antitumor ring‐fused guanidine (4 steps, 55 % yield).
A visible-light promoted three-component isocyanide-based synthesis of iminofurans is herein reported. The reaction proved to be general in scope and proceeds through a triple domino process. Control experiments with 18O-labelled water and TEMPO provided key mechanistic insights for delineating the reactivity paradigms crucial to design efficient photoredox isocyanide-based domino transformations.
The high cost and protracted time line of new drug discovery are major roadblocks to creating therapies for neglected diseases. To accelerate drug discovery we created a library of 2,687 existing drugs and screened for inhibitors of the human malaria parasite Plasmodium falciparum. The antihistamine astemizole and its principal human metabolite are promising new inhibitors of chloroquine-sensitive and multidrug-resistant parasites, and they show efficacy in two mouse models of malaria.
2-Methyltetrahydrofuran (MeTHF) is a commercially available solvent that is produced from renewable resources. The properties of MeTHF place it between tetrahydrofuran (THF) and diethyl ether in solvent polarity and Lewis base strength. In many cases, MeTHF can replace THF in organometallic reactions. The formation and reaction of Grignard reagents in MeTHF and THF are similar. MeTHF can be used as a solvent for low-temperature lithiation, for lithium aluminum hydride reductions, for the Reformatsky reaction, and for metal-catalyzed coupling reactions. MeTHF is also a good substitute for dichloromethane in biphasic reactions.
The title compounds 3 were prepared in low yields from the carbylamine reaction of amino-1,3,5-triazines 1 under phase-transfer conditions. Isocyanotriazine 3a readily reacted with amines in the presence of copper salts to afford triazinylformamidines 4, and also with active methylene compounds in the presence of base to afford addition products 5 and 6, indicating the high electrophilicity of 3. The reactions of isocyanotriazine with electrophiles such as carbonyl compounds and bromine are also described.
Die selektive aerobe Oxidation organischer Verbindungen ist eines der fundamentalsten Probleme der modernen organischen Chemie. Effektive Lösungen müssen die spezifische Reaktivität und Selektivität von molekularem Sauerstoff berücksichtigen und unterschiedliche Klassen von Oxidationsreaktionen abdecken. Die Palladiumoxidasekatalyse kombiniert die Vielseitigkeit Palladium(II)-vermittelter Oxidationen organischer Substrate mit der Oxidation des reduzierten Palladium-Katalysators durch Disauerstoff und ermöglicht so einen Zugang zu einer breiten Auswahl an selektiven aeroben Oxidationsreaktionen. Neuere Ergebnisse zeigen, dass Cokatalysatoren wie Kupfer(II), Polyoxometallate und Benzochinone in der Oxidation von Palladium(0) durch molekularen Sauerstoff verzichtbar sind. Eine große Bedeutung für diese Reaktionen haben oxidativ stabile Liganden, die die Katalysatorzersetzung minimieren, die direkte Reaktion von Palladium mit Disauerstoff fördern, die Reaktivität des organischen Substrats regulieren und asymmetrische Katalysen ermöglichen.
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.
A base-controlled synthesis of 2-substituted secondary and tertiary 1H-indole-3-carboxamides through PdCl(2)-catalyzed cyclization of o-alkynyltrifluoroacetanilides followed by isocyanide insertion has been developed. The reaction proceeds smoothly at ambient temperature using O(2) in air as the sole oxidant of the palladium catalyst.
For green and sustainable chemistry, molecular oxygen is considered as an ideal oxidant due to its natural, inexpensive, and environmentally friendly characteristics, and therefore offers attractive academic and industrial prospects. This critical review introduces the recent advances over the past 5 years in transition-metal catalyzed reactions using molecular oxygen as the oxidant. This review highlights the scope and limitations, as well as the mechanisms of these oxidation reactions (184 references).
A novel and efficient route for the preparation of quinazolin-4(3H)-imines via a palladium-catalyzed three-component reaction of carbodiimide, isocyanide, and nucleophile is described. The palladium-catalyzed isocyanide insertion is believed to be the key step during the reaction process.
Oxidation reactions are key transformations in organic chemistry because they can increase chemical complexity and incorporate heteroatom substituents into carbon-based molecules. This principle is manifested in the conversion of petrochemical feedstocks into commodity chemicals and in the synthesis of fine chemicals, pharmaceuticals, and other complex organic molecules. The utility and function of these molecules correlate directly with the presence and specific placement of oxygen and nitrogen heteroatoms and other functional groups within the molecules.
Although several recent reviews dealt with transition metal catalyzed N-arylation of amines (all classes), to date no specific review covering the N-arylation of amidines and guanidines appeared. Amidines and guanidines are considered as fundamental entities in medicinal chemistry. The appearance of these functional groups in drugs, agrochemicals and natural products justifies a separate description of the current status of the literature on the N-arylation of the amidine and guanidine functionalities. Both acyclic and cyclic derivatives are taken into account. For cyclic amidines/guanidines only systems which possess an exocyclic nitrogen atom are considered. This critical review is largely organized by the type of amidine/guanidine and transition metal used and covers literature up to May 2011 (200 references).
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.
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.
A novel electrophilic one-pot guanidine synthesis has been developed using an olefin, a cyanimide, an amine, and N-bromosuccinimide. A number of guanidine derivatives were prepared with good to excellent yields. An rTRTVI precursor was also prepared based on this useful process.
The Pd-catalyzed aminocarbonylation of carbenes, in situ generated from N-tosylhydrazones, with isocyanides represents a novel access towards carboxylic amides, e.g. (III), (V), (VIII) and (X).
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.
A titanacarborane monoamide catalyzed, one-step synthesis of mono/bicyclic guanidines from commercially available di/triamines and carbodiimides is reported. The reaction mechanism is also proposed.
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.
"Chemical Equation Presented" Center stage: Additions of nitrogen-centered radicals to cyanamide compounds provided the first radical synthesis of aromatic polycyclic guanidine derivatives (see scheme). Modular assembly of the substrates allows for a rapid increase of the molecular complexity of scaffolds, which have potential applications for medicinal chemistry.
The guanidine group defines chemical and physicochemical properties of many compounds of medical interest and guanidine-containing derivatives constitute a very important class of therapeutic agents suitable for the treatment of a wide spectrum of diseases.
To review the most important pharmacological properties, mechanisms of action and therapeutic uses of simple guanidine derivatives, cyclic analogues of guanidines as well as peptides, peptidomimetics and peptoids incorporating arginine.
The review presents both the recent patent literature and original papers dealing with guanidine derivatives that show interesting biological activity and emphasizes the newest developing drugs.
Recent achievements in the synthesis of guanidine-containing molecules with diverse chemical, biochemical and pharmacological properties make them of great importance to the design and development of novel drugs acting at CNS, anti-inflammatory agents, inhibitors of Na(+)/H(+) exchanger, inhibitors of NO synthase, antithrombotic, antidiabetic and chemotherapeutic agents as well as guanidinium-based transporters and vectors.
The synthesis of a series of 1-[(4-fluorophenyl)methyl]-N-(4-piperidinyl)-1H-benzimidazol-2-ami nes and the preliminary evaluation of their in vivo antihistamine activity are described. The title compounds were obtained starting from either 1, 4, 10, or 55 by different synthetic methods. Substitution on the phenyl nucleus of the benzimidazole ring (84-87) was achieved by two different approaches. The in vivo antihistamine activity was evaluated by the compound 48/80 induced lethality test in rats and the antihistamine-induced lethality test in guinea pigs after oral and/or subcutaneous administration. The duration of action was studied in the guinea pig for three compounds (4, 51, and 55). Compound 51, "astemizole", was also studied in histamine- and serotonin-induced cutaneous reaction and for mydriatic activity in the rat and tested for peripheral and central effects not related to histamine antagonism in a variety of systems. Astemizole has been selected for clinical investigation.
Selective aerobic oxidation of organic molecules is a fundamental and practical challenge in modern chemistry. Effective solutions to this problem must overcome the intrinsic reactivity and selectivity challenges posed by the chemistry of molecular oxygen, and they must find application in diverse classes of oxidation reactions. Palladium oxidase catalysis combines the versatility of Pd(II)-mediated oxidation of organic substrates with dioxygen-coupled oxidation of the reduced palladium catalyst to enable a broad range of selective aerobic oxidation reactions. Recent developments revealed that cocatalysts (e.g. Cu(II), polyoxometalates, and benzoquinone) are not essential for efficient oxidation of Pd(0) by molecular oxygen. Oxidatively stable ligands play an important role in these reactions by minimizing catalyst decomposition, promoting the direct reaction between palladium and dioxygen, modulating organic substrate reactivity and permitting asymmetric catalysis.
Palladium catalysed selective double insertion of isonitriles into aryl bromides with trapping by sodium alkoxides provides an efficient 4-component synthesis of unusual alpha-iminoimidates.
The reaction of molecular oxygen with a Pd(II)-hydride species to form a Pd(II)-hydroperoxide represents one of the proposed catalyst reoxidation pathways in Pd-catalyzed aerobic oxidation reactions, but well-defined examples of this reaction were discovered only recently. Here, we present a mechanistic study of the reaction of O2 with trans-(IMes) 2Pd(H)(OBz), 1 (IMes = 1,3-dimesitylimidazol-2-ylidene), which yields trans-(IMes) 2Pd(OOH)(OBz), 2. The reaction was monitored by (1)H NMR spectroscopy in benzene-d6, and kinetic studies reveal a two-term rate law, rate = k1[1] + k2[1][BzOH], and a small deuterium kinetic isotope effect, k(Pd-H)/k(Pd-D) = 1.3(1). The rate is independent of the oxygen pressure. The data support a stepwise mechanism for the conversion of 1 into 2 consisting of rate-limiting reductive elimination of BzOH from 1 followed by rapid reaction of molecular oxygen with (IMes) 2Pd(0) and protonolysis of a Pd-O bond of the eta(2)-peroxo complex (IMes) 2Pd(O2). Benzoic acid and other protic additives (H2O, ArOH) catalyze the oxygenation reaction, probably by stabilizing the transition state for reductive elimination of BzOH from 1. This study provides the first experimental validation of the mechanism traditionally proposed for aerobic oxidation of Pd-hydride species.
- Larraufie