Reductive Cyclization Reaction Research Articles

Synthesis of 2‐Substituted Bicyclo[2.1.1]Hexan‐1‐ols via SmI2‐Mediated Reductive Cyclization Reactions

AbstractThe replacement of benzene rings with saturated bioisosteric counterparts is a key priority in drug discovery programs, and disubstituted bicyclo[2.1.1]hexanes have been recognized as flexible molecular scaffolds that could act as ortho‐substituted benzene bioisosteres. In this study, we outline the synthesis of a wide range of 2‐substituted bicyclo[2.1.1]hexan‐1‐ols, which have the potential to emulate ortho‐phenolic derivatives, via SmI2‐mediated reductive cyclization reactions. The synthetic utility of this methodology was exemplified by the preparation of several saturated analogs of pharmaceutically relevant compounds.

Unraveling the ability of electronically diverse 9H-carbazoles as potential fluorophores in cellular imaging applications with BSA binding affinities

In the present study, fluorophores based on 9H-carbazole have been synthesized from readily accessible 2-nitrochalcones in a single-step reductive cyclization reaction with methyl acetoacetate. The molecular geometry was confirmed based on IR, NMR and mass analysis. The ground state geometry for all the synthesized compounds was optimized using DFT-based methods to explore the localization of frontier molecular orbitals in electronically diverse carbazoles. The photophysical studies revealed a higher Stokes shift for PPM 17 due to the presence of the naphthyl group at C-1 of carbazole. The high stability of PPM14, as evidenced by high chemical hardness, prompted us to explore its BSA binding affinity using fluorescence titration, synchronous,3-D fluorescence and energy transfer analysis. The probe (PPM 14) displayed a “turn-off” response in the presence of Fe3+ ions. The less cytotoxic behavior of PPM 14, its “turn-off” fluorescence response with Fe3+, and its utility in cell imaging application establish it as a potential small organic framework-based bio-sensor.

Synthesis of Quinoline and Quinolin-2(1H)-one Derivatives via Nickel Boride Promoted Reductive Cyclization

AbstractA mild and efficient approach for the synthesis of diversely substituted quinoline and quinolin-2-one derivatives is disclosed. In situ generated nickel boride proved to be an effective promoter of the reductive cyclization reaction. Broad substrate scope, mild reaction conditions, consistent yield, and a wide range of functional group tolerance are the other notable features of the newly discovered reaction. A large number of quinoline and quinolin-2-one derivatives may be prepared from milligram to multigram scale employing this intramolecular reductive cyclization protocol.

Formic Acid as Carbon Monoxide Source in the Palladium-Catalyzed N-Heterocyclization of o-Nitrostyrenes to Indoles.

The reductive cyclization reaction of o-nitrostyrenes to generate indoles has been investigated for three decades using CO as a cheap reducing agent, but it remains an interesting area of research and improvements. However, using toxic CO gas has several drawbacks. As a result, it is highly preferable to use safe and efficient surrogates for in situ generation of CO from nontoxic and affordable sources. Among several CO sources that have been previously explored for the generation of gaseous CO, here we report the use of cheap and readily available formic acid as an effective reductant for the reductive cyclization of o-nitrostyrenes. The reaction is air and water tolerant and provides the desired indoles in yields up to 99%, at a low catalyst loading (0.5 mol %) and without generating toxic or difficult to separate byproducts. A cheap glass thick-walled "pressure tube" can be used instead of less available autoclaves, even on a 2 g scale, thus widening the applicability of our protocol.

De Novo Diastereoselective Synthesis of 1-Hydroxyl Allogibberic Methyl Ester en Route to Diverse Bioactive Molecules.

The first de novo synthesis of 1-hydroxyl allogibberic methyl ester, en route to pharbinilic acid and other bioactive molecules, is accomplished in diastereoselective manner. Key reactions of the synthesis include a Pd-catalyzed Suzuki-Miyaura cross-coupling reaction, a Lewis acid-catalyzed reductive Prins cyclization reaction, and a SmI2-mediated transannular pinacol coupling reaction. The synthesis provides a new avenue to access diverse relevant bioactive molecules.

The Synthesis and Application of 2-Cyano and -Ester Containing Anilines: Selective Copper-Catalyzed Reductive Amination, N-Benz­ylation, and Cyclization Reactions

AbstractA convenient and practical pathway to 2-cyano and 2-ester anilines is described via efficient and selective copper(II)-catalyzed reductive amination via hydrosilylation process. Both 2-cyano and 2-ester anilines were successfully synthesized with good functional group tolerance and high selectivity. The application of the 2-cyano and -iodine containing anilines was developed in the synthesis of indoloindole derivatives via CuSO4-catalyzed N-benzylation and cyclization reaction in ‘one pot’. More interestingly, the photophysical property investigations of these 2-cyano and 2-ester containing anilines exhibit excellent fluorescent properties, which have great potential application in the development of interesting near-ultraviolet optical devices in the near future.

One-Pot Synthesis of (E)-2-(3-Oxoindolin-2-ylidene)-2-arylacetonitriles.

A highly efficient and expeditious one-pot approach towards 2-(3-oxoindolin-2-yl)acetonitriles was designed, which involves a base-assisted aldol reaction of ortho-nitroacetophenones, followed by hydrocyanation, triggering an unusual reductive cyclization reaction.

Synthesis of 3C-alkylated active methylene substituted 2H-indazole derivatives via sequential ring opening of donor–acceptor cyclopropanes and reductive cyclization reaction

A facile synthesis of 3C-alkylated active methylene substituted 2H-indazoles from o-nitrocyclopropanes and primary arylamines catalyzed by Ni(ClO4)2.6H2O/SnCl2.2H2O is reported.

Dinickel Catalyzed Vinylidene-Alkene Cyclization Reactions.

A dinickel catalyst promotes reductive cyclization reactions of 1,1-dichloroalkenes containing pendant olefins. The reactions can be conducted with a Zn reductant or electrocatalytically using a carbon working electrode. Mechanistic studies are consistent with the intermediacy of a Ni2(vinylidene) species, which adds to the alkene and generates a metallacyclic intermediate. β-Hydride elimination followed by C-H reductive elimination forms the cyclization product. The proposed dinickel metallacycle is structurally characterized and its stoichiometric conversion to product is demonstrated. Spin polarized, unrestricted DFT calculations are used to further examine the cyclization mechanism. These computational models reveal that both nickel centers function cooperatively to mediate the key oxidative addition, migratory insertion, β-hydride elimination, and reductive elimination steps.

Synthesis of 1H‐Pyrazolo[3,4‐b]quinoxaline Derivatives by Modification of the Regiospecific Reaction – the Influence of the Microwave Field

AbstractThe microwave‐assisted reductive cyclization reaction with the use of triphenylphosphine as a reducing agent in the synthesis of 1H‐pyrazolo[3,4‐b]quinoxaline derivatives was investigated. Contrary to the conventional method of conducting the reaction, the process in the reactor takes 25 minutes with moderate yields (30–38 %). This procedure was used to obtain three new 1,3‐dimethyl‐1H‐pyrazolo[3,4‐b]quinoxaline derivatives with substituents at position 6 of different donor‐acceptor character, which were used to determine the basic photophysical properties (UV‐Vis absorption spectra, fluorescence emission spectra) and the quantum yields of fluorescence were appointed. The measurement results indicate the possible use of new compounds as materials for OLEDs. The conducted research brings new knowledge in the field of 1H‐pyrazolo[3,4‐b]quinoxaline derivative systems and provides an alternative to conventional synthesis of pyrazoloquinoxalines.

Metric-Based Analysis of Convergence in Complex Molecule Synthesis.

Convergent syntheses are characterized by the coupling of two or more synthetic intermediates of similar complexity, often late in a pathway. At its limit, a fully convergent synthesis is achieved when commercial or otherwise readily available intermediates are coupled to form the final target in a single step. Of course, in all but exceptional circumstances this level of convergence is purely hypothetical; in practice, additional steps are typically required to progress from fragment coupling to the target. Additionally, the length of the sequence required to access each target is a primary consideration in synthetic design.In this Account, we provide an overview of alkaloid, polyketide, and diterpene metabolites synthesized in our laboratory and present parameters that may be used to put the degree of convergence of each synthesis on quantitative footing. We begin with our syntheses of the antiproliferative, antimicrobial bacterial metabolite (-)-kinamycin F (1) and related dimeric structure (-)-lomaiviticin aglycon (2). These synthetic routes featured a three-step sequence to construct a complex diazocyclopentadiene found in both targets and an oxidative dimerization to unite the two halves of (-)-lomaiviticin aglycon (2). We then follow with our synthesis of the antineurodegenerative alkaloid (-)-huperzine A (3). Our route to (-)-huperzine A (3) employed a diastereoselective three-component coupling reaction, followed by the intramolecular α-arylation of a β-ketonitrile intermediate, to form the carbon skeleton of the target. We then present our syntheses of the hasubanan alkaloids (-)-hasubanonine (4), (-)-delavayine (5), (-)-runanine (6), (+)-periglaucine B (7), and (-)-acutumine (8). These alkaloids bear a 7-azatricyclo[4.3.3.01,6]dodecane (propellane) core and a highly oxidized cyclohexenone ring. The propellane structure was assembled by the addition of an aryl acetylide to a complex iminium ion, followed by intramolecular 1,4-addition. We then present our synthesis of the guanidinium alkaloid (+)-batzelladine B (9), which contains two complex polycyclic guanidine residues united by an ester linkage. This target was logically disconnected by an esterification to allow for the independent synthesis of each guanidine residue. A carefully orchestrated cascade reaction provided (+)-batzelladine B (9) in a single step following fragment coupling by esterification. We then discuss our synthesis of the diterpene fungal metabolite (+)-pleuromutilin (10). The synthesis of (+)-pleuromutilin (10) proceeded via a fragment coupling involving two neopentylic reagents and employed a nickel-catalyzed reductive cyclization reaction to close the eight-membered ring, ultimately providing access to (+)-pleuromutilin (10), (+)-12-epi-pleuromutilin (11), and (+)-12-epi-mutilin (12). Finally, we discuss our synthesis of (-)-myrocin G (13), a tricyclic pimarane diterpene that was assembled by a convergent annulation.In the final section of this Account, we present several paramaters to analyze and quantitatively assess the degree of convergence of each synthesis. These parameters include: (1) the number of steps required following the point of convergence, (2) the difference in the number of steps required to prepare each coupling partner, (3) the percentage of carbons (or, more broadly, atoms) present at the point of convergence, and (4) the complexity generated in the fragment coupling step. While not an exhaustive list, these parameters bring the strengths and weaknesses each synthetic strategy to light, emphasizing the key contributors to the degree of convergence of each route while also highlighting the nuances of these analyses.

RECENT SYNTHETIC APPROACHES TO 1 H - AND 2 H -INDAZOLES

The work summarizes latest strategies for the synthesis of 1H- and 2H-indazoles published during the last five years. The strategies include transition metal catalyzed reactions, reductive cyclization reactions, and synthesis of 2H-indazoles via consecutive formation of C–N and N–N bonds without catalyst and solvent from 2-azidobenzaldehydes and amines. This review article gives a brief outline of optimized synthetic schemes with relevant examples.

Recent synthetic approaches to 1H- and 2H-indazoles (microreview)

The work summarizes latest strategies for the synthesis of 1H- and 2H-indazoles published during the last five years. The strategies include transition metal catalyzed reactions, reductive cyclization reactions, and synthesis of 2H-indazoles via consecutive formation of C–N and N–N bonds without catalyst and solvent from 2-azidobenzaldehydes and amines. This review article gives a brief outline of optimized synthetic schemes with relevant examples.

A Total Synthesis of (±)‐Ceratopicanol via Palladium Catalyzed Reductive Cyclization

An efficient total synthesis of ceratopicanol was achieved through successive Pd catalyzed reductive cycloaddition and cyclization reactions. The Pd mediated cyclization reaction to form a triquinane structure demonstrated that a small structural difference changed the reaction pathway either to form different structures or reduced non‐cyclized product depending on the reaction conditions.

A Synthesis Strategy for the Production of a Macrolactone of Gulmirecin A via a Ni(0)-Mediated Reductive Cyclization Reaction.

A synthesis strategy for the production of a key synthetic intermediate of gulmirecin A was described. The key reaction in the preparation of the 12-membered macrolactone is the Ni(0)-mediated reductive cyclization reaction of ynal using an N-heterocyclic carbene ligand and silane reductant. In addition, the α-selective glycosylation reaction of the macrolactone was performed to demonstrate the synthesis of gulmirecin and disciformycin precursors.

The Enantiomers of Trinorbornane and Derivatives Thereof

AbstractHerein, we report the synthesis of the enantiomers of trinorbornane, a tetracyclic saturated hydrocarbon with the chemical formula C11H16. The preparation of these rigid carbon scaffolds was enabled by the successful chiral separation of its tricyclic precursor, thus allowing the enantiomers to be synthesized through a reductive radical cyclization reaction. Assignment of the absolute conformation of the enantiomers was achieved through VCD experiments. Further, we report an alternative cyclization procedure providing access to hydroxyl and phenyl sulfone functionalized trinorbornanes.

Synthesis and Rh-catalyzed reductive cyclization of 1,6-enynes and 1,6-diynes containing alkynylboronate termini

Ir-catalyzed dehydrogenative borylation of terminal alkynes (DHBTA) has been used to borylate the C(sp)-H bond in a series of 1,6-enynes and 1,6-diynes. Ir catalysts based on the diarylamido/bis(phosphine) PNP ligands proved to be capable of performing DHBTA on these substrates. The alkynylboronate products were then explored as substrates in reductive cyclization reactions designed to yield five-membered carbocycles and heterocycles with preservation of the carbon-boron bond. The reductive cyclization of enynes with H2 was carried out using cationic Rh catalysts (after the work of Krische et al.) supported by bidentate phosphine ligands, of which BINAP proved to be the generally best performing. Reductive cyclization of borylated enynes typically resulted in mixtures of isomeric products. Attempts to optimize the reductive cyclization of borylated 1,6-enynes to yield a single product were not successful; in addition, the distribution of products in these reactions was poorly reproducible. On the other hand, reductive cyclization of 1,6-diynes with the same Rh catalysts was better behaved, allowing for selectivity and reproducibility. In particular, alkynylboronate derivatives of bis(propargyl)amine underwent smooth reductive cyclization to 3,4-substituted pyrroles. The influence of substituents and conditions on the product distribution was explored and representative reactions utilizing new borylated heterocycles in Suzuki coupling reactions were carried out.

Synthesis of Indolines via a Photocatalytic Intramolecular Reductive Cyclization Reaction

Synthesis of Indolines via a Photocatalytic Intramolecular Reductive Cyclization Reaction

Transition Metal Catalyzed Reductive Cyclization Reactions of Nitroarenes and Nitroalkenes

AbstractNitroarenes are the entry point for the production of most nitrogen‐containing aromatic compounds. Thus, any transformation that leads directly from them to the final product allows saving one or more synthetic steps. This review deals with homogeneously catalyzed reactions leading to the formation of N‐heterocyclic compounds from nitroarenes or nitroalkenes in one pot. Reactions that lead to the intermediate formation of amines are not considered. Carbon monoxide is the most often employed reductant because it allows selective reactions, is cheap, and only produces CO2 as stoichiometric byproduct. However, the difficulty in handling pressurized CO has stimulated in recent years the development of CO‐surrogates, that is molecules able to liberate CO during the reaction. The use of phosphines and diols has also been developed in conjunction with molybdenum catalysts. The review focusses in more detail on the literature in the period 2006–2018, but reference to earlier work is made when necessary to put recent results in a more general context.

Chemoselective Kumada‐Type Iron Catalysis with Alkyl Grignard Reagents: Reductive Cyclization and Cyclomethylation

AbstractA chemoselective reductive cyclization and cyclomethylation reaction of 7‐iodohept‐2‐yne and 7‐iodohepta‐1,2‐diene derivatives has been carried out using an iron catalyst and various alkyl Grignard reagents, resulting in the formation of pyrrolidines, tetrahydrofurans, and carbocycles with an alkene functional group. The reaction is initiated by single‐electron transfer from reduced Fe species to alkyl iodides and the resulting Fe−H or Fe−Me compound differentiated the structures of the cyclized products, which exhibited diverse complexities and synthetic utilities.