Synthesis Of Pyrrolo Research Articles

Palladium‐Catalyzed Synthesis of Pyrrolo[1,2‐α]Pyrazines From N‐Phenacyl Pyrrole‐2‐Carbonitriles and Aryl Boronic Acids

ABSTRACTHerein, we have developed palladium‐trifluoroacetate‐catalyzed carbo‐palladation reaction of pyrrole‐2‐carbonitriles and aryl boronic acids leading to functionally diverse pyrrolo[1,2‐α]pyrazines under thoroughly optimized reaction conditions. The reaction proceeded smoothly and allowed the diversity‐oriented synthesis of pyrrolo[1,2‐α]pyrazines with broad substrate scope with respect to pyrrole‐2‐carbonitriles and aryl boronic acids.

Ruthenium(II)-Catalyzed Annulation of Oximes with Maleimides: Synthesis of Pyrrolo[3,4-c]isoquinoline-1,3-diones.

A series of pyrroloisoquinoline-1,3-diones has been synthesized using ruthenium(II) as the catalyst and oxygen as the oxidant in a straightforward manner. The reaction proceeds through a tandem C-C/C-N bond formation process between maleimides and ketoximes, providing a direct approach for the synthesis of the titled products. This operationally simple reaction procedure supplies suitable conditions for synthesizing diverse isoquinoline-based heterocycles with a range of functional groups in moderate to good yields and compatible with gram-scale synthesis. Furthermore, the compatibility of this reaction with oxygen as a green and environmentally friendly oxidant raises the importance of the present method.

Synthesis of Pyrrolo[3,4-b]pyridin-5-ones via Ugi-Zhu Reaction and In Vitro-In Silico Studies against Breast Carcinoma.

An Ugi-Zhu three-component reaction (UZ-3CR) coupled in a one-pot manner to a cascade process (N-acylation/aza Diels-Alder cycloaddition/decarboxylation/dehydration) was performed to synthesize a series of pyrrolo[3,4-b]pyridin-5-ones in 20% to 92% overall yields using ytterbium triflate as a catalyst, toluene as a solvent, and microwaves as a heat source. The synthesized molecules were evaluated in vitro against breast cancer cell lines MDA-MB-231 and MCF-7, finding that compound 1f, at a concentration of 6.25 μM, exhibited a potential cytotoxic effect. Then, to understand the interactions between synthesized compounds and the main proteins related to the cancer cell lines, docking studies were performed on the serine/threonine kinase 1 (AKT1) and Orexetine type 2 receptor (Ox2R), finding moderate to strong binding energies, which matched accurately with the in vitro results. Additionally, molecular dynamics were performed between proteins related to the studied cell lines and the three best ligands.

Design and synthesis of pyrrolo[2,3-d]pyrimidine linked hybrids as α-amylase inhibitors: molecular docking, MD simulation, ADMET and antidiabetic screening.

Novel pyrrolo[2,3-d]pyrimidine-based analogues were designed, synthesized, and evaluated for their ability to inhibit the α-amylase enzyme in order to treat diabetes. In vitro antidiabetic analysis demonstrated excellent antidiabetic action for compounds 5b, 6c, 7a, and 7b, with IC50 values in the 0.252-0.281mM range. At a 200μg/mL concentration, the exceptional percent inhibition values for compounds 5a, 5b, 5d, and 6a varied from 97.79 ± 2.86% to 85.56 ± 4.13% overperforming the standard (acarbose). Molecular docking of all compounds performed with Bacillus paralicheniformis α-amylase enzyme. The most active compounds via in vitro and non-toxic via in silico ADMET and molecular docking analysis, hybrids 6c, 7a, and 7b displayed binding affinity from - 8.2 and - 8.5kcal/mol. Molecular dynamic simulations of most active compound 5b and 7a investigated into the active sites of the Bacillus paralicheniformis α-amylase enzyme for a 100-ns indicating the stability of hybrid-protein complex. Consistent RGyr values for the two complexes under study further suggest that the system's proteins are closely packed in the dynamic state. Synthesized analogs' in vitro biological assessments, ADMET, molecular docking, and MD modelling reveal that 5b, 6c, 7a, and 7b hybrid analogs may be employed in the development of future antidiabetic drugs.

Total synthesis of lamellarin G trimethyl ether through enaminone cyclocondensation.

A synthesis of pyrrolo[2,1-a]isoquinolines based on intramolecular condensation of an enaminone intermediate obtained by C-acylation of an N-alkylated 6,7-dimethoxy-1-methyl-3,4-dihydroisoquinolinium salt was developed. This methodology was further applied to the total synthesis of lamellarin G trimethyl ether from commercially available starting materials compatible with xylochemistry with an overall yield of 26% in 7 steps based on homoveratrylamine.

Studies on the [4 + 2] cycloaddition and allylic substitution of indole-fused zwitterionic π-allylpalladium.

The zwitterionic π-allylpalladium species, also known as dipoles, are important synthons widely used in various reactions including cycloaddition and allylic substitution. This study reported the development of a new indole-fused zwitterionic π-allylpalladium precursor compound and its application in [4 + 2] cycloaddition and allylic substitution reactions. As a result, the synthesis of pyrrolo[3,2,1-ij]quinazolin-3-one and 7-vinyl indole compounds was achieved with moderate to good yields. Notably, the allylic substitution reaction exhibited excellent regio- and stereoselectivity.

Synthesis of pyrrolo[3,2-d]pyrimidineone derivatives as novel FXa inhibitors

A series of pyrrolo[3,2-d]pyrimidineone compounds have been designed and synthesized as novel FXa inhibitors. Bioassay of the tested compounds showed moderate to excellent anticoagulant potency in vitro. Further FXa inhibitory and bioactivity evaluation in rats, the FeCl3-induced venous thrombosis model, showed that the compound 17a has good FXa inhibitory activity (IC50 = 1.57 nM) and in vivo antithrombotic potency. The anticoagulant effects of compound 17a were dose dependent whether in vitro or in vivo. The results further confirmed our hypothesis that the large conjugated structure is an ideal skeleton binding FXa.

Regio- and stereoselectivity of the 1,3-dipolar cycloaddition of azomethine ylides to 3-nitro-2(1H)-quinolinone derivatives: A new synthesis of Pyrrolo[3,4-c] quinolines

1,3-Dipolar cycloadditions of different azomethine ylides to 3-nitro-2(1H)-quinolinones were carried out to give 3a-nitro-4-oxo-1,2,3,3a,5,9b-hexahydropyrrolo[3,4-c]quinoline-4-one derivatives in satisfactory yield, in most cases with excellent stereoselectivity. The structure and stereochemistry of cycloadducts were studied in detail by X-ray and NMR spectroscopy methods.

3-Nitro-2(1H)-quinolone derivatives as 2π components in 1,3-dipolar cycloadditions of azomethine ylides: A new synthesis of pyrrolo[3,4-c]quinolines

The 1,3-dipolar cycloaddition of 3-nitro-2(1H)-quinolones with ester-stabilized azomethine ylides derived from sarcosine ester and various aromatic aldehydes has been investigated. The structure and stereochemistry of cycloadducts were studied in detail by X-ray and NMR spectroscopy methods.

Pyrrolo[2,1-a]isoquinolines as multitasking organophotocatalysts in chemical synthesis

We demonstrate the design and synthesis of pyrrolo[2,1-a]isoquinolines (PIqs) bearing electron-withdrawing groups, which are excited under irradiation with visible light to display wider redox windows and higher triplet-state energies. The photophysical and electrochemical characters of PIqs can be tailored by modification of the electron-withdrawing groups and their positions, enabling redox-neutral (hetero)biaryl cross-coupling between aryl halides and (hetero)arenes, nickel-catalyzed amination and oxygenation of aryl halides, and decarboxylative cross-coupling between α-amino acids and aryl halides, as well as a set of molecular transformations driven by triplet-triplet sensitization under irradiation with visible light.

Rhodium-Catalyzed C2-Alkylation of Indoles with Cyclopropanols Using N,N-Dialkylcarbamoyl as a Traceless Directing Group.

An efficient rhodium-catalyzed synthesis of C2-alkylated NH-free indoles has been achieved from substituted indoles and cyclopropanols. The reaction allows the synthesis of various C2-alkylated products in good to excellent yield. Important features of the method include the use of a N,N-dialkylcarbamoyl group as a traceless directing group, C-H/C-C bond functionalization, good functional group tolerance, broad scope, synthesis of pyrrolo[1,2-a]indole, and identification of potential intermediates.

Recent progress in the synthesis of pyrrolo[2,1-a]isoquinolines.

Pyrrolo[2,1-a]isoquinolines occur frequently in a large number of bioactive natural products and pharmaceutically important molecules. The synthesis of pyrrolo[2,1-a]isoquinoline derivatives is an easy and useful way to produce artificial molecules with potential applications. A huge number of excellent methodologies for constructing pyrrolo[2,1-a]isoquinolines have been reported in the last decade. This review summarizes the recent advances in this research field covering from 2011 to 2021.

New methods for the synthesis of pyrrolo[1,2-x][1,4]diazepines and their (het)arene-annulated analogs (microreview)

New methods for the synthesis of pyrrolo[1,2-x][1,4]diazepines and their (het)arene-annulated analogs (microreview)

Cover Feature: Synthesis of Pyrrolo[2,1‐a]isoquinoline Class of Natural Product Crispine A (Eur. J. Org. Chem. 35/2021)

The Cover Feature shows naturally occurring (2S,3S)- and (2S,3R)-tetrahydro-3-hydroxy-5-oxo-2,3-furan dicarboxylic acid bearing, chemically amenable functional groups that are an ideal choice for the enantiopure synthesis of the (−)- and (+)-Crispine A, respectively. The diastereomeric natural products are conveniently converted to desirable enantiomers of Crispine A through the chiral pool strategy. This exciting and efficient strategy is one of the well-explored trends in synthetic organic chemistry, especially regarding molecules procured from tropical plant material (Nature) and serves as key step in the enantiopure synthesis of small-molecule natural products. More information can be found in the Minireview by C. Mohan, I. Ibnusaud et al.

K2S2O8-Mediated Synthesis of Highly Functionalized Pyrroles via Oxidative Self-Dimerization of N-Propargylamines.

An efficient methodology has been developed for the synthesis of tetra- and pentasubstituted pyrroles via oxidative self-dimerization of N-propargylamines catalyzed by silver benzoate in the presence of K2S2O8 in good yields. The protocol provides a simple route for the synthesis of both tetra- and pentasubstituted pyrroles with two carbonyl groups in the side chain. The methodology can be extended toward the synthesis of pyrrolo[3,4-d]pyridazine.

Synthesis of Pyrrolo[2,1‐a]isoquinoline Class of Natural Product Crispine A

AbstractAs a naturally occurring small‐molecule, various optical isomers of chiral pyrrolo[2,1‐a]isoquinoline alkaloid crispine A represent a potential class of chiral molecules in contemporary organic chemistry, and possess diverse biological activities. The range of pharmacological activities include antidepressant, antiplatelet, antileukemic, and anticancer activities. This review provides an overview of the literature on the strategies, employed in the synthesis of crispine A in their racemic and enantiopure forms via Bischler‐Napieralski cyclization, Pictet‐Spengler cyclization, N‐Alkylation/Acylation‐cyclization, Oxidative cyclization, and Asymmetric hydrogenation in the period of 1931–2021. This study accentuates the need for the developing more effective synthesis, and search for involved biological applications for the pyrroloisoquinoline class of natural product. Attention has been drawn towards the use of relatively less documented but easily accessible naturally occurring diastereomeric scaffolds namely, garcinia and hibiscus acids. These lactones obtained from (+)‐ and (−)‐2‐hydroxycitric acids bearing chemically amenable functional groups are investigated as an ideal choice for the enantiopure synthesis of the (−)‐(R)‐ and (+)‐(S)‐Crispine A structural frame work.

Recent advances in the synthesis of pyrrolo[1,2-a]indoles and their derivatives.

The pyrrolo[1,2-a]indole unit is a privileged heterocycle found in numerous natural products and has been shown to exhibit diverse pharmacological properties. Thus, recent years have witnessed immense interest from the synthesis community on the synthesis of this scaffold. In light of the ever-increasing demand for pyrrolo[1,2-a]indoles in drug discovery, this review provides an overview of recent synthesis methods for the preparation of pyrrolo[1,2-a]indoles and their derivatives. The mechanistic pathway and stereo-electronic factors affecting the yield and selectivity of the product are briefly explained. Furthermore, we have attempted to demonstrate the utility of the developed methods in the synthesis of bioactive molecules and natural products, wherever offered.

Facile synthesis of pyrrolo[2,1-a]isoquinolines by domino reaction of 1-aroyl-3,4-dihydroisoquinolines with conjugated ketones, nitroalkenes and nitriles.

A convenient protocol for the synthesis of 5,6-dihydropyrrolo[2,1-a]isoquinolines with various electron-withdrawing substituents at C-2 atom is described. This approach is based on the two-component domino reaction of 1-aroyl-3,4-dihydroisoquinolines with α,β-unsaturated ketones, nitroalkenes and acrylonitrile. Depending on the selected substrates, the reaction was performed in TFE under reflux or under microwave irradiation. Only for the two examples, a transition metal catalyst was used.

Cyclopropenones in the synthesis of indolizidine, pyrrolo[2,1-a]isoquinoline and indolizino[8,7-b]indole alkaloids

An attempted synthesis of the indolizidine natural product castanospermine resulted in the successful addition of cyclopropenone to a sugar-derived poly-hydroxylated cyclic imine to give an indolizidinone product, but with the installation of an extra hydroxy group at the castanospermine 8a -bridgehead position. This was also observed in our previous approach to the australine and hyacinthacine pyrrolizidine natural products. The same oxidative phenomenon occurred during the synthesis of pyrrolo[1,2- a ]isoquinolines from the reaction of aldimine dihydroisoquinolines with cyclopropenones, whereas ketimine based dihydroisoquinolines gave pyrrolo[1,2- a ]isoquinolines without bridgehead oxidation. These results may have some significance for the origins of the bridgehead hydroxy natural products jenamidine B 1 /B 2 , clazamycin A/B and legonmycin A/B. The precursor cyclic aldimine for the synthesis of the indolizino[8,7- b ]indoles gave dimeric indolizino[8,7- b ]indoles, whereas the corresponding cyclic ketimines behaved as expected and gave the indolizino[8,7- b ]indole core after reaction with cyclopropenones.

Synthesis of pyrrolo[3,4-c]pyridine-1,3-diones (5-azaphthalimides) (microreview)

The review summarizes the work devoted to the preparation of pyrrolo[3,4-c]pyridine-1,3-dione (5-azaphthalimide) derivatives over the last 10 years. Methods for the synthesis of pyrrolo[3,4-c]pyridine-1,3-dione derivatives are divided into three groups: annulation of the pyrrole moiety, annulation of the pyridine ring, and tandem closure of two rings.