Petasis Reaction Research Articles

Integrated Approach for Allyl Amine Synthesis Combining the Decarboxylative Coupling of Arylacrylic Acids with the Petasis Reaction.

A metal-free multicomponent reaction strategy for synthesizing allyl amines through decarboxylative coupling combined with the Petasis reaction is described. Utilizing (E)-3-(2,4,6-trimethoxyphenyl)acrylic acid, various boronic acids, a formaldehyde solution, and primary amines, the method operates efficiently without metal catalysts. Investigations reveal that electron-donating substituents in cinnamic acid derivatives significantly enhance reactivity, which is crucial for effective transformations. Under the optimized conditions, yields of ≤78% were obtained across a diverse range of 30 allyl amines.

Sustainable synthesis of piperazine analogs using varied energy sources in the petasis reaction: A green chemistry perspective

The Petasis reaction between substituted boronic acids (1a-c), N-Boc-piperazine, and glyoxylic acid in the conventional method of synthesis needs continuous refluxing for 16 h in a solvent like acetonitrile (ACN) to obtain the products. Using the same reactants, the source of energy was changed to microwave irradiation, ultrasonication, or mechanical energy (Trituration) to obtain good yields of the products consuming much less energy and time. Apart from the use of different sources of energy, the solvents as the media of the reactants were also changed. In microwave synthesis, more than 95% yield was obtained for the products in the presence of ACN/dichloromethane as solvents. In the sonication method, the yield ranged from 76 to 98% while in the trituration method, the yield decreased to 76-82% in the presence of various polar protic/aprotic solvents. Microwave irradiation or ultrasonication provides good alternatives to refluxing the reaction mixture continuously for a long time.. KEYWORDS :Microwave synthesis, Multicomponent reactions, Petasis reaction, Sonication, Trituration.

Strategies for the Development of Asymmetric and Non-Directed Petasis Reactions.

The Petasis reaction is a multicomponent reaction of aldehydes, amines and organoboron reagents and is a useful method for the construction of substituted amines. Despite the significant advancement of the Petasis reaction since its invention in 1993, strategies for asymmetric and non-directed Petasis reactions remain limited. To date, there are very few catalytic asymmetric Petasis reactions and almost all asymmetric reports employ a chiral auxiliary. Likewise, the aldehyde component often requires a directing group, ultimately limiting the reaction's scope. In this Concept, key methods for asymmetric and non-directed Petasis reactions are discussed, focusing on how these conceptual advances can be applied to solve long-standing gaps in the Petasis literature.

Unveiling piperazine-quinoline hybrids as potential multi-target directed anti-Alzheimer's agents: design, synthesis and biological evaluation.

Multi-target directed ligands (MTDLs) have recently been popularized due to their outstanding efficacy in combating the complicated features of Alzheimer's disease. This study details the synthesis of piperazine-quinoline-based MTDLs through a multicomponent Petasis reaction, targeting multiple factors such as AChE, BuChE, metal chelation to restore metal dyshomeostasis, and antioxidant activity. Some of the synthesized compounds exhibited notable inhibitory activity against AChE and BuChE enzymes at specific concentrations. Among the synthesized compounds compound (95) containing a 4-chloroaniline moiety and a 4-methoxybenzyl group displayed the most promising inhibitory activities against AChE (IC50 3.013 µM) and BuChE (IC50 = 3.144 µM). Compound (83) featuring 2-methoxyaniline and 4-fluorobenzyl substituents, exhibited the highest BuChE inhibition (IC50 1.888 µM). Notably, compound (79) demonstrated 93-times higher selectivity for BuChE over AChE. Molecular docking and molecular dynamics simulations were also performed to explore the binding modes and stability of these compounds with the AChE amd BuChE proteins. Further, kinetics study was performed against AChE for comounds (83 and 95) which indicated mixed inhibition of the enzyme by these compounds, Amongs the synthesized compounds, nine compounds were assessed for their antioxidant activity, displaying significant antioxidant properties with IC50 values ranging from 156 µM to 310 µM. Moreover, all the compounds demonstrated metal chelating tendency with Cu+2, Zn+2, Fe+2, Fe+3 and Al+3. This study provides insights into the design of novel MTDLs, highlighting compound (95) as a potential candidate for combating Alzheimer's disease.

Ideas Behind the Tryptophan-Mediated Petasis Reaction (TMPR) Concept for Peptide Stapling.

This Concept short review offers an insightful analysis of pivotal research papers and explores the key synthetic ideas behind the intersection of two realms in peptide chemistry: using tryptophan and Petasis multicomponent reactions for macrocyclisation and labelling of peptides. The recently published tryptophan-mediated Petasis reaction (TMPR) concept represents a critical junction between these two worlds, highlighting how combining such methodologies leads to more effective and versatile synthetic strategies, setting a potentially new direction for future research in the field of peptide-drug conjugates.

Peptide Boronic Acids by Late-Stage Hydroboration on the Solid Phase.

Organoboron compounds have a wide range of applications in numerous research fields, and methods to incorporate them in biomolecules are much sought after. Here, on-resin chemical syntheses of aliphatic and vinylogous peptide boronic acids are presented by transition metal-catalyzed late-stage hydroboration of alkene and alkyne groups in peptides and peptoids, for example on allyl- and propargylglycine residues, using readily available chemicals. These methods yield peptide boronic acids with much shorter linkers than previously reported on-resin methods. Furthermore, the methods are regio- and stereoselective, compatible with all canonical amino acid residues and can be applied to short, long, and in part even "difficult" peptide sequences. In a feasibility study, the protected peptide vinylboronic acids are further derivatized by the Petasis reaction using salicylaldehyde derivatives. The ability of the obtained peptide boronic acids to reversibly bind to carbohydrates is demonstrated in a catch-release model experiment using a fluorescently labeled peptide boronic acid on cross-linked dextran beads. In summary, this highlights the potential of the target compounds for drug discovery, glycan-specific target recognition, controlled release, and diagnostics.

Synthesis of stereo-enriched bis glyco-cyclohexylamines by a one pot dual Petasis reaction

A one pot dual Petasis reaction of sugars, styrene boronic acid and cis/trans 1,2-cyclohexyldiamines was done for the diastereoselective synthesis of bis glyco-cyclohexylamines, which have multiple stereogenic centres and coordinating heteroatoms. The products were isolated and characterized by HMBC, HSQC, 1H, 13C NMR experiments, and X-ray single crystallographic analysis. A plausible mechanism for the dual Petasis reaction was proposed that involves hydroxyl directed borylation for the anti-diastereoselectivity along with N,N'-chelate tetracoordinated organoboron complex assisted syn-diastereoselectivity based on the experimental findings.

Metal‐Free 1,3‐Boronate Rearrangement to Ketones Driven by Visible Light

AbstractBoronate rearrangements, such as the Matteson and Petasis reactions, are valuable metal‐free reactions for the transfer of the carbo group on boron to intramolecular electrophilic sites. However, only highly reactive electrophiles are suitable, and ketones are too inactive for those boronate rearrangements due to the high energy barriers. We disclose here the 1,3‐boronate rearrangement to ketones, for which a high energy barrier (44.9 kcal/mol) is prohibitory for thermal reactions in the ground state. The reaction is enabled by the key keto‐enol‐boronate bidentate complex formation in situ, which absorbs visible light to reach the excited state for the chemoselective 1,3‐boronate rearrangement to ketones. Experimental and computational investigations exclude free radical intermediates from organoboronates. The aryl, alkenyl, and alkyl boronic acids react with various 1,3‐diketones driven by visible light irradiation to construct structurally diverse β‐keto tertiary alcohols under metal‐free conditions. The reaction demonstrates substrate diversity with 58 examples, yields up to 98 %, and it is suitable for gram‐scale synthesis.

Metal-Free 1,3-Boronate Rearrangement to Ketones Driven by Visible Light.

Boronate rearrangements, such as the Matteson and Petasis reactions, are valuable metal-free reactions for the transfer of the carbo group on boron to intramolecular electrophilic sites. However, only highly reactive electrophiles are suitable, and ketones are too inactive for those boronate rearrangements due to the high energy barriers. We disclose here the 1,3-boronate rearrangement to ketones, for which a high energy barrier (44.9 kcal/mol) is prohibitory for thermal reactions in the ground state. The reaction is enabled by the key keto-enol-boronate bidentate complex formation in situ, which absorbs visible light to reach the excited state for the chemoselective 1,3-boronate rearrangement to ketones. Experimental and computational investigations exclude free radical intermediates from organoboronates. The aryl, alkenyl, and alkyl boronic acids react with various 1,3-diketones driven by visible light irradiation to construct structurally diverse β-keto tertiary alcohols under metal-free conditions. The reaction demonstrates substrate diversity with 58 examples, yields up to 98 %, and it is suitable for gram-scale synthesis.

Recent Trends in the Petasis Reaction: A Review of Novel Catalytic Synthetic Approaches with Applications of the Petasis Reaction.

The Petasis reaction, also called the Petasis Borono-Mannich reaction, is a multicomponent reaction that couples a carbonyl derivative, an amine and boronic acids to yield substituted amines. The reaction proceeds efficiently in the presence or absence of a specific catalyst and solvent. By employing this reaction, a diverse range of chiral derivatives can easily be obtained, including α-amino acids. A broad substrate scope, high yields, distinct functional group tolerance and the availability of diverse catalytic systems constitute key features of this reaction. In this review article, attention has been drawn toward the recently reported methodologies for executing the Petasis reaction to produce structurally simple to complex aryl/allyl amino scaffolds.

A Palladium-Catalyzed Borylation/Silica Gel Promoted Hydrolysis Sequence for the Synthesis of Hydroquinine-6'-Boric Acid and Its Applications.

Hydroquinine-6'-boric acid was first synthesized via a palladium-catalyzed borylation/silica gel promoted hydrolysis sequence of hydroquinine-derived triflate and bis(pinacolato)diboron. The newly designed chiral building block was subjected to the Suzuki-Miyaura cross-coupling reaction, Petasis reaction, and selenylation reaction, respectively, and all these reactions worked well to afford the corresponding 6'-functionalized hydroquinines with satisfactory results, demonstrating its extraordinary application potency.

Tryptophan in Multicomponent Petasis Reactions for Peptide Stapling and Late‐Stage Functionalisation

AbstractPeptide stapling is a robust strategy for generating enzymatically stable, macrocyclic peptides. The incorporation of biologically relevant tags (such as cell‐penetrating motifs or fluorescent dyes) into peptides, while preserving their binding interactions and enhancing their stability, is highly sought after. Despite the unique opportunities offered by tryptophan‘s indole scaffold for targeted functionalisation, its utilisation in peptide stapling has been limited as compared to other amino acids. Herein, we present an approach for peptide stapling using the tryptophan‐mediated Petasis reaction. This method enables the synthesis of both stapled and labelled peptides and is applicable to both solution and solid‐phase synthesis. Importantly, the use of the Petasis reaction in combination with tryptophan facilitates the formation of stapled peptides in a straightforward, multicomponent fashion, while circumventing the formation of undesired by‐products. Furthermore, this approach allows for efficient and diverse late‐stage peptide modifications, thereby enabling rapid production of numerous conjugates for biological and medicinal applications.

Cover Feature: Catalyst‐Free Three‐Component Petasis Reactions Accelerated in Microdroplets: Reaction Optimization and Senstive Detection by Mass Spectrometry (Anal. Sens. 6/2023)

Cover Feature: Catalyst‐Free Three‐Component Petasis Reactions Accelerated in Microdroplets: Reaction Optimization and Senstive Detection by Mass Spectrometry (Anal. Sens. 6/2023)

Catalyst‐Free Three‐Component Petasis Reactions Accelerated in Microdroplets: Reaction Optimization and Senstive Detection by Mass Spectrometry

AbstractDue to their important roles in medicine, the product of the Petasis reaction has attracted extensive interest in pharmaceutical, medical and chemical communities. Traditional three‐component Petasis methods normally use various catalysts under harsh conditions (high temperature, microwave, etc.) for long reaction times. In this study, we developed a green and highly efficient microdroplet method for accelerating the Petasis reaction, which obtain good yields without the need of any catalysts under mild reaction conditions. The Petasis reaction in microdroplets was suitable for a variety of salicylaldehydes, arylboronic acids and amines. The Petasis reaction in microdroplets was accelerated by approximately 4 orders of magnitude by comparing the measured rate constants in bulk. Further, a scaled‐up amount of 0.8 g h−1 was achieved for the Petasis reaction in microdroplets. This study supplies not only a high‐efficiency and environment‐friendly methodology to constructing aryl amines in organic community but also a useful derivatization strategy for highly sensitive mass spectrometric detection of arylboronic acids and aryl aldehydes.

The Asymmetric Petasis Borono-Mannich Reaction: Insights on the Last 15 Years

The Petasis borono-Mannich reaction, commonly described as the Petasis reaction, was one of the latest famous multicomponent reactions described in the literature. Currently celebrating its 30th anniversary since it was first reported by Petasis and Akritopoulou in 1993, this reaction has emerged as a powerful tool for the synthesis of biologically relevant molecules (such as substituted amines or amino acids), among others. This three-component catalyst-free reaction (the classic model), involving the coupling of an aldehyde, an amine, and a boronic acid, enables the synthesis of polysubstituted amine-containing molecules. Several accounts regarding the catalyst-free version using different carbonyl, amine, and boron-type components have been reported thus far. In contrast, the asymmetric version is still in its infancy since it was first reported in 2007. In this work, we aim to review the asymmetric versions of the Petasis reaction reported over the last 15 years, considering the chiral pool approach (asymmetric induction by one reaction component) and the use of catalysts (organocatalysts, transition-metal catalysts, and others) to access enantiomeric and diastereomeric pure amino-derivatives. Insights regarding the catalyzed Petasis reaction and consequent sustainable synthesis will be highlighted.

Development of diphenylmethylpiperazine hybrids of chloroquinoline and triazolopyrimidine using Petasis reaction as new cysteine proteases inhibitors for malaria therapeutics

Malaria is a widespread infectious disease, causing nearly 247 million cases in 2021. The absence of a broadly effective vaccine and rapidly decreasing effectiveness of most of the currently used antimalarials are the major challenges to malaria eradication efforts. To design and develop novel antimalarials, we synthesized a series of 4,7-dichloroquinoline and methyltriazolopyrimidine analogues using a multi-component Petasis reaction. The synthesized molecules (11–31) were screened for in-vitro antimalarial activity against drug-sensitive and drug-resistant strains of Plasmodium falciparum with an IC50 value of 0.53 μM. The selected compounds were screened to evaluate in-vitro and in-silico enzyme inhibition efficacy against two cysteine proteases, PfFP2 and PfFP3. The compounds 15 and 17 inhibited PfFP2 with an IC50 = 3.5 and 4.8 μM, respectively and PfFP3 with an IC50 = 4.9 and 4.7 μM, respectively. Compounds 15 and 17 were found equipotent against the Pf3D7 strain with an IC50 value of 0.74 μM, whereas both were displayed IC50 values of 1.05 μM and 1.24 μM for the PfW2 strain, respectively. Investigation of effect of compounds on parasite development demonstrated that compounds were able to arrest the growth of the parasites at trophozoite stage. The selected compounds were screened for in-vitro cytotoxicity against mammalian lines and human red-blood-cell (RBC), which demonstrated no significant cytotoxicity associated with the molecules. In addition, in silico ADME prediction and physiochemical properties supported the drug-likeness of the synthesized molecules. Thus, the results highlighted the diphenylmethylpiperazine group cast on 4,7-dichloroquinoline and methyltriazolopyrimidine using Petasis reaction may serve as models for the development of new antimalarial agents.

Multicomponent Petasis reaction for the identification of pyrazine based multi-target directed anti-Alzheimer's agents: In-silico design, synthesis, and characterization

Multi-target directed ligands (MTDLs) have recently attracted significant interest due to their exceptional effectiveness against multi-factorial Alzheimer's disease. The present work described the development of pyrazine-based MTDLs using multicomponent Petasis reaction for the dual inhibition of tau-aggregation and human acetylcholinesterase (hAChE). The molecular structure of synthesized ligands was validated by 1H &13C NMR and mass spectrometry. The screened compounds were shown to have a strong inhibitory effect at 10 μM concentration against tau-oligomerization and hAChE, but only moderate inhibitory activity against Aβ42. Among all the compounds, the half-maximal inhibitory concentration (IC50) for 21 and 24 against hAChE were 0.71 μM and 1.09 μM, respectively, while they displayed half-maximal effective concentrations (EC50) values of 2.21 μM and 2.71 μM for cellular tau-oligomerization, respectively. Additionally, an MTT experiment using tau-expressing SH-SY5Y neuroblastoma cells revealed that 21 was more neuroprotective than the FDA-approved medication donepezil. Furthermore, an MD simulation study was performed to investigate the dynamics and stability of AChE-21 and AChE-24 complexes in an aqueous environment. The MM-PBSA calculations were performed to evaluate the binding of 21 and 24 with AChE, and the relative binding energy was calculated as −870.578 and −875.697 kJ mol−1, respectively. As a result, the study offered insight into the design of new MTDLs and highlighted 21 as a potential roadblock to the development of anti-AD medications.

Diastereoselective Synthesis of (–)-6,7-Dimethoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxylic Acid via Morpholinone Derivatives

A simple and convenient synthesis of (-)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid is described, applying a combination of two synthetic methods: the Petasis reaction and Pomeranz-Fritsch-Bobbitt cyclization. The diastereomeric morpholinone derivative N-(2,2-diethoxyethyl)-3-(3,4-dimethoxyphenyl)-5-phenyl-1,4-oxazin-2-one formed in the Petasis reaction was further transformed into 1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid via Pomeranz-Fritsch-Bobbitt cyclization, a classical method of synthesis leading to the tetrahydroisoquinoline core. We review important examples of applications of the Pomeranz-Fritsch process and its modifications in the synthesis of chiral tetrahydroisoquinoline derivatives that have been published in the past two decades.

Construction of Covalent Organic Frameworks via a Visible-Light-Activated Photocatalytic Multicomponent Reaction.

Multicomponent reactions (MCRs), as a powerful one-pot combinatorial synthesis tool, have been recently applied to the synthesis of covalent organic frameworks (COFs). Compared with the thermally driven MCRs, the photocatalytic MCR-based COF synthesis has not yet been investigated. Herein, we first report the construction of COFs by a photocatalytic multicomponent reaction. Upon visible-light irradiation, a series of COFs with excellent crystallinity, stability, and permanent porosity are successfully synthesized via photoredox-catalyzed multicomponent Petasis reaction under ambient conditions. Additionally, the obtained Cy-N3-COF exhibits excellent photoactivity and recyclability for the visible-light-driven oxidative hydroxylation of arylboronic acids. The concept of photocatalytic multicomponent polymerization not only enriches the methodology for COF synthesis but also opens a new avenue for the construction of COFs that might not be possible with the existing synthetic methods based on thermally driven MCRs.

The Chelate Effect Rationalizes Observed Rate Acceleration and Enantioselectivity in BINOL-Catalyzed Petasis Reactions.

Density functional theory (DFT) calculations afforded insight into the origin of the experimentally observed reaction rate acceleration (≥500 fold) and enantioselectivity (≥99 % ee) of 1,1'-bi-2-naphthol- (BINOL-) catalyzed three-component Petasis reactions . BINOL accelerates the rate determining step by forming a BIV chelate, which involves the loss of water from the hemiaminal moiety to generate an iminium intermediate. Subsequent vinyl group transfer from BIV to the iminium carbon affords the enantiomerically enriched product and a cyclic trigonal B(III)BINOL complex, which rapidly releases the BINOL allowing it to re-enter the catalytic cycle. In the transition state of the vinyl transfer step, C-H-O hydrogen bonding between the iminium C-H and O of (R)-BINOL directs the vinyl group addition to the Re-face of the iminium carbon. This mechanism explains both the rate acceleration and high enantioselectivity of the stereo determining step.