Parham Cyclization Research Articles

Perturbation-Theory and Machine Learning (PTML) Model for High-Throughput Screening of Parham Reactions: Experimental and Theoretical Studies.

Machine learning (ML) algorithms are gaining importance in the processing of chemical information and modeling of chemical reactivity problems. In this work, we have developed a perturbation-theory and machine learning (PTML) model combining perturbation theory (PT) and ML algorithms for predicting the yield of a given reaction. For this purpose, we have selected Parham cyclization, which is a general and powerful tool for the synthesis of heterocyclic and carbocyclic compounds. This reaction has both structural (substitution pattern on the substrate, internal electrophile, ring size, etc.) and operational variables (organolithium reagent, solvent, temperature, time, etc.), so predicting the effect of changes on substrate design (internal elelctrophile, halide, etc.) or reaction conditions on the yield is an important task that could help to optimize the reaction design. The PTML model developed uses PT operators to account for perturbations under experimental conditions and/or structural variables of all the molecules involved in a query reaction, compared to a reaction of reference. Thus, a dataset of >100 reactions has been collected for different substrates and internal electrophiles, under different reaction conditions, with a wide range of yields (0-98%). The best PTML model found using General Linear Regression (GLR) has R = 0.88 in training and R = 0.83 in external validation series for 10 000 pairs of query and reference reactions. The PTML model has a final R = 0.95 for all reactions using multiple reactions of reference. We also report a comparative study of linear versus nonlinear PTML models based on artificial neural network (ANN) algorithms. PTML-ANN models (LNN, MLP, RBF) with R ≈ 0.1-0.8 do not outperform the first PMTL model. This result confirms the validity of the linearity of the model. Next, we carried out an experimental and theoretical study of nonreported Parham reactions to illustrate the practical use of the PTML model. A 500 000-point simulation and a Hammett analysis of the reactivity space of Parham reactions are also reported.

A Parham Cyclization route to the 2,3-dihydro-1H-indazole-1,2-dicarboxylate ring systems via condensation of thermolabile aryllithium reagents and azodicarboxylate esters

The Parham Cyclization reaction of o-lithiobenzyl chlorides (generated by low temperature halogen-metal exchange of the corresponding o-bromobenzyl chlorides with n-butyllithium) with azodicarboxylate esters provides a new entry to the 2,3-dihydro-1H-indazole-1,2-dicarboxylate ring system in moderate to good yield.

A Parham cyclization approach to diaryl-fused seven-membered ring heterocyclic ketones

Aryl-fused seven membered heterocyclic frameworks appear in a variety of pharmaceutically pertinent compounds. However, only a very few methods for their preparation have been described. This work describes a novel synthesis route to diaryl-fused seven membered heterocyclic ketones through the generation of functionalized aryllithiums by bromine–lithium exchange, followed by intramolecular cyclization onto an electrophilic nitrile functional group. The resulting N-lithioimine can then be hydrolyzed to the desired ketone, generally in good yields. The order of addition of n-butyllithium is crucial to the process with inverse addition proving to mitigate side product formation and increase yields.

Multiple Organolithium Generation in the Continuous Flow Synthesis of Amitriptyline

AbstractA continuous flow protocol for the preparation of the tricyclic antidepressant (TCA) amitriptyline is reported. The advantages of flow chemistry when handling organometallic agents as well as when performing reaction with gases are demonstrated. Continuous multilithiation combined with carboxylation and the Parham cyclization, a Grignard addition and thermolytic water elimination by inductive heating are key features of the multistep protocol.magnified image

ChemInform Abstract: First and Efficient Synthesis of 14‐Aminophenanthroindolizidine Alkaloids.

AbstractA short route is developed for the synthesis of 14‐aminophenanthroindolizidines (VII) via dehydration of amides (III) with TFAA and Parham cyclization of resulting nitriles (IV).

Synthesis of 2-hydroxy-3-indolinones and 3-hydroxy-2-indolinones by anionic cyclization, in situ oxidation and rearrangement

Lithiation with butyllithium of 2-(benzylamino)benzamides (N-benzyl anthranilamides) occurs at the benzylic position to give an alpha-amino-organolithium that cyclizes to the 3-indolinone (indoxyl) ring (similar to a Parham cyclization). Autoxidation in air gives 2-hydroxy-3-indolinones. In the absence of a proton source, rearrangement of the aryl group from C-2 to C-3 occurs to give the 3-hydroxy-2-indolinone (oxindole) ring. (C) 2010 Elsevier Ltd. All rights reserved.

ChemInform Abstract: β‐Nitrostyrenes as Electrophiles in Parham Cyclization Chemistry: Reaction with o‐Lithiobenzonitrile.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

β-Nitrostyrenes as electrophiles in Parham cyclization chemistry: reaction with o-lithiobenzonitrile

β-Nitrostyrenes react with o-lithiobenzonitrile, generated from the requisite aryl bromide at −100 °C by bromine–lithium exchange with n-butyllithium in THF, to afford 2-nitro-3-phenyl-3 H-inden-1-ylamines resulting from 1,4-addition to the β-nitrostyrene followed by intramolecular capture of the resultant nitronate anion by the ortho-cyano functional group.

Synthesis of Pyrrolo[1,2-b]isoquinolines through Mesityllithium-Mediated Intramolecular Carbolithiation

Mesityllithium has proven to be an effective iodine-lithium exchange reagent. Thus, carbolithiation reactions on 2-alkenyl-substituted N-(o-iodobenzyl)pyrroles have been accomplished avoiding side reactions to afford pyrroloisoquinolines in high yields (80-92%), improving the results obtained with t-BuLi. The carbolithiation reaction requires the use of electron-deficient alkenes. Mesityllithium has also been studied as an alternative to t-BuLi in Parham cyclization with other internal electrophiles (aldehyde, ketone, ester, amide), proving to be more selective and efficient than t-BuLi.

Alternative and complementary approaches to the asymmetric synthesis of C3 substituted NH free or N-substituted isoindolin-1-ones

Complementary synthetic approaches to enantiomerically pure C3 alkylated or arylated NH free or N-substituted isoindolinones have been developed. The key step is elaboration of diversely substituted 2-alkyl- and arylbenzylamines, which can be submitted to a bis-metallation process followed by interception with a carbonylating agent. They can be also converted into N-alkylbromobenzylcarbamates or into bromobenzyldicarbamates and the assembly of the titled compounds can be readily ensured by reliance upon the Parham cyclization process.

C-10b Functionalized 5,6-dihydropyrrolo[2,1-a]isoquinolines as intermediates in the synthesis of erythrinane systems. Intra- vs. intermolecular conjugate addition based strategies

C-10b Functionalized 5,6-dihydropyrrolo(2,1-a)isoquinolines have been prepared via Parham cyclization and α-amidoalkylation reactions, using functionalized organolithium reagents. Their utility as intermediates in the synthesis of erythrinanes via intra or intermolecular conjugate addition reactions has been studied. Thus, a protocol for preparing the erythrinane skeleton through a Parham cyclization−intermolecular α-amidoalkylation−intermolecular conjugate addition−ring-closing metathesis process has been described.

A New Total Synthesis of Porritoxin

A concise and efficient total synthesis of the phytotoxin porritoxin is described. The key step of the synthesis is based upon a Parham cyclization methodology which enables the creation of the lactam unit embedded in the title compound framework with the concomitant formation of the tethered hydroxyakyl chain.

A brief total synthesis of fumaramidine

The first total synthesis of the alkaloid fumaramidine is reported. The synthetic tactics involve the sequential construction of the isoindolinone template by a Parham cyclization process followed by benzylic lactam deprotonation, interception with the suitable carboxaldehyde and ultimate E1cb elimination. Final N-lactam deprotection completes the synthesis of the Z configured title compound.

An Efficient Entry to Pyrrolo[1,2‐b]isoquinolines and Related Systems Through Parham Cyclization.

AbstractFor Abstract see ChemInform Abstract in Full Text.

First total synthesis of cichorine and zinnimidine

The first total synthesis of the phytotoxins cichorine and zinnimidine is described. The synthetic tactics involve the sequential connection of the dense and diverse functionalities on the aromatic nucleus followed by a Parham cyclization process, giving rise to the lactam unit embedded in the title compound framework.

Enantiodivergent Synthesis of Pyrrolo[2,1‐a]isoquinolines Based on Diastereoselective Parham Cyclization and α‐Amidoalkylation Reactions.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Enantiodivergent synthesis of pyrrolo[2,1-a]isoquinolines based on diastereoselective Parham cyclization and alpha-amidoalkylation reactions.

Enantiodivergent synthesis of C-10b-substituted pyrrolo[2,1-a]isoquinolines starting from an enantiomerically pure N-phenethylnorborn-5-en-endo-2,3-dicarboxyimide 3a, with a 2-exo-hydroxy-10-bornylsulfinyl group as a chiral auxiliary, has been developed. The key transformations are derived from diastereoselective intramolecular cyclization of aryllithiums and alpha-amidoalkylation reactions, with the ethylidene bridge of the norbornene moiety dictating the stereochemical outcome in both types of reactions. Thus, the organolithium addition-intramolecular alpha-amidoalkylation sequence on imide 3a afforded stereoselectively the R configuration at C-12b, whereas the tandem Parham cyclization-intermolecular alpha-amidoalkylation reactions on the corresponding iodinated imide 3b occurred with complete control of stereoselectivity, leading to the epimer at C-12b. Subsequent reductive removal of the chiral auxiliary and retro-Diels-Alder reaction afforded (10bS)- and (10bR)-pyrroloisoquinolines 1 in high yields and optical purities (>99% ee).

Recent Advances in the Parham Cyclization for the Synthesis of Heterocyclic Systems

AbstractFor Abstract see ChemInform Abstract in Full Text.

Aryl and Heteroaryllithium Compounds by Metal - Halogen Exchange. Synthesis of Carbocyclic and Heterocyclic Systems

The aromatic metalation - cyclization sequence is a valuable protocol for the regiospecific construction of carbocyclic and heterocyclic systems. Aromatic lithiation can be carried out by lithium - hydrogen or lithium - halogen exchange. The latter procedure, though mechanistically controversial, is the method of choice to introduce specifically a lithium atom into a given, non-activated position of the aromatic ring. Once generated, the aryllithiums may react with external or internal electrophiles and thus give rise to cyclization reactions, which are known as Parham cyclization. In addition to the carbon - carbon bond formation, the aromatic lithiation allows the introduction of further functionality to the molecule. Therefore, strategies based aromatic lithiation can play a crucial role in natural products synthesis. In this review we will survey some recent advances on the application of the aromatic lithiation - cyclization sequence for the synthesis of different types of carbocycles and heterocycles. We have limited it to the metalation reactions, where the aryl and hetero-aryllithium intermediates are generated by the metal - halogen exchange reaction. Major emphasis will be placed on stereoselectivity of the metalation - cyclization sequence, since it has received only sporadic attention.

Stereodivergent Synthesis of Hetero-Fused Isoquinolines by Acyliminium and Metallation Methods

Diastereodivergent syntheses of 1,10b-cis- and 1,10b-trans-thiazolo[4,3-a]isoquinoline systems are reported. The key transformations are based on the intramolecular cyclization of aryllithiums and N-acyliminium ions. With 5-substituted N-phenethylthiazolidinediones as substrates, hydride reduction or the organolithium addition−N-acyliminium cyclization sequence stereoselectively afforded the 1,10b-cis derivatives. Alternatively, the tandem Parham cyclization−hydroxyl reduction using the corresponding iodinated thiazolidinediones occurred with complete control of stereoselectivity, producing the 1,10b-trans diastereomers. Although it was not possible to synthesise imidazo[4,3-a]isoquinolinones by N-acyliminium cyclizations, application of the Parham cyclization−reduction sequence to N-phenethylhydantoins constituted an efficient alternative for the synthesis of these hetero-fused isoquinolines with 1,10b-trans stereochemistry. Ready access to 1-phenethylisoquinolines is also described.