Energizing Listless Pyrimidines by Pre-Distortion for the General Synthesis of 7-Aza-Indazoles from 2-Hydrazonylpyrimidines via Intramolecular Diels-Alder Reactions

2019 ◽  
Author(s):  
Vincent Le Fouler ◽  
yu Chen ◽  
Vincent Gandon ◽  
Vincent Bizet ◽  
Christophe Salomé ◽  
...  
Keyword(s):  
Transition State ◽  
Medicinal Chemistry ◽  
Functional Group ◽  
Diels Alder ◽  
Quantum Mechanical ◽  
Quantum Mechanical Calculations ◽  
Mild Conditions ◽  
General Synthesis

<p>Pyrimidines are almost unreactive partners in Diels-Alder cycloadditions with alkenes and alkynes, and usually only reactions under drastic conditions were historically reported. We describe how 2-hydrazonylpyrimidines, easily obtained in two steps from commercially available 2-halopyrimidines can be exceptionally activated by trifluoro acetylation. This allows a Diels-Alder cycloaddition under very mild conditions, leading to a large diversity of <i>aza</i>-indazoles, a ubiquitous scaffold in medicinal chemistry. This reaction is general, scalable and has an excellent functional group tolerance. Quantum mechanical calculations show how the simple <i>N</i>-trifluoromethylation of 2-hydrazonylpyrimidines distorts the substrate into a transition state-like geometry that readily undergoes the intramolecular Diels-Alder cycloaddition. </p>

Energizing Listless Pyrimidines by Pre-Distortion for the General Synthesis of 7-Aza-Indazoles from 2-Hydrazonylpyrimidines via Intramolecular Diels-Alder Reactions

2019 ◽  
Author(s):  
Vincent Le Fouler ◽  
yu Chen ◽  
Vincent Gandon ◽  
Vincent Bizet ◽  
Christophe Salomé ◽  
...  
Keyword(s):  
Transition State ◽  
Medicinal Chemistry ◽  
Functional Group ◽  
Diels Alder ◽  
Quantum Mechanical ◽  
Quantum Mechanical Calculations ◽  
Mild Conditions ◽  
General Synthesis

<p>Pyrimidines are almost unreactive partners in Diels-Alder cycloadditions with alkenes and alkynes, and usually only reactions under drastic conditions were historically reported. We describe how 2-hydrazonylpyrimidines, easily obtained in two steps from commercially available 2-halopyrimidines can be exceptionally activated by trifluoro acetylation. This allows a Diels-Alder cycloaddition under very mild conditions, leading to a large diversity of <i>aza</i>-indazoles, a ubiquitous scaffold in medicinal chemistry. This reaction is general, scalable and has an excellent functional group tolerance. Quantum mechanical calculations show how the simple <i>N</i>-trifluoromethylation of 2-hydrazonylpyrimidines distorts the substrate into a transition state-like geometry that readily undergoes the intramolecular Diels-Alder cycloaddition. </p>

Decarboxylative, diastereoselective and exo-selective 1,3-dipolar cycloaddition for diversity-oriented construction of structurally spiro-[butyrolactone-pyrrolidine-chromanone] hybrids

Synlett ◽  
2021 ◽  
Author(s):  
Dong-Gui Guo ◽  
Zheng Li ◽  
Xiao-Xue Han ◽  
Lei Zhang ◽  
Min Zhang ◽  
...  
Keyword(s):  
Carboxylic Acid ◽  
Transition State ◽  
Medicinal Chemistry ◽  
Homoserine Lactone ◽  
Azomethine Ylides ◽  
Dipolar Cycloaddition ◽  
Mild Conditions ◽  
Good Substrate ◽  
Substrate Tolerance

Inspired by the chemistry and biology of butyrolactones, pyrrolidines and chromanones, herein we successfully developed a simple domino 1,3-dipolar cycloaddition of homoserine lactone-derived azomethine ylides for construction of biologically important spiro-[butyrolactone-pyrrolidine-chromanone] hybrids in the presence of the catalyst Et3N under mild conditions. It is based on the application of carboxylic acid activated chromones as dienophiles followed by a decarboxylation process. This reaction displayed good substrate tolerance and gave the desired products in moderate to good yields with high diastereoselectivities via an exo-transition state (up to 85% yield and >20:1 diastereomeric ratio). In particular, this is the first example of introduction of chromanone moiety into spiro [butyrolactone-pyrrolidine] frameworks, which might be valuable in medicinal chemistry.

The acidity of β-phosphoglucomutase monofluoromethylenephosphonate ligands probed by NMR spectroscopy and quantum mechanical methods

2016 ◽  
Vol 94 (11) ◽  
pp. 902-908 ◽  
Author(s):  
Stephanie M. Forget ◽  
Eric A.C. Bushnell ◽  
Russell J. Boyd ◽  
David L. Jakeman
Keyword(s):  
Nmr Spectroscopy ◽  
Transition State ◽  
Quantum Mechanical ◽  
Phosphoryl Transfer ◽  
Quantum Mechanical Calculations ◽  
Transition State Analogues ◽  
Mechanical Methods ◽  
Insight Into ◽  
Computational Quantum

We recently described the binding of 1-β-phosphonomethylene-1-deoxy-d-glucopyranose, (S)-1-β-phosphonofluoromethylene-1-deoxy-D-glucopyranose (βG1CFSP), and (R)-1-β-phosphonofluoromethylene-1-deoxy-d-glucopyranose (βG1CFRP) to the enzyme β-phosphoglucomutase as transition state analogues of phosphoryl transfer through formation of stable MgF3− and AlF4− complexes (Proc. Natl. Acad. Sci. U.S.A. 2014, 111, 12384). Herein, we describe in detail the five-fold difference in acidity (pKa2) for the (S)- and (R)-configured diastereomeric fluorophosphonates through a series of NMR spectroscopy experiments. The differences in acidity were corroborated using computational quantum mechanical calculations to determine structures of lowest energy conformers and provide insight into why the (S) isomer is substantially more acidic.

Quantum Mechanical Calculations to Assess the Antireversion Effects of Several Dienophiles

2001 ◽  
Vol 74 (4) ◽  
pp. 574-582
Author(s):  
A. G. Talma ◽  
R. N. Datta ◽  
J. Aerts
Keyword(s):  
Double Bond ◽  
Alder Reaction ◽  
Diels Alder ◽  
Experimental Results ◽  
Quantum Mechanical ◽  
Quantum Mechanical Calculations ◽  
Diels Alder Reaction

Abstract The utilization of Quantum mechanical calculations for substituted dienophiles in the Diels—Alder reaction is very useful in assessing the antireversion effect of various dienophiles. It has been demonstrated that citraconimides provide better antireversion properties than maleimides. A useful explanation is that although maleimides are better dienophiles, they do not survive the vulcanization medium and consequently are not available during the onset of reversion. The antireversion effect of dienophiles varies with the electronic and steric nature of the substituents on the double bond of the dienophile. Calculations are made to demonstrate the effectiveness of various dienophiles in a Diels—Alder reaction. A good correlation has been obtained between the calculations and experimental results.

Simple Synthesis of Complex Amines from the Diels–Alder Adducts of (–)-Cytisine

Synthesis ◽  
2021 ◽  
Author(s):  
Alexander Shivanyuk ◽  
Alexey Chuyko ◽  
Grygoriy Dolgonos ◽  
Volodymyr Fetyukhin ◽  
Oleg Lukin
Keyword(s):  
Quantum Chemical ◽  
Alder Reaction ◽  
Diels Alder ◽  
Secondary Amines ◽  
Quantum Mechanical ◽  
Quantum Mechanical Calculations ◽  
Carbonyl Groups ◽  
Model Compounds ◽  
Reaction Progress ◽  
Diels Alder Reaction

AbstractThe Diels–Alder reaction of N-benzylcytisine with N-methyl- and N-benzylmaleimides is 100% endo-selective and gives the corresponding syn- and anti-diastereomers in 11–42% isolated yields. The studies of the reaction progress with LCMS and NMR along with detailed quantum chemical calculations revealed that some Diels–Alder adducts are kinetically and their isomers are thermodynamically controlled products. The Pd/C-catalyzed hydrogenation of benzyl-protected cytisine amine derivatives resulted in the removal of the benzyl group and the addition of hydrogen to the C=C double bond to give the corresponding secondary amines in 45–84% yield. The complete reduction of carbonyl groups in a cytisine derivative with LiAlH4 in THF under reflux afforded the respective tricyclic triamine. Quantum mechanical calculations for the mechanism of the Diels–Alder reaction between the simplest model compounds are presented.

SuFEx Activation with Ca(NTf2)2: A Unified Strategy to Access Sulfamides, Sulfamates and Sulfonamides from S(VI) Fluorides

2020 ◽  
Author(s):  
Subham Mahapatra ◽  
Cristian P. Woroch ◽  
Todd W. Butler ◽  
Sabrina N. Carneiro ◽  
Sabrina C. Kwan ◽  
...  
Keyword(s):  
Room Temperature ◽  
Medicinal Chemistry ◽  
Mild Conditions ◽  
Broad Array

<p><br></p> <p>A method to activate sulfamoyl fluorides, fluorosulfates, and sulfonyl fluorides with calcium triflimide, and DABCO for SuFEx with amines is described. The reaction was applied to a diverse set of sulfamides, sulfamates, and sulfonamides at room temperature under mild conditions. Additionally, we highlight the application of this transformation to parallel medicinal chemistry to generate a broad array of nitrogen-based S(VI) compounds. </p>

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