Analogy of the Reactions of Aromatic and Aliphatic π-Electrophiles with Nucleophiles.

The aim of this essay is to disclose the similarity of a great variety of reactions that proceed between nucleophiles and π-electrophiles-both aromatic and aliphatic. These reactions proceed via initial reversible addition, followed by a variety of transformations that are common for the adducts of both aliphatic and aromatic electrophiles. We hope that understanding of this analogy should help to expand the scope of the known reactions and inspire the search for new reactions that were overlooked.

Synthesis of Isoindole N-Oxides by Palladium-Catalyzed C-H Functionalization of Aldonitrones.

A palladium-catalyzed strategy for isoindole N-oxide ring construction by C-H functionalization of aldonitrones is described. Our protocol is of general character, providing isoindole N-oxides with a variety of functional groups, including very sterically congested products. Further transformations into spirocyclic isoindolines, isoindoles, or a polycyclic isoquinolinium salt have been demonstrated as well. A mechanistic study suggests that the catalytic process proceeds via a Heck-type addition to the double C═N bond.

Synthesis of quinoxaline derivatives via aromatic nucleophilic substitution of hydrogen.

The electrophilic nature of quinoxaline has been explored in the vicarious nucleophilic substitution (VNS) of hydrogen with various carbanions as nucleophiles in an attempt to develop a general method for functionalizing the heterocyclic ring. Only poorly stabilized nitrile carbanions were found to give the VNS products. 2-Chloroquinoxaline gave products of SNAr of chlorine preferentially. A variety of quinoxaline derivatives containing cyanoalkyl, sulfonylalkyl, benzyl or ester substituents, including fluorinated ones, have been prepared in the VNS reactions with quinoxaline N-oxide.

Palladium-Catalyzed Access to Benzocyclobutenone-Derived Ketonitrones via C(sp2)-H Functionalization.

The palladium-catalyzed C(sp2)-H functionalization of bromoaryl aldonitrones leading to benzocyclobutenone-derived ketonitrones is described. This method allows for the preparation of a wide range of strained, four-membered ketonitrones with broad functional group tolerance. Downstream transformations of the formed products were readily demonstrated, illustrating the synthetic utility of the obtained benzocyclobutenone-derived nitrones for the construction of polycyclic nitrogen-containing scaffolds.

Molecule Edit Graph Attention Network: Modeling Chemical Reactions as Sequences of Graph Edits.

The central challenge in automated synthesis planning is to be able to generate and predict outcomes of a diverse set of chemical reactions. In particular, in many cases, the most likely synthesis pathway cannot be applied due to additional constraints, which requires proposing alternative chemical reactions. With this in mind, we present Molecule Edit Graph Attention Network (MEGAN), an end-to-end encoder-decoder neural model. MEGAN is inspired by models that express a chemical reaction as a sequence of graph edits, akin to the arrow pushing formalism. We extend this model to retrosynthesis prediction (predicting substrates given the product of a chemical reaction) and scale it up to large data sets. We argue that representing the reaction as a sequence of edits enables MEGAN to efficiently explore the space of plausible chemical reactions, maintaining the flexibility of modeling the reaction in an end-to-end fashion and achieving state-of-the-art accuracy in standard benchmarks. Code and trained models are made available online at https://github.com/molecule-one/megan.

α-Chlorobenzylation of Nitroarenes via Vicarious Nucleophilic Substitution with Benzylidene Dichloride: Umpolung of the Friedel-Crafts Reaction.

Readily available α,α-dichlorotoluenes enter a vicarious nucleophilic substitution (VNS) reaction with electron-deficient arenes to give α-chlorobenzylated nitrobenzenes, as well as six- and five-membered heterocycles. Oxidation of the initially formed α-chlorobenzylic carbanions instead of protonation results in formation of diaryl ketones, providing a means for overall nucleophilic C-H benzoylation of electron-deficient aromatic rings. Alternatively, benzoylated nitroarenes can be obtained via the reaction of isolated α-chlorodiarylmethanes with sodium azide.

Synthesis of α-Fluoro-α-nitroarylacetates via Vicarious Nucleophilic Substitution of Hydrogen.

Readily available ethyl chlorofluoroacetate, when treated with a strong base, forms an α-chloro-α-fluorocarbanion that adds to nitroarenes at a position ortho or para to the nitro group with formation of anionic σH adducts. Subsequent base-induced ß-elimination of HCl proceeds selectively to give nitrobenzylic α-fluorocarbanions and, upon protonation, ethyl α-fluoro-α-nitroarylacetates.

A three-component synthesis of aryl(heteroaryl)acylamides.

A three-component reaction of azole or azine N-oxides, 1,1-difluorostyrenes and amines gives amides of α-aryl-α-heteroarylacetic or propionic acids. The key step is 1,3-dipolar cycloaddition between N-oxide and difluorostyrene leading to the acyl fluoride intermediate, which has been identified and characterized by NMR spectroscopy. The whole process is an example of selective functionalization of C-H bonds in both 5- and 6-membered heterocyclic systems.

Synthesis of alkyl aryl(heteroaryl)acetates from N-oxides, 1,1-difluorostyrenes, and alcohols.

Derivatives of aryl(heteroaryl)acetic acids or aryl(heteroaryl)methanes are formed from imidazole or thiazole N-oxide, 1,1-difluorostyrene, and an alcohol, amine, or water in a three-component reaction, which probably occurs via 1,3-dipolar cycloaddition. The whole process is a novel method for functionalization of a heterocyclic ring in a position originally occupied by hydrogen. Preliminary experiments show that it occurs for 6-membered N-oxides as well.

Selective modifications of hydrophobic vitamin B12 derivatives at c-and d-positions.

The acid-sensitivity of vitamin B(12) derived mono- and diamides was studied. It was found that the use of reductive ring-opening of the lactone moiety deactivated undesired decomposition of c-mono- and c,d-diamides under acidic conditions. As a result, reactions gave respectively c- or d-acids which were further functionalized via coupling with amino acids. Though mono- and diamides exhibited acid sensitivity, they were used for the preparation of several highly functionalized molecules showing their stability under various reaction conditions.

Synthesis of alpha-trifluoromethyl-beta-lactams and esters of beta-amino acids via 1,3-dipolar cycloaddition of nitrones to fluoroalkenes.

Nitrones derived from aromatic or aliphatic aldehydes or ketones react with hexafluoropropene (HFP) or 2H-pentafluoropropene (PFP) to give the respective fluorinated isoxazolidine derivatives in good yields with complete regioselectivity and moderate diastereoselectivity. Catalytic hydrogenolysis of the N-O bond under ambient pressure and temperature leads to fluorides of beta-amino acids that undergo cyclization to alpha-trifluoromethylated beta-lactams or, under acidic conditions, form esters of alpha-trifluoromethylated beta-amino acids.

New synthesis of 2-heteroarylperfluoropropionic acids derivatives by reaction of azine N-oxides with hexafluoropropene.

Hexafluoropropene reacts with aromatic azine N-oxides under mild conditions to produce fluorides of 2-heteroarylperfluoropropionic acids. The reaction proceeds as 1,3-dipolar cycloaddition followed by spontaneous scission of the N--O bond in the isoxazolidine ring and elimination of HF. When the reaction is carried out in the presence of alcohols or N-alkyl anilines, the in situ formed acyl fluorides give the corresponding esters and amides. They can be also treated separately with nucleophiles to produce the respective acylation products, whereas their hydrolysis leads to unstable carboxylic acids that undergo spontaneous decarboxylation to 1-aryl-1,2,2,2-tetrafluoroethanes. This new reaction provides a simple and general method of synthesizing 2-heteroarylperfluoropropionic acid derivatives that were previously unknown and unavailable.

Synthesis of trifluoromethylated azines via nucleophilic oxidative substitution of hydrogen by trifluoromethyl carbanions.

A novel, three-step method of trifluoromethylation of azines via oxidative nucleophilic substitution of hydrogen in the heteroaromatic ring by a CF3- carbanion is presented. The key reaction of this process is the addition of the CF3- carbanion, generated by treatment of Me3SiCF3 with KF(s) and Ph3SnF catalyst, to N-alkylazinium salts. The resulting dihydroazines containing a trifluoromethyl group are relatively stable compounds and can be isolated in a pure form. Deprotection of the N-p-methoxybenzyl substituent and aromatization of the heterocyclic ring upon treatment with CAN provides azines with a CF3 group in the ring position originally occupied by hydrogen. The whole process can be thus considered as a nucleophilic oxidative displacement of hydrogen by a CF3- carbanion.

Synthesis of perfluoroalkyl-substituted azines via nucleophilic substitution of hydrogen with perfluoroisopropyl carbanions.

Perfluoroisopropyl carbanions generated in situ by treatment of perfluoropropene (HFP) with solid KF in the appropriate solvents add to N-alkylpyridinium, quinolinium, and other azinium salts to give reasonably stable N-alkyldihydroazines containing a perfluoroisopropyl group. In most cases, addition proceeds in position 2 of the heterocyclic ring. Stability of these dihydroazines depends on the nature of the N-alkyl group and other substituents present in the azine ring. The least stable of them were converted into their stable C-trifluoroacetyl derivatives in reaction with trifluoroacetic anhydride. Treatment of N-benzyl- or N-p-methoxybenzyl-2-perfluoroisopropyl dihydroazines with oxidizing agents such as DDQ or cerium(IV) ammonium nitrate results in cleavage of the benzylic C-N bond followed by oxidation of the ring, giving pyridines or quinolines with a perfluoroisopropyl group in the aromatic ring. On the basis of these findings, a new protocol for introduction of perfluoroalkyl substituents into azine rings was elaborated via oxidative nucleophilic substitution of hydrogen. It involves three chemical steps: (i) alkylation of azine with p-MeOC6H4CH2Br, (ii) reaction of the resulting salt with fluorinated carbanions generated in situ from HFP and KF, and (iii) N-deprotection and aromatization of the isolated dihydroazine on treatment with CAN. The first two reactions, (i) and (ii), can be performed as a one-pot operation.

Application of peptidyl radicals into a new radical cascade leading to unsaturated gamma-lactams.

Radical cyclization of dipeptides 1a-h proceeds smoothly to give five- and seven-membered rings in good to moderate total yields using Stork's catalytic tin hydride method. A radical is generated on a protecting group and translocated to the peptide moiety. Following a cyclization reaction, the vinyl radical can abstract hydrogen from a benzyl group on an amine, which results in elimination of the protected amine group. Encouraging results have notably been obtained with amino acids other than glycine.