Benzyl N‐[(Benzyloxy)methyl]carbamate: An Improved Aminomethylation Electrophile for the Synthesis of (Benzyloxy)carbonyl (Cbz)‐Protected Chiral β2‐Amino Acids

α‐Aminomethylation of (R)‐DIOZ‐alkylated (DIOZ=4‐isopropyl‐5,5‐diphenyloxazolidin‐2‐one) substrates is a key step in the asymmetric synthesis of β²‐amino acids, but it is unfortunately often accompanied by formation of transcarbamation by‐products. Aminomethylation was tested using a range of electrophiles, and the amount of by‐product formation was assessed in each case. Benzyl N‐[(benzyloxy)methyl]carbamate electrophile 3d is unable to form this by‐product due to its inherent benzyl substitution. Use of electrophile 3d showed an improved impurity profile in aminomethylation, thus leading to easier intermediate purification.     

Properties and Reactions of Substituted 1,2‐Thiazetidine 1,1‐Dioxides: Functionalization and Reactions at C(4) of the β‐Sultam

The introduction of functional groups at the 4‐position of the β‐sultam ring was realized by the synthesis of mono‐ and disubstituted derivatives by reactions of N‐silylated β‐sultams with electrophiles in the presence of BuLi or LDA. As electrophiles, ketones, chlorosilanes, a β‐sultam, CO₂, chloroformiate, halogen, azodicarboxylate, phenyltriazoledione, tosyl azide, 1,3,5‐triazine, propyl nitrate, and phenyl isocyanate were used. Furthermore, a number of derivatives of these substitution products were synthesized. All products were characterized by standard spectroscopic methods, and conformations were studied, supported by calculation.     

Synthesis of N‐Substituted‐6‐alkoxypteridin‐4‐amine

A novel seven‐step methodology for the synthesis of N‐substituted‐6‐alkoxypteridin‐4‐amine has been developed with the total yields of 35.4–41%. Twenty new compounds were synthesized by heterocyclization of easily prepared 3‐amino‐6‐bromopyrazine‐2‐carboxamide, subsequent alkoxylation, chlorination, and nucleophilic substitution. Their structures were confirmed by ¹H‐NMR, ¹³C‐NMR, ESI‐MS, and elemental analysis. The structure of N‐(3‐chloro‐4‐fluorophenyl)‐6‐ethoxypteridin‐4‐amine was further determined by X‐ray crystallographic analysis. It was found that different chlorinating reagents gave different products. The possible chlorination mechanism was discussed.     

Nickel‐Catalyzed Domino Heck‐Type Reactions Using Methyl Esters as Cross‐Coupling Electrophiles

While esters are frequently used as traditional electrophiles in substitution chemistry, their application in cross‐coupling chemistry is still in its infancy. This work demonstrates that methyl esters can be used as coupling electrophiles in Ni‐catalyzed Heck‐type reactions through the challenging cleavage of the C(acyl)?O bond under relatively mild reaction conditions at either 80 or 100 °C. With the σ‐Ni^II intermediate generated from the insertion of acyl Ni^II species into the tethered C=C bond, carbonyl‐retentive products were formed by domino Heck/Suzuki–Miyaura coupling and Heck/reduction pathways when organoboron and mild hydride nucleophiles are used.     

The Efficiency of the Metal Catalysts in the Nucleophilic Substitution of Alcohols is Dependent on the Nucleophile and Not on the Electrophile

In this study, we investigate the effect of the electrophiles and the nucleophiles for eight catalysts in the catalytic S_N1 type substitution of alcohols with different degree of activation by sulfur‐, carbon‐, oxygen‐, and nitrogen‐centered nucleophiles. The catalysts do not show any general variance in efficiency or selectivity with respect to the alcohols and follow the trend of alcohol reactivity. However, when it comes to the nucleophile, the eight catalysts show general and specific variances in the efficiency and selectivity to perform the desired substitution. Interestingly, the selectivity of the alcohols to produce the desired substitution products was found to be independent of the electrophilicity of the generated carbocations but highly dependent on the ease of formation of the cation. Catalysts based on iron(III), bismuth(III), and gold(III) show higher conversions for S‐, C‐, and N‐centered nucleophiles, and Bi^III was the most efficient catalyst in all combinations. Catalysts based on rhenium(I) or rhenium(VII), palladium(II), and lanthanum(III) were the most efficient in performing the nucleophilic substitution on the various alcohols with the O‐centered nucleophiles. These catalysts generate the symmetrical ether as a by‐product from the reactions of S‐, C‐, and N‐centered nucleophiles as well, resulting in lower chemoselectivity.     

Reduction Process of Tetraplatin in the Presence of Deoxyguanosine Monophosphate (dGMP): A Computational DFT Study

The reduction mechanism of [Pt^IV(dach)Cl₄] (dach=diaminocyclohexyl) in the presence of dGMP was studied. The first step is substitution of a chloro ligand by dGMP, followed by nucleophilic attack of a phosphate or sugar oxygen atom to the C8‐position of guanine. Subsequent reduction forms the [Pt^II(dach)Cl₂] complex. The whole process is completed by a hydrolysis. Two different pathways for the substitution reaction were examined: a direct associative and a Basolo–Pearson autocatalytic mechanism. All the explored structures were optimized at the B3LYP‐D3/6‐31G(d) level and by using the COSMO solvation model with Klamt's radii. Single‐point energetics was determined at the B3LYP‐GD3BJ/6‐311++G(2df,2pd)/PCM/scaled‐UAKS level. Activation barriers were used for an estimation of the rate constants and these were compared with experimental values. It was found that the rate‐determining step is the nucleophilic attack with a slightly faster performance in the 3′‐dGMP branch than in the case of 5′‐dGMP with activation barriers of 21.1 and 20.4 kcal mol^?1 (experimental: 23.8 and 23.2 kcal mol^?1). The reduction reaction is connected with an electron flow from guanine. The product of the reduction reaction is a chelate structure, which dissociates within the last reaction step, that is, a hydrolysis reaction. The whole redox process (substitution, reduction, and hydrolysis) is exergonic by 34 and 28 kcal mol^?1 for 5′‐dGMP and 3′‐dGMP, respectively.     

Quaternary Chiral β2,2‐Amino Acids with Pyridinium and Imidazolium Substituents

The reactions of cyclic sulfamidates as electrophiles with a variety of nitrogen‐containing aromatic heterocycle nucleophiles, such as pyridines, N‐alkylimidazoles and N‐methylbenzimidazol, was explored. In all cases, although the nucleophilic substitution reactions occurred on quaternary centres, elimination products were not detected. The inversion of configuration at this quaternary centre was determined by X‐ray diffraction analysis and the enantiomeric excess of the reactions was checked by chiral HPLC. This synthetic approach allowed us to obtain a new family of chiral charged β^2,2‐amino acids, including a new bisamino acid that incorporates an imidazolium salt as a cross‐linker. In this context, the treatment of these chiral imidazolium salts with Ag₂O opens the way to new chiral N‐heterocyclic carbenes, which are important substrates in the fields of organometallic and organocatalytic chemistry. Additionally, we have done a thorough conformational analysis of these β‐amino acid derivatives, both in the solid state and in solution. The most important conformational feature of these acyclic systems is the rigidity of the N‐CH₂‐C‐N⁺ dihedral angle, which is essentially due to the gauche effect.     

Mechanisms in the Reaction of Palladium(II)–π‐Allyl Complexes with Aryl Halides: Evidence for NHC Exchange Between Two Palladium Complexes

A detailed experimental and DFT study (PBE level) of the reaction of [Pd(η³‐C₃H₅)(tmiy)(PR₃)]BF₄ (tmiy=tetramethylimidazolin‐2‐ylidene, PR₃=phosphane), precursors to monoligated Pd⁰ species, with aryl electrophiles yielding 2‐arylimidazolium salt is reported. Experiments establish that an autocatalytic ligand transfer mechanism is preferred over Pd^IV and σ‐bond metathesis pathways, and that transmetalation is the rate‐determining step. Calculations indicate that the key step involves the concerted exchange of NHC and iodo ligands between two different Pd^II complexes. This is corroborated by experimental results showing the slower reaction of complexes containing the bulkier dipdmiy (dipdmiy = diisopropyldimethylimidazolin‐2‐ylidene).     

Enantioselective Synthesis of Tertiary Allylic Fluorides by Iridium‐Catalyzed Allylic Fluoroalkylation

Few allylic electrophiles containing two different substituents at a single allyl terminus and none in which one of the two substituents is a heteroatom, have been shown previously to react with iridium catalysts to form substitution products. We report that iridium‐catalysts are uniquely suited to form tertiary allylic fluorides enantioselectively by the addition of a diverse range of carbon‐centered nucleophiles at the fluorine‐containing terminus of 3‐fluoro‐substituted allylic esters. The products contain tertiary stereogenic centers bearing a single fluorine, which are isosteric with common tertiary stereocenters containing a single hydrogen. Computational studies reveal the principal steric interactions influencing the stability of endo and exo π‐allyl intermediates formed from 3,3‐disubstituted allylic electrophiles.     

Configurationally Labile Lithiated O‐Benzyl Carbamates: Application in Asymmetric Synthesis and Quantum Chemical Investigations on the Equilibrium of Diastereomers

The title compounds were generated by deprotonation of different benzyl‐type carbamates with sec‐butyllithium in the presence of chiral diamines (?)‐sparteine or diisopropyl and di‐tert‐butyl bis(oxazoline)s. These lithiated species exhibit configurational lability at ?78 °C. In the case of the chiral di‐tert‐butyl bis(oxazoline), the equilibrium of the epimeric complexes can be used synthetically to obtain highly enantioenriched secondary benzyl carbamates. The enantiodetermining step was proven to be a dynamic thermodynamic resolution. The absolute configurations of the products were determined, and the stereochemical pathways of selected substitution reactions were thus elucidated. High‐level quantum chemical investigations were performed to gain insight into the experimentally investigated system. To obtain an accuracy for the energy difference (ΔΔH) between two epimeric complexes of about 0.5 kcal mol^?1 as well as the correct sign, a theoretical procedure was established. It included geometry optimization at the dispersion‐corrected DFT level, computation of zero‐point vibrational energies, and single‐point SCS‐MP2 energy calculations with large atomic‐orbital basis sets.     

Diastereoselective synthesis of highly functionalized β2,2,3-substituted amino acids from 4-substituted-1,3-oxazinan-6-ones

1,3-Oxazinan-6-ones were used to generate substituted β^2,2,3-substituted amino acid derivatives. The enolates of 1,3-oxazinan-6-ones were trans-selectively intercepted with electrophiles. This alkylation was subsequently optimized for a one-pot dialkylation to form 5,5-disubstituted oxazinanones. The initial 5-monomethylated compounds could be enolized and then diastereoselectively intercepted with different electrophiles to form differentially 5,5-disubstituted products. The 5,5-dialkylated oxazinanones were then transformed to N-methyl β^2,2,3-substituted amino acids by reductive cleavage. Hydrolysis or solvolysis of the oxazinanones afforded β^2,2,3-substituted amino acids or esters, respectively. The chemistry thus provides access to a range of symmetrical and stereopure β^2,2,3-substituted amino acids and further establishes 1,3-oxazinan-6-ones as useful intermediates.     

Reactions of 6-Alkoxy(alkylthio)carbonylamino-4-hydroxy-2H-pyran-2-ones with Some Electrophilic Reagents

Alkoxy(alkylthio)-4-hydroxy-2H-pyran-2-ones readily react with electrophiles to give substitution products at C³. Hard electrophilic reagents replace hydrogen both in position 3 and in position 5 of the pyran ring. Methylation of 6-alkoxy(alkylthio)-4-hydroxy-2H-pyran-2-ones with diazomethane leads to formation of O- and N-methyl derivatives.     

Control of Stereoselectivity in Diverse Hapalindole Metabolites is Mediated by Cofactor‐Induced Combinatorial Pairing of Stig Cyclases

Stereospecific polycyclic core formation of hapalindoles and fischerindoles is controlled by Stig cyclases through a three‐step cascade involving Cope rearrangement, 6‐exo‐trig cyclization, and a final electrophilic aromatic substitution. Reported here is a comprehensive study of all currently annotated Stig cyclases, revealing that these proteins can assemble into heteromeric complexes, induced by Ca²⁺, to cooperatively control the stereochemistry of hapalindole natural products.     

Sulfur(VI) Fluoride Exchange (SuFEx): Another Good Reaction for Click Chemistry

Aryl sulfonyl chlorides (e.g. Ts‐Cl) are beloved of organic chemists as the most commonly used S^VI electrophiles, and the parent sulfuryl chloride, O₂S^VICl₂, has also been relied on to create sulfates and sulfamides. However, the desired halide substitution event is often defeated by destruction of the sulfur electrophile because the S^VI? Cl bond is exceedingly sensitive to reductive collapse yielding S^IV species and Cl^?. Fortunately, the use of sulfur(VI) fluorides (e.g., R‐SO₂‐F and SO₂F₂) leaves only the substitution pathway open. As with most of click chemistry, many essential features of sulfur(VI) fluoride reactivity were discovered long ago in Germany. ^6a Surprisingly, this extraordinary work faded from view rather abruptly in the mid‐20th century. Here we seek to revive it, along with John Hyatt’s unnoticed 1979 full paper exposition on CH₂?CH‐SO₂‐F, the most perfect Michael acceptor ever found. ⁹⁸ To this history we add several new observations, including that the otherwise very stable gas SO₂F₂ has excellent reactivity under the right circumstances. We also show that proton or silicon centers can activate the exchange of S? F bonds for S? O bonds to make functional products, and that the sulfate connector is surprisingly stable toward hydrolysis. Applications of this controllable ligation chemistry to small molecules, polymers, and biomolecules are discussed.     

Regioselective Acceptorless Dehydrogenative Coupling of N‐Heterocycles toward Functionalized Quinolines,Phenanthrolines, and Indoles

A new strategy has been developed for the oxidant‐ and base‐free dehydrogenative coupling of N‐heterocycles at mild conditions. Under the action of an iridium catalyst, N‐heterocycles undergo multiple sp³ C? H activation steps, generating a nucleophilic enamine that reacts in situ with various electrophiles to give highly functionalized products. The dehydrogenative coupling can be cascaded with Friedel–Crafts addition, resulting in a double functionalization of the N‐heterocycles.     

Regioselective Acceptorless Dehydrogenative Coupling of N‐Heterocycles toward Functionalized Quinolines,Phenanthrolines, and Indoles

A new strategy has been developed for the oxidant‐ and base‐free dehydrogenative coupling of N‐heterocycles at mild conditions. Under the action of an iridium catalyst, N‐heterocycles undergo multiple sp³ C H activation steps, generating a nucleophilic enamine that reacts in situ with various electrophiles to give highly functionalized products. The dehydrogenative coupling can be cascaded with Friedel–Crafts addition, resulting in a double functionalization of the N‐heterocycles.     

Synthesis,Reactions, and Anticancer Activity of Some 1,3,4-Thiadiazole/Thiadiazine Derivatives of Carbazole

A novel method for the synthesis of 1,3,4-thiadiazole and 1,3,4-thiadiazine derivatives bearing a carbazole moiety is described. Carbazole was transformed into carbazole-9-thiocarbohydrazide in two steps. This compound was allowed to react with various electrophiles to yield 1,3,4-thiadiazole derivatives. The reaction with bifunctional electrophiles led to 1,3,4-thiadiazines. 2-(Carbazol-9-yl)-5,6-dihydro-4H-1,3,4-thiadiazin-5-one reacted with piperidine and formaldehyde to yield the 4-(piperidin-1-ylmethyl) derivative. The reaction with aromatic aldehydes led to the corresponding 6-arylidene derivatives, which were transformed into pyrimidino[4,5-e]-1,3,4-thiadiazines and pyrazolo[3,4-e]-1,3,4-thiadiazines by a reaction with guanidine, acetamidine, or phenylhydrazine, respectively. Structures of the products were confirmed by ¹H NMR, ¹³C NMR, IR, and mass spectrometric measurements. Selected examples of products were screened for anticancer activity.     

Atroposelective Synthesis of Axially Chiral N‐Arylpyrroles by Chiral‐at‐Rhodium Catalysis

A transformation of fluxional into configurationally stable axially chiral N‐arylpyrroles was achieved with a highly atroposelective electrophilic aromatic substitution catalyzed by a chiral‐at‐metal rhodium Lewis acid. Specifically, N‐arylpyrroles were alkylated with N‐acryloyl‐1H‐pyrazole electrophiles in up to 93 % yield and with up to >99.5 % ee, and follow‐up conversions reveal the synthetic utility of this new method. DFT calculations elucidate the origins of the observed excellent atroposelectivity.     

Biaryl and Aryl Ketone Synthesis via Pd‐Catalyzed Decarboxylative Coupling of Carboxylate Salts with Aryl Triflates

A bimetallic catalyst system has been developed that for the first time allows the decarboxylative cross‐coupling of aryl and acyl carboxylates with aryl triflates. In contrast to aryl halides, these electrophiles give rise to non‐coordinating anions as byproducts, which do not interfere with the decarboxylation step that leads to the generation of the carbon nucleophilic cross‐coupling partner. As a result, the scope of carboxylate substrates usable in this transformation was extended from ortho‐substituted or otherwise activated derivatives to a broad range of ortho‐, meta‐, and para‐substituted aromatic carboxylates. Two alternative protocols have been optimized, one involving heating the substrates in the presence of Cu^I/1,10‐phenanthroline (10–15 mol %) and PdI₂/phosphine (2–3 mol %) in NMP for 1–24 h, the other involving Cu^I/1,10‐phenanthroline (6–15 mol %) and PdBr₂/Tol‐BINAP (2 mol %) in NMP using microwave heating for 5–10 min. While most products are accessible using standard heating, the use of microwave irradiation was found to be beneficial especially for the conversion of non‐activated carboxylates with functionalized aryl triflates. The synthetic utility of the transformation is demonstrated with 48 examples showing the scope and limitations of both protocols. In mechanistic studies, the special role of microwave irradiation is elucidated, and further perspectives of decarboxylative cross‐couplings are discussed.     

Decarboxylative C(sp3)−O Cross‐Coupling

Alkyl aryl ethers are an important class of compounds in medicinal and agricultural chemistry. Catalytic C(sp³)?O cross‐coupling of alkyl electrophiles with phenols is an unexplored disconnection strategy to the synthesis of alkyl aryl ethers, with the potential to overcome some of the major limitations of existing methods such as C(sp²)?O cross‐coupling and S_N2 reactions. Reported here is a tandem photoredox and copper catalysis to achieve decarboxylative C(sp³)?O coupling of alkyl N‐hydroxyphthalimide (NHPI) esters with phenols under mild reaction conditions. This method was used to synthesize a diverse set of alkyl aryl ethers using readily available alkyl carboxylic acids, including many natural products and drug molecules. Complementarity in scope and functional‐group tolerance to existing methods was demonstrated.