Aminolysis of 2,4-dinitrophenyl X-substituted benzoates and Y-substituted phenyl benzoates in MeCN: effect of the reaction medium on rate and mechanism

Second‐order rate constants (k_N) have been determined spectrophotometrically for the reactions of 2,4‐dinitrophenyl X‐substituted benzoates ( 1 a – f ) and Y‐substituted phenyl benzoates ( 2 a – h ) with a series of alicyclic secondary amines in MeCN at 25.0±0.1 °C. The k_N values are only slightly larger in MeCN than in H₂O, although the amines studied are approximately 8 pK_a units more basic in the aprotic solvent than in H₂O. The Yukawa–Tsuno plot for the aminolysis of 1 a – f is linear, indicating that the electronic nature of the substituent X in the nonleaving group does not affect the rate‐determining step (RDS) or reaction mechanism. The Hammett correlation with σ^? constants also exhibits good linearity with a large slope (ρ_Y=3.54) for the reactions of 2 a – h with piperidine, implying that the leaving‐group departure occurs at the rate‐determining step. Aminolysis of 2,4‐dinitrophenyl benzoate ( 1 c ) results in a linear Brønsted‐type plot with a β_nuc value of 0.40, suggesting that bond formation between the attacking amine and the carbonyl carbon atom of 1 c is little advanced in the transition state (TS). A concerted mechanism is proposed for the aminolysis of 1 a – f in MeCN. The medium change from H₂O to MeCN appears to force the reaction to proceed concertedly by decreasing the stability of the zwitterionic tetrahedral intermediate (T^±) in aprotic solvent.     

The solvent effect on two competing reaction mechanisms involving hypervalent iodine reagents (λ3‐iodanes): Facing the limit of the stationary quantum chemical approach

Trifluoromethylation of acetonitrile with 3,3‐dimethyl‐1‐(trifluoromethyl)?1λ³,2‐ benziodoxol is assumed to occur via reductive elimination (RE) of the electrophilic CF₃‐ligand and MeCN bound to the hypervalent iodine. Computations in gas phase showed that the reaction might also occur via an S_N2 mechanism. There is a substantial solvent effect present for both reaction mechanisms, and their energies of activation are very sensitive toward the solvent model used (implicit, microsolvation, and cluster‐continuum). With polarizable continuum model‐based methods, the S_N2 mechanism becomes less favorable. Applying the cluster‐continuum model, using a shell of solvent molecules derived from ab initio molecular dynamics (AIMD) simulations, the gap between the two activation barriers ( ) is lowered to a few kcal mol^?1 and also shows that the activation entropies ( ) and volumes ( ) for the two mechanisms differ substantially. A quantitative assessment of will therefore only be possible using AIMD. A natural bond orbital‐analysis gives further insight into the activation of the CF₃‐reagent by protonation. © 2014 Wiley Periodicals, Inc.     

Borazine‐CF3− Adducts for Rapid,Room Temperature,and Broad Scope Trifluoromethylation

A fluoroform‐derived borazine CF₃⁻ transfer reagent is used to effect rapid nucleophilic reactions in the absence of additives, within minutes at 25 °C. Inorganic electrophiles spanning seven groups of the periodic table can be trifluoromethylated in high yield, including transition metals used for catalytic trifluoromethylation. Organic electrophiles included (hetero)arenes, enabling C−H and C−X trifluoromethylation reactions. Mechanistic analysis supports a dissociative mechanism for CF₃⁻ transfer, and cation modification afforded a reagent with enhanced stability.     

Borazine‐CF3− Adducts for Rapid,Room Temperature,and Broad Scope Trifluoromethylation

A fluoroform‐derived borazine CF₃^? transfer reagent is used to effect rapid nucleophilic reactions in the absence of additives, within minutes at 25 °C. Inorganic electrophiles spanning seven groups of the periodic table can be trifluoromethylated in high yield, including transition metals used for catalytic trifluoromethylation. Organic electrophiles included (hetero)arenes, enabling C?H and C?X trifluoromethylation reactions. Mechanistic analysis supports a dissociative mechanism for CF₃^? transfer, and cation modification afforded a reagent with enhanced stability.     

Direct C?H Functionalization of Enamides and Enecarbamates by Using Visible‐Light Photoredox Catalysis

Direct C? H functionalization of various enamides and enecarbamates was realized through visible‐light photoredox catalyzed reactions. Under the optimized conditions using [Ir(ppy)₂(dtbbpy)PF₆] as photocatalyst in combination with Na₂HPO₄, enamides such as N‐vinylpyrrolidinone could be easily functionalized by irradiation of the reaction mixture overnight in acetonitrile with visible light. The scope of the reaction with respect to enamide and enecarbamate substrates by using diethyl 2‐bromomalonate for the alkylation reaction was explored, followed by an investigation of the scope of alkylating reagents used to react with the enamides and enecarbamates. The results indicated that reaction takes place with quite broad substrate scope, however, tertiary enamides with an internal C?C double bond in the E configuration could not be alkylated. Alkylation of N‐vinyl tertiary enamides and enecarbamates gave monoalkylated products exclusively in the E configuration. Alkylation of N‐vinyl secondary enamides gave doubly alkylated products. Double bond migration was observed in the reaction of electron‐deficient bromides such as 3‐bromoacetyl acetate with N‐vinylpyrrolidinone. A mechanism is proposed for the reaction that is different from reported reactions of SOMOphiles with a nonfunctionalized C?C double bond. Further tests on the trifluoromethylation and arylation of enamides and enecarbamates under similar conditions showed that the reactions could serve as a mild, practical, and environmentally friendly approach to various functionalized enamides and enecarbamates.     

Silver‐Mediated N‐Trifluoromethylation of Amides and Peptides

We report herein the direct N‐trifluoromethylation of N‐H amides. Promoted by AgOTf and 2‐fluoropyridine, the reaction of a variety of amides with Selectfluor, TMSCF₃ and CsF proceeds smoothly at room temperature leading to the corresponding N‐trifluoromethylated products in satisfactory yields. The protocol is also applicable to amino acid derivatives, resulting in efficient and chemoselective N‐trifluoromethylation of di‐ and tri‐peptides with retention of configuration. A mechanism involving reductive elimination of Ag(III) intermediates to form N—CF₃ bonds is proposed.     

Synthesis of Aryl Tri‐ and Difluoromethyl Thioethers via a CH‐Thiocyanation/Fluoroalkylation Cascade

An AlCl₃‐catalyzed C?H thiocyanation was discovered and combined with a Langlois‐type trifluoromethylation to afford aryl trifluoromethyl thioethers directly from arenes, N‐thiocyanatosuccinimide (NTS) and Ruppert–Prakash reagent. An analogous combination with a copper‐mediated difluoromethylation gives access to aryl difluoromethyl thioethers. Both processes proceed with exceptional regioselectivity for the most electron‐rich, sterically least hindered position of the arene. The sulfur and fluoroalkyl groups originate from different sources, so that the use of expensive, preformed fluoroalkylthiolation reagents is avoided.     

Phenolysis and aminolysis of 4‐nitrophenyl and 2,4‐dinitrophenyl S‐methyl thiocarbonates in aqueous ethanol

The reactions of S‐methyl O‐(4‐nitrophenyl) thiocarbonate ( 1 ) and S‐methyl O‐(2,4‐dinitrophenyl) thiocarbonate ( 2 ) with a series of secondary alicyclic (SA) amines and phenols are subjected to a kinetic investigation. Under nucleophile excess, pseudo‐first‐order rate coefficients (k_obs) are obtained. Plots of k_obs against the free nucleophile concentration at constant pH are linear with slopes k_N. The Brønsted plots (log k_N vs. nucleophile pK_a) for the reactions are linear with slope (β) values in the 0.5–0.7 range, in accordance with concerted mechanisms. Comparison of the SA aminolysis of 1 with the same one carried out in water shows that the change of solvent from water to aqueous ethanol destabilizes the zwitterionic tetrahedral intermediate, changing the mechanism from stepwise to concerted. This destabilization is greater than that due to the change from SA amines to quinuclidines. For the phenolysis reactions, the k_N values in aqueous ethanol are smaller than those for the same reactions in water. Considering that the nucleophile is an anion, this result is unexpected because the anion should be more stabilized in the more polar solvent. This result is explained by the facts that the phenoxide reactant has a negative charge that is delocalized in the aromatic ring and the transition state is highly polar. © 2011 Wiley Peiodicals, Inc. Int J Chem Kinet 43: 353–358, 2011     

Free‐radical 4‐nitrophenylation of thieno[2,3‐b]pyridine. Part 3: Consideration of mechanistic and selectivity factors involved in the substitution process

A 1:1 geometrically oriented encounter complex between thieno[2,3‐b]pyridine (1) and 4‐nitrophenyldia‐zoacetate (2) is proposed to account for the dominant formation (ca. 64%) of the 2‐isomer in the mixture of 4‐nitrophenyl‐l isomers obtained previously. A mechanism involving one‐electron transfer from 1 to 2 plus fragmentation of 2· into 4‐nitrophenyl free radical, N₂, and acetate ion is invoked. Formation of other isomers is discussed. It is noted that there is a close correlation between orientational rules plus mechanisms of reaction for numerous free‐radical substitutions (S_R) with S_N reactions of alkyllithiums on furan, thiophene, N‐alkylpyrroles, pyridine, and their condensed aromatic molecules, including 1, as substrates. Also isomeric selectivities for S_E, S_N, and S_R substitutions into 1 were shown to be qualitatively consistent with one another. While S_E reactions occur largely at position 3 and then at 2, S_N and S_R reactions occur either at 2 or 6. Selectivity for positions 4 or 5 is small or zero.     

Photoinduced Cobalt(III)−Trifluoromethyl Bond Activation Enables Arene C−H Trifluoromethylation

Visible‐light capture activates a thermodynamically inert Co^III−CF₃ bond for direct C−H trifluoromethylation of arenes and heteroarenes. New trifluoromethylcobalt(III) complexes supported by a redox‐active [OCO] pincer ligand were prepared. Coordinating solvents, such as MeCN, afford green, quasi‐octahedral [(^SOCO)Co^III(CF₃)(MeCN)₂] ( 2 ), but in non‐coordinating solvents the complex is red, square pyramidal [(^SOCO)Co^III(CF₃)(MeCN)] ( 3 ). Both are thermally stable, and 2 is stable in light. But exposure of 3 to low‐energy light results in facile homolysis of the Co^III−CF₃ bond, releasing ^.CF₃ radical, which is efficiently trapped by TEMPO^. or (hetero)arenes. The homolytic aromatic substitution reactions do not require a sacrificial or substrate‐derived oxidant because the Co^II by‐product of Co^III−CF₃ homolysis produces H₂. The photophysical properties of 2 and 3 provide a rationale for the disparate light stability.     

Ketones from Nickel‐Catalyzed Decarboxylative,Non‐Symmetric Cross‐Electrophile Coupling of Carboxylic Acid Esters

Synthesis of the C?C bonds of ketones relies upon one high‐availability reagent (carboxylic acids) and one low‐availability reagent (organometallic reagents or alkyl iodides). We demonstrate here a ketone synthesis that couples two different carboxylic acid esters, N‐hydroxyphthalimide esters and S‐2‐pyridyl thioesters, to form aryl alkyl and dialkyl ketones in high yields. The keys to this approach are the use of a nickel catalyst with an electron‐poor bipyridine or terpyridine ligand, a THF/DMA mixed solvent system, and ZnCl₂ to enhance the reactivity of the NHP ester. The resulting reaction can be used to form ketones that have previously been difficult to access, such as hindered tertiary/tertiary ketones with strained rings and ketones with α‐heteroatoms. The conditions can be employed in the coupling of complex fragments, including a 20‐mer peptide fragment analog of Exendin(9–39) on solid support.     

Kinetics and Mechanism of Certain Acetylation Reactions with Acetamide/Oxychloride in Acetonitrile under Vilsmeier?Haack Conditions

Vilsmeier? Haack (VH) acetylation reactions with benzaldehydes or acetophenones in MeCN followed second‐order kinetics and afforded acetyl derivatives under kinetic conditions, irrespective of the nature of the oxychloride (SOCl₂ or POCl₃) used for the preparation of the VH reagent along with acetamide. The present finding contributes to the understanding of the nature of the reactive species of the VH reagent as well as of the acetylation mechanism.     

Ketones from Nickel‐Catalyzed Decarboxylative,Non‐Symmetric Cross‐Electrophile Coupling of Carboxylic Acid Esters

Synthesis of the C?C bonds of ketones relies upon one high‐availability reagent (carboxylic acids) and one low‐availability reagent (organometallic reagents or alkyl iodides). We demonstrate here a ketone synthesis that couples two different carboxylic acid esters, N‐hydroxyphthalimide esters and S‐2‐pyridyl thioesters, to form aryl alkyl and dialkyl ketones in high yields. The keys to this approach are the use of a nickel catalyst with an electron‐poor bipyridine or terpyridine ligand, a THF/DMA mixed solvent system, and ZnCl₂ to enhance the reactivity of the NHP ester. The resulting reaction can be used to form ketones that have previously been difficult to access, such as hindered tertiary/tertiary ketones with strained rings and ketones with α‐heteroatoms. The conditions can be employed in the coupling of complex fragments, including a 20‐mer peptide fragment analog of Exendin(9–39) on solid support.     

Rhodium‐Catalyzed Geminal Oxyfluorination and Oxytrifluoro‐Methylation of Diazocarbonyl Compounds

A new reaction for the rhodium‐catalyzed geminal‐difunctionalization‐based fluorination is presented. The substrates are aromatic and aliphatic diazocarbonyl compounds. As the fluorine source a stable and easily accessible benziodoxole reagent was used. A variety of alcohol, phenol, and carboxylic acid reagents were employed to introduce the second functionality. The reaction was extended to trifluoromethylation using a benziodoxolon reagent. The fluorination and trifluoromethylation reactions probably proceed by a rhodium‐containing onium ylide type intermediate, which is trapped by either the F or CF₃ electrophiles.     

S‐Trifluoromethylation of Thiols by Hypervalent Iodine Reagents: A Joint Experimental and Computational Study

The radical trifluoromethylation of thiophenol in condensed phase applying reagent 1 (3,3‐dimethyl‐1‐(trifluoromethyl)‐1λ³,2‐benziodoxol) has been examined by both theoretical and experimental methodologies. On the basis of ab initio molecular dynamics and metadynamics we show that radical reaction mechanisms favourably compete with polar ones involving the S‐centred nucleophile thiophenol, their free energies of activation, ΔF^≠, lying between 9 and 15 kcal mol^?1. We further show that the origin of the proton activating the reagent is important. Hammett plot analysis reveals intramolecular protonation of 1 , thus generating negative charge on the sulfur atom in the rate‐determining step. The formation of a CF₃ radical can be thermally induced by internal dissociative electron transfer, its activation energy, ΔF^≠, amounting to as little as 10.8 and 2.8 kcal mol^?1 for reagent 1 and its protonated form 2 , respectively. The reduction of the iodine atom by thiophenol occurs either subsequently or in a concerted fashion.     

Application of N,N'-Diiodo-N,N'-1,2-ethandiylbis(p-toluene sulfonamide)as a New Reagent for Synthesis of2-Arylbenzimidazoles and 2-Arylbenzothiazoles under Solvent-free Conditions

N,N′‐Diiodo‐N,N′‐1,2‐ethandiylbis(p‐toluene sulfonamide) (NIBTS) is a good and new reagent for synthesis of 2‐arylbenzimidazoles and 2‐arylbenzothiazoles at room temperature under solvent‐free condition with good to high yield. Absence of solvent, short reaction times, non‐corrosive, operational simplicity and environmentally friendliness are the main advantages of this procedure.     

A Mechanistic Investigation of the Visible‐Light Photocatalytic Trifluoromethylation of Heterocycles Using CF3I in Flow

Photocatalytic radical trifluoromethylation strategies have impacted the synthesis of trifluoromethyl‐containing molecules. However, mechanistic aspects concerning such transformations remain poorly understood. Here, we describe in detail the mechanism of the visible‐light photocatalytic trifluoromethylation of N‐methylpyrrole with gaseous CF₃I in flow. The use of continuous‐flow microreactor technology allowed for the determination of different important parameters with high precision (e.g., photon flux, quantum yield, reaction rate constants) and for the handling of CF₃I in a convenient manner. Our data indicates that the reaction occurs through a reductive quenching mechanism and that there is no radical chain process present.     

Isotope Effects in the Solvolysis of Sterically Hindered Arenesulfonyl Chlorides

Solvent isotope effects in the ethanolysis of sterically hindered arenesulfonyl chlorides ruled out a proton transfer in the rate‐determining step and agreed with a S_N2 mechanism involving at least a second solvent molecule in the transition state (TS). The lack of a secondary kinetic isotope effect in the o‐alkyl groups allows us to disregard the possible contribution of σ–π hyperconjugation. The measured activation parameters are consistent with a S_N2 mechanism involving the participation of solvent molecules in the TS, possibly forming a cyclic TS through a chain of solvent molecules.     

A simple one pot synthesis of condensed 1,2,4‐triazines by using the tandem aN‐SNipso and SNH‐SNipsa reactions

A new synthetic approach to condensed 1,2,4‐triazines based on using the tandem A_N‐S_N^ipso and S_N^H‐S_N^ipso reactions has been developed. 5‐Methoxy‐3‐penyl‐1,2,4‐triazine and its N₁‐methyl quaternary salt were found to react with C,N‐, C,O‐ and N,N'‐bifunctional nucleophiles (m‐phenylenediamine, resor‐cinol, semicarbazide and ureas) into triazacarbazoles, benzofuro[2,3‐e][1,2,4]‐triazines, and 6‐azapurine derivatives. In all cases nucleophiles attack first the unsubstituted C‐6 carbon of the triazine ring, while the final stage is replacement of the methoxy group affording cyclization products.     

Structure and reactivity of a sulfoximine-stabilized chiral dilithiocarbanion

The synthesis and X-ray analysis of a racemic dilithiated S-ethyl-N-methyl-S-phenylsulfoximine cluster 2 with N,N,N′,N′-tetramethylethane-1,2-diamine (TMEDA) as coordinating solvent is presented. The lithium complex 2 consists of a mixed tetrameric mono- and dilithio salt. Unexpectedly, a separation of the enantiomers in mono-and dilithiated antipodes with respect to the chirality center on the S-atom is observed. Dilithiation of S-ethyl-N-methyl-S-phenylsulfoximine ( 1 ) affords a chiral dinucleophile which undergoes highly regie- and stereoselective alkylation reactions with bis-electrophiles.