Transition‐Metal‐Free Formal Sonogashira Coupling and α‐Carbonyl Arylation Reactions

Transition‐metal‐free formal Sonogashira coupling and α‐carbonyl arylation reactions have been developed. These transformations are based on the nucleophilic aromatic substitution (S_NAr) of β‐carbonyl sulfones to electron‐deficient aryl fluorides, producing a key intermediate that, depending on the reaction conditions, gives the aromatic alkynes or α‐aryl carbonyl compounds. The development of these reactions is presented and, based on investigations under basic and acidic conditions, mechanisms have been proposed. To develop the formal Sonogashira coupling further, a milder, two‐step protocol is also disclosed that expands the reaction concept. The scope of these reactions is demonstrated for the synthesis of Sonogashira and α‐carbonyl arylated products from a range of electron‐deficient aryl fluorides with a variety of functional groups and aryl‐, heteroaryl‐, alkyl‐, and alkoxy‐substituted sulfone nucleophiles. These transition‐metal‐free reactions complement the metal‐catalyzed versions in terms of substitution patterns, simplicity, and reaction conditions.     

Enantio‐ and Site‐Selective α‐Fluorination of N‐Acyl 3,5‐Dimethylpyrazoles Catalyzed by Chiral π–CuII Complexes

Catalytic enantioselective α‐fluorination reactions of carbonyl compounds are among the most powerful and efficient synthetic methods for constructing optically active α‐fluorinated carbonyl compounds. Nevertheless, α‐fluorination of α‐nonbranched carboxylic acid derivatives is still a big challenge because of relatively high pK_a values of their α‐hydrogen atoms and difficulty of subsequent synthetic transformation without epimerization. Herein we show that chiral copper(II) complexes of 3‐(2‐naphthyl)‐l ‐alanine‐derived amides are highly effective catalysts for the enantio‐ and site‐selective α‐fluorination of N‐(α‐arylacetyl) and N‐(α‐alkylacetyl) 3,5‐dimethylpyrazoles. The substrate scope of the transformation is very broad (25 examples including a quaternary α‐fluorinated α‐amino acid derivative). α‐Fluorinated products were converted into the corresponding esters, secondary amides, tertiary amides, ketones, and alcohols with almost no epimerization in high yield.     

Enantioselective Alkylation of N‐Arylhydrazones Derived from α‐Keto Esters and Isatin Derivatives through Asymmetric Phase‐Transfer Catalysis

The phase‐transfer‐catalyzed asymmetric alkylation reactions of N‐arylhydrazones derived from α‐keto‐esters and isatin derivatives afford enantioenriched azo compounds that bear a tetra‐substituted carbon stereocenter in good yields with high chemo‐ and enantioselectivity. The alkylation products can be readily converted into chiral amino esters, hydrazine derivatives, and aza‐β‐lactams without loss of enantiopurity.     

Ureas as a New Nucleophilic Reagents for SNAr Amination and Carbamoyl Amination Reactions in 1,3,7‐Triazapyrene Series

The ability of urea anions to react as nucleophiles with alkoxy derivatives of 1,3,7‐triazapyrenes has been investigated. It was found that against all expectations, the products of the substitution of an alkoxy groups (S_N^ipso ) by amino group were isolated in good yields. The reactions proceed in anhydrous dimethyl sulfoxide solution at room temperature. But when anions of the mono‐substituted ureas containing bulky substituents were used, the first products of the earlier unknown S_NAr reactions of alkyl carbamoyl amination were obtained.     

Catalytic Asymmetric Synthesis of 3,3′‐Diaryloxindoles as Triarylmethanes with a Chiral All‐Carbon Quaternary Center: Phase‐Transfer‐Catalyzed SNAr Reaction

Catalytic asymmetric synthesis of unsymmetrical triarylmethanes with a chiral all‐carbon quaternary center was achieved by using a chiral bifunctional quaternary phosphonium bromide catalyst in the S_NAr reaction of 3‐aryloxindoles under phase‐transfer conditions. The presence of a urea moiety in the chiral phase‐transfer catalyst was important for obtaining high enantioselectivity in this reaction.     

Side‐Arm Effect of a Methyl α‐d‐Glucopyranoside Based Lariat Ether Catalysts in Asymmetric Syntheses

Methyl α‐d ‐glucopyranoside based monoaza‐15‐crown‐5 type lariat ethers with different heteroatom‐containing side arm attached to the nitrogen of the macrocyclic ring have been synthesized. These compounds were used as chiral phase transfer catalysts in a few asymmetric reactions, such as Michael additions, Darzens condensation, and epoxidation of chalcone. The side arms of the macrocycles had a significant impact on the chemical yields and the enantioselectivity. The effect of the lariat ethers with side arms having heteroatom (O, N, and S) was compared with the effect of the analogues having substituents without a heteroatom. The terminal allyl group also generated a significant enantioselectivity (79% enantiomeric excess) in one of the Michael additions. The application of crown ethers with substituents (CH₂)₃OH or (CH₂)₃OCH₃ leads to the best enantioselectivities 85% and 99%, respectively.     

The α‐effect exhibited in gas‐phase SN2@N and SN2@C reactions

In order to explore the existence of α‐effect in gas‐phase S_N2@N reactions, and to compare its similarity and difference with its counterpart in S_N2@C reactions, we have carried out a theoretical study on the reactivity of six α‐oxy‐Nus (FO^?, ClO^?, BrO^?, HOO^?, HSO^?, H₂NO^?) in the S_N2 reactions toward NR₂Cl (R = H, Me) and RCl (R = Me, i‐Pr) using the G2(+)_M theory. An enhanced reactivity induced by the α‐atom is found in all examined systems. The magnitude of the α‐effect in the reactions of NR₂Cl (R = H, Me) is generally smaller than that in the corresponding S_N2 reaction, but their variation trend with the identity of α‐atom is very similar. The origin of the α‐effect of the S_N2@N reactions is discussed in terms of activation strain analysis and thermodynamic analysis, indicating that the α‐effect in the S_N2@N reactions largely arises from transition state stabilization, and the “hyper‐reactivity” of these α‐Nus is also accompanied by an enhanced thermodynamic stability of products from the n_(N) → σ*_(O?Y) negative hyperconjugation. Meanwhile, it is found that the reactivity of oxy‐Nus in the S_N2 reactions toward NMe₂Cl is lower than toward i‐PrCl, which is different from previous experiments, that is, the S_N2 reactions of NH₂Cl is more facile than MeCl. © 2013 Wiley Periodicals, Inc.     

Ethyl 6‐amino‐2‐methoxypyridine‐3‐carboxyl­ate,interplay of molecular and supramolecular structure

The title compound, C₉H₁₂N₂O₃, crystallizes with two mol­ecules in the asymmetric unit. There is extensive hydrogen bonding which results in the formation of a two‐dimensional corrugated sheet. This supramolecular structure is determined by the formation of hydrogen‐bonded chains resulting from the presence of a 6‐amino group and an ethoxy­carbonyl group as substituents on a pyridine ring in relative para positions which constitute a π‐electron `push–pull' system.     

Chemo‐ and Enantioselective Oxidative α‐Azidation of Carbonyl Compounds

We report high‐performance I⁺/H₂O₂ catalysis for the oxidative or decarboxylative oxidative α‐azidation of carbonyl compounds by using sodium azide under biphasic neutral phase‐transfer conditions. To induce higher reactivity especially for the α‐azidation of 1,3‐dicarbonyl compounds, we designed a structurally compact isoindoline‐derived quaternary ammonium iodide catalyst bearing electron‐withdrawing groups. The nonproductive decomposition pathways of I⁺/H₂O₂ catalysis could be suppressed by the use of a catalytic amount of a radical‐trapping agent. This oxidative coupling tolerates a variety of functional groups and could be readily applied to the late‐stage α‐azidation of structurally diverse complex molecules. Moreover, we achieved the enantioselective α‐azidation of 1,3‐dicarbonyl compounds as the first successful example of enantioselective intermolecular oxidative coupling with a chiral hypoiodite catalyst.     

Efficient Syntheses of Novel Fluoro‐Substituted Pentacenes and Azapentacenes: Molecular and Solid‐State Properties

Non‐symmetrical 6,13‐disubstituted pentacenes bearing trifluoromethyl and aryl substituents have been synthesized starting from pentacenequinone. Diazapentacenes with a variety of fluorine substituents were prepared either via a Hartwig–Buchwald aryl amination route or by a S_NAr strategy. As a result of a non‐symmetric substitution pattern containing electron‐donating substituents in combination with electron‐accepting fluorine substituents, the synthesized compounds feature distinct molecular dipoles. All compounds are analyzed regarding their optoelectronic properties in solution with special focus on the frontier orbital energies as well as their molecular packing in the crystal structures. The analyses of isolated molecules are complemented by thin‐film studies to examine their solid‐state properties. A precise comparison between these and the molecular properties gave detailed insights into the exciton binding energies of these compounds, which are explained by means of a simple model considering the molecular packing and polarizabilities.     

Synthesis of 3,4,5‐Trisubstituted Isoxazoles from Morita–Baylis–Hillman Acetates by an NaNO2/I2‐Mediated Domino Reaction

An efficient NaNO₂/I₂‐mediated one‐pot transformation of Morita–Baylis–Hillman (MBH) acetates into alkyl 3‐nitro‐5‐(aryl/alkyl)isoxazole‐4‐carboxylates is described. In a cascade event, initial Michael addition of NaNO₂ to the MBH acetate furnishes the allylnitro intermediate which undergoes I₂‐catalyzed oxidative α‐C H nitration of the nitromethyl subunit followed by [3+2] cycloaddition to afford the title compounds. Structural elaborations of these highly substituted isoxazoles by S_NAr reactions and hydrogenolysis allows access to useful products.     

α‐Sila‐Dipeptides: Synthesis and Characterization

The first two α‐sila‐dipeptides, 7 and cyclo‐sila‐dipeptide 8 , were synthesized and characterized by several methods, including X‐ray crystallography. Bulky t‐BuMe₂Si substituents provide some kinetic stabilization to the synthesized molecules. 7 and 8 are the first examples of a “Si for C switch” in the central α‐position of an amino acid or a peptide, in which silicon is bonded to both the amino and the carbonyl groups.     

N‐(tert‐Butoxycarbonyl)‐α‐aminoisobutyryl‐α‐aminoisobutyric acid methyl ester: two polymorphic forms in the space group P21/n

The title compound (systematic name: methyl 2‐{2‐[(tert‐butoxycarbonyl)amino]‐2‐methylpropanamido}‐2‐methylpropanoate), C₁₄H₂₆N₂O₅, (I), crystallizes in the monoclinic space group P2₁/n in two polymorphic forms, each with one molecule in the asymmetric unit. The molecular conformation is essentially the same in both polymorphs, with the α‐aminoisobutyric acid (Aib) residues adopting ϕ and ψ values characteristic of α‐helical and mixed 3₁₀‐ and α‐helical conformations. The helical handedness of the C‐terminal residue (Aib2) is opposite to that of the N‐terminal residue (Aib1). In contrast to (I), the closely related peptide Boc‐Aib‐Aib‐OBn (Boc is tert‐butoxycarbonyl and Bn is benzyl) adopts an α_L‐P_II backbone conformation (or the mirror image conformation). Compound (I) forms hydrogen‐bonded parallel β‐sheet‐like tapes, with the carbonyl groups of Aib1 and Aib2 acting as hydrogen‐bond acceptors. This seems to represent an unusual packing for a protected dipeptide containing at least one α,α‐disubstituted residue.     

1,2‐Diphenyl‐2‐(phenyldiazenyl)‐2‐tosylethanone,an example of a fungicide containing a sulfonyl group

The mol­ecule of the title compound, C₂₇H₂₂N₂O₃S, adopts an irregular propeller shape with the tetrahedral C1 atom pivotal. The α‐azo­phenyl and α‐phenyl moieties are approximately coplanar. Electrostatic attraction of the oppositely charged atoms generates several short intramolecular contacts involving the sulfonyl, azo and carbonyl groups. Characteristic bond‐length distribution of the central part of the mol­ecule indicates that the Coulombic charge transfer is supplemented by hyperconjugation involving donation of electron density from the azo moiety towards the sulfonyl and carbonyl groups.     

SNAr reaction of 2,5‐dinitrofuran: A mild and efficient method for the preparation of 2‐aryloxy‐5‐nitrofuran

2,5‐Dinitrofuran which can be easily prepared by nitration of 2‐nitrofuran, on phase transfer catalysed S_NAr reaction with phenol gave good yield of 2‐aryloxy‐5‐nitrofuran. J. Heterocyclic Chem., (2011).     

Radical Stability Directs Electron Capture and Transfer Dissociation of β‐Amino Acids in Peptides

We report on the characteristics of the radical‐ion‐driven dissociation of a diverse array of β‐amino acids incorporated into α‐peptides, as probed by tandem electron‐capture and electron‐transfer dissociation (ECD/ETD) mass spectrometry. The reported results demonstrate a stronger ECD/ETD dependence on the nature of the amino acid side chain for β‐amino acids than for their α‐form counterparts. In particular, only aromatic (e.g., β‐Phe), and to a substantially lower extent, carbonyl‐containing (e.g., β‐Glu and β‐Gln) amino acid side chains, lead to N? C_β bond cleavage in the corresponding β‐amino acids. We conclude that radical stabilization must be provided by the side chain to enable the radical‐driven fragmentation from the nearby backbone carbonyl carbon to proceed. In contrast with the cleavage of backbones derived from α‐amino acids, ECD of peptides composed mainly of β‐amino acids reveals a shift in cleavage priority from the N? C_β to the C_α? C bond. The incorporation of CH₂ groups into the peptide backbone may thus drastically influence the backbone charge solvation preference. The characteristics of radical‐driven β‐amino acid dissociation described herein are of particular importance to methods development, applications in peptide sequencing, and peptide and protein modification (e.g., deamidation and isomerization) analysis in life science research.     

Nonlinear Brønsted and Hammett Correlations Associated with Reactions of 4‐Chloro‐7‐nitrobenzofurazan with Anilines in Dimethyl Sulfoxide Solution

The kinetics and mechanism of nucleophilic aromatic substitution reactions of 4‐chloro‐7‐nitrobenzofurazan 1 with 4‐X‐substituted anilines 2a–g (X = OH, OCH₃, CH₃, H, I, Cl, and CN) are investigated in a dimethyl sulfoxide (Me₂SO) solution at 25°C. The Hammett plot of log k₁ versus σ is nonlinear for all the anilines studied due to positive deviations of the electron‐donating substituents. However, the corresponding Yukawa–Tsuno plot resulted in a good linear correlation with σ+r (σ⁺?σ). The corresponding Brønsted‐type plot is also nonlinear, i.e., the slope (β_nuc) changes from 1.60 to 0.56 as the basicity of anilines decreases. These results indicate a change in a mechanism from a polar S_NAr process for less basic nucleophiles (X = I, Cl, and CN) to a single electron transfer for more basic nucleophiles (X = OH, OCH₃, and CH₃). The satisfactory log k₁ versus E^o correlation obtained for the reactions of 1 with anilines 2a–d in the present system is consistent with the proposed mechanism. Interestingly, the β_nuc = 1.60 value measured for 1 in Me₂SO reflects one of the highest coefficients Brønsted ever observed for S_NAr reactions. © 2013 Wiley Periodicals, Inc. Int J Chem Kinet 45: 152–160, 2013     

Study of the Air‐Tolerant 1,3‐Diphosphacyclobutane‐2,4‐diyl through the Direct Arylation

Installing π‐functional substituents on the skeletal phosphorus atoms of the air‐tolerant 1,3‐diphosphacyclobutane‐2,4‐diyl unit are promising for tuning the open‐shell singlet P‐heterocyclic chromophore. The sterically encumbered 1,3‐diphosphaCycloButen‐4‐yl Anion ( CBA ), generated from the phosphorus‐carbon triple bond, was available for the regioselective arylation via nucleophilic aromatic substitution (S_NAr) reaction, addition to arynes, and single‐electron transfer (SET) process affording the corresponding P‐arylated 1,3‐diphosphacyclobutane‐2,4‐diyls. The photo‐absorption and redox properties correlated with the effects of the aryl substituents on the 1,3‐diphosphacyclobutane‐2,4‐diyl unit. The X‐ray analyses enabled not only to discuss the metric parameters but also to visualize the radicalic electrons via the electron‐density distribution analysis. The electron‐donating character of the P‐heterocyclic chromophores induced the p‐type semiconductor behavior. Detection of hydrogen fluoride via formation of the 1λ⁵,3λ⁵‐diphosphete derivative was also developed.     

SmI2－Mediated Addition Reaction of α－Halomethylsulfones to Carbonyl Compounds. A Convenient Synthesis of β－Hydroxysulfones

Due to the chemoselective dehalogenation by SmI2, the addition of a-halomethylsulfones to carbonyl compounds afforded ,β-hydroxysulfones. Those reactions with α-bromomethylsulfones gave the products in moderate to good yields. The SmI2-mediated addition of gem-dihalomethylsulfones to ketones also afforded α-halo-β-hydroxysulfones in moderate yields.     

1,ω‐Bis(4‐amino‐1,2,4‐triazole‐5(1H)‐thion‐3‐ylsulfanyl)alkanes: Versatile precursors for novel bis(S‐triazolo[3,4‐b][1,3,4]thiadiazines) as well as novel bis(macrocyclic schiff bases)

Two synthetic routes were attempted for the synthesis of the novel bis(5,6‐dihydro‐S‐triazolo[3,4‐b]thiadiazines) 12a,b and 14 . In the first route the bis(aminotriazoles) 4a,b were reacted with the appropriate α‐haloketones or α‐haloesters to give the corresponding bis(S‐triazolo[3,4‐b]thiadiazines) 11a‐d followed by reduction with NaBH₄. In the second route, the bis(Schiff bases) 13d were reacted with the appropriate α‐haloesters in refluxing DMF containing TEA to give the target compound 14 . Cyclocondensation of 4a,b with the appropriate bis(carbonyl) ethers 15a,b in refluxing acetic acid under high dilution conditions afforded the corresponding macrocyclic Schiff bases 16a‐c . The latter underwent alkylation with the appropriate halo compounds to give the corresponding alkylated derivatives 17a‐d .