Stereospecific 1,3‐Aminobromination of Donor–Acceptor Cyclopropanes

Sn(OTf)₂‐catalyzed 1,3‐aminobromination of donor–acceptor cyclopropanes with various sulfonyl amides or electron‐poor anilines and N ‐bromosuccinimide is reported. These experimentally straightforward reactions occurred with complete regio‐ and stereospecificity (for anilines) to give γ‐aminated α‐brominated malonic diesters in good to excellent yields (up to 98 %). These compounds served as valuable substrates for subsequent reactions to provide substituted azetidines and γ‐lactams in high yields.     

New Highlights in the Synthesis of 4‐Aryl‐1,4‐dihydropyrazines

The 4‐aryl‐1,4‐dihydropyrazines were prepared via the cyclization of N,N‐bisalkylated anilines with ammonium acetate. These reactions were aided by improvements in the synthesis of N,N‐bisalkylated anilines which were alkylated with anilines using ethyl 2‐diazo acetoacetate in a reaction catalyzed by rhodium acetate in the absence of oxygen. A possible mechanistic route is postulated on the basis of the isolation of the N‐alkylation intermediates, which were determined to be N‐aryloxamates by ¹H NMR data and X‐ray diffraction.     

Ligand‐Promoted Rhodium(III)‐Catalyzed ortho‐C−H Amination with Free Amines

Ligand development for rhodium(III)‐catalyzed C−H activation reactions has largely been limited to cyclopentadienyl (Cp) based scaffolds. 2‐Methylquinoline has now been identified as a feasible ligand that can coordinate to the metal center of Cp*RhCl to accelerate the cleavage of the C−H bond of N ‐pentafluorophenylbenzamides, providing a new structural lead for ligand design. The compatibility of this reaction with secondary free amines and anilines also overcomes the limitations of palladium(II)‐catalyzed C−H amination reactions.     

A facile one‐pot regioselective synthesis of [1,2,4]triazolo[4,3‐a]5(1H)‐pyrimidinones via tandem Japp–Klingemann,Smiles rearrangement,and cyclization reactions

Coupling of active [(4‐oxo‐6‐phenyl‐3H‐pyrimidin‐2‐yl)thio]methine compounds ( 3 ) with diazotized anilines in the presence of base gave [1,2,4]triazolo[4,3‐a]pyrimidines ( 7 ). The latter products were also obtained by reactions of hydrazonoyl chlorides ( 10 ) with either 6‐phenyl‐2‐thiouracil ( 1 ) or the 2‐methylthio derivative 9 . The mechanisms and the regiochemistry of the reactions studied are discussed. © 2002 Wiley Periodicals, Inc. Heteroatom Chem 13:136–140, 2002; Published online in Wiley Interscience (www.interscience.wiley.com). DOI 10.1002/hc.10008     

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     

Solvent and substituent effects on the reaction of 2‐ and 4‐chloro‐3,5‐dinitrobenzotrifluorides with substituted anilines

The solvent effect on a nucleophilic substitution reaction of 2‐ and 4‐chloro‐3,5‐dinitrobenzotrifluoride with substituted anilines was studied in methanol, acetonitrile, and toluene at 25°C. This reaction is of second order, except 2‐chloro‐3,5‐dinitrobenzotrifluoride in toluene shows third order. The k_A values are found to be dependent on the substituent in aniline and give good Hammett correlations. The obtained ρ values are ?4.07 and ?4.62, for the reaction of anilines with 2‐chloro‐3,5‐dinitrobenzotrifluoride in methanol and acetonitrile, respectively. The ρ values for the reaction of the anilines with 4‐chloro‐3,5‐dinitrobenzotrifluoride are ?3.38, ?4.11, and ?4.34 in methanol, acetonitrile, and toluene, respectively. The reaction of the former compound with anilines in toluene shows a second order in aniline. The dependence of the reaction on the external base such as DABCO suggests a proton transfer controlling step. © 2009 Wiley Periodicals, Inc. Int J Chem Kinet 41: 777–786, 2009     

Kinetics and reactivity of substituted anilines with 2‐chloro‐5‐nitropyridine in dimethyl sulfoxide and dimethyl formamide

The kinetics of the reaction of substituted anilines with 2‐chloro‐5‐nitropyridine were studied in dimethyl sulfonide (DMSO) and dimethyl formamide (DMF) at different amine concentrations and temperatures in the range 45–60°C. In both solvents the reaction was not a base‐catalyzed one. A plot of ΔH^# versus ΔS^# for the reaction in DMSO and DMF gave good straight lines with isokinetic temperatures 128°C and 105°C, respectively. Good linear relationships were obtained from the plots of log k₁ against σ° values at all temperatures with negative ρ values (?1.63 to ?1.28 in DMSO) and (?1.26 to ?0.90 in DMF). © 2002 Wiley Periodicals, Inc. Int J Chem Kinet 34: 645–650, 2002     

Visible‐Light‐Driven Chemoselective Hydrogenation of Nitroarenes to Anilines in Water through Graphitic Carbon Nitride Metal‐Free Photocatalysis

Green and efficient procedures are essential for the chemoselective hydrogenation of functionalized nitroarenes to form industrially important anilines. Herein, it is shown that visible‐light‐driven, chemoselective hydrogenation of functionalized nitroarenes with groups sensitive to forming anilines can be achieved in good to excellent yields (82–100 %) in water under relatively mild conditions and catalyzed by low‐cost and recyclable graphitic carbon nitride. The process is also applicable to gram‐scale reaction, with a yield of aniline of 86 %. A study of the mechanism reveals that visible‐light‐induced electrons are responsible for the hydrogenation reactions, and thermal energy can also promote the photocatalytic activity. A study of the kinetics shows that this reaction possibly occurs through one‐step hydrogenation or stepwise condensation routes. A wide range of applications can be expected for this green, efficient, and highly selective photocatalysis system in reduction reactions for the synthesis of fine chemicals.     

Kinetic Studies on Nucleophilic Addition Reactions of 4‐X‐substituted Anilines to N1‐methyl‐4‐nitro‐2,1,3 benzothiadiazolium terafluoroborate in Acetonitrile: Reaction Mechanism and Mayr's Approach

The kinetics of the coupling of N1‐methyl‐4‐nitro‐2,1,3 benzothiadiazolium tetrafluoroborate 1 with a series of 4‐X‐substituted anilines 2a–f (X = OH, OMe, Me, H, Cl, and CN) have been investigated in acetonitrile at 20°C. The second‐order rate constants result in a nonlinear Brönsted‐type plot. The Hammett plot is also nonlinear, whereas the Yukawa–Tsuno plot exhibits an excellent linear correlation with ρ = –1.62 and r = 1.44. The large Brönsted (β_nuc = 1.24) and Hammett (ρ = –5.16) values suggest that the reactions proceed trough a single electron transfer mechanism. The finding of satisfactory correlation between the log k₁ of the reactions and the oxidation potentials (E°) of anilines 2a–d supports this mechanism. On the other hand, electrophilicity parameter E of benzothiadiazolium cation 1 as defined by the correlation log k_20°C = s(E + N) has been determined and compared with the electrophilic reactivities of a large variety of electrophiles.     

A Cascade Synthesis of Hetero‐arylated Triarylmethanes Through a Double 5‐endo‐dig Cyclization Sequence

A sequential two‐step method for the synthesis of hetero‐arylated triarylmethanes through a Ag‐catalyzed sequential double cyclization–nucleophilic addition cascade is described. This methodology basically involves an initial 5‐endo‐dig cyclization of o‐alkynyl anilines to provide 2‐substituted indole derivatives, which then react with 2‐(2‐enynyl)‐pyridines to afford indolizine‐containing unsymmetrical triarylmethanes through another 5‐endo‐dig cyclization.     

New C(2)‐substituted 8‐alkylsulfanyl‐9‐phenylmethyl‐hypoxanthines III

Title compounds were obtained starting from the key imidazole intermediate, 5‐amino‐1‐phenyl‐methyl‐2‐mercapto‐1H‐imidazole‐4‐carboxylic acid amide 5 , readily derived from the base catalyzed rearrangement of a thiazole, 5‐amino‐2‐phenylmethylaminothiazole‐4‐carboxylic acid amide 4 . Alkylation of the thiol function on 5 with phenylmethyl and allylic chlorides gave compounds 6 and 7 respectively. Cyclization of 6 with a variety of esters afforded 8‐phenylmethylthiohypoxanthines, 8–11 . Similarly, 7 was cyclized to 8‐allylthiohypoxanthines, 20–21 . Compound 5 was also cyclized, but formed 8‐mercaptohypox‐anthines, 22–24 . Alkylation of 8‐mercaptohypoxanthines afforded 8‐alkylthiohypoxanthines, 8, 9,25 and 26 (see Scheme 2). Chlorination of 9–11 afforded 16–18 ; adenine 19 was derived from 16 . Oxidation of hypox‐anthines 8–11 with m‐chloroperbenzoic acid gave the corresponding 8‐phenylmethylsulfonyl derivatives 12 ‐ 15 . These derivatives proved resistant to nucleophilic displacement reactions with primary amines.     

Anilinolysis of nitro‐substituted diphenyl ethers in acetonitrile: The effect of some ortho‐substituents on the mechanism of SNAr reactions

Rate data are reported for the reactions of a series of X‐phenyl 2,4,6‐trinitrophenyl ethers 1a–e [X = H, 4‐NO₂, 2‐NO₂, 2,4‐(NO₂)₂, or 2,6‐(NO₂)₂] with substituted anilines 2a–e [Y = H, 2‐CH₃, 2,4‐(CH₃)₂, 2,6‐(CH₃)₂, or N‐CH₃] in acetonitrile as solvent. For individual amine, kinetic data show that there is little steric hindrance to attack at the 1‐position of the parent molecules, even in the presence of di‐ortho substitution. With each substrate, however, there is evidence for significant steric interactions; such effects leading to rate retardation were very severe for 2,6‐dimethylaniline 2d (2,6‐(CH₃)₂) and N‐methylaniline 2e (Y = N‐CH₃), the deactivating effect of N‐CH₃ in most cases is slightly higher than that of 2,6‐(CH₃)₂. However, the reactions with 2e are base catalyzed whereas those of 2d are not. The corresponding reactions with aniline 2a (Y = H) and mono‐ortho methyl‐substituted aniline 2b (Y = CH₃) are wholly base catalyzed. Only with the dinitro substrates, an uncatalyzed reaction is observed and when X = 2,6‐(NO₂)₂ this pathway takes all the reaction flux. A rationale is provided for the dichotomy of amine effects observed in this investigation. © 2009 Wiley Periodicals, Inc. Int J Chem Kinet 42: 37–49, 2010     

High‐Yielding Synthesis of the Anti‐Influenza Neuraminidase Inhibitor (−)‐Oseltamivir by Two “One‐Pot” Sequences

The efficient asymmetric total synthesis of (?)‐oseltamivir, an antiviral reagent, has been accomplished by using two “one‐pot” reaction sequences, with excellent overall yield (60 %) and only one required purification by column chromatography. The first one‐pot reaction sequence consists of a diphenylprolinol silyl ether mediated asymmetric Michael reaction, a domino Michael reaction/Horner–Wadsworth–Emmons reaction combined with retro‐aldol/Horner–Wadsworth–Emmons reaction and retro Michael reactions, a thiol Michael reaction, and a base‐catalyzed isomerization. Six reactions can be successfully conducted in the second one‐pot reaction sequence; these are deprotection of a tert‐butyl ester and its conversion into an acyl chloride then an acyl azide, Curtius rearrangement, amide formation, reduction of a nitro group into an amine, and a retro Michael reaction of a thiol moiety. A column‐free synthesis of (?)‐oseltamivir has also been established.     

A computational study of base‐catalyzed reactions between isocyanates and epoxides affording 2‐oxazolidones and isocyanurates

Title reactions were investigated with ab initio calculations. Methyl isocyanate and ethylene oxide were adopted as model reactants. The products, 2‐oxazolidones and isocyanurates, cannot be yielded without a base catalyst. The 2‐oxazolidone may be produced by a dual S_N2 reaction, where the catalyst base (e.g., Cl⁻) is a nucleophile and a leaving group on the ethylene–oxide carbon. Isocyanurate is generated by the stepwise association of three isocyanate molecules, where one of the molecules is initially linked with a base. The six‐membered ring isocyanurate is isomerized stepwise into the components isocyanate and 2‐oxazolidone. A tetrahedral type of complex between the isocyanurate and a base‐catalyzed ethylene oxide is the key intermediate for the isomerization. © 2001 John Wiley & Sons, Inc. J Comput Chem 22: 316–326, 2001     

Rhodium‐Catalyzed Intramolecular Hydroarylation of 1‐Halo‐1‐alkynes: Regioselective Synthesis of Semihydrogenated Aromatic Heterocycles

The regioselective intramolecular hydroarylation of (3‐halo‐2‐propynyl)anilines, (3‐halo‐2‐propynyl) aryl ethers, or (4‐halo‐3‐butynyl) aryl ethers was efficiently catalyzed by Rh₂(OCOCF₃)₄ to give semihydrogenated aromatic heterocycles, such as 4‐halo‐1,2‐dihydroquinolines, 4‐halo‐3‐chromenes, or 4‐(halomethylene)chromans, in good to excellent yields. Some synthetic applications taking advantage of the halo‐substituents of the products are also illustrated.     

Multistep Flow Synthesis of 5‐Amino‐2‐aryl‐2H‐[1,2,3]‐triazole‐4‐carbonitriles

1,2,3‐Triazole has become one of the most important heterocycles in contemporary medicinal chemistry. The development of the copper‐catalyzed Huisgen cycloaddition has allowed the efficient synthesis of 1‐substituted 1,2,3‐triazoles. However, only a few methods are available for the selective preparation of 2‐substituted 1,2,3‐triazole isomers. In this context, we decided to develop an efficient flow synthesis for the preparation of various 2‐aryl‐1,2,3‐triazoles. Our strategy involves a three‐step synthesis under continuous‐flow conditions that starts from the diazotization of anilines and subsequent reaction with malononitrile, followed by nucleophilic addition of amines, and finally employs a catalytic copper(II) cyclization. Potential safety hazards associated with the formation of reactive diazonium species have been addressed by inline quenching. The use of flow equipment allows reliable scale up processes with precise control of the reaction conditions. Synthesis of 2‐substituted 1,2,3‐triazoles has been achieved in good yields with excellent selectivities, thus providing a wide range of 1,2,3‐triazoles.     

Silver(I)‐Catalyzed N‐Trifluoroethylation of Anilines and O‐Trifluoroethylation of Amides with 2,2,2‐Trifluorodiazoethane

A straightforward N‐trifluoroethylation of anilines has been developed based on silver‐catalyzed N? H insertions with 2,2,2‐trifluorodiazoethane (CF₃CHN₂). Mechanistically, the reaction is proposed to involve migratory insertion of a silver carbene as the key step. In contrast, when amides are employed as the substrates under similar reaction conditions, O‐trifluoroethylation occurs to afford trifluoroethyl imidates.     

One‐Pot synthesis of functional poly(methacrylate) by ATRP and 1,8‐Diazacyclo‐[5,4,0]undec‐7‐ene catalyzed transesterification

A facile one‐pot 1,8‐diazacyclo‐[5,4,0]undec‐7‐ene (DBU) catalyzed transesterification/atom transfer radical polymerization (ATRP) strategy has been successfully developed through the combination of copper/DBU‐catalyzed ATRP and DBU‐catalyzed transesterification reactions. Well‐defined poly(methacrylate)s with various side ester groups have been synthesized by ATRP and transesterification of acyl donor 2,2,2‐trifluoethyl methacrylate with various alcohols, such as benzyl alcohol, n‐butanol, iso‐propyl alcohol, methanol, triethylene glycol monomethyl ether, propargyl alcohol, and 6‐azido‐1‐hexanol by the one‐pot process. Kinetic studies indicate that the ATRP process proceeded in a controllable manner without the interference of the transesterification reactions. Expansion of the binary system to a higher level ternary system has been successfully achieved by the combination of copper(I)‐catalyzed azide–alkyne cycloaddition, transesterification, and ATRP reactions. © 2014 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2014 , 52, 2998–3003     

Ligand‐free CuTC‐catalyzed N‐arylation of amides,anilines and 4‐aminoantipyrine: synthesis of N‐arylacrylamides, 4‐amido‐N‐phenylbenzamides and 4‐amino(N‐phenyl)antipyrenes

N‐Arylation of amides and anilines with aryl iodides was efficiently catalyzed by copper thiophenecarboxylate under ligand‐free conditions with good to excellent yields. A variety of substituted aryl iodides, amides, anilines and 4‐aminoantipyrine were found to be applicable to the simple catalytic system. Furthermore, some practical, unique secondary amides, such as N‐arylacrylamides and 4‐amido‐N‐phenylbenzamides, and 4‐amino(N‐phenyl)antipyrenes, which are difficult to obtain by the classical methods, were prepared. Copyright © 2013 John Wiley & Sons, Ltd.     

Ruthenium‐Catalyzed Allylation–Cyclization Reactions of Cyclic 1,3‐Dicarbonyl Compounds with 1‐Vinyl Propargyl Alcohols

Ruthenium‐catalyzed allylation–cyclization reactions of cyclic 1,3‐dicarbonyl compounds with 1‐vinyl propargyl alcohols that lead to diverse carbo‐ or heterocyclic products in a one‐pot cascade process are reported. These mechanistically distinct reactions are catalyzed by a single ruthenium(0) complex that contains a redox‐coupled dienone ligand. The reaction pathway strongly depends on the substrate substitution pattern, which determines the mode of activation of the 1‐vinyl propargyl alcohol. The environmentally benign process, which generates water as the only waste product, is of wide scope and allows the atom‐economic synthesis of highly functionalized furans, pyrans, and spirocarbocycles.