Ring‐Opening Reactions of 3‐Aryl‐1‐benzylaziridine‐2‐carboxylates and Application to the Asymmetric Synthesis of an Amphetamine‐Type Compound

Nucleophilic ring‐opening reactions of 3‐aryl‐1‐benzylaziridine‐2‐carboxylates were examined by using O‐nucleophiles and aromatic C‐nucleophiles. The stereospecificity was found to depend on substrates and conditions used. Configuration inversion at C(3) was observed with O‐nucleophiles as a major reaction path in the ring‐opening reactions of aziridines carrying an electron‐poor aromatic moiety, whereas mixtures containing preferentially the syn‐diastereoisomer were generally obtained when electron‐rich aziridines were used (Tables 1–3). In the reactions of electron‐rich aziridines with C‐nucleophiles, S_N2 reactions yielding anti‐type products were observed (Table 4). Reductive ring‐opening reaction by catalytic hydrogenation of (+)‐trans‐(2S,3R)‐3‐(1,3‐benzodioxol‐5‐yl)aziridine‐2‐carboxylate (+)‐trans‐ 3c afforded the corresponding α‐amino acid derivative, which was smoothly transformed into (+)‐tert‐butyl [(1R)‐2‐(1,3‐benzodioxol‐5‐yl)‐1‐methylethyl]carbamate((+)‐ 14 ) with high retention of optical purity (Scheme 6).     

Two‐ and Three‐Component Reactions Leading to New Enamines Derived from 2,3‐Dicyanobut‐2‐enoates

The three‐component reactions of 1‐azabicyclo[1.1.0]butanes 1 , dicyanofumarates (E)‐ 5 , and MeOH or morpholine yielded azetidine enamines 8 and 9 with the cis‐orientation of the ester groups at the C?C bond ((E)‐configuration; Schemes 3 and 4). The structures of 8a and 9d were confirmed by X‐ray crystallography. The formation of the products is explained via the nucleophilic addition of 1 onto (E)‐ 5 , leading to a zwitterion of type 7 (Scheme 2), which is subsequently trapped by MeOH or morpholine ( 10a ), followed by elimination of HCN. Similarly, two‐component reactions between secondary amines 10a – 10c and (E)‐ 5 gave products 12 with an (E)‐enamine structure and (Z)‐oriented ester groups. On the other hand, two‐component reactions involving primary amines 10d – 10f or NH₃ led to the formation of the corresponding (Z)‐enamines, in which the (E)‐orientation of ester groups was established.     

Chemoselectivity of the Reactions of Diazomethanes with 5‐Benzylidene‐3‐phenylrhodanine

The reactions of 5‐benzylidene‐3‐phenylrhodanine ( 2 ; rhodanine=2‐thioxo‐1,3‐thiazolidin‐4‐one) with diazomethane ( 7a ) and phenyldiazomethane ( 7b ) occurred chemoselectively at the exocyclic C?C bond to give the spirocyclopropane derivatives 9 and, in the case of 7a , also the C‐methylated products 8 (Scheme 1). In contrast, diphenyldiazomethane ( 7c ) reacted exclusively with the C?S group leading to the 2‐(diphenylmethylidene)‐1,3‐thiazolidine 11 via [2+3] cycloaddition and a ‘two‐fold extrusion reaction’. Treatment of 8 or 9b with an excess of 7a in refluxing CH₂Cl₂ and in THF at room temperature in the presence of [Rh₂(OAc)₄], respectively, led to the 1,3‐thiazolidine‐2,4‐diones 15 and 20 , respectively, i.e., the products of the hydrolysis of the intermediate thiocarbonyl ylide. On the other hand, the reactions with 7b and 7c in boiling toluene yielded the corresponding 2‐methylidene derivatives 16, 21a , and 21b . Finally, the reaction of 11 with 7a occurred exclusively at the electron‐poor C?C bond, which is conjugated with the C?O group. In addition to the spirocyclopropane 23 , the C‐methylated 22 was formed as a minor product. The structures of the products (Z)‐ 8, 9a, 9b, 11 , and 23 were established by X‐ray crystallography.     

Investigation of Some Functionalization Reactions of 4‐Benzoyl‐5‐phenyl‐1‐(4‐methoxyphenyl)‐1H‐pyrazole‐3‐carbonyl Chloride and Their Antimicrobial Activity

The 1H‐pyrazole‐3‐carboxylic acid 1 was converted via reactions of its acid chloride 3 with various asymmetrical disubstituted urea and alcohol derivatives into the corresponding novel 4‐benzoyl‐N‐(N′,N′‐dialkylcarbamyl)‐1‐(4‐methoxyphenyl)‐5‐phenyl‐1H‐pyrazole‐3‐carboxamide 4a , b and alkyl 4‐benzoyl‐1‐(4‐methoxyphenyl)‐5‐phenyl‐1H‐pyrazole‐3‐carboxylate 7a‐c , respectively, in good yields (57%‐78%). Friedel‐Crafts reactions of 3 with aromatic compouns for 15 min.‐2 h led to the formation of the 4‐3‐diaroyl‐1‐(4‐hydroxyphenyl)‐5‐phenyl‐1H‐pyrazoles 9a‐c , 4‐benzoyl‐1‐(4‐methoxyphenyl)‐3‐aroyl‐5‐phenyl‐1H‐pyrazoles 10a , b and than from the acylation reactions of 9a‐c were obtained the 3,4‐diaroyl‐1‐(4‐acyloxyphenyl)‐5‐phenyl‐1H‐pyrazoles 13a‐d . The structures of all new synthesized compounds were established by NMR experiments such as ¹H, and ¹³C, as well as 2D COSY and IR spectroscopic data, and elemental analyses. All the compounds were evaluated for their antimicrobial activities (agar diffusion method) against eight bacteria and two yeasts.     

Synthesis and Anti‐HIV‐1 Evaluation of New Sonogashira‐Modified Emivirine (MKC‐442) Analogues

The MKC‐442 analogue 6‐(3,5‐dimethylbenzyl)‐5‐ethyluracil substituted with a (propargyloxo)methyl group at N(1) has previously been found highly active against HIV‐1. The C?C bond in the substituent at N(1) is here utilized in a series of chemical reactions in order to develop new agents with higher activity against HIV‐1‐resistant mutants. The syntheses involved Pd‐catalyzed C,C‐coupling reactions, addition of disulfides, and click chemistry on the terminal C?C bond as well as addition of bromine to the so formed internal C?C bonds. Sonogashira coupling were performed with silyl‐derivatized iodobenzyl alcohols which, after deprotection, were oxidized to aldehydes by means of IBX. The isomeric alcohol 37 was obtained in the Sonogashira reaction of propargyl alcohol with the N(1)‐substituted (4‐iodobenzyloxy)methyl derivative of the above mentioned uracil. Compound 37 turned out to be the most effective compound against problematic HIV‐1 mutants. The general observation in the present work is that a combination of alkyne and aryl in the substituent at N(1) leads to highly active compounds against HIV‐1.     

Organocatalytic Stereoselective Synthesis of 3‐Alkyl‐3‐hydroxy‐2‐oxindoles Catalyzed by Novel Water‐compatible Axially Unfixed Biaryl‐based Bifunctional Organocatalysts

In this work, six novel axially unfixed biaryl‐based water‐compatible bifunctional organocatalysts were designed and synthesized for the organocatalytic access to a variety of 3‐alkyl‐3‐hydroxy‐2‐oxindole derivatives via aldol reactions in water. Organocatalyzed by 5a , the direct aldol reactions of isatins with enolisable ketones underwent readily in water, furnishing the structurally diverse 3‐alkyl‐3‐hydroxy‐2‐oxindoles in various stereoselectivities (up to>99% dr and >99% ee). Moreover, a plausible transition state of the conducted aldol reactions was hypothesized to shed light on the observed stereoselectivities of the obtained 3‐alkyl‐3‐hydroxy‐2‐oxindoles.     

Nickel‐Catalyzed Cross‐Coupling Reactions of o‐Carboranyl with Aryl Iodides: Facile Synthesis of 1‐Aryl‐o‐Carboranes and 1,2‐Diaryl‐o‐Carboranes

A nickel‐catalyzed arylation at the carbon center of o‐carborane cages has been developed, thus leading to the preparation of a series of 1‐aryl‐o‐carboranes and 1,2‐diaryl‐o‐carboranes in high yields upon isolation. This method represents the first example of transition metal catalyzed C,C′‐diarylation by cross‐coupling reactions of o‐carboranyl with aryl iodides.     

Synthesis and Structure of Low‐valent η4‐Cinnamaldehyde Cobalt Complexes

Three η⁴‐(C=C–C=O) coordination cobalt(I) complexes 1 – 3 were synthesized by the reactions of cinnamaldehyde, p‐fluorocinnamaldehyde, and p‐chlorocinnamaldehyde with CoMe(PMe₃)₄. Complex 4 as η²‐(C=C) coordination was prepared by the reaction of chalcone with Co(PMe₃)₄. The structures of complexes 1 – 4 were confirmed by single‐crystal X‐ray diffraction. Although the reactions didn't undergo C–H bond activation and decarbonylation, the formation of complexes 1 – 4 deepens our understanding of the reactions between α,β‐unsaturated aldehyde or ketone with low‐valent central cobalt atom.     

Synthesis of N,N‐Dialkyl‐9‐oxoacridine‐10(9H)‐carbothioamides via the Reaction of (2‐Halophenyl)(2‐isothiocyanatophenyl)methanones with Secondary Amines,Followed by Cyclization with NaH

The first preparation of acridin‐9(10H)‐ones carrying a tertiary thiocarbamoyl group at C(10), i.e., N,N‐dialkyl‐9‐oxoacridine‐10(9H)‐carbothioamides 9 , is described. The method is based on the reaction of (2‐halophenyl)(2‐isothiocyanatophenyl)methanones 7 , prepared from (2‐aminophenyl)(2‐halophenyl)methanones 5 by a convenient three‐step sequence, with secondary amines in DMF at room temperature to generate the corresponding thiourea derivatives 8 in situ, which are treated with NaH at 100–120° to provide the desired products in one‐pot reactions in generally good yields.     

Reactions of Acid Chlorides/Ketenes with 2‐Substituted 4,5‐Dihydro‐4,4‐dimethyl‐1,3‐thiazoles: Formation of Penam Derivatives

Addition reactions of acid chlorides with various 2‐substituted 4,5‐dihydro‐4,4‐dimethyl‐5‐(methylsulfanyl)‐1,3‐thiazoles under basic conditions were studied. Two kinds of products were obtained from these additions, β‐lactams and non‐β‐lactam adducts. When the reaction was carried out with 4,5‐dihydro‐1,3‐thiazoles with a Ph substituent at C(2), the reaction proceeded via formal [2+2] cycloaddition and led to the correspoding β‐lactam. On the other hand, acid chlorides and 4,5‐dihydro‐1,3‐thiazoles bearing an α‐H‐atom at the C(2)‐substituent underwent C(α)‐ and/or N‐addition reactions and furnished non‐β‐lactam adducts, i.e., C(α)‐ and/or N‐acylated 1,3‐thiazolidines. The attempted transformations of sulfonyl esters of exo‐6‐hydroxy penams to endo‐6‐azido penams failed, although they were successful with mono‐β‐lactams under the same conditions.     

Copper‐Catalyzed Domino Synthesis of 2‐Imino‐1H‐imidazol‐5(2H)‐ones and Quinoxalines Involving CC Bond Cleavage with a 1,3‐Dicarbonyl Unit as a Leaving Group

Although 2‐imino‐1H‐imidazol‐5(2H)‐ones have important biological activities in metabolism, their synthesis has rarely been investigated. Quinoxalines as “privileged scaffolds” in medicinal chemistry have been extensively investigated, but the development of novel and efficient synthetic methods remains very attractive. Herein, we have developed two copper‐catalyzed domino reactions for the synthesis of 2‐imino‐1H‐imidazol‐5(2H)‐ones and quinoxalines involving C?C bond‐cleavage with a 1,3‐dicarbonyl unit as a leaving group. The domino sequence for the synthesis of 2‐imino‐1H‐imidazol‐5(2H)‐ones includes aza‐Michael addition, intramolecular cyclization, C?C bond‐cleavage, 1,2‐rearrangement, and aerobic dehydrogenation reaction, whereas the domino sequence for the synthesis of quinoxalines includes aza‐Michael addition, intramolecular cyclization, elimination reaction, and C?C bond‐cleavage reaction. The two domino reactions have significant advantages including high efficiency, mild reaction conditions, and high tolerance of various functional groups.     

The ambident electrophilic behavior of 5‐nitro‐3‐X‐thiophenes in σ‐complexation processes

Kinetics of the reactions of 3,5‐dinitrothiophene 1 and 3‐cyano‐5‐nitrothiophene 2 with a series of parasubstituted phenoxide anions 3a–c have been investigated in aqueous solution at 20°C. Two unsubstituted electrophilic centers (C(2) and C(4)) of the two thiophenes have been identified. The Fukui functions correctly predict the C(2) and C(4) atoms as the most electrophilic centers of these electron‐deficient thiophenes 1 and 2 . Analysis of the experimental data in terms of Brønsted relationships reveals that the reaction mechanism likely involves a single‐electron transfer (SET) process. The excellent correlations upon plotting the rate constants versus the oxidation potentials E^o values is an additional evidence that reactions between thiophenes and phenoxide anions are proceeding through an initial electron transfer. It is of particular interest to note that the systems studied in this paper provide a rare example of a SET mechanism in σ‐complexation reactions. According to the free energy relationship log k = s(N + E) (Angew. Chem., Int. Ed. Engl., 1994, 33, 938–957), the electrophilicity parameters E of the C‐4 and C‐2 positions of the thiophenes have been determined and compared with the reactivities of other ambident electrophiles. On the other hand, the second‐order rate constants for the reactions of these thiophenes with the hydroxide ion has been measured in water and 50% water–50% acetonitrile and found to agree with those calculated theoretically using Mayr's equation from the E values determined in this work and from the previously published N and s parameters of OH⁻.     

Chain‐transfer reaction in the radical polymerization of di‐n‐butyl itaconate at high temperatures

Radical polymerizations of di‐n‐butyl itaconate were investigated. Unexpected resonances (C resonances) were observed in ¹³C NMR spectra of C?O of poly(di‐n‐butyl itaconate)s [poly(DBI)s] obtained at temperatures higher than 60 °C, although two kinds of carbonyl groups showed splittings due to triad tacticities in the spectra of polymers obtained at lower temperatures. The poly(DBI)s formed by the different kinds of initiators or formed in the presence of chain‐transfer agents showed hardly any changes in the intensities of the C resonances; this indicated that the C resonances were not due to the structures formed through initiating and terminating reactions. The poly(DBI)s obtained at different yields showed only a slight increase in the intensities of the C resonances with the yield, which suggested that the C resonances were not attributable to the intermolecular chain‐transfer reaction to the monomer and/or polymer. However, the intensities of the C resonances significantly increased with a decreasing feed monomer concentration; this suggested that intramolecular chain‐transfer reactions took place at high temperatures. Furthermore, a Cu complex‐catalyzed atom transfer radical polymerization mechanism was revealed to be effective for suppressing the intramolecular chain‐transfer reaction at 60 °C. © 2002 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 40: 2415–2426, 2002     

Synthesis of 15‐Cyano‐12‐oxopentadecano‐15‐lactone and 15‐Cyano‐ 12‐oxopentadecano‐15‐lactam

15‐Cyano‐12‐oxopentadecano‐15‐lactone was synthesized in 59% total yield starting from 2‐nitrocyclododecanone by Michael addition to acrylaldehyde, followed by reaction with trimethylsilylcyanide, hydrolysis, ring‐expansion, and Nef reaction. A two‐step, one‐pot synthesis of intermediate 2‐hydroxy‐4‐(1‐nitro‐2‐oxycyclododecyl)butanenitrile from 3‐(1‐nitro‐2‐oxocyclododecyl)propanal was developed and the conditions for the Nef reaction were studied. 15‐Cyano‐12‐oxopentadecano‐15‐lactam was synthesized in 40% total yield starting from 2‐nitrocyclododecanone by Michael addition to acrylaldehyde, followed by Strecker reaction, ring‐expansion, and Nef reaction. The conditions for the Strecker and Nef reactions were studied. The structures of the target compounds, intermediates, and by‐product were characterized by IR, ¹H‐ and ¹³C‐NMR, and elemental analysis or MS.     

Kinetics of hexene‐1 polymerization using [(N,N′‐diisopropylbenzene)‐2,3‐(1,8‐napthyl)‐1,4‐diazabutadiene] dibromonickel/methylaluminoxane catalyst system

Kinetics of hexene‐1 polymerization was investigated using [(N,N′‐diisopropylbenzene)2,3‐(1,8‐napthly)‐1,4‐diazabutadiene]dibromonickel/methylaluminoxane catalyst. Experiments were performed at varying catalyst and monomer concentrations in the temperature range of ?10 to 35 °C. First order time‐conversion plot shows a downward curvature at temperatures of 20 °C and 35 °C indicating the presence of finite termination reactions. A nonlinear plot of degree of polymerization (P_n) with respect to conversion indicates occurrence of transfer reactions and slow initiation. The experimental molar masses are higher than predicted, which implies that a fraction of catalyst species could not be activated or is deactivated at the early stages of the reactions. The efficiency of the catalyst (Cat_eff) varies from 0.77 to 0.89. The observed polydispersity of the poly(hexene‐1) s is in the range of 1.18–1.48. The reaction order was found to be 1.11 with respect to catalyst. The Arrhenius plot obtained using the overall propagation rate constant, k_p, at five different temperatures (?10, 0, 10, 20, and 35 °C) was found to be linear with an activation energy, E_a = 4.3 kcal/mol. Based on the results presented it is concluded that the polymerization of hexene‐1 under the above‐mentioned conditions shows significant deviation from ideal “living” behavior. © 2006 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 45: 1093–1100, 2007     

Microwave‐assisted Synthesis of Novel 3,4‐Bis‐chalcone‐N‐arylpyrazoles and Their Anti‐inflammatory Activity

A series of 3,4‐bis‐chalcone‐N‐arylpyrazoles 3a‐h was prepared conveniently from diacetyl pyrazoles 2a,b . All reactions were carried out under conventional thermal heating and/or microwave irradiation. The structure of the latter functionally pyrazoles was confirmed under the bases of their IR, mass, ¹H NMR and ¹³C NMR. The X‐ray diffraction of compound 3e not only confirmed the chemical structure of 3a‐h , but also showed the E configuration of their chalcone moieties. Treatment of compound 3e with phenyl hydrazine in presence of acetic acid afforded the tri‐pyrazle 4 . The anti‐inflammatory activity of the newly synthesized compounds was investigated. Some of these compounds showed a moderate activity when compared with indomethacin as a reference drug. The combination between chalcone and pyrazole moieties revealed a variable effect in anti‐inflammatory activity.     

Regioselective Arylation and Alkynylation of 2,3‐Dibromo‐1H‐inden‐1‐one by Suzuki?Miyaura and Sonogashira Cross‐Coupling Reactions

Suzuki? Miyaura reactions of 2,3‐dibromo‐1H‐inden‐1‐one afforded a wide range of arylated 1H‐inden‐1‐ones. Sonogashira cross‐coupling reactions gave alkynylated indenones. The reactions proceeded with very good regioselectivity in the less sterically hindered and more electron‐deficient position 3.     

Pd‐Catalyzed Decarboxylative Cross‐Coupling of 2‐Carboxyazine N‐Oxides with Various (Hetero)aryl Halides

Decarboxylative cross‐coupling reactions of substituted 2‐carboxyazine N‐oxides, with a variety of (hetero)aryl halides, by bimetallic Pd⁰/Cu^I and Pd⁰/Ag^I catalysis are reported. Two possible pathways, a conventional bimetallic‐catalyzed decarboxylative arylation, as well as a protodecarboxylative/direct C?H arylation sequence have been considered. These methods provide the first general decarboxylative arylation methodology for the 2‐carboxyazine series.     

Toward product control in ring‐opening oligomerization of 9H‐9‐borafluorenes

To get deep insights into the structure–reactivity relationship for ring‐opening oligomerization reactions toward targeted design of novel main‐chain boron‐containing materials, detailed DFT B97D/TZVP calculations are carried out to compare the ring‐opening oligomerization of both unsubstituted and tert‐butyl (tBu)‐substituted 9H?9‐borafluorenes. In contrast to substituent exchange between normal boranes, such reactions are initiated by substituent exchanges involving double B? C? B bridged intermediates. On tBu‐substitution, the B? C? B, and B? H? B bridged dimer intermediate is stabilized mainly due to enhanced barrier of 18.1 kcal/mol toward further trimerization channel and higher isomerization barrier of 22.5 kcal/mol toward the double B? H? B bridged dimer. In good agreement with available experiments, it is clearly shown that various product channels can be efficiently controlled by bulky substitution and by reaction temperatures, pointing out the way toward desired higher oligomers with improved thermal stability. © 2014 Wiley Periodicals, Inc.     

Structural Features of Certain p‐substituted Phenyl 2‐nitrovinyl Sulfones

The structure of p‐substituted phenyl 2‐nitrovinyl sulfones was studied through different spectral methods. It has been found that the nucleophilic substitution reactions of sodium phenylsulfinates with 1‐chloro‐2‐nitroethene occur stereospecifically. The formation of E‐isomers of this type of substituted phenyl vinyl sulfones was confirmed by FTIR and NMR spectroscopy. It was suggested that the E‐isomers formation was determined by the more stable conformation of the carbanionic intermediate as a result of intramolecular rotation around single Cα‐Cβ bond. This appears to be the product‐determining pathway during the interaction of sodium phenyl sulfinates with the highly activated substrate 1‐chloro‐2‐nitroethene.