1,2‐Bis(trifluoromethyl)ethene‐1,2‐dicarbonitrile: Enol Ethers and Ketene Acetals as Cycloaddition Partners

(E)‐ and (Z)‐1,2‐bis(trifluoromethyl)ethene‐1,2‐dicarbonitrile ((E)‐ and (Z)‐BTE, resp., =(E)‐ and (Z)‐2,3‐bis(trifluoromethyl)but‐2‐enedinitrile) were used as a stereochemical probe in studying (2+2) cycloadditions of acceptor with donor alkenes. The additions to methyl (E)‐ and (Z)‐propenyl ether gave rise to the eight conceivable cyclobutanes 8 , although in different ratios in reactions of (E)‐ and (Z)‐BTE. The ¹⁹F‐NMR data served the structural assignment and the quantitative analysis. The mechanistic discussion is based on rotations and ring closures of the assumed 1,4‐zwitterionic intermediates. Dimethylketene dimethyl acetal, methylketene dimethyl acetal, and ketene diethyl acetal show an increasing rate in their reactions with BTE as well as in the equilibration of the cycloadducts.     

1,2‐Bis(trifluoromethyl)ethene‐1,2‐dicarbonitrile: (2+2) Cycloadditions with Vinyl Ethers

The title compound (short version: BTE) occurs in (E)‐ and (Z)‐isomers (both with b.p. of ca. 100°) which equilibrate with nucleophilic catalysts. Both undergo (2+2) cycloadditions with methyl vinyl ether at 25°. Three stereogenic centers in the cyclobutanes led to four rac‐diastereoisomers, which were obtained in pure and crystalline state. The structures were elucidated by ¹⁹F‐NMR spectroscopy and confirmed by two X‐ray analyses. The cycloadditions were not stereospecific: e.g., (E)‐BTE furnished 73% trans‐adducts (with respect to the CF₃ groups) and 27% cis‐adducts. The loss of stereochemical integrity occurs in the intermediate gauche‐zwitterions which can cyclize or rotate, but not dissociate. Under extreme conditions (2M LiClO₄ in Et₂O, 70°, 3 months), the thermodynamic equilibrium of the four cyclobutanes was achieved. Considerations of Coulombic attraction and conformational strain in the zwitterionic intermediates allow us to rationalize the observed proportions of diastereoisomeric cyclobutanes. Ethyl vinyl ether and butyl vinyl ether furnished cyclobutanes in similar diastereoisomer ratios.     

1,2‐Bis(trifluoromethyl)ethene‐1,2‐dicarbonitrile and Vinyl Ethers: Cyclic Ketene Imines on the Pathway to 1 : 2 Cycloadducts

(E)‐ and (Z)‐1,2‐bis(trifluoromethyl)ethene‐1,2‐dicarbonitrile (BTE; (=E)‐ and (Z)‐1,2‐bis(trifluoromethyl)but‐2‐enedinitrile) were reacted with an excess of methyl vinyl ether, used as solvent, and furnished 1 : 2 adducts 6 (54%) and cyclobutanes 3 as 1 : 1 adducts (41%). The four diastereoisomeric bis‐adducts 6 (different ratios from (E)‐ and (Z)‐BTE) are derivatives of 1‐azabicyclo[4.2.0]oct‐5‐ene; X‐ray analyses and ¹⁹F‐NMR spectra revealed their structures. Since the cyclobutanes 3 are resistant to vinyl ether, the pathways leading to mono‐ and bis‐adducts must compete on the level of the intermediate l,4‐zwitterions 1 and 2 . The latter either cyclize to the cyclobutanes 3 or to six‐membered cyclic ketene imines 8 which accept a second molecule of vinyl ether to yield the bis‐adducts 6 . The occurrence of the highly strained ketene imines 8 gains credibility by comparison to stable seven‐membered cyclic ketene imines recently reported.     

Reactions of Methyl Diazoacetate with (E)‐ and (Z)‐1,2‐Bis(trifluoromethyl)ethene‐1,2‐dicarbonitrile: Novel and Unanticipated Pathways

The cycloadditions of methyl diazoacetate to 2,3‐bis(trifluoromethyl)fumaronitrile ((E)‐ BTE ) and 2,3‐bis(trifluoromethyl)maleonitrile ((Z)‐ BTE ) furnish the 4,5‐dihydro‐1H‐pyrazoles 13 . The retention of dipolarophile configuration proceeds for (E)‐ BTE with > 99.93% and for (Z)‐ BTE with > 99.8% (CDCl₃, 25°), suggesting concertedness. Base catalysis (1,4‐diazabicyclo[2.2.2]octane (DABCO), proton sponge) converts the cycloadducts, trans‐ 13 and cis‐ 13 , to a 94 : 6 equilibrium mixture (CDCl₃, r.t.); the first step is N‐deprotonation, since reaction with methyl fluorosulfonate affords the 4,5‐dihydro‐1‐methyl‐1H‐pyrazoles. Competing with the cis/trans isomerization of 13 is the formation of a bis(dehydrofluoro) dimer (two diastereoisomers), the structure of which was elucidated by IR, ¹⁹F‐NMR, and ¹³C‐NMR spectroscopy. The reaction slows when DABCO is bound by HF, but F^? as base keeps the conversion to 22 going and binds HF. The diazo group in 22 suggests a common intermediate for cis/trans isomerization of 13 and conversion to 22 : reversible ring opening of N‐deprotonated 13 provides 18 , a derivative of methyl diazoacetate with a carbanionic substituent. Mechanistic comparison with the reaction of diazomethane and dimethyl 2,3‐dicyanofumarate, a related tetra‐acceptor‐ethylene, brings to light unanticipated divergencies.     

Reactions of 2‐Unsubstituted 1H‐Imidazole 3‐Oxides with 2,2‐Bis(trifluoromethyl)ethene‐1,1‐dicarbonitrile: A Stepwise 1,3‐Dipolar Cycloaddition

The reaction of 1,4,5‐trisubstituted 1H‐imidazole‐3‐oxides 1 with 2,2‐bis(trifluoromethyl)ethene‐1,1‐dicarbonitrile ( 7 , BTF) yielded the corresponding 1,3‐dihydro‐2H‐imidazol‐2‐ones 10 and 2‐(1,3‐dihydro‐2H‐imidazol‐2‐ylidene)malononitriles 11 , respectively, depending on the solvent used. In one example, a 1 : 1 complex, 12 , of the 1H‐imidazole 3‐oxide and hexafluoroacetone hydrate was isolated as a second product. The formation of the products is explained by a stepwise 1,3‐dipolar cycloaddition and subsequent fragmentation. The structures of 11d and 12 were established by X‐ray crystallography.     

A New Sterically Highly Hindered 7‐Membered Cyclic Nitroxide for the Controlled Living Radical Polymerization

The synthesis of a new sterically highly hindered 7‐membered alkoxyamine, 2,2,7,7‐tetraethyl‐1‐(1‐phenylethoxy)‐1,4‐diazepan‐5‐one ( 4 ), starting from known 2,2,6,6‐tetraethyl‐1‐(1‐phenylethoxy)piperidin‐4‐one ( 3 ) via a Beckmann‐type rearrangement is presented. It is shown that ring‐enlargement by insertion of an NH moiety in going from 3 to 4 leads to a more efficient regulator for nitroxide‐mediated controlled living radical styrene (= ethenylbenzene) and butyl acrylate (= butyl prop‐2‐enoate) polymerization. In addition to the polymerization experiments, kinetic data on the reversible C? O bond homolysis of alkoxyamines 3 and 4 are presented.     

Photocyclodimers of ‘Made‐to‐Measure’ Seven‐ and Six‐Membered Cyclic Enones

On irradiation (350 nm) in benzene as solvent, dioxepinone 6 and benzoxepinone 7 afford quantitatively mixtures of two diastereoisomeric head‐to‐head dimers, respectively. In both cases, on contact with SiO₂ the minor dimer containing trans‐ring fusions undergoes spontaneous isomerization to the (major) cis‐transoid‐cis diastereoisomer. In contrast, thiopyranone 8 is converted selectively, but in very low yield, to dimer 13 .     

Catalytic Asymmetric Construction of 3,3′‐Spirooxindoles Fused with Seven‐Membered Rings by Enantioselective Tandem Reactions

The first catalytic asymmetric construction of a spirooxindole scaffold incorporated with a seven‐membered benzodiazepine moiety has been established by a three‐component (isatin, 1,2‐phenylenediamine, cyclohexane‐1,3‐dione) tandem reaction catalyzed by a chiral phosphoric acid. Structurally complex spirobenzodiazepine oxindoles with one quaternary stereogenic center are obtained in high yield with excellent enantioselectivity (up to 99 % yield, enantiomeric ratio>99.5:0.5). This approach takes advantage of organocatalytic asymmetric tandem reactions to efficiently construct the structurally rigid spirobenzodiazepine oxindole architecture with high enantiopurity in a single transformation, which involves a cascade enamine–imine formation/intramolecular Mannich reaction sequence.     

Massive Steric Hindrance in Two ‘Thiocarbonyl Ylides': Cycloadditions with Tetra‐Acceptor‐Substituted Ethylenes via Zwitterionic Intermediates

The switch from a concerted to a two‐step pathway of 1,3‐dipolar cycloadditions was recently established for the reactions of sterically hindered ‘thiocarbonyl ylides' with acceptor ethylenes. This mechanism via zwitterionic intermediates is studied here for 1,3‐dipoles 5A and 5B , which are derived from 2,2,5,5‐tetramethylcyclopentanethione and 1,1,3,3‐tetramethylindan‐2‐thione, respectively, and contain a highly screened reaction center. In the reactions of 8A and 8B (the precursors of 5A and 5B ) with dimethyl 2,3‐dicyanofumarate ( 15 ) and 2,3‐dicyanomaleate ( 16 ), virtually identical ratios of cis‐ and trans‐thiolanes were observed ( 17 / 18 93 : 7 for 5a and 94 : 6 for 5B ). Thus, full equilibration of rotameric zwitterions precedes cyclization; an anteceding disturbing isomerization 15 ⇌ 16 had to be circumvented. The cis,trans assignment of the cycloadducts rests on three X‐ray analyses. The kinetically favored cis‐thiolanes 17 isomerize at >80° to 18 (trans), and irreversible cleavage leads to thione 7 and trans,cis isomeric dimethyl 1,2‐dicyanocyclopropane‐1,2‐dicarboxylates ( 27 and 28 , resp.). Furthermore, the zwitterionic intermediates equilibrate with the cyclic seven‐membered ketene imine 21 , which was intercepted under conditions where the solvent contained 2 vol‐% of H₂O or MeOH. Lactams 22 were obtained with H₂O in high yields, and the primary products of capturing by MeOH were the cyclic ketene O,N‐acetals 23 , which subsequently tautomerized to the lactim methyl ethers 24 . When 5B was reacted with ethenetetracarbonitrile in CDCl₃/MeOH (98 : 2 vol‐%), the analogous cyclic ketene imine 13B was trapped to the extent of 93%.     

A Cationic Chlorido‐bridged Palladium(II) Complex of the Sterically Hindered Bis(4‐methylthiazolyl)isoindoline Ligand (4‐Mebti)

The treatment of chlorido[bis(4‐methylthiazolyl)isoindoline]palladium(II) [(4‐Mebti)PdCl] with sodium tetrakis[bis‐3,5(trifluoromethyl)phenyl]boranate Na[BAr^F] in the absence of donor ligands or solvents results in the exclusive formation of the dinuclear cationic complex [{(4‐Mebti)Pd}₂Cl]⁺ independent of the stoichiometry of the reactants. The new compound crystallizes either in the space group or in C2/c depending on the amount of co‐crystallized solvent. In both cases, the molecular structure of the dinuclear cation reveals a sterically crowded situation with the Pd²⁺ ion bound in a non‐planar coordination environment. In solution, [{(4‐Mebti)Pd}₂Cl]⁺ reacts with acetonitrile to form the neutral [(4‐Mebti)PdCl] and an equilibrium mixture of different complexes, from which the mononuclear species [(4‐Mebti)Pd(NCCH₃)]⁺ can be isolated as the pure BAr^F derivative.     

Bis(1,2‐diselenoquadratato)metallate

Bis(1,2‐diselenosquarato) Metalates A series of 1,2‐diselenosquarato metalates [M(dssq)₂]^2– (M = Pd²⁺, Pt²⁺, Cu²⁺, Ni²⁺, Zn²⁺, Cd²⁺, Pb²⁺, VO²⁺) was available by direct synthesis from the appropriate metal salt with dipotassium 1,2‐diselenosquarate in deoxygenized water under an argon athmosphere. The copper(II)complex, [Cu(dssq)₂]^2–, and the oxovanadium(IV)complex, [VO(dssq)₂]^2–, were identified in solution by EPR spectroscopy (parameters: [Cu(dssq)₂]^2–: g₀ = 2.073; a = –76.0 · 10^–4 cm^–1, a = 47.0 · 10^–4 cm^–1; [VO(dssq)₂]^2–: g₀ = 1.986; a = 74.9 · 10^–4 cm^–1). The complexes bis(tetraphenylphosphonium)[bis(1,2‐diselenosquarato)nickelate(II)], (Ph₄P)₂[Ni(dssq)₂], and bis(tetraphenylphosphonium)[bis(1,2‐diselenosquarato)zincate(II)], (Ph₄P)₂[Zn(dssq)₂], were characterized by X‐ray structure analysis. The square‐planar Ni^II complex (Ph₄P)₂[Ni(dssq)₂] crystallizes in the monoclinic spacegroup P2₁/n with the unit cell parameters a = 11.1472(8) Å, b = 15.331(1) Å, c = 14.783(1) Å, β = 94.441(1)° and Z = 2. The Zn^II‐complex (Ph₄P)₂[Zn(dssq)₂] is tetrahedral coordinated and crystallizes in the monoclinic spacegroup P2₁/c with the unit cell parameters a = 9.4238(1) Å, b = 18.5823(3) Å, c = 29.5309(5) Å, β = 96.763(1)° and Z = 4.     

New Bis(dihydropyridine‐3,5‐dicarbonitrile) Derivatives: Green Synthesis and Cytotoxic Activity Evaluation

A synthesis of bis(dihydropyridine‐3,5‐dicarbonitrile) by a three‐component reaction of one equivalent of bis‐cyanoacetamides with two equivalents of both arylaldehydes and malononitrile in ethanol‐containing piperidine is reported. Bis‐cyanopyridones could also be obtained by the condensation of bis‐cyanoacetamides with substituted arylidenemalononitriles in the presence of piperidine, chitosan, or montmorillonite as basic catalysts. The cytotoxicity of the synthesized products against the heterogeneous human epithelial colorectal adenocarcinoma cell line (Caco‐2) was assessed by WST‐1 assay with concentration dependent cellular growth inhibitory effect especially for compounds 5l , 5h , and 5d . The dose response curves indicate that IC50 were 87 ± 3.11 μg/mL, 104 ± 4.78 μg/mL, and 108 ± 5.12 μg/mL, respectively.     

Synthesis of Functionalized Polynorbornanes Employing 2,5‐Bis(trifluoromethyl)‐1,3,4‐oxadiazole

Cycloaddition reaction of 2,5‐bis(trifluoromethyl)‐1,3,4‐oxadiazole with strained olefinic bonds of norbornenes was used to synthetize functionalized polynorbornanes. This simple, one step procedure was more effective when reaction was carried out by classical heating, in comparison to microwave‐assisted reactions. Various functional groups were stable in the reaction conditions (ester, imide, phthalimide, piperidyl, and carboxylic acid), whereas anhydride, N‐Boc, or TMS functionalities do not withstand reaction conditions.     

Carboboration Reactions of 1,2‐Bis[(diarylphosphino)ethynyl]benzenes with Tris(pentafluorophenyl)borane

The 1,2‐bis[(diarylphosphino)ethynyl]benzene derivatives 1a (R=Ph) and 1b (R=o‐tolyl) undergo 1,1‐carboboration at one of their acetylene units upon treatment with (C₆F₅)₃B at elevated temperature to give the products 5a and 5b , respectively. At room temperature, we observed the formation of the corresponding phosphireniumborate zwitterions, 7a and 7b , respectively, which may be intermediates of the 1,1‐carboboration reactions. The reaction of the more bulky 1,2‐bis[(dimesitylphosphino)ethynyl]benzene 1c with (C₆F₅)₃B takes a different course. At 110°, we observed the complete conversion to the benzopentafulvene derivative 8 which is probably formed in a typical carbocation rearrangement sequence after the initial (C₆F₅)₃B Lewis acid‐addition step. The compounds 5a, 5b, 7b , and 8 were characterized by X‐ray crystal‐structure analyses.     

A Convenient,Selective Synthesis of Bis[2,4‐bis(trifluoromethyl)phenyl]phosphane Derivatives Starting from 1,3‐Bis(trifluoromethyl)benzene

The reaction of the sterically shielded phosphane derivative, dichlorodiethylaminophosphane, Cl₂PNEt₂, with an excess of a mixture of 2,6‐bis(trifluoromethyl) and 2,4‐bis(trifluoromethyl)phenyl lithium gives bis[2,4‐bis(trifluoromethyl)phenyl]diethylaminophosphane, [2,4‐(CF₃)₂C₆H₃]₂PNEt₂, in 72 % yield as a colourless solid, while 2,6‐bis(trifluoromethyl)phenyl lithium remains unchanged in solution. The amino derivative crystallizes in the monoclinic space group P2₁/c (a 869.2(1), b 1857.4(1), c 1357.6(1) pm, β 100.57(4)°, Z = 4). Treatment of [2,4‐(CF₃)₂C₆H₃]₂PNEt₂ in CHCl₃ solution with conc. HCl allows the synthesis of [2,4‐(CF₃)₂C₆H₃)]₂PCl. [2,4‐(CF₃)₂C₆H₃]₂PCl reacts with H₂O in THF solution with quantitative formation of the corresponding secondary phosphane oxide. To obtain bis[2,4‐bis(trifluoromethyl)phenyl]phosphinic acid, [2,4‐(CF₃)₂C₆H₃]₂P(O)OH, quantitatively, a CHCl₃ solution of [2,4‐(CF₃)₂C₆H₃]₂P(O)H, has to be stirred in an NO₂ atmosphere. The phosphinic acid crystallizes is the triclinic space group (a 754.2(1), b 927.6(2), c 1305.5(2) pm, α 85.11(2)°, β 75.45(1)°, γ 79.99(2)°, Z = 2). From the reaction of the phosphinic acid with either elemental sodium or with cyanide salts, the corresponding phosphinate salts are obtained in an almost quantitatively yield.