1,6-Conjugate sulfonylation of para-quinone methides: An expedient approach to unsymmetrical gem-diarylmethyl sulfones

A novel sulfonylation of para-quinone methides with sodium arylsulfinates has been developed via acetic acid promoted sulfa-Michael addition. This reaction provides an inexpensive and efficient method to synthesize various unsymmetrical diarylmethyl sulfones, displaying the advantages of high atom economy, good functional group tolerance, scalability, and environmentally friendly operation. Derivations of target products are also demonstrated.     

Visible-light mediated trifluoromethylation of p-quinone methides by 1,6-conjugate addition using pyrylium salt as organic photocatalyst

A transition metal free visible light mediated organo photoredox catalyzed trifluoromethylation of p-quinone methides (p-QMs) to construct fluoro-analogs of dichlorodiphenyltrichloroethane (DDT) is reported using a bench stable, inexpensive Langlois reagent as a trifluoromethyl radical source. This protocol could generate a benzylic C(sp³)-CF₃ bond with excellent yield under mild reaction conditions using 1,6-conjugate addition/aromatization of trifluoromethyl radical in the absence of any external additives. Further, we demonstrate di-trifluoromethylation and gram scale synthesis of this reaction.     

Organocatalytic cascade 1,6-conjugate addition/annulation/tautomerization of functionalized para-quinone methides: Access to chiral 2-amino-4-aryl-4H-chromenes

A novel organocatalytic cascade process initiated by 1,6-conjugated addition has been successfully developed. A range of pharmaceutically active 2-amino-4-aryl-4H-chromenes were readily obtained in high yields (88%-99%) and excellent enantiopurities (86%–99% ee).     

A highly regio- and chemoselective addition of carbon nucleophiles to pyrimidinones. A new route to C4 elaborated Biginelli compounds

Ethyl 6-methyl-pyrimidine-2-one-5-carboxylates react with C-nucleophiles in a diversity oriented synthetic sequence to afford C4 substituted congeners of medicinally potent Biginelli dihydropyrimidinones, in a highly regioselective manner.     

Synthesis of 1,3-bis(N,N-difluoroamino)adamantane: addition of difluoramino radicals to 1,3-dehydroadamantane

1,3-Dehydroadamantane undergoes a facile reaction with tetrafluorohydrazine to give 1,3-bis(N,N-difluoroamino)adamantane, the product of 1,3-NF₂ radical addition.     

Solvent-free 1,6-conjugate arylation of para-quinone methides: A greener approach to unsymmetrical triarylmethanes

A highly efficient arylation of para-quinone methides (p-QMs) with N,N-dimethylaniline under solvent free condition has been developed, which proceeded via a para-toluenesulfonic acid (TsOH)-promoted 1,6-conjugated addition pathway. This methodology provided a green and sustainable methodology to construct various novel unsymmetrical triarylmethanes (TAMs) with the advantages of good functional group tolerance, scalability, and regioselectivity.     

Synthesis of heteroarylated ketones via bismuth(III) triflate-promoted regioselective 1,4- and 1,6-additions of electron-rich heteroarenes to cyclic enones and dienones

The development and optimization of bismuth(III) triflate-promoted regioselective 1,4- and 1,6-additions of electron-rich heteroarenes to cyclic, β,β-disubstituted enones and dienones is described. Additions of a range of heteroarenes, including furan, thiophene, pyrrole, and indole nucleophiles, to cyclic, β,β-disubstituted enones occur to form all-carbon quaternary centers in up to 88% yield. In addition, regioselective 1,6-additions of electron-rich heteroarenes to 3-vinyl-2-cyclohexenone occur to produce a variety of δ-heteroarylated, β,β-disubstituted enones in up to 93% yield. The high 1,6-selectivity for these reactions is attributed to the increased steric bulk at the β-position relative to the δ-position, and no competing 1,4-conjugate addition is observed.     

Effects of nitrogen and alkene substitution on the PtCl2 catalyzed cycloisomerization of N-tethered 1,6-enyne precursors to the triple reuptake inhibitor GSK1360707

The effects of nitrogen and alkene substitution on the cycloisomerization of N-tethered 1,6-enynes into 3-azabicyclo[4.1.0]heptene precursors to the triple reuptake inhibitor GSK1360707 are described. In general, electron donating substituents proved beneficial both in terms of the reaction rate and chemoselectivity.     

Tandem Michael addition of amines to maleic anhydride and 1,3-prototropic shift: experimental and theoretical results

Amines, namely diethylamine, diphenylamine, benzylamine, and pyrrolidine react with maleic anhydride to form Michael adducts. The Michael adducts formed with the first three amines undergo tandem 1,3-prototropic shift to give the final products. Computational calculations at the DFT (B3LYP/6-31+G*) level reveal that a reactant-complex formed between the initially formed Michael adduct and the respective amine plays a crucial role in the 1,3-prototropic shift. In the reaction of pyrrolidine with maleic anhydride, Michael addition is not followed by 1,3-prototropic shift. The theoretical studies of the latter reaction show that a reactant-complex is not formed in this case. Dimethyl maleate and dimethyl fumarate react with pyrrolidine to give the same Michael addition product.     

Synthesis of functionalized α-amino-phosphine oxides and -phosphonates by addition of amines and aminoesters to 4-phosphinyl- and 4-phosphonyl-1,2-diaza-1,3-butadienes

1,2-Diaza-1,3-butadienes derived from phosphine oxides and phosphonates and with optically active substituents on N-1 and C-3 are obtained by 1,4-elimination from chlorohydrazonoalkyl-phosphine oxides and -phosphonates in the presence of bases. Michael addition (1,4-addition) of ammonia, aliphatic and aromatic amines and aminoesters to these azo-alkenes gives functionalized α-amino-phosphine oxides and -phosphonates.     

Unusual O-conjugate addition reactions of β-ketoesters and 1,3-diketones to ethyl propynoate: applications to the synthesis of furans

Divinyl ethers were synthesized from 1,3-dicarbonyl compounds. Reactions of β-ketoesters and 1,3-diketones with ethyl propynoate in the presence of N-methylmorpholine produced unusual O-conjugate addition products in good yields. The divinyl ethers derived from 1,3-diketones were utilized for the synthesis of 2,3,5-trisubstituted furans under the standard radical cyclization conditions.     

1,3-Dipolar addition of nitrones to symmetrically substituted allenes: for the determination of absolute configuration of chiral allenes by NMR spectroscopy

5-Methyl-5-phenylpyrroline N-oxide was proved to be a useful 1,3-dipole for determining the absolute configuration of chiral allenes by means of NMR spectroscopy.     

First nucleophilic addition of acetylide to 1,3-diketonate anions: reaction of 1-aryl-4,4,4-trifluorobutane-1,3-diones with sodium acetylide

The nucleophilic addition of sodium acetylide to 1,3-diketonates derived from 1-aryl-4,4,4-trifluorobutane-1,3-diones is reported. Tertiary 1,4-alkynediols containing CF₃ and aroylmethyl groups are synthesized. 5,5′-Diaryl-3,3′-bis(trifluoromethyl)-2,2′-bifurans are prepared via a novel double cyclization of these alkynediols.     

Synthesis of pyrrolo[3,2-b]benzofurans and pyrrolo[3,2-b]naphthofurans via addition of a silyloxypyrrole to activated quinones

The uncatalyzed reaction of N-(tert-butoxycarbonyl)-2-tert-butyldimethylsilyloxypyrrole 3 with 1,4-quinones bearing an electron withdrawing group at C-2 has been studied. Use of 1,4-quinones 4, 5 bearing an ester group at C-2 provided an efficient synthesis of the respective pyrrolidinobenzofuran adduct 9 or pyrrolidinonaphthofuran adduct 10 whereas use of 1,4-quinones 6, 7 and 8 bearing an acetyl group at C-2 afforded silyloxypyrroles 11, 12 and 13 resulting from direct electrophilic substitution of the silyloxypyrrole by the electrophilic quinone. Addition of Eu(fod)₃ to the reaction of 2-acetyl-1,4-naphthoquinone 7 and 3-acetyl-5-methoxy-1,4-naphthoquinone 8 with N-(tert-butoxycarbonyl)-2-tert-butyldimethylsilyloxypyrrole 3 provided a method for obtaining the pyrrolidinonaphthofuran adducts 14 and 15 together with silyloxypyrroles 12 and 13. Oxidative rearrangement of pyrrolidinonaphthofuran adduct 15 to pyrrolidino pyranonaphthoquinone 16 using ceric ammonium nitrate in acetonitrile provided a novel approach for the synthesis of an aza-analogue of the pyranonaphthoquinone antibiotic kalafungin.     

Organocatalytic Domino Oxa‐Michael/1,6‐Addition Reactions: Asymmetric Synthesis of Chromans Bearing Oxindole Scaffolds

An asymmetric organocatalytic domino oxa‐Michael/1,6‐addition reaction of ortho‐hydroxyphenyl‐substituted para‐quinone methides and isatin‐derived enoates has been developed. In the presence of 5 mol % of a bifunctional thiourea organocatalyst, this scalable domino reaction affords 4‐phenyl‐substituted chromans bearing spiro‐connected oxindole scaffolds and three adjacent stereogenic centers in good to excellent yields (up to 98 %) and with very high stereoselectivities (up to >20:1 d.r., >99 % ee).     

Two alternative approaches to modification of a cage complex: nucleophilic substitution and electrophilic addition for the synthesis of an iron(II) clathrochelate with an annulated imidazole fragment

A rib-functionalized iron(II) tris-dioximate clathrochelate bearing an annulated phenylimidazole fragment was prepared using nucleophilic substitution and electrophilic addition at the chelating α-dioximate fragment of the macrobicyclic framework. The resultant cage complex was identified with single crystal XRD, analytical data, ¹H, ¹³C, ¹⁹F, ¹¹B NMR spectroscopy, and examined with UV–vis spectroscopy and CVA. Two approaches to modification of the clathrochelate framework are compared.     

Reactions of 2-(perfluoroalkyl)ethane thiols with 1,6-heptadiene and 4-substituted 1,6-heptadienes: the synthesis of RFethanethio-cyclopentanoic and -dioic acids; and, “geminal-twin-tail” bis-(perfluoroalkylethanethio)alkanoic acids

Kinetic analysis of the free radical addition of n-C₆F₁₃I to 1,6-heptadiene gives a rate ratio of cyclization to addition (k_d1/k_c) of 0.568 at 70 °C; thus, the rate of cyclization (k_c) is twice that of iodine transfer (k_d1). By contrast, for n-C₆F₁₃CH₂CH₂SH (k_d1/k_c) = 14.4 at 70 °C, and radical transfer of H from the thiol is 14.4 times the faster than cyclization. Substitution at the center of 1,6-heptadiene has a profound effect on the linear/cyclic adduct ratio. For the addition of n-C₃F₇I (R_FI:diene=2:0) the adduct ratios dramatically decrease in the order: 1,6-heptadiene (1.17) > 4-carboxy-1,6-heptadiene (0.0613) > 4,4-bis-ethoxycarbonyl-1,6-heptadiene (<0.001). Bis-addition to the 4,4-substituted dienes is strongly disfavored, and the desired “geminal-twin-tail” [R_F(CH₂)₃]₂CHCO₂R, or [R_F(CH₂)₃]₂C(CO₂R)₂ must be synthesized by other means. For the reaction of R_FCH₂CH₂SH with the dienes (1:1), the respective adduct ratios are 11.3 (n-C₆F₁₃), 0.370 (n-C₈F₁₇), and 0.0716 (n-C₆F₁₃). However, adding the 4-carboxy-1,6-heptadiene slowly to four mols of n-C₈F₁₇CH₂CH₂SH yields 98% of the geminal bis-adduct [R_FCH₂CH₂S(CH₂)₃]₂CHCO₂H, which is a new, fluorophilic, geminal-twin-tail acid.     

Synthesis of the H-phosphonate dibenzo[d,f][1,3,2]dioxaphosphepine 6-oxide and the phospha-Michael addition to unsaturated compounds

A series of phosphonate-containing compounds based on dibenzo[d,f][1,3,2]dioxaphosphepine 6-oxide (BPPO) is presented. BPPO is synthesized by a three–component condensation and is added to activated alkenes with systematically varied structure via phospha-Michael addition. Acrylates, α,β-unsaturated carboxylic acid diesters and benzoquinone are used as activated alkenes. The new compounds are characterized by ¹H, ¹³C and ³¹P NMR spectroscopy. The as-prepared phosphonates are envisioned to have flame retardant properties.     

New routes to low-coordinate iron hydride complexes: The binuclear oxidative addition of H2

The oxidative addition and reductive elimination reactions of H₂ on unsaturated transition-metal complexes are crucial in utilizing this important molecule. Both biological and man-made iron catalysts use iron to perform H₂ transformations, and highly unsaturated iron complexes in unusual geometries (tetrahedral and trigonal planar) are anticipated to give unusual or novel reactions. In this paper, two new synthetic routes to the low-coordinate iron hydride complex [L^tBuFe(μ-H)]₂ are reported. Et₃SiH was used as the hydride source in one route by taking advantage of the silaphilicity of the fluoride ligand in three-coordinate L^tBuFeF. The other synthetic method proceeded through the binuclear oxidative addition of H₂ or D₂ to a putative Fe(I) intermediate. Deuteration was verified through reduction of an alkyne and release of the deuterated alkene product. Mössbauer spectra of [L^tBuFe(μ-H)]₂ indicate that the samples are pure, and that the iron(II) centers are high-spin.