A dearomatizing, thionium ion cyclization for the synthesis of functionalized, azaspirocyclic cyclohexadienones

Thionium ions, generated by the addition of thiols to N-benzylglyoxamides, undergo a dearomatizing spirocyclization. The alkyl or arylsulfanyl group introduced during the thionium ion cyclization can act as a synthetic handle and a stereochemical control element during modifications of the azaspirocyclic frameworks (R(F) = CH(2)CH(2)C(8)F(17)).     

Electrochemical annulation of five-membered rings through dearomatization of furans and thiophenes

A new methodology for the annulation of five-membered carbocyclic rings onto enones through the dearomatizing electrochemical cyclization of furans and thiophenes has been developed.     

Nucleophilic addition to electron-rich heteroaromatics: dearomatizing anionic cyclizations of pyrrolecarboxamides

[reaction: see text] Despite its electron-rich nature, a pyrrole ring is susceptible to intramolecular nucleophilic attack by organolithiums. The resulting dearomatizing anionic cyclization yields new 5- or 7-membered heterocyclic rings. Formation of a new 5-membered ring, by cyclization of an N-benzylpyrrolecarboxamide, is accompanied by ring opening of the original pyrrole to yield 3-aminovinylpyrrolinones. Formation of a new 7-membered ring, by cyclization of an N-allyl pyrrolecarboxamide, yields bicyclic pyrroloazepinones.     

Stereospecific photochemical ring expansion of lithiated benzamides

Treatment of N-benzyl benzamides with a strong base (LDA or t-BuLi) followed by irradiation with a 500 W tungsten lamp provides, according to the substitution pattern of the starting amides, either norcaradienes or cycloheptadienones by overall insertion of the N-benzyl group into the benzamide's aromatic ring system. Chiral benzamides undergo the ring expansion with high (sometimes complete) stereospecificity. The reaction appears to occur via a series of pericyclic reactions (photochemical or thermal sigmatropic rearrangements and thermal electrocyclic reactions) following an initial dearomatizing cyclization.     

Reaction of a stable aminoarylcarbene with 2-chloroacrylonitrile: dearomatizing cyclization rather than cyclopropanation

The reaction of a stable aminoarylcarbene with 2-chloroacrylonitrile is reported. The resulting 1/1 adduct has been spectroscopically and structurally characterized. The initial Michael addition is not followed by cyclopropane formation but by a dearomatizing cyclization affording an original bicyclic structure.     

The synthesis of (-)-isodomoic acid C

The neuroactive algal metabolite (-)-isodomoic acid C, a kainoid amino acid, has been synthesized for the first time. Asymmetric dearomatizing cyclization of an aromatic amide using a chiral lithium amide base generates a bicyclic enone containing a pyrrolidinone ring with the relative and absolute stereochemistry of the target. A further 15 synthetic steps, including conjugate cuprate addition to the enone of a side chain precursor, a Ru-promoted oxidation of the phenyl ring to the C2-carboxylic acid substituent, a regioselective Baeyer-Villiger reaction, and an E-selective Horner-Wadsworth-Emmons reaction, elaborate the cyclization product into the target molecule.     

Synthesis of α-methyl kainic acid by stereospecific lithiation-dearomatizing cyclization of a chiral benzamide

Stereospecific lithiation of N-α-methylbenzyl benzamides gives configurationally stable tertiary benzyllithiums which undergo a stereospecific dearomatizing cyclization with >99% retention of stereochemistry. The products are partially saturated isoindolinones which carry a new fully-substituted stereogenic centre. A ten-step sequence converts one of these products to the α-methyl analogue of kainic acid.     

Lithium Bromide/Water as Additives in Dearomatizing Samarium‐Ketyl (Hetero)Arene Cyclizations

New conditions for dearomatizing samarium‐ketyl (hetero)arene cyclizations are reported. In many examples of these samarium diiodide‐mediated reactions, lithium bromide and water can be used as additives instead of the carcinogenic and mutagenic hexamethylphosphoramide (HMPA). The best results were obtained for the cyclizations of N‐acylated indole derivatives delivering the expected indolines in good yields and excellent diastereoselectivities. A new type of cyclization delivering indolyl‐substituted allene derivatives is also described. The scope and limitations of the lithium bromide/water system are discussed.     

Stereoselective Cascade Cyclizations with Samarium Diiodide to Tetracyclic Indolines: Precursors of Fluorostrychnines and Brucine

A series of γ-indolylketones with fluorine, cyano or alkoxy substituents at the benzene moiety was prepared and subjected to samarium diiodide-promoted cyclization reactions. The desired dearomatizing ketyl cascade reaction forming two new rings proceeded in all cases with high diastereoselectivity, but with differing product distribution. In most cases, the desired annulated tetracyclic compounds were obtained in moderate to good yields, but as second product tetracyclic spirolactones were isolated in up to 29 % yield. The reaction rate was influenced by the substituents at the benzene moiety of the substrate as expected, with electron-accepting groups accelerating and electron-donating groups decelerating the cyclization process. In case of a difluoro-substituted γ-indolylketone a partial defluorination was observed. The intermediate samarium enolate of the tetracyclic products could be trapped by adding reactive alkylating agents as electrophiles delivering products with quarternary carbons. In the case of a dimethoxy-substituted tetracyclic cyclization product a subsequent reductive amination stereoselectively provided a pentacyclic compound that was subsequently N-protected and subjected to a regioselective elimination. The obtained functionalized pentacyclic product should be convertible into the alkaloid brucine by four well-established steps. Overall, the presented report shows that functionalized tetracyclic compounds with different substituents are rapidly available with the samarium diiodide cascade cyclization as crucial step. Hence, analogues of the landmark alkaloid strychnine, for example, with specific fluorine substitutions, should be easily accessible.     

Dearomatizing anionic cyclization of N-alkyl-N-benzyl(dinaphthyl)phosphinamides. A facile route to gamma-(amino)dihydronaphthalenylphosphinic acids

The dearomatizing anionic cyclization of N-alkyl-N-benzyldi(n-naphthyl)phosphinamides (n = 1, 2) and subsequent trapping with a series of electrophiles (MeOH, MeI, CF3SO3Me, Me3O+BF4-, AllylBr, and PhCH2Br) have been accomplished. Optimized reaction conditions (base, temperature, reaction time) allow for synthesizing tetrahydro-1H-naphtho[1,2-c][1,2]-azaphosphole 1-oxides 13 and 18 and tetrahydro-1H-naphtho[2,1-c][1,2]azaphosphole 3-oxides 16 and 27-29 in high yield and diastereoselectivity. Appropriate selection of the base proved to be critical for promoting anionic cyclization of 2-naphthyl derivatives. The dearomatized heterocycles are transformed quantitatively into gamma-(N-alkylamino)phosphinic acids by acid hydrolysis of the P-N linkage. Bioactivity assays on five human tumor cell lines for one of these amino acids revealed growth inhibition factors (GI50) at a micromolar scale. Additionally, evidence for the feasibility of intermolecular nucleophilic dearomatization and sequential nucleophilic attack to both aromatic rings of dinaphthylphosphinamides have been obtained.     

Iron-Catalyzed Trifluoromethylation of Indole-Tethered Alkene Enables Synthesis of CF3-Containing Spiroindolenines and Tetrahydrocarbazoles

An iron-catalyzed trifluoromethylation of indole-tethered alkene with Togni's reagent to construct CF₃-containing spiro[indole-3,3′-pyrrolidine] and tetrahydrocarbazole derivatives under mild and convenient conditions has been disclosed. Mechanistic studies indicate that the reaction proceed through a CF₃ radical addition to the alkene, followed by sequential dearomatizing spiocyclization of the indole and oxidation to afford the spiro[indole-3,3′-pyrrolidine] derivatives. Meanwhile, when the substituent at the C2 position of the indole is hydrogen, the CF₃-containing tetrahydrocarbazole is obtained through trifluoromethylation of alkene and cyclization of indole.     

Dearomatizing anionic cyclizations of N-benzyl-N-methyldiphenylphosphinamides. Synthesis of gamma-(N-methylamino)phosphinic acids

The first dearomatizing anionic reaction of a phenyl ring promoted by an N-benzyl-N-methylphosphinamide group is described. The intermediate lithium species can be trapped with different electrophiles, affording tetrahydrobenzo[c]-1-aza-2lambda(5)-phospholes with excellent diastereoselectivity. The new process is a simple and very efficient entry to the stereoselective synthesis of functionalized gamma-(N-methylamino)phosphinic acids and esters.     

Dearomatizing anionic cyclization of N-methyl-N-benzyldi(1-naphthyl)phosphinamide: a route for access to a new class of functionalized tricyclic azaphospholes with antitumor properties

The dearomatizing anionic cyclization of N-alkyl-N-benzyldi(1-naphthyl)phosphinamide 1d followed by trapping with a series of carbonyl reagents and α,β-unsaturated ketones under optimized conditions provided new tetrahydro-1H-naphtho[1,2-c][1,2]-azaphosphole 1-oxides from moderate to high yields and diastereoselectivities. In addition, two doubly dearomatized compounds as a result of double dearomatization on the two naphthalene rings of 1d have been isolated at first time. Three functionalized azaphospholes have been evaluated on three different human tumor cell lines showing growth inhibition factors (GI₅₀) at a micromolar scale. One of these heterocycles has also shown cytostatic properties.     

Charge donation to and dearomatization of benzene attending complexation: DFT estimates of binding energies of TpMXO(L) with benzene, for Tp = hydridotris(pyrazolyl) borate, MXO = MoNO, ReCO, and WNO, and L = ammonia, N-methylimidazole, pyridine, phosphine, methyl isocyanide, and carbon monoxide

By density functional methods we characterize the bonding and charge distribution in complexes of benzene with dearomatizing agents tpReCO(L), tpMoNO(L), and tpWNO(L), where tp = hydrido Tris (pyrazolyl)borate), for a range of ligands L. Our LSDA and B3LYP density functional calculations use the Spartan LACVP+ basis and pseudopotential on Re, Mo, and W and 6-31G* on light atoms. The binding energy is strongly dependent on the nature of the ligand L, being greatest for L = ammonia and N-methylimidazole and weakest for CH3NC and CO. We find a correlation between strength of binding and electron transfer from the dearomatizing agents toward benzene. For the most strongly bound systems we find substantial (up to 500 millielectrons) charge transfer towards benzene, while for the most weakly bound systems charge is withdrawn from benzene. Structural details illustrate the ability of Re, Mo, and W species to dearomatize complexed benzene, which is extensive for all but the most weakly bound species with L = MeNC and CO. Re and W dearomatizing agents, which are computed and observed to form stable complexes with benzene, may be economic alternatives to osmium dearomatizing agents.     

Cu(II)-promoted transformations of α-thienylcarbinols into spirothienooxindoles: regioselective halogenation of dienyl sulfethers containing electron-rich aryl rings

Under the promotion of Cu(II) salts, the α-thienylcarbinols with an N-phenyl carbonyl group at the other α-position are converted into three different ranges of spirothienooxindoles involving dearomatizing Friedel-Crafts reaction. In addition, the unprecedented regioselective CuX(2)-mediated C-H functionalization/halogenation of dienyl sulfether containing electron-rich aryl rings is presented.     

Co(III)/Zn(II)-catalyzed dearomatization of indoles and coupling with carbenes from ene-yne ketones via intramolecular cyclopropanation

A straightforward and efficient protocol for dearomatizing indoles is described. The reaction, catalyzed by an inexpensive Co(III)/Zn(II) catalyst, starts from easily accessible N-pyrimidinyl indoles and ene-yne ketones. Mild reaction conditions, high diastereoselectivity, a broad substrate scope, effective functional group tolerance, and reasonable to remarkable yields were observed.     

Deuterium-labeling and NMR study of the dearomatization of N-alkyl-N-benzyldiphenylphosphinamides through anionic cyclization: ortho and benzylic lithiation directed by complex-induced proximity effects

The mechanism of the anionic cyclization dearomatizing reaction of N-benzyl-N-methyldiphenylphosphinamide (1) upon treatment with s-BuLi in tetrahydrofuran (THF) at -90 degrees C has been analyzed by deuterium-labeling and natural abundance multinuclear magnetic resonance ((1)H, (2)H, (7)Li, (13)C, (31)P) studies. In the absence of coordinating cosolvents such as hexamethylphosphoramide (HMPA), eight major anionic species were identified, which allowed us to unravel the pathway of the metalation reaction. In agreement with the complex-induced proximity effect (CIPE) mechanism, the sequence of transformations emerging from this study involves the coordination of the lithium base to the P=O group of 1 to give four dimeric precomplexes whose NMR data are consistent with structures Va/Vb and VIIIa/VIIIb. The diastereomers Va/Vb are the precursors of the monomeric benzylic anion II, whereas the VIIIa/VIIIb diastereomers are assumed to undergo ortho deprotonation leading to anions I. Translocation from the ortho anion to the benzylic one is not observed. Intramolecular conjugate addition of anion II to the P-phenyl rings happens in a reversible way, affording the monomeric dearomatized anions III, IV, VI, and VII. The reaction progresses to yield a mixture containing only the species I, III, and IV. HMPA acts as a catalyst for the ortho-to-benzylic translocation and anionic cyclization reactions. Two-dimensional (2D) (7)Li,(31)P[(1)H] shift correlations and (7)Li[(31)P] NMR spectra proved to be crucial for the structural assignment of the anionic species. These techniques also demonstrated the diastereotopicity of the two achiral ligands involved in a dimer with s-BuLi (Vb) owing to the slow configuration inversion of the carbanion center.     

Facile synthesis of 3a,6a-dihydro-furo[2,3-b]furans and polysubstituted furans involving dearomatization of furan ring via electrocyclic ring-closure

A facile and atom-economic method for the synthesis of 3a,6a-dihydro-furo[2,3-b]furan derivatives and polysubstituted furans starting from furylcarbionls has been developed. This protocol involved a domino Claisen rearrangement/dearomatizing electrocyclic ring-closure/aromatizing electrocyclic ring-opening sequence.     

A novel entry to functionalized benzofurans and indoles via palladium(0)-catalyzed arylative dearomatization of furans

A novel entry to functionalized benzofurans and indoles from furans in moderate to good yields has been developed. This protocol involves palladium(0)-catalyzed dearomatizing intramolecular arylation of the furan ring, formation of a π-allylic palladium complex, furan ring opening, and a β-hydride elimination sequence.     

Total synthesis of (+)-grandifloracin by iron complexation of a microbial arene oxidation product

(+)-Grandifloracin was synthesized from sodium benzoate by means of a dearomatizing dihydroxylation that proceeds with unusual regioselectivity. Iron diene complexes formed from the arene oxidation product permit the use of otherwise inaccessible transformations. The synthetic material was shown to be antipodal to the natural product, thus determining the absolute configuration of grandifloracin for the first time.