Indene Products Research Articles

Regiodivergent C−H Annulation of Imines with Unsymmetrical Alkynes Using Transient Directing Alcohols via Rh(III) Catalysis

AbstractRegiodivergent [3+2] and [4+2] C−H annulation of imines and imidate esters with unsymmetrical alkynes has been achieved under Rh(III) catalysis. Further transformation of the aldehyde and TMS functionality on the indene products is also demonstrated. The current work highlights the alcohols‐directed multiple C−H annulation of imines and imidate esters, leading to diverse fused heterocycles.

Identification of a Fully Dechlorinated Product of Chlordecone in Soil Microcosms and Enrichment Cultures

Anaerobic microcosms constructed with soil from Guadeloupe, amended with electron donor (ethanol and acetone) and incubated for more than a decade, transformed chlordecone (CLD) into a suite of progressively more dechlorinated products, including a fully dechlorinated carboxylated indene product. This fully dechlorinated transformation product has never before been observed and indicates that complete dechlorination of CLD is possible. The carboxylated indene was detected by LC-MS and structure was confirmed by LC-MS/MS using a Q-Exactive Orbitrap mass spectrometer.

Gold-catalyzed ketene dual functionalization and mechanistic insights: divergent synthesis of indenes and benzo[d]oxepines

An unprecedented gold-catalyzed ketene C=O/C=C bifunctionalization method has been developed. Mechanistic studies and density function theory (DFT) calculations indicate that the reaction is initiated by gold-catalyzed Wolff rearrangement of diazoketone to form the ketene intermediate, followed by intermolecular nucleophilic addition and terminated with two divergent cyclization processes via enol intermediates. In the case with alcohols as the nucleophiles, the reaction goes through a C-5-endo-dig carbocyclization to give the indene products; whereas, O-7-endo-dig cyclization occurs dominantly when indoles/pyrroles are used as the nucleophiles, delivering the 7-membered benzo[d]oxepines. In comparison with the well-documented cycloaddition and nucleophilic addition reactions, this cascade reaction features a novel reaction pattern for the ketene dual functionalization through addition with nucleophile and electrophile in sequence.

Synthesis of Trifluoromethylated Tetrasubstituted Allenes via Palladium-Catalyzed Carbene Transfer Reaction.

Herein, we report on the palladium-catalyzed synthesis of trifluoromethylated, tetrasubstituted allenes from vinyl bromides and trifluoromethylated diazoalkanes in good to excellent yield. This reaction proceeds via oxidative addition of a Pd(0) complex with vinyl bromide. Subsequent base-promoted reductive elimination generates the allene. This methodology provides an efficient strategy even on gram scale to valuable trifluoromethylated, tetrasubstituted allenes under mild reaction conditions. The allene products can be used in acid catalyzed cyclization reactions to give trifluoromethylated indene products.

Co(III)-Carbene Radical Approach to Substituted 1H-Indenes.

A new strategy for the catalytic synthesis of substituted 1H-indenes via metalloradical activation of o-cinnamyl N-tosyl hydrazones is presented, taking advantage of the intrinsic reactivity of a Co(III) carbene radical intermediate. The reaction uses readily available starting materials and is operationally simple, thus representing a practical method for the construction of functionalized 1H-indene derivatives. The cheap and easy to prepare low spin cobalt(II) complex [Co(II)(MeTAA)] (MeTAA = tetramethyltetraaza[14]annulene) proved to be the most active catalyst among those investigated, which demonstrates catalytic carbene radical reactivity for a nonporphyrin cobalt(II) complex, and for the first time catalytic activity of [Co(II)(MeTAA)] in general. The methodology has been successfully applied to a broad range of substrates, producing 1H-indenes in good to excellent yields. The metallo-radical catalyzed indene synthesis in this paper represents a unique example of a net (formal) intramolecular carbene insertion reaction into a vinylic C(sp(2))-H bond, made possible by a controlled radical ring-closure process of the carbene radical intermediate involved. The mechanism was investigated computationally, and the results were confirmed by a series of supporting experimental reactions. Density functional theory calculations reveal a stepwise process involving activation of the diazo compound leading to formation of a Co(III)-carbene radical, followed by radical ring-closure to produce an indanyl/benzyl radical intermediate. Subsequent indene product elimination involving a 1,2-hydrogen transfer step regenerates the catalyst. Trapping experiments using 2,2,6,6-tetra-methylpiperidine-1-oxyl (TEMPO) radical or dibenzoylperoxide (DBPO) confirm the involvement of cobalt(III) carbene radical intermediates. Electron paramagnetic resonance spectroscopic spin-trapping experiments using phenyl N-tert-butylnitrone (PBN) reveal the radical nature of the reaction.

Mechanistic Understanding of the Divergent Cyclizations of o-Alkynylbenzaldehyde Acetals and Thioacetals Catalyzed by Metal Halides.

The mechanisms of regiodivergent cyclizations of o-alkynylbenzaldehyde acetals and thioacetals catalyzed by Pd and Pt halides are studied. DFT calculations found that both reactions are initiated by electrophilic activation of the acetylenic moiety instead of the previously proposed metal-triggered CX (X=O, S) cleavage. Both the regioselective cyclization of the π-alkyne complex and the chemoselective [1,2]-migration in the carbenoid intermediate were determined as key steps to achieving the observed divergence. For acetal derivatives containing an internal alkyne, the 6-endo-dig cyclization is more favorable and leads to the carbenoid intermediate easily through further steps of CX fragmentation and carbocation cyclization. Then, from the carbenoid intermediate, the [1,2]-migration of sulfur is easier than that of H, Me, and Ph; whereas, a reversed aptitude was predicted for the oxygen analogue, which is consistent with the greater ability of sulfur atoms to stabilize β-carbocations. However, for precursors containing a terminal alkyne, the 5-exo-dig pathway is preferred and only the 1,2-disubstituted indene product is seen, irrespective of the nature of the acetal; thus, a different product from that reported in the literature is predicted for benzaldehyde acetal with a terminal alkyne at the ortho position. This prediction led us to reconsider some of the reported results and hidden realities were uncovered with solid new experimental evidence.

Oxidative metabolism of ferrocene analogues of tamoxifen: characterization and antiproliferative activities of the metabolites.

Ferrociphenols have been found to have high antiproliferative activity against estrogen-independent breast cancer cells. The rat and human liver microsome-mediated metabolism of three compounds of the ferrocifen (FC) family, 1,1-bis(4-hydroxyphenyl)-2-ferrocenyl-but-1-ene (FC1), 1-(4-hydroxyphenyl)-1-(phenyl)-2-ferrocenyl-but-1-ene (FC2), and 1-[4-(3-dimethylaminopropoxy)phenyl]-1-(4-hydroxyphenyl)-2-ferrocenyl-but-1-ene (FC3), was studied. Three main metabolite classes were identified: quinone methides (QMs) deriving from two-electron oxidation of FCs, cyclic indene products (CPs) deriving from acid-catalyzed cyclization of QMs, and allylic alcohols (AAs) deriving from hydroxylation of FCs. These metabolites are generated by cytochromes P450 (P450s), as shown by experiments with either N-benzylimidazole as a P450 inhibitor or recombinant human P450s. Such P450-dependent oxidation of the phenol function and hydroxylation of the allylic CH2 group of FCs leads to the formation of QM and AA metabolites, respectively. Some of the new ferrociphenols obtained in this study were found to exhibit remarkable antiproliferative effects toward MDA-MB-231 hormone-independent breast cancer cells.

ChemInform Abstract: Cyclodehydrations Leading to Indene Products Having N‐Heterocyclic Substituents.

In this Note, we describe superacid-promoted cyclodehydrations leading to functionalized indenes. The product indenes are synthesized having N-heterocyclic substituents, including pyridyl, imidazolyl, pyrimdyl, and other groups. A mechanism is proposed involving dicationic, superelectrophilic intermediates. The protonated N-heterocyclic rings are shown to dramatically lower the LUMO energy level of the carboxonium electrophile (compared to that of a similar uncharged system).

Gold(I)-catalyzed 1,4- and/or 1,5-heteroaryl migration reactions through regiocontrolled cyclizations.

Gold(I)-catalyzed regioselective cycloisomerizations of furan-ynes have been described. The reaction provides a concise access to stereodefined trisubstituted alkenes by endo cyclization with concomitant 1,5-migration of the furanyl group in the presence of unactivated 3 Å molecular sieves. In the absence of molecular sieves, indene products are generated by exo cyclization, followed by 1,4-furanyl migration/cyclization. The scope for 1,5-migrations can be extended to other heterocycles, such as benzofurans, thiophenes, and pyrroles.

Cyclodehydrations leading to indene products having N-heterocyclic substituents.

In this Note, we describe superacid-promoted cyclodehydrations leading to functionalized indenes. The product indenes are synthesized having N-heterocyclic substituents, including pyridyl, imidazolyl, pyrimdyl, and other groups. A mechanism is proposed involving dicationic, superelectrophilic intermediates. The protonated N-heterocyclic rings are shown to dramatically lower the LUMO energy level of the carboxonium electrophile (compared to that of a similar uncharged system).

Understanding the Reactions of Aryl Iodides with Alkynes to Give New C-C and C-I Bonds: A DFT Study

The reactions of 2-iodo-α-methyl styrene (S1) with diphenyl acetylene (S2) (equation 1) and iodo-benzene (S3) with diphenyl acetylene (S2) (equation 2) have been theoretically studied with the aid of density functional theory calculations. Equation 1 reaction involves four major steps, aryl-I oxidative addition, alkyne insertion, C=C bond insertion, and (sp3)C-I reductive elimination. Equation 2 reaction involves aryl-I oxidative addition, alkyne insertion, and further alkyne insertion. Based on the mechanistic study, we revealed why the indene product P could be obtained in equation 1 while the proposed product P2 could not be obtained in equation 2. In addition, the bulkiness of the ligand PtBu3 plays an important role for the steps involved undergoing mono-L or non-L paths. Keywords: Alkyne insertion, aryl iodide, carbohelogenation, DFT calculation, steric effect.

Mechanisms of the PtCl2-catalyzed intramolecular cyclization of o-isopropyl-substituted aryl alkynes for the synthesis of indenes and comparison of three sp3 C-H bond activation modes.

Chatani and He respectively reported an efficient way to synthesize indenes through PtCl2 catalyzed sp(3) C-H bond activation. Interestingly, the R group (R = H or Br) in the alkyne moiety of the substrates in Chatani's experiments migrates to the C3 position in indenes, whereas the R group (R = Ar) stays in the original C2 position of final indenes in He's experiments. DFT calculations indicated that there are two competing pathways a and c for the cyclization reaction. Pathway a involves [1,2]-R migration, [1,5]-H shift, and 4π-electrocyclization, giving the indenes with the R group at the C3 position. Pathway c takes place through irreversible [1,5]-H shift/cyclization and [1,2]-H shift, generating indenes with the R group at the C2 position. DFT calculations found that, when R = H or Br, pathway a is favored. When R = alkyl group, the [1,2]-R migration is difficult and pathway c is preferred. When R = Ar, DFT calculations predicted and experiments verified that both pathways a and c occur to give two indene products. Comparison of different models of sp(3) C-H activations has been presented to guide further understanding and prediction of new C-H bond activations.

Unexpected iron(iii) chloride-catalysed dimerisation of 1,1,3-trisubstituted-prop-2-yn-1-ols as an expedient route to highly conjugated indenes

A method to prepare highly conjugated indenes efficiently by iron(III) chloride-catalysed dimerisation of trisubstituted propargylic alcohols under very mild conditions at room temperature is described. The reactions are rapid and operationally straightforward, giving the indene products in good yields and regioselectivity.

Regioselective Intermolecular Coupling Reaction of Arylketones and Alkenes Involving C−H Bond Activation Catalyzed by an in Situ Formed Cationic Ruthenium Hydride Complex

The cationic ruthenium-hydride complex, formed in-situ from the treatment of the tetranuclear ruthenium-hydride complex {[(PCy(3))(CO)RuH](4)(mu(4)-O)(mu(3)-OH)(mu(2)-OH)} with HBF(4).OEt(2), was found to be a highly effective catalyst for the intermolecular coupling reaction of arylketones and 1-alkenes to give the substituted indene and ortho-C-H insertion products. The formation of the indene products was resulted from the initial alkene isomerization followed by regioselective ortho-C-H insertion of 2-alkene and the dehydrative cyclization. The preliminary mechanistic studies revealed a rapid and reversible ortho-C-H bond activation followed by the rate-limiting C-C bond formation step for the coupling reaction.

An efficient synthesis of polysubstituted tetrahydrofuran and indene derivatives via the Lewis acid-mediated cycloadditions of VCPs with aldehydes

A variety of polysubstituted tetrahydrofuran and indene derivatives were prepared in moderate to excellent yields via the cycloadditions of vinylidenecyclopropanes with common aldehydes in the presence of Lewis acid. The polysubstituted tetrahydrofuran 3 could undergo further transformations to the indene product 4 and furan derivatives 5.

Palladium-catalyzed synthesis of indene derivatives via propargylic carbonates with in situ generated organozinc compounds

The palladium-catalyzed carboannulation and arylation reaction of propargylic carbonates with in situ generated organozinc compounds produced an important new class of indene derivatives. The reaction proceeded under mild conditions, and indene products were isolated in good to excellent yields.

The tamoxifen cation reacts to give indene products

The tamoxifen carbocation (Ph(Ar)C=CPh-CH+-CH3, Ar = 4-Me2NCH2CH2OC6H4) is generated from acetate and sulfate precursors by SN1 ionization in water. The cation exists in (E) and (Z) forms which equilibrate before reaction. The major products are the α-hydroxytamoxifens Ph(Ar)C=CPh-CHOH-CH3, both (E) 64% and (Z) 29%, with the ratio independent of the configuration of the starting ester. Two minor products with a total yield of 7% account for the rest of the products. These have been characterized as indenes derived from intramolecular cyclization, a 4.5% yield of the indene derived from cyclization into the Ar ring with 2.5% due to cyclization into the phenyl ring. Experiments in acid solutions (0.01-0.1 M HCl) starting with pure (E)- or (Z)-α-hydroxytamoxifen reveal that the two alcohols equilibrate. This occurs by H+-catalyzed formation of the carbocation followed by water capture. Occurring about 10-fold slower than this isomerization is an irreversible process resulting in the two indenes. This cyclization will result in the destruction of the α-hydroxytamoxifens upon exposure to acidic conditions and also makes the direct observation of the tamoxifen carbocation under super-acid conditions difficult, if not impossible. The indenes do form in low yield whenever the tamoxifen carbocation is generated from an SN1 precursor. Thus these products could serve as markers for the formation of the tamoxifen carbocation in cellular systems or in in vivo experiments.Key words: carbocation, indene, allylic cation, isomerization.

The tamo×ifen cation reacts to give indene products

The tamo×ifen cation reacts to give indene products

Mechanistic Studies on the Reaction of Fischer Carbene Complex with Alkynes: Does the Alkyne Insertion Intermediate Form Irreversibly?

The regioselectivity of the formation of three different products from the reaction of 1-phenylpropyne with (methoxy)(2-methoxyl-1-phenyl)methylene pentacarbonyl chromium 12 was examined in detail. The phenol product is formed with a substantial regioselectivity which is temperature-dependent, but the indene products (obtained as two compounds: indene and indenone) are formed as a nearly equal mixture of regioisomers. The proportion of indene and phenol products is dependent on the concentration with greater amounts of phenol products being formed at higher concentrations. The total regioselectivity of all of the products is also a function of the concentration. This result could be due either to an equilibration of the η1,η3-vinyl carbene intermediates in this reaction or to a change in mechanisms in the formation of the η1,η3-vinyl carbene intermediates from one involving a dissociative incorporation of the alkyne to one involving an associative incorporation of the alkyne. Kinetic studies reveal that at 45 °C and at 0.5 M (but not 0.0001 M) the reaction is bimolecular with a first-order dependence on both the carbene complex and the alkyne. However, at 90 °C the reaction is first-order in carbene complex and zero-order in alkyne over the concentration range of 0.05−0.005 M where the total regioselectivity changes from 2.5:1.0 to 1.5:1. This observation constitutes the first experimental evidence for the equilibration of regioisomeric vinyl carbene intermediates during the benzannulation reaction. This equilibration could occur as a result of a deinsertion of the alkyne or via a cyclopropene intermediate. Finally the generality of the unprecedented bimolecular reaction of complex 12 with 1-phenylpropyne at high concentrations was examined for the reaction methoxy(phenyl)methylene pentacarbonyl chromium 28 with diphenylacetylene and phenylacetylene at 0.5 M, and it was found that both reactions are first-order in carbene complex only.

A new approach to hydrindenones by tautomer-arrested annulations of Fischer carbene complexes

The reactions of 2,6-disubstituted aryl carbene complexes with alkynes give hydrindenone products if a phenol function is present which prevents aromatization to an indene product by a tautomerization of a metal complexed vinyl alcohol intermediate.