Base Mediated 7-exo-dig Intramolecular Cyclization of Betti-propargyl Precursors: An Efficient Approach to 1,4-oxazepine Derivatives.

The first general protocol for the synthesis of 1,3-benzothiazepine derivatives was established. With the aid of bench-stable hypervalent iodine promoter fluoro-HTIB, these seven-membered heterocycles can be rapidly synthesized from readily available thioamides under air atmosphere and metal-free conditions. The transformation can be completed within 1 min at room temperature and features a broad substrate scope.

Unsaturated tellurides are widely used in organic synthesis as intermediate products and synthons [1]. Cross coupling of vinyl tellurides underlay stereoselective syntheses of functionalized alkenes [1]. Development of new efficient procedures for the preparation of unsaturated tellurides containing both double [2, 3] and triple bond [4] from acetylene derivatives and nucleophilic [2] or electrophilic [3, 4] tellurium-containing reagents constitutes a line of our studies. Allenyl aryl selenides are generally prepared by isomerization of propargyl selenides under basic conditions [5]. Only a few data are available on the synthesis of allenyl aryl tellurides. Pourcelot [6] reported on the reaction of phenylchalcogenolate anions with propargyl bromide, which led to the formation of propargyl phenyl chalcogenides or mixtures of propargyl phenyl chalcogenides and allenyl phenyl chalcogenides. Following this procedure, allenyl phenyl telluride was synthesized in 27% yield. We have developed an efficient procedure for the synthesis of allenyl phenyl telluride (I) and previously unknown allenyl 4-tolyl telluride (II) in 90–93% yield from diaryl ditellurides and propargyl bromide (Scheme 1). The reaction was highly selective, and no aryl propargyl telluride was detected. Sodium tetrahydridoborate was gradually added to a solution of propargyl bromide and diaryl ditelluride in methanol at room temperature. The reduction of diaryl ditelluride with NaBH4 generates arenetellurolate anion which replaces the halogen atom in propargyl bromide. The reaction of diphenyl diselenide with propargyl bromide under analogous conditions gave 95% of phenyl propargyl selenide with high selectivity, while allenyl phenyl selenide was not detected. The spectral parameters of phenyl propargyl selenide were consistent with published data [5]. Selective formation of allenyl aryl tellurides indicates that the reaction follows 1,3-nucleophilic substitution pattern rather than usual 1,1-nucleophilic substitution that could lead to propargyl tellurides. Presumably, attack by bulky highly nucleophilic arenetellurolate anions on the terminal carbon atom at the triple bond is more favorable than on the carbon atom attached to halogen. In the former case, nucleophilic attack is accompanied by shift of electron density with simultaneous formation of allenyl fragment and bromide ion. ISSN 1070-4280, Russian Journal of Organic Chemistry, 2012, Vol. 48, No. 12, pp. 1569–1570. © Pleiades Publishing, Ltd., 2012. Original Russian Text © M.V. Musalova, M.V. Musalov, V.A. Potapov, S.V. Amosova, 2012, published in Zhurnal Organicheskoi Khimii, 2012, Vol. 48, No. 12, pp. 1598–1599.

Many natural products and bioactive molecules are built on hydroquinolines, hydrofluorenones, and fluorenones. In addition, aryl fluorenones and their derivatives, such as spirobifluorene, are widely used as a key molecular framework for the development of organic electronic materials. The synthesis of aryl fluorenones relies on multiple steps involving at least two transition metal-catalyzed C(sp2)-C(sp2) coupling reactions to build the fluorenone ring, which impede the easy accessibility of these materials for academic research and follow-up practical applications. Herein, we report a fundamentally unique method to build the fluorenone skeleton via a one-pot reaction under metal-free conditions. The method relies on the formation of hydroquinolines and hydrofluorenones via a diastereo- and regio-selective multi-bond forming reaction of feedstock chemicals. Up to 8 new (C-C, C-N, and C-O) bonds, 3 cycles, and up to 4 stereocenters were built in a single operation with exclusive diastereo and regioselectivity. DFT studies provided insights into the diastereo- and regioselectivity of this reaction. The aryl groups of aryl fluorenones, which are generally installed via transition metal-catalyzed coupling reaction of pre-functionalized arene moiety, are incorporated from readily available aryl aldehyde under metal-free conditions. The spirobifluorenes derived from these arylated fluorenones showed to have appropriate triplet energy, HOMO/LUMO levels, and thermal stability which indicate their potential as a host material for PhOLED.

This chapter describes the use of various nanomaterials as a heterogeneous catalyst, which are efficient and modular routes for the preparation of useful seven-membered heterocyclic intermediates in drug discovery and development. Heterocyclic motifs demonstrate noteworthy chemistry with important applications in medicinal, organic chemistry, pharmaceuticals, and related industries. Benzazepines, which are seven-membered azaheterocyclic fused aromatic ring motifs, has received more attention due to their broad range of biological activity and are used as building blocks in the synthesis of various natural products, drug discovery, and developments. Benzodiazepines (BZDs) represent one of the important and highly explored classes of seven-membered aromatic heterocycles that contain a two-ring N that are critical for numerous applications in the pharmaceutical industry and the organic synthesis of complex molecules. BZD and its derivatives have been successfully employed in the treatment of various psychotic disorders, infections, and microbial infections that are caused by resistant bacteria.

Isothiouronium andthiazolidinium salts are sulfur-containing scaffoldscommonly found in bioactive molecules. We report an expeditive one-pot,two-step procedure for the rapid synthesis of isothiouronium saltsfrom carbon disulfide under microwave irradiation, allowing theirisolation in less than 30 min and in good to excellent yields, withoutthe need for a catalyst. When propargyl bromide is used as an alkylatingagent, the corresponding isothiouronium salt undergoes an intramolecularcyclization during silica gel chromatography, affording a thiazolidiniumsalt. This rearrangement, not observed under the reaction conditions,was investigated via DFT calculations. Computations show that theuncatalyzed isomerization is not feasible but becomes accessible inthe presence of silica gel, which acts as a proton shuttle. The rearrangementis shown to comprise two main steps that can take place in any order,i.e., [1,3] hydrogen shift and C–N bond formation. This leadsto two alternative mechanisms with similar free energy barriers ofca. 18–19 kcal·mol–1, in both casesassociated with the rate-determining C–N bond formation step.

ConspectusChiral organosilicon compounds bearing a Si-stereogenic center have attracted increasing attention in various scientific communities and appear to be a topic of high current relevance in modern organic chemistry, given their versatile utility as chiral building blocks, chiral reagents, chiral auxiliaries, and chiral catalysts. Historically, access to these non-natural Si-stereogenic silanes mainly relies on resolution, whereas their asymmetric synthetic methods dramatically lagged compared to their carbon counterparts. Over the past two decades, transition-metal-catalyzed desymmetrization of prochiral organosilanes has emerged as an effective tool for the synthesis of enantioenriched Si-stereogenic silanes. Despite the progress, these catalytic reactions usually suffer from limited substrate scope, poor functional-group tolerance, and low enantioselectivity. The growing demand for Si-stereogenic silanes with structural diversity has continued to drive the development of new practical methods for the assembly of these chiral molecules.Five years ago, our research group embarked on a project aimed at developing a general catalytic approach that can unlock access to various functionalized Si-stereogenic organosilanes with high efficiency. This Account describes our laboratory's endeavor in the exploration and development of catalytic asymmetric dehydrogenative Si-H/X-H coupling toward Si-stereogenic silanes. This approach features (1) readily accessible dihydrosilane starting materials; (2) diverse X-H (X═C, N, O, etc.) coupling partners; (3) platform transformable Si-stereogenic monohydrosilane products; and (4) high efficiency and atomic economy.At the initial stage of the research, a biaryl dihydrosilane was selected as the model substrate to conduct an enantioselective intramolecular C-H/Si-H dehydrogenative coupling reaction. Rh/Josiphos catalytic system was found to be effective at the early stage of this process, while the final enantiocontrol was elusive. Mechanistic studies indicated that a rhodium silyl dihydride complex is the resting state in the catalytic cycle, which may undergo racemization of the Si-stereogenic center. Enlightened by the mechanistic investigations, two strategies, the tandem alkene hydrosilylation strategy and bulky alkene-assisted dehydrogenative strategy, were adopted to avoid racemization, delivering the corresponding Si-stereogenic 9-silafluorenes with excellent yields and enantioselectivities. Further enantioselective intramolecular C(sp2)-H or C(sp3)-H silylation gave access to a series of five-, six- and seven-membered Si-stereogenic heterocycles with high efficiency. Next, we extended the reaction to an intermolecular version, realizing asymmetric Si-H/C-H, Si-H/O-H, and Si-H/N-H dehydrogenative coupling reactions toward a variety of acyclic Si-stereogenic monohydrosilanes, silyl ethers, siloxanes, silanols, and silazanes. We also presented our endeavors to apply the resulting Si-stereogenic compounds, including further derivatization, polymerization, and chiroptical property investigations, which successfully introduced Si-stereocenters into bioactive molecules, polymers, and chiroptical materials. Lastly, based on the understanding of silyl metal species, we developed a new type of chiral silyl ligand that can be applied to enable an atroposelective intermolecular C-H/Si-H dehydrogenative coupling reaction. We anticipate that our research, including synthetic methodology, mechanistic insights, and property studies, will not only inspire the further development of chiral organosilicon chemistry but also contribute to the creation of novel chiral molecules to be applied in synthetic chemistry, medicinal chemistry, and materials science.

A direct CH silylation strategy for synthesizing silylated N1-oxide derivatives of azauracil has been reported in a simple and environmentally benign way under metal-free conditions using triphenylsilane as a silyl precursor and TBHP as an oxidant. This methodology is useful for late-stage modification of various bioactive molecules such as ibuprofen and gemfibrozil. As suggested by mechanistic investigation, the reaction undergoes through a radical pathway.

Recent advances in sulfenylation of C(sp3)[sbnd]H bond under transition metal-free conditions

A phosphine-catalyzed three-component cyclization reaction between anilines, carbon dioxide, and chloroalkanes was developed for the synthesis of oxazolidinones. This strategy not only proceeds under ambient CO2 pressure and metal-free condition but also shows a broad substrate scope, including aromatic amines, aliphatic amines, chiral amino acid esters, and bioactive molecules, providing an efficient and environmentally benign route to synthesize pharmaceutically relevant N-aryl-oxazolidinones. Mechanistic investigations utilizing mass spectrometry (MS) indicate the involvement of multiple phosphine intermediates in this process, thereby elucidating the underlying mechanism. Moreover, the relationships between these phosphine intermediates and Tolman cone angles or the solvent effect of phosphines were examined through mass spectrometry.

Tf2O-mediated phospha-Michael addition to unactivated α,β-unsaturated amides has been developed under mild, metal-free conditions, providing efficient access to γ-aminophosphine oxides with excellent regioselectivity. This protocol features a broad substrate scope and good functional group tolerance, accommodating a range of electron-rich, electron-deficient, and base-sensitive groups such as methoxyl, nitro, cyano, ester, and carboxylic acid groups. Primary, secondary, and tertiary amides, as well as structurally complex acrylamides derived from bioactive molecules, are compatible, affording the phosphorylated amides in moderate to excellent yields.

2-Bromo(chloro)indoles were readily prepared through TBAF-promoted intramolecular cyclization of 2-(gem-dibromo(chloro)vinyl)anilines in excellent yields under metal-free and microwave irradiation conditions.

Reaction of thiacalixarenes with propargyl bromide in the presence of potassium or cesium carbonates leads mainly to mixture of the corresponding tetrasubstituted derivatives adopting 1,3-alternate and partial cone conformations. Sodium salts like carbonate and hydride are not effective as the base for the etherification of lower rim of thiacalix[4]arenes by propargyl bromide. It was established that propargyl derivatives of thiacalix[4]arenes are in conformational exchange between forms due rotation of one aryl ring.

Transition-Metal-free Double-Insertive Coupling of Isocyanides with Arylboronic Acids Enabled Diarylmethanamines

The flavonoid family is a set of well-known bioactive natural molecules, with a wide range of potential therapeutic applications. Despite the promising results obtained in preliminary in vitro/vivo studies, their pharmacokinetic and pharmacodynamic profiles are severely compromised by chemical instability. To address this issue, the scaffold-hopping approach is a promising strategy for the structural optimization of natural leads to discover more potent analogues.In this scenario, this Perspective provides a critical analysis on how the replacement of the chromon-4-one flavonoid core with other bioisosteric nitrogen/sulphur heterocycles might affect the chemical, pharmaceutical and biological properties of the resulting new chemical entities. The investigated derivatives were classified on the basis of their biological activity and potential therapeutic indications. For each session, the target(s), the specific mechanism of action, if available, and the key pharmacophoric moieties were highlighted, as revealed by X-ray crystal structures and in silico structure-based studies. Biological activity data, in vitro/vivo studies, were examined: a particular focus was given on the improvements observed with the new heterocyclic analogues compared to the natural flavonoids. This overview of the scaffold-hopping advantages in flavonoid compounds is of great interest to the medicinal chemistry community to better exploit the vast potential of these natural molecules and to identify new bioactive molecules.

Alkynes are fundamental building blocks in synthetic chemistry with high pharmaceutical applications. Among the bioactive acetylenic molecules, propargylic alcohol is most important as almost all the marketed drugs contains quaternary centered propargylic alcohol functionality. In this study we have synthesised and evaluated 3-hydroxy-3-ethynylindolin-2-one derivatives for in vitro cytotoxic activity. An expeditious method for direct alkynylation of isatins (ketones) has been developed using tetrabutylammonium fluoride (TBAF) as a catalyst in THF solvent at room temperature under metal-free conditions. Furthermore, this method is an economically viable process that also compliments green aspects like being a ligand/metal free process under ambient conditions. This reaction tolerated a wide range of substrates with good to excellent yields (80-94%). The results showed that the synthesized compounds (4m, 4n and 4p) has the ability to inhibit Akt kinase activity with IC50 values ranging from 7.7 to 9.8 µM. All the 3-hydroxy-3-ethynylindolin-2-one derivatives were subjected for in vitro cytotoxic activity on five different cancer cell lines. Further, the synthesized compounds (4m, 4n and 4p) were evaluated for their ability to inhibit Akt kinase activity and exhibited good inhibition with IC50 values ranging from 7.7 to 9.8 µM..