The Bis(indolylmethyl) ethers: Design, Prototypical Synthesis, and Scope Studies.

The design, prototypical synthesis, isolation, and characterization of bis(indolylmethyl) ethers from corresponding indolylcarbinols is described. This approach involves very mild conditions and exhibits good scope for indolylcarbinols (both N-electron withdrawing group and N-electron donating group). Cross etherification between two electronically different indolylcarbinols is also demonstrated for the generation of unsymmetrical ethers. For the first time, the intermediacy of the bis(indolylmethyl) ethers for the formation of bis(indolyl)methanes from indolylcarbinols is proved experimentally and by 1H NMR analysis.

Diastereoselective Biomimetic Synthesis of Dimeric Tetrahydrocarbazoles via a Copper(II)-Catalyzed Cycloisomerization-[3+2] Cyclodimerization Cascade.

The cyclodimerization (homochiral- and heterochiral-) of monomeric units for the construction of stereodefined polycyclic systems is a powerful strategy in both biosynthesis and biomimetic synthesis. Herein we have discovered and developed a CuII - catalyzed, biomimetic, diastereoselective tandem cycloisomerization-[3+2] cyclodimerization of 1-(indol-2-yl)pent-4-yn-3-ol. This novel strategy operates under very mild conditions, providing access to structurally unprecedented dimeric tetrahydrocarbazoles fused to a tetrahydrofuran unit in excellent yields of the products. Several fruitful control experiments, isolation of the monomeric-cycloisomerized products and their subsequent conversion into the corresponding cyclodimeric products supported their intermediacy and the possible mechanism as a cycloisomerization-diastereoselective [3+2] cyclodimerization cascade. The cyclodimerization involves a substituent controlled, highly diastereoselective homochiral [3+2] annulation or heterochiral [3+2] annulation of in situ generated 3-hydroxytetrahydrocarbazoles. The key and important features of this strategy are: a) construction of three new C-C bonds & one new C-O bond; b) creation of two new stereocenters, and c) construction of three new rings, in a single operation; d) low catalyst loading (1-5 mol %); e) 100 % atom economy; and f) rapid construction of structurally unprecedented natural product like polycyclic frameworks. A chiral pool version using an enantio- and diastereopure substrate was also demonstrated.

Tunable Lewis Basicity and Nucleophilicity of Water against α,α-Dihalo-ß-acetoxyketones for the Selective Synthesis of α-Haloenones and 1,2-Diketones.

The discovery and systematic study of tunable yet competitive nucleophilicity and Lewis basicity of water against novel building blocks α,α-dihalo-ß-acetoxyketones (possessing a tertiary acetate) have been reported. This distinct reactivity resulted in the formation of two competitive and different products 1,2-diketones and α-haloenones from a common intermediate α,α-dihalo-ß-acetoxyketones through the nucleophilicity and Lewis basicity of water, respectively. A systematic study to understand the effect of temperature and amount of water on the product distribution revealed that a lower temperature in combination with a higher amount of water shows a high preference for 1,2-diketones over α-haloenones. Measuring the dielectric constant (permittivity, ε) of various reaction media at various temperatures and a correlation with the experimental observations suggested that the reaction media with a higher dielectric constant exhibit the nucleophilic character and hence show a preference for 1,2-diketones over α-haloenones.

Recent approaches for the synthesis of pyridines and (iso)quinolines using propargylic Alcohols.

Propargylic alcohols are one of the readily available and highly explored building blocks in organic synthesis. They show distinct reactivities compared to simple alcohols and/or alkynes, and hence provide diverse possibilities to develop novel synthetic strategies for the construction of polycyclic systems, including heterocycles. The six-membered heterocycles, pyridines, quinolines, and isoquinolines, are very important privileged structures in medicinal chemistry and drug discovery due to their broad spectrum of biological activities. They are also part of vitamins, nucleic acids, pharmaceuticals, antibiotics, dyes, and agrochemicals. Many synthetic strategies have been developed for the rapid and efficient generation of these cyclic systems. One such strategy is employing the propargylic alcohols as reactants in the form of either a 3-carbon component or 2-carbon unit. Thus, in this review article, we aimed to summarize various approaches to pyridines, quinolines, and isoquinolines from propargylic alcohols. To the best of our knowledge, so far, no focused reviews have appeared on this topic in the literature. Due to the many reports available, we also restricted ourselves to the developments during the past 17 years, i.e., 2005-2021. We strongly believe that this review article provides comprehensive coverage of research articles on the title topic, and will be of great value for the organic synthetic community for further developments in this area of research.

Evidence for Atropisomerism in Polycyclic γ-Butenolides: Synthesis, Scope, and Spectroscopic Studies.

Design and development of a domino cyclative approach for the synthesis of new polycyclic γ-butenolides from ß-aryl-Z-enoate propargylic alcohols, through the interception of an intermediate of the Z-enoate-assisted Meyer-Schuster rearrangement, has been reported. A systematic NMR analysis of various derivatives of this class revealed and supported the potential atropisomerism associated with them. These molecules represent first examples of butenolide ring-based atropisomeric compounds in organic chemistry. The synthetic process involves a synchronous construction of both rings with concurrent creation of the potential stereogenic rotational axis.

Fe-Catalysed Coupling Reactions Between Alkynes and Alcohols.

In this review, we discussed about the synthetic developments in the field of Fe-catalysis for the formation of - bonds through the coupling of alkynes and alcohols, for the period of 13 years (2008-2020). These strategies fulfil important Green Chemistry principles, as they are highly atom economic (up to 100 %), no toxic by-products (only water), employs highly abundant and low toxic alcohols (no need for any pre-functionalization hence step economy) and cheaper Fe-catalysts. Having these advantages, one can predict that in the coming years a large number of fascinating new iron-catalyzed reactions will be developed for the organic synthesis. We hope that this review article will be highly useful for the synthetic community to design and develop new Fe-catalyzed coupling reactions and keeps the content in the right prospect.

Ag(I)-Promoted homo-dimerization of 2-(alk-2-yn-1-onyl)-1-alkynylbenzenes via a [4 + 2] cycloaddition of benzopyrylium ions: access to structurally unique naphthalenes.

Herein we report a Ag(I)-promoted homo-dimerization of 2-(alk-2-yn-1-onyl)-1-alkynylbenzenes for the synthesis of structurally novel and functionalized naphthalene derivatives. This transformation exhibits a broad scope for the alkyl as well as aryl groups present on alkynes. Observations made from control experiments suggest the possible mechanism as (i) the homo-dimerization of the in situ generated benzopyrylium ion intermediates through a head-tail [4 + 2] cycloaddition, followed by (ii) the competitive ring-opening vs. decarbonylative aromatization of the adduct to give formylated and deformylated naphthalenes, respectively.

The α,α-Dihalocarbonyl Building Blocks: An Avenue for New Reaction Development in Organic Synthesis.

The α,α-dihalocarbonyl moiety is a bifunctional system with a gem-dihalocarbon and a carbonyl carbon in 1,2-fashion. This is one of the privileged scaffolds in medicinal chemistry due to its chemical and metabolic stability and lipophilicity. They have also been found in numerous structurally divergent natural products and most of their fabricated structures have already been in medicinal use. Apart from their important use in medicinal chemistry, the α,α-dihalocarbonyl groups have been employed as key building blocks for the development of novel synthetic strategies and utilized as intermediates in total synthesis. In addition to the traditional transformations such as oxidations, reductions, and C-C bond formations, recently several new and non-classical reactions have also been developed. This review provides short description of existing methods for their synthesis and detailed discussion on the efforts for the discovery and development of new reactions by employing α,α-dihaloketones as synthetic building blocks. We have presented their use as key functional groups for the synthesis of polycyclic systems of medicinal and material importance and natural products.

Formal Halo-Meyer-Schuster Rearrangement of Propargylic Acetates through a Novel Intermediate and an Unexampled Mechanistic Pathway.

A formal, highly stereoselective halo-Meyer-Schuster rearrangement of inactivated propargylic acetates to (Z)-α-haloenones has been reported, under metal free conditions. This cascade process involves a new class of intermediate, i.e., α,α-dihalo-ß-acetoxyketones and mechanism to generate the α-haloenones, employing water as Lewis base. The outcome of the reaction is temperature-dependent, as room temperature, selectively provides α,α-dihalo-ß-acetoxyketones whereas reactions at 100 °C give direct access to α-haloenones. Either type of product can be obtained in excellent yield. A suitable rationale for the observed high Z-selectivity for α-haloenones (based on conformational population) and distinct reaction rates for various N-halosuccinimide (NXS) reagents (based on C-X bond strengths) has also been provided.

Unusual Formation of Cyclopenta[ b]indoles from 3-Indolylmethanols and Alkynes.

Acid-promoted synthesis of cyclopenta[ b]indole frameworks from 3-indolylmethanols and alkynes has been reported. The overall transformation represents a formal [3 + 2] annulation via rearrangement. This protocol showed good generality for the carbinol substrates as well as alkynes and allowed the generation of structurally diverse cyclopenta[ b]indoles. Terminal alkynes, dialkyl-substituted internal alkynes, and alkynes with electron-deficient substituents were found to be not suitable for this transformation. Similarly, N-Ts and N-Boc groups were compatible with reaction conditions, whereas N-Ac and N-Tf failed to undergo this reaction. Isolation of vinyl chloride intermediate suggested the involvement of a vinylic carbocation intermediate. A mechanism has been proposed involving a ring-opening-ring-closing cascade followed by a 1,3-indole migration process via a spirocyclobutene intermediate.

Acid catalysed rearrangement of isobenzofurans to angularly fused phthalides.

An acid catalysed, cascade process for the construction of angularly fused polycyclic phthalides from isobenzofurans under transition metal free conditions has been reported. This process is very general for diverse gem-disubstituted isobenzofuran substrates. Control experiments supported the mechanism as the nucleophilic attack of the carboxylate onto the acid activated furan ring for the simultaneous ring closing-ring opening cascade followed by dehydration. This method serves as a greener alternative for the synthesis of angularly fused polycyclic phthalides.

α-bisabolol ß-D-fucopyranoside as a potential modulator of ß-amyloid peptide induced neurotoxicity: An in vitro &in silico study.

Alzheimer's disease (AD) is a multifaceted neurodegenerative disorder affecting the elderly people. For the AD treatment, there is inefficiency in the existing medication, as these drugs reduce only the symptoms of the disease. Since multiple pathological proteins are involved in the development of AD, searching for a single molecule targeting multiple AD proteins will be a new strategy for the management of AD. In view of this, the present study was designed to synthesize and evaluate the multifunctional neuroprotective ability of the sesquiterpene glycoside α-bisabolol ß-D-fucopyranoside (ABFP) against multiple targets like acetylcholinesterase, oxidative stress and ß-amyloid peptide aggregation induced cytotoxicity. In silico computational docking and simulation studies of ABFP with acetylcholinesterase (AChE) showed that it can interact with Asp74 and Thr75 residues of the enzyme. The in vitro studies showed that the compound possess significant ability to inhibit the AChE enzyme apart from exhibiting antioxidant, anti-aggregation and disaggregation properties. In addition, molecular dynamics simulation studies proved that the interacting residue between Aß peptide and ABFP was found to be involved in Leu34 and Ile31. Furthermore, the compound was able to protect the Neuro2 a cells against Aß25-35 peptide induced toxicity. Overall, the present study evidently proved ABFP as a neuroprotective agent, which might act as a multi-target compound for the treatment of Alzheimer's disease.

Alkane desaturation by concerted double hydrogen atom transfer to benzyne.

The removal of two vicinal hydrogen atoms from an alkane to produce an alkene is a challenge for synthetic chemists. In nature, desaturases and acetylenases are adept at achieving this essential oxidative functionalization reaction, for example during the biosynthesis of unsaturated fatty acids, eicosanoids, gibberellins and carotenoids. Alkane-to-alkene conversion almost always involves one or more chemical intermediates in a multistep reaction pathway; these may be either isolable species (such as alcohols or alkyl halides) or reactive intermediates (such as carbocations, alkyl radicals, or σ-alkyl-metal species). Here we report a desaturation reaction of simple, unactivated alkanes that is mechanistically unique. We show that benzynes are capable of the concerted removal of two vicinal hydrogen atoms from a hydrocarbon. The discovery of this exothermic, net redox process was enabled by the simple thermal generation of reactive benzyne intermediates through the hexadehydro-Diels-Alder cycloisomerization reaction of triyne substrates. We are not aware of any single-step, bimolecular reaction in which two hydrogen atoms are simultaneously transferred from a saturated alkane. Computational studies indicate a preferred geometry with eclipsed vicinal C-H bonds in the alkane donor.

Total synthesis of selaginpulvilins A and C.

An efficient formal total synthesis of two compounds from the selaginpulvilin family of natural products, selaginpulvilin A and C, has been successfully achieved. The tetradehydro Diels-Alder (TDDA) reaction between an enyne and alkyne has been utilized for the creation of the necessary fluorene skeleton. Attempts at the conversion of selaginpulvilin A to selaginpulvilin B, F and H were unsuccessful.

Highly regioselective, electrophile induced cyclizations of 2-(prop-1-ynyl)benzamides.

We report an electrophile promoted, highly regioselective (∼100%) synthesis of 5-membered haloimidiates from 2-(1-alkynyl)benzamides under metal free conditions. The steric bulk in association with neighbouring group assistance at the propargylic carbon of an alkyne has been employed as the dictating factor to achieve the regioselectivity. A very broad structural diversity has been observed for propargylic alcohols and acetates, and for amide functional groups. Control experiments supported the role of the steric bulk as well as neighbouring group assistance from the oxygen atom of the substituent for the observed high regioselectivity.

The hexadehydro-Diels-Alder reaction.

Arynes (aromatic systems containing, formally, a carbon-carbon triple bond) are among the most versatile of all reactive intermediates in organic chemistry. They can be 'trapped' to give products that are used as pharmaceuticals, agrochemicals, dyes, polymers and other fine chemicals. Here we explore a strategy that unites the de novo generation of benzynes-through a hexadehydro-Diels-Alder reaction-with their in situ elaboration into structurally complex benzenoid products. In the hexadehydro-Diels-Alder reaction, a 1,3-diyne is engaged in a [4+2] cycloisomerization with a 'diynophile' to produce the highly reactive benzyne intermediate. The reaction conditions for this simple, thermal transformation are notable for being free of metals and reagents. The subsequent and highly efficient trapping reactions increase the power of the overall process. Finally, we provide examples of how this de novo benzyne generation approach allows new modes of intrinsic reactivity to be revealed.

Unconventional Reactivity of (Z)-Enoate Propargylic Alcohols in the Presence of Acids.

The unconventional reactivity of (Z)-enoate-attached propargylic alcohols in the presence of acids (nucleophilic and non-nucleophilic) was described. This study led to the discovery and development of a new strategy for the collective synthesis of the synthetically useful building blocks α-OMs-, α-OTs-, and α-Cl-enones, as well as 4,5-dioxonoates. The reaction proceeded under very mild conditions and showed a broad substrate scope.

A coherent study on the Z-enoate assisted Meyer-Schuster rearrangement.

A systematic study has been performed on the Z-enoate assisted Meyer-Schuster rearrangement of propargylic alcohols. The impact of various factors such as temperature, solvent, concentration of a counter ion of an acid, and the nature of the arene nucleophile was studied. The relative nucleophilicity of various arenes estimated in this study is in good agreement with that of Herbert Mayr's nucleophilicity scale.

Formal total synthesis of selaginpulvilin D.

An efficient and mild synthetic strategy for the total synthesis of selaginpulvilin D has been reported. A highly chemoselective enyne-alkyne dehydro Diels-Alder reaction has been employed for the construction of the tricyclic fluorene framework present in the natural product selaginpulvilin D. An improved overall yield (10.5%) has been achieved for selaginpulvilin D, starting from commercially available m-anisaldehyde in 9 linear, operationally simple synthetic transformations.

Mild Approach to 2-Acylfurans via Intercepted Meyer-Schuster Rearrangement of 6-Hydroxyhex-2-en-4-ynals.

We have developed a mild, intramolecular intercepted Meyer-Schuster (M-S) rearrangement for the synthesis of 2-acylfurans from corresponding cis-6-hydroxyhex-2-en-4-ynals. This reaction was found to be very general, and the starting materials are easily accessible. By this methodology the first synthesis of deoxy-nor-abiesesquine B, a sesquiterpene, was also achieved in three steps. The concept of adding two nucleophiles during the M-S rearrangement was introduced.