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.

Synthesis of Functionalized Pyrimidines from Propargylic alcohols and their Derivatives: Two Decades of Developments.

Pyrimidine is a six-membered diaza-heterocycle i. e., 1,3-diazine. It is found to be present in many biologically and pharmacologically active scaffolds like nucleotides, natural products, and drugs. The bioactivities of pyrimidine include anti-tubercular, anti-bacterial, anti-fungal, anti-viral, anti-inflammatory, anti-malarial, anti-cancer, anti-neoplastic and many more. In this review article we have summarized various synthetic approaches that involve the synthesis of these privileged building blocks by employing propargylic alcohols and their derivatives like propargylic esters and propargylic ynones as three carbon-components. Here, we have confined ourselves to the developments appeared during the period of 23 years i. e., 2000-2022.

An approach to functionalized carbazoles from Z-enoate propargylic alcohols. A unified total synthesis of N-Me-carazostatin, N-Me-carbazoquinocin C and N-Me-lipocarbazole A4.

Development of an acid catalyzed, intramolecular benzannulation of indoles for the synthesis of functionalized carbazoles has been reported. The indole appended Z-enoate propargylic alcohols have been employed. The N-EDG-indoles involve the 5-exo-dig cyclization followed by 1,2-migration to give the carbazole-butenoates, whereas the N-EWG-indoles undergo the Z-enoate assisted Meyer-Schuster rearrangement to give the dihydrocarbazole-4-oxo-butanoates. Utilizing one of the 2-methyl-carbazole-butyraldehyde (obtained from the corresponding carbazole-butanoate) as the key intermediate, we have developed a simple approach for an efficient synthesis of N-Me-carazostatin, N-Me-carbazoquinocin C and N-Me-lipocarbazole A4.

Ag(I)-Promoted, Diastereoselective Cyclo-isomerization of N-Alkynyl-7-azaindole-2-carbinols. Selective Synthesis of syn-1,2-Diarylpyrrolo[1,2-a]indol-3-ones and (Z)-8-Benzylideneoxazolo[3',4'':1,5]pyrrolo[2,3-b]pyridines.

The design and development of an Ag(I)-promoted, highly diastereoselective cycloisomerization strategy for the synthesis of syn-1,2-diarylpyrrolo[1,2-a]indol-3-ones from N-alkynyl-indole-2-carbinols is reported. The H218O control experiment and identification of 18O-labeled product suggested the involvement of an external water. The 7-azaindole substrates showned a distinct reactivity to give the (Z)-8-benzylideneoxazolo[3',4':1,5]pyrrolo[2,3-b]pyridines. Key features of this strategy are its 100% atom economy, access to important heterocycles, diverse substrate scope, yields up to 95%, operationally simple procedure, and distinct reactivity of indole vs 7-azaindoles.

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.

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.

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.

TfOH catalysed domino-double annulation of arenes with propargylic alcohols: a unified approach to indene polycyclic systems.

The design and development of a TfOH catalysed domino strategy for the double annulation of arenes with propargylic alcohols for the rapid generation of indene based polycyclic systems is reported. The dehydration, intramolecular 6-endo-dig hydroarylation, and cationic cyclization were consecutively promoted by TfOH. The key features of this strategy are the formation of two C-C bonds, unified access to indene polycyclic systems, excellent yields (up to 95%), high atom economy (>90%), an operationally simple procedure, and water being the only byproduct. By extending this strategy, a two-step synthesis of the pentacyclic systems of hypoxylonol A (43% overall yield from α-tetralone), daldinone A (63% overall yield from ß-tetralone) and spiro-tetracyclic framework of incarviatone A has also been achieved.

An Approach for the Generation of γ-Propenylidene-γ-butenolides and Application to the Total Synthesis of Rubrolides.

Design and synthesis of a new class of γ-butenolides, viz. ß-aryl-γ-propenylidene-γ-butenolides, have been reported from ß-aryl-Z-enoate propargylic alcohols in the presence of acid. Isolation of ß-aryl-γ-propenylidene-γ-butenolides and their O18-isomer confirmed the intermediacy of the allenyl-lactonium ion as well as the cyclic-hemiacetal during the proposed mechanism. By utilizing the ß-aryl-γ-methylenecyclohexenylidene-γ-butenolides as starting materials, a highly stereoselective and efficient approach has been developed for the syntheses of frameworks of rubrolide natural products. This strategy was further extended for the total synthesis of rubrolide E.

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.

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.

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.

Aggregation-Induced Emission Active Donor-Acceptor Fluorophore as a Dual Sensor for Volatile Acids and Aromatic Amines.

In the present work, a novel donor (D)-acceptor (A) fluorophore based on indeno-pyrrole derivative (PYROMe) has been utilized as a dual sensor for volatile acids and aromatic amines, where sensory responses were regulated by the aggregation-induced emission (AIE) property. The twisted structural framework of PYROMe, confirmed by crystal study, avoids closed cofacial encounter upon aggregation and aided with augmented rigidity via different noncovalent interactions that ultimately ensued restricted intramolecular rotation (RIR). Consequently, PYROMe exhibited AIE in THF/H2O mixture along with bright solid-state emission. The accessibility of protonation at carbonyl site and feasible HOMO energy to accept electrons from aromatic amines during photoexcitation enabled PYROMe as a potential dual sensor. A thin film of PYROMe was utilized for the quantitative detection of volatile acids and aromatic amines, and the detection limit (DL) was found to be as low as 0.77 ppm and 6.04 ppb for trifluoroacetic acid (TFA) and aniline vapors, respectively. Beyond the established scopes of substituted indeno-pyrroles, the present study paves the way, for the first time, toward an AIE-driven dual-stimuli response in indeno-pyrrole based D-A fluorophores.

An Unusual Conversion of 2-(Alkynonyl)Alkynylbenzenes to Isocoumarins by a Retro-Favorskii-like Degradation.

We report the discovery of an anomalous reaction of 2-(alkynonyl)alkynylbenzenes under AgI catalysis for the selective formation of isocoumarins. This reaction is previously undocumented for 2-(alkynonyl)alkynylbenzenes in terms of the reaction mechanism and the product formed. Water (H2 O18 ) labeling studies suggested a possible mechanistic pathway in which the initial formation of a pyrylium ion is followed by hydrative dealkynylation, that is, water incorporation and alkyne expulsion, similar to a retro-Favorskii reaction.

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.

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.

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.

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.