Chemoselective deoxygenative α-arylation of carboxylic acids, amides, and esters: synthesis of anesthetic and anti-inflammatory compounds.

A metal-free strategy has been developed for the α-arylation of carboxylic acids, secondary amides, and esters employing arenes as key reagents. This process entails the Lewis-acid catalyzed reductive Friedel-Crafts alkylation of arenes utilizing α-ketoacids, facilitated by silane in HFIP solvent. The transformation exhibits exceptional functional group tolerance, enabling late-stage functionalization of natural products. This one-step protocol has been successfully used to synthesize commercially available drugs, such as adiphenine, piperidolate, derivatives of ketoprofen, ibuprofen, flurbiprofen, and the pesticide bromopropylate.

Synthesis of tetralone and indanone derivatives via cascade reductive Friedel-Crafts alkylation/cyclization of keto acids/esters.

We disclose herein a metal-free cascade reductive Friedel-Crafts alkylation/cyclization of keto acids/esters for the synthesis of tetralones and indanones. Owing to the simple reaction conditions and setup, this protocol features broad substrate generality, facile scalability, and remarkable functional group tolerance, including the synthesis of bioactive molecule sertraline.

Synthesis of Azepinoindoles and Oxepinoindoles through Brønsted-Acid-Catalyzed Cyclization of an In Situ Generated Dihydrospiroquinoline Intermediate.

We have developed a straightforward and efficient synthetic protocol to produce 5,6,7,12-tetrahydrobenzo[2,3]azepino[4,5-b]indole and 7,12-dihydro-6H-benzo[2,3]oxepino[4,5-b]indole derivatives under mild conditions. This annulation process involves the intramolecular cyclization of the in situ generated ketimine moiety via the formation of dihydrospiroindolequinoline, which serves as a key intermediate in the reaction pathway. Several control experiments and spectroscopic studies were performed to elucidate the underlying reaction mechanism.

Sustainable Sulfonic Acid Functionalized Tubular Shape Mesoporous Silica as a Heterogeneous Catalyst for Selective Unsymmetrical Friedel-Crafts Alkylation in One Pot.

The development of general and more sustainable heterogeneous catalytic processes for Friedel-Crafts (FC) alkylation reactions is a key objective of interest for the synthesis of pharmaceuticals and commodity chemicals. Sustainable heterogeneous catalysis for the typical FC alkylation of an easily accessible carbonyl electrophile and arenes or with two different arene nucleophiles in one-pot is a prime challenge. Herein, we present a resolution to these issues through the design and utilization of a mesoporous silica catalyst that has been functionalized with sulfonic acid. For the synthesis of sulfonic acid-functionalized mesoporous silica (MSN-SO3H), thiol-functionalized mesoporous silica was first synthesized by the co-condensation method, followed by oxidation of the thiol functionality to the sulfonic acid group. Sulfonation of mesoporous silica was confirmed by 13C CP MAS NMR spectroscopy. Further, the devised heterogeneous catalysis using MSN-SO3H has been successfully employed in the construction of diverse polyalkanes including various bioactive molecules, viz arundine, tatarinoid-C, and late-stage functionalization of natural products like menthol and Eugenol. Further, we have utilized this sustainable technique to facilitate the formation of unsymmetrical C-S bonds in a one-pot fashion. In addition, the catalyst was successfully recovered and recycled for eight cycles, demonstrating the high sustainability and cost-effectiveness of this protocol for both academic and industrial applications.

Brønsted Acid-Mediated Multicomponent One-Pot Approach to Direct Construction of 4-Aryl-hydrocoumarin Derivatives.

The facile and efficient synthesis of a unique class of 4-aryl-hydrocoumarins having enormous applications in medicinal chemistry and natural products is presented. We have for the first time developed a Brønsted acid-catalyzed, multicomponent, one-pot approach for producing various 4-aryl-coumarin derivatives. The feedstock availability of these precursors allowed access to a wide range of 2-chromanone derivatives in good to excellent yields under mild conditions. The practicality of this protocol was justified by the synthesis of bioactive compounds, late-stage functionalization of natural products, and gram-scale synthesis.

Nondirected, Site-Selective Arylation of Quinone Imine Ketals Derived from Arylamines: One-Pot Access to meta-Substituted Anilines.

Herein, we develop a metal-free, nondirected, site-selective, one-pot approach to meta-arylation of arylamines. This Brønsted acid-catalyzed, direct C-C bond formation offers a broad substrate scope and scalability and creates the ideal conditions for overriding the conventional site-selectivity to furnish meta-substituted anilines. Additionally, the protocol applies to the meta-allylation of anilines and has been extended to afford late-stage functionalization and synthesis of medicinally privileged arylated diamines and densely functionalized anilines. The control experiments and density functional theory studies provide evidence for the proposed mechanism and selectivity.

Pentafluorophenol (C6 F5 OH) Catalyzed Pictet-Spengler Reaction: A Facile and Metal-Free Approach Towards Tetrahydro-ß-Carbolines.

Herein, we have disclosed pentafluorophenol as an operative catalyst for synthesizing (spirocyclic) tetrahydro-ß-carbolines via the Pictet-Spengler reaction. This straightforward catalytic protocol works under mild conditions resulting indole alkaloids in excellent yield with remarkable functional group tolerance, including late-stage modifications. This transformation demonstrates a practical and adaptable approach to produce a highly effective gram-scale synthesis of the natural alkaloid Komavine and enables the synthesis of the commercial drug Tadalafil.

Practical Access to meta-Substituted Anilines by Amination of Quinone Imine Ketals Derived from Anisidines: Efficient Synthesis of Anti-Psychotic Drugs.

Reversing the conventional site-selectivity of C-H activation provides efficient retrosynthetic disconnections to otherwise unreactive bonds. Described herein is the Brønsted acid-catalyzed reaction that selectively performs meta-amination of anisidines with aliphatic-, heterocyclic- and aromatic amines in a one-pot procedure. In addition to dramatically simplifying the synthesis of meta-substituted anilines, our approach has the advantage of the scalability and remarkable functional group tolerance, including late-stage functionalization of pharmaceutical compounds and natural products. The control experiments and detailed computational analysis provide insight into the reaction mechanism and the origin of meta-selectivity. The protocol extended to the synthesis of challenging tri-aminated arenes and successfully applied for the efficient synthesis of 5-HT6 receptor antagonists, the anti-psychotic drugs viz.. SB-214111, SB-258510, and specifically, anti-schizophrenic drug SB-271046.

Cooperative Friedel-Crafts Alkylation of Electron-Deficient Arenes via Catalyst Activation with Hexafluoroisopropanol.

A Friedel-Crafts alkylation of electron-deficient arenes with aldehydes through ''catalyst activation'' is presented. Through hydrogen bonding interactions, the solvent 1,1,1,3,3,3, -hexafluoroisopropanol (HFIP) interacted with the added Brønsted acid catalyst pTSA•H2 O, increasing its acidity. This activated catalyst enabled the Friedel-Crafts alkylation of electron-neutral as well as electron-deficient arenes. Strongly electron withdrawing arenes including arenes with multiple halogen atoms, NO2 , CHO, CO2 R, and CN, groups acted as efficient nucleophiles in this reaction. DFT studies reveal multiple roles of solvent HFIP viz; increasing the Brønsted acidity of the catalyst pTSA•H2 O, and stabilization of the transition states through a concerted pathway enabling the challenging reaction.

Silyl Cation-Initiated, Brønsted Acid-Catalyzed Strategy toward Unsymmetrical 3,3-Disubstituted 2-Oxindoles and Azonazine Cores.

Herein, a mild, metal-free, robust approach for synthesizing valuable and sterically demanding unsymmetrical 3,3-disubstituted 2-oxindoles via reductive cyclization of α-ketoamides is reported. This operationally simple protocol is initiated by a silyl cation and further catalyzed by a Brønsted acid. We have utilized a wide range of arenes, amines, and thiols as coupling partners with various α-ketoamides. The products were afforded in excellent regioselectivity and good functional group tolerance. This procedure provides easy access to the scaffolds of azonazine and its derivatives with an excellent syn-diastereoselectivity bearing all-carbon quaternary stereocenters.

Catalyst-Switchable Divergent Synthesis of Bis(indolyl)alkanes and 3-Alkylated Indoles from Styrene Oxides.

A novel and effective Brønsted acid-catalyzed chemoselective synthesis of bis(indolyl)alkanes and 3-alkyl indoles is reported. The selectivity of two significant indole derivatives is attained by allowing the same substrates to go through divergent reaction routes catalyzed by different catalysts. Furthermore, this mild approach is applicable to a wide range of substrates and has high efficacy in large-scale reactions. A plausible mechanism is provided based on the control experiments and spectroscopic studies.

Lewis Acid-Promoted Typical Friedel-Crafts Reactions Using DMSO as a Carbon Source.

This study reports a mild and efficient synthetic protocol for the synthesis of symmetrical and unsymmetrical diarylmethanes (DAMs). Using DMSO as the C1 source and TMSOTf as the Lewis acid promoter, a series of functionalized symmetrical and unsymmetrical DAMs were synthesized in high yields. Gratifyingly, DMSO plays a dual role as a solvent and a C1 source and can also be replaced with its deuterated counterpart, DMSO-d6, enabling the incorporation of the -CD2 moiety into the diarylmethane skeleton. The developed approach has been applied to a wide range of substrates having various functional groups, and this protocol has also been extended to the synthesis of an anti-breast cancer agent and an anticoagulant agent using common feedstock compounds. In addition, the postulated mechanism has been explicitly demonstrated via control experiments.

Rapid Access to Arylated and Allylated Cyclopropanes via Brønsted Acid-Catalyzed Dehydrative Coupling of Cyclopropylcarbinols.

A regioselective protocol for the synthesis of cyclopropyl derivatives that relies on Brookhart acid-catalyzed dehydrative coupling over substituted cyclopropylcarbinols without rearrangement is reported herein. The reactions proceed promptly at 25 °C with only 2.0 mol % catalyst loading and produce the cyclopropyl derivatives in excellent yields. This method is well tolerated with a vast range of cyclopropylcarbinols including aliphatic cyclopropylcarbinols, where no elimination product was obtained, demonstrating the protocol's utility. Further, the Hammett correlation suggested the formation of a cyclopropylcarbinyl cation followed by a coupling reaction. An extremely effective gram-scale reaction has also been demonstrated with a high turnover number.

Brønsted Acid-Catalysed Epoxide Ring-Opening Using Amine Nucleophiles: A Facile Access to ß-Amino Alcohols.

A mild, efficient, and metal-free synthetic protocol for the synthesis of ß-amino alcohols is reported. The reaction proceeds at room temperature with only 0.5 mol % catalyst loading and affords ß-amino alcohol derivatives in excellent yield. This protocol is well-tolerated by a wide range of styrene oxide and aniline derivatives. A notably efficacious gram-scale synthesis is also reported with a high TON=842. Further, the Hammett correlation study was also performed to identify the rate-determining step.

Reductive Carbocyclization of Homoallylic Alcohols to syn-Cyclobutanes by a Boron-Catalyzed Dual Ring-Closing Pathway.

The organoborane-catalyzed reductive carbocyclization of homoallylic alcohols has been developed by using hydrosilanes as reducing reagents to provide a range of 1,2-disubstituted arylcyclobutanes. The reaction proceeds in a cis-selective manner with high efficiency under mild conditions. Mechanistic studies, including deuterium scrambling and Hammett studies, and DFT calculations, suggest a dual ring-closing pathway.

1,1,1,3,3,3-Hexafluoroisopropanol as a Remarkable Medium for Atroposelective Sulfoxide-Directed Fujiwara-Moritani Reaction with Acrylates and Styrenes.

Axially chiral biaryls are ubiquitous structural motifs of biologically active molecules and privileged ligands for asymmetric catalysis. Their properties are due to their configurationally stable axis, and therefore, the control of their absolute configuration is essential. Efficient access to atropo-enantioenriched biaryl moieties through asymmetric direct C-H activation, by using enantiopure sulfoxide as both the directing group (DG) and chiral auxiliary, is reported. The stereoselective oxidative Heck reactions are performed in high yields and with excellent atropo-stereoselectivities. The pivotal role of 1,1,1,3,3,3-hexafluoropropanol (HFIP) solvent, which enables a drastic increase in yield and stereoselectivity of this transformation, is evidenced and investigated. Finally, the synthetic usefulness of the herein disclosed transformation is showcased because the traceless character of the sulfoxide DG allows straightforward conversions of the newly accessed, atropopure sulfoxide-biaryls into several differently substituted axially chiral scaffolds.

Synthesis of axially chiral biaryls through sulfoxide-directed asymmetric mild C-H activation and dynamic kinetic resolution.

A mild and robust direct C-H functionalization strategy has been applied to the synthesis of axially chiral biaryls. Such an efficient and stereoselective transformation occurs through an original dynamic kinetic resolution pathway enabling the conversion of diastereomeric mixtures of non-prefunctionalized substrates into atropisomerically pure, highly substituted biaryl scaffolds. The main feature of this transformation is the use of an enantiopure sulfoxide as both chiral auxiliary and traceless directing group. The potential of newly synthesized biaryls as valuable building blocks is further illustrated.