A rapid, efficient and solvent‐free – green – protocol for Groebke–Bienaymé–Blackburn reaction (G−B‐B reaction) for the synthesis of fused‐imidazo heterocycles has been developed. The methodology reported here involves multi‐component reaction (MCR) catalyzed by reusable Yb(OTf)3 (a mild and water‐compatible Lewis acid) under microwave irradiation which allows fast and efficient preparation of the title compounds in excellent yield. The salient features of our protocol are solvent‐free, low catalyst loading (2.5–0.1 mol%) with good turnover number (TON: 890) and turnover frequency (TOF: 178/min), less reaction time (5 min), no dependency over specialized purification (by either column chromatography or recrystallization) and very high isolated yield (95–99 %) with excellent green chemistry metrics (E‐factor: 0.071 and Mass Intensity: 1.071). The water compatibility of the catalyst Yb(OTf)3 has been exploited for its efficient recovery through water washings. In addition, the other exciting milestones of the protocol are catalyst and workup solvent recycling, excellent conversion with notorious substrates such as enolizable aldehyde or isonitrile bearing reactive substituent, very efficient at higher scale (50 mmol) and easy to couple with other methods (one‐pot two‐step cyclization: G−B‐B reaction and Ullmann‐type coupling).
A rapid and elegant tandem azide–isocyanide cross‐coupling/cyclization protocol has been developed based on a nitrene transfer reaction. The palladium‐catalyzed ligand‐free methodology led to the synthesis of three different heterocyclic scaffolds with excellent atom/step/redox economy. Studies based on first‐principles‐based quantum calculations and control experiments unraveled a concerted process of nitrene transfer reaction on isocyanides, ruling out the metallaaziridine intermediate reported earlier. This finding could pave the way for novel applications of nitrene transfer reactions to generate bioactive heterocycles.magnified image
A rapid and efficient synthesis of aminotetrazole from aryl azides, isocyanides, and TMSN is developed. The reaction is promoted by sequential Pd(0)/Fe(III) catalysis. The reaction sequence utilizes the Pd-catalyzed azide-isocyanide denitrogenative coupling reaction to generate unsymmetric carbodiimide in situ, which reacts with TMSN in the presence of FeCl in a single pot. The methodology has distinct advantages over traditional synthetic approaches where toxic Hg and Pb salts are employed at stoichiometric scale.
Synthesis of pyrazolo[1,5-c]quinazolines from four easily available precursors is presented through a one-pot tricyclic Pd(ii)/Ag(i) relay catalysis. The bimetallic relay cascade forges five new chemical bonds by concatenating six discrete chemical steps. The relay catalysis enables four-component assembly of pyrazolo[1,5-c]quinazolines that selectively inhibit EGFR, exhibit apoptosis through the ROS-induced mitochondrial-mediated pathway, and arrest the cell cycle at the G1 phase.
A ruthenium catalyzed intramolecular C-S coupling reaction of N-arylthioureas for the synthesis of 2-aminobenzothiazoles has been developed. Kinetic, isotope labeling, and computational studies reveal the involvement of an electrophilic ruthenation pathway instead of a direct C-H activation. Stereoelectronic effect of meta-substituents on the N-arylthiourea dictates the final regioselective outcome of the reaction.
A novel and efficient metal free, redox-neutral method for the synthesis of secondary thiocarbamates by cross-coupling of readily available thiophenol and isocyanides has been developed. The present methodology exhibits a broad substrate scope with good to excellent yields without an additive/extra oxidant under mild reaction conditions catalyzed by inexpensive iodine as the catalyst.
2,3,5‐Trisubstituted tetrahydrofuran moiety is ubiquitous in natural products. These have served as appealing candidates for total synthesis due to their varied bio‐ and pharmaceutical activities. This tutorial review delineates the ingenious efforts by many researchers in the total synthesis of selected natural products based on a common 2,3,5‐trisubstituted tetrahydrofuran core structure. Many of the syntheses display nuanced interplay between new methods and the ingenuity of planned strategies achieved through catalysis or cascade chemistry. In some cases, the chiron approach has come quite handy, wherein the structural features and the stereochemistry in select molecules could map well with naturally available starting materials. This compilation also aims to enhance the diversity space based on these natural products and further interest in sustainable total synthesis.
The rapid synthesis of the isoindolinone skeleton has been accomplished by a palladium‐catalyzed one‐pot tandem process, which consists of an isocyanide insertion/hydration (carboxamidation) and 5‐exo‐dig cycloisomerization (hydroamidation) reaction sequence that afforded the products in good to excellent yields. Preliminary mechanistic studies of this sequential C–C/C–O/C–N bond formation process suggests that the carboxamidation step is palladium‐dependent, whereas the hydroamidation step is solely mediated by the base and is driven by the electrophilicity of the alkyne.
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