Catalytic,Cascade Ring‐Opening Benzannulations of 2,3‐Dihydrofuran O,O‐ and N,O‐Acetals

An Al(OTf)₃‐catalyzed intramolecular cascade ring‐opening benzannulation of 2,3‐dihydrofuran O,O‐ and N,O‐acetals is described. The cascade sequence involves the dihydrofuran ring‐opening by acetal hydrolysis, an intramolecular Prins‐type cyclization, and aromatization to generate an array of benzo‐fused (hetero)aromatic systems in up to 95 % yield. This method represents the first example of dihydrofuran acetal usage in benzannulation reactions. The approach provides excellent regiocontrol based on the choice of alkenes used to form the requisite dihydrofuran acetals.     

Programming Organic Molecules: Design and Management of Organic Syntheses through Free‐Radical Cascade Processes

Cascade, domino, or tandem processes, that link together two or more transformations in one pot, are increasing in popularity because they lead to improvements in synthetic efficiency and decreases in environmental impact. Not only do these cascades contain choice mechanistic gems but they also deliver compact and elegant syntheses of complex natural products. Longer cascades require more functional groups precisely configured within carefully designed initial molecular architectures. Such “purposeful” molecules can be thought of as chemical algorithms.This article surveys the phenomenal range of unimolecular free‐radical cascades. A convenient system for classifying free‐radical cascades is described that is useful for evaluating and comparing cascades and aids the design of synthetic routes to polycyclic structures.Double cyclization cascades lead to cyclopentylcyclopentane or bicyclo[3.3.0]octane derivatives. Precursors that contain a ring as a template have been used to control stereochemistry in syntheses of triquinanes and many related compounds. Of the cascades containing ring‐cleavage steps, the most useful are the ring expansions which have opened up new synthetic routes to medium ring polycycles.The key design features of three‐stage unimolecular free‐radical cascades that yielded steroid structures, are linear arrays of radical acceptor units associated with methyl groups distributed every fifth C‐atom in the precursor polyenes. Ring cleavage is the reverse of cyclization. In special, symmetrical structures, therefore, this led to sequences that were reversible, thus launching endlessly repeating cascades supported by delightfully fluxional structures. The science of “programming” organic molecules to achieve particular target structures is maturing rapidly. Coordination and classification of the welter of information in this area is intended to facilitate design and hence to extend the range and complexity of attainable structures.     

(4+3) cycloaddition reactions of nitrogen-stabilized oxyallyl cations

The use of heteroatom-substituted oxyallyl cations in (4+3) cycloadditions has had a tremendous impact on the development of cycloaddition chemistry. Extensive efforts have been exerted toward investigating the effect of oxygen, sulfur, and halogen substituents on the reactivity of oxyallyl cations. Most recently, the use of nitrogen-stabilized oxyallyl cations has gained prominence in the area of (4+3) cycloadditions. The following article will provide an overview of this concept utilizing nitrogen-stabilized oxyallyl cations.     

A Straightforward Approach to Tetrahydroindolo[3,2‐b]carbazoles and 1‐Indolyltetrahydrocarbazoles through [3+3] Cyclodimerization of Indole‐Derived Cyclopropanes

A rapid new approach to produce biologically relevant bisindoles, namely indolyltetrahydrocarbazoles and indolo[3,2‐b]carbazoles, has been developed, based on the Ga(OTf)₃‐catalyzed [3+3] cyclodimerization of indole‐derived donor–acceptor cyclopropanes. Chemoselectivity of the process depends on the location of the three‐membered ring at the indole core.     

Cascade Syntheses Routes to the Centrocountins

Cascade and domino reactions that proceed through multiple steps in one pot and include multiple bond formations are promising methods for the rapid and efficient generation of complex molecular architectures, including the scaffolds of classes of complex natural product. We describe the development of various one‐pot cascade reaction sequences to yield centrocountins, which are tetracyclic indole derivatives with the basic scaffold of numerous polycyclic alkaloids. The mechanistic investigation of a sequence employing readily available alkynes and 3‐formylchromones as starting materials provided evidence that this one‐pot synthesis proceeds through at least twelve consecutive transformations and includes at least nine different chemical reactions, making it the longest cascade reaction sequence known to date. We describe the scope and limitations of the cascade synthesis approaches and the development of an enantioselectively catalyzed centrocountin synthesis.     

An Enolate-Structure-Enabled Anionic Cascade Cyclization Reaction: Easy Access to Complex Scaffolds with Contiguous Six-, Five-, and Four-Membered Rings

Catalyst-free addition of ketone enolate to non-activated multiple C−C bonds involves non-complementary reaction partners and typically requires super-basic conditions. On the other hand, highly aggregated or solvated enolates are not reactive enough to undergo direct addition to alkenes or alkynes. Herein, we report a new anionic cascade reaction for one-step assembly of intriguing molecular scaffolds possessing contiguous six-, five-, and four-membered rings, representing a formal [2+2] enol–allene cycloaddition. Reaction proceeds under very mild conditions and with excellent diastereoselectivity. Deeper mechanistic and computational studies revealed unusually slow proton transfer phenomenon in cyclic ketone intermediate and explained peculiar stereochemical outcome.     

Asymmetric Alkynylation/Lactamization Cascade: An Expeditious Entry to Enantiomerically Enriched Isoindolinones

An unprecedented Cu^I–pybox‐diPh‐catalyzed highly enantioselective (up to >99 % ee) alkynylation/lactamization cascade has been developed as a general catalytic system for the synthesis of diversely substituted isoindolinones of immense biological importance. The cascade effects one C? C and two C? N bond‐forming events in one reaction vessel under operationally simple, additive‐free reaction conditions in good to excellent yields. The methodology was further extended to the synthesis of tetrahydroisoquinoline scaffolds common to several biologically active natural products in a two‐step sequence with remarkable selectivity (up to 94 % ee).     

Inter- and Intramolecular Hetero Diels-Alder Reactions, 49[1] Kinetics and Selectivity of the Intramolecular Hetero Diels-Alder Reaction of 1-Oxa-1,3-butadienes using a Benzylidenebarbituric Acid Derivative Effect of Pressure,Temperature, and Solvent

The intramolecular hetero Diels-Alder reaction of the benzy-lidenebarbituric acid derivative 1 to give the ortho and meta products 2 and 3 is studied under high pressure up to 6 kbar in various solvents. The kinetics is measured by on-line FT-IR spectroscopy up to 3 kbar. The cycloaddition shows a pressure-dependent increase in regioselectivity in favour of the ortho adduct 2. The activation volumes, ΔV, are determined to be -(33.1· 1.2) and -(34.2· 1.5) cm³· mol⁻¹ for the reactions in dichloromethane and tetrahydrofuran at 100°C, respectively. For the cycloaddition in toluene and acetonitrile the activation volumes are found to be -(13.4· 1.5) and -(17.0· 4.1) cm³· mol⁻¹, respectively. Contrary to the large solvent effect on the activation volume, only a minor effect on the activation volume differences, ΔΔV, is observed. Measurement of the molar volumes of 1 and the cycloadducts 2 and 3 show a strong solvent dependency.     

The Construction of Molecular Complexity from Functionalized Alkylidenecyclopropanes (FACPs)

As a special family of cyclopropanes, alkylidenecyclopropanes (ACPs), exhibit outstanding physical and chemical activities, which provide opportunities to participate in fascinating chemical transformations to access cyclopropane-containing units without ring-opening processes and other unavailable compounds through conventional routes with ring-opening processes owing to their strain-driven reactivity and synthetic accessibility. Nowadays, intramolecular reactions of methylenecyclopropanes (MCPs) or ACPs with adjacent functionalities have emerged as a powerful synthetic protocol for the construction of a variety of polycyclic and heterocyclic compounds with different sized skeletons through catalytic methods. Recently, we put forward the concept of functional alkylidenecyclopropanes (FACPs) and in this Minireview, we will summarize the reactions of FACPs after 2016 including several important early works from three aspects: 1) reactions with distal C−C bond cleavage, 2) reactions with proximal C−C bond cleavage (including ring-expansion reactions), and 3) reactions without C−C bond cleavage.     

Domino 6pi-electrocyclization/Diels-Alder reactions on 1,6-disubstituted (E,Z,E)-1,3,5-hexatrienes: versatile access to highly substituted tri- and tetracyclic systems

The (E,Z,E)-1,3,5-hexatrienes 1a, 2a,b and 3b undergo 6pi-electrocyclization within 15-30 min upon heating to 200-215 degrees C. While the cyclohexene-annelated products 8a,b were stable, the analogous cyclopentene- and cycloheptene-annelated derivatives 7a and 9b easily underwent dehydrogenation to the corresponding aromatic compounds 10a and 12b during the work-up. The cyclohexadiene derivatives 8a,b were employed in thermal Diels-Alder reactions with 4-phenyl-3H-1,2,4-triazoline-3,5-dione (PTAD) and tetracyanoethylene (TCNE) to give the expected [4+2] cycloadducts 13a and 14a in good yields (60 and 78%). The initially formed cycloadduct of 8a and dimethyl acetylenedicarboxylate (DMAD) underwent a subsequent retro-Diels-Alder reaction to give the tetrahydronaphthalene 11b (47%). Under high pressure (10 kbar), the cycloadduct 15a was formed at room temperature and could be isolated in 44% yield. TCNE and N-phenylmaleimide with 8a under high pressure also led to the [4+2] cycloadducts 14a and 16a in good yields (60 and 77%). The 6pi-electrocyclization and subsequent Diels-Alder reaction, when performed as a one-pot domino process, provided direct access to Diels-Alder products of intermediately formed 6pi-electrocyclization products, for example from the 1,3,5-hexatrienes 1a,b, 2a,b, 3b and TCNE to the corresponding tricyclic products 17a,b, 14a,b, 18b in moderate to good yields (27-80%) depending on the nature of the alkoxycarbonyl group. Such sequential reactions with N-phenylmaleimide, maleic anhydride, dimethyl maleate and fumarodinitrile, the latter two under high pressure (10 kbar), worked as well to yield 16b (70%), 19a,b (19, 32%) and 20b (39%) and 21b (76%), respectively. With PTAD, however, the hexatrienes 2a,b reacted at ambient temperature without 6pi-electrocyclization to give the formal [4+2] cycloadducts 27a,b (48 and 46%), most probably via zwitterionic intermediates 23a,b and 25a,b.     

Cascade Triple‐Aldehyde Addition of 1,2,3,4‐Tetrakis(pinacolatoboryl)but‐ 2‐ene: Stereoselective Synthesis of 2,3‐Bis(alkylidene)alkane‐1,5‐diols

Treatment of (Z)‐1,2,3,4‐tetrakis(pinacolatoboryl)but‐2‐ene, prepared from 2,3‐bis(pinacolatoboryl)buta‐1,3‐diene and bis(pinacolato)diboron, with three molar equivalents of aldehyde in toluene at 100 °C gave the 2,3‐bis(alkylidene)alkane‐1,5‐anti‐diol as a single stereoisomer. The reaction is applicable to both aromatic and α‐unbranched aliphatic aldehydes. The 1,5‐anti‐diols were also synthesized by the one‐pot preparation/triple‐aldehyde addition of the tetraborylated butene. Experimental results for the stepwise treatment of the butene with two types of aldehydes suggest that the rate‐determining step of the triple‐aldehyde addition is the third allylation.