Intramolecular Addition Reactions Research Articles

Novel Palladium‐Catalyzed Intramolecular Addition of Aryl Bromides to Aldehydes as Key to the Synthesis of 3,3‐Dimethylchroman‐4‐ones and 3,3‐Dimethylchroman‐4‐ols

AbstractMany benzofused cyclic chiral alcohols are biologically active and a variety of synthetic methods has been developed to access these structures. Palladium‐catalyzed intramolecular nucleophilic addition reactions of aryl boron and aryl halide compounds to carbonyls are useful, but control over the cyclization to give a single product has to‐date proven challenging. Here, we describe the first controlled intramolecular nucleophilic addition of aryl bromides to aldehydes, providing the corresponding cycloalkanol or cyclic ketone derivatives simply by changing the base or the ligand. Ten new 3,3‐dimethylchroman‐4‐ol derivatives and six new 3,3‐dimethylchroman‐4‐ones were prepared (with up to 91% conversion and 46% ee).

Rapid One‐Pot Access to Unique 3,4‐Dihydrothiopyrano[3,4‐b]indol‐1(9H)‐imines via Bi(OTf)3‐Catalysed Tandem Friedel–Crafts Alkylation/Thia‐Michael Addition

A highly efficient and atom economical one‐pot annulation strategy for novel tetrahydrothiopyrano[3,4‐b]indoles is presented. This protocol involves a Bi(OTf)3 catalyzed tandem Friedel–Crafts alkylation and intramolecular thia‐Michael addition reactions to furnish target molecules in an efficient manner. The method works effectively on substrates with unprotected indoles and also it is successfully employed to make tetrahydrothiepino[3,4‐b]indoles. The scaffolds synthesized are diverse and first of the kind. The reaction is practically simple with broad substrate scope and vast functional group compatibility.

The Palladium-Catalyzed Ullmann Cross-Coupling Reaction: A Modern Variant on a Time-Honored Process.

Cross-coupling reactions, especially those that are catalyzed by palladium, have revolutionized the way in which carbon-carbon bonds can be formed. The most commonly deployed variants of such processes are the Suzuki-Miyaura, Mizoroki-Heck, Stille, and Negishi cross-coupling reactions, and these normally involve the linking of an organohalide or pseudohalide (such as a triflate or nonaflate) with an organo-metallic or -metalloid such as an organo-boron, -magnesium, -tin, or -zinc species. Since the latter type of coupling partner is often prepared from the corresponding halide, methods that allow for the direct cross-coupling of two distinct halogen-containing compounds would provide valuable and more atom-economical capacities for the formation of carbon-carbon bonds. While the venerable Ullmann reaction can in principle achieve this, it has a number of drawbacks, the most significant of which is that homocoupling of the reaction partners is a competitive, if not the dominant, process. Furthermore, such reactions normally occur only under forcing conditions (viz., often at temperatures in excess of 250 °C). As such, the Ullmann reaction has seen only limited application in this regard, especially as a mid- to late-stage feature of complex natural product synthesis. This Account details the development of the palladium-catalyzed Ullmann cross-coupling reaction as a useful method for the assembly of a range of heterocyclic systems relevant to medicinal and/or natural products chemistry. These couplings normally proceed under relatively mild conditions (<100 °C) over short periods of time and, usually, to the exclusion of (unwanted) homocoupling events. The keys to success are the appropriate choice of coupling partners, the form of the copper metal employed, and the choice of reaction solvent. At the present time, the cross-coupling partners capable of engaging in the title reaction are confined to halogenated and otherwise electron-deficient arenes and, as complementary reactants, α- or β-halogenated, α,β-unsaturated aldehydes, ketones, esters, lactones, lactams, and cycloimides. Nitro-substituted (and halogenated) arenes, in particular, serve as effective participants in these reactions, and the products of their coupling with the above-mentioned carbonyl-containing systems can be manipulated in a number of different ways. Depending on the positional relationship between the nitro and carbonyl groups in the cross-coupling product, the reduction of the former group, which can be achieved under a range of different conditions, provides, through intramolecular nucleophilic addition reactions, including Schiff base condensations, access to a diverse range of heterocyclic systems. These include indoles, quinolines, quinolones, isoquinolines, carbazoles, and carbolines. Tandem variants of such cyclization processes, in which Raney cobalt is used as a catalyst for the chemoselective reduction (by dihydrogen) of nitro and nitrile groups (but not olefins), allow for the assembly of a range of structurally challenging natural products, including marinoquinoline A, (±)-1-acetylaspidoalbidine, and (±)-gilbertine.

Asymmetric Cycloetherification by Bifunctional Organocatalyst

Attempts to obtain enantiomerically enriched tetrahydrofuran derivatives via an intramolecular oxy-Michael addition reaction of ε-hydroxyenone is discussed. Despite previous difficulties associated with the asymmetric induction of this reaction, which can proceed even without a catalyst, a highly efficient asymmetric induction was realized using a bifunctional organocatalyst derived from a cinchona alkaloid. The reaction could be extended to ζ-hydroxyenone to yield an optically active tetrahydropyran derivative with a high ee. In these reactions, it is important for the gentle acidic and basic sites in the bifunctional organocatalyst to be arranged properly within the molecular skeleton of the catalyst. The high performance asymmetric induction relied on the affinity of the catalyst for the substrate, which played an important role. A disubstituted tetrahydropyran synthesis could be effectively performed via kinetic resolution using ζ-hydroxyenone containing a secondary alcohol moiety using a chiral phosphoric acid catalyst.

Diversity-Oriented Approach to N-Heterocyclic Compounds from α-Phenyl-β-enamino Ester via a Mitsunobu-Michael Reaction Sequence.

Herein we delineate a novel route for the diastereoselective construction of diversely substituted N-heterocyclic ring systems as valuable scaffolds for natural products and pharmaceuticals, starting from an easily accessible prochiral α-phenyl-β-enamino ester. The reaction sequence relies on the unexplored reactivity of α-phenyl-β-enamino ester as a nucleophilic partner in the Mitsunobu reaction to forge the N-tethered alkene-alcohol/thiol/amine intermediate, which was subjected to an intramolecular hetero-Michael addition reaction under mild conditions to furnish the respective N-heterocyclic compounds embedded with an exocyclic chiral center in high yields and excellent diastereoselectivities. The methodology is amenable for a broad range of substrates based on a metal-free approach.

Asymmetric Total Syntheses and Structure Confirmation of Chlorofucins and Bromofucins.

Substrate-controlled asymmetric total syntheses and structure confirmation of (+)-(3E)- and (-)-(3Z)-chlorofucin [(E)-1 a and (Z)-1 a], and (+)-(3E)- and (-)-(3Z)-bromofucin [(E)-1 b and (Z)-1 b] were accomplished. Our syntheses feature as key steps haloetherification (either 'conventional' or 'one-pot organoselenium-mediated') of α,α'-trans-γ,δ-unsaturated oxocene alcohol 9 and our (E)- and (Z)-selective cross-metathesis (CM) protocols. More importantly, a rationale is provided for the strikingly different pathways followed by α,α'-trans-γ,δ-unsaturated oxocene alcohol 9 and its α,α'-cis isomer 9' in the presence of different electrophiles during the intramolecular electrophilic addition reactions.

Synthesis of 2,2-Difluorinated 4-Isoflavanols/4-Thioisoflavanols via a Base-Catalyzed [4 + 2] Annulation Reaction of gem-Difluoroolefins.

DBU-catalyzed sequential intermolecular and intramolecular nucleophilic addition reactions between gem-difluoroolefins and o-hydroxy/mercapto benzaldehydes have been developed to provide a [4 + 2] annulation strategy for facile synthesis of gem-difluorinated isoflavanol derivatives. The competitive addition-elimination reaction of gem-difluoroolefins with nucleophiles was avoided under mild conditions, affording 2,2-difluorinated 4-isoflavanols or 2,2-difluoriated 4-thioisoflavanols in good to excellent yields.

Frontispiece: Short Total Synthesis of (±)‐γ‐Lycorane by a Sequential Intramolecular Acylal Cyclisation (IAC) and Intramolecular Heck Addition Reaction

Frontispiece: Short Total Synthesis of (±)‐γ‐Lycorane by a Sequential Intramolecular Acylal Cyclisation (IAC) and Intramolecular Heck Addition Reaction

Short Total Synthesis of (±)-γ-Lycorane by a Sequential Intramolecular Acylal Cyclisation (IAC) and Intramolecular Heck Addition Reaction.

An intramolecular acylal cyclisation (IAC) approach to the synthesis of a range of bicyclic heterocycles is reported. As an example of the utility of the IAC reaction, the methodology was applied in a protecting-group-free five-step total synthesis of (±)-γ-lycorane, incorporating a new intramolecular Heck addition reaction to generate the pentacyclic core structure of the natural product in good yield.

ChemInform Abstract: Controlled Ring‐Opening of Siloxydifluorocyclopropanes for Carbocyclization: Synthesis of Difluorocyclopentenones.

AbstractThe reaction proceeds via intermediary siloxydifluorocyclopropanes.

Total Synthesis of (±)-Decytospolides A and B

Total synthesis of (±)-decytospolides A and B have been accomplished by an efficient and stereoselective construction of 2,6- cis -tetrahydropyrans by an intramolecular oxa-conjugate addition reaction.

Synthetic studies on enfumafungin: stereoselective synthesis of the CD ring segment

The stereoselective synthesis of the right-hand segment of enfumafungin, a potent antifungal agent isolated from a Hormonema sp., was achieved. The contiguous two quaternary carbon atoms at the angular positions of the trans-fused CD ring system was constructed through the stereoselective reduction of 4-cyano-3,4-dimethyl-2-cyclohexen-1-one and the Johnson–Claisen rearrangement. After elongation of the side chains, the D ring was formed via a stereoselective intramolecular conjugate addition reaction which was originally developed by our laboratory.

Access to Fluoropyrrolidines by Intramolecular Aza-Michael Addition Reaction

Study of the intramolecular aza-Michael addition reaction from an aminofluorovinylsulfone opens a new route for the synthesis of pyrrolidine derivatives. An unexpected diastereoselective cyclization reaction was observed, leading preferentially to the anti-N-benzylpyrrolidine sulfone. The resulting sulfone was reacted with aldehydes to access β-substituted α-fluoroalkenyl pyrrolidines in one step.

Controlled Ring-Opening of Siloxydifluorocyclopropanes for Carbocyclization: Synthesis of Difluorocyclopentenones.

A highly controlled ring opening of siloxydifluorocyclopropanes, formed by nBuN4Br-catalyzed difluorocyclopropanation of methyl vinyl ketones bearing a β-alkylthio group by using TMSCF2Br as a unique difluorocarbene source, results in metal difluorohomoenolates with assistance of copper or silver followed by an intramolecular addition and elimination reaction leading to α-gem-difluorocyclopentenones efficiently.

ChemInform Abstract: Aza‐Conjugate Addition Methodology for the Synthesis of N‐Hydroxy‐isoindolin‐1‐ones.

AbstractAryl aldehydes containing an ortho‐propiolate or propiolamide moiety are efficiently cyclized to N‐hydroxyisoindoline‐1‐ones, which are subsequently converted into the parent isoindoline‐1‐ones.

ChemInform Abstract: Three‐Component Reaction Between Substituted 2‐(2‐Nitrovinyl)‐phenols, Acetylenedicarboxylate and Amines: Diversity‐Oriented Synthesis of Novel Pyrrolo[3,4‐c]coumarins.

AbstractThis reaction involves the sequential iron trichloride‐mediated nucleophilic addition followed by intramolecular transesterification and intramolecular nucleophilic addition reaction.

Aza-Conjugate Addition Methodology for the Synthesis of N-Hydroxy-isoindolin-1-ones.

Aryl-aldehydes containing ortho-substituted propiolate fragments react with hydroxylamine to afford carbinolamine intermediates that undergo intramolecular aza-conjugate addition reactions to afford N-hydroxy-2.3-dihydro-isoindolin-1-ones that can be reduced to their corresponding isoindolin-1-ones and isoindoles.

Asymmetric Synthesis of Multisubstituted Dihydrobenzofurans by Intramolecular Conjugate Addition of Short-Lived C-O Axially Chiral Enolates.

Enantioselective intramolecular conjugate addition reactions of short-lived C-O axially chiral enolates have been developed. The reactions proceeded with inversion of the configuration and provided dihydrobenzofurans with contiguous tetra- and trisubstituted carbon centers in up to 96% enantiomeric excess (ee).

ChemInform Abstract: Chiral Phosphoric Acid Catalyzed Asymmetric Synthesis of 2‐Substituted 2,3‐Dihydro‐4‐quinolones by a Protecting‐Group‐Free Approach.

Chiral 2-substituted 2,3-dihydro-4-quinolones were synthesized based on the chiral phosphoric acid catalyzed intramolecular aza-Michael addition reaction using N-unprotected 2-aminophenyl vinyl ketones as substrates in good yields with high enantioselectivities.

ChemInform Abstract: Diversity‐Oriented Synthesis of β‐Lactams and γ‐Lactams by Post‐Ugi Nucleophilic Cyclization: Lewis Acids as Regioselective Switch.

AbstractHeterocyclic fused α‐methylene β‐lactams are synthesized by a InCl3‐catalyzed intramolecular addition reaction.