Synthesis of 3-substituted isoindolin-1-ones via a palladium-catalysed 3-component carbonylation/amination/Michael addition process

A novel palladium-catalysed three component cascade process is described involving carbonylation of an aryl iodide to generate an acyl palladium species which is intercepted by a primary aliphatic/aromatic amine, amide or sulfonamide followed by intramolecular Michael addition to afford 3-substituted isoindolin-1-ones in good yield.     

One-pot, three-component synthesis of novel δ-sultam scaffolds via N-sulfonylation—intramolecular Michael sequences

The synthesis of novel δ-sultam scaffolds utilizing one-pot, three-component reactions of 1,3-dicarbonyl compounds, primary aliphatic amines and substituted styrenesulfonyl chlorides is reported. A variety of six-membered sultams are obtained in moderate to good yields presumably via N-sulfonylation—intramolecular Michael addition sequences.     

Synthesis of carbo- and heterocycles via a palladium-catalysed allene insertion-nucleophile incorporation-Michael addition cascade

A novel palladium catalysed three-component cascade process is described involving allenylation of an aryl iodide to generate a (π-allyl)palladium species which is intercepted by a carbon or nitrogen nucleophile followed by intramolecular Michael addition to afford carbo- and heterocycles in good yield.     

Sequential 1,3-dipolar cycloadditions in the synthesis of bis-isoxazolo substituted piperidinones

A strategy for the efficient synthesis of novel bis-isoxazolo substituted piperidinones has been developed. The protocol consists of the Michael addition of an unsaturated alkoxide to beta-nitrostyrene followed by an intramolecular nitrile oxide cycloaddition (INOC) or an intramolecular silyl nitronate olefin cycloaddition (ISOC) to give III. Grignard addition to this isoxazoline intermediate followed by DCC coupling of the resulting isoxazolidine with nitroacetic acid gave II, and a second intramolecular cycloaddition via 1,3-dipoles result in the formation of the targeted novel tetracycles (I). A solid-supported scavenger was employed to increase the efficiency and yield of the Michael addition step.     

A novel and chemoselective synthesis of substituted 3,4-dihydroisoquinolin-1(2H)-ones from o-oxiranylmethylbenzonitrile intermediates and TBAB/NaCN

A novel synthesis of substituted 3,4-dihydroisoquinolin-1(2H)-ones is described. o-Oxiranylmethylbenzonitriles, prepared from isovanillin via five synthetic steps, were treated with NaCN/tetra-n-butylammonium bromide (TBAB) to yield 3,4-dihydroisoquinolin-1(2H)-ones in good yields. This one pot reaction demonstrates the novel and chemoselective nature of ring-opening of epoxide by cyanide to generate an iminoisochroman ring via cyclization, again ring-opening by cyanide to generate a Michael acceptor and a donor, and ring re-cyclization through an intramolecular conjugate addition. The detailed mechanism is also rationally proposed.     

Highly stereoselective Michael reduction/intramolecular Michael reaction cascade to synthesize trans-stereodiad comprising an all-carbon quaternary stereogenic center

A highly stereoselective Michael reduction/intramolecular Michael reaction cascade is described. The cascade is initiated by the regioselective Michael reduction of an α-methylidene ester with L-Selectride. This is followed by the highly stereoselective intramolecular Michael reaction which efficiently constructs a six-membered carbocyclic ring with formation of the trans-stereodiad, composed of an all-carbon quaternary center and a tertiary stereogenic center. The stereoselectivity is perfectly controlled by the choice of alkene geometry in the Michael acceptor.     

Triple domino reaction for the synthesis of pyrazole/indoline linked chromenes

A simple and convenient method towards the synthesis of highly diversified chromenopyrazole/indoline frameworks in excellent yields via iodine promoted triple domino reaction involving Michael addition followed by intramolecular cyclization and dehydrogenation sequence has been described for the first time.     

Organocatalytic asymmetric cascade Michael/hemiketalization/retro-aldol reaction of 3-acetyl-oxindole with β,γ-unsaturated ketoesters catalyzed by bifunctional amino-squaramides

An unprecedented organocatalytic asymmetric Michael/Hemiketalization/retro-aldol cascade sequence catalyzed by bifunctional amino-squaramides is described. The corresponding adducts were generally obtained in high yields (up to 97%) with moderate diastereo- (up to 79:21 dr) and good enantioselectivities (up to 90% ee).     

Total synthesis of marine diterpenoid stolonidiol

Marine dolabellane diterpenoid stolonidiol was synthesized from l-ascorbic acid. The method for this total synthesis involves formation of the bicyclo[2.2.1]heptane derivative using a diastereoselective sequential Michael reaction, formation of cyclopentane derivative by the retro-aldol reaction and construction of an 11-membered carbocyclic ring through the intramolecular Horner–Wadsworth–Emmons reaction.     

Three-component glycolate Michael reactions of enolates, silyl glyoxylates, and α,β-enones

Silyl glyoxylates react with enolates and enones to afford either glycolate aldol or Michael adducts. Product identity is controlled by the countercation associated with the enolate. Reformatsky nucleophiles in the presence of additional Zn(OTf)(2) result in aldol coupling (A), while lithium enolates provide the Michael coupling (B). Deprotonation of the aldol product A with LDA induces equilibration to form the minor diastereomer of Michael product B. This observation suggests that formation of the major diastereomer of Michael product B does not occur via an aldol/retro-aldol/Michael sequence.     

Antibody-catalyzed asymmetric intramolecular Michael addition of aldehydes and ketones to yield the disfavored cis-product

The development of new catalytic asymmetric reactions continues to be a major goal in organic chemistry. Here we report a novel antibody-catalyzed intramolecular Michael addition of aldehydes and ketones to enones. The reaction is enantioselective and diastereoselective with a high ee value and cis/trans ratio. This is the first example of asymmetric intramolecular Michael addition of ketones. Antibody 38C2 is the only catalyst to date capable of generating this selectivity in Michael addition products.     

Cascade intermolecular Michael addition-intramolecular azide/internal alkyne 1,3-dipolar cycloaddition reaction in one pot

A rapid one-pot protocol for the synthesis of indole-based polyheterocycles via a sequential Lewis acid catalyzed intermolecular Michael addition and an intramolecular azide/internal alkyne 1,3-dipolar cycloaddition reaction has been described. The generality of the method has been demonstrated by treating a series of aromatic/aliphatic 2-alkynyl indoles with substituted (E)-1-azido-2-(2-nitrovinyl)benzenes to furnish annulated tetracyclic indolo[2,3-c][1,2,3]triazolo[1,5-a][1]benzazepines in good yields.     

Rapid Construction of the Aza-Propellane Core of Acutumine via a Photochemical [2 + 2] Cycloaddition Reaction

Synthetic efforts toward the chlorinated aza-propellane alkaloid acutumine (1) are described. The key vicinal quaternary centers were constructed by a photochemical [2 + 2] cycloaddition reaction of a furanyl-tetrahydroindolone. Dihydroxylation of the [2 + 2] product enabled a tandem retro-aldol/intramolecular ketalization reaction, which revealed the aza-propellane core of 1 while generating an unusual, caged, pentacyclic hemiketal product.     

Polycyclic N-heterocyclic compounds. Part 61: A novel Truce-Smiles type rearrangement reaction of 4-(2-cyanovinyloxy)butanenitriles to give cycloalkeno[1,2-d]furo[2,3-b]pyridines

The cycloalkeno[1,2-d]furo[2,3-b]pyridine skeleton was conveniently synthesized from fused 4-(2-cyanovinyloxy)butanenitriles in one step through sequential intramolecular Michael addition, β-elimination and intramolecular nucleophilic addition. This sequence thus consists of a novel Truce-Smiles type rearrangement followed by cyclization. The 5-amino derivatives were transformed further to lactams in good yields.     

Intramolecular Heck cyclization to the galanthamine-type alkaloids: total synthesis of (±)-lycoramine

A novel approach towards the construction of the galanthamine skeleton was demonstrated by the total synthesis of (±)-lycoramine. The key steps include a Pd-catalyzed intramolecular cyclization to form the seven-membered azepane ring and a spontaneous intramolecular Michael addition to afford the five-membered furan ring. This synthetic route has also been demonstrated to be useful for the preparation of novel derivatives with simplified galanthamine skeletons.     

The intramolecular tandem Michael/Mannich-type reaction of α,β-unsaturated carbonyl compounds with acyliminium ions provides access to chiral indolizidines

The intramolecular tandem Michael/Mannich-type (Michael addition/halo-Mannich-type) reaction using TiCl₄/n-Bu₄NI system between the α,β-unsaturated carbonyl compounds possessing an Evans oxazolidinone as a chiral auxiliary and N-acyliminium ion intermediates is described. The reaction was promoted in a mixed solvent of AcOEt–CH₂Cl₂ to afford indolizidine compounds with three stereogenic centers.     

Combining two-directional synthesis and tandem reactions: desymmetrisation by intramolecular cycloaddition/triazoline fragmentation

A tandem azide formation/intramolecular cycloaddition/triazoline fragmentation/Michael addition, which results in a non-symmetrical quinolizidine from an acyclic symmetrical precursor, is presented.     

A novel synthesis of functionalized tetrahydrofurans by an Oxa-Michael/Michael cyclization of gamma-hydroxyenones

An approach to highly functionalized tetrahydrofuran derivatives based upon a novel Oxa-Michael/Michael dimerization of cis-gamma-hydroxyenones is presented. The reaction begins with either 1,2-dioxines or trans-gamma-hydroxyenones and proceeds by addition of one molecule of trans-gamma-hydroxyenone to another molecule of cis- or trans-gamma-hydroxyenone catalyzed by an alkoxide or hydroxide base. Subsequent intramolecular Michael addition of the keto-enolate gives the observed tetrahydrofurans. Substitution at both the 2- and 4-positions of the gamma-hydroxyenone is tolerated; however, for 4-substituted gamma-hydroxyenones, selectivity issues arise due to the possibility of heterochiral or homochiral dimerizations. The major products were those with all contiguous groups trans.     

A Straightforward One‐Pot Synthesis of 3,4‐Dihydroquinazoline‐2(1H)‐thione Derivatives in Aqueous Organic Solvent

A novel and efficient method has been developed for the synthesis of a series of 3,4‐dihydroquinazoline‐2(1H)‐thione derivatives in aqueous organic solvent starting from 3‐(2‐aminophenyl)acrylates with isothiocyanates via a tandem intermolecular nucleophilic addition/intramolecular Michael addition reaction under mild conditions. A broad substrate scope has been demonstrated, which shows wide functional group tolerance and chemical specialization. The efficiency of the methodology could make this process available on gram‐scale.     

Formal synthesis of (±)-aplykurodinone-1 through an intramolecular Michael addition

A concise and straightforward formal synthesis of (±)-aplykurodinone-1, a degraded steroid natural product isolated from sea hare Syphonota geographica is described, based on an intramolecular Michael addition. The route also includes an intermolecular Michael addition, a Riley selenium dioxide oxidation, and a Krapcho dealkoxycarbonylation. The relative stereochemistries of key intermediates have been determined through single-crystal X-ray diffraction analysis.