Intramolecular Heck Cyclization Research Articles

Asymmetric synthesis of the tricyclic core of cyathin diterpenoids via intramolecular Heck reaction

The enantioselective synthesis of the ketones 3 which displays the carbon core of NGF-inducing cyathane diterpenes is described. The key tricyclic trienone 22 was assembled in 13 steps from Michael adduct ( R)- 8a via intramolecular Heck cyclization of the chiral triflate 21 . The trienone 22 was further elaborated into ketone 3 through trimethylaluminum-promoted expansion of the C-ring with trimethylsilyldiazomethane.

Synthesis of Tricyclic Quinolones and Naphthyridones by Intramolecular Heck Cyclization of Functionalized Electron‐Rich Heterocycles.

AbstractFor Abstract see ChemInform Abstract in Full Text.

1,3-Dipolar Cycloaddition Chemistry for the Preparation of Novel Indolizinone-Based Compounds

[Chemical reaction: See text] Starting from methyl 5-oxo-6-trifluoromethanesulfonyloxy-1,2,3,5-tetrahydroindolizine-8-carboxylate, obtained by a Rh(II)-catalyzed 1,3-dipolar cycloaddition reaction of 1-(2-benzenesulfonyl-2-diazoacetyl)pyrrolidin-2-one and methyl acrylate, several indolo- and furano-fused indolizinones were efficiently prepared. In the first case, a palladium-mediated C-N coupling of the triflate with a variety of substituted anilines provided the desired methyl 5-oxo-6-(arylamino)-1,2,3,5-tetrahydroindolizine-8-carboxylates in high yield. Methyl 6-(2-bromophenylamino)-5-oxo-1,2,3,5-tetrahydroindolizine-8-carboxylate as well as its decarboxylated analogue, 6-(2-bromophenylamino)-2,3-dihydro-1H-indolizin-5-one, were synthesized in excellent yield and were found to undergo an intramolecular Heck cyclization to give 1,2,3,6-tetrahydroindolizino[6,7-b]indol-5-ones. To prepare furano-fused indolizinones, methyl 6-hydroxy-5-oxo-1,2,3,5-tetrahydroindolizine-8-carboxylate was etherified with different allyl halides, and the resultant allyl ethers were subjected to a thermal Claisen rearrangement to give the corresponding methyl 7-allyl-6-hydroxy-5-oxo-1,2,3,4-tetrahydroindolizine-8-carboxylates. Cyclization under Wacker oxidation conditions afforded methyl 2-methyl-8-oxo-5,6,7,8-tetrahydro-1-oxa-7a-aza-s-indacene-4-carboxylates in near-quantitative yield.

Regioselective Synthesis of 3,3‐Diethyl‐4‐(methylene)‐1‐quinol‐2‐ones by an Intramolecular Microwave Assisted Heck Reaction.

A protocol for the intramolecular Heck cyclization to afford 3,3-diethyl-4-(methylene)-1-quinol-2-ones is described. We observed that the use of microwave irradiation increased the efficiency of the reaction. Several examples are presented which show the versatility of the reaction.

Sequential Catalytic Asymmetric Heck−Iminium Ion Cyclization: Enantioselective Total Synthesis of the Strychnos Alkaloid Minfiensine

A catalytic asymmetric method for the chemical synthesis of alkaloids containing the 1,2,3,4-tetrahydro-9a,4a-(iminoethano)-9H-carbazole (1) moiety is reported and verified by the enantioselective total synthesis of (+)-minfiensine (4). The central step in this total synthesis is the sequential catalytic asymmetric Heck-N-acyliminium ion cyclization of dienyl carbamate triflate 10, prepared in six steps from 1,2-cyclohexanedione, to give enantiopure 3,4-dihydro-9a,4a-(iminoethano)-9H-carbazole (12) in 75% yield. Iminoethano-9H-carbazole 12 is transformed in six steps to dienyl iodide 17, which undergoes diastereoselective intramolecular Heck cyclization to form pentacyclic intermediate 18. In eight additional steps, this latter intermediate is transformed to (+)-minfiensine (4).

Synthesis of Tricyclic Quinolones and Naphthyridones by Intramolecular Heck Cyclization of Functionalized Electron‐Rich Heterocycles

AbstractStarting from commercially available pyrrole‐ and thiophene‐2‐carboxylic acids 1 or thiophene‐ and furan‐3‐carboxylic acids 6, we report the synthesis of tricyclic fused quinolone and naphthyridone derivatives, in only three steps, by an intramolecular Heck cyclization. We also report the use of microwave irradiation to obtain, in some cases, better yields of cyclized products. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005)

Intramolecular Heck Cyclization to the Galanthamine‐Type Alkaloids: Total Synthesis of (.+‐.)‐Lycoramine.

Abstract 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.

Regioselective synthesis of 3,3-diethyl-4-(methylene)-1-quinol-2-ones by an intramolecular microwave assisted heck reaction

A protocol for the intramolecular Heck cyclization to afford 3,3-diethyl-4-(methylene)-1-quinol-2-ones is described. We observed that the use of microwave irradiation increased the efficiency of the reaction. Several examples are presented which show the versatility of the reaction.

1,1,6,7-Tetrafluoroindanes: improved liquid crystals for LCD-TV application

New materials based on the 1,1,6,7-tetrafluoroindane skeleton were synthesized via ortho-metallation and intramolecular Heck cyclization followed by an oxidative fluorination procedure. The materials offer improved properties over liquid crystals currently employed in flat panel LCD-TVs.

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 Heck Reaction and the Synthesis of Indolizidinone, Quinolizidinone and Benzoazepinone Derivatives

The intramolecular Heck cyclization of N-allyl-, -aryl- or -benzyl-5-allyl-2-pyrrolidinones and N-allyl-, -aryl- or -benzyl-6- allyl-2-piperidinones ( 1a f), prepared through allyltrimethylsilane addition to the corresponding cyclic N-acyliminium ions, afforded indolizidinones (3a, 5a, 5b), quinolizidinones (3b, 4b) and ben- zoazepinones (7a, 8a, 7b, 8b) in moderate to good yields (56 90%). Exclusive exo-trig over endo-trig mode of cyclization was observed in all examples investigated, and it was accompanied by double bond migration, which precluded our attempts of a one-pot tandem Diels-Alder cycloaddition with dienophiles such as maleic anhydride, methyl vinyl ketone and diethyl azodicarboxylate. Cata- lytic hydrogenation of a 2:1 mixture of regioisomeric indolizidino- nes 5a-5b afforded the stereoisomerically enriched cis indolizidinone 6a (20:1 mixture) in quantitative yield. A similar be- havior was observed in the catalytic hydrogenation of regioisomeric benzoazepinones 7b-8b.

Sequential Ugi/Heck cyclization strategies for the facile construction of highly functionalized N-heterocyclic scaffolds

A new strategy employing an Ugi four-component reaction and a microwave-assisted intramolecular Heck cyclization in a sequential fashion to access an array of N-containing heterocycles is reported. The two-step sequence generated compounds of significant molecular complexity from trivial starting materials in an expedient fashion with excellent yields. The route was also amenable to solid-phase chemistry demonstrating potential for library generation.

Synthesis of Galanthamine Analogs as Acetylcholinesterase Inhibitors via Intramolecular Heck Cyclization

AbstractA novel approach towards the construction of the galanthamine skeleton was demonstrated by the Pd‐catalyzed cyclization of N‐[2‐(1,4‐dioxa‐spiro[4,5]dec‐7‐en‐8‐yl)‐ethyl]‐2‐iodo‐4‐methoxy‐N‐methyl‐benzamide (23), with formation of the benzazepine ring and creation of a quaternary carbon.

Aza-Diels–Alder/intramolecular Heck cyclization approach to the tetrahydro-β-carboline skeleton of the ajmaline/sarpagine alkaloids

The aza-Diels–Alder reactions of 2-iodo-3-indoleacetaldehydes in the presence of zinc triflate provides 2-(2-iodoindolylmethyl)-4-pyridones in high yield. Palladium-mediated intramolecular Heck cyclization gives access to the tetracyclic tetrahydro-β-carboline framework of the ajmaline/sarpagine alkaloids.

Unexpected Rearrangement in the Heck Cyclization of Positional Isomers of Chiral 2,3-Disubstituted Perhydro-1,3-benzoxazines

The intramolecular Heck cyclization on 2,3-disubstituted perhydro-1,3-benzoxazines, derived from (-)-8-amino menthol, easily proceeds at reflux of acetonitrile or DMF. The behavior of positional isomers was quite different. Reaction of 2-aryl-3-allyl perhydro-1,3-benzoxazines occurred as expected giving exclusively 6-exo cyclization products. On the contrary, regioisomeric 3-(iodobenzyl)-2-vinyl derivatives gave the normal cyclization compounds and rearranged 1,2-dihydroisoquinoline nucleus.

Asymmetric Heck cyclization route to indolizidine and azaazulene alkaloids: synthesis of (+)-5-epiindolizidine 167B and indolizidine 223AB

Asymmetric intramolecular Heck cyclization of endocyclic enamides occurs at room temperature to give indoloizidine and azaazulene ring systems in up to 86% enantiomeric excess. A synthesis of (+)-epiindolizidine 167B and formal synthesis of 5 E,9 Z-indolizidine 223AB is described.

Synthesis of a Phenolic Analog of Aphidicolin. Diminished Stereoselection in Intramolecular 6-Exo Heck Reactions of Substrates Having a Hydrocarbon Tether

Spirotetracycle 14, generated by intramolecular Heck cyclization of 13, was converted to the phenolic analog 20 of aphidicolin. That the nature of the tether connecting insertion partners can dramatically alter diastereoselection in intramolecular Heck reactions is also demonstrated.

Total synthesis of (+/-)-cytisine via the intramolecular heck cyclization of activated N-alkyl glutarimides.

[reaction:see text] A synthesis of racemic cytisine 1 has been developed utilizing an intramolecular Heck cyclization to prepare the bridged tricyclic intermediate 2. The cyclization employs activated glutarimide-derived ketene aminals 3 (X = P(O)OEt(2) or SO(2)CF(3)) and represents the first use of such intermediates in metal-catalyzed processes.

Intramolecular Heck cyclization of α-sulfenyl enol triflates. Asymmetric synthesis of a pentacyclic cardenolide precursor having functionality at C-11

A concise route to the core of complex cardenolides is described. The sequence features use of a sulfone to join enantioenriched A and D ring fragments and also control intramolecular aldolization to generate ring C and an intramolecular Heck cyclization of an α-sulfenyl enol triflate to form the steroid skeleton.

Palladium(II) Catalyzed Cyclization: A Facile Access to New Difunctionalized Thieno[3,2-f]indolizine

The 9-benzoyl-7,8-dihydro-7,7,8,8-tetramethylthieno[3,2-f]indolizin-6(4H)-one 4a was successfully prepared via the intramolecular Heck cyclization of the appropriate activated enamidone 3a.