Synthesis of pyrroles through a 4π-electrocyclic ring-closure reaction of 1-azapentadienyl cations

1-Azapenta-1,4-diene-3-ols 4a-m are easily accessible from 1-azapenta-1,4-dien-3-ones 3a-i and organolithium compounds. Treatment of the compounds 4a-m with strong acid (triflic acid) generates 1-azapentadienyl cations in situ upon protonation at the hydroxyl oxygen atom and subsequent water elimination. The intermediate cations undergo facile 4π-electrocyclization under ambient condition to give diversely substituted pyrroles 6a-m in moderate to good yield. The product pyrrole 6k could be characterized by X-ray diffraction. Quantum chemical calculations were performed to elucidate the mechanism of this reaction with respect to starting compounds, transition states, and products. They support the proposed mechanism of a 4π-conrotatory M?bius-type electrocyclic ring-closure reaction.     

Palladium-catalyzed cascade cyclization of ynamides to azabicycles

Cascade reactions: A modular assembly of azabicycles by using a cascade cyclization/Suzuki coupling/6π-electrocyclization of bromoenynamides is reported. The reaction offers a wide substituent scope on the bicyclic aminodiene products, which can be selectively oxidized as a general approach to aromatic azabicycles.     

Reactivity of conformationally constrained bispropargyl sulfones: complete preference for 6π-electrocyclization process

The reactivity of a series of conformationally constrained bispropargyl sulfones with an ortho alkenyl moiety was studied. Under basic condition, these molecules underwent isomerization, first to monoallene followed by 6π-electrocyclization (6π-EC). Another cycle of isomerization and 6π-EC gave the bis naphthyl sulfones. No Garratt–Braverman (GB) Cyclization product could be isolated even on easing up the strain. Computations with DFT (at BP86-D3/def2-SVP level) indicated that, it is energetically more favorable for the initially formed monoallenic intermediate to undergo electrocyclization rather than isomerize to bisallene. This is in contrast to the acyclic unconstrained counterpart, where isomerization to bisallene is preferred and competing GBC/6π-EC of bisallenes results in mixture of products.     

Trisubstituted thiazoles by a 6π-electrocyclization of iminothiocarbonyl ylides

Iminothiocarbonyl ylides are generated by a sulfur ligand exchange reaction of sulfonium salts and undergo a 6π-electrocyclic closure and aromatization to trisubstituted thiazoles. Related carbonyl ylides preferred a 4π-electrocyclization.     

A benzannulation strategy for the synthesis of phenols and heteroaromatic compounds based on the reaction of (trialkylsilyl)vinylketenes with lithium ynolates

(Trialkylsilyl)vinylketenes react with lithium ynolates to generate 3-(oxido)dienylketenes, which undergo rapid 6π-electrocyclization. The ultimate products of this benzannulation are highly substituted resorcinol monosilyl ethers, which are formed via a [1,3] carbon to oxygen silyl group shift. Further transformations of the benzannulation products are described providing efficient access to ortho-benzoquinones and benzofuran, benzoxepine, and benzoxocine ring systems.     

An investigation of the scope of the 1,7-electrocyclization of α,β:γ,δ-conjugated azomethine ylides

Substituents on the diene component have little influence on the periselectivity of the cyclizations of α,β:γ,δ-conjugated azomethine ylides, with 1,7-electrocyclizations predominating. In some cases, subtle changes to these substituents can, however, influence the product formed, through their effect on the relative energies of the transition states for the 1,5- (6π) and 1,7-electrocyclization (8π) processes. The most striking changes in periselectivity occur for phenylethenyl-substituted azomethine ylides 3d–f, which can give either a pyrroline 4d,f or dihydrobenzazepine 6e, depending upon the alkene configuration.     

Palladium-catalyzed cross-coupling reactions and electrocyclizations—efficient combinations for new cascade reactions

Palladium-catalyzed cross-coupling reactions and electrocyclic transformations as well as cycloadditions can efficiently be combined in one-pot sequences to build up complex molecules from simple precursors. 1,3-Dicyclopropyl-1,2-propadiene (1) could be coupled to various aryl halides, and the 1,3,5-hexatrienes resulting after rearrangement were trapped with different dienophiles. Further exploration of the highly reactive building block bicyclopropylidene (8) demonstrates the combinatorial potential of the two reaction modes in terms of two different three-component reactions, and even a novel four-component reaction was readily developed. Additional increase of complexity was gained by combining an intramolecular Heck reaction with consecutive trapping by 8, which can be carried out with or without 6π-electrocyclization. Finally a Stille-Heck-coupling sequence of substituted 2-bromocycloalkenyl triflates with functionally substituted alkenylstannanes and acrylic esters led to highly substituted 1,3,5-hexatrienes, which smoothly underwent 6π-electrocyclization at elevated temperatures to yield bi- and tricyclic skeletons. With this methodology at hand, a new versatile access to steroid-analogues with a diene moiety in the B ring and a functionality at C-7 was developed.     

Microwave-assisted 6π-electrocyclization in water

The recent development of microwave-assisted aqueous synthesis of polyheterocyclic-fused quinoline-2-thiones through 6π-electrocyclization was highlighted.     

Copper-catalyzed tandem alkynylation, propargyl-allenyl isomerization, 6π-electrocyclization of Morita-Baylis-Hillman adducts to naphthalenes

An expedient synthetic approach of naphthalenes was developed by the reaction of Morita-Baylis-Hillman bromides and arylacetylenes. The synthesis was carried out via a tandem copper-catalyzed alkynylation, propargyl-allenyl isomerization, and 6π-electrocyclization protocol.     

Synthesis of 2,6-diaryl-1,2-dihydropyridines through a 6π-electrocyclization of N-sulfonylazatrienes

The development of an efficient synthetic method toward substituted 1,2-dihydropyridines from cinnamylideneacetophenones is reported. The key intermediates N-sulfonylazatrienes were synthesized through a TiCl₄-mediated direct condensation of primary sulfonamides with the substituted (E,E)-cinnamylideneacetophenones. The 6π-electrocyclization of these intermediates, catalyzed by a Lewis acid, selectively afforded the desired products in good yields.     

Scope and limitations of a novel synthesis of 3-arylazonicotinates

The reaction of 3-oxo-3-phenyl-2-phenylhydrazonal with functionally substituted and heteroaromatic substituted acetonitrile to yield arylazonicotinic acid derivatives and 5-arylsubstituted pyridines was established. In some cases the produced nicotinates could not be isolated as they underwent thermally induced 6π-electrocyclization yielding polynuclear pyridine derivatives.     

Total synthesis of angelone enabled by a remarkable biomimetic sequence

The natural product angelone was readily accessed with a remarkable biomimetic journey that sequentially features carbonyl formation–elimination, 6π-electrocyclization, visible light-promoted singlet O₂ Diels–Alder reaction, Kornblum–DeLaMare-type peroxide rearrangement, 6π-electrocyclic ring-opening, and conjugative addition–elimination as the key steps. With key intermediates isolated and characterized, this study stands to reveal a rare system in which bio-inspired synthetic strategies were found to mirror experimental realities.     

Synthesis of 1,6-dihydropyrimidines via copper-catalyzed multistep cascade reactions between O-propargylic aldoximes and isocyanates

Multi-step cascade reactions of O-propargylic oximes with isocyanates were carried out in the presence of copper catalysts to afford the corresponding 1,6-dihydropyrimidines in good yields. The multi-step reactions consisted of a 2,3-rearrangement, a [3+2] cycloaddition, decarboxylative ring opening involving a 1,4-hydrogen shift, and a 6π-electrocyclization.     

Synthesis of functionalized benzothiophenes by twofold Heck and subsequent 6π-electrocyclization reactions of 2,3-dibromothiophene

The Heck reaction of 2,3-dibromothiophene afforded 2,3-di(alkenyl)thiophenes which were transformed into benzothiophenes by domino ′6π-electrocyclization/dehydrogenation′ reactions.     

Total syntheses of anominine and tubingensin A

A divergent strategy for the total syntheses of the indole terpenoid anominine (1) and its natural congener tubingensin A (2) has been developed. The common intermediate 11 bearing all of the required stereogenic centers for both natural products was first assembled by employing a Ueno-Stork radical cyclization and a Sc(OTf)(3)-mediated Mukaiyama aldol reaction to form the key C-C bonds in a stereocontrolled manner. The route to anominine features a radical deoxygenation followed by an efficient side-chain installation, while the path to tubingensin A exploits a CuOTf-promoted 6π-electrocyclization/aromatization sequence to forge the central region of the pentacyclic scaffold.     

Microwave-assisted generation and reactivity of aza- and diazafulvenium methides: heterocycles via pericyclic reactions

Azafulvenium methides and diazafulvenium methides have been generated under microwave irradiation from 2,2-dioxo-1H,3H-pyrrolo[1,2-c]thiazoles and 2,2-dioxo-1H,3H-pyrazolo[1,5-c]thiazoles, respectively. Pericyclic reactions of these 1,7-dipole intermediates, namely, sigmatropic [1,8]H shifts, 1,7-electrocyclization or [8π+2π] cycloaddition led to the synthesis of a range of pyrrole and pyrazole derivatives. The first evidence for the azafulvenium methides by intermolecular trapping via [8π+2π] cycloaddition is reported.     

6π/10π-Electrocyclization of ketene-iminium salts for the synthesis of substituted naphthylamines

An intramolecular 6π/10π-electrocyclization from ketene-iminium salts was developed for the preparation of naphthylamines. Various substituents on the nitrogen, on the aromatic ring, and on the olefin were studied. Tricyclic skeletons were obtained in few steps and good overall yields. The electrocyclization of ketene-iminium salts has been computationally explored by means of DFT calculations and their activation barriers were compared to the parent triene as well as the corresponding dienyl allenes and dienyl ketenes. Electrocyclizations for ketene-iminium salts were shown to be highly exergonic and have much smaller barriers to activation.     

Total synthesis of the pyranocoumaronochromone lupinalbin H

The pyranocoumaronochromone lupinalbin H was synthesized in three major steps, which involved preparation of 2′-hydroxygenistein by the Suzuki-Miyaura reaction, followed by oxidative cyclodehydrogenation into lupinalbin A. The final step was the regiospecific introduction of the dimethylpyran moiety to ring A of lupinalbin A via an aldol-type condensation with 3-methyl-2-butenal and 6π-electrocyclization.     

Concise total synthesis of calothrixins A and B

The concise total synthesis of calothrixins A and B has been accomplished by utilizing the one-pot formation of hexatriene as a key intermediate via the palladium-catalyzed tandem cyclization/cross-coupling reaction of triethyl(indol-2-yl)borate. In another key transformation, the indolo[3,2-j]phenanthridine core was prepared in high yield via Cu(I)-mediated 6π-electrocyclization.     

Synthetic studies toward (+)-cortistatin A

We describe herein the synthesis of a late-stage intermediate en route to cortistatin A. Key transformations included a Snieckus-like cascade sequence culminating in a 6π-electrocyclization, an alkylative dearomatization, and the stereoselective functionalization of the cortistatin A-ring. While the total synthesis we sought was not accomplished, the work sets the stage for several approaches to the preparation of novel analogs via diverted total synthesis.