Sigmatropische Umlagerungen von Aryl-propargyläthern; Synthese von 1, 5-Dimethyl-6-methylen-tricyclo[3, 2, 1, 02,7]-oct-3-en-8-on-Derivaten. Vorläufige Mitteilung

2, 6-Dimethylphenyl propargyl ether ( 10 ) and its derivatives 12–15 rearrange thermally to 1, 5-dimethyl-6-methylene-tricyclo [3.2.1.0^2,7]oct-3-en-8-one ( 9 ) and related compounds 16–19 . The ethers undergo first an aromatic [3, 3]-sigmatropic rearrangement to ortho-allenyldienones 11 , which then undergo ring closure to the tricyclic products by an electrocyclic reaction. Only in the case of the γ-methylpropargyl ether 13 , the ortho-dienone 11 is further rearranged in low yield to the para-butynylphenol 20 , but the tricyclic ketone 17 is again the main product. New data show that the known thermal cyclisation of aryl propargyl ethers to chromenes (e. g. 4 → 8 ) involves a preliminary [3, 3]-sigmatropic rearrangement.     

A [4 + 4] annulation strategy for the synthesis of eight-membered carbocycles based on intramolecular cycloadditions of conjugated enynes

A [4+4] annulation strategy for the synthesis of eight-membered carbocycles is reported that proceeds via a cascade involving two pericyclic processes. In the first step, the [4+2] cycloaddition of a conjugated enyne with an electron-deficient cyclobutene generates a strained six-membered cyclic allene that isomerizes to the corresponding 1,3-cyclohexadiene. In the second step, this bicyclo[4.2.0]octa-2,4-diene intermediate undergoes thermal or acid-promoted 6-electron electrocyclic ring opening to furnish a 2,4,6-cyclooctatrienone. The latter transformation represents the first example of the promotion of 6-electron electrocyclic ring opening reactions by acid.     

DFT study of pericyclic reaction cascades in the synthesis of antibiotic TAN-1085

DFT calculations show that aromatic and bis-methoxy substituent effects in a synthetic precursor of TAN-1085 strongly favor a [1,7] sigmatropic hydrogen shift over the 6 pi electrocyclic pathway, rendering the latter unfavorable in synthesis.     

A theoretical study of cyclohexyne addition to carbonyl-Cα bonds: allowed and forbidden electrocyclic and nonpericyclic ring-openings of strained cyclobutenes

The mechanism of cyclohexyne insertion into a C(O)-C(α) bond of cyclic ketones, explored experimentally by the Carreira group, has been investigated using density functional theory. B3LYP and M06-2X calculations were performed in both gas phase and THF (CPCM, UAKS radii). The reaction proceeds through a stepwise [2 + 2] cycloaddition of cyclohexyne to the enolate, followed by three disparate ring-opening possibilities of the cyclobutene alkoxide to give the product: (1) thermally allowed conrotatory electrocyclic ring-opening, (2) thermally forbidden disrotatory electrocyclic ring-opening, or (3) nonpericyclic C-C bond cleavage. Our computational results for the model alkoxide and potassium alkoxide systems show that the thermally allowed electrocyclic ring-opening pathway is favored by less than 1 kcal/mol. In more complex systems containing a potassium alkoxide (e-f), the barrier of the allowed conrotatory ring-opening is disfavored by 4-8 kcal/mol. This suggests that the thermodynamically more stable disrotatory product can be formed directly through a "forbidden" pathway. Analysis of geometrical parameters and atomic charges throughout the ring-opening pathways provides evidence for a nonpericyclic C-C bond cleavage, rather than a thermally forbidden disrotatory ring-opening. A true forbidden disrotatory ring-opening transition structure was computed for the cyclobutene alcohol; however, it was 19 kcal/mol higher in energy than the allowed conrotatory transition structure. An alternate mechanism in which the disrotatory product forms via isomerization of the conrotatory product was also explored for the alkoxide and potassium alkoxide systems.     

Preparation of cyclic molecules bearing “strained” olefins using olefin metathesis

Recent advancements in metathesis catalyst design have allowed chemists to re-examine olefin metathesis as a route to systems bearing strained olefins embedded in their skeletons. Such ring systems include various azabicyclo [3.3.1] and [4.2.1] rings systems, the unique tricyclic ring system of the natural product ingenol, and strained macrocyclic systems exhibiting atropisomerism. Several examples of forming strained aromatic systems is also presented. The variety of different catalysts that have been developed allows for the possibility to select a catalyst having the necessary level of reactivity to access a strained system but also to avoid catalysts which may be so reactive as to favour ring-opening of the desired ring system.     

Electrocyclic ring opening of cis-bicyclo[m.n.0]alkenes: the anti-Woodward-Hoffmann quest

The dubbed anti-Woodward-Hoffmann ring-opening reaction of cis-bicyclo[4.2.0]oct-7-ene to yield cis,cis-cycloocta-1,3-diene has been intensively studied with robust, high-level computational methods. This reaction has been found to proceed through a conrotatory allowed pathway to afford cis,trans-cycloocta-1,3-diene followed by E to Z isomerization, instead of a disrotatory forbidden pathway, as suggested. Computational calculations of kinetic isotope effects are consistent with this interpretation and the experimental values. The study of lower bicyclic homologues with [3.2.0], [2.2.0] and [2.1.0] skeletons indicates the feasibility of a mechanistic change towards the anti-Woodward-Hoffmann disrotatory path. This is clearly favored for the ring opening of the highly strained cis-bicyclo[2.1.0]pent-2-ene and is highly competitive with the conrotatory path for cis-bicyclo[2.2.0]hex-2-ene. Therefore, the rearrangement of the smallest bicyclic cyclobutene is predicted computationally to be an anti-Woodward-Hoffmann disrotatory electrocyclic ring-opening reaction.     

Domino carbocationic cyclization of functionalized cyclopropyl ketones: facile one-pot access to peri- and angularly fused polycyclic aromatic and heteroaromatic frameworks

Conjugate adducts obtained by base-induced 1,4-addition-elimination of various aryl/heteroaryl acetonitriles with 1-(2-arylcyclopropyl)-3,3-(bismethylthio)-2-propen-1-ones have been shown to undergo facile acid-induced domino carbocationic rearrangement yielding a variety of substituted tricyclic aromatic and heteroaromatic frameworks in high yields in a one-pot operation. The methodology provides efficient, high-yield routes for synthesis of novel substituted dihydrophenalenes, dihydrobenzo[d,e]anthracene, cyclopenta[a]naphthalene, and fused heteroaromatics such as substituted 4,5-dihydrobenzo[c,d]indole, dihydronaphtho[1,8-b,c]thiophene, dihydroindeno[5,4-b]- and -[4,5-b]-thiophenes, cyclopenta[a]carbazole, and dihydrocyclopenta[e]indazol-3-one derivatives. The probable mechanism of this interesting domino process appears to involve stepwise or concomitant acid-induced ring opening and intramolecular cyclocondensation of cyclopropyl ketones to give benzo-fused arene (or heteroarene) intermediates bearing a reactive benzylic carbocation that is captured intramolecularly either by a preexisting aromatic (or heteroaromatic) ring or by a newly formed benzene ring to give either peri-fused or angularly fused products, respectively. Thus, the overall domino process entails formation of two C-C bonds, a substituted benzene ring along with a peri-fused cyclohexane or angularly fused cyclopentane ring in a single operation.     

Access to ring-fused homo- and heteroaromatic derivatives via an initial ring-opening of 3-nitro-4-(phenylsulfonyl)thiophene

Within an overall ring-opening/ring-forming protocol, the (E,E)-4-methylthio-2-nitro-3-phenylsulfonyl-1-pyrrolidino-1,3-butadiene (7) [derived from the initial opening of 3-nitro-4-(phenylsulfonyl)thiophene (6) with pyrrolidine and silver nitrate in EtOH] is revealed to be an excellent precursor of nitro(phenylsulfonyl) derivatives of ring-fused aromatic (naphthalene, phenanthrene) or heteroaromatic (benzothiophene) compounds whose substitution pattern cannot be easily achieved by conventional methods. The key step is represented by a thermal electrocyclic rearrangement of (E,E)-1-aryl-4-methylsulfonyl-2-nitro-3-phenylsulfonyl-1,3-butadienes (9), which, thanks to proper geometric and electronic factors, occurs in unprecedentedly mild conditions and is followed by an irreversible, concerted syn beta-elimination of methanesulfinic acid to aromatize the newly formed cyclohexadienic ring.     

Taming of Furfurylidenes by Chiral Bismuth-Rhodium Paddlewheel Catalysts. Preparation and Functionalization of Optically Active 1,1-Disubstituted (Trifluoromethyl)cyclopropanes

Although 2-furyl-carbenes (furfurylidenes) are prone to instantaneous electrocyclic ring opening, chiral [BiRh]-paddlewheel complexes empowered by London dispersion allow (trifluoromethyl)furfurylidene metal complexes to be generated from a bench-stable triftosylhydrazone precursor. These reactive intermediates engage in asymmetric [2+1] cycloadditions and hence open entry into valuable trifluoromethylated cyclopropane or -cyclopropene derivatives in optically active form, which are important building blocks for medicinal chemistry but difficult to make otherwise.     

Synthetic studies on potential metabolites of carcinogenic aza aromatic hydrocarbons. Part II. Non-k-region oxidised and reduced derivatives of 7-methylbenz[c]acridine

Two phenolic derivatives of the weakly carcinogenic aza aromatic hydrocarbon 7-methylbenz[c]acridine were prepared as reference compounds for studies of the mammalian metabolism of the carcinogen. Also, 1, 2, 3, 4- and 8, 9, 10, 11-tetrahydro-7-methylbenz[c]acridine were made as intermediates for synthetic studies directed toward preparation of dihydrodiols of 7-methylbenz[c]acridine.     

1,2-Didehydro[10]annulenes: structures, aromaticity, and cyclizations

The conformational space of C(10)H(8) 1,2-didehydro[10]annulenes, along with their unimolecular conversion to isonaphthalenes (cyclic allenes), has been studied computationally using DFT (B3LYP), single-reference [CCSD(T)], and multireference (MCQDPT2) post-HF methods. The introduction of the linear alkynyl moiety releases enough angle strain to make a nearly planar "heart" aromatic form the preferred conformer by more than 6 kcal/mol [CCSD(T)] over a localized C(2) "twist" structure, as opposed to the closely related C(10)H(10) [10]annulene system. Computations also show that electrocyclic ring-opening of isonaphthalenes to the heart C(10)H(8) annulene takes place through a low barrier of 15 kcal/mol, and this should be considered the working mechanism for the reported isomerizations during dehydro Diels-Alder reactions of phenylacetylenes.     

Stereoselective formal [3 + 3] cycloaddition approach to cis-1-azadecalins and synthesis of (-)-4a,8a-diepi-pumiliotoxin C. evidence for the first highly stereoselective 6pi-electron electrocyclic ring closures of 1-azatrienes

Evidence is described here to support that a highly stereoselective 6pi-electron electrocyclic ring closure of 1-azatrienes is a key step in formal [3 + 3] cycloaddition or annulation reactions of chiral vinylogous amides with alpha,beta-unsaturated iminium salts. This would represent the first highly stereoselective 6pi-electron electrocyclic ring closure of 1-azatrienes. We have also unambiguously demonstrated that these specific ring closures are reversible, leading to the major diastereomer that is also thermodynamically more stable, and that a rotation preference likely also plays a role. A synthetic application is illustrated here to stereoselectively transform the resulting dihydropyridines to cis-1-azadecalins with unique anti relative stereochemistry at C2 and C2a, leading to synthesis of epi isomers of (-)-pumiliotoxin C.     

Cycloaddition/Ring opening reaction sequences of N-alkenyl aziridines: influence of the aziridine nitrogen on stereoselectivity

The cycloaddition of (Z)-7-(prop-1-enyl)-7-azabicyclo[4.1.0]heptane with dimethyl acetylene dicarboxylate (DMAD) was reported previously to proceed with complete stereoselectivity. Quantum chemical calculations (B3LYP) were used to evaluate the mechanism of the cyclization process, and it was discovered that a stepwise pathway is preferred. The subsequent electrocyclic ring opening reaction of the cyclobutene was also studied, and it was found that ring opening to the "methyl-in" dienamine is preferred to the "methyl-out" product by some 4-5 kcal/mol.     

Isolation of planar four-membered aromatic systems by using confined spaces of cobalt pentaaryl[60]fullerene complexes

As a new class of neutral closed-shell aromatic four-membered ring systems, CoE(3) (E = S, Se) was constructed inside the bowl-shaped space of pentaaryl[60]fullerene. X-ray crystallographic analysis of CoS(3)(η(5)-C(60)Ar(5)) revealed that the CoS(3) unit is planar, and DFT calculations suggested an aromatic 6π-electron system. Steric protection by the pentaaryl[60]fullerene ligand is critical for isolation and characterization of the aromatic hetero cobaltacyclobutane. Unique reactivity of the CoS(3) unit was demonstrated by disruption of 6π-conjugation with abstraction of the sulfur atom, affording a dimer, [CoS(2)(η(5)-C(60)Ar(5))](2). This work provides new insight into the aromaticity of four-membered ring systems and advances the understanding of aromatic organometallic compounds.     

Cine Substitution in 2-Oxabicyclo[4.2.0]octanones and Subsequent Unusual Rearrangements(1)

Reaction of 2-chlorooxabicyclo[4.2.0]octanone 5 with several nucleophiles was examined and found to differ significantly from those of carbon analog 1. MeO(-) and PhS(-) led either to products of cine substitution 9 or of ring opening to cyclobutenones 8. With most enolates cine substitution occured via C-alkylation of the intermediate oxidoallyl cation in spite of formation of a new C-C bond between two quaternary carbons; with nitroalkanes O-alkylation was preferred. With azide as a nucleophile, further transformations occurred, among them an oxy-promoted electrocyclic cyclobutane opening, with incorporation of a phenyl triazole unit and final formation of the unusual product 19a. Evidence for a mechanism explaining formation of 19a was obtained by isolation of intermediates. Thermolysis or photolysis of 8e or9b led via electrocyclic ring opening to a vinyl ketene which was trapped by MeOH, alkenes, dienes, or oxygen to produce polyfunctional unsaturated esters 29 and 30 or 8-membered ring lactone 31, fused cyclobutanones 33 and 34, pyranone 38, or gamma-lactone 39, respectively.     

Studies on the chemistry of thienoanellated O,N- and S,N-containing heterocycles. 3. Synthesis of tricyclic thieno[2,3-b][1,4]thiazines via nucleophilic substitution of activated precursors

Starting from thieno[2,3][1,4-b]thiazine 1 new synthetic pathways to the tricyclic compounds 5, 12, 13, 14, 20 and the tetracyclic ring system 19 are described. Under mild reaction conditions some intermediates can be isolated. Reaction of 8 with several amines leads to the amidines 15–18 .     

Cyclization reactions of 3,4-diazaheptatrienyl metal compounds. Pyridines from an anionic analogue of the Fischer indole synthesis: experiment and theory

Unsymmetrical N,N'-bisalkylidene hydrazines 7a,b, 10a-c and 13, which are accessible in good to excellent yields from hydrazones 6, 9, and 12 and commercially available α,β-unsaturated carbonyl compounds, are converted into 3,4-diazaheptatrienyl anions 14a,b, 16a-c, and 18 by treatment with KO-t-Bu as base. These anionic species form pyridines 15a,b, 5,6-dihydrobenzo[h]quinolones 17a-c, and bipyridine 19 in moderate yields. We interpret thermodynamics and kinetics of these reactions by quantum chemical calculations and discuss this multistep anionic rearrangement, based on an electrocyclic ring formation with a Mo?bius aromatic transition structure 22, the N-N bond fission (25), and the 6-exo-trig cyclization (27) as key steps, considering the results of NICS and NBO-charge calculations. This novel anionic reaction sequence bears an interesting analogy to the mechanism of the (cationic) Fischer indole synthesis. Precursor 10c and product 16c could be characterized by X-ray diffraction.     

Regiochemistry of the Condensation of 2-Aroyl-cyclohexanones and 2-Cyanoacetamide: (13)C-Labeling Studies and Semiempirical MO Calculations

Hydroxy-aryl-5,6,7,8-tetrahydroisoquinoline-4-carbonitriles represent interesting chemical scaffolds, but synthetic access to these compounds is limited. The reaction of 2-aroyl-cyclohexanones with 2-cyanoacetamide and base in ethanol has been reported to lead to the formation of the tetrahydroisoquinoline isomer. We show that depending on the electronic nature of the para-substituent on the aryl ring, formation of the regioisomeric tetrahydroquinoline isomer can significantly compete. The electron-donating or -withdrawing properties of the para-substituent of the aryl ring determines the ratio of product isomers. A series of 2-aroyl-cyclohexanones, with para-substituents ranging from electron-donating to electron-withdrawing, were reacted with [2-(13)C]-cyanoacetamide. The product ratio and absolute regiochemistry were directly determined by quantitative (13)C, HMBC, and NOESY NMR spectroscopy on the reaction mixtures. A clear relationship between the regioisomeric product ratio and the Hammett sigma values of the substituents is demonstrated. This is explained by the separate in situ yields, which reveal that the pathway leading to the tetrahydroquinoline regioisomer is significantly more sensitive toward the electronic nature of the para-substituent than the pathway leading to the tetrahydroisoquinoline. Semiempirical AM1 molecular orbital calculations on the starting electrophile 2-aroyl-cyclohexanone support a correlation between the energy of the LUMOs and the regioisomeric product ratio. Our results facilitate synthetic access to a range of these interesting synthetic intermediates.     

Demonstrating the synergy of synthetic, mechanistic, and computational studies in a regioselective aniline synthesis

Tri- and tetrasubstituted anilines are formed in good to excellent yields by the addition of ketones to vinamidinium salts (up to 98%). The reaction proceeds via the formation of dienone intermediates, which react to form an enamine with the liberated amine. In the case of a nitro, or dimethylaminomethylene substituent, the enamines undergo a facile electrocyclic ring closure to form a cyclohexadiene, which goes on to form anilines with a high degree of selectivity (up to 50:1) with a minor competing pathway proceeding via the enol providing phenols. Competition experiments using isotopic substitution reveal that the rate determining step en route to dienone is enol/enolate addition to the vinamidinium salt, which is characterized by an inverse secondary isotope effect (k(H/D) 0.7-0.9). Computational studies have been used to provide a framework for understanding the reaction pathway. The original proposal for a [1,5]-H shift was ruled out on the basis of the calculations, which did not locate a thermally accessible transition state. The minimum energy conformation of the enamine is such that a facile electrocyclic ring closure is ensured, which is corroborated by the experimental studies. A framework for understanding the reaction pathway is presented.     

Theoretical studies on formal hetero [3+3] cycloaddition reaction between vinylogous amide and α,β-unsaturated imine cation

Density functional theory (DFT) calculations at B3LYP/6-31G** level have been carried out to study the mechanism of title reaction. The whole picture for the possible mechanism has been explored and verified both in gas phase and C₆H₅CH₃ solvent. The calculated results show that this reaction proceeds via the following several steps: (1) addition of two reactant molecules; (2) removing of H⁺ and succedent elimination of NH₃ from intermediates; (3) isomerization and final cyclization of intermediates, in which the elimination step of NH₃ is the rate-controlling one in the whole reaction process. The final product has two competitive parallel paths, in which the 6π-electron electrocyclic ring closure is not reversible.