A New Samarium Diiodide Induced Reaction: Intramolecular Attack of Ketyl Radical Anions on Aryl Substituents with Formation of 1,4-Cyclohexadiene Derivatives

Beware of samarium diiodide and aryl ketones! If the ketyl radical anion which is formed by electron transfer finds a properly placed aryl group, a highly diastereoselective cyclization may occur. After the transfer of a second electron and protonation bi- and polycyclic products with a common 1,4-cyclohexadiene moiety may be isolated [Eq. (a)]. X=CHCO₂R, NCH₂Ph; HMPA=(Me₂N)₃PO.     

Steric buttressing in the Pauson-Khand reactions of aryl enynes

A variety of aryl enynes have been constructed from o-iodophenol derivatives containing ortho-tert-butyl groups via O-alkylation and a Sonogashira cross-coupling reaction. These substrates undergo efficient thermal and oxidative intramolecular Pauson-Khand reactions leading to the formation of sterically congested cyclopentenones, as well as the formation of medium-sized rings, although in the latter case with unusual regioselectivity. Incorporation of a TMS moiety on the alkyne group in a higher homolog led to cyclization via the normal mode, albeit in relatively low yield.     

1,4-Addition of benzene to a dihydrocyclopent[a]indene diradical: synthesis and DFT study

Photochemical cyclization of compound 1, a homoenediyne (-CCC=CCH2CC-) bearing two ethynylanthracene chromophores, yields two isomeric dihydrocyclopent[a]indene ring systems, spiro-fused to the 9-position of a 9,10-dihydroanthracene moiety. Evidence of a photochemically initiated diradical cyclization pathway is proposed on the basis of (i) hydrogen abstraction from reaction with 1,4-cyclohexadiene (1,4-CHD) and (ii) the observation of 1,4-addition of benzene (solvent). The reaction was further analyzed by a complete density functional theory (DFT) study, using an unrestricted approach (UBLYP) with a 6-31G* basis set for the open-shell triplet states of the reactants, products, and diradical intermediates to model the photochemical nature of observed transformation. A mechanism detailing the observed cyclization/addition reaction is proposed.     

4-Arylation of 3-alkoxypyrazoles

Following the study of the alkoxypyrazoles nitrogen's reactivity toward arylation or alkylation reactions, we report here our results on the introduction of various aryl groups on carbon 4 position of 3-alkoxypyrazoles. This was achieved from the corresponding 4-halogeno derivatives via a Suzuki-Miyaura aryl-aryl coupling reaction. The unexpected difficulties (lack of reactivity or unwanted halogen reduction) encountered in the C-4 arylation of NH-free 4-halogenopyrazoles led us to design solutions to this recurrent problem. The cleavage of the 3-alkoxy group was also investigated using hydrogen bromide in acetic acid or boron tribromide in dichloromethane. This led, in one case, to the observation of a remarkable neighboring group-assisted electrophilic aryl boronylation. This second part of our work paves the way to the synthesis of many original chemical libraries featuring 3-alkoxy 1,4-diaryl pyrazoles as well as the corresponding 1,4-diaryl pyrazol-3-ones.     

A new five-membered ring forming process based on palladium(0)-catalyzed arylative cyclization of allenyl enones

A palladium(0)/monophosphine catalyst promotes a novel arylative cyclization reaction of C1-, C2-, and C3-tethered allenyl enones with arylboronic acids to produce five-membered ring containing products. The regioselectivity of the process, associated with aryl group introduction into the allene moiety, depends on the length of the tether. This finding suggests that the cyclization reaction does not proceed through a carbopalladation pathway but rather via a route involving palladacycle-forming or "anti-Wacker"-type oxidative addition to the Pd(0) catalyst.     

Regioselectivity in iron-catalyzed [2+2+1] cycloadditions: a DFT investigation of substituent effects in 1,4-diazabutadienes

The transition-metal-catalyzed [2+2+1] cycloaddition reaction of 1,4-diazabutadienes, in which the imine-carbon atoms are part of an oxazine ring system, with ethylene and carbon monoxide leads to the regioselective formation of pyrrolidinone derivatives. To explain this regioselectivity, the transition states and intermediates of the rate-determining step of the catalysis are determined by high-level DFT calculations. The experimentally observed regioselectivity is consistent with the lower activation energy of the addition of ethylene towards the carbon atom next to the oxazine oxygen atom. Furthermore, the activation barrier of a conceivable back reaction is higher for the intermediates with the experimentally observed regioselectivity. These thermodynamic and kinetic arguments at first sight appear to be confirmed by the calculated NPA charges in the transition states, which reveal that the differences in these charges are greatest for those transition states that lead to the formation of the energetically favored transition structures. Nevertheless, calculations of analogous transition structures and reaction products starting from 1,4-diazabutadienes with a 2-fluoro, 2-hydroxo or 2-amino substituent revealed that the regioselectivity is not determined by the electronegativity of the heteroatom and thus by the differences in the NPA charges or the resulting Coulombic interactions in the transition structures. The main reason for the observed regioselectivities is the pi-donor ability of the substituent to contribute to a delocalized pi system incorporating the adjacent imine moiety. The increasing pi-donor capability results in decreased reactivity of this moiety and increases the (relative) reactivity of the second imine group. This effect can even overcompensate for strong intramolecular Coulombic attractions in the transition structures.     

Development of highly regioselective amidyl radical cyclization based on lone pair-lone pair repulsion

The substituent effect on the reactivity and regioselectivity of N-(4-pentenyl)amidyl radical cyclization was investigated. Exclusive 6- endo cyclization was observed for N-(4-pentenyl)amidyl radicals with internal vinylic heteroatom substitution (Cl, Br, I, OMe, SEt). The substituent on the carbonyl group also showed a significant influence on the reactivity of amidyl radicals, which increases in the order of Ph < Me < OEt. As a result, the photostimulated reactions of N-(4-halopent-4-enyl)amides and carbamates (X = Cl, Br, I) with DIB/I 2 or Pb(OAc) 4/I 2 led to the efficient and exclusive formation of the corresponding piperidines while those of N-(5-halopent-4-enyl)amides afforded the pyrrolidine products only. The halogen-substitution effect also allowed the 6- exo and 7- endo amidyl radical cyclization to proceed in a highly regioselective manner. The above experimental results, in combination with theoretical analyses, revealed that the lone pair-lone pair repulsion between the nitrogen radical and the vinylic heteroatom played an important role in controlling the regioselectivity of cyclization.     

Aromatic ring transfer—a new synthesis of 2,4-diaryl-4H-3,1-benzothiazines

A new synthetic approach to 2,4-diaryl-4H-3,1-benzothiazines is described based on the rearrangement of 2-isothiocyano triarylmethanes in the presence of AlCl₃. An aryl ring is found to migrate to the carbon atom of an isothiocyano group followed by intramolecular cyclization as a result of electrophilic attack of the benzhydryl carbocation on the sulfur atom.     

Synergistic Pd/Cu-catalyzed regio- and stereoselective cascade Heck cyclization/borylation/cross-coupling

A cooperative Pd/Cu-catalyzed three-component cross-coupling reaction of alkynes, B₂Pin₂ and alkene-tethered aryl halides is reported. This reaction proceeds under mild conditions and shows broad substrate scope, providing a variety of heterocycles containing tetrasubstituted alkenylboronate moieties in synthetically useful yields with excellent chemoselectivity and regioselectivity. This transformation features the catalytic generation of β-borylalkenylcopper intermediates and their use in Pd-catalyzed Heck cyclization/cross-couplings. An enantioselective cascade cyclization/cross-coupling process has also been developed for the synthesis of enantiomerically enriched oxindole bearing a tetrasubstituted alkenylboronate moiety.     

Understanding the 1,3-Dipolar Cycloadditions of Allenes

We have quantum chemically studied the reactivity, site-, and regioselectivity of the 1,3-dipolar cycloaddition between methyl azide and various allenes, including the archetypal allene propadiene, heteroallenes, and cyclic allenes, by using density functional theory (DFT). The 1,3-dipolar cycloaddition reactivity of linear (hetero)allenes decreases as the number of heteroatoms in the allene increases, and formation of the 1,5-adduct is, in all cases, favored over the 1,4-adduct. Both effects find their origin in the strength of the primary orbital interactions. The cycloaddition reactivity of cyclic allenes was also investigated, and the increased predistortion of allenes, that results upon cyclization, leads to systematically lower activation barriers not due to the expected variations in the strain energy, but instead from the differences in the interaction energy. The geometric predistortion of cyclic allenes enhances the reactivity compared to linear allenes through a unique mechanism that involves a smaller HOMO–LUMO gap, which manifests as more stabilizing orbital interactions.     

Substituent Effect on the Photolability of 4‐Aryl‐1,4‐Dihydropyridines

The electronic nature of substituents attached to the 4‐aryl moiety of 1,4‐dihydropyridines strongly affects the photophysical and photochemical behavior of these family of compounds. The presence of an electron donor substituent on the 4‐aryl moiety (or the absence of electron‐withdrawing ones) modifies the luminescence lifetimes (τ < 100 ps) and diminishes the photodecomposition quantum yields. For electron‐withdrawing substituents, the photodegradation quantum yield is affected by the media, changing more than two orders of magnitude as the polarity is increased. Studies in micellar media allow us to conclude that 4‐aryl‐1,4‐dihydropyridines are located near to the interface; however, the surface charge of micelles has no effect on the photodegradation rate constant or the photoproducts profile. The main conclusion of this work is that the photolability of 4‐aryl‐1,4‐dihydropyridines can be significantly reduced by the incorporation of antioxidant moieties.     

Cationic Cobalt(III) Catalyzed Indole Synthesis: The Regioselective Intermolecular Cyclization of N‐Nitrosoanilines and Alkynes

The unique regioselectivity and reactivity of cobalt(III) in the direct cyclization of N‐nitrosoanilines with alkynes for the expedient synthesis of N‐substituted indoles is demonstrated. In the presence of a cobalt(III) catalyst, high regioselectivity was observed when using unsymmetrical meta‐substituted N‐nitrosoanilines. Moreover, internal alkynes bearing electron‐deficient groups, which are almost unreactive in the [Cp*Rh^III]‐catalyzed system, display good reactivity in this transformation.     

Carbazoles from the [4C+2C] Reaction of 2,3‐Allenols with Indoles

A mild and efficient method using readily available 1‐aryl‐2,3‐allenols and unprotected‐N indoles, Au⁺‐catalyzed cyclization, and aromatization to afford the final [4C+2C] products, carbazoles 4, with an excellent selectivity, is reported. The reaction demonstrates excellent regioselectivity and allows the N?H unit to undergo reactivity unprotected. A mechanism involving a spiropolycyclic intermediate has been proposed and synthetic application is also demonstrated.     

Formal homo-Nazarov and other cyclization reactions of activated cyclopropanes

The Nazarov cyclization of divinyl ketones gives access to cyclopentenones. Replacing one of the vinyl groups by a cyclopropane leads to a formal homo‐Nazarov process for the synthesis of cyclohexenones. In contrast to the Nazarov reaction, the cyclization of vinyl‐cyclopropyl ketones is a stepwise process, often requiring harsh conditions. Herein, we describe two different approaches for further polarization of the three‐membered ring of vinyl‐cyclopropyl ketones to allow the formal homo‐Nazarov reaction under mild catalytic conditions. In the first approach, the introduction of an ester group α to the carbonyl on the cyclopropane gave a more than tenfold increase in reaction rate, allowing us to extend the scope of the reaction to non‐electron‐rich aryl donor substituents in the β position to the carbonyl on the cyclopropane. In this case, a proof of principle for asymmetric induction could be achieved using chiral Lewis acid catalysts. In the second approach, heteroatoms, especially nitrogen, were introduced β to the carbonyl on the cyclopropane. In this case, the reaction was especially successful when the vinyl group was replaced by an indole heterocycle. With a free indole, the formal homo‐Nazarov cyclization on the C3 position of indole was observed using a copper catalyst. In contrast, a new cyclization reaction on the N1 position was observed with Brønsted acid catalysts. Both reactions were applied to the synthesis of natural alkaloids. Preliminary investigations on the rationalization of the observed regioselectivity are also reported.     

Versatile One‐Pot Synthesis of Polysubstituted Cyclopent‐2‐enimines from α,β‐Unsaturated Amides: Imino‐Nazarov Reaction

The imino‐Nazarov cyclization of the polysubstituted pentan‐1,4‐diene‐3‐imines was realized. To this aim, a one‐pot procedure involving reductive alkenyliminylation of α,β‐unsaturated secondary amides with potassium organotrifluoroborates, followed by acid‐catalyzed imino‐Nazarov cyclization of the polysubstituted pentan‐1,4‐diene‐3‐imine intermediates, was studied systematically. This mild, operationally simple, flexible, and high‐yielding protocol efficiently affords polysubstituted pentan‐1,4‐diene‐3‐imines, cyclopentenimines, and α‐amino cyclopentenones, which are useful scaffolds in organic synthesis. The substituent effect at the C2 position of the polysubstituted pentan‐1,4‐diene‐3‐imines was studied by means of density‐functional theory calculations. Results suggested that the electron‐donating group facilitates the imino‐Nazarov cyclization process.     

Regiocontrolled benzannulation of diaryl(gem-dichlorocyclopropyl)methanols for the synthesis of unsymmetrically substituted alpha-arylnaphthalenes: application to total synthesis of natural lignan lactones

[reaction: see text] An efficient synthesis of highly substituted alpha-arylnaphthalene analogues has been developed utilizing Lewis acid-promoted regiocontrolled benzannulation of aryl(aryl')-2,2-dichlorocyclopropylmethanols (aryl not equal aryl'; abbreviated as AACMs). Both AACM diastereomers were easily prepared via highly stereoselective addition (>95/5) of ArLi to gem-dichlorocyclopropropyl aryl' ketones. The choice of Lewis acids determined the cyclization regioselectivity of the present benzannulation. TiCl4 and SnCl4 used the chelation pathway, whereas silyl triflates used a nonchelation pathway to give unsymmetrically substituted regioisomeric alpha-arylnaphthalenes in 40-91% yields with moderate to excellent regioselectivity (TiCl4 or SnCl4; >99/1-3/1, TBDMSOTf; >1/99-1/4). Thus, the alpha-aryl or alpha-aryl' moiety (accessory aryl group) was alternatively introduced to alpha-arylnaphthalenes by choosing either the order of the reaction sequences or the appropriate catalyst. Application of the present method to the total synthesis for unsymmetrically substituted natural lignan lactones, justicidin B, retrojusticidin B, dehydrodesoxypodophyllotoxin, and a related analogue, 5'-methoxyretrochinensin, was demonstrated. Lignan retrolactones (retrojusticidin B and 5'-methoxyretrochinensin) were synthesized by the conventional lactonization of the diol precursor, whereas a novel Bu2SnO-mediated monoacylation method was applied to the synthesis of normal lignan lactones (justicidin B and dehydrodesoxypodophyllotoxin).     

Palladium-catalyzed heteroannulation leading to heterocyclic structures with two heteroatoms: a highly regio- and stereoselective synthesis of (Z)-4-alkyl-2-alkyl(aryl)idene-3,4-dihydro-2H-1,4-benzoxazines and (Z)-3-alkyl(aryl)idene-4-tosyl-3,4-dihydro-2H-1,4-benzoxazines.

A highly convenient method has been developed for the synthesis of (Z)-4-alkyl-2-alkyl(aryl)idene-3,4-dihydro-2H-1,4-benzoxazines 9 and (Z)-3-alkyl(aryl)idene-4-tosyl-3,4-dihydro-2H-1,4-benzoxazines 34-38 through palladium-copper-catalyzed reactions. Aryl halides 7 reacted with 2-[N-alkyl(benzyl)-N-prop-2'-ynyl]aminophenyl tosylate 6 in the presence of (PPh3)2PdCl2 (3 mol %), CuI(5 mol %) in triethylamine at room temperature to yield 2-[N-alkyl(benzyl)-N-(3-aryl-prop-2'-ynyl)]-aminophenyl tosylates 8 in extremely good yields (72-96%). The latter could then be cyclized with KOH in ethanol-water to Z-9 in a highly regio- and stereoselective manner. Similarly, palladium-copper-catalyzed reaction of 2-(prop-2'-ynyloxy)aniline (21) with aryl iodides 7 led to 22-26 which after tosylation and cyclization with cuprous iodide in CH3CN in the presence of K2CO3 and Bu4-NBr led to the (Z)-3-alkyl(aryl)idene-4-tosyl 3,4-dihydro-2H-1,4-benzoxazines 34-38 in good overall yields. The Z-stereochemistry of the products was established from 1H NMR spectra, 3JCH values (between vinylic proton and methylenic carbon of the heterocyclic ring), NOE experiments, and X-ray analysis. The method was also found to be suitable for the synthesis of bis(benzoxazinylated) derivatives 17, 39, and 2-alkyl-3,4-dihydro-2H-1,4-benzoxazines 18. Our method for the synthesis of 3,4-dihydro-2H-1,4-benzoxazines is highly efficacious, using easily available starting materials under very mild conditions. Also the synthesis of some novel 5-substituted uracil derivatives 40 and 41 containing the benzoxazinyl moiety and of potential biological interest is being reported.     

Aryl Triflates in On-Surface Chemistry

The reactivity of aryl triflates in on-surface C−C coupling is reported. It is shown that the triflate group in aryl triflates enables regioselective homo coupling with preceding or concomitant hydrodetriflation on Cu(111). Three different symmetrical π-systems with two and three triflate functionalities were used as monomers leading to oligomeric conjugated π-systems. The cascade, comprising different intermediates at different reaction temperatures as observed for one of the molecules, proceeds via initial removal of the trifluoromethyl sulfonyl group to give an aryloxy radical which in turn is deoxygenated to the corresponding aryl radical. Thermodynamically driven regioselective 1,2-hydrogen atom transfer leads to a translocated aryl radical which in turn undergoes coupling. For a sterically more hindered bistriflate, where one ortho position was blocked, dehydrogenative coupling occurred at remote position with good regioselectivity. Starting materials, intermediates as well as products were analyzed by scanning tunneling microscopy. Structures and suggested mechanism were further supported by DFT calculations.     

A Garratt-Braverman route to aryl naphthalene lignans

A series of aryl naphthalene lignans were prepared in good yields starting from substituted bis-propargyl ethers. The method involved a base-mediated Garratt-Braverman cyclization followed by benzylic oxidation to the lactone. The chemoselectivity in the GB cyclization and the regioselectivity in the benzylic oxidation could be achieved by controlling the electronic nature of the aryl-substituents as well as by changing the substitution pattern of the two aryl rings.     

Arylphosphonylation and Arylazidation of Activated Alkenes

Two radical‐mediated processes of activated alkenes, namely arylphosphonylation and arylazidation, are described. The difunctionalization of alkenes by a tandem process that involves radical addition, 1,4‐aryl migration, and desulfonylation generates α‐aryl‐β‐heterofunctionalized amides bearing a quaternary stereocenter when the substituent on the nitrogen atom is an aryl group. Alternatively, heterooxindoles or spirobicycles can be obtained with excellent regioselectivity in the presence of an alkyl substituent on the nitrogen atom.