Gold(I)-catalyzed intramolecular [4+2] cycloadditions of arylalkynes or 1,3-enynes with alkenes: scope and mechanism

The cyclizations of enynes substituted at the alkyne gives products of formal [4+2] cyclization with Au(I) catalysts. 1,8-Dien-3-ynes cyclize by a 5-exo-dig pathway to form hydrindanes. 1,6-Enynes with an aryl ring at the alkyne give 2,3,9,9a-tetrahydro-1H-cyclopenta[b]naphthalenes by a 5-exo-dig cyclization followed by a Friedel-Crafts-type ring expansion. A 6-endo-dig cyclization is also observed in some cases as a minor process, although in a few cases, this is the major cyclization pathway. In addition to cationic gold complexes bearing bulky biphenyl phosphines, a gold complex with tris(2,6-di-tert-butylphenyl)phosphite is exceptionally reactive as a catalyst for this reaction. This cyclization can also be carried out very efficiently with heating under microwave irradiation. DFT calculations support a stepwise mechanism for the cycloaddition by the initial formation of an anti-cyclopropyl gold(I)-carbene, followed by its opening to form a carbocation stabilized by a pi interaction with the aryl ring, which undergoes a Friedel-Crafts-type reaction.     

Synthesis of spirocyclic γ-lactones by cascade Beckwith-Dowd ring expansion/cyclization

A range of spirocyclic γ-lactones have been prepared exploiting a Beckwith-Dowd ring expansion cascade involving 1-, 3-, 4-, and 5-carbon expansion of cyclopentanone and cyclohexanone followed by 5-exo-trig or 5-exo-dig cyclization. This radical cascade reaction can be achieved with various substrates to provide a broad range of γ-lactones spirofused to 6- to 10-membered cycloalkanones.     

Reverse cope elimination of hydroxylamines and alkenes or alkynes: theoretical investigation of tether length and substituent effects

Quantum mechanical calculations have been used to study the intramolecular additions of hydroxylamines to alkenes and alkynes ("reverse Cope eliminations"). In intermolecular reverse Cope eliminations, alkynes are more reactive than alkenes. However, competition experiments have shown that tethering the hydroxylamine to the alkene or alkyne can reverse the reactivity order from that normally observed. The exact outcome depends on the length of the tether. In agreement with experiment, a range of density functional theory methods and CBS-QB3 calculations predict that the activation energies for intramolecular reverse Cope eliminations follow the order 6-exo-dig < 5-exo-trig < 5-exo-dig ≈ 7-exo-dig. The order of the barriers for the 5-, 6-, and 7-exo-dig reactions of alkynes arises mainly from differences in tether strain in the transition states (TSs), but is also influenced by the TS interaction between the hydroxylamine and alkyne. Cyclization onto an alkene in the 5-exo-trig fashion incurs slightly less tether strain than a 6-exo-dig alkyne cyclization, but its activation energy is higher because the hydroxylamine fragment must distort more before the TS is reached. If the alkene terminus is substituted with two methyl groups, the barrier becomes so much higher that it is also disfavored compared to the 5- and 7-exo-dig cyclizations.     

Chameleonic reactivity of vicinal diazonium salt of acetylenyl-9,10-anthraquinones: synthetic application toward two heterocyclic targets

The nature of products in the diazotization of 1-amino-2-acetylenyl-9,10-anthraquinones strongly depends on the nature of substituents at both the alkyne and at the anthraquinone core. Donor substitution (NHAr, OH) at the fourth position stabilizes the diazonium salt at C1, decelerating electrophilic cyclization at the arylethynyl substituent at C2. This effect allows the replacement of the diazonium with azide group and subsequent closure into isoxazole ring with preservation of the alkyne. In contrast, electrophilic 5-exo-dig cyclizations to condensed pyrazoles is observed for the combination of donor substituents at the aryl alkyne moiety and an OAc substituent at C4. The latter process provides a new synthetic route to 3-ethynyl-[1,9-cd]isoxazol-6-ones that are difficult to access otherwise. DFT calculations suggest that donor substituents have only a minor effect on alkyne and diazonium polarization in the reactant but provide specific transition state stabilization by stabilizing the incipient vinyl cation. This analysis provides the first computational data on electrophilic 5-exo-dig cyclization in its parent form and the nucleophile-promoted version. This cyclization is a relatively fast but endothermic process that is rendered thermodynamically feasible by the enol-keto tautomerization with concomitant aromatization in the five-membered heteroaromatic ring. Computations suggest that the importance of nucleophilic assistance in the transition state for a relatively weak nucleophile such as water is minor because the energy gain due to the Lewis base coordination to the carbocationic center is more than compensated for by the unfavorable entropic term for the bimolecular proces.     

Gold(III) chloride catalysed synthesis of 5-alkylidene-dihydrothiazoles

A two step synthesis of dihydrothiazoles is presented. First, the previously unknown N-propargylic dithiocarboimidates are produced in good yields from easily available, cheap starting materials. The subsequent gold catalysed ring closure is fast and efficient, leading to dihydrothiazoles through a cascade of 5-exo-dig cyclisation and 1,3-alkyl migration. The yields range from 74% to 95%.     

alpha-(Arylthio)imidoyl Radicals: [3 + 2] Radical Annulation of Aryl Isothiocyanates with 2-Cyano-Substituted Aryl Radicals

A novel cascade radical reaction is described involving aryl isothiocyanates and 2-cyanoaryl radicals. The mechanism entails the formation of an alpha-(arylthio)imidoyl radical, a 5-exo-dig cyclization onto a cyano group, and a final 6-membered ring closure of an iminyl radical. The competitive 5-membered spiro-cyclization of the iminyl, leading to an isomeric product, was only observed in the case of a disubstituted aryl isothiocyanate. The whole process involves a rare example of [3 + 2] radical annulation and allows the one-pot synthesis of tetracondensed nitrogen heterocycles in good yields.     

Direct carbocyclization of aldehydes with alkynes: combining gold catalysis with aminocatalysis

A combination of gold(I) complexes and amine bases catalyzes the 5-exo-dig cyclization of formyl alkynes. This direct alpha-functionalization of aldehydes with unactivated alkynes does not involve the use of preformed enol equivalents.     

Reaction of enol ethers with alkynes catalyzed by transition metals: 5-exo-dig versus 6-endo-dig cyclizations via cyclopropyl platinum or gold carbene complexes

The intramolecular reaction of enol ethers with alkynes in methanol is catalyzed by electrophilic Pt(II), Pd(II), and Au(III) chlorides and by a Cu(I) complex to give five- or six-membered rings bearing dimethyl acetals. The reaction takes place by an anti addition of the enol ether and the metal to the alkyne. The possible involvement of vinylidene complexes in this reaction is excluded. In addition to the usual 5-exo-dig (or 6-exo-dig) pathways, a 6-endo-dig pathway has also been found to take place with certain enynes. One case of 5-endo-dig cyclization has also been found. A general scheme for the alkoxycyclization of enynes catalyzed by transition metals based on DFT calculation of PtCl(2) and AuCl(3) complexes that includes exo and endo cyclizations is presented.     

Iron(III)-catalyzed Conia-ene cyclization of 2-alkynic 1,3-dicarbonyl compounds

A cheap, simple, and effective FeCl(3)-catalyzed Conia-ene cyclization of 2-alkynic 1,3-dicarbonyl compounds was stereospecific to afford alkylidenecyclopentanes in (E)-isomers via the 5-exo-dig pathway. The 5-endo-dig and 6-exo-dig cyclizations were also possible, depending on the structure of the substrates.     

Atom-economic and stereoselective syntheses of the ring a and B subunits of the bryostatins

This article describes chemoselective and atom-economic methods for the stereoselective assembly of the ring A and B subunits of bryostatins. A Ru-catalyzed tandem alkene-alkyne coupling/Michael addition reaction was developed and applied to the synthesis of bryostatin ring B. We explored an acetylide-mediated epoxide-opening/6-exo-dig cyclization route to access the bryostatin ring A, although ring A was eventually furnished through an acid-catalyzed tandem transketalization/ketalization sequence. In addition, a dinuclear zinc-catalyzed methyl vinyl ketone (MVK) aldol strategy was evaluated for the construction of the polyacetate moiety. Utilization of these methods ultimately led to the rapid assembly of the northern bryostatin fragment containing both the ring A and B subunits.     

Radical cascade transformations of tris(o-aryleneethynylenes) into substituted benzo[a]indeno[2,1-c]fluorenes

Oligomeric o-aryleneethynylenes with three triple bonds undergo cascade radical transformations in reaction with a Bu 3SnH/AIBN system. These cascades involve three consecutive cycle closures with the formation of substituted benzo[ a]indeno[2,1- c]fluorene or benzo[1,2]fluoreno[4,3- b]silole derivatives. The success of this sequence depends on regioselectivity of the initial attack of the Bu 3Sn radical at the central triple bond of the o-aryleneethynylene moiety. The cascade is propagated through the sequence of 5-exo-dig and 6-exo-dig cyclizations which is followed by either a radical attack at the terminal Ar substituent or radical transposition which involves H-abstraction from the terminal TMS group and 5-endo-trig cyclization. Overall, the transformation has potential to be developed into an approach to a new type of graphite ribbons.     

A novel synthesis of pyrromethenones

Pyrromethenones are prepared by a process involving acylation of an N-aminopyrrole with a suitable acetylenic acid,followed by sequential 5-exo-dig cyclization and 3,5-sigmatropic shift.     

Thermodynamic and strain effects in the competition between 5-exo-dig and 6-endo-dig cyclizations of vinyl and aryl radicals

Electronic and structural factors controlling the competition between 5-exo-dig and 6-endo-dig cyclizations of sp2-radicals were analyzed using a combination of available experimental data and computation. Although the stereoelectronically favored 5-exo pathways usually has the lower activation energy, formation of a new aromatic ring not only makes the 6-endo process favorable thermodynamically in conjugated systems but also lowers its activation barrier to the extent where the 5-exo/6-endo selectivity is controlled by subtle factors such as the different sensitivity of the two pathways to strain effects in polycyclic systems. In particular, the stronger sensitivity of the 5-exo pathway to strain leads to a crossover in selectivity. The 6-endo cyclization is kinetically favored in smaller (and strained) cycles, whereas the 5-exo cyclization has lower barriers in the larger rings.     

Cascade radical reaction of 2-alkynyl-substituted aryl radicals with aryl isothiocyanates: a novel entry to benzothieno[2,3-b]quinolines through alpha-(Arylsulfanyl)imidoyl radicals

The novel cascade radical reaction of 2-(phenylalkynyl)aryl radicals with 4-Y-phenyl isothiocyanates (Y = H, OMe, Me, Cl, CN) provides a useful one-pot protocol for the production of 8-Y-substituted (12) and/or 9-Y-substituted benzothieno[2,3-b]quinolines (11). The whole process entails primary formation of an alpha-(2-alkynylarylsulfanyl)imidoyl radical that undergoes smooth 5-exo-dig cyclization onto the alkynyl triple bond. The derived 1-phenylvinyl radical then exhibits six-membered cyclization onto the isothiocyanate ring, to give 11, and/or five-membered ipso-cyclization to an azaspiro intermediate, whose eventual rearrangement affords 12. The overall findings clearly showed that the relative proportion of the outcoming isomeric benzothienoquinolines 11 and 12 can be markedly affected by the nature of the original isothiocyanate substituent. Moreover, the findings also furnished the first chemical evidence that enhancing the electrophilic power of the employed radical can properly enhance the reactivity of aryl radicals toward isothiocyanates.     

Free radical 5-exo-dig cyclization as the key step in the synthesis of bis-butyrolactone natural products: experimental and theoretical studies

Radical cyclization reactions were performed by 5-exo-dig mode to yield cis-fused bicyclic systems, leading to the synthesis of bis-butyrolactone class of natural products. The study was aimed at understanding the impact of alkyl side chains of furanoside ring systems in L-ara configuration on the radical cyclization. It was amply demonstrated by experimental studies that the increase in the length of the alkyl side chain has an effect on the cyclization: while efficient cyclization reactions could be realized with methyl and ethyl side chains, the yields were significantly reduced in the case of n-pentyl side chain. Theoretical studies using DFT and (RO)MP2 methods were carried out to analyze the influence of the substitution pattern on the cyclization barriers.     

Silver-catalyzed regioselective carbomagnesiation of alkynes with alkyl halides and Grignard reagents

A silver-catalyzed carbomagnesiation of alkynes with alkyl halides and Grignard reagents afforded alkenyl Grignard reagents regioselectively, where the alkyl group of the alkyl halide, but not that of the Grignard reagent, was introduced into the alkyne. Application to δ-haloalkylacetylenes yielded cyclopentanes or a tetrahydrofuran containing an exo-methylene substituent via 5-exo-dig cyclization.     

Reaction of alkynes with iodine monochloride revisited

6-Exo-dig and/or 7-endo-dig iodocyclization reactions of functionalized acetylenic derivatives with ICl are disfavored in comparison with the corresponding electrophilic addition reactions providing regioselectively (E)-1-chloro-2-iodoethene derivatives. On the contrary, 6-endo-digand 5-exo-dig iodocyclizations of methyl ynoates with ICl seem to be favored in comparison with the corresponding electrophilic addition reactions.     

Tungsten and molybdenum catalyst-mediated cyclisation of N-propargyl amides

Tungsten and molybdenum catalysts were employed to promote the cyclisation of N-propargylic amides to afford the corresponding oxazolines or oxazines via 5-exo-dig or 6-endo-dig mode.     

Copper(II)chloride-mediated cyclization reaction of N-alkoxy-ortho-alkynylbenzamides

A regioselective intramolecular cyclization/halogenation reaction of N-alkoxy-o-alkynylbenzamides with CuCl(2)/NCS was developed. The corresponding 3-(chloromethylene)isobenzofuran-1-ones were exclusively obtained via 5-exo-dig cyclization in moderate to excellent yields within 0.5-1 h. This approach has been successfully used to synthesize a biaryl compound by the Suzuki-Miyaura reaction.     

Cyclization of alkenyl radicals in 5- and 6-(pi-Exo)-exo-dig modes: new entry to exo-cyclic dienes

Radical cyclizations of alkenyl iodides in both 5- and 6-(pi-exo)-exo-dig modes were effected by tributyltin hydride and AIBN to give exo-cyclic dienes fused to five- and six-membered rings in good yields.