Stereoselective synthesis of contiguous THF–THF and THF–THP units via Pd-catalyzed tandem reaction with 1,3-chirality transfer

The Pd^II-catalyzed tandem cyclization of chiral allylic alcohols possessing an internal epoxide and a terminal alcohol provided a contiguous THF–THP and THF–THP ring units stereospecifically. The cyclizations take place via a 5-exo-tet-5-exo-trig mode, however, the cyclization of methyl substituted epoxy diols proceeded via 6-endo-tet-6-exo-trig fashion in a part to construct the oxygen-fused THP–THP ring. The different reaction rates of precursors, which are different stereochemistry at allylic alcohol have been elucidated.     

Efficient intramolecular hydroamination of aminoalkynes catalyzed by a zirconium(IV) complex

The neutral zirconium(IV) bis(thiophosphinic amidate) complex was demonstrated to be an effective precatalyst for 5-exo-, 6-exo-, and 7-exo-dig intramolecular hydroamination of aminoalkynes, producing the cyclic imines in excellent yields (92-98%).     

Diastereospecific synthesis of novel [3.6.6.4.7]-fused pentacyclic β-lactams by 6-exo-trig, 7-endo-dig tandem radical cyclization

An efficient synthesis of pentacyclic β-lactams has been achieved in high yield via a novel 6-exo-trig, 7-endo-dig tandem radical cyclization.     

Synthesis of nitrogen-containing heterocycles using exo- and endo-selective radical cyclizations onto enamides

The effect of positional change of the carbonyl group of enamides on Bu₃SnH-mediated alkyl radical cyclization leading to five-, six-, seven-, and eight-membered nitrogen-containing heterocycles was examined. A 5-exo cyclization is generally preferred over a 6-endo ring closure in systems having an alkyl radical center on the enamide-acyl side chain, whereas enamides having an alkyl radical center opposite to the acyl side chain predominantly gave 6-endo cyclization products. These results suggest that the exo or endo selectivity of radical cyclization onto the alkenic bond of enamides can be controlled by positional change of the carbonyl group. For an understanding of these selectivities, heat of formation for each transition state was calculated. 6-endo-Selective radical cyclization was applied to the radical cascade, enabling a concise synthesis of a cylindricine skeleton. A 7- or 8-endo alkyl radical cyclization, however, predominated over a corresponding 6- or 7-exo ring closure regardless of the positional change of the carbonyl group of enamides.     

Radical cyclization of homopropargylic bromomethyldimethylsilyl ethers. Evidence for a hetero-trans-cycloheptene intermediate

This communication describes our preliminary results on the radical cyclization of homopropargylic bromomethyldimethylsilyl ethers, an unknown reaction. With precursor 5a, only the very rare 7-endo-dig process was observed. The reduction of the resulting vinyl radical is not stereoselective and gives a cis/trans, 1.35:1 mixture of silaoxepan derivatives, as determined after a methyllithium treatment yielding olefins 11 and 12. This represents a new example of formation of a trans heterocyclic cycloheptene. With disubstituted precursor 5b, the system is less reactive and still no 6-exo-dig radical cyclization has been observed.     

Accessing Extended Fused Isoindolinones Via Sequential Anionic Intramolecular Cyclizations

Sequential anionic intramolecular cyclizations and modelling were used for the first time to access unusual fused heterocyclic frameworks in excellent yields. 5-Exo-dig cyclizations yielded isoindolinone motifs and a subsequent 6-exo- and 7-endo-dig cyclization was directed to provide either fused isoquinoline or azepine frameworks. Regioselectivities were controlled by exploiting stereoelectronic effects via n_C−→π*_(Ph) interactions, and modelling studies provided reaction scope.     

Synthesis of cyclopropyl silyl ethers and their facile ring opening by photoinduced electron transfer as key step in radical/radical cationic cascade reactions

Various ring-fused cyclopropyl silyl ethers with an benzylic, olefinic or acetylenic side chain have been synthesized. Upon oxidative photoinduced electron transfer (PET) the cyclopropane ring opens and forms a reactive β-keto radical, which undergoes intramolecular cyclization. In some cases we observed only formation of ring opened non-cyclized products. With olefinic side chain 5-exo-trig mode of cyclization rather than 6-endo-trig mode of cyclization takes place whereas in case of acetylenic side chain we observed 6-endo cyclization.     

6-endo Versus 5-exo radical cyclization: streamlined syntheses of carbahexopyranoses and derivatives by 6-endo-trig radical cyclization

Three factors that can direct 6-endo radical cyclization over 5-exo ring closure: substitution at C-5, vinyl radical cyclization and ring strain, have been considered in the context of the preparation of carbapyranoses from carbohydrate derivatives. As a result, alkyl radicals in substrates containing a strain inducing 2,3-O-isopropylidene ring, and vinyl radical in non-strained compounds undergo a completely regioselective 6-endo-trig ring closure leading to carbasugar derivatives.     

Chemo- and Regioselective Catalyst-Controlled Carbocyclization of Alkynyl Ketones: Rapid Synthesis of 1-Indanones and 1-Naphthols

A catalyst-controlled intramolecular carbocyclization of 2-alkynyl aryl ketones is presented. Under rhodium(III) catalysis, 1-indanones are formed through 5-exo-dig carbocyclizations with exclusive chemo-, regio- and stereoselectivity. When catalyzed by copper(I), 1-naphthols are obtained through 6-endo-dig carbocyclizations with exclusive chemo- and regioselectivity.     

Facile and efficient synthesis of polyfunctionalized benzofurans: three-component coupling reactions from an alkynylsilane, an o-hydroxybenzaldehyde derivative, and a secondary amine by a Cu(I)-Cu(II) cooperative catalytic system

The combination of 5 mol % Cu(OTf)₂ and CuCl in the presence of DMAP effectively catalyzed a three-component coupling reaction involving an alkynylsilane, an o-hydroxybenzaldehyde derivative, and a secondary amine. The reaction proceeded via intramolecular 5-exo-dig cyclization, resulting in direct synthesis of the corresponding benzofuran derivatives in moderate to excellent yields.     

Versatile synthesis of (Z)-1-alkylidene-1,3-dihydroisobenzofurans and 1H-isochromenes by palladium-catalyzed cycloisomerization of 2-alkynylbenzyl alcohols

An easy synthesis of (Z)-1-alkylidene-1,3-dihydroisobenzofurans and 1H-isochromenes by palladium-catalyzed cycloisomerization of readily available 2-alkynylbenzyl alcohols under neutral conditions is reported. Reactions were carried out at 70-100°C in the presence of catalytic amounts (1-2%) of PdI₂ in conjunction with 2 equiv. of KI for 1.5-24 h. The preference towards the 5-exo-dig cyclization mode (leading to 1,3-dihydroisobenzofurans) or the 6-endo-dig cyclization mode (leading to isochromenes) turned out to be dependent on the substitution pattern of the substrate as well as reaction conditions. In several cases, by properly adjusting the reaction conditions, the same substrate could be selectively converted into either the dihydroisobenzofuran or the 1H-isochromene derivative.     

Gold-catalyzed cyclization of 1-alkynyl cyclopropyl tert-butyl carbonate to construct multifunctionalized vinyl cyclopropane derivatives

A convenient new method was developed to prepare two types of vinyl cyclopropane derivatives through gold-catalyzed cyclization of 1-alkynyl cyclopropyl tert-butyl carbonates 2. Different from the previous reported 5-exo-dig route, the 6-endo-dig addition is the preferred pathway to provide six-membered cyclized carbonates. Two factors, including stereoelectronic effect and steric effect might affect the regioselectivity. Therefore, low steric aliphatic substrates afforded only six-membered isomers. The synthetic utility of compound 3 was also explored to afford a series of β-carbonyl cyclopropanol derivatives.     

Regioselective synthesis of phthalans via Cu(OTf)2-catalyzed 5-exo-dig intramolecular hydroalkoxylation of 2-(ethynyl)benzyl alcohols

An efficient, regioselective Cu(OTf)₂-catalyzed 5-exo-dig intramolecular hydroalkoxylation of 2-(ethynyl)benzyl alcohol, which provides a concise access to functionalized phthalan in high yields has been developed. A wide range of substrates possessing terminal, internal, and heteroaromatic alkynes can be efficiently transformed into the targeted phthalans. Substrates with primary, secondary, and tertiary benzyl alcohols also proceed well to produce the corresponding phthalans in good yields. Irrespective of the nature of the substrates, the cyclization follows highly selective 5-exo-dig regiochemistry when regioselectivity is an issue.     

4-exo-dig and 5-exo-dig Cyclocarbopalladations: an expeditious solution toward molecular complexity?

The 4-exo-dig and 5-exo-dig cyclocarbopalladations have been efficiently used to produce molecular complexity in a straightforward manner. Strained 1,2-cyclobutanediols are rapidly obtained under microwave irradiation in high yields. In many cases, the cyclocarbopalladation cascade reaction is associated with a 6 or 8π electrocyclic reaction. During the process of the 5-exo-dig cyclocarbopalladation on benzosuberone derivatives, an aromatic C-H activation leads to vinylic substituted aromatics. Polycyclic skeletons of natural products of the family of Ophiobolin and Aleurodiscal can be prepared in few steps from simple starting material.     

Platinum(II)-catalyzed intramolecular cyclization of alkynylbenzonitriles: synthesis of 1-alkoxyisoquinolines and isoquinolones

A facile synthesis of a series of 1-alkoxyisoquinolines and (2H)-isoquinolones by an intramolecular 6-endo-dig cyclization of ortho-alkynylbenzonitriles in the presence of a catalytic amount of hydrido(dimethylphosphinous acid-κP)[hydrogen bis(dimethylphosphinito-κP)]platinum(II) in various alcohols at 65-90 °C is described for the first time.     

A cascade radical-mediated macrocyclisation–transannulation approach to oestrogen steroids

A new approach to ring A aromatic steroids, based on cascade 13-endo-trig/dig macrocyclisations followed by sequential 5-exo-trig and 6-exo-trig transannulations, exemplified in the syntheses of the cis,anti,trans tetracycle 9 and the trans,syn tetracycle 13 from the ortho-substituted aryl polyen(yne) precursors, 8 and 12 respectively, is described.     

Radical cascade cyclizations and platinum(II)-catalyzed cycloisomerizations of ynamides

Ynamides are tested as new partners in radical and organometallic transformations. A radical cascade involving a 5-exo-dig cyclization followed by a 6-endo-trig radical trapping transforms ynamides into hetero-polycyclic compounds such as isoindoles, isoindolinones and pyrido-isoindolones. Various ene-tosylynamides react with platinum(II) chloride and lead to bicyclic nitrogenated heterocycles. This unprecedented and easily operated process can be coupled with a hydrolysis of the intermediate cyclic tosylenamides in a one-pot transformation, which provides cyclobutanones.     

5-Nitroisocoumarins from tandem Castro-Stephens coupling—6-endo-dig cyclisation of 2-iodo-3-nitrobenzoic acid and arylethynes and ring-closure of methyl 2-alkynyl-3-nitrobenzoates with electrophiles

Reaction of 2-iodo-3-nitrobenzoic acid with arylalkynyl copper(I) reagent gave 3-aryl-5-nitroisocoumarins. Castro-Stephens coupling was followed by in situ Cu-catalysed ring-closure. ¹H NMR and X-ray crystallography showed the cyclisations to be 6-endo, contrasting with reports of 5-exo cyclisation of analogous 2-iodobenzoate esters with alkynes. Sonogashira couplings of methyl 2-iodo-3-nitrobenzoate with phenylacetylene and with trimethylsilylacetylene gave the corresponding 2-alkynyl-3-nitrobenzoate esters. With HgSO₄, the phenylalkyne underwent 6-endo cyclisation to give 5-nitro-3-phenylisocoumarin. The disubstituted alkyne esters gave 4-phenylselenylisocoumarins with PhSeCl. 5-Nitro-3-phenyl-4-phenylselenylisocoumarin shows significant sterically-driven distortion of the isocoumarin ring. Reaction of methyl 3-nitro-2-phenylethynylbenzoate with ICl gave the 4-iodoisocoumarin. Thus the nitro group tends to direct these electrophile-driven cyclisations towards the 6-endo mode.     

Expeditious synthesis of indolizine derivatives via iodine mediated 5-endo-dig cyclization

Iodine-mediated 5-endo-dig cyclization of propargylic esters 2 at room temperature proceeded smoothly to give highly functionalized indolizines 3 in excellent yields. A pyridine group was employed as a nucleophilic partner in this facile process for the first time.     

Oxythallation of norbornene derivatives with thallium(III) acetate in methanol

Treatment of norbornene, norbornadiene, benzonorbornadiene, and chloro- and methoxy-benzonorbornadiene with thallium(III) acetate in methanol affords only the corresponding cis-exo-acetoxythallation adducts in a sharp contrast to oxymercuration of such strained olefins where methoxymercuration prevails. In the cases of substituted benzonorbornadienes the products are obtained as the regioisomeric mixtures, the isomer ratio being determined by ¹³C NMR. In the cases of 5-norbornene-2,3-dicarboxylic anhydride, 5-norbornene-2-methyl-2,3-dicarboxylic anhydride, and 5-norbornen-2-endo-carboxylic acid, lactonization occurs to give a trans-oxythallation adduct having a lactone ring, no introduction of either methoxy or acetoxy groups being observed. ¹H and/or ¹³C NMR data for several new oxythallation adducts are provided. The alkaline sodium borohydride reduction of adducts in methanol affords mainly the parent olefin together with 10–16% yields of the corresponding exo-alcohol.