Metal-catalyzed cycloisomerization of enyne functionalities via a 1,3-alkylidene migration

We report a new metal-catalyzed 6-endo-dig cyclization of cis-4,6-dien-1-yn-3-ols, which produces substituted benzene and naphthalene derivatives with structural reorganization. In this process, we observe a 1,3-alkylidene migration via cleavage of the olefin double bond of the starting substrates. The ease and reliability of this cyclization are manifested by its compatibility with a wide array of diverse substrates and several pi-alkyne activators, including PtCl2, Zn(OTf)2, AuCl, and AuCl3.     

Intramolecular cyclopropanation of unsaturated terminal epoxides and chlorohydrins

Lithium 2,2,6,6-tetramethylpiperidide (LTMP)-induced intramolecular cyclopropanation of unsaturated terminal epoxides provides an efficient and completely stereoselective entry to bicyclo[3.1.0]hexan-2-ols and bicyclo[4.1.0]heptan-2-ols. Further elaboration of C-5 and C-6 stannyl-substituted bicyclo[3.1.0]hexan-2-ols via Sn-Li exchange/electrophile trapping or Stille coupling generates a range of substituted bicyclic cyclopropanes. An alternative straightforward cyclopropanation protocol using a catalytic amount of 2,2,6,6-tetramethylpiperidine (TMP) allows for a convenient (1 g-7.5 kg) synthesis of bicyclo[3.1.0]hexan-2-ol and other bicyclic adducts. The synthetic utility of this chemistry has been demonstrated in a concise asymmetric synthesis of (+)-beta-cuparenone. The related unsaturated chlorohydrins also undergo intramolecular cyclopropanation via in situ epoxide formation.     

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.     

Palladium-catalyzed polycyclizations of substituted dienynes: Stereoselective routes to highly complex polycycles

12-Substituted 2-bromo-1,11-dien-6-ynes were found to undergo a palladium-catalyzed biscyclization followed by a diastereospecific 6π-electrocyclic rearrangement or a Diels-Alder reaction to give substituted angularly bisanellated cyclohexadienes or polycyclic bicyclo[4.1.0]hept-2-ene derivatives containing a three-membered ring, depending on the type and pattern of substituents.     

Thermal and metal-catalyzed cyclization of 1-substituted 3,5-dien-1-ynes via a [1,7]-hydrogen shift: development of a tandem aldol condensation-dehydration and aromatization catalysis between 3-en-1-yn-5-al units and cyclic ketones

This work investigates the feasibility of thermal and catalytic cyclization of 6,6-disubstituted 3,5-dien-1-ynes via a 1,7-hydrogen shift. Our strategy began with an understanding of a structural correlation of 3,5-dien-1-ynes with their thermal cyclization efficiency. Thermal cyclization proceeded only with 3,5-dien-1-ynes bearing an electron-withdrawing C(1)-phenyl or C(6)-carbonyl substituent, but the efficiencies were generally low (20-40% yields). On the basis of this structure-activity relationship, we conclude that such a [1,7]-hydrogen shift is characterized by a "protonic" hydrogen shift, which should be catalyzed by pi-alkyne activators. We prepared various 6,6-disubstituted 3,5-dien-1-ynes bearing either a phenyl or a carbonyl group, and we found their thermal cyclizations to be greatly enhanced by RuCl(3), PtCl(2), and TpRuPPh(3)(CH(3)CN)(2)PF(6) catalysts to confirm our hypothesis: the C(7)-H acidity of 3,5-dien-1-ynes is crucial for thermal cyclization. To achieve the atom economy, we have developed a tandem aldol condensation-dehydration and aromatization catalysis between cycloalkanones and special 3-en-1-yn-5-als using the weakly acidic catalyst CpRu(PPh(3))(2)Cl, which provided complex 1-indanones and alpha-tetralones with yields exceeding 65% in most cases. The deuterium-labeling experiments reveal two operable pathways for the metal-catalyzed [1,7]-hydrogen shift of 3,5-dien-1-ynes. Formation of alpha-tetralones d(4)-56 arises from a concerted [1,7]-hydrogen shift, whereas benzene derivative d(4)-9 proceeds through a proton dissociation and reprotonation process.     

Versatile synthesis of quinoline-3-carboxylic esters and indol-2-acetic esters by palladium-catalyzed carbonylation of 1-(2-aminoaryl)-2-yn-1-ols

1-(2-Aminoaryl)-2-yn-1-ols, easily obtained by the Grignard reaction between 1-(2-aminoaryl)ketones and alkynylmagnesium bromides, were subjected to carbonylative conditions in the presence of the PdI2-KI catalytic system, in the presence and in the absence of an external oxidant. Under oxidative conditions (80 atm of a 4:1 mixture of CO-air, in MeOH as the solvent at 100 degrees C and in the presence of 2 mol % of PdI2 and 20 mol % of KI), 1-(2-aminoaryl)-2-yn-1-ols bearing a primary amino group were selectively converted into quinoline-3-carboxylic esters in fair to good yields [45-70%, based on starting 1-(2-aminoaryl)ketones], ensuing from 6-endo-dig cyclization followed by dehydration and oxidative methoxycarbonylation. On the other hand, indol-2-acetic esters, deriving from 5-exo-dig cyclization followed by dehydrating methoxycarbonylation, were selectively obtained in moderate to good yields [42-88%, based on starting 1-(2-aminoaryl)ketones] under nonoxidative conditions (90 atm of CO, in MeOH as the solvent at 100 degrees C and in the presence of 2 mol % of PdI2 and 20 mol % of KI), in the case of 1-(2-aminoaryl)-2-yn-1-ols bearing either a primary or secondary amino group and substituted with a bulky group on the triple bond.     

Intramolecular [4 + 2] cycloadditions of 1,3-enynes or arylalkynes with alkenes with highly reactive cationic phosphine Au(I) complexes

New Au(I) complexes with bulky, biphenyl phosphines are the most reactive catalysts for the cyclizations of enynes. 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 Nazarov-type ring expansion. 1,8-Dien-3-ynes also cyclize by a 5-exo-dig pathway to form hydrindanes.     

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.     

Electronic and Steric Structure of Thermal Isomerization Products of 1-Methyltricyclo[4.1.0.02,7]heptane Radical Cation

Distributions of the positive charge and unpaired electron in stable conformers of the thermal isomerization products of 1-methyltricyclo[4.1.0.02,7]heptane radical cation, having bicyclo[3.1.1]heptane, bicyclo[4.1.0]heptane, bicyclo[3.2.0]hept-6-ene, and 1,3-cycloheptadiene skeletons, were estimated by the PM3 semiempirical method.     

Ruthenium-catalyzed formation of aryl(diphenyl)phosphine oxides by reactions of propargylic alcohols with diphenylphosphine oxide

1,1-Diaryl-1-penten-4-yn-3-ols react with diphenylphosphine oxide in the presence of a thiolate-bridged diruthenium complex as a catalyst and give high yields of aryl(diphenyl)phosphine oxide products via an initial substitution followed by a cyclization at the produced allene intermediate. [reaction: see text]     

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.     

Mn(III)-mediated formal [3+3]-annulation of vinyl azides and cyclopropanols: a divergent synthesis of azaheterocycles

Mn(III)-mediated formal [3+3]-annulation has been developed using readily available vinyl azides and cyclopropanols with a wide range of substituents. Vinyl azides were successfully applied as a three-atom unit including one nitrogen to prepare pyridines and δ-lactams by the reactions with monocyclic cyclopropanols as well as to construct 2-azabicyclo[3.3.1] and 2-azabicyclo[4.3.1] frameworks with bicyclic cyclopropanols, bicyclo[3.1.0]hexan-1-ols, and bicyclo[4.1.0]heptan-1-ols. These reactions were initiated by a radical addition of β-carbonyl radicals, generated by the one-electron oxidation of cyclopropanols with Mn(III), to vinyl azides to give iminyl radicals, which cyclized with the intramolecular carbonyl groups. In addition, application of the present methodology to a synthesis of the quaternary indole alkaloid, melinonine-E, was accomplished.     

Palladium-catalyzed approach for the general synthesis of (E)-2-arylmethylidene-N-tosylindolines and (E)-2-arylmethylidene-N-tosyl/nosyltetrahydroquinolines: access to 2-substituted indoles and quinolines

A facile and efficient method for the synthesis of (E)-2-arylmethylidene-N-tosylindolines and (E)-2-arylmethylidene-N-tosyl/nosyltetrahydroquinoline variants has been developed through palladium-catalyzed cyclocondensation of aryl iodides with readily available 1-(2-tosylaminophenyl)prop-2-yn-1-ols and their higher homologues, respectively. The proposed reaction mechanism invokes the operation of trans-aminopalladation during cyclization (5/6-exo-dig), which ensures exclusive (E)-stereochemistry in the products. The method is fast, operationally simple, totally regio- and stereoselective, and versatile enough to access a variety of 2-substituted indoles and quinolines. The reactions proceeded efficiently with a wide variety of substrates and afforded the corresponding products in moderate to excellent yields.     

Desymmetrization of 1,4-dien-3-ols and related compounds via Ueno-Stork radical cyclizations

[formula: see text] Desymmetrization of 1,4-dien-3-ols and related compounds via Ueno-Stork radical cyclizations is reported. The stereochemistry of the cyclization is controlled by the acetal center. Excellent stereocontrol at C(4) and C(5) of the newly formed tetrahydrofuran rings is observed. Use of a chiral auxiliary allows the preparation of enantiomerically pure material. The utility of this method has been demonstrated by achieving a short synthesis of (+)-eldanolide, the pheromone of the male African sugarcane stem borer Eldana saccharina.     

Enantioselective synthesis of bicyclo[3.n.1]alkanes by chiral phosphoric acid-catalyzed desymmetrizing Michael cyclizations

2,2-Disubstituted cyclic 1,3-diketones containing a tethered electron-deficient alkene undergo chiral phosphoric acid-catalyzed desymmetrizing Michael cyclizations to give bridged bicyclic products in high enantioselectivities. Both bicyclo[3.2.1]octanes and bicyclo[3.3.1]nonanes are accessible using this methodology.     

Synthesis of spiro[5.4]decenones and their transformation into bicyclo[4.4]deca-1,4-dien-3-ones by domino "elimination- double-Wagner-Meerwein-rearrangement" reactions

The [3+3] cyclization of 1,3-bis-silyl enol ethers with 1,1-diacylcyclopentanes allows a convenient synthesis of spiro[5.4]decenones. Treatment of these compounds with trifluoroacetic acid (TFA) afforded a great variety of bicyclo[4.4.0]deca-1,4-dien-3-ones containing an angular alkyl group. This core structure occurs in a number of pharmacologically relevant natural products.     

Synthesis of an ethynyl carbamate and application for enantioselective cyclocarbolithiation

[reaction: see text] The intramolecular trans-cyclocarbolithiation of the alpha-lithiated 4-substituted 5-hexynyl carbamate (1S,4RS)-14 employing lithiodestannylation is presented. The 5-exo-dig cyclization products cis-/trans-16a were formed exclusively. The highly enantioenriched organotin precursor (S)-11 was synthesized via an asymmetric deprotonation of the corresponding alkyl carbamate 10 by the chiral complex sec-butyllithium/(-)-sparteine and subsequent substitution with tributyltin chloride.     

1,4-pentadienyl-3-sulfonamides: frameworks for "disfavored" radical cascade cyclizations

[reaction: see text]. 1,4-pentadienyl-3-sulfonamides afford products including those resulting from disfavored 5-endo-trig reactions when subjected to radical cyclization conditions. Products resulting from pathways featuring 4-exo-trig cyclizations are also detected, even when the 4-exo-trig reaction leads to a highly strained bicyclo[3.2.0] ring system.     

13C-NMR-spektren von bicyclo[n.1.0]alkenen

The ¹³C-NMR spectra of some bicyclo[3.1.0]hex-3-en-2-ols and of some bicyclo[3.1.0]hex-3-en-2-ones are described. The bond parameters of bicyclo[3.1.0]hex-3-en-2-one are derived from a structure determination of endo-6-methoxy-1,3,6-triphenylbicyclo[3.1.0]hex-3-en-2-one. The electron density is calculated by the EHT method, and correlated with the ¹³C NMR shifts. For comparison the ¹³C NMR spectrum of a bicyclo[4.1.0]hepta-1,5-dione derivative is analysed. The influence of a cyclopropane system attached to a five-membered and to a six-membered ring is elucidated. Whereas the five-membered ring shows conjugation between the carbonyl group and the cyclopropane system, the same effect is not observed in the six-membered ring analogue. This is explained by the highly rigid structure of the five-membered ring.     

A two step facile synthesis of new steroidal linear and angular pyranones having anti-mycobacterial activity

Title compounds 2′,2′-dimethylcholesta-2,4-dien[3,2-b]-pyran-4′-one(3),2′,2′-dimethyl-3β-substituted cholesta-4,6-dien[7,6- b]-pyran-4′-one(6a,b)and(6c)were prepared by the cyclization of 2-acetylcholesta-2,4-dien-3-ol(2),6-acetyl-3β-substituted- cholesta-4,6-dien-7-ol(5a,b)and(5c)respectively,with pyrrolidine,dry benzene and dry acetone using Dean Stark separator through conventional heating.Furthermore,compounds were also found to be active against Mycobacterium tuberculosis.