Alkyne tethered

To avoid problems with the separation of regiomers, dimethyl acetylene dicarboxylate (DMAD) was chosen as a dienophile. The intermolecular Diels-Alder reactions were performed in refluxing dichlorobenzene (bp 132 °C), while the intramolecular reaction of alkyne tethered pyrazinone required a solvent with a higher boiling point (bromobenzene, bp 156 °C). In the case of 3-methoxy or 3-phenyl pyrazinones a mixture of pyridinones and pyridines was obtained, while for the alkyne tethered analogue only the di-hydrofuropyridinone was isolated as the single reaction product. 

For the microwave-assisted experiments, both solvents were replaced by 1,2-dichlorobenzene, as it couples very effectively with microwaves (loss-tangent (tan 5) at 20 °C 1,2-dichlorobenzene 0.280 as compared to 0.101 for chlorobenzene). Diels-Alder reactions of 3-methoxy or 3-phenyl pyrazinones with DMAD were performed at a pre-selected maximum temperature of 200 °C, whereas the intramolecular reaction of alkyne tethered pyrazinone required a higher temperature (220 °C). The yields obtained under microwave irradiation are comparable with those obtained under conventional conditions, while for the dihydrofuropyridinone the yield was improved from... 

A synthesis of 2-acyl and 2-alkoxycarbonyl-indoles was carried out by Tamariz and coworkers via an intramolecular Friedel-Crafts heteroannulation of enaminone precursors <06SL749>. A lac type palladium-catalyzed intramolecular indolization of alkyne-tethered 2-chloroanilines has been reported by Lu and co-workers <06OL3573>. 

Scheme 6.186) [347]. The condensation of O-allylic and O-propargylic salicylalde-hydes with a-amino esters was carried out either in the absence of a solvent or - if both components were solids - in a minimal volume of xylene. All reactions performed under microwave conditions rapidly proceeded to completion within a few minutes and typically provided higher yields compared to the corresponding thermal protocols. In the case of intramolecular alkene cycloadditions, mixtures of hexa-hydrochromeno[4,3-b]pyrrole diastereoisomers were obtained, whereas transformations involving alkyne tethers provided chromeno[4,3-b]pyrroles directly after in situ oxidation with elemental sulfur (Scheme 6.186). Independent work by Pospisil and Potacek involved very similar transformations under strictly solvent-free conditions [348]. 

Vollhardt and colleagues have explored the reactions between diynes and enami-nes338-341. The reactions between symmetrically substituted alkynes and alkyne tethered uracil derivatives proceeded in moderate yields, producing adducts with predominant anti configurations342-343. On the other hand, the reactions between diynes and uracil derivatives produced predominantly syn isomers. 

One of the important challenges in modern synthetic and pharmaceutical chemistry is to design and develop efficient, clean, and fast routes to obtain architectural molecules from simple starting materials [102, 103]. The ewdo-selective cydoisome-rization (Scheme 4.13a) of terminal alkynes tethered to alcohols, nitrogen, and sulfur nudeophiles is one of the interesting transformations widely utilized in effident syntheses of antiviral nucleosides [104, 105], polycyclic ethers [106], and oligosac-... 

Taking advantage of a tandem sulfoxide elimination-sulfenic acid addition approach to cyclic sulfoxides <1977J(P1)1574>, the synthesis of a number of novel 1,4-oxathiane oxides 229 and 230 based on the intramolecular addition of sulfenic acids to alkenes or alkynes tethered through an ether linkage has been reported (Equation 38) <20050BC404>. 

Similar results are observed in the intramolecular double silylation of alkynes.59cd Both terminal and internal alkynes lead to exocyclic olefin formation. Interestingly, the reaction is not successful for internal alkynes tethered to a disilanyl functionality by a four atom chain, but is accomplished when four atoms link a disilanyl to a terminal alkyne. Internal alkynes with ester or olefin in conjugation with the C-C triple bond undergo chemoselective double silylation, and alkynes with substituents in the tether are also good substrates for the reaction. 

Diynes 6, which consist of a trimethylsilyl alkyne tethered to a tertiary propargyl alcohol, undergo ruthenium catalyzed cycloisomerization in aqueous acetone to form the dienone intermediate 7. Concomitant electrocyclization affords 2-trimethylsilyl-2-//-pyrans in high yield (Scheme 3) <2004OL4235>. 

Dimcthyl 2-(but-2-ynyl)-2-(5-oxopent-3-enyl)malonates 96 undergo ruthenium-catalyzed intramolecular cycli-zations to yield cyclohexyl fused 4//-pyrans 97, most likely via formation of and reductive elimination from the ruthenacycle intermediate 98 (Scheme 32). Likewise, internal alkynes tethered to an a, 3-unsaturated ketone via a three-component chain undergo mthenium-catalyzed cyclizations furnishing 4//-pyrans that are fused to five-membered rings 99 (Equation 50) <2000JA5877>. 

Electrophile-mediated cyclization reactions of alkynes tethered to pendant heteroatom nucleophiles is an emerging strategy for the synthesis of heterocycles. This methodology has now been applied to the synthesis of pyrroles. The iodocyclization of 3-aminoalkynes 1 led to the formation of dihydropyrrole 2 <07TL7906>. Treatment of the latter with mesyl chloride in the presence of triethylamine then gave (i-iodopyrrolcs 3. 

An asymmetric synthesis of aminocyclopentitols 134-137 has been used in the synthesis of trehazolin via free-radical cycloisomerization of enantiomerically pure, alkyne-tethered oxime ethers derived from D-mannose (Scheme 17).84 Treatment of 2,3 5,6-di-(9-isopropylidene-D-mannofuranose (128)85 with ethynylmagnesium bromide gave compound 129, which underwent sequential one-pot acid hydrolysis plus diol cleavage to give 130, oximation of which afforded the radical precursor 131, in 41% overall yield from 129. The free hydroxyl group of 131 was protected as acetate 132 and tert-butyldimethylsilyl ether 133, which were isolated as inseparable... 

J. Marco-Contelles, C. Destabel, P. Gallego, J. L. Chiara, and M. Bemabe, A new synthetic approach to the carbocyclic core of cyclopentane-type glycosidase inhibitors Asymmetric synthesis of amino-cyclopentitols via free radical cycloisomerization of enantiomerically pure alkyne-tethered oxime ethers derived from carbohydrates, J. Org. Chem., 61 (1996) 1354-1362. 

An intramolecular iminoannulation reaction of alkyne-tethered indole 169 gave y-carboline 170. Employing this methodology, a wide variety of y-carbolines and related fused systems were obtained <03JOC5132>. 

Thioamides and thioureas also undergo the silyl-mediated cascade reaction. For example, compound 503 gave 504 in 67% yield, while structural variants generally afforded related cyclized products in 50-87% yield. Thiourea 505 provided 506 in 64% yield, although a related substrate whose alkyne tether was conformationally more flexible failed to produce any cyclized product. 

We have recently reported an intramolecular variant of this annulation process using an alkyne tethered to an indole (Eq. 81) [117,118]. 

The alkyne-tethered diazo imide 522 leads to furan 524, resulting from a retro-Diels-Alder loss of benzyl isocyanate from adduct 523 (Fig. 4.157). ... 

The intramolecular variant of the nickel-catalyzed alkylative coupling is especially robust and has been extensively developed for the cycUzation of alkynes tethered to a variety of a,P-unsaturated systems in the presence of organozinc and organozirconium reducing agents (Scheme 8.2) [22]. Alkylative cycUzations were effective for both terminal and internal alkynes with high levels of chemo-and stereo-selectivity. The scope and tolerance of the electron-deficient alkene component was broad as enones, alkylidene malonates, nitroalkenes, and unsaturated imides were all tolerated (Scheme 8.3) [23]. 

Lautens reported a new enantioselective Rh-catalyzed domino reaction that gives access to fused heterocycles 122 by desymmetrization of alkyne-tethered cyclohexa-dienones 120 [40]. The syn addition of the Rh-aryl species 124 onto the alkyne led to two new C-C bonds and two stereocenters with good enantioselectivity (Scheme 11.25). 

Scheme 8.44 Rhodium/diene-catalyzed arylative cyclization of alkyne-tethered electron-deficient olefins.

Remarkable chemoselectivity was also observed when alkyne-tethered electron-deficient olefins 158 were employed as substrates (Scheme 8.44) [123]. Rhodium/ diene catalysis led preferentially to carborhodation of the alkyne, followed by 1,4-addition to the a,P-unsaturated moiety to provide adducts 159 in high yield and excellent enantioselectivity. The difference between phosphines and chiral dienes as ligands in this reaction setting was striking. Whereas, rhodium-bisphosphines complexes catalyzed the 1,4-addition to a,P-enoates more effectively than the aryla-tion of alkynes, rhodium/diene catalysts favored the arylation of alkynes over the 1,4-addition. 

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