Cycloisomerization, diynes

The first examples of a consecutive radical 5 -exo-/dig-5-exo-dig cyclization of 1,5-diynes have been accomplished by the same researchers [43]. These authors were able to show that their cycloisomerization procedure provides access to strained semicyclic, conjugated dienes with a functionalized dioxatriquinane framework which occurs in the aglycones of steroidal cardiac glycosides, such as isogenine (3-96) [44] and C-norcardanolide (3-97) (Scheme 3.24) [45]. 

Hashmi et al. investigated a number of different transition metals for their ability to catalyze reactions of terminal allenyl ketones of type 96. Whereas with Cu(I) [57, 58] the cycloisomerization known from Rh(I) and Ag(I) was observed (in fact the first observation that copper is also active for cycloisomerizations of allenes), with different sources of Pd(II) the dimer 97 was observed (Scheme 15.25). Under optimized conditions, 97 was the major product. Numerous substituents are tolerated, among them even groups that are known to react also in palladium-catalyzed reactions. Examples of these groups are aryl halides (including iodides ), terminal alkynes, 1,6-diynes, 1,6-enynes and other allenes such as allenylcarbinols. This che-moselectivity might be explained by the mild reaction conditions. 

Uemura and coworkers discovered another unique rhodium vinylidene-mediated cycloisomerization reaction [11]. They found that in the presence of an electron-rich Rh(I)-complex, [ RhCl(iPr3P)2]2, (Z)-hexa-3-en-l,5-diynes bearing an alkyl substituent at one terminus undergo cycloisomerization to give allylbenzenes (Equation 9.3). 

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>. 

Diynes 8 that contain a heteroatom in the tether can undergo ruthenium catalyzed cycloisomerization, in the presence of only five equivalents of water, to afford 2-silyl 2//-pyrans (Equation 3) <2004OL4235>. 

Ruthenium-catalyzed cycloisomerization of diyn-ols to diene-ones or diene-als was discovered by Trost and Rudd [34], and provided the potential for the intramolecular aldol condensation. In the reaction, water acts as a reactant (Eqs. 15,16). The reaction was proposed to proceed via a ruthenacyclopenta-diene intermediate. 

Finally, reductive cycloisomerizations of 1,6- and 1,7-diynes 82 provide access to 1,2-dialkylidenecycloalkanes 83 by a palladium-catalyzed reaction... 

An intramolecular rhodium-catalyzed [2+2+2] cycloaddition of diynenitriles <07OL1295> diyne esters <07T12853> and alkynevinyl oximes <07TL6852> also afforded pyridine versions of dihydrobenzo[c]furans. Trost prepared these pyridine derivatives employing a similar ruthenium-catalyzed cycloisomerization-6 cyclization route as depicted in the following scheme <07OL1473>. 

Enyne metathesis reactions in the context of natural product synthesis have been reviewed recently by Mori <2007ASC121>. Using the same ruthenium catalyst, a novel tandem diyne cycloisomerization-CM process has been devised to furnish 3,4-divinyl-2,5-dihydrofurans (Equation 57) <1999CC237>. 

A mechanism which involved the allylic carbon-hydrogen bond activation of the alkene moiety was proposed for the cycloisomerization of 1,6-diyne to alkylidenecy-cloheptene on the basis of stereochemical consideration and deuterium labeling experiment (Scheme 12.7). 

An illustration of the preparation of six-membered rings by enyne cycloisomerizations is found in Trost s total synthesis of (-t-)-cassiol (113) (Scheme 6-19) [44]. The key step of this synthesis involved conversion of enyne 111 to 1,4-diene 112. Although a mixture of diastereomers is produced, the offending stereocenter is not found in the natural product, allowing both diastereomers of 112 to be used. A reductive diyne cyclization (114 115) was recently described as the key step in a total synthesis of ( )-siccanin (116) [45]. Hydropalladation of the terminal alkyne, insertion of the internal alkyne, hydride transfer to palladium, and reductive elimination are proposed to account for the observed reaction. 

A most useful application of this process is the invention of a highly atom economic synthesis of pyridines, wherein the only stoichiometric by-product is water. Cycloisomerization of diyne 22 followed by reaction with hydroxylamine provides the tricyclic pyridine 23 with only water as the stoichiometric by-produd (Equation 1.26) [24]. The Ru-catalyzed cycloisomerization of propargyl alcohols can also generate six membered rings, which then form tetrahydroisoquinolines as shown in Equation 1.27. 

The synthesis of heterocycles via the olefin metathesis reaction (RCM, ring closing metathesis, section 2) and via the cycloisomerization of dienes, diynes, and enynes (section 3) belongs to category 1... 

Intramolecular Reaction of 1,6-Dienes, -Enynes, and -Diynes Cycloisomerization, Tandem Addition-Cyclization, and Cycloaddition... 

Scheme 15. Synthesis of Heterocycles from 1,6-Dienes, Enynes, and Diynes via (a) Cycloisomerization, (b) Tandem Addition—Cyclization, and (c) Cycloaddition...

As 1,/2-alkenes, 1,6-derivatives are used very frequently leading to five-membered heterocycles, while the use of 1,7-derivatives, which produce six-mem-bered heterocycles, is very rare. The reactions of 1,6-dienes, -enynes, and -diynes are classified into three groups (a) cycloisomerization, (b) tandem addition— cyclization, and (c) cycloaddition, such as the Pau-son—Khand reaction, cyclotrimerization, and the Diels—Alder reaction (Scheme 15).97 In these reactions five-membered heterocycles are constructed upon the carbon—carbon bond-forming processes. 

Cycloisomerization. l,o)-Diynes undergo cyclization to provide conjugated enynes on exposure to the title complex. 

Facile Pd-catalyzed cyclizations of 1,6-enyne 133 and diynes is a useful synthetic method for substituted cyclopentanes, and called cycloisomerization. The reactions... 

The cycloisomerization of 1,6-diyne 171 in the presence of AcOH is terminated by reduction of the alkenylpalladium 172 with hydride such as H-SiEt3 to afford the conjugated diene 173. 

Representative procedure for the gold-catalyzed cycloisomerization of 1,4-diynes. 3-Ethynyl-2-methylene-3-phenyltetrahydroJuraiP ... 

A gold(I)-catalysed cycloisomerization of 1,6-diynes containing propargylic esters and arenynes is reported for the synthesis of 3-pyrrolines or pyrroles (Scheme 111). ... 

A synthesis of bicyclo[5.3.0]decatrienes through a Rh(I)-catalysed cycloisomerization of 3-acyloxy-4-ene-l,9-diynes has been reported " to proceed by [l,2]-acyloxy migration, 6n electrocyclization, migratory insertion, and reductive elimination. The overall process viewed as a intramolecular 5 -I- 2-cycloaddition with concomitant [l,2]-acyloxy migration (Scheme 146). 

A highly e fi o-selective gold- and silver-catalyzed cycloisomerization of 1,4-diynes has been developed (Wilckens et al. 2010). By employing electron-rich phosphines and A-heterocyclic carbenes as ligands, a number of 1,4-diynes could be cyclized in a desymmetrizing fashion to form dihydrodioxepines and enantiomeri-cally enriched tetrahydrooxazepines (Scheme 11.11). 

In 2012, our group investigated diynes of type 29 [39]. We were quite surprised that not only a-30 but also P-30 was isolated. The compound P-30 was neither formed by a rearrangement of a-30 nor by an initial hydroarylation of one of the two alkynes and a subsequent enyne cycloisomerization. Control experiments clearly excluded that possibility. Obviously, the reaction pathway leading to P-30 was unprecedented (Scheme 4.11). 

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