Tethered acetylene

A one-step method has been developed for elaboration of fused indole 87 via a palladium-catalyzed intramolecular indolization of 2-chloroaniline 86 bearing tethered acetylene (Equation (11) (2006OL3573)). 

Z. Xi, J. Rong, and J. Chattopadhyaya, Diastereospecific synthesis of 2 - or 3 -C-branched nucleosides through intramolecular free-radical capture by silicon-tethered acetylene, Tetrahedron 50 5255 (1994). 

Transition metal (Cr, Mo) carbene complexes, e.g. 28, 30, 32, participate in additions to dienes and diene-tethered acetylenes with concomittant generation of divinyl-cyclopropanes, which undergo ring expansion under the reaction conditions to cycloheptadiene-annulated ring systems such as 29, 31 and 33. 

Scheme 10-127 A tethered acetylene ensures the correct regioselectivity in the benzannulation reaction.

Novikov and coworkers described an intramolecular variant of their difluorocar-bene/Schiff base chemistry discussed above. Iminodifluoromethanides derived from the reaction of difluorocarbene with Schiff bases react with tethered acetylenes to produce fluorinated chromeno[4,3-Z ]pyrroles, for example, 78 (Fig. 3.38). ... 

Larock heteroannulation reaction was further extended and an intramolecular Larock indole synthesis of 2-chloroanilines bearing tethered acetylenes 106 was developed for the elaboration of a variety of polycyclic indole skeletons 107, for example, in 108-112. This intramolecular indolization method unveiled an unusual >sy -anidopalladation pathway of a tethered alkyne. The major side product is the dechlorinated starting material as a result of a reductive process. 

Sporothriolide 85 has been synthesized from carbohydrate derivative 84, utilizing intramolecular radical cyclization onto a tethered acetylene, and 4-epi-ethisolide 87 has been prepared similarly from 86 (Scheme 16). ... 

The regioselectivity of the reaction with unsymmetrical alkynes is poor. Mixtures of isomers are obtained with alkyl substituted acetylenes, if the alkyl groups do not differ much in size. A solution to this problem has been reported by Semmelhack et al. The reactants are connected by a -OCHaCHaO-tether, which can later be removed the coupling step thus becomes intramolecular ... 

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. 

Lautens and coworkers [9] ultimately used this approach to prepare a multitude of different polyheterocyclic ring systems 4-29, using 4-20 and 4-28 as substrates (Table 4.1). Unsymmetrical tethered bisfurans and acetylene dicarboxyclic acid derivatives have also been used in this domino process to allow the formation of three new rings with up to six stereogenic centers. 

Murai and Chatani speculated that the two acetylene carbons should be converted into two carbene equivalents to give XVIII during the reaction." To trap this intermediate, the reaction of 6,11-dien-l-yne 69c, which has an olefin moiety in a tether, is carried out in the presence of [RuCl2(CO)3]2 in toluene at 80 °C for 4 h to give tetracyclic compound 71 in 84% yield. It is interesting to note that other transition metal complexes, such as PtCl2, [Rh(OOCCF3)2]2, [IrCl(CO)3] , arid ReCl(CO)s also show catalytic activity for this very complex transformation (Scheme 27). 

Pericas and Jeong demonstrated independently that sulfur-tethered substrates, when subjected to the PKR conditions, afforded the desired bicyclic products. The sulfur tether is removed cleanly by Pummerer reaction after oxidation of sulfur to sulfoxide or 1,4-addition of bisalkyl cuprate followed by hydrogenolysis of sulfide with Raney nickel. It is worth mentioning that the regioselectivity regarding the acetylene part is opposite to that of the intermolecular version (Equation (30)). 

Branched phenylacetylene monomers can be used to construct dendrimers on supports. This was accomplished using a triazene tether as a focal point, the reaction triad outlined above, and an AB2 monomer, as seen in Scheme 7.16 As in similar solution-phase convergent dendrimer syntheses, the first step was to prime the periphery of the dendrimer with t-butyl groups by di-coupling of a triazene-tethered dibromoaryl monomer with (di-f-butyl-phenyl)acetylene. In this and all subsequent coupling steps, an excess amount of the monodendron acetylene was used to drive the reaction to completion. The reagents and catalysts were washed away and the excess monodendron was recovered. At the end of the first step, the tri-aryl dendron I-M3-(t-Bu)4 was cleaved from the support (M represents the dendritic monomer unit). Two equivalents of this product were then coupled with the triazene-tethered di-acetylene ary] monomer to produce the heptaaryl dendron I-M7-(r-Bu)8. 

In light of the facile 5-exo-dig carbolithiation reaction of simple acetylenic alkyllithiums, Bailey and Longstaff have studied the analogous 5-exo cyclization of a benzyne-tethered alkyllithium. Regioselectively 4-functionalized indanes 281 have been prepared... 

In a variation of the reactions in Scheme 44, Rudler has reported that the alkene which intercq)ts the vinyl carbene complex leading to cyclopropane products can be tethered onto the starting carbene complex.This was extensively studied for the reaction of the carbene complex (334) with a number of alkynes leading to bicycloheptanones of the type (336). ° This reaction is quite general (14 examples, 44-95%) and is regioselective with terminal alkynes, i.e. it occurs in the same sense that has been observed for the benzannuladon reaction (R = H in 336). Acetylene fails and cyclooctyne gives a reduced... 

Figure 42. The preparation of a photoenzyme by the reconstitution of a heme protein with Co(II)-protoporphyrin IX and the chemical modification of the protein backbone with a tethered chro-mophore. Hydrogen evolution and hydrogenation of acetylene derivatives photobiocatalyzed by the assembly.

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