Alkenes tethers

Scheme 23 Microwave-enhanced Diels-Alder reactions of alkene-tethered 2(lff)-pyra-zinones in ionic liquid doped solvents...

Another important reaction principle in modem organic synthesis is carbon-hydrogen bond activation [159]. Bergman, Ellman, and coworkers have introduced a protocol that allows otherwise extremely sluggish inter- and intramolecular rhodium-catalyzed C-H bond activation to occur efficiently under microwave heating conditions. In their investigations, these authors found that heating of alkene-tethered benzimidazoles in a mixture of 1,2-dichlorobenzene and acetone in the presence of di-//-... 

A pyran ring is formed in the intramolecular Diels-Alder cycloaddition of alkene-tethered enantiopure (lS,2R)-l,2-dihydroxycyclohexa-3,5-diene-l-carboxylic acid derivatives (derived from the biodihydroxylation of benzoic acid). For the three cases illustrated in Scheme 6.246, Mihovilovic and colleagues found that moderate to high yields of the desired cycloadducts could be obtained by exposing a solution of the precursor to microwave irradiation at 135-210 °C for extended periods of time... 

Several investigators have studied intramolecular Heck reactions on alkene-tethered haloindoles. Black prepared several l-allyl-7-bromoindoles and found that they undergo cyclization in the presence of palladium as shown for 242 to 243 [267]. Although this new synthesis of pyrroloquinolines is reasonably general, some of the products are unstable. Substrate 242 was prepared by bromination of 4,6-dimethoxy-2,3-diphenylindole (92%) and //-alkylation. 

This transformation is undoubtedly the best-known cathodically initiated cycliza-tion. Substrates consist of two electron deficient alkenes tethered to one another. As illustrated in Table 1, the methodology is exceptionally useful for the construction of three-, five-, and six-membered... 

Little has investigated monoactivated and doubly activated alkenes tethered to butenolide with respect to electroreductive cyclization [202]. The geminally activated systems 227 undergo cyclization to diastereomeric products 228 and 229 in an 1 1 mixture, whereas both the a,j8-unsaturated monoester and a,/ -unsaturated mononitrile fail to cyclize. Only saturation of the C-C double bond of butenolide is observed. The author explains these results by distinct reactivity and lifetime of the intermediate radical anions. The radical anions derived from the monoactivated olefins are less delocalized than those of 227 and therefore should be shorter lived and more reactive. In this case preferential saturation occurs. The radical anions derived from the doubly activated alkene 227 are comparatively long-lived and less basic and thus capable of attacking the C-C double bond of the butenolide moiety. A decrease in saturation, accompanied by a marked increase in cyclization, is observed. 

With this revision in our original plans, both alkenes and allenes were found to undergo efficient cycloadditions to produce cyclooctenone products in a new [6+2] cycloaddition process. This novel cycloaddition has been shown to proceed efficiently with alkenes tethered with sulfonamide, ether, or geminal diester Hnkers (Tab. 13.15, see page 294). Isomerization of the olefin, a potential competing reaction in this process, is not observed. Methyl substitution of either alkene in the substrate is well tolerated, resulting in the facile construction of quaternary centers. Of mechanistic importance, in some cases cycloheptene byproducts were isolated from [6+2] cycloaddition reactions in addition to the expected cyclooctenone products (that is, entries 3 and 4). 

The stereochemical outcome of such cycloadditions may be altered by substituents attached to the nitrile oxide-olefin linker. Hassner and co-workers (75,240,253-255) and Kurth and co-workers (256) examined the influence of a stereogenic center a to the dipole in the cycloaddition of alkene-tethered nitrile oxides that feature a sulfur or oxygen atom within the connecting chain (Table 6.13). As expected, the diastereofacial selectivity is increased in the presence of fragments with increasing steric demand. Cycloadditions of thioethers show lower... 

A number of intramolecular cycloadditions of alkene-tethered nitrile oxides, where the double bond forms part of a ring, have been used for the synthesis of fused carbocyclic structures (18,74,266-271). The cycloadditions afford the cis-fused bicyclic products, and this stereochemical outcome does not depend on the substituents on the alkene or on the carbon chain. When cyclic olefins were used, the configuration of the products found could be rationalized in terms of the transition states described in Scheme 6.49 (18,74,266-271). In the transition state leading to the cis-fused heterocycle, the dipole is more easily aligned with the dipolarophile if the nitrile oxide adds to the face of the cycloolefin in which the tethering chain resides. In the trans transition state, considerable nonbonded interactions and strain would have to be overcome in order to achieve good parallel alignment of the dipole and dipolarophile (74,266). 

Reductive couplings of 1,6-enynes and aldehydes, catalysed by Ni(cod)2, show regioselectivity effects that are switchable via addition of a phosphine.198 Chelation (g) control and steering effects due to the alkene tether have been invoked to explain this. 

The opposite sequence is described with alkynyl silyloxy-tethered enynes. A cascade CM-RCM reaction proceeds in the presence of a second generation ruthenium carbene to give cyclic siloxanes. The initial CM is directed to occur on the alkyne by employing sterically hindered substituted alkenes tethered to the alkyne via a silyl ether group [24] (Scheme 11). 

More interesting reactions are possible when the carbonyl-alkene cyclizations are applied in a tandem reaction sequence [4b]. The three precursor motifs of spiro , separated , and fused ring systems 22, 24 and 26, respectively, were each constructed however, not all cyclized readily (Scheme 6). In each reaction the intermediate alkene bearing the EWG, which both receives the radical and transfers the radical in the last cyclization, was activated for addition from the <9-stannyl ketyl. With the appropriate placement of the alkene tether in the starting substrate, complex ring structures can be synthesized in a one-pot procedure. 

Photocatalysed lir plus lir cycloadditions between a pair of tethered 4-pyridones as shown below, can also generate complex rings systems spectacularly easily. Photocatalysed plus cycloaddition between the 5,6-bond of 2-pyridones and an alkene tethered to nitrogen are also known. 

TT-allylpalladium moiety produced on a ring is trans-positioned with respect to the alkene tether and thus can only insert into the double bond via a highly strained transition structure, epimerization may occur before the bicyclic compound is formed (entry 5 in Scheme 11). 

A copper-catalyzed aminobromination of alkene-tethered thiohydroxi-mic acids 54 provides a rapid approach to unnatural thiazoline scaffolds 55 (14OL2074). Moderate to high yields of bromothiazolines 55 are obtained with alkyl- and aryl-substituted thiohydroximic acid building blocks containing mono-, di-, and tri-substituted alkenes. The reaction provides high levels of 5-exo selectivity, and terminally mono-substituted alkenes result in predominant syn-diastereoselectivity. 

In a narrower sense, this review covers intramolecular Mizoroki-Heck [1] reactions forming carbocycles [2] that is, the palladium-catalyzed intramolecular coupling of vinyl/aryl (pseudo-)halides with an alkene tethered by a hydrocarbon chain. Ring closures furnishing heterocycles are covered in Chapter 6 also beyond the scope of this chapter are the domino/cascade or tandem (Chapter 8) and asymmetric processes (Chapters 12 and 16) dealing with formation of a carbocycle. 

As in the case of bis-silylation of acetylenes, intramolecular bis-silylation of alkenes is more effectively performed compared to the intermolecular reactions. The isonitrile-palladium catalyst provides 5-exo cyclization products stereospeciflcally from (Z)- and ( )-alkenes tethered to disilanyl groups by ether linkage (Scheme... 

In addition, vinyl bromides (2) bearing an extra alkene tether were used for the preparation of differently sized, fused bicyclic -lactames of nonconventional structure via Heck cyclization. 

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