Cyclopentenes, addition 4- carbenes

Scheme 3-5 Cyclopentene annulations via a tandem Michael addition-carbene insertion reaction [51].

The vinylcyclopropane rearrangement is an important method for the construction of cyclopentenes. The direct 1,4-addition of a carbene to a 1,3-diene to give a cyclopentene works only in a few special cases and with poor yield. The desired product may instead be obtained by a sequence involving the 1,2-addition of a carbene to one carbon-carbon double bond of a 1,3-diene to give a vinylcyclopropane, and a subsequent rearrangement to yield a cyclopentene ... 

The cyclopentene derivatives 9 undergo both 1,5- and 1,7-dipolar electrocyclizations to yield mixtures of pyrazoles 10 and benzodiazepines 11. In addition, loss of nitrogen results in the carbenes 12, which cyclize to the tetrahydrocyclopent[fl]indenes 13.117... 

In 1986, we found that alkynyl-A3-iodanes serve as good Michael acceptors toward soft nucleophiles, because of the highly electron-deficient nature of the /3-acetylenic carbon atom. This conjugate addition of nucleophiles constitutes a key step of a highly versatile cyclopentene annulation of alkynyl-A3-iodanes via the tandem Michael-carbene insertion (MCI) reaction [Eq. (103)] [185]. 

These highly reactive yet stable species are strong electrophiles of tetraphilic character, since nucleophiles may attack three different carbon atoms (a,/ ,a ) and iodine. In most reactions the first step is a Michael addition at fi-C with formation of an alkenyl zwitterionic intermediate (ylide) which normally eliminates iodoben-zene, generating an alkylidene carbene then, a 1,2-shift of the nucleophile ensues. The final result is its combination with the alkynyl moiety which behaves formally as an alkynyl cation. The initial adduct may react with an electrophile, notably a proton, in which case alkenyl iodonium salts are obtained also, cyclopentenes may be formed by intramolecular C-H 1,5-insertion from the alkylidenecarbenes ... 

In addition to the key question as to whether carbene 6 is an intermediate in this isomerization, was whether or not the ring expansion was unique to silicon systems. To answer this latter question we laboriously synthesized the all-carbon analog of 5, 8, and established that it does not perform the analogous thermal isomerization to cyclopentene 10 (Eq. 10). Indeed 8 does nothing until ca 550°C where it begins an apparent molecular explosion into a myriad of products. 

With respect to the arylcarbenes, however, the carbene addition is not stereospecific the aryl-cyclopropanes are generally formed as mixtures of diastereomers. In almost all cases reported, the sj -isomer predominates, and this is the case even when the corresponding uw/z-isomer is far less sterically crowded. Thus, when 1-naphthylcarbene reacted with cyclopentene, the corresponding cyclopropane 6-(l-naphthyl)bicyclo[3.1.0]hexane (4) was obtained in 62% yield with endojexo ratio of 84 16. ... 

Conjugated chain enynes such as 4 behave more like the previously mentioned ethynyl-cyclopentenes, a small percentage of the carbene undergoes addition to the triple bond only in the case of the phenyl derivative. ... 

These two observations were explained by the intermediacy of carbene species. Nucleophilic P-addition generates a vinyliodonium ylide - iodoallene intermediate (83), which loses iodobenzene giving the alkylidenecarbene (84). If either the substituent R or the nucleophile Nu has a high migratory aptitude, a 1,2-shift leads to the rearranged alkyne products. However, when the substituent of the alkylidenecarbene has a y-hydrogen and if both the substituent and nucleophile have a poor migratory aptitude, intramolecular 1,5-C-H insertion takes place to form the cyclopentene derivatives. If a viable external trap is present, intermolecular insertion then occurs preferentially, 7,21,22,24... 

Scheme 3-6 Bis-cyclopentene formation via double Michael addition and carbene insertions in the reaction of nucleophiles with bis-iodonium diynes.

Ochiai and coworkers have used these tandem Michael-carbene-insertion process in a nice synthesis of cyclopentene derivatives as illustrated by 69 and 70 using alkynyl(phenyl)iodonium salts (equation 31). Similarly, PhS02H addition to alkynyl(phenyl)iodonium salts in methanol results in the formation of e.g., 71 that, upon treatment with Et3N, gives both rearranged sulfone 72 and the cyclopentene 73 via the unsaturated carbene, as illustrated by the example in equation 32. 

Insertion reactions of alkylidene carbenes offer a useful entry to cyclopentene ring systems (4.81). Insertion is most effective with dialkyl-substituted alkylidene carbenes (R = alkyl), since rearrangement of the alkylidene carbene to the alkyne occurs readily when R = H or aryl. A number of methods have been used to access alkylidene carbenes. One of the most convenient uses a ketone and the anion of trimethylsilyl diazomethane. Addition of the anion to the ketone and eUmination gives an intermediate diazoalkene, which loses nitrogen to give the alkylidene carbene. For example, a synthesis of the antibiotic (-)-malyngolide started from the ketone 102 (4.82). The insertion reaction takes place with retention of configuration at the C—H bond. 

A general method for the cyclization of an unactivated 1,1-disubs-tituted alkene to the corresponding cyclopentene has been described. Bromination followed by the addition of KHMDS in the same pot gave the vinyl bromide intermediate, which reacted further in situ to give the alkylidene carbene. This is then inserted in a 1,5-fashion into a C-H bond to yield the corresponding cyclopentene (eq 44). KHMDS proved to be superior in this process as compared to LiHMDS and NaHMDS. 

Scheme 25) was observed when cyclic alkenes (e.g., 214) were treated with ruthenium carbene complex 18 in the presence of terminal alkynes (e.g., 215). A mechanism involving initial ROM, followed by alkyne insertion of the intermediate carbene complex, followed by ROM from intermediate 217, was proposed. In order to account for the unexpectedly high yield (the yield is higher than the anticipated E Z selectivity in the formation of 217) of the process, a second source of the observed product involving metathesis of an additional mole of cyclopentene from intermediate 217 was suggested. 

The 1,4-addition of carbenes to 1,3-dienes to give cyclopentenes is extremely rare, since 1,2-addition to give a vinylcyclopropane is much more favorable. Unfortunately, vinylcyclopropanes can be converted into cyclopentenes on heating at higher temperature. In special conditions direct 1,4-addition reactions are observed, but only in poor yield (Scheme 5.40). 

In addition to the two- and three-component entries to five-membered rings in Scheme 3-39, the nickel-catalyzed rearrangement of vinyl cyclopropanes to cyclopentenes has also been developed. Whereas various catalysts promote the rearrangement of vinyl cyclopropanes under harsh conditions, nickel-iV-heterocyclic carbene (NHC) complexes were found to catalyze the rearrangement under mild conditions with relatively broad scope (Scheme 3-40). ... 

In 2006, Nair disclosed the synthesis of ( )-tra s-l,3,4-trisubstituted cyclopentenes resulting from the addition of enals to chalcones catalysed by an achiral carbene." " Mechanistically, the addition of the generated homo-enol to enones to give adduct II, followed by intramolecular acylation to afford cyclopentane-fused p-lactone IV. The final cyclopentene 67 was formed by the in situ decarboxylation of the p-lactones (Scheme 20.32). The enantioselective variant of the process to access ds-cyclopentenes was reported by Bode et al. in 2007. ... 

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