Intramolecular alkene insertion reactions

The most common rearrangement reaction of alkyl carbenes is the shift of hydrogen, generating an alkene. This mode of stabilization predominates to the exclusion of most intermolecular reactions of aliphatic carbenes and often competes with intramolecular insertion reactions. For example, the carbene generated by decomposition of the tosylhydrazone of 2-methylcyclohexanone gives mainly 1- and 3-methylcyclohexene rather than the intramolecular insertion product. 

Under the influence of nickel catalysts, 1,5- and 1,6-dienes undergo isomerization and cyclization, preferably to five-membered ring compounds. The cyclization takes place probably via an intramolecular insertion reaction ( , ) involving a ir-5-alken-l-ylnickel complex such as 33, Table III, and 34, Table IV formed by Ni — C, and Ni — C2 additions... 

The debate on the mechanism of polymerization, whether an insertion mechanism (Cossee-Arlman) [6], or a metathesis-type mechanism initiated by a-H elimination from the alkyl complex to give a hydrido-carbene intermediate (Green-Rooney) [108], was solved in favor of the former on the basis of the absence of isotope effect on the rates of insertion, and on the stereochemistry of alkene intramolecular insertion, when a-D alkyls were used in the cyclizafion reaction shown in Eq. 6.21 [109]. 

Intramolecular insertion reactions lead to rearranged structures and are equivalent to a 1,2-migration of hydrogen. Alkylcarbenes almost invariably react by intramolecular C-H insertion to give cycloalkanes, which is transannular in the case of cycloalkylidenes, or by rearrangement to give alkenes (Scheme 5.43). 

Intramolecular insertion reactions of alkenes into cyclobutanone C-C bonds were catalyzed by cationic rhodium(l) complexes (Scheme 3.45) [54]. 3-(2-Vinylphenyl)cyclobutanone 81 were transformed into ketone 82 having a bicyclo[3.2.1] skeleton. 

Intramolecular Reaction with Alkenes. Palladium r-allyl complexes can undergo intramolecular insertion reactions with alkenes to produce five- and six-membered rings through a metallo-ene-type cycUzation. This reaction produces good... 

Experimental evidence for insertion of alkenes into the metal-nitrogen bond was reported recently in the studies of aminopalladation reactions [41,42]. Intramolecular insertion reaction was confirmed to be a yn-addition process and was monitored by NMR spectroscopy of the well-defined palladium(aryl)(amido) complexes (Scheme 11) [41, 43]. The reaction proceeded as insertion into Pd-N bond with complete chemoselectivity and the alternative route of alkene insertion into the Pd-C bond was not observed. The activation enthalpy determined for the insertion step A// = 24.8 zb 0.6 kcal/mol was comparable with the values reported for other insertion reactions, and small activation entropy = 4.6 zb 1.8 eu is consistent with intramolecular transformation [41, 43]. The final product of the reaction was formed after C-C reductive elimination, which is known to be rather fast step if at least one aryl group is involved [44, 45]. The mechanistic study of the alkene insertion into the Pd-N bond has also pointed out on possible reversible nature of such process [46]. 

A interesting and useful reaetion is the intramolecular polycyclization reaction of polyalkenes by tandem or domino insertions of alkenes to give polycyclic compounds[l 38]. In the tandem cyclization. an intermediate in many cases is a neopentylpalladium formed by the insertion of 1,1-disubstituted alkenes, which has no possibility of /3-elimination. The key step in the total synthesis of scopadulcic acid is the Pd-catalyzed construction of the tricyclic system 202 containing the bicyclo[3.2. Ijoctane substructure. The single tricyclic product 202 was obtained in 82% yield from 201 [20,164). The benzyl chloride 203 undergoes oxidative addition and alkene insertion. Formation of the spiro compound 204 by the intramolecular double insertion of alkenes is an exam-ple[165]. 

The alkenylpalladium intermediate 364, formed by the intramolecular insertion of 363, is terminated by hydrogenolysis with formic acid to give the terminal alkene 365[266]. The intramolecular insertion of 366 is terminated by the reaction of the alkynylstannane 367 to afford the conjugated dienyne system 368[267j. 

Similarly to alkenes. alkynes also insert. In the reaction of 775 carried out under a CO atmosphere in AcOH, sequential insertions of alkyne, CO. alkene. and CO take place in this order, yielding the keto ester 776[483]. However, the same reaction carried out in THF in the presence of LiCl affords the ketone 777, but not the keto ester[484]. The tricyclic terpenoid hirsutene (779) has been synthesized via the Pd-catalyzed metallo-ene carbonylation reaction of 778 with 85% diastereoselectivity as the key reaction[485], Kainic acid and allo-kainic acid (783) have been synthesized by the intramolecular insertion ol an alkene in 780, followed by carbonylation to give 781 and 782[486],... 

The intramolecular insertion of a conjugated diene into 7r-allylpalladium, initially formed in 789, generates another rr-allyl complex 790, which is trapped with acetate anion to give a new allylic acetate 791. No further reaction of the allylic acetate with alkene takes place[489]. 

The alkenyl iodide or triflate 369 reacts in the absence of Cul with two moles of terminal alkyne 370 to form the substituted fulvene 371. The reaction can be explained by the intermolecular insertion of the alkyne twice, followed by the intramolecular insertion of the alkene, and / -elimination to form the fulvene 371(268]. 

Intramolecular insertion of alkenes into ir-allylpalladium complexes has been shown to proceed regio-selectively to yield five-membered rings.2621263 TTiis transformation is equivalent to a palladium ene reaction and is completed by a (3-hydride elimination. The C==C bond of ketenes is also capable of undergoing insertion into ir-allylpalladium intermediates.264 The final course of this reaction is dependent on the leaving group in the initial allyl-X precursor. For X = OAc, dienes are observed for X = Me0C02, a methoxycarbonyl adduct is obtained (equation 303).264... 

A variation on the thermal reactions of diazo compounds with alkenes is the decomposition of salts of sulfonylhydrazones. This procedure, known as the BamfoTd-Stevens reaction, is believed to occur via the formation of diazo compounds. Subsequent 1,2-hydrogen shifts generally lead to the formation of alkenes as the final products. Cyclopropanes may also be formed as the result of intramolecular 1,3-C—H insertion reactions or when the original hydrazone substrate contains a remote alkenic group as a site for intramolecular cyclopropanation.10... 

As discussed earlier, the generally accepted mechanism for the Heck reaction involves the steps of oxidative addition, coordination of the alkene, migratory insertion, and P-hydride elimination [2,3], With the intramolecular Heck reaction emerging as an important synthetic reaction over the past decade, the individual steps of this mechanism have come under closer scrutiny, and attention is beginning to be directed at determining the identity of the enantioselective step [41],... 

Intramolecular versions of the Heck reaction are very useful for the construction of ring systems. The entropic advantage of having both coupling partners present in the same molecule increases the efficiency of the insertion reaction and leads to efficient reactions. Moreover the intramolecular version can be carried out on hindered substituted alkenes, whereas the intermolecular Heck reaction is largely restricted to monosubstituted alkenes. These reactions illustrate the syn stereochemistry of both the insertion reaction and the elimination. A number of multicyclic natural products have been synthesized using intramolecular Heck reactions to assemble the skeletons, and this has become a powerful synthetic tool for such compounds. 

The Heck reaction of 1,3 -diene systems via 7r-allylpalladium is also useful. This cyclization, which forms very congested quaternary carbon centers involving the intramolecular insertion of di-, tri- and tetrasubstituted alkenes, is particularly useful for natural products synthesis. In the synthesis of morphine, bis-cyclization of the octahydroisoquninoline precursor 112 by the intramolecular Heck reaction proceeded using palladium trifluoroacetate and 1,2,2,6,6-pentamethylpiperidine (PMP). The insertion of the diene system forms the 7i-allylpalladium intermediate 113, which attacks the phenol intramolecularly to form the benzofuran ring 114. Based on this method, the elegant total syntheses of (—)- and (+)-dihydrocodeinone, and (—)- and (+)-morphine (115) have been achieved [50],... 

The alkyne insertion reaction is terminated by anion capture. As examples of the termination by the anion capture, the alkenylpalladium intermediate 189, formed by the intramolecular insertion of 188, is terminated by hydrogenolysis with formic acid to give the terminal alkene 192. Palladium formate 190 is formed, and decarboxylated to give the hydridopalladium 191, reductive elimination of which gives the alkene 192 [81]. Similarly the intramolecular insertion of 193 is terminated by transmetallation of 194 with the tin acetylide 195 (or alkynyl anion capture) to give the dienyne 196 [82], Various heterocyclic compounds are prepared by heteroannulation using aryl iodides 68 and 69, and internal alkynes. Although the mechanism is not clear, alkenylpalladiums, formed by insertion of alkynes, are trapped by nucleophiles... 

However, whereas intermolecular insertion of alkene to 7r-allylpalladium is difficult, intramolecular insertion proceeds smoothly. This reaction is known as the metalla-ene (pallada-ene) reaction [124]. Use of AcOH as the solvent is crucial. The Pd-catalysed reaction of 277 under CO atmosphere affords the keto ester 279 by one-pot reaction... 

Nucleophilic attack occurs at C(2) of the diene. The 1,3-cyclohexadiene complex 66 is converted to the homoallyl anionic complex 67 by nucleophilic attack, and the 3-alkyl-1-cyclohexene 68 is obtained by protonation. Insertion of CO to 67 generates the acyl complex 69, and its protonation and reductive elimination afford the aldehyde 70 [20]. Reaction of the butadiene complex 56 with an anion derived from ester 71 under CO atmosphere generates the homoallyl complex 72 and then the acyl complex 73 by CO insertion. The cyclopentanone complex 74 is formed by intramolecular insertion of alkene, and the 3-substituted cyclopentanone 75 is obtained by reductive elimination. The intramolecular version, when applied to the 1,3-cyclohexadiene complex 76 bearing an ester chain at C(5), offers a good synthetic route to the bicyclo[3.3.1]nonane system 78 via intermediate 77 [21]. 

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