Endo cyclization alkenes

The 7, i5-unsaturated alcohol 99 is cyclized to 2-vinyl-5-phenyltetrahydro-furan (100) by exo cyclization in aqueous alcohol[124]. On the other hand, the dihydropyran 101 is formed by endo cyclization from a 7, (5-unsaturated alcohol substituted by two methyl groups at the i5-position. The direction of elimination of /3-hydrogen to give either enol ethers or allylic ethers can be controlled by using DMSO as a solvent and utilized in the synthesis of the tetronomycin precursor 102[125], The oxidation of the optically active 3-alkene-l,2-diol 103 affords the 2,5-dihydrofuran 104 in high ee. It should be noted that /3-OH is eliminated rather than /3-H at the end of the reac-tion[126]. 

Unlike the intermolecular reaction, the intramolecular aminopalladation proceeds more easily[13,14,166], Methylindole (164) is obtained by the intramolecular exo amination of 2-allylaniline (163). If there is another olefinic bond in the same molecule, the aminopalladation product 165 undergoes intramolecular alkene insertion to give the tricyclic compound 166[178]. 2,2-Dimethyl-l,2-dihydroquinoline (168) is obtained by endo cyclization of 2-(3,3-dimethyiallyl)aniline (167). The oxidative amination proceeds smoothly... 

The above-mentioned important and impressive applications of titanocene mediated and catalyzed epoxide opening have been achieved by using the already classical 5-exo, 6-exo and 6-endo cyclizations with alkenes or alkynes as radical acceptors. Besides these achievements, the high chemoselectiv-ity of radical generation and slow reduction of the intermediate radicals by Cp2TiCl has resulted in some remarkable novel methodology. 

Palladium-catalyzed cyclization of alkenes and alkynes were reported by Balme and co-workers.143 144 Intramolecular carbopalladation occurs to give polycyclic compounds. It has been shown that the nucleophile type has a large influence on the cyclization process. Both 5-exo- and 6-endo-cyclization are observed for substrates with nitrile (116 and 118) and ester (120, 122, and 124) substituents, respectively (Scheme 36). When a mixed nucleophile (CN and C02Me) is used, a mixture of 5-exo and 6-endo products is obtained. The chemoselectivity is controlled by the size of the nucleophile used. The stereochemistry of the initial double bond plays an important role on the stereoselectivity of the cyclization. (Z)-olefins (118 and 120) and (/. )-olefins (116 and 124) afford as- (119 and 121) and trans-cyclization products (117 and 123), respectively. 

An example of a 6-endo cyclization of an alcohol onto an alkene radical cation/phosphate anion pair has also been described (Scheme 22). In order to bring about fragmentation of the primary alkyl phosphate bond in this reaction it was necessary to work in a 1 1 mixture of benzene and acetonitrile [139,140],... 

The intramolecular reaction of alkenes with various O and N functional groups offers useful synthetic methods for heterocycles[l3,14,166]. The reaction of unsaturated carboxylic acids affords lactones by either exo- or endo-cyclization depending on the positions of the double bond. The reaction of sodium salts of the 3-alkenoic acid 143 and 4-alkenoic acid 144 with Li2PdCU affords mostly five-membcrcd lactones in 30-40% yields[ 167]. Both 5-hexe-noic acid (145) and 4-hexenoic acid (146) are converted to five- or six-mem-bered lactones depending on the solvents and bases[168]. Conjugated 2,4-pentadienoic acid (147) is cyclized with Li2PdCl4 to give 2-pyrone (148) in water[169]. 

Steric effects similar to those shown in equations (39) and (40) are found when the substitution pattern leads to tetrahydropyran systems through 6-endo cyclization. Cyclizations of systems with an allylic oxygen and a syn alkene substituent give products rationalized by cyclization through H-in-plane conformations as shown earlier in equations (31) and (32).105 128 Examples with allylic methyl substitution have been reported also.1040... 

Cyclizations with nitrogen nucleophiles involving alkynes and allenes have received little attention until recently. The cyclizations of several a-aminoallenes to 3-pyrrolines with silver tetrafluoroborate was reported by Claesson and coworkers (equation 133).264 A similar cyclization to form A -carba-penems has been reported (equation 134).265 Diastereomeric allenes (R1 R2) were shown to cyclize with complete stereocontrol. Cyclization with palladium chloride in the presence of allyl bromide or electrophilic alkenes allowed for the intermediate vinylpalladium species to be trapped by the electrophile.2651 A related product was obtained by cyclization of an alkynic substrate (equation 13S).265 Other examples of 5-endo cyclization of p-aminoalkynes50 include the formation of indoles by cyclization of 2-alkynylanilines with mercury salts200 or palladium chloride,266a,266b,266c formation of 1-pyrrolines with catalytic palladium chloride (equation 136)198 and formation of pyrroles by cyclization of hydroxy-substituted p-aminoalkynes.198,2666... 

All of these decelerating effects are easily overridden by appropriate alkene substitution. Indeed, any terminal alkene substituent will decelerate 6-endo cyclization. To accelerate S-exo cyclization, one requires only an electronegative alkene substituent at C-6. 

Intramolecular hydrosilylations of functionalized alkenes followed by hydrogen peroxide oxidation provide powerful methods for organic syntheses86-88. The reactions of allylic O-dimethylsilyl ethers 59 promoted by platinum catalysts, e.g. Karstedt s catalyst and Pt(PPh3)2(CH2=CH2), or rhodium catalysts, e.g. Rh(acac)(COD) and [RhCl(CH2=CH2)2]2> proceed via 5-endo cyclization to give oxasilacyclopentanes 60 with a couple of exceptions in which siloxatanes 61 are formed (Scheme ll)87,89. 

Scheme 22 A 6-endo cyclization of an alcohol onto an alkene radical cation/phosphate anion pair...

Radical addition to P-alkoxyalkylidenemalonate 347 provides highly electrophilic malonyl radical intermediates 348 that undergo t>-endo cyclization onto tethered unactivated alkenes to afford tetrahydropyrans 349. The diaster-eoselectivity in the product can be improved by using bulky radicals (Scheme 84, Table 17) <2004EJ0372>. 

Some mechanistic aspects of the above cascade reaction deserve comment. Thus, after the intermolecular addition of the nucleophilic acyl radical to the alkene, the electrophilic radical adduct A, instead of undergoing reduction, reacts intramolecularly at the indole 3-position (formally a 5-endo cyclization) to give a new stabilized captodative radical B, which is oxidized to the fully aromatic system. (For a discussion of this oxidative step, see Section 1.5.)... 

Satisfactorily, the 1-endo closure became the predominat route when a temporary substituent was introduced at the 6-exo position of the alkene acceptor, a tactic previously used in similar 1-endo cyclizations involving aryl <4TL2335>, vinyl <05JOC519> or alkyl <06OL831> radicals. Hence, cyclization of selenoester 30b, which incorporates a 2-bromo-2-propenyl instead of an allyl moiety, led to the tricyclic substructure of mersicarpine 32 in a synthetically acceptable 62% yield, pyridoindole 31 being now the minor product (19%). The excess hydride ensured the final reductive removal of the bromine atom after the cyclization step <07JOC4562>. 

As the azocinoindole 40 constitutes the tricyclic substructure of the indole alkaloid apparicine , we attempted to improve the cyclization yield. Satisfactorily, the regioselectivity was completely switched to the 8-endo mode when the alkene acceptor was substituted at the internal position by a bromine atom. Thus, cyclization of selenoester 43 led to the desired target 40 as the only reaction product in 75% yield. Clearly, the bromine atom not only sterically prevented the competitive 1-exo attack, but also benefited the cyclization by activation of the double bond. It should be noted that similar halogen-controlled 8-endo cyclizations are known in the literature, but involving amidyl-type radicals <06OL2647>. 

Bachi and Bosch used Sn radicals as mediator for the cyclization of the p-lactam-substimted alkynes 119 through a sequence consisting of radical addition and 1,5-HAT, followed by a 6-endo cyclization of the radical intermediate 122, to give the bicyclic p-lactam 120 after p-fragmentation and release of Bu3Sn radicals (Scheme 2.22). The moderately low yield of this cyclization is due to the competing fast reduction of the vinyl radical 121 to the corresponding alkene by the tin hydride (not shown). 

Grande s group has studied the titanocene-promoted intramolecular addition of epoxides to activated alkenes in both 5-exo and 6-endo cyclization modes as a new way of preparing polycyclic b-lactam antibiotics [ 110-112]. 

The regioselectivity in diene addition reactions can also be influenced by ring strain effects in cyclization reactions. The regioselectivity is highly predictable in those cases, in which addition to the preferred diene center forms the preferred ring size. Thus, the cyclization of radical 15 proceeds readily to form the ct s-disubstituted cyclopentyhnethyl radical 16 with high selectivity. Similarly, cyclization of 17 affords exclusively bicyclic radical 18, in which the additional cyclopentane ring has been formed by addition to the terminal position of the butadiene subunit. This preference for 5-exo cyclizations onto dienes is not even dismpted by substiments at the C1 or C4 positions of the diene system, as seen for radical 19, which cyclizes to 20 (equation lO). This is in contrast to alkyl radical cyclizations to alkenes, in which major amounts of 6-endo cyclization is observed for 5-substituted systems. ... 

On the other hand, carbonylation via a one-electron reduction system by reducing metals can also lead to useful transformations [Scheme 4-33]. The first example in Scheme 4-34 shows that a zinc reduction system of pent-4-enyl iodide undergoes dual annulations, a [4-f1] radical annulation with CO and a [3-f2] anion annulation with alkenes, to give a bicyclo[3.3.0]octanol, in which four C-C bonds are produced [59]. An extension of the present strategy to the construction of bicyclo[3.2.1]octanol skeletons has also been successful with a system in which 6-endo cyclization is favored over 5-exo cyclization. In these two reactions three C-C bonds were created by radical reactions and one by anionic reaction. 

Type III An exo or endo cyclization where the alkene-bearing side chain is attached to the carbonyl oxygen gives cyclic ethers as products. The carbonyl ene reaction mechanism is disfavored because the reaction is thought to proceed via a stepwise process. 

Normally the terminal double bond is attacked by bulky electrophiles, such as the phenylselenyl cation. A 6-endo cyclization of the -configurated carbinol 6 leads stereoseleclively to the traMS-annulated tetrahydrofuran system 7. The corresponding (Z)-alkene 8 yields a mixture of trans-tetrahydrofuran 7 and the monocyclic compound 9 as a byproduct according to a stepwise process97. 

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