22-endo-trig

Endo-Trig, 4-Endo-Trig and 5-Endo-Trig are disfavored 6-Endo-Trig, 7-Endo-Trig, etc. are favored... 

Cyclic ethers were also obtained by cyclization of alkoxyl radicals, generated in a radical chain reaction by reacting the thione 42 with (TMSfsSiH under photochemical conditions at 20 °C (Reaction 46). Regioselectivities of cyclization have been investigated and a progressive increase of the 6-endo-trig selectivity along the series R2 = H[Pg.140]

When free radicals are added to 1,5- or 1,6-dienes, the initially formed radical (9) can add intramolecularly to the other bond, leading to a cyclic product (10). When the radical is generated from an precursor that gives vinyl radical 11, however, cyclization leads to 12, which is in equilibrium with cyclopropylcarbinyl radical 13 via a 5-exo-trig reaction. A 6-endo-trig reaction leads to 14, but unless there are perturbing substituent effects, however, cyclopropanation should be the major process. 

Scheme 3.59. Sevenfold domino radical 6-endo-trig cyclization.

The same approach (Scheme 12) was used with the amide 35 involving a 5-endo 6-endo-trig-tandem cyclization, which afforded exclusively indolizidinone 36 <1998TL7197>. 

The major product of the keto olefin cyclizations often corresponds to what one would predict, assuming the intermediate ketyl behaves like the corresponding monoradical (Eq. 34). For example, given an option between a 5-exo and a 6-endo-trig cyclization, the former predominates in radical cyclizations [51], and constitutes the exclusive cyclization path in the electrochemical counterpart, 110 - 112 [47]. In addition, the stereochemical outcome parallels that of the radical... 

The principle side reaction corresponds to reduction of the carbonyl without cyclization. For example, reduction of 6-methylhept-6-en-2-one (113) leads to a 12% yield of alcohol 114 no cyclized adduct 115 is produced. Were the intermediate to behave precisely like the monoradical, one would have anticipated that the presence of the methyl group on the alkene would have slowed the rate of 5-exo-trig cyclization to a point where closure to form 115, the product of a 6-endo-trig cyclization, would have dominated it did not. 

Scheme 6.2 Preference for 6-endo-trig cyclization of silyl radicals...

Amino-l,4-naphthoquinone 492 was reacted as a bidentate nucleophile in condensations with acetals 493 to form m-2,4 disubstituted-l,4-dihydro-27f-naphth[2,3-,7 [l,3]oxazine-5,10-diones 494 stereoselectively by 6-endo-trig-nng closure of the N,C-dialkylated intermediates (Equation 56) <1995T6565>. 

Tricyclic skeletons such as 85, 87, 89 with a central benzene ring are formed in the fully intramolecular Pd-catalyzed cascade cyclization of 2-bromo-l-ene-//,w-diynes 84, 86, 88 and analogs (Scheme 24). This process involves two alkyne relays in a row and a final 67r-electrocyclization or 6-endo-trig carbopalladation with ensuing / -dehydropalladation. 

The cr-alkenylpalladium 400, formed as an intermediate, is converted into the benzene derivative 401 by the intermolecular insertion of acrylate[278], A formal [2 + 2 + 2] cycloaddition takes place by the reaction of 2-iodonitroben-zene with the 1,6-enyne 402. The neopentylpalladium intermediate 403 undergoes 6-endo-trig cyclization on to the aromatic ring to give 404[279]. 

A facile intramolecular carbomagnesiation becomes possible by inserting one more carbon between the reactive magnesium center and the double bond. For example, when a 6-chloro-l-heptene was refluxed with magnesium, 1,2-dimethylcyclopentane (cis/trans = ca 1/4) was obtained in 88% yield after hydrolysis (Scheme 47) °. The cyclization shows a 5-exo-trig selectivity and the product derived from 6-endo-trig cyclization (methylcyclohexane) is not observed. 

Application of similar considerations to homolytic ring closures indicates that a 5-exo-trig closure will be preferred to a 6-endo-trig mode (Scheme 6) (80CC482). For cationic closures the 5-endo-trig mode is unknown in contrast to the well-established 6-endo-trig closure (Scheme 7). 

Endo-trig disfavored 5-Exo-trig disfavored 6-Endo-trig favored... 

As expected from Baldwin s rules, with suitable substrates, both regiospecific 5- or 6-exo addition could be observed. The electronically symmetrical alkene 10 underwent both 5-exo and 6-endo-trig addition in a ratio of 18 1. This is in accord with Baldwin s rule in that, whilst both processes are favourable, five-membered rings are formed more readily than six-membered rings. They also showed that 6-endo-trig and 6-exo-trig were both favourable processes with rate constants differing by a factor of less than 3. 

In contrast, to the difficulty of ring closure by the 5-Endo-Trig pathways, the 6-Endo-Trig reaction occurs readily on treatment with methanolic sodium methoxide the 0, B-unsaturated ketones 186 smoothly closed to the 4-chroma-nones 1187) (56). 

Scheme 10. Concuirent 5-exo-trig and 6-endo-trig process...

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