S-endo-trig cyclization

The primary allene adducts of general structure 99 as introduced in Section 8.2.2.1 generally are able to undergo (Baldwin disfavored) S-endo-trig cyclizations to furnish products of type 100. These isomerizations are either promoted by bases or catalyzed by Lewis acids or transition metal complexes. 

The competitive kinetics of Scheme 3.1 can also be applied to calibrate the unimolecular radical reactions provided that kn is a known rate constant. In particular the reaction of primary alkyl radicals with (Mc3Si)3SiH has been used to obtain kinetic data for some important unimolecular reactions such as the p-elimination of octanethiyl radical from 12 (Reaction 3.5) [12], the ring expansion of radical 13 (Reaction 3.6) [8] and the S-endo-trig cyclization of radical 14 (Reaction 3.7) [13]. The relative Arrhenius expressions shown below for the... 

Regiochemistry of the electrophilic cyclization of 166 has been studied. Interestingly, 6(S)-endo-Trig cyclization seems to be more favoured than the expected 5(S)-exo-Trig... 

The formation and the hydrolysis of acyclic and cyclic acetals have been studied in rather great detail [91]. Several reviews on this topic are available [92] and some conunents have been made [13] concerning the carbohydrate series. We have shown in Schemes 1,2, and 3 that a common feature of this reaction seems to be the intermediacy of an oxocatbenium ion. However, the cyclization of such.ati intermediate has been questioned more recently [93] in the light of the Baldwin s rules for ring closure [94]. At least for the five-membeted ting, an Sj type displacement mechanism for the protonated >rm (B) of die hemiacetal (A) (favmable S-exo-tet cyclization) has been proposed ratho than the imfavorable S-endo-trig cyclization of the oxocatbenium ion (Q (Scheme 5). Except when the formation of die enol edier (D) is structurally impossible, the intermediacy of such a compound remains feasible. 

In contrast, the corresponding 3,2 adduct underwent non-stereoselective 8-endo-trig cyclization. However, in the case of the 3,2 adduct 77, stereoselective S-endo-trig cyclization led to formation of the methyl y5-C-lactoside 78 after deprotection (Scheme 14). 

Gribble described a novel radical cyclization of 2-bromoindole-3-carboxamides 160 lo provide a synthesis of hexahydropyrrolo(3,4-h]indoles <01CC805>. It is believed that the reaction involves the sequence (1) generation of the expected indole C-2 radical, (2) 1,5-H atom abstraction to give the a-amidoyl radical, (3), S-endo-trig cyclization to the indole C-2 position, and (4) hydrogen abstraction to give indoline 161. 

This stereoelectronic requirement would lead to a large distortion of the normal geometry of a five-membered ring and introduce strain. It is this distortion and strain that disfavor the S-endo-trig cyclization. In contrast, 5-endo-dig cyclization is feasible because the acetylenic system provides an orbital that is available for a nearly planar mode of approach. 

Several 1-exo-trig cyclizations of 2-halo-l,8-nonadiene systems have been reported over the last decade however, a substantial fraction of S-endo-trig cyclization product has been observed in these cases (Scheme 16, Table 11). 

The Sasai research group found an intramolecular Heck-type approach to simple 3-pyrrolin-2-ones (Scheme 50 2010CC9064). For example, treatment of P,y-unsaturated amide 218 with palladium acetate in the presence of the isoxazoline ligand 219 and p-benzoquinone gives 3-pyrroUn-2-one 220 via a S-endo-trig cyclization. 

Allyloxysilanes (14) undergo radical chain cyclization in the presence of di-tert-butyl hyponitrite as radical initiator and thiol as a catalyst at ca 60 °C (Reaction 6.3) [5]. The thiol promotes the overall abstraction from the Si—H moiety as shown in Scheme 6.4 and the silyl radical undergoes a rapid 5-endo-trig cyclization. Indeed, EPR studies on the reaction of t-BuO radical with silanes 14 detected only spectra from the cyclized radicals even at — 100°C, which implies that the rate constants for cyclization are > 10 s at this temperature. 

Intramolecular cyclization can also be initiated from the radical-cation of a styrene residue [57], Oxidative cyclization of 31, n = 1 and 31, n = 2 give five and seven membered ring products respectively but in contrast 32 failed to yield a five membered ring product, giving only intractable mixtures. This difference in reactivities can be explained in terms of Baldwin s rules where the 5-endo-trig cyclization of the radical-cation from 32 is disfavoured [58]. 

In contrast to the large body of data pertaining the 5-exo and 6-exo cyclization modes, the 6-endo-trig mode has limited applications. This is simply because the 5-exo-trig cyclization is kinetically favored for S-hexenyl radical intermediates. Nevertheless, when the usually favored 5-exo-trig regioselectivity is surpressed by a substituent (e.g. bromine or ethyl) at the 5-position, the 6-endo-trig cyclization mode prevails. 

Compounds of type 77, passing through the seleniranium intermediates 78, give rise to the four-membered cyclic compounds 79 which, according to Baldwin s rules [61], are the result of a 4-exo-trig cyclization, or to the five-membered derivatives 80 as the result of a 5-endo-trig cyclization. Only very few cases are known in which the cyclization affords a four-membered heterocyclic... 

Cyclizations of pent-4-enyl radicals are very interesting, because neither the 4-exo trig nor the 5-endo trig cyclizations are considered favorable (Eq. 4). The 4-exo cyclizations are unfavorable because of the strain and rapid opening of the cyclo-butylmethyl radical to pent-4-enyl radical, whereas the 5-endo trig cyclization is disfavored based on Baldwin s rules of ring closures [18]. As in the case of 3-exo cyclizations, neither the 4-exo nor 5-endo radical cyclization reactions were reported in the literature prior to 1988. 

As indole-annulated sulfur heterocycles continue to gain popularity as synthetic targets, Majumdar s approach to trihydrothieno[2,3- ]indole [118] and benzo[c] thiopyrano[2,3-6]indole derivatives [119] is well placed as a viable route. As seen with sulfide 226 and sulfoxide 228, 5-endo- and 6-endo-trig cyclizations onto the C-3 position of the ring occurred in fair yields. 

For example, the octahydrophenanthrene skeleton 237 was obtained from the 2-bromotetradeca-l-ene-7,13-diyne 233 when the triple bond was terminally substituted by a trialkylsilyl group. Formation of the benzene rings 237 at the last step can be understood either in terms of 67T-electrocyclization of the intermediate 234 to yield 235, followed by /S-H elimination, or 6-endo-trig cyclization of 234 to produce 236 and fi-Yi elimination. 

According to Baldwin s rules, the anionic 5-endo-trig cyclization is a disfavoured process, but it has been found to be facilitated by the introduction of two fluorine atoms at the terminal carbon atom. ° Extensive ab initio calculations (Gaussian 94 and Mulliken) for homoallylic alkoxides found that the highly electronegative fluorine atoms stabilized both transition state and product. 

The uncyclized enamine 183 was treated in boiling toluene for 5 h. prior to radical cyclization, and then further treated with tri-n-butyltin hydride in boiling toluene. A successful tandem double S-exo-trig, 6-endo-trig cyclization of the aryl radical generated from 184 afforded the tetrahydrolysergate 185 which was obtained as die only isolable product in 75% yield as a 3 1 mixture of two epimers at the 10-position (Scheme 39). 

Iminium ion-alkene cyclizations accomplished under standard Eschweiler-Clarke methylation conditions have been employed to prepare five-, six- and seven-membered azacycles (Scheme 25). It is important to note timt under identical conditions amines (62) and (63) did not cyclize but afforded the corresponding, /V-dimethylamines. With regard to the alkene participant these results are in full accord with Baldwin s rules for ring formation. However, the formation of pyrrolidine (61) demonstrates that 5-endo-trig cyclizations can take place with respect to the iminium ion ir-paiticipant. The observed regioselectivity and the failure of (ti) to cyclize are in accord with obligatory formation of an intermediate with tertiary carbocation character. 

Yamazaki T, Hiraoka S, Sakamoto J, Kitazume T. Anionic 5-endo-trig cyclization of terminally difluorinated homoaUyhc alkoxides. J. Phys. Chem. A 1999 103 6820-6824. 

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