Endo-trig cyclization reactions

Cyclization also occurs easily in the case of 0-allyl hydroxylamines 152 (Scheme 23) which, on treatment with phenylselenyl sulfate 16, afford M-alkyl isoxazolines in good yields [87]. The presence of a methyl group in the allylic position has no substantial effect on the stereochemical course of this 5-endo-trig cyclization reaction, the two diastereomers 153 and 154 being formed in equal amounts. 

Kilburn et al. [72] have investigated the atom transfer 1-endo and %-endo trig cyclization reactions of the methylene cyclopropanes 285 to generate the bicyclic compounds 286, and found that the efficiency of the reaction increased when a trimethylsilyl group was present on the cyclopropane. 

Related reactions were described by Vernon and Gallagher [110] and endo-trig cyclization to dihydropyrroles by Ibuka et al. [111]. 

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. 

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... 

The endo-mode of cyclization is found to be the preferred path also in the lower homologues. Reaction (6.2) shows the reactions of two silanes (8) with thermally generated t-BuO radicals to afford the five-membered ring in low yields via a 5-endo-trig cyclization [1], EPR spectra recorded from these two silanes with photogenerated t-BuO radicals are assigned to secondary alkyl radical intermediates formed by an intermolecular addition involving the expected silyl radical and the parent silane [2],... 

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 hydrosilylation of alkenyloxysilyl radicals has also been investigated using silylated cyclohexadienes as the starting substrates [6]. Scheme 6.5 shows the reaction of 21 in hexane at 80-85 °C and in the presence of di-tert-hvAy hyponitrite as radical initiator. The crude reaction mixture was treated with an excess of PhLi to provide alcohol 22 in moderate yields. Intermediates 23 and 24 are the expected species involved in the 5-endo-trig cyclization. 

Sequences (or cascades) of radical reactions involving the 5-endo-trig cyclization of silyl radical to an allyloxy-type substituent as the key step have been developed and applied to the synthesis of natural products [7 11]. The concept and the sequence of radical reactions is outlined in Scheme 6.7. A radical of... 

Scheme 6.7 Sequential radical reactions including 5-endo-trig cyclization of silyl radical...

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]. 

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 comments 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 oxocarbenium ion. However, the cyclization of such an intermediate has been questioned more recently [93] in the light of the Baldwin s rules for ring closure [94]. At least for the five-membered ring, an SN2-type displacement mechanism far the protonated form (B) of die hemiacetal (A) (favorable 5-exo-tet cyclization) has been proposed rather than the unfavorable 5-endo-trig cyclization of the oxocarbenium ion (C) (Scheme 5). Except when the formation of the enol ether (D) is structurally impossible, the intermediacy of such a compound remains feasible. 

Thus, this method takes advantage of a relatively rapid 9-endo-trig cyclization, rather than undergoing other possible reactions with samarium iodide [32],... 

In this case, the intermediate vinyl radical (cf Scheme 9) underwent a remarkable [1,51-hydrogen abstraction from the non-activated C—H bond of the proximal isopropyl group. Furthermore, the resulting primary alkyl radical underwent a unique, stereoselective 5-endo-trig cyclization onto the adjacent double bond to generate a tertiary radical, which is a precursor of the highly substituted cyclopentanols 22 and 23. The reaction with Bu3SnH as radical mediator totally reversed the products ratio obtained in 88% yield, i.e. 22 23 = 19 81. 

Whereas 5-endo-trig processes are unfavorable, 6-endo-trig cyclizations are allowed. For this reason the reaction conditions used for several well-known preparations of six-membered rings cannot be used to prepare the corresponding five-membered rings. For example, treatment of phenethylamines with aldehydes and acid yields tetrahydroisochinolines (Pictet-Spengler synthesis), but treatment of benzylamines under these conditions does not yield dihydroisoindoles (Scheme 9.6). 

In some cases, such as with the allylic bromosulfone 17, the best reaction conditions to add to imines are obtained under Barbier conditions, reaction in this manner gives the unsaturated aminosulfone 18. Treatment with catalytic potassium hydride, results in a 5-endo-trig cyclization to form the pyrrolidine 19 in 65% yield (Scheme 1.8).25,26... 

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