Cyclization 6- endo-trig

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 5-endo-trig cyclization. In contrast, 5-endo-dig cychzation is feasible because the acetylenic system provides an orbital that is available for a nearly planar mode of approach. 

Scheme 3.69. General scheme of a 5-exo-dig cyclization/1,5-hydrogen transfer/5-endo-trig cyclization.

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...

They transformed L-serine in seven steps to the iV-2-(trimethylsilyl)ethyl-sulfonyl(SES)-protected aziridine 104. The latter reacted with the lithio-an-ion of ( )-3-phenyl-l-(phenylsulfonyl)-2-propene (105) to a diastereomeric mixture of the sulfones 106 (Scheme 27). This mixture was treated with TBAF, yielding the pyrrolidine 107 as a single diastereoisomer with 2,3-frans-2,5-czs-configuration previously observed for 5-endo-trig cyclizations of this type. In three additional steps the pyrrolidine 107 was transformed to (+)-preussin (2), with 5% yield overall and in twelve steps altogether. 

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]. 

Difluoromethyl proline has been prepared by a related approach. Synthesis of cis- and fra 5-4-trifluoromethyl-D-prolines has been performed starting from the Garner aldehyde. 4-Trifluoromethyl, difluoromethylene, or difluoromethyl prolines could also be prepared by 5-endo-trig cyclization of A-(homoallyl)-sulfonamides. ... 

Sulfonyl-substituted homoallylic alcohols tmdergo 5-endo-trig cyclization reactiorrs on treatment with base, with cyclization stereoselectively depending on double bond geometry, to give substituted tetrahydrofurans <99T13471>. 

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. 

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. 

The Pd(II)-catalysed cyclization of 283 exhibits lower stereoselectivity ( 43% d.e.) than its Ag(I)-mediated counterpart (up to 81% d.e.)413. A Pd(II)-catalysed 5-endo-Trig cyclization of 2-hydroxybut-3-enylamines 327 has been reported to occur with moderate to good yields. The OH group is essential for the cyclization441. 

For earlier reports on die seemingly anti-Baldwin 5-endo-Trig cyclization, see e.g. Reference 197 and references cited therein and P. KoCovsky and V. Cemy, Collect. Czech. Chem. Commun., 43, 1924 (1978). 

Erythrina alkaloids, possessing curare-like activity, are a large class of natural products found in Erythrina plants (Leguminosae). In a study towards construction of the erythrina skeleton, disfavored 5-endo-trig cyclizations were achieved by Ikeda et al. by BusSnH-mediated radical cyclization of an //-vinylic a-chloroacetamide to give five-membered lactams... 

It might, at first glance, come as a surprise that, despite the ban on 5-endo-trig cyclizations, 5-endo-dig cyclizations are allowed. A possible reason for this observation is that intramolecular nucleophilic or electrophilic attack at an alkyne can proceed with the substrate in a flat conformation, because two orthogonal jt (or jt) orbitals are available. Similarly, hydroxymethyl allenes cyclize on treatment with a base (Scheme 9.7), because the terminal Jt orbital of the allene and the hydroxymethyl group can readily achieve a synperiplanar orientation. Intramolecular... 

Scheme9.7. Examples of 5-endo-dig cyclizations [1 7-21] and 5-endo-trig cyclizations of allenes [22],...

Grigg, R. Kemp, J. Malone, J. Tangthong-kum, A. 5-Endo-trig cyclization and 1,3-anion-ic cycloaddition in arylimine derivatives of a-amino acid esters. J. Chem. Soc. Chem. Commun. 1980, 648-650. 

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... 

By utilizing a 5-endo-trig cyclization process, several p, 3-difluorostyrenes (71) were transformed to the 2-fluoroindoles 72. Modifications of this method also proved to be useful for the synthesis of numerous other fluorinated heterocycles <02S1917>. A series of 3-arylamino-2-chloroindoles have been prepared by thermal cyclization of l,2-diarylamino-l,2-dichloroethenes, an event which takes place via intermediate arylaminochlorocarbenes <02S2426>. 

The unexpected formation of cyclopenta[fo]indole 3-339 and cydohepta[i>]indole derivatives has been observed by Bennasar and coworkers when a mixture of 2-in-dolylselenoester 3-333 and different alkene acceptors (e. g., 3-335) was subjected to nonreductive radical conditions (hexabutylditin, benzene, irradiation or TTMSS, AIBN) [132]. The process can be explained by considering the initial formation of acyl radical 3-334, which carries out an intermolecular radical addition onto the alkene 3-335, generating intermediate 3-336 (Scheme 3.81). Subsequent 5-endo-trig cyclization leads to the formation of indoline radical 3-337, which finally is oxidized via an unknown mechanism (the involvement of AIBN with 3-338 as intermediate is proposed) to give the indole derivative 3-339. 

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