Cyclization Reactions of Silyl Radicals

The importance of carbon-centred radical cyclizations in organic chemistry has been documented in the large number of papers published each year and numerous reviews and books dealing with this subject. In Chapter 7 the reader can find a collection of such processes mediated by organosilanes. The silicon-centred radical cyclizations have instead received very little attention, although there has been a growing interest in silicon-containing compounds from a synthetic point of view, due to their versatility and applicability to material science. As we shall see, this area of research is very active and some recent examples show the potentiality of silyl radical cyclization in the construction of complex molecules. 

On the other hand, product studies of volatile materials for the reaction of silane 4 (no allylic hydrogen available) with thermally generated t-BuO radicals at 46 °C revealed the formation of cyclic silanes in a 46 % overall yield 

Organosilanes in Radical Chemistry C. Chatgilialoglu 2004 John Wiley Sons, Ltd ISBN 0-471-49870-X 

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], 

Intramolecular hydrosilylation of the higher homologues 15 and 20 under similar conditions gave also excellent yields of cyclized products [5]. The homo-allyloxysilanes 15 afforded a mixture of six- and five-membered ring products in a ratio of 4.5 1 for R = Me and 2.5 1 for R = Ph in favour of the larger ring (Reaction 6.4). The EPR spectra obtained by the reaction of t-BuO radical 

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Photoinduced electron transfer promoted cyclization reactions of a-silyl-methyl amines have been described by two groups. The group of Pandey cyclized amines of type 135 obtaining pyrrolidines and piperidines 139 in high yields [148]. The cyclization of the a-silylated amine 140 leads to a 1 1 mixture of the isomers 141 and 142 [149]. The absence of diastereoselectivity in comparison to analogous 3-substituted-5-hexenyl radical carbocyclization stereochemistry [9] supports the notion that a reaction pathway via a free radical is unlikely in this photocyclization. The proposed mechanism involves delocalized a-silylmethyl amine radical cations as reactive intermediates. For stereochemical purposes, Pandey has investigated the cyclization reaction of 143, yielding... 

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 chemoselective addition of silyl radical to the double bond of the (3-alkenyloxyenone derivative 24 was instead planned in Reaction (7.29) and accompanied by a 5-exo-trig radical cyclization leading to the diastereomeric cyclic ether products [40]. 

Silyl substituted carbon-centred radicals, which are produced when adding RsSi to unsaturated bonds can participate in consecutive reactions other than cyclization. A simple example is given in Reaction (7.66) where the adduct of silyl radical to (3-pinene rearranged by opening the four-membered ring prior to H atom transfer [33,77],... 

Substrates containing an electron-rich double bond, such as enol ethers and enol acetates, are easily oxidized by means of PET to electron-deficient aromatic compounds, such as dicyanoanthracene (DCA) or dicyanonaphthalene (DCN), which act as photosensitizers. Cyclization reactions of the initially formed silyloxy radical cation in cyclic silyl enol ethers tethered to an olefinic or an electron-rich aromatic ring, can produce bicyclic and tricyclic ketones with definite stereochemistry (Scheme 9.14) [20, 21]. 

Narasaka and coworkers reported radical-polar crossover addition/cyclization reactions of phenacyl bromides 204 and electron-rich alkenes such as (silyl) enol ethers 205, catalyzed by the rhenium(I) complex 206 (Fig. 57) [302], The active catalyst 206A formed after thermal nitrogen elimination from 206 reduced 204 either directly or by oxidative addition/homolysis via rhenium enolate 204A to... 

Jeon, Y. T., Lee, C. P, Mariano, P. S., Radical Cyclization Reactions of a Silyl Amine a,P Unsaturated Ketone and Ester Systems Promoted by Single Electron Transfer Photosensitization, J. Am. Chem. Soc. 1991, 113, 8847 8863. 

Silyl ethers incorporating an a-haloallg lsilyl moiety have been used to generate a-silyl radicals for radical cyclization (Scheme 17). Recent progress in the radical cydization of (aUyloxy)(bromomethyl)silanes, pioneered by Stork ] and Nishiyama, is summarized in an excellent review. The initial product 53 of the reaction of silyl ether 52 is oxidatively cleaved to give a diol 54. Alternatively, treatment of 53 with potassium tert-butox-ide in dimethyl sulfoxide gives the methyl-substituted alcohol 55. Exceptional levels of stereocontrol are obtained in the acyclic series (e.g., 56 57). xhe reaction is usually... 

Xu, W., Zhang, X.M., and Mariano, PS., Single electron transfer promoted photocyclization reactions of (aminoethyl)cyclohexenones. Mechanistic and synthetic features of process involving the generation and reaction of amine cations and a-amine radicals,/. Am. Chem. Soc., 113,8863,1991. Jeon, Y.T., Lee, C.P., and Mariano, PS., Radical cyclization reaction of a-silyl amine a, P-unsatur-ated ketones and esters promoted by single electron transfer sensitization,/. Am. Chem. Soc., 113, 8847,1991. 

An efficient two-step annelation of functionalized orthoesters with trimethyl-silyloxyfuran derivatives has been reported that produces bicyclo[3. .0]lactones. ° The reaction in Scheme 7 shows an example in which the initial condensation between silyl enol ether and orthoester is followed by the radical cyclization reaction under standard conditions. It is worth underlining the complete diastereocontrol in which three contiguous stereocenters are generated in one step with >95% stereoselectivity. 

This radical cyclization strategy was utilized for the synthesis of the smaller fragment silyl ether 54 as well (Scheme 8). Evans aldol reaction of the boron eno-late derived from ent-32 with aldehyde 33, samarium(III)-mediated imide methyl ester conversion, and protecting group exchange led to tosylate 51. Elaboration of 51 to ketone 53 was achieved under the conditions used for construction of the second tetrahydrofuran moiety of 49 from 46. A highly diastereoselective reduc-... 

Since enol silyl ethers are readily accessible by a number of methods in a regioselective manner and since the trialkylsilyl moiety as a potential cationic leaving group facilitates the termination of a cyclization sequence, unsaturated 1-trialkylsilyloxy-1-alkenes represent very promising substrates for radical-cation cyclization reactions. Several methods have been reported on the synthesis of 1,4-diketones by intermolecular oxidative coupling of enol silyl ethers with Cu(II) [76, 77], Ce(IV) [78], Pb(IV) [79], Ag(I) [80] V(V) [81] or iodosoben-zene/BFa-etherate [82] as oxidants without further oxidation of the products. 

Scheme 19)." Homoallyloxysilanes gave a mixture of five- and six-membered rings, but the intermediate silyl radical underwent predominantly 6-endo cyclization. Pentenyloxysilane gave the 1-endo product only. The stereochemistry of these reactions was found to be determined by steric effects, even in the presence of chiral thiol catalysts. The structures of the radical intermediates were studied by EPR. 

It is worth mentioning that in a few cases the (3-elimination of the silyl radical from the a-silyl alkoxyl radical (47) with the formation of corresponding carbonyl derivative was observed [63,64]. Evidently the fate of a-silyl alkoxyl radical depends on the method of radical generation and/or the nature of the substrate. Two examples that delineate the potentialities of this rearrangements are reported in Reactions (5.33) and (5.34). In the former, the 5-exo cyclization of secondary alkyl radical on the carbonyl moiety followed by the radical Brook rearrangement afforded the cyclopentyl silyl ether [65], whereas Reaction (5.34) shows the treatment of an a-silyl alcohol with lead tetracetate to afford the mixed acetyl silyl acetal under mild conditions [63]. 

Early work was focused to establish the preference for exo- vs endo-mode of cyclization. However, the absence of an effective method for generation of alkyl and/or aryl substituted silyl radicals made this task difficult. The reaction of prototype alkanesilane I with thermally generated t-BuO radicals at 145 °C after 4 h afforded a 48 % yield of unreacted starting material and 19 % yield of a six-membered cyclic product (Scheme 6.1) [1]. Moreover, EPR studies of the same reaction recorded the spectra at temperatures between —30 and 0°C, which were identified as the superimposition of two species having allylic-type (2) and six-membered ring (3) structures, respectively [2]. At higher temperatures radical 2 predominates therefore, the low yield detected in the product studies could derive from the extensive t-BuO attack on the allylic hydrogens. 

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. 

Extensive mechanistic investigation of the ring expansion 33 —> 34 was performed in order to differentiate between a ring-opening reaction to give a silyl radical 39 (path a), followed by the 6-endo cyclization, or a pentavalent silicon transition state 40 (path b). It was clearly demonstrated that the ring expansion proceeds via a pentavalent silicon transition state (Scheme 6.10) [16]. 

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