Radicals allylic strain

The addition of (TMS)3SiH to prochiral diethyl methyl fumarate (5) gave both diastereoisomers with preferential formation of the threo isomer (Reaction 5.7) [25]. This suggests that the intermediate adduct 6 adopts a preferred conformation due to the allylic strain effect, in which the silyl moiety shields one face of the prochiral radical center, favouring hydrogen transfer to the opposite face, and therefore the threo product is predominantly formed. 

Sugars have also been used as chiral auxiliaries in acetal formation for diaste-reoselective radical cyclizations [52]. In Eq. (13.40) a chiral acetal is utilized to control the stereochemistry of a 5-exo-dig cyclization resulting in the formation of quaternary carbon-based stereocenters. Product 129 is formed as a single diaste-reomer in 35% yield. An allylic strain model is proposed to account for the stereochemical outcome of this reaction. 

Relative stereochemistry can be established through allylic strain present in transition states. In this context, conjugate radical additions to / -substituted dehydroamino acid derivatives have been examined [62]. Allylic strain provides selectivity of the ensuing hydrogen atom trap, and relative stereochemistry between the a and P centers is established as shown in Eq. (13.49). The anti product 156 is modestly favored by a ratio of 2.3 1, and the combined yield of 156 and 157 is 41%. 

The interconversion of butadiene radical cations and ionized cyclobutene represents a model case for a formal pericyclic process. Much work has been invested to study not only the distinguishability of these isomers and their derivatives by mass spectrometry, but also to check the role of orbital symmetry in the ionic species. Hass has addressed the latter problem in depth in a review on pericyclic reactions in radical cations in both the gas and condensed phases and no further survey on the papers mentioned there will be given here. The topic pertains also to the ring-opening of ionized benzocyclobutene to ionized ortho-quinodimethane (cf Section V) and various otha- phenyl-, methyl- and carboxy-substituted derivatives. In this context, we restrict ourselves hwe mentioning that an upper limit of 7 kcalmol only has been detemined by CE mass spectrometry for the activation barrier of the cycloreversion of the parent cyclobutene radical cations. The energy requirement for the cycloreversion of ionized 1- and 3-substituted cyclobutenes were found, by experiment, to be markedly different. Obviously, dissociation of the (in a sense bis-allylic) strained C—C bond is much more facile when the substituent is at C-3,... 

The diastereoselectivity of the ester- or amide-substituted radicals is rationalized, and can also be predicted, by invoking the concept of allylic strain (see Section D.2.2.1.2.1.). This concept is also valid for amino-substituted radicals95. 

A related carbocycle is synthesized starting from carbohydrate precursors. The radicals are generated via Barton deoxygenation of the intermediate 5-heptenolsiei. The effect of 1-, 2-, 3-and 4-substituents on the stereoselectivity of the cyclization reaction has also been described 17-18. The formation of the 1,5-m-product is rationalized by the Beckwith modelThe 4,5-configuration of the main product is tram and is explained by the influence of allylic strain. 

A further example of the stereoselective synthesis of /ran.v-subsiituted tetrahydropyrans is the radical cyclization of ethyl (4R)-(Z)-4-(2-bromo-l-ethoxyethoxymethyl)-2-hexenoate3" The radical cyclization is performed by heating the bromoacetal in the presence of tributyltin hydride and AIBN in benzene. A mixture of two diastereomers is formed in 97% yield. Reduction, benzylation, hydrolysis and oxidation gives the /ran.v-substituted ( + )-(4S,57 )-4-(2-benzyloxyethyl)-5-ethyltetrahydro-2//-pyran-2-one (5), which is a potential synthetic intermediate for (—)-emetine35. The highly selective formation of the tram-substituted pyrans is rationalized by an allylic strain effect that destabilizes the transition state leading to the cis- isomers. 

In nitrile- or alkyl-substituted chiral radicals there is no allylic strain and little or no diastereose-lectivity is observed18. 

The preferred formation of the sun-products in the hydrogen abstraction of radicals substituted with a dialkylamino group is explained by applying the concept of allylic strain whereas the reversed selectivity for the monoalkylated amino substituent is best rationalized by a Felkin-Anh-like transition state36. 

The conformation of the intermediate radical originating from the malonate is controlled by allylic strain [101b, 104]. The diastereoselectivity increases with the difference in size of R and R and the size of the coradical R. ... 

Substituents at the Radical Center that Induce Allylic Strain... 

The intermediate a-amide radical generally prefers an s-cis orientation 13, minimizing allylic strain. However, when R is small, allylic strain is decreased and the s-trans conformation 14 is more accessible (Eq. 5). The lower selectivity generally observed with the a-bromide substrates is presumably due to the fact that the a-halo amide carbonyl is not as good a donor as the a, 5-unsaturated amide carbonyl and that this may be adversely affecting interactions with the chiral Lewis acid. No selectivity was observed using these conditions when R = H. 

The orientation of the radical orbital relative to the growing chain is controlled by allylic strain and 1,3-steric interactions. This is supported by evidence from EPR studies on similar radicals [6]. 

The chemistry shown in Eq. (21) uses a / -amino selenide as a radical precursor. /S-Amido radical cyclizations in which y -amido selenides served as the radical precursors have also been reported. One example has been described within the context of an approach to the ABC-ring system of manzamine A [47]. Another appears in an efficient synthesis of indolizidine 72, a component of castoreum derived from the Canadian beaver scent gland (Eq. 22) [48]. It is notable that allylic strain plays a role in the latter free-radical cyclization, as the furyl residue undoubtedly occupies an axial site on the incipient tetrahydropiperidone ring. 

In every case of conformationally locked systems reported in the literature [12, 13] and in the ones so far discussed 34, 36, 42), the but-3-enyl groups are in an equatorial orientation. In the absence of any special effects, such as the allylic strain, all these systems yield 1,5-cw selectivity. These results cast some doubt on the original contention [3] that efficient ring closure can occur only through an effective overlap of SOMO of the radical with the p-orbitals of an axially oriented but-3-enyl group. On the contrary, a careful examination of the cis decalin-like transition state reveals that if the but-3-enyl group were in an axial orientation, a chair-like transition state should yield predominantly 5-trans product (vide infra. Fig. 7.13). 

Also, it was demonstrated that acyclic radicals can react with high stereoselectivity [45]. In order for the reactions to be stereoselective, the radicals have to adopt preferred conformations where the two faces of the prochiral radical centers are shielded to different extents by the stereogenic centers. Giese and coworkers [49] demonstrated with the help of Electron Spin Resonance studies that ester-substituted radicals with stereogenic centers in (3-positions adopt preferred conformations that minimize allylic strain [49] (shown below). In these conformations, large (L) and medium sized substituents (M) shield the two faces. The attacks come preferentially from the less shielded sides of the radicals. Stereoselectivity, because of A-strain conformation, is not limited to ester-substituted radicals [50]. The strains and steric control in reactions of radicals with alkenes can be illustrated as follows [50] ... 

Apparently, the driving force for the ring opening is the relief of the strain in the spiro system and the formation of the stable carbonate double bond. The double ring opening is probably a concerted process from the initial radical addition product to the open-chain radical. Even though the spiro compound XI is an allyl monomer, it does copolymerize with a wide variety of comonomers. 

Trisubstituted carbon-centred radicals chemically appear planar as depicted in the TT-type structure 1. However, spectroscopic studies have shown that planarity holds only for methyl, which has a very shallow well for inversion with a planar energy minimum, and for delocalized radical centres like allyl or benzyl. Ethyl, isopropyl, tert-butyl and all the like have double minima for inversion but the barrier is only about 300-500 cal, so that inversion is very fast even at low temperatures. Moreover, carbon-centred radicals with electronegative substituents like alkoxyl or fluorine reinforce the non-planarity, the effect being accumulative for multi-substitutions. This is ascribed to no bonds between n electrons on the heteroatom and the bond to another substituent. The degree of bending is also increased by ring strain like in cyclopropyl and oxiranyl radicals, whereas the disubstituted carbon-centred species like vinyl or acyl are bent a radicals [21]. 

One of the problems associated with thermal cyclodimerization of alkenes is the elevated temperatures required which often cause the strained cyclobutane derivatives formed to undergo ring opening, resulting in the formation of secondary thermolysis products. This deficiency can be overcome by the use of catalysts (metals Lewis or Bronsted acids) which convert less reactive alkenes to reactive intermediates (metalated alkenes, cations, radical cations) which undergo cycloaddilion more efficiently. Nevertheless, a number of these catalysts can also cause the decomposition of the cyclobutanes formed in the initial reaction. Such catalyzed alkene cycloadditions are limited specifically to allyl cations, strained alkenes such as methylenccyclo-propane and donor-acceptor-substituted alkenes. The milder reaction conditions of the catalyzed process permit the extension of the scope of [2 + 2] cycloadditions to include alkene combinations which would not otherwise react. 

Novel results were reported for allylic bromination. In radical bromination of cyclohexene in CCI4 under light the selectivity of substitution over addition was shown to be controlled by bromine concentration.304 Substitution via the corresponding allyl radical, while relatively slow, is irreversible and fast enough to maintain the concentration of bromine at a sufficiently low level to prevent significant addition. The reaction of two strained alkenes, fZ)-1,2-dimethyl-1,2-di-ferf-butylethylene and the -isomer (14), leads to the corresponding bromosubstituted product, instead of addition 305... 

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