Radical ester-substituted

Hart [4] and Giese [5] have recognized that the concept of A-strain can be applied to ester-substituted radicals. Thus, radical 2 reacts stereoselectively because the upper side of the semioccupied / -orbital in 2 is shielded to a larger extent (L large substituent) than the lower side (M medium-sized substituent). 

Quantum chemical calculations demonstrated that the change of this dihedral angle increases the strain by up to 7 kcal/mol (Fig. 2), so that conformer 6A has a relatively deep minimum conformation that should be attacked anti to the bulky tert-butyl group. 

The transition state energies in Fig, 4 demonstrate that the less strained con-formcr 7A leads to the lowest transition state and that the attack anti to the tert-butyl group is the energetically favored pathway. 

As a result, the qualitative order of the ground state energies remains unchanged 

This decrease of the stereoselectivity shows the influence of A -strain effects. If the size of the group R at the radical center becomes smaller, the repulsion between R and the large substituent L at the stereogenic center decreases. As a consequence, the dihedral angle between these groups is reduced and the shielding of the syn face becomes less effective. This will be demonstrated by radicals 7 and 20. In tertiary radical 7A the (1-tert-butyl substituent and the jff-H atom are on opposite faces of the 

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From the Fischer rate study, it appears that primaiy ester-substituted radicals are not electrophilic but ambiphilic and the borderline between ambiphilic and electrophilic radicals is not at all clear. Consider our results68 (Scheme 16) on the atom transfer additions of ester-substituted radicals to alkynes (with the caution that it may be dangerous to compare yields in place of rate constants). The primary ester-substituted radical adds more efficiently to 1-heptyne but the tertiary ester-substituted radical prefers ethyl propiolate. 

The low temperature ( —78 C) radical allylation of 3-alkoxy-substituted ethyl 2-iodo-3-phenylbutanoates proceeds via an ester-substituted radical that undergoes stereoselective addition across the double bond of tributyl(2-propenyl)stannanc8. The diastereomeric excess of the products is influenced only to a small extent by the steric bulk of the alkoxy substituent in the 3-position. 

This essentially absolute stereocontrol is rationalized by presuming a stable conformation of the intermediate radical due to dipole dipole interactions of the sulfinyl and the ester groups. 1,2-Induction is not restricted to ester-substituted radicals. It can also be observed with a trifluoromethyl group9 1. 

Through chelation of the /J-alkoxy and the carbonyl moieties of ester-substituted radicals with magnesium iodide as a bidentate Lewis acid the steric outcome of the hydrogen abstraction can be completely altered21. 

Ester-substituted radicals are intermediates in the stannane-mediated radical cyclization of iodolactones24. The hydrogen abstraction affords frans-perhydroindane substructures, important precursors for the synthesis of pleurolin and dihydropleurotin, with high selectivities23. 

Asymmetric induction is used in the stereoselective synthesis of silanes via the hvdrosilyla-tion of a,/l-unsaturated esters30. The addition of the tris(trimethylsilyl)silyl radical to the double bond is highly regioselective. yielding an ester-substituted radical that abstracts hydrogen diastereoselectively. 

For the heterocoupling of 52 and 54 with the coacids 33 and 35, respectively, the temperature dependence (—15 to 53 °C) of the diastereoselectivity has been determined. The yields in heterocoupling products ranged from 9 to 79%, the diastereoselectivity from 2.24 1 to 14.6 1. Side-products were formed by hydrogen abstraction of the ester-substituted radical (3-69%) and with the acid 54, the methylether 60 originating from the cation that is formed by further oxidation of the intermediate benzyl radical (19-33%). 

The stereoselectivities of ester-substituted radicals 9a-f show that with tertiary radicals 9a-c the anti products 10 are always formed predominantly. In secondary radicals 9d-f the selectivity is lower and can even lead to a loss of selectivity with the substituent L=Ph (Scheme 4) [6, 7],... 

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] ... 

It could be shown that the stereochemical outcome of such radical polycycliza-tions is influenced by the nature of the substituents (H, Me, C02R). For instance, as in the example 3-225, the all-( )-methyl-substituted polyene 3-228 also gave the corresponding all-trans-anti polycycle 3-229 in the presence of Bu3SnH and AIBN. However, the ester-substituted polyene 3-230 led to the cis-anti-cis-anti-cis tetracycle 3-231 under similar reaction conditions (Scheme 3.60). A certain degree of preorganization of the precursor is assumed to be the reason for this result [97]. 

According to results from laser flash photolysis, the p-(methoxyphenyl) sulfanyl radical adds exclusively to the central atom in of 2,4-dimethylpenta-2,3-diene (If) with a rate constant of 1.1 x 10s M-1 s-1 (23 1 °C) (Scheme 11.6) [45], A correlation between the measured rate constants for addition of para-substituted arylsulfanyl radicals to allene If was feasible using Brown and Okomoto s o+ constant [46], The p+ value of 1.83, which was obtained from this analysis, was interpreted in terms of a polar transition state for C-S bond formation with the sulfanyl radical being the electrophilic part [45]. This observation is in agreement with an increase in relative rate constant for phenylsulfanyl radical addition to 1-substituted allene in the series of methoxyallene lg, via dimethylallene Id, to phenylsulfanylallene lh, to ester-substituted 1,2-diene li (Table 11.2). 

Scheme 11.16 Diastereocontrol via chelate effect stereoselective 5-exo-trig cyclization on to a cumulated Jt-bond of a chelated ester-substituted ketyl radical anion 50 [74]. a 94 6 mixture of diastereomers.

The tertiary a-ester (26) and a-cyano (27) radicals react about an order of magnitude less rapidly with Bu3SnH than do tertiary alkyl radicals. On the basis of the results with secondary radicals 28-31, the kinetic effect is unlikely to be due to electronics. The radical clocks 26 and 27 also cyclize considerably less rapidly than a secondary radical counterpart (26 with R = H) or their tertiary alkyl radical analogue (i.e., 26 with R = X = CH3), and the slow cyclization rates for 26 and 27 were ascribed to an enforced planarity in ester- and cyano-substituted radicals that, in the case of tertiary species, results in a steric interaction in the transition states for cyclization.89 It is possible that a steric effect due to an enforced planar tertiary radical center also is involved in the kinetic effect on the tin hydride reaction rate constants. 

C. S. Wilcox and L. M. Thomasco, New syntheses of carbocycles from carbohydrates. Cycliza-tion of radicals derived from unsaturated halo sugars, J. Org. Chem. 50 546 (1985) see also S. Hanessian, D. S. Dhanoa, and P, L. Beaulieu, Synthesis of tt-substituted a,P-unsaturated esters via radical-induced cyclizations, Can. J. Chem. 65 1859 (1987). 

There are several examples of the addition reactions of caibonyl-substituted radicals to alkenes by the tin hydride method. The first reaction cited in Scheme 32 is a clear-cut example of reversed electronic requirement an electrophilic radical pairing with a nucleophilic alkene.60 Because enol ethers are not easily hydrostannylated, the use of a chloride precursor (which is activated by the esters) is possible. Indeed, the use of a bromomalonate results in a completely different product (Section 4.1.6.1.4). The second example is more intriguing (especially in light of die recent proposals on the existence of ambiphilic radicals) because it appears to go against conventional wisdom in the pairing of radicals and acceptors.118,119... 

EPR experiments on carbon-centred radicals with either a- or /J-boronic ester substituents have been reported.168 While the a-substituted radicals were modestly thermodynamically stable, the /J-substituted radicals underwent easy /J-climination. An EPR experiment on the photo-oxidation of phenolic compounds containing at least one free ortho position has indicated the formation of persistent secondary radicals derived from dimerization or polymerization from C-0 coupling.169 The structure of the succinimidyl radical has been re-examined using density functional theory with a variety of basis sets. The electronic ground state was found to be of cr-symmetry allowing for facile -scission. These conclusions were also predicted using MP2 but... 

Dehalogenation of a-substituted ketones and esters via radical anions has also been examined for its synthetic utility. As reported by Molander, Sml2 is an especially effective reagent for this transformation (equation l)44. Yields are typically high (70-100%) for X = Cl, OAc, OSiMe3, OCOCH2PI1, OTs, etc.). A mechanism for the reduction of esters (Scheme 10) has been suggested. 

Fig. 17.10. Mechanism of the Cr(VI) oxidation of alcohols to carbonyl compounds. The oxidation proceeds via the chromium(VI) acid ester A ("chromic acid ester") and yields chromium(IV) acid. The chromium(IV) acid may either disproportionate in an "inorganic" reaction or oxidize the alcohol to the hydroxy-substituted radical B. This radical is subsequently oxidized to the carbonyl compound by Cr(VI), which is reduced to Cr(V) acid in the process. This Cr(V) acid also is able to oxidize the alcohol to the carbonyl compound while it is undergoing reduction to a Cr(III) compound.

Another useful reaction for the difunctionalization of olefins involves a group transfer carbonylation starting from a a-(phenylseleno)carbonyl (or related derivatives) and a terminal alkene under 80 atm of CO. An alkyl radical is first formed by the photocleavage of a C-SePh bond. The addition of this radical to the olefin, followed by the incorporation of CO and radical coupling with PhSe-, gave substituted selenoesters via a three-component coupling reaction [74], The intermolecular formation of C—C bonds via phenylseleno group transfer has been likewise adopted in the reaction between ester-substituted O,Se-acetals and an olefin [75],... 

The 3-exo cychsation of ester-substituted 3-butenyl radicals is important in the rearrangement of 2-methyleneglutamate to 3-methyl itaconate catalysed by a-methyleneglutamate mutase. Newcomb and co-workers have applied laser flash photolysis to cleverly designed precursors to show that an ester group at the 1-position of 3-buten-l-yl accelerates the 3-exo cychsation by a factor of about 3, but that the same substituent at the 3-position slows the process by a factor of about 50 [45]. 

Bulk controlled-potential electrolysis experiments have shown that most of the (O) ester anion radicals decay via a simple bond cleavage mechanism to form car-boxylate anions in very high yield, while the (S) ester radicals decay via a very complicated mechanism often involving aromatic substitution reactions [442], Using CV, many of the compounds are shown to display chemically (and electrochemi-cally) reversible behavior at slow scan rates, in the sense that the ratios... 

The components used in these two sequences cannot be interchanged without some adjustment. Thus the Z-substituent in the radical 7.74 is necessary for an efficient reaction—in its absence the allylstannane has to be used in large excess. Similarly, a vinylogously X-substituted radical 7.79, derived from cyclohexenone 7.78, will have a high-energy SOMO it does not add at all to allyltributyltin 7.75, but it does add to the allylstannane 7.80 equipped with a Z-substituent to give the radical 7.81 and hence the ester 7.82.1026... 

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. 

The live-ring closure of prostereogenic radicals constructs two new stereogenic centers with good diastereoselectivity, as demonstrated by the trimethyltin hydride mediated cyclization of an ester-substituted diene4. The reaction proceeds via regioselective addition of the stannyl radical to the terminal end of the less substituted alkene and subsequent cyclization. 

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