Heteroatom radicals

The following data (Table 1) for molecules, including hydrocarbons, strained ring systems, molecules with heteroatoms, radicals, and ions comes from a review by Stewart.For most organic molecules, AMI reports heats of formation accurate to within a few kilocalories per mol. For some molecules (particularly inorganic compounds with several halogens, such asperchloryl fluoride, even the best semi-empirical method fails completely. 

Although some of the oxidative ring closures described above, e.g. reactions with lead tetraacetate (Section 4.03.4.1.2), may actually involve radical intermediates, little use has been made of this reaction type in the synthesis of five-membered rings with two or more heteroatoms. Radical intermediates involved in photochemical transformations are described in Section 4.03.9. Free radical substitutions are described in the various monograph chapters. 

Heteroatom radical addition-cyclization and its synthetic application 99H(50)505. 

A trivalent n radical is planar, and a trivalent a radical is pyramidyl. Both types of trivalent radicals have staggered and eclipsed conformations. For a planar radical, staggered and eclipsed refer to the substituents at the radical center and not to the p orbital. A divalent n radical is linear, and a divalent a radical is bent. In the case of heteroatom radicals, such as alkoxyl and aminyl radicals, two low-energy electronic states exist, and the odd electron can be in a p orbital with the lone pair in a hybrid orbital (ti radical) or vice versa (a radical). 

In a similar manner, many additions of heteroatom radicals to unsaturated positions have been studied. In many cases, addition reactions of heteroatom radicals to alkenes are reversible and thermodynamically disfavored, but their occurrence is apparent. For example, the rapid addition and elimination of thiyl radicals to unsaturated fatty acid methyl esters results in isomerization reactions from which kinetic parameters can be obtained. Additions of group 14 (IV A) metal-centered... 

Scheme 86 Reactions of heteroatom radicals with alkenes...

Intramolecular addition of heteroatom radicals to olefins constitutes a convenient method for the synthesis of heterocycles. The photochemical ring closure reaction of oxyl radical derived from 44 provides access to tetrahydrofuran 45 [95JOC6706]. The regioselectivity in this cyclization is excellent, however, the stereoselectivity is only modest. The stereoselectivity was dependent on the temperature of the reaction. 

Figure 12. Stabilization of a heteroatom radical cation by hyperconjugation with the C-Si 0 orbital.

The fact that the 9.8 G coupling is observed for the subbituminous and high-volatile bituminous coals, which have high heteroatom contents (18.5 wt % and 11.4 wt %, respectively (35)), andmot for the low-volatile bituminous coal, which contains only 3.6% (35), suggests that its assignment to a heteroatomic radical is not unreasonable. 

Examples of stereoselective cyclizations involving heteroatom radicals are rare. Tandem oxy radical cyclization and diastereoselective hydrogen atom transfer reactions, however, have also been studied (Eq. (13.58)) [74]. These reactions take advantage of chirality at the y carbon to induce anti-/ cycloaddition. Hydrogen... 

Corresponding reactions to those noted above with alcohols are found to occur with amines, the radical produced being derived by hydrogen abstraction from the carbon linked to the heteroatom. Radical generation can be effected with y-irradiation or UV light (> 250 nm or > 290 nm) using either liquid amines or aqueous solutions. The tendency to lose the heteroatom from the radical moiety is more pronounced than with the alcohol derivatives. The extreme case is found with 6-unsubstituted purines, in which no 6-aminoalkylpurine is obtained concomitant deamination occurs giving the 6-alkylpurine as product (Scheme 7). 

The cerium(IV)-mediated generation of heteroatom radicals by oxidation of anions such as azides was discovered many years ago [10], However, Nair et al. applied this strategy for a C-S bond-forming reaction by oxidation of ammonium thiocyanate le only recently [11], Addition of thiocyanate radical to indole 18 provides an intermediate radical, which is further oxidized to the cation by CAN. Loss of proton from the cationic intermediate provides the substituted arene 19 in excellent yield (Scheme 6). 

Most studies involve reactions of carbon-centered radicals with alkenes and alkynes as radical traps. Heteroatom radical traps such as carbonyl groups, imines, and nitriles have received much less attention. Since radical reactions involving carbon-centered radicals and C=C bonds lead to the loss of the two participating functional groups, one of the advantages in radical reactions using heteroatom radical traps is to retain synthetically useful functionality for further manipulations. 

This chapter deals with recent advances in efficient radical traps and also includes newly developed radical acceptors for both intramolecular and intermolecular addition. Special attention will be given to the synthetic importance of newly developed heteroatom radical traps, particularly carbon-nitrogen double bonds. 

Zhang s interest in addition of heteroatom radicals to aromatic rings was extended recently to indoles [18]. Using ammonium thiocyanate and manganese (111) acetate in acetic acid at room temperature, a simple intermolecular thiocyana-tion of the 3-position of a variety of substituted indoles (24) was realized. The highest yield of 93% was obtained with 7-methylindole. 

Intramolecular additions of heteroatomic radicals have been studied much less than the corresponding processes involving carbon free radicals. In fact, when we began work in this area in 1964, no unambiguous example of intramolecular addition by a heteroatomic radical had been reported, although this possibility had been considered in some cases. 

In general many of the features which govern the cyclization of carbon radicals are met with again in reactions involving heteroatomic radicals. But it is also true that the nature of Z may introduce subtle, or dramatic, changes in I I... 

Reports of the intramolecular addition of heteroatomic radicals other than alkoxyl, aminyl, and thiyl are rather scarce, although very interesting and unexpected behavior has often been reported. 

Intramolecular addition of heteroatomic radicals to a double bond is, in most of the cases studied, a more general and more efficient process than intramolecular addition of carbon radicals. It is thus possible to propose new methods for the preparation of heterocyclic compounds and to consider that these processes are involved in important biogenetic schemes such as penicillin or prostaglandin biosynthesis. It is not always easy to conclude that a free radical process is involved because of the possibility of competitive ionic cyclizations. 

Finally, it must be said that while the main features concerning the cyclization of unsaturated 0-, N-, or S-centered radicals are beginning to be understood, very little is known about the behavior of other heteroatomic radicals, although some very interesting features emerge from the first reports published. 

Intramolecular Addition of Heteroatomic Radicals to Acetylenic Bonds... 

Very little is known of the intramolecular addition of other heteroatomic radicals to triple bonds, although very promising results have been reported by Markl. By AIBN initiation, phenylphosphine (X = P) and phenylarsine (X = As) add to hexa-l,5-diyne (162). The yields of cyclized products 163 are quite good (17% for X = As and 33%, for X = P), if one considers the multistep pathway probably involved (Scheme 73). It must also be emphasized that the (Cy7) compound 163 is exclusively obtained in this Cy6/Cy7 case and this is clearly reminiscent of the results obtained with ethylenic phosphines (Section VIII.5.A). 

Similar results have been observed with heteroatomic radicals such as aminyl radical (in an example already discussed in Section VIII.3.A, Scheme 44, and more recently as an important step in the total synthesis of the alkaloid dendrobine ) and with the carboxamidyl radical. The intramolecular addition of thiyl radicals to cyclohexenes generally gives a mixture of the (Cy5) and (Cy6) products. In the same way, intramolecular addition to an unsaturated chain of a thiyl radical on a cyclohexane ring also gives a mixture of (Cy5) and (Cy6) products. This lack of selectivity is in accord with the behavior of unsaturated thiyl radicals discussed in Section VIII.4. An interesting exception of possible relevance to the biosynthetic route to cepham has been discussed in Section VIII.4.B (Scheme 58). The behavior of ethylenic aminothiols such as 107 under free radical initiation (Scheme 52, Section VIII.4.A) has been generalized to compounds such as 267, which affords 268 in 87% yield (Scheme 109). 

In the preceding section, most of the studies were devoted to carbon-centered radicals rather than to heteroatomic-centered radicals. The inverse is true for bridged ring formation where most of the known examples involve heteroatomic radicals. An example which involves a carbon-centered radical is due to Wilt, (Scheme 116) who described the ring closure of 291 to 292 by tri-n-butyltin hydride reduction. 

Examples of heteroatomic radical cyclizations leading to bridged rings will now be described. Oxabicyclic compounds 306 (R = H) have been obtained by photolysis of the nitrites (305) (oxime not isolated) (Scheme 121). When R = Me compounds 307 are obtained and, although yields are modest, this shows that intramolecular addition of an alkoxy radical is possible and that it gives exclusively the (Cy 5) radical in the Cy5/Cy6 case. 

In the meantime, other intramolecular additions were studied, which afforded new preparative methods and which are probably involved in biogenetic schemes. Much less is known at this time of the scope and the quantitative aspect of these reactions. Among the many problems not satisfactorily solved at this time one may cite the origin of the stereospecificity observed in mono- and polycyclization reactions, the scope of polycyclizations reactions and of intramolecular additions to acetylenic and polar bonds, a better knowledge of intramolecular additions of heteroatomic radicals and radicals bearing heteroatoms in the chain, and the limits of the cyclization processes applied to higher homologs than the Cy5/Cy6 case. 

Second, since radical reactions lead to no displacements of charge, the electronegativities of the atoms involved play no role. The ease of addition to a double bond depends solely on the strength of its n component. Since CC 71 bonds are weaker than those involving heteroatoms, radical addition takes place most readily to C=C bonds. 

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