Intramolecular free radical reactions

Free radical intramolecular reactions are of synthetic value for the preparation of bi- and polycyclic compounds. These reactions are often... 

Some years later, Kochi investigated extensively by esr the structure of alkyl radicals in nonaqueous solution. He showed that by this technique it was possible to observe the low-temperature cyclization of the 5-hexenyl radical and the opening of the cyclopropylcarbinyl radical. This led Ingold to use the esr technique in order to obtain accurate kinetic data for free radical intramolecular reactions. In this way the room temperature cyclization rate of the 5-hexenyl radical was confirmed and its temperature dependence was determined ... 

R = H) undergoes a variety of enzyme-catalyzed free-radical intramolecular cyclization reactions, followed by late-stage oxidations, eliminations, rearrangements, and O- and N-alkylations. Working from this generalization as an organizing principle, the majority of known AmaryUidaceae alkaloids can be divided into eight stmctural classes (47). 

Wawzonek et al. first investigated the mechanism of the cyclization of A-haloamines and correctly proposed the free radical chain reaction pathway that was substantiated by experimental data. "" Subsequently, Corey and Hertler examined the stereochemistry, hydrogen isotope effect, initiation, catalysis, intermediates, and selectivity of hydrogen transfer. Their results pointed conclusively to a free radical chain mechanism involving intramolecular hydrogen transfer as one of the propagation steps. Accordingly, the... 

T. V. RajanBabu, Stereochemistry of intramolecular free-radical cyclization reactions, Acc. Chem. Res. 24 139 (1991). 

Free-radical cyclization reactions nicely complement the Pd(0)-catalyzed intramolecular Heck reaction, which also provides cyclic products from unsaturated halides. Free radicals can be generated easily at saturated carbons from saturated alkyl bromides, and the products are reduced relative to the reactants. In contrast, intramolecular Heck reactions work best for vinyl and aryl bromides (in fact they do not work for alkyl halides), and the products are at the same oxidation level as the reactants. Moreover, free radicals attack the double bond at the internal position, whereas palladium insertion causes cyclization to occur at the external carbon. 

Both intermolecular and intramolecular additions of carbon radicals to alkenes and alkynes continue to be a widely investigated method for carbon-carbon bond formation and has been the subject of a number of review articles. In particular, the inter- and intra-molecular additions of vinyl, heteroatomic and metal-centred radicals to alkynes have been reported and also the factors which influence the addition reactions of carbon radicals to unsaturated carbon-carbon bonds. The stereochemical outcome of such additions continues to attract interest. The generation and use of alkoxy radicals in both asymmetric cyclizations and skeletal rearrangements has been reviewed and the use of fi ee radical reactions in the stereoselective synthesis of a-amino acid derivatives has appeared in two reports." The stereochemical features and synthetic potential of the [1,2]-Wittig rearrangement has also been reviewed. In addition, a review of some recent applications of free radical chain reactions in organic and polymer synthesis has appeared. The effect of solvent upon the reactions of neutral fi ee radicals has also recently been reviewed. ... 

The disproportionation reaction of the free radical chain can generate the monomer as a successive process. There are, however, some other issues regarding the propagation for free radical chain reactions. In addition to the "regular" propagation step, different reactions may occur in a so-called transfer step. In this step, the free radical chain reacts with another molecule and generates a different radical chain and a new polymeric molecule. There are two possible types of transfer reactions. The transfer step can be an intermolecular chain transfer or an intramolecular chain transfer. An example of an intermolecular chain transfer is... 

Free-radical cyclization reactions (i.e., the intramolecular addition of an alkyl radical to a C=C ir bond) have emerged as one of the most interesting and widespread applications of free-radical chemistry to organic synthesis. Free-radical cyclizations are useful because they are so fast. The cyclization of the 5-hexenyl radical to the cyclopentylmethyl radical is very fast, occurring at a rate of about 1.0 X 105 s-1. In fact, the rate of formation of the cyclopentylmethyl radical is much faster than the rate of cyclization to the lower energy cyclohexyl radical. This stereoelectronic effect is derived from the fact that the overlap between the p orbital of the radical and the rr MO of the double bond is much better when Cl attacks C5 than when it attacks C6. The relative rates of 5-exo and 6-endo ring closures are strongly dependent on the nature of the substrate and especially on the amount of substitution on the ir bond. Cyclization of the 6-heptenyl radical in the 6-exo mode is also very favorable. 

Intramolecular cyclization of unsaturated acyl chlorides. Tributyltin hydride reduces acyl chlorides to aldehydes by a free-radical chain reaction involving an acyl radical (I, 1193). Cekovic10 now finds that treatment of acyl chlorides with a double bond in the S- or 6-position with tributyltin hydride (azobisisobutyronitrile initiation) gives cyclohexanone derivatives. Thus 5-hexenoyl chloride (1) is converted into cyclohexanone (2), and citronelloyl chloride (3) is converted into menthone (4). 

With this information in hand, it seemed reasonable to attempt to use force field methods to model the transition states of more complex, chiral systems. To that end, transition state.s for the delivery of hydrogen atom from stannanes 69 71 derived from cholic acid to the 2.2,.3-trimethy 1-3-pentyl radical 72 (which was chosen as the prototypical prochiral alkyl radical) were modeled in a similar manner to that published for intramolecular free-radical addition reactions (Beckwith-Schicsscr model) and that for intramolecular homolytic substitution at selenium [32]. The array of reacting centers in each transition state 73 75 was fixed at the geometry of the transition state determined by ah initio (MP2/DZP) molecular orbital calculations for the attack of methyl radical at trimethyltin hydride (viz. rsn-n = 1 Si A rc-H = i -69 A 6 sn-H-C = 180°) [33]. The remainder of each structure 73-75 was optimized using molecular mechanics (MM2) in the usual way. In all, three transition state conformations were considered for each mode of attack (re or ) in structures 73-75 (Scheme 14). In general, the force field method described overestimates experimentally determined enantioseleclivities (Scheme 15), and the development of a flexible model is now being considered [33]. 

In the Hofmann-Loejfler-Freytag reaction, an Af-chloroammonium ion is converted by a free-radical substitution reaction into a 4-chloroalkylammonium ion, which then undergoes intramolecular Sn2 substitution to give a pyrrolidine. In the free-radical substitution mechanism, the abstraction step occurs in an intramolecular fashion. Entropic and stereoelectronic factors make the regioselec-tivity very high for the C4 hydrogen. 

Free-radical cyclization reactions (i.e., the intramolecular addition of an alkyl radical to a C=C rrbond) have emerged as one of the most interesting and widespread applications of free-radical chemistry to organic synthesis. Free-radical... 

The mechanisms of intramolecular free-radical cyclization reactions are no different from their intermolecular counterparts. The propagation part of the mechanism usually involves (1) abstraction of -Br, T, or -SeR by Bu3Sn- to give an alkyl radical, (2) one or more additions of an alkyl radical to a tt bond, and... 

A novel intra-ion-pair electron(i) transfer cleavage of the —C-B— bond is reported by Chatterjee et al. [98] from the photoreaction of triphenyl alkyl borate salts of cyanine dye (110) to generate a carbon-centered radical (113) whose utility for initiating a free radical polymerization reaction has been demonstrated (Scheme 26). An intramolecular concerted bond cleavage/coupling process is described [99] from phenyl anthracene sulphoniiun salt derivatives as a part of designing a novel Photoacid system. 

In 1988, Boger and co-worker found that the intramolecular free-radical cyclization reactions of acyl radicals generated from selenol esters proceeded efficiently, suppressing competing reduction and decarbonylation (Eq. 47) [98]. 

The observed first-order rate constant for decomposition is independent of the initial concentration and experiments to distinguish an intramolecular mechanism from a free-radical chain reaction rule out the former. It is rather more difficult to establish whether the a-H atom is transferred to Ta initially or directly to the more basic axial alkyl group (Scheme 1). 

In further illustrations of the use of free-radical cyclization reactions in terpene synthesis Snider et al. have described the 5-exo-trig cyclization from the imidazolide (29) to produce both B-copaene (30a) and B-ylangene (30b), Stork and Baine have synthesized seychellene (32) [from (31)], and Ladlow and Pattenden have featured a novel, stereoselective intramolecular radical cyclization step onto an enolic double bond, viz. (33) - (34), in their synthesis of ( )-alliacolide (35). 

An interesting aspect of the radiolysis of longer-chain alkyl bromides and chlorides is the high yield of isomerization (G(isomer) > 6 pmol e.g., 1-chloroalkane isomerizes to 2-chloroalkane). These reactions are attributed to free-radical chain reactions, which involve intramolecular shift of a halogen atom. 

Within a few years, a large number of papers devoted to intramolecular free radical addition reactions appeared, particular attention often being given to the matter of ring size. Before discussing these results we shall first endeavor to analyze and rationalize the behavior of 5-hexenyl radicals. 

---