Radical cyclization concentration effects

The submitters report that this free radical cyclization was also effected by heating a solution of 5.00 g. (0.026 mole) of ethyl (E)-2-cyano-6-octenoate and 1.25 g. (0.0086 mole) of di-ferf-butyl peroxide [bis(l,l-dimethylethyl)peroxide] in 500 ml. of freshly distilled cyclohexane at 140° in an autoclave for 30 hours. The solution was concentrated and the residue was distilled to yield 3.4 g. (68%) of ethyl l-cyano-2-methylcyclohexanecarboxylate. 

At this time, no absolute rate constants have been determined for a reaction of an aminium cation radical. However, for synthetic utility, one needs to consider the relative rate constants for competing reactions. Competition between two unimolecular reactions depends only upon the relative rate constants for the processes. For competition between a unimolecular and a bimolecular reaction whose rate constants are comparable, product distributions can easily be controlled by the concentration of the second species in the ratio of rate laws. The ratio of reaction products from cyclization (unimolecular) versus hydrogen atom trapping before cyclization (bimolecular) can be expressed by the equation %(42 + 65)/%41 = Ar/(A H[Y - H]) (Scheme 20). Competition between two bimolecular reactions is dependent on the relative rate constants for each process and the effective, or mean, concentration of each reagent. The ratio of the products from H-atom transfer trapping of the cyclized radical versus self-trapping by the PTOC precursor can be expressed by the equation %42/%65 = (kH /kT) ([Y - H]/[PTOC]). 

The free-radical mechanism frequently leads to long primary chains. Extensive cyclization reactions in these primary chains lead to the appearance of a distribution of microgels, each one composed of one or more primary chains (Sun et al., 1997 see Chapter 8). This may lead to different concentrations of monomers and initiator molecules inside and outside the microgels. This partition effect implies that elementary steps may occur with a different rate in both regions. 

In contrast with the above discussion, a radical itself (rather than a radical acceptor) can be activated by complexation with a Lewis acid. The aminyl radical cycliza-tion shown in Eq. (304) is a slow process and yields of the cyclic product are often low. It is, however, known that a Brpnsted acid promotes this cyclization [676], and by analogy the reaction proved to be promoted by the addition of a Lewis acid, which should coordinate with the nitrogen atom to increase the reactivity of the nitrogen radical. The effect of a series of titanium salts, Ti(0-i-Pr) CL , at a concentration of 0.025 M, is shown in Eq. (304). It is apparent that use of Ti(0-i-Pr)Cl3 resulted in significantly improved yield. 

Azocino[3,2-6]indoles were obtained when seleno ester precursors bearing 3-butenylamino and allylaminomethyl chains on the C-3 position of the indole were subjected to the same reductive radical conditions used previously with indole 237. Inclusion of a bromine atom on the alkene acceptor gave the most rewarding result (shown below) at a hydride concentration of 0.02 M yielding 75% of the %-endo product 241, without the detection of any products, formed as a result of reductirm or the alternative 1-exo cyclization. This method proved to be a nice complement to the ring-closing metathesis protocol used in this laboratory to effect similar cyclizations and recently resulted in the total synthesis of apparicine [126, 127]. 

V. T. Perchyonok and Kellie L. Tuck of Monash University found (Tetrahedron Lett. 2008, 49, 4777) that a concentrated solution of Bu NCl and HjPOj in water effected free radical reductions and cyclizations. Stephane G. Ouellet of Merck Frosst demonstrated (Tetrahedron Lett. 2008, 49, 6707) that an oxazoline such as 3 could be converted to the alcohol 4 by acylation followed by reduction. Elizabeth R. Burkhardt of BASF developed (Tetrahedron I tt. 2008, 49, 5152) a protocol for scalable reductive amination using an easily metered liquid pyridine-borane complex. Mohammad Movassaghi of MIT devised (Angew. Chem. Int Ed. 2008, 47, 8909) a strategy for conversion of an allyUc carbonate 8 by way of the ally lie diazene to the terminal alkene 9. 

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