III. Intramolecular Addition (Cyclization) Reactions

In addition to describing cyclization reactions by the size of the ring produced, the terms exo and endo indicate the way in which the ring is formed. The meaning of these terms is illustrated in the reactions shown is Scheme 8. When the exo/endo terminology is used to describe ring for­ma­tion from reaction of the 5-hexenyl radical, the five-membered ring is seen as arising from exo closure and the six-membered one from endo closure (Scheme 7).

2. Transition-State Structure

Transition-state structures for radical addition and radical cyclization are given in Figure 6 in a general form. For cyclization reactions not only ring size but also ring conformation affect trans­i­tion-state energy; thus, both chair-like^25,27 and boat-like^27,30 structures are possible during five-mem­bered ring formation. For the unsub­sti­tuted 5-hexenyl radical the chair-like transition state leading to a five-mem­bered ring is calculated to be lower in energy, but only slightly so, than the boat-like transition state (Scheme 9).²⁷ (The “flagpole” interactions that con­trib­ute to making the boat conformation of cyclohexane much less stable than the chair confor­mation are less severe in the boat-like transition state for radi­cal cyc­li­zation.) Both trans­ition states (boat-like and chair-like) leading to a five-membered ring (Scheme 9) are calculated to be lower in energy than any transition states lead­ing to a six-membered ring. These calculations match well the exper­i­mental observation that cyclization of the 5-hexenyl radical gives a five-membered ring in a highly regioselective fashion (eq 14, R = H).^25,31

3. Altering Normal Regioselectivity

a. Steric Interactions and Adduct-Radical Stability

Although ring size is the primary factor affecting regioselectivity in cyclization reactions, other factors sometimes have a modifying effect; for example, in the reaction of the 5-meth­yl-5-hex­enyl radical the presence of the methyl group increases the amount of six-membered-ring formation (eq 14, R = CH₃).^25,27 In this reaction steric effects and adduct-radical stability both favor a six-membered ring. The transition state in this reaction presumably is reached late enough that either steric effects or adduct-radical stability or both have a substantial impact on regio­se­lectivity. Predicting when the transition state in this type of reaction will be early enough to cause highly regio­selective, five-membered-ring formation is not easy. In the reaction shown in Scheme 10, where steric interactions and adduct-radical stability favor six-membered-ring formation at least as much as they do in the reaction shown in eq 14 (R=CH₃), only a product with a five-mem­bered ring forms.³²

b. Thermodynamic Control

Although kinetically controlled reaction is the norm in radical cycli­zation, thermodynamic control is observed in the reaction shown in eq 15 where the substrate is an unsaturated silyl ether and the hydrogen donor (Bu₃SnH) is maintained at a low level.³³ When this reac­tion is conducted with a high Bu₃SnH concentration, kinetically controlled, five-membered ring formation is the major reaction pathway. An explanation for this dependence on hydrogen-donor concentration begins with the radical 18 cyclizing to form 19, a radical with a new five-membered ring (Scheme 11). If the concen­tra­tion of Bu₃SnH is high, hydrogen-atom abstraction rapidly completes the reaction, but if the donor concentration is low, rearrangement to the more stable radical 20, via the transition state 21, takes place before hydrogen-atom abstraction can occur.³⁴ Hydrogen-atom abstraction by 20 then gives the thermodynamically favored product. An alternative mechanism for this reaction, also shown in Scheme 11, is that ring opening of 19 produces a silicon-centered radical that undergoes ring closure to give the intermediate radical 20.³⁵

c. Reversal Due to Stereochemistry

One situation where six-membered ring formation is favored consist­ently over reaction pro­ducing a five-membered ring is when cyclization would produce a pair of trans-fused, five-mem­bered rings. Reactions of iodides 22 and 23 illustrate the effect that stereo­chem­istry can have on radical cyclization. The acyclic iodide 22 undergoes an expected cyclization to give a five-mem­bered ring (Scheme 12),³⁶ but reac­tion of the iodide 23 forms a six-membered ring (Scheme 13).³⁷ Since a trans fusion between two five-membered rings would produce the highly strained radical 25, the stereo­chemistry of the radical 24 dictates the regio­selectivity of the cyclization reaction. Six-membered-ring formation also occurs in the reaction shown in Scheme 14³⁸, again, because the other option would force the formation of trans-fused, five-membered rings.