Page 991 - Advanced Organic Chemistry Part B - Reactions & Synthesis

10.3.3. Cyclization of Free Radical Intermediates 967

Cyclization of radical intermediates is an important method for ring synthesis. 320 SECTION 10.3
The key step involves addition of a radical center to an unsaturated functional group. Reactions Involving Free
Many of these reactions involve halides as the source of the radical intermediate. The Radical Intermediates
radicals are normally generated by halogen atom abstraction using a trialkylstannane
as the reagent and AIBN as the initiator. The cyclization step must be fast relative to
hydrogen abstraction from the stannane. The chain is propagated when the cyclized
radical abstracts hydrogen from the stannane.
.
initiation In + Bu 3 Sn H In H + Bu 3 Sn .
.
.
propagation Bu 3 Sn + X CH 2 CH CH 2 Bu 3 Sn X + CH 2 CH CH 2 CH 2 CH CH 2 .
CH 2 CH CH 2 . + Bu 3 Sn H CH 2 CH CH 3 + Bu 3 Sn .

From a synthetic point of view, the regioselectivity and stereoselectivity of the
cyclization are of paramount importance. As discussed in Section 11.2.3.3 of Part A,
the order of preference for cyclization of alkyl radicals is 5-exo > 6-endo;6-exo >
7-endo;8-endo > 7-exo because of stereoelectronic preferences. For relatively rigid
cyclic structures, proximity and alignment factors determined by the specific geometry
of the ring system are of major importance. Theoretical analysis of radical addition
indicates that the major interaction of the attacking radical is with the alkene LUMO. 321
The preferred direction of attack is not perpendicular to the system, but rather at an

angle of about 110 .

⋅

Figure 10.13 shows the preferred geometries and calculated energy differences based
on MM2 modeling.
Another major influence on the direction of cyclization is the presence of
substituents. Attack at a less hindered position is favored by both steric effects and
the stabilizing effect that most substituents have on a radical center. These have been
examined by DFT (UB3LYP/6-31+G ) calculations, and the results for 5-hexenyl
∗∗
radicals are shown in Figure 10.14. For the unsubstituted system, the 5-exo chair TS
is favored over the 6-endo chair by 2.7 kcal/mol. A 5-methyl substituent disfavors the
5-exo relative to the 6-endo mode by 0.7 kcal/mol, whereas a 6-methyl substituent
increases the preference for the 5-exo TS to 3.3 kcal/mol. 322

320
D. P. Curran, Synthesis, 417 (1988); Synthesis, 489 (1988); C. P. Jasperse, D. P. Curran, and T. L. Fervig,
Chem. Rev., 91, 1237 (1991); K. C. Majumdar, P. K. Basu, and P. P. Mukhopadhyay, Tetrahedron, 60,
6239 (2004).
321 A. L. J. Beckwith and C. H. Schiesser, Tetrahedron, 41, 3925 (1985); D. C. Spellmeyer and K. N. Houk,
J. Org. Chem., 52, 959 (1987).
322
A. G. Leach, R. Wang, G. E. Wohlhieter, S. I. Khan, M. E. Jung, and K. N. Houk, J. Am. Chem. Soc.,
125, 4271 (2003).