Baldwin's Rules - Department of Medicinal Chemistry

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Figure 18. Reactant SOMO (left) and transition state geometries for 5-exo-dig (center) and 6-endo-dig (right) cyclizations of the 1,3-hexadien-5-yn-1yl
radical. (CASSCF/6-31G(d)). Reproduced with permission from refs 135 and 147. Copyright 2005 and 2000 American Chemical Society.
RCCSD(T)) calculations and found that the 5-exo activation
barrier is only 1.4 kcal/mol lower than the 6-endo barrier (at
the ZPVE-corrected RCCSD(T)6-311+G(3df,2p)//CASSCF/6-
31G(d) level): a noticeable leveling in comparison to the difference
between the respective digonal cyclizations of motifs B and C. 148
Even still, the authors suggested that the lowest energy pathway for
the formation of phenyl radical involves the rearrangement of the
5-exo product via bicyclo[3.1.0]hex-3,5-dien-2-yl radical intermediate
instead of direct 6-endo cyclization.
The difference between the reaction energies of 5-exo and
6-endo cyclizations is close to the difference in the stabilities of
benzene and fulvene. Interestingly, the incipient C 333 C bonds in
the fully conjugated radicals are 0.3 0.6 Å shorter than in
radicals with a saturated bridge. This trend, along with the high
exothermicities, accounts for very early transition states for motif
C digonal cyclizations (Figure 18). 135
The majority of the literature examples agree with the
calculated intrinsic 5-exo preference for the addition of vinyl
radicals to triple bonds in conjugated systems. For example,
K€onig, Schreiner and co-workers 149 reported an example of the
5-exo-dig cyclization of an enediyne promoted by TEMPO
(2,2,5,5-tetramethyl-4-piperidin-1-oxyl) radical (Scheme 40).
Alabugin and co-workers found that Bu3Sn-initiated cyclizations
of diaryl substituted enediynes proceed through the same
pathway but with considerably improved yields, 150 thus providing
a convenient synthetic approach to substituted fulvenes
and indenes (Scheme 40). 151 Schmittel et al. found that triplet
diradicals formed photochemically from enyne-carbodiimides
(Scheme 40) and enyne-ketenimines undergo exclusively
5-exo-dig cyclization. 152 Similar to the examples discussed previously
(Scheme 39), aryl radicals (made by abstraction of a
bromine atom) also close regioselectively in a 5-exo-dig fashion
in conjugated systems. 153
However, this “intrinsic preference” is not absolute and
aromaticity-driven 6-endo cyclizations in conjugated systems
can compete with the 5-exo pathway. 154 For example, Anthony
and co-workers 153,155 reported that initial 5-exo-dig closure is
followed by a surprisingly efficient 6-endo cyclizations in several
constrained enediyne systems (Scheme 41). Matzger et al. 156
also described thermal cycloaromatization of tri- and tetraynes
where, following the 5-exo-dig closure dicussed above (Scheme 40),
formation of the final product may potentially include, among other
possibities, a selective 6-endo-dig closure (Scheme 41).
Scheme 40. Regioselective 5-exo-dig Cyclizations in Conjugated
Systems
Scheme 41. Selective 6-endo-dig Cyclizations
Moreover, in many cases, the ratio of 5-exo- and 6-endo-dig
products is sensitive to the substitution pattern, for example, in
the cyclizations of R-Bu3Sn-imidoyl radicals 3.238 157 reported
by Rainier and Kennedy (Scheme 42). 158 As with the previous
Y dx.doi.org/10.1021/cr200164y |Chem. Rev. XXXX, XXX, 000–000