Baldwin's Rules - Department of Medicinal Chemistry

Chemical Reviews REVIEW
process that can only occur for exocyclic closure. The regioselectivity
of the electrophilic closures of primary and secondary
carbenium ions depends upon the substitution of the alkyne,
directing nucleophilic attack via the buildup of partial positive
charge. Cyclization is not observed for tertiary carbocations in
the presence of weak nucleophiles (Scheme 8).
3.2. 4-exo versus 5-endo Cyclizations
Figure 14
Competition in this pair of cyclizations is fundamentally
different from other pairs discussed in this work where the
thermodynamic driving forces for the two competing cyclizations
are similar (both products are either strained (3-exo/4-endo) or
free of strain (5-exo/6-endo)) and where, in the case of
nucleophilic and radical closures, there is usually a clear kinetic
preference for the exo path. However, for the 4-exo/5-endo pair,
one of the products (exo) is much more strained than the other
(endo). As the result, the endo cyclization is much more
exothermic, and the competition between 4-exo and 5-endo
closure, onto both olefins 77 and alkynes, becomes delicately
balanced due to the thermodynamic contributions selectively
facilitating the endo closure (see section 2.6).
This competition also represents an interesting unresolved
question regarding stereoelectronic factors in organic reactions.
While the product of the stereoelectronically favorable 4-exo-dig
closure suffers from considerable strain, the formation of a
five-membered ring, via a nucleophilic closure, has to overcome
stereolectronic factors which disfavor anionic endo-dig cyclizations
(Figure 6).
3.2.1. Radical Cyclizations (Table 9). Whereas both 3-exoand
4-endo-dig radical closures were found to be endothermic
processes with no examples in the literature (vide supra), 4-exo
radical cyclization of the parent radical is essentially thermoneutral
(ΔE r ≈ 0), and 5-endo closure is significantly exothermic
(Table 10). Remarkably, the calculated activation barriers suggest
that the 4-exo-dig closure should still be capable of competing
kinetically with the much more exothermic 5-endo-dig closure. For
the parent carbon-centered radical, the 4-exo and 5-endo barriers
are very close. 78
While 4-exo-trig cyclizations are relatively well-documented, 79
the literature examples of regioselective 4-exo-dig radical closures
are scarce. 15 A single example of 4-exo-dig closure of an alkyl
radical (motif A, Table 9) has been observed experimentally
(3.026, Scheme 9). This transformation has been reported by
Malacria et al. as part of radical cascade leading to the formation
of bicyclo[3.1.1]heptanes. 80,81 The overall yield for the product
is 85% yield after reaction with MeLi, serving as a lower boundary
estimate for the 4-exo-dig step. The surprising efficiency of this
unprecedented transformation has been attributed to the fast
intramolecular trapping of the exocyclic vinyl radical via 1,6-H
transfer from a SiCH3 moiety.
The only reported literature attempt of a 5-endo-dig cyclization
of a simple alkyl radical led to quantitative formation of acyclic
reduced product 3.030 (Scheme 10). 82
Alabugin and co-workers investigated the apparent discrepancy
between the Baldwin rules and the lack of an efficient
Table 9. Literature Examples of 4-exo/5-endo-dig Radical Closure
with Respect to the Environment of the Radical Center b
a Outside scope of Baldwin Rules. b x marks denote gaps in the literature.
Motif structures are given in Scheme 1, and motifs D G are unknown.
Table 10. Activation, Reaction, and Intrinsic Energies (kcal/mol)
for the Parent (A), (σ-vinylexo, B), (σ-vinylendo, C), and (Callylendo3,
H) 4-exo- and 5-endo-dig Radical Digonal Cyclizations c
a B3LYP/6-31+G(d,p) and M05 2X/6-31+G(d,p) levels, ref 24.
b B3LYP/6-31G** level, ref 83. c Ring-closing bonds are shown in red.
M dx.doi.org/10.1021/cr200164y |Chem. Rev. XXXX, XXX, 000–000