Baldwin's Rules - Department of Medicinal Chemistry

Chemical Reviews REVIEW
Table 17. Literature Examples of 5-exo/6-endo-dig Radical
Closure with Respect to the Environment of the Radical
Center a
a x marks denote gaps in the literature. Motif structures are given in
Scheme 1. Motif B is unknown.
present in the reactant, possibly due to the lower strain in the 6-endo
product (Scheme 30, 3.155). 124
Further accumulation of strain, for example, via annealing of a
trans-fused 5-membered cycle, 125 completely reverses the 5-exo/
6-endo selectivity in favor of the larger cycle. Hoffmann and
co-workers have shown that the trans-fused ring does not have to
be preinstalled but can be synthesized as part of a cascade. The
secondary carbon radical initially underwent a 5-exo cyclization
at the adjacent alkene or alkyne, giving either an alkyl or a vinyl
radical, respectively. Interestingly, the reactivity of these two
radicals was drastically different. The alkyl radical was converted
into a tricyclic product via an efficient 6-endo-dig closure. 126,127
By substituting the relay olefin for a 1-cyclopentenyl group,
the yield can be increased to 78%. In contrast, the analogous
vinyl radical underwent neither 5-exo- nor 6-endo-dig closure
(Scheme 31). 126 Although this difference in reactivity suggests
that dig-cyclizations of vinyl radicals are more sensitive to
strain effects than analogous cyclizations of alkyl radicals,
numerous examples of vinyl and aryl radicals undergoing
5-exo-/6-endo-dig closure are known in less strained systems
(vide infra).
Table 18. Activation, Reaction, and Intrinsic Energies
(kcal/mol) for the Parent 5-exo- and 6-endo-dig Radical
Cyclizations at the B3LYP/6-31+G(d,p) and M05-2X/6-31
+G(d,p) Levels of Theory c
a B3LYP/6-31+G(d,p) and M05-2X/6-31+G(d,p) levels of theory. The
M05-2X data are given in parentheses. 24 b B3LYP/6-31G** level. 135
c The M05-2X data are given in parentheses. Corresponding motifs are
given and the ring-closing bond is shown in red.
The sensitivity of radical cyclizations to the nature of substituents
of the triple bond increases when the radical center is a part
of a conjugated system. While Zhou et al. found that primary
carbon radicals close regioselectively (5-exo) whether the alkynyl
substituent was aromatic or aliphatic (Scheme 28), 118 Choi and
Hart observed that carbon-radicals R to the nitrogen of a lactam
undergo relatively inefficient but regioselective 6-(π-vinylendo)endo-dig
closure (motif E) onto sterically hindered alkynes (R =
Me, 27% in addition to 61% of the reduced product). Only in the
presence of bulkier groups such as TMS, t-Bu C(CH 3) 2OMe, at
the alkyne terminus is the 5-exo-dig selectivity restored. Mediumsized
groups (i-Pr and n-Pr) gave mixtures with the 5-exo/6-endo
ratio correlating with the steric bulk of the substituents (∼2:1 and
∼5:4, respectively, Scheme 32). 128 Carbamoylmethyl radicals, (both
C-allylendo2 129 and C-allylexo, 130 Scheme 32) also undergo selective
5-exo-dig cyclizations with terminal and TMS-substituted alkynes,
respectively.
Benzylic radicals (motif H) closeefficiently despite being conjugated
with the aromatic system, as shown by the regioselective
5-exo closure of an R-pyridyl radical onto the alkyl-substituted alkyne.
The resulting vinyl radical was trapped via hydrogen abstraction from
U dx.doi.org/10.1021/cr200164y |Chem. Rev. XXXX, XXX, 000–000