Baldwin's Rules - Department of Medicinal Chemistry

Chemical Reviews REVIEW
products. 133 In a similar way, conjugation with a β-pyridine moiety
does not affect the exocyclic regioselectivity either (Scheme 34). 134
Because of the stereoelectronic features of the alkyne moiety, the
incipient radical in these two examples remains orthogonal to the
internal π-systems in the transition state and, thus, the 6-endo-dig
closure does not receive any conjugative assistance.
Scheme 33. Regioselective 5-exo-dig Cyclizations of
Benzylic Radical
Scheme 34. Regioselective 5-exo-dig Cyclizations of Internal
Alkynes with Acyclic Carbon Radicals
As with the smaller rings (4-exo/5-endo cyclizations, Table 10), 83
the closures of sp 2 -hybridized radicals (motifs B, C) have lower
activation barriers due the higher exothemicity of the conjugated
products formation (Table 20) relative to the parent systems
(Table 18). However, while the exo/endo barriers are close for
4-exo/5-endo pair, a clear stereoelectronic 5-exo preference is
observed for σ-vinylexo and σ-vinylendo closures, despite these
processes being less exothermic than their 6-endo counterparts.
135 The slight differences observed for motifs B and C
are due to the greater stability of endocyclic alkenes and
trans-dienes relative to exocyclic alkenes and cis-dienes 136
(Table 20).
The 5-exo barriers are relatively insensitive to structural
changes (Table 20, entries 1, 3, 5), while the 6-endo barriers
vary significantly. As the result, the kinetic preference for the
formation of 5-exo products significantly decreases in motif B
compared to motif C. It is interesting that the intrinsic barriers for
both the 5-(σ-vinylendo)-exo and 6-(σ-vinylendo)-endo cyclizations
(motif C) are ∼2 kcal/mol higher than for the respective
“σ-vinylexo” cyclizations. Although these differences are consistent
with the orientation of radical orbitals in the two reagents
(the radical orbital for the σ-vinylexo radical is tilted outward,
which should facilitate attack at the alkyne’s terminal carbon,
see red arrows in Table 20), it is not clear whether this is a
determining factor. Because of the unfavorable orientation of the
radical orbital in the reactant, locking the reacting vinyl group in a
benzene ring (motif C) leads to a further increase in the 6-endo
barrier.
Starting from the vinyl bromide (motif B), Montevicchi
and co-workers found that, as with the other cyclizations
Table 20. Activation Barriers, Reaction Energies, and
Intrinsic Barriers (kcal/mol) for 5-exo-dig and 6-endo-dig
Cyclizations of sp 2 -Radicals with a Saturated Bridge
between the Vinyl and a Terminal Alkyne Moieties
(B3LYP/6-31G** Level) a
a Arrows overlaid with the SOMOs of parent vinyl radicals (motif B, C)
show projection of the radical orbital in space. 135 Ring-closing bonds are
shown in red.
Scheme 35. Regioselective 5-(σ-Vinylexo)-exo-dig Cyclizations
of Carbon-Centered Radicals
discussed in this section, TMS-substitution facilitates regioselective
5-exo attack (54% yield, Scheme 35). 137 Journet and
Malacria published an efficient cascade initiated by a similar
regioselective closure onto an alkyl-substituted triple bond
(Scheme 35). 138
Sha and co-workers have found that both R-andβ-vinyl radicals
(motif C) in an enone system undergo clean 5-(σ-vinylendo)exo-dig
cyclizations onto TMS-substituted alkynes. Both [4.3.0] and
[3.3.0]-bicyclic ring systems, as well as heterocycles, are formed in
70 89% yields (Scheme 36). 139 It is noteworthy that in the second
example, even when n = 1, the cyclization is regioselective for
exocyclic closure onto the TMS substituted alkyne, forming the
5 5 bicyclic system (Scheme 36). 140
Five-membered heterocycles can also be efficiently and regioselectively
synthesized using aryl radicals (motif C, Scheme 37). 141
The experimental data are in good agreement with the DFT analysis
W dx.doi.org/10.1021/cr200164y |Chem. Rev. XXXX, XXX, 000–000