Baldwin's Rules - Department of Medicinal Chemistry

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cyclization has a 0.6 kcal/mol lower barrier than the 6-endo
closure in the gas phase, introduction of solvation reverses this
preference. Moreover, the 5-exo-dig cyclization is predicted to be
endothermic and readily reversible in solution, whereas the
6-endo-dig closure is ∼10 kcal/mol exothermic. The higher
computed activation barriers for both 6-endo and 5-exo cyclizations
of alkyl substituted alkynes are consistent with experimental
observations (Scheme 62). 56
These anionic cyclizations lack a significant thermodynamic
driving force because the gain in stability due transformation
of a weak π-bondintoastrongerσ-bond is offset by the
transformation of a stable nitrogen anion into an inherently less
stable carbanionic center. Formation of the finalproductsisnegotiated
through several proton shifts, ultimately leading to the most
stable tautomeric anion as a thermodynamic sink (Scheme 63). 56
Scheme 63. Full Potential Energy Surface for the Competing
6-endo and 5-exo Cyclizations of Hydrazide Anions at
B3LYP/6-31+G(d,p) Level of Theory
In contrast, aryl amides cyclize under basic conditions into the
6-membered products even with a phenyl-substituted alkyne
(73%, Scheme 64). 197 However, when the linking chain is
saturated, the cyclizations of β-alkynyl amides proceed exclusively
through the 5-(N-allylendo2)-exo-dig pathway (Scheme 64). 198
Scheme 64. Regioselectivity of Anionic Cyclizations of β-
Alkynyl Amides Is Influenced by the Nature of the Linking
Carbons
The regioselectivity of anionic closure of o-ethynyl-benzenehydroxamic
acids has been found to depend on the nature of the
aromatic linker. Interestingly, change to a pyrazolyl core again
leads to the switch from 5-exo to 6-endo selectivity, even in the
case where only 5-exo product has been observed for a benzenederived
substrate (Scheme 65). This observation is likely to have
its origin in the same strain effects as those discussed previously
for radical closures (Figure 19). O-attack via a 6-exo or 7-endo
closure was not observed. 199
Scheme 65. Switch in the 5-exo/6-endo Selectivity As the
Function of Annealed Ring Size
3.3.3. Electrophilic Cyclizations (Table 25). Unlike
the 3-exo/4-endo and 4-exo/5-endo pairs, electrophilic 5-exo/
6-endo cyclizations are relatively well studied. The electrophilic
closure of carbocations (motif A) and oxonium ions (π-vinylexo/
endo, motifs D, E) are particularly well represented. The latter
processisreferredtoasthe“Prins-type” closure. Cyclizations
onto diazonium salts (σ-vinylendo, motifs B, C), called the Richter
cyclization, have also been investigated.
Table 25. Literature Examples of 5-exo/6-endo-dig
Electrophilic Closure with Respect to the Environment
of the Electrophilic Center a
a x marks denote gaps in the literature. Motif structures are given in
Scheme 1. Motifs B and F H are unknown.
The regioselectivity of the parent carbocationic system
is dictated, as with the 3/4 analogs, by the substituent on
AG dx.doi.org/10.1021/cr200164y |Chem. Rev. XXXX, XXX, 000–000