Baldwin's Rules - Department of Medicinal Chemistry

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Scheme 22. Aromatic Products Obtained Directly via a
5-endo-dig Closure of Heteroatom- or Carbon-Centered
Anions
Scheme 23. Selective 5-endo Pathway in a Strained
Polycyclic System
when compound 3.105 is exposed to n-BuLi, the resulting
carbanion closes regioselectively in a 5-endo-dig fashion. The
deformation necessary for annealing the highly strained fourmembered
ring at the peri-positions 105 shifts the balance in favor
of the 5-endo pathway (Scheme 23). 20
An interesting example of electronic control of 5-endo-dig
cyclization of o-ethynyl substituted heteroaromatic amines was
reported by Vasilevsky et al. 106 The authors could not force the
5-endo-dig closure in 4-phenylethynyl-5-amino pyrazole 3.107
where electronic properties of the substituents were mismatched
(the fifth position in pyrazoles where the nucleophile
is attached is the most electron poor whereas the fourth
position is electron rich). In contrast, the cyclization proceeded
smoothly in 3.109 where the two substituents are switched
(Scheme 24).
Knight et al. obtained 5-endo pyrrole products in 76 86%
yields in the reaction of γ-alkynyl-ss-hydroxy-R-amino esters
3.111 with 0.5 equiv of p-toluene sulfinic (or sulfonic) acid
(Scheme 25). 107 It has been suggested that intramolecular
coordination of alkyne with the protonated propargylic alcohol
3.112 assists the cyclizations, in analogy to similar 5-endo-dig
cyclizations promoted by electrophiles such as I2. 108
3.2.3. Electrophilic Cyclizations. As discussed above, the
4-exo/5-endo competition is much closer than it is for the 3-exo/
4-endo and 5-exo/6-endo pairs of cyclizations, owing largely to
the strain destabilization of only one (the four-membered) of
the two products. However, the situation changes in cationic
closures where the 5-endo product would be highly strained as
well because of the inclusion of an sp-hybridized cationic
center in the ring. The instability of vinyl cations is the likely reason
why electrophilic 4-exo/5-endo closures are not described in the
literature and several reactions which could potentially follow these
paths were found to give different products. For example, Hanack
reported that no cyclic products were observed in the solvolysis of
primary triflates 3.114, 109 whereas Rychnovsky and co-workers have
found that the formation of oxycarbenium intermediates did not
lead to either 4-exo- or 5-endo-dig cyclizations (Scheme 26). 110
Scheme 24. (Top) No Cyclization Observed when the
Amine Was Attached to the Most Electron-Poor Position in
the Ring, whereas Efficient Cyclization Occurs when the
Amine Is in the Most Electron-Rich Position (Bottom)
Scheme 25. Acid-Catalyzed Transformation of γ-Alkynyl-sshydroxy-r-amino
Esters to the Corresponding Pyrroles a
a The possible proton-coordination is shown in red.
A more detailed study is needed to shed the light on this topic,
but this lack of cyclic products is presumably due to the higher
themodynamic stability of the acyclic cations relative to that of
the cyclic vinyl cations.
Scheme 26. Neither 4-exo nor 5-endo Products Are
Observed upon Generation of Either Primary Carbocations
3.114A/B or Oxycarbenium Ion 3.115
3.2.4. Effect of Metal/External Electrophiles on 4-exo/
5-endo Regioselectivity. As has been shown by Toste 111 and
Iwasawa 112 using Au(I) and W(CO)5(L) catalysts, respectively
(Scheme 27), enolates exhibit complete 5-(C-allylexo)-endo-dig
regioselectivity without the need for built-in bond polarization,
such as the carbonyl group in Scheme 21. A variety of oxygen
nucleophiles undergo 5-endo-dig closure as well when exposed
to I 2, 113 Cu(I), 114 and Zn(II) 115 salts. A number of regioselectively
5-endo-dig cyclizations has been reported for nitrogen
nucleophiles in the presence of soft Lewis acids. 116
3.2.5. Summary of 4/5. DFT calculations illustrated in
Figure 16 suggest that the radical 4-exo-/5-endo-dig competition
is delicately poised. For the parent C-, N-, and O-centered
radicals, the difference between 4-exo- and 5-endo-dig activation
energies lies with the expected computational margin of error.
Although there is currenly not enough experimental data to fully
S dx.doi.org/10.1021/cr200164y |Chem. Rev. XXXX, XXX, 000–000