Organic Letters
Letter
Figure 2. Plausible mechanism of (A) intramolecular cross-coupling and (B) indole synthesis.
tendency to favor the trans-conformer at low temperature.8 For
this reason, Pd-mediated intramolecular cross-coupling requires
a high temperature (120 °C) to form the desired cis-conformer.
Despite these rotamer problems, our electrochemical cyclization
smoothly occurred at room temperature. Changing the MsOH
additive to TfOH was also ineffective (Table 1, entry 9). We
thought the cathodic-generated base (electrogenerated base,
EGB) was important for deprotonation from the dication
intermediate (Figure 2A). The acidity of TfOH (pKa = −14) is
stronger than that of MsOH (pKa = −2.6), but the basicity of the
corresponding anion (TfO−) is weaker than that of MsO−.
Moderate basicity of EGB is probably needed for deprotonation.
Note that AcOH (pKa = 4.76) and trifluoroacetic acid (pKa =
−0.25) gave trace yields. This indicates that the reactivity of the
radical cation could also be decreased by solvation with the
corresponding anion, such as acetate. Methanesulfonate anion is
suitable for the cross-coupling reaction, because of its weak, but
sufficient, basicity. Finally, we determined that increasing the
acid concentration was effective (Table 1, entry 10).
Next, the indole synthesis reaction was optimized (see Table
1). Trifluoroethanol (TFE) and dimethylformamide (DMF)
were not suitable for this reaction (Table 1, entries 11 and 12),
and increasing the electrolyte concentration was also ineffective
(Table 1, entry 13). Inorganic and polymer-supported bases
were not suitable (Table 1, entries 14−16). The MeCN−
Bu4NClO4 system gave the best yield, while the MeNO2−HFIP
system and inorganic electrolytes did not work well (Table 1,
entries 17−19). Under these conditions, high voltage (between
+2.5 V and +6.0 V) and overoxidation of indole were observed.
To solve this problem, we used a collidine-MsOH (2:1) mixture
(Table 1, entry 20), and the yield was improved. Protonated
collidine acted as a sacrificial reagent in the cathodic reduction,
and low voltage (+1.6 V) was maintained throughout the
electrochemical reaction.
We performed mechanistic studies on both reactions by
means of cyclic voltammetry (see Figure 3, as well as Figures
S1−S4 in the Supporting Information). The reduction waves of
1a and 1c were not observed, indicating that overoxidation and
polymerization easily occurred on the electrode surface. The Eox
value of cyclized product 1a was similar to that of substrate 1, but
Figure 3. Cyclic voltammogram of 1 and its moieties (2 mM) in
MeCN−Bu4NClO4 (0.05 M). Scan rate = 10 mV/s.
the yield of the intramolecular cross-coupling reaction was high.
The basicity of the nitrogen lone pair was increased by structural
strain-induced delocalization breakage of the sp2 amide plane,9
and it was indicated by the Rf value on TLC (see Figure S5 in the
Supporting Information). This suggests that the interaction of
the amide nitrogen of 1a with the Lewis acid is stronger than that
of 1. The Lewis acidity of the Li cation derived from LiClO4 is
stronger than the tetrabutylammonium cation. A Lewis acidic
lithium cation is an important factor to increase the Eox value of
the cyclized product and suppress undesired overoxidation. To
support this hypothesis, the coupling yield is dramatically
affected by supporting electrolytes (Table 1, entries 4 and 5).
For indole synthesis, a neutral benzyl radical (e) is generated
from radical cation (a) via base-mediated deprotonation (Figure
2B). Continuous anodic oxidation and a second deprotonation
from the N-α position give the corresponding indole.
We applied these reactions to the total synthesis of
pyrrolophenanthridone alkaloids (see Scheme 1). The simple
pyrrolophenanthridonesoxoassoanine (1a), pratosine (1c),
anhydrolycorinone (2a), and hippadine (2b)were synthe-
sized from the corresponding 3,4-dimethoxy or 3,4-methyl-
enedioxybenzoyl indolines in one or two steps.
Pratorinine (1d) and pratorimine (1e) were isolated from the
Crinum species.10a,b These compounds exhibit cytotoxic activity
C
Org. Lett. XXXX, XXX, XXX−XXX