Angewandte
Chemie
the arene moiety that bears the isonitrile functionality. For all
biaryls tested in this series, the corresponding phenanthri-
dines 3r–x were obtained in good yields, thus showing the
robustness of our method with respect to the substitution
pattern of the starting biphenyl. We also successfully ran one
reaction at larger scale (2 mmol) and isolated phenanthridine
compared to reagent 2, this process is likely to represent only
a minor reaction pathway.
In order to rank the acidity of the proton in cyclo-
hexadienyl radicals of type B, relative pKa values were
obtained from DFT calculations (PW6B95-D3/def2-
[
19]
TZVP).
Solvent effects of 1,4-dioxane (e = 2.25) were
3
e in 82% yield (0.48 g).
It is important to note that regioselective direct trifluor-
accounted for with the COSMO solvation model, and free
enthalpies (for T= 298 K) were obtained from harmonic
vibrational frequencies (for details see the Supporting
Information). Calculations were conducted on the intermedi-
omethylation of CH of such phenanthridines would be highly
challenging, showing a clear benefit of our approach. For
example, considering the directing effect of the N atom in
pyridines in homolytic aromatic substitutions, regiocontrol
in the preparation of 3q through radical trifluoromethylation
of the parent phenanthridine would be a difficult task. In
addition, the precursor biphenyls we use in the cascade can be
prepared in a modular approach (see the Supporting Infor-
mation), which allows the fast and efficient formation of
different phenanthridine core structures (Figure 3).
1
2
ate cyclohexadienyl radical B (R = R = H), which was
[
15]
1
2
derived from the unsubstituted biarylisonitrile 1t (R = R =
H), using ortho-iodobenzoate as base to generate the
1
2
corresponding deprotonated radical anion C (R = R = H).
The calculated pK value of ortho-iodobenzoic acid was set to
a
0 as relative reference (Figure 4). To evaluate the effect of the
N atom and the CF substituent on the acidity of B, two
3
congeners lacking these moieties were included into the
studies.
We suggest the following mechanism for the phen-
anthridine formation (Scheme 2). In the initiation step, the
iodide reacts with the Togni reagent 2 to give ortho-
Figure 4. Relative pK values of the cyclohexadienyl radical B, its
a
derivatives, and 2-iodobenzoic acid, obtained by DFT calculations
using a continuum solvent model (298 K, e=2.25).
The calculated relative pKa value of B versus ortho-
[
20]
iodobenzoic acid (exp. pK = 2.85 in aqueous solution) is
a
À18.3, resulting in an extremely low predicted pK value of
a
circa À15.5 for B. This result shows that the benzoate can
readily deprotonate B to give C, which is in line with our
suggested mechanism. Successive replacement of the CF3
group by CH and N by CH lowers the acidity of B by circa
3
1
0 and 4 pK units, respectively. Thus, even the least activated
a
radical (X = CH, R = CH ) is more acidic than 2-iodobenzoic
3
acid and will be deprotonated by the benzoate. Obviously, the
incorporation of the 2,5-cyclohexadienyl radical moiety into
a larger aromatic system and the CF3 group account for
a large part of the extraordinary acidity of B. This aspect will
be subject to further studies.
Scheme 2. Suggested mechanism.
Finally, we showed that the method can also be applied to
the synthesis of perfluoroalkylated phenathridines. To this
iodobenzoate, the CF radical, and iodine. The addition of
3
III
[9f]
the CF radical to the isonitrile functionality in 1 generates the
end, the I reagents 6a and 6b were prepared and applied
to the cascade reaction using isonitrile 1a as substrate
(Scheme 3). Reactions were conducted under the above-
described optimized conditions, and the targeted products 7a
and 7b were obtained in good yields, clearly showing the
potential of the new method for preparation of 6-perfluor-
oalkylated phenanthridines.
3
imidoyl radical A, which cyclizes to the arene to give
[16]
cyclohexadienyl radical B. The radical nature of the process
was supported by the facts that in the presence of the TEMPO
radical, phenanthridine synthesis did not occur and TEMPO–
1
9
CF3 was detected in the reaction mixture by F NMR
spectroscopy. We assume that the radical B gets deprotonated
À
by ortho-iodobenzoate (ArylCO ) to the radical anion C
2
which then reacts with the Togni reagent 2 through single-
electron transfer (SET) to product 3 and the CF radical,
3
[17,18]
thereby sustaining the radical chain reaction.
C can also
react with I generated in the initiation step to phenanthridine
2
3
and iodide. This process allows the regeneration of the
initiator. However, because of the low concentration of I2
Scheme 3. Formation of perfluoroalkylated phenanthridines.
Angew. Chem. Int. Ed. 2013, 52, 1 – 5
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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