Organic Letters
Letter
14
class of molecules by Fischer in 1886. A few attempts to
construct unsymmetrical BIMs have already been reported
the Friedel−Crafts reaction of H and indole B1 occurred to
construct the BIM product C1 (Scheme 2B).
1
5
too. However, they have drawbacks such as multistep
synthetic routes, environmentally unfriendly reaction conditions
and specific limited product structures. Therefore, the develop-
ment of efficient and practical methods to form unsymmetrical
BIMs and even broader diarylmethane derivatives from readily
available substrates is still highly desired.
Here we report a redox-neutral decarboxylative coupling that
delivers symmetrical and unsymmetrical BIM derivatives with
wide functional group tolerance. The transformation could be
broadly extended to other diarylmethane derivatives too. We
also describe mechanistic experiments that provide evidence for
radical−radical cross coupling instead of radical-polar crossover
coupling in this photocatalyzed redox-neutral transformation.
To examine the possibility for the designed redox-neutral
coupling, readily available IAA derivative A1 and indole B1 were
selected as model substrates. Subjecting A1 and B1 to irradiation
with 6 W blue LEDs in the presence of 3 mol % Ru(bpy) (PF )
As the first discovered and studied plant hormones, auxins are
a family of small organic molecules which can lead growth
responses of plants. Indole-3-acetic acid (IAA) is the most
16a
common one of the family, discovered by Salkowski in 1885,
which regulates various aspects of plant growth and develop-
ment. As IAA is a very important molecule in chemical industry,
the IAA industry has maintained a steady sales growth recently.
It is expected that the market size of IAA will reach 13.9 million
3
6 2
under an argon atmosphere delivered BIM product C1 in high
yield (Scheme 3, entry 1). Decarboxylation alkylation does not
16
US dollars in 2021. Thus, transformation of IAA, a bulk
chemical material, to various fine organic chemicals with high
added value is particularly appealing in organic chemistry.
Based on the above research background, we intended to
develop a photocatalyzed decarboxylic coupling method for the
preparation of 3,3′-bisindolylmethane from the IAA NHPI ester
and indole. As depicted in Scheme 2, we hypothesized that there
Scheme 3. Screening of Reaction Conditions
Scheme 2. Two Plausible Reaction Pathways of This Work
a
Reaction conditions: A1 (0.2 mmol), B1 (2 equiv), Ru(bpy) (PF )
6 2
3
b
(3 mol %), DCM (2 mL), Ar, Blue LEDs, 12 h. Isolated yields.
proceed in the absence of photosensitizer or light source,
resulting in the recovery of substrates A1 and B1 (Scheme 3,
entries 2 and 3). Other ruthenium or iridium photosensitizers
are relative ineffective compared to Ru(bpy) (PF ) Organic
3
6 2.
photocatalysts Eosin Y and Rosebengal were of no use in this
transformation (Scheme 3, entries 4−9). While dichloro-
methane was found to be the best solvent choice for the
transformation, the desired reaction proceeded with good yield
in DCE and MeCN (Scheme 3, entries 10−11). Finally, we
found that only trace amounts of BIM are formed under air
atmosphere (Scheme 3, entry 13). This result provides support
for radical involved mechanism due to the biradical feature of the
O molecule.
2
With optimal reaction conditions in hand, we evaluated the
scope of the reaction. Notably, as shown in Scheme 4, a wide
variety of indoles can smoothly undergo the decarboxylative
coupling reaction, affording the unsymmetrical BIM derivatives
in generally good to excellent yield (C2−C20). NHPI ester of
IAA derivatives generated the desired BIM products in high
isolated yields too (C21−C24). It is worthwhile to mention that
the nonsteroidal drug indomethacin is also a good substrate to
provide the corresponding BIM product (C24) in good yield.
Furthermore, the developed method was successfully applied for
late-stage derivatization of a range of drugs and complex
bioactive compounds derivatives (C25−C33). More broadly, as
shown in Scheme 5, this method can be successfully extended to
the synthesis of other kinds of diarylmethane derivatives (C34−
C72). It is noteworthy that a range of drug molecules, such as
are two pathways to realize the designed transformation.
Mechanism depiction: IAA NHPI ester A1 can be one-electron
reduced by the excited state of a photoredox catalyst to form the
radical anion intermediate D. D goes through the cleavage of the
O−N bond followed by decarboxylation to deliver the C-
centered radical intermediate E. Then, Detour I (radical−radical
cross coupling): indole B1 was one-electron oxidized by the
oxidized photocatalyst to form the radical cation intermediate F.
Subsequently, F goes through deprotonation to form the radical
intermediate G. Finally, the radical−radical cross coupling of E
and G occurred to form the BIM product C1 (Scheme 2A).
Detour II (radical-polar crossover coupling): the C-centered
radical intermediate E was one-electron oxidized by the oxidized
photocatalyst to form the carbocation intermediate H. Finally,
B
Org. Lett. XXXX, XXX, XXX−XXX