Organic Letters
Letter
of 4-aminoindole, thus producing the π-extended heterocyclic
3-oxindole (3ma) in good yield.
We next examined the generality of this C−H activation
cascade with respect to the diazo compound component. As
shown in Scheme 2, we found that this protocol tolerates a
directed C−H activation of aniline is feasible.25 To gain insight
into the positional C2/C8 selectivity of the reaction, we
conducted control experiments employing D2O/CD3OD as
the solvent (Scheme 3). (1) We observed exclusive C−H/C−
Scheme 3. Labelling Experiments
a b
,
Scheme 2. Substrate Scope of Naphthylamines
D exchange at the C2 position (Scheme 3A). Importantly, the
scrambling occurred in the absence of the diazo compound. It
should be noted that there is no H/D exchange in the absence
of ruthenium. (2) Furthermore, significant C−H/C−D
exchange occurred at the methyl position in 3aa when the
reaction was performed in the presence of the diazo compound
(Scheme 3B). It should be noted that H/D exchange was not
observed in the reisolated substrate. We believe that the H/D
exchange in the methyl group is a result of keto/enol exchange
under the reaction conditions. (3) Furthermore, control
reactions with 2-naphthylamine, 2-toluidine, and aniline as
C−H activation substrates resulted in unproductive reactions,
emphasizing the key role of the 1-naphthylamine template. It
should be noted that deuterium incorporation at the
exchangeable NH position is not observed due to product
isolation on silica gel. There is no productive reaction using
diazo substrates from 1,3-diketones or TMS diazomethane. We
believe that naphthylamines are preferred substrates due to the
conjugated system stabilizing the four-membered intermediate.
A possible mechanism could also involve activation of the
diazo compound with the formation of metal carbene, followed
by attack of the amino group at the electrophilic carbene
center with concomitant C−H activation. Ongoing work in our
laboratory is focused on mechanistic studies in Ru-catalysis,
and this work will be published in due course.
Since one of the major goals of C−H activation methods is
preparing novel structural motifs for pharmaceutical and
biochemical research, we were interested in testing the activity
of these novel products as potential cytotoxic lead compounds.
Thus, all of the synthesized products were tested against
human prostate cancer cells (PC3), human lung cancer cells
(A549), and human breast adeno-carcinoma cells (MCF-7).
The results of inhibitory activity are summarized in the
most potent activity (IC50 = 22.98 mM against PC3 cells, IC50
= 21.06 mM against A549 cells, IC50 = 21.29 mM against
MCF-7 cells). These results demonstrate that π-extended 3-
oxo-indole derivatives represent promising leads for the
development of new cytotoxic agents.26
a
Conditions: 1 (1.0 equiv), 2a (2.0 equiv), [RuCl2(p-cym)]2 (5 mol
%), CsOAc (25 mol %), H2O/EtOH (6.7/1 v/vol, 0.043 M), 65 °C,
b
16 h. Isolated yields. X-ray structure, 3ai (50% ellipsoids). Inset
shows angles around the quaternary center. CCDC 1965995.
wide range of diazo compounds, thus enabling the selective
synthesis of various C3-substituted π-extended 3-oxindoles.
We were pleased that various esters, including ethyl (3aa),
methyl (3ab), benzyl (3ac), and tert-butyl (3ad), can be
installed using this new protocol. Gratifyingly, the reaction also
tolerates various alkyl groups, including n-alkyl, such as methyl,
ethyl, or propyl (3ad−3af) as well as 2° alkyl, such as i-Pr
(3ag), and 3° alkyl, such as tert-Bu (3ah), and aromatic rings,
such as Ph (3ai). Notably, the reaction enables the synthesis of
extremely hindered α-branched C2-disubstituted π-extended 3-
oxindoles that are not accessible by other methods.
Even more interestingly, we observed that these C−H
activation products show bright cyan fluorescence in aqueous
solutions, which renders them attractive for fluorescent
S1; see SI for discussion).27
While a full understanding of the mechanism is premature at
this point, Uchimaru established that Ru-catalyzed ortho-
C
Org. Lett. XXXX, XXX, XXX−XXX