Organic Letters
Letter
indoles were also competent substrates for this cyclization
reaction, giving satisfactory product yields (3g and 3h). The
indoles bearing a F atom at benzene positions were proven to
be applicable under the standard conditions to furnish the
desired pyrrolo[1,2-α] indoles 3 in 58−85% yield (3i−l). It is
of note that the substrates with a F or Br atom at the C7
position slightly depressed the reaction activity, which gave low
yields (3l and 3m). A diverse set of substituents, as exemplified
by electron-rich groups (methoxyl, phenoxy, trifluoromethoxy)
and electron-deficient halogen (Cl, Br) at the C5 position of
the indoles, tolerated the reaction conditions, affording the
corresponding products in high yields (3n−r, 75−91% yield).
However, the substrate with a CF3 moiety at the C5 position
was unable to complete the C(sp3)−H/N−H annulation (3u).
Likewise, the presence of the strong electron-withdrawing
group (ester, 3v) and steric hindrance group (isopropyl, 3w) at
the C2 position significantly suppressed this process. Indoles
with 2-ethyl substituents (3s and 3t) went through this process
in low yield (42 and 45% yields), which could be ascribed to
the increased steric hindrance during the bond formation. In
addition, benzoindole was investigated, but unfortunately we
only got N-hydroxyalkylation product 3x.
Scheme 4. Synthetic Applicability
On the basis of our experimental data and previous reports, a
plausible mechanism for the Fe-catalyzed sequential C(sp3)−
H/N−H annulation can be proposed. As shown in Scheme 3,
Scheme 3. Proposed Reaction Mechanism
annulation products 3a, 3f, and 3n exhibited good anticancer
activities and potential in anticancer drug discovery. To further
illustrate the synthetic utility of this reaction, we proceeded
with the derivatization of the annulation products. As shown in
the Scheme 4B, the Heck reaction, Sonogashira reaction, and
Suzuki coupling of 3r with 4a, 4b, and 4c proceeded smoothly,
affording the corresponding products 5a, 5b, and 5c in 84, 72,
and 68% yield, respectively. Furthermore, the asymmetric
catalytic version of this annulation reaction was initially
attempted (Scheme 4C), and we found that the reactions
between 2,3-dimethylindole (1a and 1n) and ethyl trifluor-
opyruvate 2a under the Cu/BOX system proceeded smoothly,
affording 3a and 3n in good yield (68 and 72%) with moderate
enantioselectivity (36 and 31% ee).12 A further exploration of
asymmetric studies is currently underway in our group.
the C3 position of indole might initially be attacked by Fe3+
followed by deprotonation to form the imine B, in general,
which easily produces N-hydroxyalkylation with an electrophile
to generate the product D (see our previous report).9f,10
However, gratifyingly, the acidity of the C2-methyl hydrogen
atom may be increased by Fe3+, and the active species imine B
tautomerizes to the nucleophilic enamine C. Then, the
carbonyl group of 2a attacks enamine species C via a transition
state E to give adduct F, with the release of the iron catalyst at
the same time. Subsequently, the ester group undergoes
lactamization with the indole motif under the effect of TMG,
affording the final cyclization product 3a.
To demonstrate the practicality and effectiveness of our
protocol, the [3 + 2] annulation was performed on a gram
scale, as shown in Scheme 4A. The desired pyrrolo[1,2-
a]indole 3a was obtained in 84% yield (2.2 g) under these mild
and green conditions. Moreover, the antitumor activity of our
pyrrolo[1,2-a]indole products was tested,11 including gastric
cancer cell MGC803 and breast cancer cells MCF-7. The
In summary, the first Fe-catalyzed C(sp3)−H/N−H
annulation of 2-methylindoles with ethyl trifluoropyruvates
for the synthesis of pyrrolo[1,2-α]indoles has been developed.
This strategy features convenient operation, environmentally
benign conditions, and the use of an abundant iron catalyst,
which holds promise for application in the synthesis of more
C
Org. Lett. XXXX, XXX, XXX−XXX