Organic Letters
Letter
a
Scheme 1. Bioactive Indololactams and Their Synthesis by
Scheme 2. Optimization of Reaction Conditions
Transition Metal-Catalyzed C−H/N−H Annulation
a
Reaction conditions: 1a (0.1 mmol), 2a (0.2 mmol), Co(NO3)3·
6H2O (20 mol %), Ag2O (2 equiv), KH2PO4 (2.0 equiv), and L4 (50
mol %) in 1 mL of 2-MeTHF at 100 °C under air for 12 h. Yields
1
determined by H NMR using CH2Br2 as the internal standard. Q
denotes 8-aminoquinoline.
matching that of the Co catalyst. Other ligands such as salicylic
acid (L5), 2-methoxybenzaldehyde (L6), MesCOOH (L7),
and amino acids did not promote the reaction. These results
indicated that this is a unique salicylaldehyde-promoted cobalt-
catalyzed C−H and N−H annulation reaction.
With the optimal conditions in hand, we next investigated
the scope of the alkynes for Co-catalyzed C−H and N−H
annulation (Scheme 3). Diaryl alkynes with various common
functional groups such as Me, MeO, F, and Cl could react with
indole-2-amide (1a), giving the corresponding indololactam
products (3a−3f) in moderate to high yields (62−84%). It was
worth mentioning that the active Br substituent on the diaryl
alkyne (2d) could survive under our reaction conditions,
affording the desired six-membered indololactam (3d) in 72%
yield, which could be further diversified by metal-catalyzed
cross coupling reactions. In addition, symmetric dialkyl alkynes
could participate in the Co-catalyzed annulation reaction,
affording the corresponding products in medium yields.
Moreover, an asymmetric internal alkyne (2j) was also
effective for this transformation, giving the product in good
yield but low regioselectivity (1:1 3j:3j′). Furthermore,
terminal alkynes such as phenylacetylene (2k) and highly
steric trimethylsilyl acetylene (2l) were compatible with our
Co catalytic system, giving the corresponding products (3k
and 3l, respectively) in moderate to excellent regioselectivity
(10:1 to >20:1). The six-membered structure of 3k was
determined by X-ray analysis. These results highlight the broad
scope of the method.
After examining the compatibility of the Co catalytic
annulation reaction with a variety of alkyne substrates, we
turned our attention to the reactivity of different indole
substrates (1) (Scheme 4). Indole-3-amides having diverse
functional groups at positions 4−7 such as Me smoothly
participated in the annulation reaction to provide the
corresponding products (4a, 4d, 4g, and 4j, respectively) in
moderate yields, which showed high positional tolerance.
Different substituents such as MeO (1c), F (1b and 1i), Cl
(1f), and even Br (1e, 1h, and 1k) groups on the phenyl ring
of indole were all tolerated in the transformation. Notably, an
N-benzyl-protected indole substate (1l) also worked and
afforded the product (4l) in good yield. Indole-2-amide could
react under reaction conditions, affording the corresponding
2-amides with alkynes assisted by an 8-aminoquinolinyl
directing group (Scheme 1c). A notable feature of our strategy
includes (i) the use of an inexpensive and commercial Co salt
as the catalyst, (ii) using salicyaldehyde as a ligand in cobalt-
catalyzed C−H activation for the first time, (iii) a good
substrate scope, including both terminal and internal alkynes,
and (iv) one-step efficient and economic synthesis of a 5-HT3
receptor analogue via an intramolecular version, which has
potential in drug discovery.
Initially, we chose 1-methyl-N-(quinolin-8-yl)-1H-indole-3-
carboxamide 1a and diphenylacetylene 2a as the model
substrates to test this Co-catalyzed C−H and N−H annulation
reaction (for details, see Table S1). To our delight, a 12% yield
of desired indololactam product 3a was observed in the
presence of 20 mol % Co(NO3)2·6H2O, 2 equiv of Mn(OAc)2,
and 2 equiv of KH2PO4 in 2-methyl tetrahydrofuran (2-
MeTHF) at 100 °C under air. The structure of product 3a was
determined by X-ray analysis. We first investigated the effect of
a base on the reaction.
The KH2PO4 could promote the reaction, giving the product
in 27% yield, while the K2CO3 afforded a lower yield. No
product was detected using K3PO4 as the base. These results
showed that the weak base is favorable for the reaction. We
envisioned that the electronic properties of cobalt can be
regulated by ligands to improve its catalytic activity. Inspired
by the oxygen affinity of cobalt, we assumed that the addition
of dioxygen-coordinative salicylaldehyde would promote the
activity of the Co catalyst. When the salicylaldehyde (L1) was
added to the reaction mixture, a high yield of product 3a
(42%) was detected. Then, a series of substituted salicylalde-
hydes were extensively screened (Scheme 2). Although most of
substituted salicylaldehydes could promote the reaction, the
salicylaldehyde with a Cl substituent at position 6 (L4) gave
the best results, probably due to its electronic property
B
Org. Lett. XXXX, XXX, XXX−XXX