Angewandte
Communications
Chemie
À
C H Activation
Cobalt-Catalyzed Oxidative Annulation of Nitrogen-Containing
Arenes with Alkynes: An Atom-Economical Route to Heterocyclic
Quaternary Ammonium Salts
Sekar Prakash, Krishnamoorthy Muralirajan, and Chien-Hong Cheng*
Abstract: Four cobalt-catalyzed oxidative annulation reactions
ever, only few synthetic methods are available in the
literature, and they generally require prefunctionalized start-
ing materials, multiple steps, and either stoichiometric or
catalytic amounts of noble-metal catalysts.[6] Previously, we
reported the synthesis of isoquinolinium salts from the
annulation of either 2-halobenzaldimines[5b] or 2-iodoketimi-
nes[6c] with alkynes catalyzed by low-valent nickel complexes.
Later, we used rhodium and ruthenium complexes as the
À
of nitrogen-containing arenes with alkynes proceeds by C H
activation, thus leading to biologically useful quaternary
ammonium salts, including pyridoisoquinolinium, cinnoli-
nium, isoquinolinium, and quinolizinium salts, in high yields.
The results are comparable to those reactions catalyzed by
rhodium and ruthenium complexes. The transformation of the
salts into various N-heterocycles has also been demonstrated.
À
catalysts for preparing the nitrogen salts by C H bond
T
ransition metal catalyzed oxidative annulations of arenes
functionalization.[7] Our continuing interest in metal-cata-
[8]
À
À
through C H bond activation has drawn substantial attention
lyzed C H bond activation and first-row transition metal
because of their broad synthetic utility in the synthesis of
natural products, drugs, and materials.[1] Recently, many
nitrogen-containing, group-directed oxidative annulation
reactions catalyzed by noble metals such as rhodium,
catalyzed reactions[5b,6c] have stimulated us to investigate the
À
nitrogen-directed ortho C H bond activation of arenes by
cobalt complexes, followed by oxidative annulation with
alkynes. Herein, we report the synthesis of various quaternary
ammonium salts using pyridine, imine, and azo as the
directing groups and [CoCp*(CO)I2] as the catalyst.
Guided by our previous studies on oxidative annulation
by C H activation, we started examining the reaction of 2-
phenylpyridine (1a) with diphenylacetylene (2a) under
various reaction conditions (Table 1). The reaction of 1a
(0.10 mmol) with 2a (0.15 mmol) in the presence of [CoCp*-
(CO)I2] (10 mol %), AgOAc (10 mol %), NaHCO3
(0.12 mmol), and AgBF4 (0.20 mmol) in DCE at 1308C
under N2 for 24 hours gave the pyrido-[2,1-a]isoquinolin-5-
ium salt 3aa in 89% yield (entry 7). The compound was
carefully characterized and the structure was confirmed by
comparison to data in our previous reports.[7] The choice of
additive, oxidant, and solvent are crucial to obtaining high
product yields. Particularly, the selection of the OAcÀ source
À
ruthenium, palladium, and iridium, through C H activation
have been developed.[2] However, similar reactions using
more abundant, less expensive, and less toxic first-row
transition metals as the catalysts are still rare.
À
À
Recently, first-row transition metal catalyzed C H bond
activation of arenes has become very attractive because these
metals are less expensive, more abundant, and less toxic.[3]
Thus, cobalt catalysts have been employed as alternative
À
active C H activation catalysts for rhodium and ruthenium
complexes. In this context, the groups of Kanai,[4a–c] Acker-
mann,[4d,e] Glorius,[4f,g] Ellman,[4h-i] and Chang[4j,k] reported
À
using high-valent cobalt catalysts for C H functionalization
of arenes by various electrophiles. Recently, Matsunaga,
Kanai, and co-workers demonstrated the catalytic activity of
[CoIIICp*] and [RhIIICp*] in the synthesis of pyrroloindolones
from N-carbamoyl indoles and alkynes.[4l] Very recently, the
groups of Kanai and Matsunaga,[4m] Ackermann,[4n] and
Sundararaju[4o] individually reported isoquinoline synthesis
by a redox-neutral strategy in the presence of [CoCp*(CO)I2]
as the catalyst. However, there is still no report on the cobalt-
catalyzed C H oxidative annulation of arene with alkyne in
the presence of an external oxidant.
N-heterocyclic quaternary ammonium salts such as pyr-
idoisoquinolinium, cinnolinium, pyridinium, and quinolizi-
nium salts are found in the core structures of many bioactive
compounds, pharmaceuticals, and organic materials.[5] How-
À
is important for the present C H functionalization. It is well-
known that a coordinated OAc group acts as a proton
acceptor in cobalt-catalyzed C H activation reactions.
[4b–h,j–q]
À
In addition, the silver salts AgOAc and AgBF4 serve to
remove IÀ as an oxidant to regenerate the cobalt(III) active
À
À
species, and as an anion source (BF4 ) for the final product. It
should be noted that AgBF4 is used in a stoichiometric
amount relative to the substrates. Initial studies showed that
AgOAc afforded 3aa in 72% yield, while other salts such as
KOAc, NaOAc, and Cu(OAc)2, are much less effective
(entries 4–6). The addition of NaHCO3 (1.2 equiv) to the
reaction solution increases the yield of 3aa from 72 to 89%,
but the use of other bases such as Na2CO3, K2CO3, and
Cs2CO3 reduces the product yield (entries 8–10). It is note-
worthy that the chlorinated solvents 1,2-dichloroethane
(DCE) and chlorobenzene are suitable for this reaction
(entries 7 and 11), while others such as alcohol and ether
solvents are totally ineffective for the product formation.
Finally, various cobalt(II) and cobalt(III) complexes were
[*] S. Prakash, Dr. K. Muralirajan, Prof. Dr. C.-H. Cheng
Department of Chemistry, National Tsing Hua University
Hsinchu 30013 (Taiwan)
E-mail: chcheng@mx.nthu.edu.tw
Supporting information for this article is available on the WWW
1844
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2016, 55, 1844 –1848
Prakash, Sekar
