Cobalt-Catalyzed Bis-alkynylation of Amides via Double C-H Bond Activation

Article abstract of DOI:10.1021/acs.orglett.6b00095

The first example of cobalt-catalyzed selective bis-alkynylation of amides via double C-H bond activation with the directing assistance of a removable bidentate auxiliary is reported. The developed alkynylation strategy is simple, efficient, and tolerant

Full text of DOI:10.1021/acs.orglett.6b00095

Letter
pubs.acs.org/OrgLett
Cobalt-Catalyzed Bis-alkynylation of Amides via Double C−H Bond
Activation
Vinod G. Landge,†,‡ Garima Jaiswal,†,‡ and Ekambaram Balaraman*,†,‡
†Catalysis Division, Dr. Homi Bhabha Road, CSIR-National Chemical Laboratory (CSIR-NCL), Pune - 411008, India
‡Academy of Scientific and Innovative Research (AcSIR), New Delhi - 110 025, India
S
* Supporting Information
ABSTRACT: The first example of cobalt-catalyzed selective
bis-alkynylation of amides via double C−H bond activation
with the directing assistance of a removable bidentate auxiliary
is reported. The developed alkynylation strategy is simple,
efficient, and tolerant of various functional groups including
ether, amine, halides, and heterocyclic motifs. The reaction can
be scaled up under mild conditions.
been independently reported by Yu6a and Shi,6b demonstrating
ransition-metal catalyzed direct functionalization of the
Tinert C−H bond has emerged as a powerful strategy for the the significant potential of inexpensive, first-row transition metals
in C(sp2)-alkynylation; however, these transformations required
straightforward synthesis of value-added products with great step
a stoichiometric amount of copper salts. More recently, Shi,7a,b
economy and low waste production. Over the past decades,
Li,7c and our group7d have independently developed a nickel(II)-
considerable efforts have been dedicated toward catalysts based
upon precious metals such as Pd, Ru, Rh, and Ir.1 The
catalyzed alkynylation of arenes with the directing assistance of a
bidentate auxiliary.2f,8 During the past decade, cobalt catalysts in
replacement of expensive noble metal catalysts by utilizing
various oxidation states have been recognized as simple, efficient,
and increasingly viable catalysts for C−H bond functionaliza-
tion.2d,h,i,2,9 Noteworthy works from the research groups of
Kanai,10 Nakamura,11 Daugulis,12 Glorius,13 Yoshikai,14 Song,15
Ackermann,16 Chang,17 Ellman,18 Sundararaju,19 and others20
demonstrated the high potential of cobalt catalysts in C−H bond
activation reactions. A recent report from Shi20b and
Ackermann16g on the Cp*Co(III)-catalyzed C(sp2)-alkynylation
of pyrimidin-2-yl)-1H-indoles with hypervalent iodine(III)
reagents and 1-bromoalkyne, respectively, prompted us to
disclose our first report on a simple, efficient, air-stable,
cobalt(III)-catalyzed C(sp2)-alkynylation of amides with the
directing assistance of a removable 8-aminoquinoline. The
present alkynylation strategy has a broad substrate scope and
functional group tolerance and can be scaled up under mild
conditions. Remarkably, halide groups could be reserved under
our reaction conditions and, thus, extend the spectrum for
further modification of the products, wherein synthesis of halide-
substituted alkyne derivatives using the classical approach,
“Sonogashira coupling,” is extremely difficult.
economical, and environmentally benign first-row transition-
metal catalysts is an important paradigm in chemical synthesis. In
this regard, earth-abundant first-row late transition metals have
been intensely used in C−H bond activation strategy to emulate
the selectivity and reactivity of precious-metal catalysts and thus
broaden the scope and practical viability.2 However, their
successful application in C−H bond functionalizations still
remains at an early stage and can make it difficult to envisage and
control catalytic reactivity, as they have a propensity to
participate in one-electron chemistry as opposed to classical
two-electron transformation ubiquitous in the second- and third-
row transition metals.
Alkynes are an exceptionally versatile functional group and are
ubiquitous in pharmaceuticals, material science, and other
functional compounds.3 Thus, the development of an efficient
strategy for the construction of alkynyl scaffolds is a key
motivation in contemporary science and is usually achieved with
the Sonogashira cross-coupling reaction between an aryl halide
and a terminal alkyne.4 However, the complementary approach,
‘‘inverse Sonogashira coupling’’ involving the direct alkynylation
of inert aryl C−H bonds with easily accessible alkynyl halides, is
very attractive and highly desirable in organic synthesis. In this
context, alkynylation of unactivated arenes with the assistance of
different directing groups has been developed as an efficient
protocol to construct C(sp2)−C(sp) bonds, which was mainly
accomplished by Pd-,5a−d Ru-,5e and Rh-catalysts.5f,g A copper-
mediated alkynylation of arenes assisted by bidentate amide
oxazoline and PIP (2-pyridinyl isopropyl) directing groups has
Optimization studies on the ortho C−H bond alkynylation are
summarized in Table 1. We began our investigation using 2-
chloro-N-(quinolin-8-yl)benzamide (1a) as a model substrate
and (triisopropylsilyl)ethynyl bromide 2 as a coupling reagent in
the presence of Co(acac)3 (10 mol %), PhCO2Na (0.2 equiv),
Received: January 11, 2016
© XXXX American Chemical Society
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DOI: 10.1021/acs.orglett.6b00095
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Letter
a
Table 1. Optimization of the Reaction Conditions
Scheme 1. Cobalt-Catalyzed Alkynylation of Amides: Scope of
Amides
a b
,
b
entry
reaction conditions
yield (%)
1
toluene used a solvent
PhF used a solvent
31
2
43
3
1,4-dioxane used a solvent
standard conditions (using 2)
without PhCO2Na
n.r.
80
4
5
52
6
NaOAc instead of PhCO2Na
without Ag2CO3
47
7
6
8
AgOAc instead of Ag2CO3
AgSbPF6 instead of Ag2CO3
at 80 °C
55
9
n.r.
28
10
11
12
13
14
15
16
without [Co] cat.
nr
Co(OAc)2 used as [Co] source
CoCl2 used as [Co] source
CoBr2 used as [Co] source
[Cp*Co(C6H6)][PF6]2
standard conditions (using 2a)
63
trace
trace
n.r.
28
a
Reaction conditions: Condition A: 1a (0.1 mmol), Co(acac)3 (0.01
mmol), Ag2CO3 (0.25 mmol), 2 (0.12 mmol), sodium benzoate (0.02
mmol), and 1,3-bis(trifluoromethyl)benzene (1 mL) heated at 150 °C
b
for 18 h under argon. Isolated yields.
and Ag2CO3 as the oxidant in toluene heated at 150 °C (bath
temperature) for 18 h to yield the expected product 3a in 31%
isolated yield (Table 1, entry 1). The solvent dependency of the
same reaction was carried out (Table 1, entries 1−4), and we
found that the reaction proceeds efficiently in 1,3-bis(trifluoro-
methyl)benzene compared to other solvents to afford 3a in an
isolated yield of 80% (Table 1, entry 4).21 Notably, the efficiency
of the reaction was significantly affected in the absence of
PhCO2Na (Table 1, entry 5) and clearly revealed the
coordination of the 8-aminoquinolylamide to the cobalt complex
followed by a ligand exchange that was accelerated by the base.22
By lowering the temperature we obtained the product in lower
yield (Table 1, entry 10), and no reaction was observed in the
absence of the cobalt catalyst (Table 1, entry 11). Among a
variety of different cobalt complexes, Co(acac)3 proved to give
optimal results (Table 1, entries 4, 12−15). Gratifyingly,
ethynyltriisopropylsilane (2a) was also effective for this
alkynylation reaction and gave 3a in lower yield (28%) under
optimal conditions (Table 1, entry 16). Notably, no (or trace)
alkynylation was observed in the absence of an oxidant.23
With an optimized catalytic system in hand (Table 1), we set
out to probe its versatility in the C(sp2)-alkynylation of various
substituted amides. The developed synthetic methodology is
general and has a broad substrate scope. As shown in Scheme 1,
the present cobalt-catalyzed alkynylation is compatible with
various benzamides containing an electron-rich or deficient
substituent, affording the expected alkynylated products in good
to excellent yields. Alkynylation of ortho-substituted benzamides
(1a−d) containing a range of functional groups, such as alkyl,
methoxy, fluoro, and chloro, survived and gave the mono-
alkynylation products (3a−3d) in good yields (up to 80%). Bis-
alkynylated amides are the precursors of conjugated polymers by
oxidative coupling on catalysts such as with the Cp*Ru catalyst,
a
Reaction conditions: 1 (0.1 mmol), Co(acac)3 (0.01 mmol), Ag2CO3
(0.25 mmol), 2 (0.12 mmol (1a−1d) or 0.25 mmol (1e−1s)),
PhCO2Na (0.02 mmol), and 1,3-bis(trifluoromethyl)benzene (1 mL)
b
c
heated at 150 °C for 18 h under argon. Isolated yields. The ratio of
mono- and bis-alkynylation products is based upon the individual
isolated yields. In the absence of PhCO2Na.
d
as the alkyne groups cannot interact intramolecularly. However,
selective bis-alkynylation of unactivated C−H bonds of
benzamide (1) through a double C−H activation strategy is
difficult and rather rare, as it often tends to afford a mixture of
both mono- and bis-alkynylated amides. Gratifyingly, our
optimal conditions gave the bis-alkynylated product as a single
product with complete selectivity (3e−3i, 3m−3p, and 3r).
Notably, with 3-bromo-N-(quinolin-8-yl)benzamide (1h), the
alkynylation occurred at a sterically hindered position and
yielded bis-alkynylation as a major product in 73% isolated yield.
However, the electron-deficient 3-(CF3)-substituted amides
(1k−1l) underwent the reaction smoothly and gave mono-
alkynation as a single product with moderate yields (75% of 3k
and 40% of 3l), perhaps because of the combination of both
steric hindrance (in case of 1l) and strong electron deficiency. It
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is noteworthy that the synthetically valuable halide substituents
could be reserved under our reaction conditions and can extend
the spectrum for further modification of the products, wherein
synthesis of halide-substituted alkyne derivatives using the
classical approach, the Pd-catalyzed “Sonogashira coupling,” is
extremely difficult. In this regard, benzamides bearing halides
such as chloro, bromo groups (1a, 1g−h, 1j, and 1n) proceeded
efficiently and yielded the corresponding alkynylated products in
good yields under our catalytic conditions. To our delight, a
challenging heteroaromatic amide (1s) selectively gave the
corresponding mono-alkynylated product in good yield (3s in
43% isolated yield) in the absence of PhCO2Na. Selective mono-
alkynylation and sequential bis-alkynylation were achieved
successfully under conditions B and A, respectively (Scheme 2).
substrate (Scheme 4b).25 This finding showed that the acidity of
the ortho C−H bond is important. A similar trend was also
observed in previously reported C(sp2)-alkynylation.7c,d Im-
portantly, the requirement of the oxidant is essential for the
success of the alkynylation, and no alkynylated products were
observed when AgSbF6 (Table 1, entry 9) was used, indicating
the classical electrophilic-type C−H bond activation mechanism
by the cationic cobalt(III) complex can be ruled out.9,20b
On the basis of these experiments and previous reports,20b,26
a
plausible catalytic cycle is outlined in Scheme 5. The first step of
Scheme 5. Plausible Mechanism
Scheme 2. Sequential Bis-alkynylation of 1m
The removal of the directing bidentate auxiliary (8-amino-
quinonyl group) was easily accomplished under mild reaction
conditions.7d Subsequently, the chemoselective removal of the
TIPS group was achieved under standard reaction conditions,
with further conversion to a phenyl group to yield 5 in 72%
overall yield through the Pd-catalyzed Sila−Sonogashira
coupling reaction (Scheme 3).24
the catalytic reaction is the coordination of the amide 1a to the
Co(III) followed by the base assisted or carboxylate assisted C−
H bond cobaltation leading to complex B. The attack of an in situ
generated alkyne radical into complex B gives the intermediate C,
which undergoes reductive elimination to give 3a and generates
the Co(II) species. The oxidation of Co(II) to Co(III) by silver
salts further continues the catalytic cycles. Notably, ethynyl-
triisopropylsilane (2a) was also effective for this alkynylation
reaction and yielded 3a in lower yield (28%) under optimal
conditions (Table 1, entry 16).
Scheme 3. Diversification of Alkynylated Amides
We have also successfully shown the scalability of this catalytic
protocol under mild conditions. In this regard, the present
cobalt-catalyzed alkynylation was tested for gram-scale synthesis
of 3a (4.0 mmol scale), and it worked excellently with an
expected alkynylated product (3a) in 72% yield.25 The reaction
performed in the presence of the radical scavenger 2,2,6,6-
tetramethylpiperidine-1-oxyl (TEMPO; 3 equiv) was completely
inhibited, indicating that the radical reaction pathway could be
involved in the catalytic cycle (Scheme 4a). In addition,
competitive experiments performed with an electron-rich and
deficient amide using (triisopropylsilyl)ethynyl bromide 2
showed that alkynylation is favored with an electron-deficient
The synthetic utility of the versatile cobalt-catalyzed
alkynylation was also demonstrated by further diversification of
the products (Schemes 3 and 6).
Scheme 6. Removal of Directing Group and Click Reaction of
Alkynylated Amide
Scheme 4. Mechanistic Studies
In conclusion, we have reported the first example of expedient
cobalt-catalyzed selective bis-alkynylation of C(sp2)−H bonds of
amides through a double C−H bond activation strategy using
commercially available, inexpensive 8-aminoquinoline as a
removable bidentate directing group. The present ortho-
alkynylation has a broad substrate scope as well as functional
group tolerance and can thereby be scaled up in gram-scale
synthesis.
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DOI: 10.1021/acs.orglett.6b00095
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b00095.
■
S
Details on experimental procedures, characterization data
of all compounds and copies of NMR spectra (PDF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: eb.raman@ncl.res.in.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research is supported by the SERB (SB/FT/CS-065/2013),
EMR/2015/30, and CSIR-NCL. V.G.L. thanks CSIR and G.J.
thanks UGC for fellowships. E.B. thanks S. Sen for his
suggestions.
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(21) Further screening using common solvents, including apolar
arenes (o-xylene and PhCl) or polar DMF, DMSO, DMA, DCE, and
CF3CH2OH, proved ineffective in the C−H bond alkynylation.
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yield of the alkynylated product 3a under optimal conditions (see the
Table 1, entries 8−9).
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