Cobalt-catalyzed cyclization of benzamides with alkynes: A facile route to isoquinolones with hydrogen evolution

Article abstract of DOI:10.1039/c8ob01924j

The reaction of benzamides with alkynes assisted by an 8-aminoquinoline ligand in the presence of Co(OAc)₂·4H₂O and pivalic acid under an air atmosphere provided isoquinolone derivatives in good to excellent yields. In this reaction,

Full text of DOI:10.1039/c8ob01924j

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Takeharu Haino et al.
Solvent-induced emission of organogels based on tris(phenylisoxazolyl)
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Cobalt-Catalyzed Cyclization of Benzamides with Alkynes: A Facile
Route to Isoquinolones with Hydrogen Evolution
Ramasamy Manoharana and Masilamani Jeganmohanb*
Received 00th January 20xx,
Accepted 00th January 20xx
.
DOI: 10.1039/x0xx00000x
The reaction of benzamides with alkynes assisted by 8-aminoquinoline ligand in the presence of Co(OAc)2 4H2O and pivalic
acid under air provided isoquinolone derivatives in good to excellent yields. In the reaction, the active Co(III) species is
regenerated by the reaction of Co(I) species with pivalic acid under air with hydrogen evolution. The proposed mechanism
was supported by competition experiments, deuterium labelling studies, radical scavenger experiment and kinetic studies.
www.rsc.org/
Introduction
species from Co(I) species (eq 1).5b Later, this concept has been
Isoquinolone is an important heterocyclic structural unit
which presents in various natural products, biologically active
molecules and conjugated materials.1 In addition, isoquinolone
derivatives are widely used as a key intermediate in various
organic transformations.1 Several methods are available in
literature for synthesizing isoquinolone derivatives.2 Among
them, the transition-metal-catalyzed oxidative cyclization of
benzamides with carbon-carbon π-components via C-H bond
activation is an efficient method to construct isoquinolones
from easily available starting materials.3 For this type of
transformation, the second and third row transition metal
complexes such as Pd, Rh, Ru and Ir are widely employed
which are less abundant in the nature.3 The use of cheaper,
more abundant and environmentally benign first row
transition metal complexes such as Fe, Co, Cu and Ni as
catalysts in the C-H bond activation reaction is highly
desirable.4 In this context, very recently, a cobalt complex has
gained tremendous attention in the C-H bond functionalization
reaction due to the low toxicity as compared with other early
transition metals.5 Particularly, a simple and easily affordable
Co(OR)2-catalyzed C-H bond functionalization reaction assisted
by the auxiliary ligand has gained much attention in recent
years.5 In 2014, Daugulis’s group reported the oxidative
cyclization of benzamides with alkynes assisted by 8-
successfully extended for various heterocyclic molecules in the
presence of metal oxidants and base.5
O
O
O
Co(OAc)2.4H2
O
.
Co(OAc)2 4H2O
Q
Q
Q
N
N
H
N
(10 mol %)
(10 mol %)
NaOPiv, O2
(1)
R2
PivOH (1.3 eqiv)
under air
H
R2
R1
R2
R1
R1
Mn(OAc)2
(1.0 equiv)
R2
R2
R2
present work
previous work
In the metal-catalyzed oxidative cyclization reaction, the
oxidation step such as a metal with lower oxidation state into
the higher oxidation state [Rh(I) to Rh(III), Co(I) to Co(III), Pd(0)
to Pd(II), and Ru(0) to Ru(II)] is required to regenerate the
active catalyst. Generally, a stoichiometric amount of inorganic
or organic oxidants is required to regenerate the active
catalyst. Particularly, in the Co(II)-catalyzed reaction,
a
stoichiometric amount Mn(OAc)2 or silver salt along with O2
was used as an oxidant.4-5 An equivalent amount of reduced
form of metal salt was formed as a by-product. To avoid the
oxidants, several new methods such as having internal
oxidizing agent on the directing group,6 molecular oxygen as a
terminal oxidant7 and electrochemical oxidant8 are developed
in the literature. Recently, we have reported redox-neutral
ruthenium(II)-catalyzed C-H alkenylation reaction by using
carboxylic acid with the elimination of hydrogen.9 In the
reaction, the alkenylation was done in the ruthenium (II)
oxidation state and the typical Ru(0) to Ru(II) oxidation step
was avoided. This result prompted us to explore the possibility
of cobalt-catalyzed cyclization of aromatic amides with alkynes
in the presence of carboxylic acid in the redox-neutral version.
.
aminoquinoline ligand in the presence of Co(OAc)2 4H2O as a
catalyst, stoichiometric amount of Mn(OAc)2 (1.0 equiv) as a
co-oxidant, NaOPiv (2.0 equiv) as a base and O2 as a terminal
oxidant providing isoquinolone derivatives. In the reaction,
Mn(OAc)2 and NaOPiv was used to regenerate the active Co(III)
Results and discussion
Herein, we report
a cobalt-catalyzed 8-aminoquinoline-
directed oxidative cyclization of benzamides with alkynes
giving substituted isoquinolones with the liberation of
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hydrogen in good to excellent yields (eq 1). The present products 3ia and 3ja in 92% and 95% yields, respectively
cyclization reaction was compatible with various functional (entries 8 and 9). 2,3-Dimethoxy benzamide 1k and 1-
group substituted benzamides as well as internal and terminal naphthylamide 1l yielded cyclized products 3ka and 3la in 84%
alkynes and 1,3-diynes. Treatment of benzamide having 8- and 60% yields, respectively (entries 10 and 11).
aminoquinoline ligand 1a with diphenylacetylene (2a) (1.3
.
equiv) in the presence of Co(OAc)2 4H2O (10 mol %) and pivalic
Table 1 Scope of substituted benzamidesa
Entry
Benzamide 1
Product 3
Yield (%)b
acid (1.3 equiv) in chlorobenzene under air at 100 °C for 4 h
gave isoquinolone derivative 3aa in 93% yield (Scheme 1).
Along with product 3aa, H2 gas was formed as a side product in
the reaction. It was confirmed by GC analysis with a TCD
detector (see ESI for more details). It is important to note that
the cyclization reaction proceeds very smoothly without any
metal oxidant.
1
2
3
4
5
6
7
1b: R1 = H
1c: R1 = OMe
1d: R1 = I
1e: R1 = Br
1f: R1 = Cl
1g: R1 = F
1h: R1 = CF3
3ba: R1 = H
3ca: R1 = OMe
3da: R1 = I
94
58
46
82
87
54
66
3ea: R1 = Br
3fa: R1 = Cl
3ga: R1 = F
3ha: R1 = CF3
Scheme 1 Oxidative cyclization of benzamide 1a with 2a
Initially, the cyclization reaction was examined with various
solvents such as toluene, tert-amyl alcohol, NMP, iso-PrOH,
CF3CH2OH, CH3CN, DMF, chlorobenzene, 1,2-dichloroethane,
DMSO and THF. Among them, chlorobenzene was very
effective, giving product 3aa in 93% yield. 1,4-Dioxane,
toluene, iso-PrOH, CF3CH2OH, and THF were partially effective,
providing 3aa in 56-29% yields. Other solvents were totally
ineffective. The same reaction was tried without pivalic acid
8
9
1i: R1 = Me
1j: R1 = Ph
3ia: R1 = Me
3ja: R1 = Ph
92
95
10
.
84
60
51
under air in the presence of Co(OAc)2 4H2O. However, product
3aa was observed only in 27% yield. This result clearly reveals
that the pivalic acid is crucial for the success of the reaction.
This observation prompted us to examine various organic acid
sources such as Adm-1-COOH, p-toluic acid, trifluoroacetic
acid, p-toluene sulphonic acid and mesitylenic acid. Among
them, Adm-1-COOH and p-toluic acid were partially effective,
giving 3aa in 72% and 67% yields, respectively. Mesitylenic
acid was less effective, giving product 3aa in 43% yield. The
cyclization reaction was tried in the presence of NaOPiv (1.3
equiv) instead of PivOH under similar reaction conditions. In
the reaction, product 3aa was not observed. The cyclization
reaction was tried under inert atmosphere with degassed
chlorobenzene. In the reaction, only trace amount of product
3aa was observed. This result clearly reveals that the air
atmosphere along with pivalic acid is crucial for the reaction
(see ESI for the detailed optimization studies).
11
12
O
X
N
The scope of cyclization reaction was examined with various
substituted benzamides under the optimized reaction
conditions (Table 1). Benzamide 1b and 4-methoxybenzamide
1c reacted with 2a providing the expected isoquinolone
derivatives 3ba and 3ca in 94% and 58% yields, respectively
(entries 1 and 2). Benzamides having halogen groups such as I,
Br, Cl and F at the para position 1d-g reacted with 2a providing
cyclized products 3da-ga in 46%, 82%, 87% and 54% yields,
respectively (entries 3-6). An electron-withdrawing CF3-
substituted benzamide 1h was also effective for the reaction,
affording 3ha in 66% yield (entry 7). ortho Methyl-1i and
phenyl-1j substituted benzamides reacted with 2a giving
H
N
H
13
14
1n: X=S
3na: X=S
3oa: X=O
89
79
1o : X=O
aAll reactions were carried out using 1b-n (50 mg), 2a (1.3 equiv), Co(OAc)2 4H2O
(10 mol %) and pivalic acid (1.3 equiv) in chlorobenzene (3.0 mL) under air at 100
°C for 4-36 h. bIsolated yield.
.
A sterically hindered 2-bromo-4,5-dimethoxy benzamide 1m
reacted with 2a giving cyclized product 3ma in 51% yield (entry
12). The present reaction was compatible with heterocyclic 2-
thiophene and 2-furan amides 1n and 1o. In these reactions,
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products 3na and 3oa were observed in 89% and 79% yields and 94% yields, respectively, in a highly selective manner.
respectively (entry 13 and 14). Functional group such as OH 2l and silyl 2m substituted
To examine the regioselective outcome of benzamides, alkynes were also effectively involved in the reaction,
unsymmetrical benzamides 1p-t were subjected for the providing cyclized products 3al and 3am in 75% and 92%
cyclization reaction with 2a (Scheme 2). The reaction of meta yields, respectively, in a highly selective manner. Methyl
methoxy 1p and meta fluoro 1q substituted benzamides with propiolate (2n) was also compatible for the reaction giving
2a produced regioisomeric cyclized products 3pa and 3pa’ in cyclized products 3an and 3an’ in 94% yield in a 1:0.08
combined 65% yields with 1:0.07 ratio and 3qa and 3qa’ in regioisomeric mixtures. It was expected that the reaction
combined 92% yields in 1:0.5 ratio, respectively. Interestingly, proceeds via a Co-alkynyl intermediate which leads to the
meta iodo benzamide 1r reacted with 2a at the C-6 position regioselectivity observed in products 3ai-an in the case of
producing cyclized product 3ra in 57% yield in a highly terminal alkynes.5s The present methodology was further
regioselective manner. Similarly, 3,4-dimethoxybenzamide 1s extended with substituted 1,3-diynes (Scheme 5). Symmetrical
reacted with 2a at the C-6 position giving product 3sa in 69% 1,3-diynes having phenyl 2o, ether 2p and n-hexyl 2q groups
yield in a regioselective manner. Finally, 3-furan amide 1t reacted with 1a providing cyclized products having internal
reacted with 2a furnishing corresponding cyclized product 3ta alkynes 3ao-aq in 85%, 79% and 89% yields, respectively. In
in 74% yield, in which, the C-H activation takes place at the C-2 case of 1,3-diynes there would be a coordination between
position.
neighbouring alkyne and cobalt intermediate formed during
insertion which resulted in the observed regioselectivity of
products 3ao-aq 5t
.
N
N
O
Co(OAc)2.4H2O (10 mol %)
pivalic acid (1.3 equiv)
O
H
R2
R2
N
H
100 °C
chlorobenzene
N
Me
R2
Me
3ab-ah R2
1a
2b-h
N
O
N
O
N
N
O
N
N
O
Me
Me
Me
S
S
3ab, 90%
O
3ad, 88%
3ac, 92%
N
N
N
N
N
O
O
N
N
O
O
N
O
Me
Me
Me
Me
O
3ae, 86% (1:0.15 )
3ah, 88% (1:0.22 )
3af, 87% (1:0.01)
3ag, 80% (1:0.09)
Scheme 3 Scope of symmetrical and unsymmetrical alkynes
Scheme 2 Scope of unsymmetrical benzamides
The scope of cyclization reaction was examined with
symmetrical and unsymmetrical alkynes 2b-n (Scheme 3). The
reaction of less reactive symmetrical aliphatic alkynes such as
3-hexyne
yielding cyclized products 3ab and 3ac in 90% and 92% yields,
respectively. Similarly, 1,2-di(thiophen-2-yl)ethyne 2d
(2b) and 1,4-dimethoxybut-2-yne (2c) with 1a
(
)
reacted with 1a providing cyclized product 3ad in 88% yield.
Unsymmetrical alkynes such as 1-phenyl-1-propyne (2e), 1-
phenyl-1-butyne (2f) and 1-phenyl-1-hexyne (2g) reacted with
1a giving regioisomeric mixtures of cyclized products 3ae and
3ae’, 3af and 3af’ and 3ag and 3ag’ in 80-87% yields in 1:0.09
to 1:0.15 ratios, respectively. Ethyl 2-butynoate (2h) reacted
with 1a providing regioisomeric mixture of products 3ah and
3ah’ in 88% yield in a 1:0.22 ratio.
Scheme 4 Scope of terminal alkynes
It is important to note that the substituted terminal alkyne was
also compatible for the reaction (Scheme 4). Phenylacetylene
To understand the reaction mechanism, competition
experiments and deuterium labelling studies were performed
(Scheme 6). The reaction between a 1:1 mixture of 4-methoxy
benzamide (1c) and 4-fluorobenzamide (1g) with 2a under
(
2i), 1-hexyne (2j) and cyclohexylacetylene (2k) reacted with
1a providing cyclized products 3ai, 3aj and 3ak in 94%, 95%
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similar reaction conditions provided products 3ba and 3ga in some non-productive coordination of amide with cobalt
16% and 19% yields, respectively (Scheme 6a). This result involved which renders the formation of desired product and
clearly reveals that the electrophilic cobaltation as a key step is alkyne exhibited first order kinetics. It is important to mention
unlikely in the reaction. Meanwhile, the competition reaction that the order of benzamide can vary depending upon the
of 2a and 2i with 1a under similar reaction conditions giving reaction conditions and coupling partner. 5l,5p
only cyclization product 3ia in 86% yield (Scheme 6b). In the Based on the known cobalt-catalyzed C-H bond cleavage
reaction, product 3aa was not observed. In the competition reactions and the observation of hydrogen gas, a possible
experiment between 1b and [D]-1b, the distribution value of reaction mechanism is proposed in Scheme 7. The reaction
1.12 of the products 3ba and [D]-3ba were observed by NMR starts with aerobic oxidation of cobalt(II) to Co(III) in the
analysis (Scheme 6c). A similar type of result was also observed presence of pivalic acid under air followed by the irreversible
when the reaction was carried out in the two parallel manners. C-H bond cleavage providing intermediate
5
. Coordinative
into a C-Co bond of intermediate affords
Reductive elimination of intermediate 6
Furthermore, amide [D]-1b with 2a under the reaction insertion of
conditions, yielding product [D]-3ba in 52% yield with the loss intermediate
2
5
6.
of 5% of ortho deuterium (95% of deuterium was retained, provides cyclized product
3
and Co(I) species
converts into Co(III)-H intermediate
of PivOH.10 Later, intermediate
7
. Later, the Co(I)
Scheme 6d).
species
7
8
in the presence
8
converts into Co(II) spices
probably via a homolytic or heterolytic cleavage along with the
hydrogen gas. Finally, the active catalyst was generated by
9
4
the aerobic oxidation of cobalt(II) to Co(III) in the presence of
pivalic acid. In the reaction, organic acid plays a dual role; it
acts as a base to deprotonate the ortho aromatic C-H bond and
oxidizing the reduced form of Co(I) to Co(III).
Scheme 5 Scope of substituted 1,3-diynes
Scheme 7 Proposed mechanism
Conclusions
In conclusion, we have demonstrated a cobalt-catalyzed
cyclization of benzamides with alkynes assisted by 8-
aminoquinoline ligand providing isoquinolones in good yields.
In the reaction, the active Co(III) species was regenerated by
the reaction of Co(I) species with pivalic acid under air with the
evolution of hydrogen gas. The mechanistic investigation
clearly reveals that the irreversible C−H bond cleavage might
not be the rate-limiting step and the radical intermediate may
be involved in the reaction.
Scheme 6 Preliminary mechanistic studies
These results clearly indicating that the irreversible C−H bond
cleavage could not be the rate-limiting step (see SI). The
present cyclization reaction was completely inhibited in the
presence of radical scavengers TEMPO and BHT under the
reaction conditions. This observation shows that the radical Conflicts of interest
intermediate may be involved in the reaction. Further, the
There are no conflicts to declare
kinetic experiments were performed to determine the rate
laws of the reaction. The order with respect to benzamide was
found to be approximately -0.5 which shows that there may be
Acknowledgements
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We thank the DST-SERB (EMR/2014/000978), India for the
support of this research. R. M. thank the CSIR for a fellowship.
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General Information. All reactions were carried out under the
air atmosphere in flame-dried glassware. Syringes which were
used to transfer anhydrous solvents or reagents were purged
with nitrogen prior to use (three times). Dry solvents were
used for the reaction. Column chromatographical purifications
were performed using SiO2 (120-200 mesh ASTM) from Merck
if not indicated otherwise. Abbreviations for signal coupling
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General Procedure for Synthesis of Isoquinolone derivatives
(GP 1)
‐
To a 15-mL pressure tube containing Co(OAc).4H2O (10 mol %),
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1 (50 mg, 1 equiv), alkynes 2 (1.3 equiv),
chlororobenzene 3 mL and pivalic acid (1.3 equiv) were added
under open air conditions.(Liquid alkynes were added via a
micro pipette after the addition of pivalic acid). After that, a
screw cap was used to cover the tube. Again, the reaction
mixture was stirred at room temperature for 5 minutes. Then,
the reaction mixture was allowed to stir at 100 °C for indicated
time. After cooling to ambient temperature, the reaction
mixture was diluted with CH2Cl2, filtered through Celite and
the filtrate was concentrated. The crude residue was purified
through a silica gel column using hexanes and ethyl acetate as
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General Procedure for Synthesis of Isoquinolone derivatives
(GP 2)
4
To a 10-mL R. B flask fitted with reflux condenser containing
Co(OAc).4H2O (10 mol %), amides
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(1.3 equiv), chlororobenzene 3 mL and pivalic acid (1.3 equiv)
were added under open air conditions.(Liquid alkynes were
added via a micro pipette after the addition of pivalic acid).
After that, the reaction mixture was stirred at room
temperature for 5 minutes. Then, the reaction mixture was
allowed to stir at 100 °C for indicated time. After cooling to
ambient temperature, the reaction mixture was diluted with
CH2Cl2, filtered through Celite and the filtrate was
concentrated. The crude residue was purified through a silica
gel column using hexanes and ethyl acetate as eluent to give
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a Department of Chemistry, Indian Institute of Science Education and
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5
b Department of Chemistry, Indian Institute of Technology Madras, Chennai
600036, India; E-mail: mjeganmohan@iitm.ac.in
† Electronic Supplementary Information (ESI) available: Detailed
experimental
procedures
and
spectroscopic
data.
See
DOI: 10.1039/b000000x/
Ackermann, ACS Catal., 2015,
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