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Iridium-catalyzed oxidative Ar–H/Ar–H cross-

Cite this: Org. Chem. Front., 2018, 5,
coupling of primary benzamides with thiophenes†
2930
Guangying Tan, Chunhao Ran and Jingsong You *

(2-Thienyl)benzamide frameworks are prevalent in pharmaceuticals and advanced materials. Herein, we

Received 31st July 2018,
Accepted 6th September 2018
DOI: 10.1039/c8qo00796a
rsc.li/frontiers-organic
disclose an iridium-catalyzed oxidative Ar–H/Ar–H cross-coupling reaction of primary benzamides with
thiophenes, which provides a rapid pathway to (2-thienyl)benzamide skeletons. Furthermore, the coupled
products can be transformed to the corresponding important thiophene-fused 1-isoquinolinones via a
copper-catalyzed intramolecular annulation.

(2-Thienyl)benzamide and thiophene-fused 1-isoquinolinone

frameworks are prevalent in pharmaceuticals and advanced
materials (Scheme 1).1,2 Consequently, the efficient synthesis
of such structures is a longstanding interest for synthetic che-
mists. Although numerous strategies have been developed,
most of them are dependent on transition metal-catalyzed
C–X/C–M coupling reactions, which generally suffer from
tedious multistep synthesis, inaccessible synthetic precursors,
and poor substrate generality.1–3 Alternatively, transition metal-
catalyzed oxidative Ar–H/Ar–H cross-coupling between two
Scheme 1 Pharmaceuticals and advanced materials containing the
(hetero)arenes has been recently identified as one of the most (2-thienyl)benzamide or thiophene-fused 1-isoquinolinone motif.
straightforward approaches for the construction of bi(hetero)
aryl motifs due to obvious step and atom advantages.4,5 Given
that primary benzamides are easily available, their oxidative
Ar–H/Ar–H cross-coupling reactions with thiophenes would be auxiliary group is indispensable. To the best of our knowledge,
a straightforward route to diverse (2-thienyl)benzamides. transition metal-catalyzed oxidative Ar–H/Ar–H cross-coupling
In recent years, transition metal-catalyzed oxidative between primary benzamides and heteroarenes has not been
Ar–H/Ar–H cross-coupling reactions of tertiary and secondary achieved yet, largely because the non-protected NH2 is dis-
benzamides with thiophenes have attracted much attention favoured in these oxidative reactions. As part of our ongoing
(Scheme 2a).6–9 For example, in 2012, Glorius and coworkers efforts regarding the iridium-catalyzed C–H activation of thio-
demonstrated the first example of rhodium(III)-catalyzed oxi-
dative heteroarylation of N,N-diisopropyl benzamides with
thiophenes.6 Later on, the Su group developed a rhodium-cata-
lyzed amide-directed oxidative heteroarylation of pyridines.7
Recently, the Shi and Yin groups reported a copper- or nickel-
catalyzed oxidative cross-coupling reaction of benzamides and
thiophenes with the aid of removable bidentate auxiliary
(( pyridin-2-yl)isopropyl and 8-quinolinyl), respectively.8,9
Although these methods are efficient, the arene substrates are
limited to tertiary and secondary benzamides and a strong

Key Laboratory of Green Chemistry and Technology of Ministry of Education,

College of Chemistry, Sichuan University, 29 Wangjiang Road, Chengdu 610064,
P. R. China. E-mail: jsyou@scu.edu.cn Scheme 2 Transition metal-catalyzed oxidative heteroarylation of
† Electronic supplementary information (ESI) available: Experimental procedures benzamides with thiophenes. PIP = ( pyridin-2-yl)isopropyl. Q =
and characterization data. See DOI: 10.1039/c8qo00796a 8-quinolinyl.

2930 | Org. Chem. Front., 2018, 5, 2930–2933 This journal is © the Partner Organisations 2018

Organic Chemistry Frontiers
phenes,10 we herein disclose an iridium-catalyzed oxidative
Ar–H/Ar–H cross-coupling of primary benzamides with thio-
phenes (Scheme 2b).
Our investigation commenced with the reaction between
benzamide (1a) and benzothiophene (2a) (Table 1). To our
delight, the desired coupled product 2-(benzo[b]thiophen-2-yl)
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benzamide (3a) was obtained in 70% yield when the optimal
catalytic system was identified as [IrCp*Cl2]2 (5 mol%) and
Ag2O (3.0 equiv.) in HFIP (hexafluoro-isopropanol) at 120 °C
under an air atmosphere for 6 h (Table 1, entry 1). The control
experiments demonstrated that both [IrCp*Cl2]2 and Ag2O
were indispensable for this reaction (Table 1, entries 2 and 3).
The addition of AgSbF6 (20 mol%) did not improve the yield of
3a (Table 1, entry 4) and the reaction of 1a with 2a could
proceed smoothly under an N2 atmosphere (Table 1, entry 5).
On replacing [IrCp*Cl2]2 with [IrCp*(MeCN)3][SbF6]2 and
[IrCp*(C6H6)][SbF6]2, the yields of 3a were reduced to 68% and
49%, respectively (Table 1, entries 6 and 7). Moreover, by
employing [RhCp*Cl2]2 or [Cp*Co(CO)I2] instead of [IrCp*Cl2]2
as the catalyst, [RhCp*Cl2]2 produced 3a in 24% yield, and
[Cp*Co(CO)I2] did not give any desired product (Table 1, entry
8). Other metal oxidants such as Ag2CO3, AgOAc, and Cu(OAc)2
showed inferior efficiency, and the transformation was shut
down completely when employing AgNO3 as the oxidant
(Table 1, entries 9 and 10). Solvents significantly affected the
reactions and HFIP was proven to be superior to DCE, 1,4-
dioxane, toluene, and tBuOH (Table 1, entry 11). The addition
of 1.0 equiv. of PivOH was of little value to promote the reac-
tion (Table 1, entry 12). Reducing the dosage of Ag2O or 2a led
Table 1 Optimization of the reaction conditionsa
Entry Variation from the standard conditions Yieldb (%)
1 — 70
2 Without [IrCp*Cl2]2 N.R.
3 Without Ag2O N.R.
4 With AgSbF6 (20 mol%) 65
5 Under N2 atmosphere 68
6 10 mol% of [IrCp*(MeCN)3][SbF6]2 instead of 68
[IrCp*Cl2]2
7 10 mol% of [IrCp*(C6H6)][SbF6]2 instead of 49
[IrCp*Cl2]2
8 [RhCp*Cl2]2 or [Cp*Co(CO)I2] instead of 24, N.D.
[IrCp*Cl2]2
9 Ag2CO3, AgOAc, or AgNO3 instead of Ag2O 39, 44, N.D.
10 Cu(OAc)2·H2O instead of Ag2O 8
11 DCE, 1,4-dioxane, toluene, or tBuOH instead N.D., 6, N.D.,
of HFIP 15
12 Addition of PivOH (1.0 equiv.) 61
13 2.0 equiv. of Ag2O or 2a 55, 41
a
Reaction conditions: 1a (0.2 mmol), 2a (0.6 mmol), [IrCp*Cl2]2
(5.0 mol%), and Ag2O (0.6 mmol) at 120 °C for 6 h under an air atmo-
sphere. b Isolated yield.
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to a reduced yield of 3a (Table 1, entry 13). In addition, the
diheteroarylation product was not detected under the standard
reaction conditions.
With the optimal conditions in hand, the scope of primary
benzamides was first tested. To our delight, various benz-
amides could react with benzothiophene (2a). Benzamides
bearing electron-donating groups such as methyl, methoxyl,
ethyl, butyl, and ethoxyl at the meta- or para-position of the
phenyl ring smoothly underwent this coupling reaction, deli-
vering the desired products in good yields (Table 2, 3a–3i).
This protocol was also compatible with a variety of electron-
withdrawing groups such as halide (F and Cl) and ester
(Table 2, 3j–3l). 1-Naphthamide and 2-naphthamide also par-
ticipated in this oxidative heteroarylation, producing 3m and
3n in 66% and 72% yields, respectively. Moreover, this method
could be extended to thiophene carboxamides, affording the
heteroaryl skeletons in synthetically useful yields (Table 2, 3o–
3p). Other heteroarene carboxamides such as furan carboxa-
mides, indole carboxamides, and pyridine carboxamides were
incompatible with this protocol.
Next, we examined the scope of thiophenes using benz-
amide (1a) as the coupling partner. As shown in Table 3,
various thiophenes possessing both electron-rich and electron-
deficient groups at the α-position could afford the ortho-
heteroarylated benzamides in good yields (Table 3, 4a–4e).
3-Methoxylthiophene and 3-bromothiophene reacted at the
C2-position of the thienyl ring with high selectivity (Table 3,
Table 2 Scope of primary benzamidesa,b
a
Reactions were performed with 1 (0.2 mmol), 2a (0.6 mmol),
[IrCp*Cl2]2 (5.0 mol%), and Ag2O (0.6 mmol) at 120 °C for 6 h under
an air atmosphere. b Isolated yield.
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Table 3 Scope of thiophenesa,b
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a
Reactions were performed with 1a (0.2 mmol), 2 (0.6 mmol),
[IrCp*Cl2]2 (5.0 mol%), and Ag2O (0.6 mmol) at 120 °C for 6 h under
an air atmosphere. b Isolated yield.
4f–4g). Bromide, which is useful for further synthetic trans-
formations, was compatible with this protocol (Table 3, 4g–4i).
5-Chlorobenzothiophene, 3-methylbenzothiophene, and
thieno[3,2-b]thiophene were compatible with this reaction
(Table 3, 4j–4l).
Considering the synthetic usefulness of this oxidative
Ar–H/Ar–H cross-coupling method, we performed a gram-scale
reaction of 1a with 2a. To our delight, 3a could be obtained in
62% yield under the standard conditions for 10 h (Scheme 3a).
Additionally, the coupled product 3a could be converted into
benzo[4,5]thieno[3,2-c]isoquinolin-5(6H)-one (5) via a copper-
catalyzed intramolecular annulation (Scheme 3b).11 It is worth
noting that compound 5 could be potentially used as a HCV
protease inhibitor (Scheme 1).2a
To gain some insights into the mechanism of these reac-
tions, deuteration experiments were conducted (Scheme 4a–c).
Treating benzamide (1a) with 20 equiv. of D2O in either the
absence or presence of 2a under the standard conditions for
1 h did not led to any ortho-deuterated benzamide (Scheme 4a
Scheme 3 Gram-scale reaction and the conversion of 3a.
2932 | Org. Chem. Front., 2018, 5, 2930–2933
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Scheme 4 Mechanistic studies.
and c) and the conversions of 1a and 2a were 47% and 23%,
respectively, and 3a was obtained in 34% yield in the presence
of 2a (Scheme 4c), while significant deuterations (20% and
25%) occurred at the non-protected NH2 group. These results
suggested that the cleavage of the ortho-C–H bond of 1a could
be an irreversible process and the NH2 auxiliary might partici-
pate in the ortho-C–H activation process. The same experiments
of 2a with D2O were also run in either the absence or presence
of 1a and 48% and 44% of 2a were deuterated, respectively
(Scheme 4b and c), suggesting that the C–H metalation of 2a
could be a reversible process. Moreover, a kinetic isotopic effect
(KIE) of 1.12 was observed from two parallel competition reac-
tions between 1a or [D5]-1a with 2a (Scheme 4d). Similarly, the
parallel reactions of 1a with 2a or [D]-2a did not yet give a sig-
nificant KIE value (kH/kD = 1.24) (Scheme 4e). These above
results reveal that the C–H cleavage of 1a and 2a might not be
related to the rate-determining step.12
In light of the above results and previous reports,13 a plaus-
ible mechanistic pathway for this iridium-catalyzed ortho-het-
eroarylation is proposed in Scheme 5. Initially, the coordi-
nation of the NH2 group of 1a to Ir(III) species and subsequent
ortho-C–H activation gave the five-membered intermediate
IM1, which further reacts with 2a in the presence of Ag2O to
afford the high-valent iridium(V)-aryl intermediate IM2. Then,
IM2 undergoes a reductive elimination to produce the desired
product 3a along with the release of the reactive Ir(III)Cp*
species.
In summary, we have disclosed an iridium-catalyzed oxi-
dative Ar–H/Ar–H cross-coupling reaction of primary benz-
amides with thiophenes, which provides a rapid pathway to
(2-thienyl)benzamides. The protocol features easy accessibility,
broad substrate scope, and good tolerance of functional
groups. Moreover, the coupled products can be converted to
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Scheme 5 Plausible mechanistic pathway.
thiophene-fused 1-isoquinolinone derivatives via a copper-
catalyzed intramolecular annulation. Further efforts are cur-
rently under way for the application of this methodology.
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
We thank the financial support from the National NSF of
China (No 21432005) and the Graduate Student’s Research
and Innovation Fund of Sichuan University (Grant No.
2018YJSY006).
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