Direct c-h/c-h cross-coupling of benzimidates with heteroarenes to access biheteroaryl-2-carbonitriles

Article abstract of DOI:10.1039/c9cc05314j

A Rh-catalyzed C-H/C-H oxidative cross-coupling reaction of benzimidates with heteroarenes is developed, yielding biheteroaryl-2-carbonitriles directly after in situ dealcoholization. This protocol features high atom- and step-economy, and a broad substrate scope with good functional group tolerance.

Full text of DOI:10.1039/c9cc05314j

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DOI: 10.1039/C9CC05314J
COMMUNICATION
Direct C–H/C–H Cross-Coupling of Benzimidates with
Heteroarenes to Access Biheteroaryl-2-carbonitriles
Zhigang Wang, Fei Wang, Zheng Liu, Shuang He, Xingwen Pu, Yudong Yang, and Ge Gao*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
A Rh-catalyzed C–H/C–H oxidative cross-coupling reaction of arylboronic pinacol esters directly provided bi(hetero)aryl-2-
benzimidates with heteroarenes is developed, yielding carbonitriles in solvent dimethoxyethane, while the imidate
biheteroaryl-2-carbonitriles directly after in situ dealcoholization. group remained products, bi(hetero)aryl-2-carbimidates were
This protocol features high atom- and step economy, and a broad obtained in trifluoroethanol (Scheme 1c).8 However, these
substrate scope with good functional group tolerance.
methods still need to preactivate one coupling partner.
[Pd]/L
C-X/C-H type
CN
Bi(hetero)aryl-2-carbonitriles are useful intermediates widely
used in industrial synthesis,1 as the cyano group can be
conveniently converted into various functional groups,2 such as
imidate, aldehyde, carboxylic acid, amide, tetrazolium etc.
Moreover, bi(hetero)aryl-2-carbonitriles can also be utilized to
construct heteroatom-containing polycyclic aromatics, such as
fluorenones, dibenzopyranones, benzoisoquinolines and
benzoisoquinolinones.3 Classical transition-metal catalyzed C–
X/C–M cross-coupling reactions4 between benzonitriles and
(hetero)arenes provide reliable synthetic strategy toward these
scaffolds, but both substrates need either prehalogenation or
premetalation. Especially, site selective ortho-activation is
required for benzonitrile, but there is no general and
straightforward protocol available. During the past decades, the
fast development of C–H bond activation strategy has improved
the synthetic methodology. For example, Doucet and Hierso et
CN
H
HetAr
+
+
HetAr
X
a) Doucet &
Hierso's work
[Pd]
C-H/C-X type
CN
CN
R
R
R
X
Ar
(Het)Ar
b) Sun's work
H
[Rh]
C-H/C-M type
(pin)B (Het)Ar
EtO
EtO
c) Yang's work
NH
NH
R
[Rh]
C-H/C-H type
+
(Het)Ar
H
H
HetAr
d) This work
Scheme 1. Cross-coupling reactions for the synthesis of
bi(hetero)aryl-2-carbonitriles.
No doubt, the direct C–H/C–H cross-coupling of
(hetero)arenes is the most efficient strategy to access
bi(hetero)aryl-2-carbonitriles in regard to the atom- and step-
economy.9 Due to our continuous interest in this field,10
preliminary explorations of the cross-coupling between
benzonitrile and 2-methylthiophene was conducted. However,
no desired products could be detected, which was attributed to
the weak π-coordination of the nitrile group. Therefore, a
reinforced directing group capable of transforming into the
nitrile group after cross-coupling might be necessary.11
Encouraged by Yang’s work, we report herein a C–H/C–H cross-
coupling reaction of benzimidates with heteroarenes to directly
furnish biheteroaryl-2-carbonitriles under rhodium catalysis.
Our study commenced with the coupling of benzimidate 1a
with 2-methylthiophene 2a under different transition metal
catalysts. Fortunately, the desired 2-(5-methylthiophen-2-
yl)benzonitrile, 3aa, was detected in 14% yield in a Rh-catalyzed
system in the presence of silver fluoride as the oxidant, and
sodium acetate as the additive in 1,2-dichloroethane (DCE) at
al reported
a
Pd-catalyzed cross-coupling of 2-
chlorobenzonitrile with various heteroarenes in the presence of
a special triphosphane ligand (Scheme 1a).5 Sun et al succeeded
in Pd-catalyzed cross-coupling of benzonitriles with
iodobenzenes by taking advantage of the π-coordination of the
nitrile group (Scheme 1b).6 Hong et al developed a ligand-
promoted C–H arylation of simple arenes with aryl bromides,
but only giving 3 examples of biaryl-2-carbonitriles as mixed
regioisomers.7 Very recently, Yang group disclosed that a Rh-
catalyzed cross-coupling reaction between benzimidates and
a. Key Laboratory of Green Chemistry and Technology of Ministry of Education,
College of Chemistry, Sichuan University, 29 Wangjiang Road, Chengdu 610064,
P.R. China.
† Footnotes relating to the title and/or authors should appear here.
Electronic Supplementary Information (ESI) available: [details of any supplementary
information available should be included here]. See DOI: 10.1039/x0xx00000x
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1
120 °C for 24 h, as determined by H NMR analysis (Table 1, hydroxyalkyl, methoxy, cyano, acetyl, benzoyl, formyl, ester and
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entry 1), while iridium and ruthenium catalysts were ineffective halide groups were all compatible. 1a couDpOleId: 1a0t.1t0h3e9/CC59CpCo0s5it3i1o4nJ
(Table S1 entries 2-3). It is noted that 3aa was obtained directly of 2,3-dibromothiophene 2j to afford 3aj in 55% yield. Other
and no extra step to dealcoholize the imidate group to the heteroarenes such as benzothiophenes and benzofuran were
cyano group was needed. The solvent screening showed that also applicable, but N-protected indoles resulted in complicated
tBuOH gave the best yield of 43% (Table 1, entry 1-6 and Table reaction mixtures without any product. Thieno[3,2-b]thiophene
S1, entries 4-14). Interestingly, the optimal solvents for the C–H 2p, an important heterocyclic unit in organic functional
arylation of benzimidates with arylboronic pinacol esters were materials, could successfully couple with 1a to give the
inferior: dimethoxyethane (DME) and trifluoroethanol (TFE) corresponding product 3ap in 62% yield. Various bromo-
gave lower yields of 25% and 12, respectively (Table 1, entries substituted benzothiophenes (2q-s) could couple with 1a to
3-4). The oxidant screening indicated that silver fluoride was the provide the desired products (3aq-3as) with opportunity for
most efficient (Table 1, entries 6-8, and Table S1, entries 16-21). further modification at different positions. To demonstrate the
Other silver salts provided lower yields while copper salts did synthetic practicability of this reaction, a gram-scale reaction of
not work at all. Increasing the amount of AgF to 3.0 equiv led to 1a with 2n was also carried out, provding 3an in a slightly lower
a 50% yield of 3aa (Table 1, entry 9). After testing different yield of 60%.
additives, 0.4 equiv of KOAc increased the yield to 55% (Table 1,
entry 10, and Table S1, entries 23-28). Significant improvement
Scheme 2. Scope of heteroarenesa,b
was achieved after Increasing the amount of 2a to 3.0 equiv,
NH
OEt
CN
[Cp*Rh(MeCN)3](SbF6)2
AgF, KOAc
tBuOH, 100 ºC, 24 h
and 3aa was detected in 72% yield (Table 1, entry 11). Finally,
lowering the reaction temperature to 100 °C promoted the yield
to 80%, and 3aa was isolated in 75% yield after workup (Table
1, entry 12).
R
H
R
+
X
X
H
1a
CN
2
3
CN
CN
CN
Table 1. Optimization of the reaction conditionsa
OH
S
, 75%
S
, 76%
S
, 53%
nHex
S
OMe
2
3ac
3ab
3ad
, 43%
3aa
NH
OEt
CN
CN
CN
CN
CN
[Cp*Rh(MeCN)3](SbF6)2 (5 mol%)
oxidant, additive
H
O
+
solvent, 120 ºC, 24 h
S
S
S
S
, 59%
S
, 62%
S
H
Cl
CN
Ph
3ag
, 66%
3af
3ae
3ah
1a
, 70%
2a
3aa
CN
CN
CN
CN
nHex
Br
Br
Br
Ac
Oxidant
(equiv)
Additive
(equiv)
Entry
Solvent
Yieldb (%)
S
S
S
S
CO2Me
1
2
AgF/2.0
AgF/2.0
NaOAc/0.2
NaOAc/0.2
DCE
toluene
14
20
3ak
3ai
, 72%
3aj
, 55%
, 41%
3al
, 66%
CN
CN
CN
CN
S
3
4
AgF/2.0
AgF/2.0
AgF/2.0
AgF/2.0
AgOAc/2.0
CuF2/1.0
AgF/3.0
AgF/3.0
AgF/3.0
AgF/3.0
NaOAc/0.2
NaOAc/0.2
NaOAc/0.2
NaOAc/0.2
NaOAc/0.2
NaOAc/0.2
NaOAc/0.2
KOAc/0.4
DME
TFE
25
12
S
, 46%
S
O
S
CHO
c
3am
3ap, 62%
3ao
, 68%
3an
, 76% (60%)
Br
CN
5
DMSO
tBuOH
tBuOH
tBuOH
tBuOH
tBuOH
tBuOH
tBuOH
0
CN
CN
CN
S
6
43
S
S
S
Br
7
18
Br
3aq
3at
, 60%
3as
, 62%
, 38%
3ar
, 37%
8
0
aReaction conditions: 1a (0.2 mmol, 1.0 equiv), 2 (0.6 mmol, 3.0
equiv), [Cp*Rh(MeCN)3](SbF6)2 (5.0 mol %), AgF (3.0 equiv),
KOAc (0.4 equiv) and tBuOH (1.0 mL) at 100 °C for 24 h under
ambient atmosphere. Isolated yields. Yield for a gram-scale
reaction (2 mmol).
9
50
10
11c
12c,d
55
b
c
KOAc/0.4
72
80 (75e)
KOAc/0.4
aReaction conditions: 1a (0.2 mmol, 1.0 equiv), 2a (0.4 mmol, 2.0
equiv), [Cp*Rh(MeCN)3](SbF6)2 (5.0 mol%), oxidant, additive and
solvent (1.0 mL) at 120 °C for 24 h under ambient atmosphere. bNMR
yields calculated by using CH2Br2 as the internal standard. c3.0 equiv
2a was used. dThe reaction was carried out at 100 oC. eIsolated yield.
Subsequently, an investigation on the scope of the ethyl
imidates 1 was carried out (Scheme 3). A set of benzimidates
provided the desired coupled products in moderate to good
yields. The functionalities on the phenyl ring affected
significantly on the stabilities of benzimidates in the catalytic
system, which caused dealcoholization of
1 to release
benzonitriles, and thus diminished the coupling reaction. except
the reactions of 1b and 1c, we observed significant amount of
benzonitriles along with the desired products after reactions.
For example, ethyl 2-naphthimidate 1l coupled with 2l to afford
3ll in 46% yield, while 2-naphthonitrile was obtained in 36%.
Moreover, ortho-substituted benzimidates are too labile to be
With the optimized conditions in hand (Table 1, entry 12), we
next investigated the substrate scope of heteroarenes 2
(Scheme 2). Benzimidate 1a coupled with a variety of
thiophenes bearing electron-donating or electron-withdrawing
substituents to furnish 2-(thiophen-2-yl)benzonitrile 3aa-am in
moderate to excellent yields. The functionalities such as alkyl,
2 | J. Name., 2012, 00, 1-3
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prepared, and only ortho-fluorinated benzimidates 1j and 1k subsequent reductive elimination releases bi(hetero)aryl-2-
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were obtained. The coupling reactions of them with 2a and 2l carbimidate 4aa and a Rh(II) species.16 Finally, dealcoholisation
DOI: 10.1039/C9CC05314J
furnished the corresponding products 3ja and 3kl in 46% and 38% of 4aa provides the targeted product 3aa,8,11 and the Rh(II)
yields, respectively. Finally, the coupling between two species is oxidized by Ag(I) to revive the Rh(III) species for the
heteroaryls, 1m and 2l was conducted, giving no desired next catalytic cycle. It needs to point out that 4aa was only
product but benzothiophene-3-carbonitrile. To balance the detected by HRMS analysis (See ESI) and could not be isolated
dealcolization and cross coupling processes, 1m was slowly due to its easy dealcoholisation in reaction system.
added into the reaction mixture with 2l over 2 h. The targeted
In conclusion, we have developed a Rh-catalyzed C–H/C–H
product 3ml was obtained in 26% yield, but a significant amount oxidative coupling and dealcoholization reaction of
of benzothiophene-3-carbonitrile was still detected.
benzimidates with heteroarenes to directly furnish
biheteroaryl-2-carbonitriles. A variety of functionalities could
be tolerant in this reaction, Moreover, this reaction was run
under ambient atmosphere and no inert gas protection was
needed. The simple operation, high atom- and step-economy of
this reaction make this protocol highly attractive for the
synthesis of biheteroaryl-2-carbonitriles.
Scheme
3.
Scope
of
ethyl
benzimidatesa,b
NH
OEt
CN
[Cp*Rh(MeCN)3](SbF6)2
AgF, KOAc
tBuOH, 100 ºC, 24 h
R1
R2
R2
H
+
R1
Ph
S
H
S
2a 2l
or
1
3
CN
CN
CN
CN
OEt
NH
S
S
S
S
CO2Me
CO2Me
CO2Me
MeO
3cl
3dl
, 69%
CN
, 56%
CN
3ba
, 80%
3el, 45%
Ag(0)
H
[Cp*RhIIIX2]
CN
CN
1a
HX
S
S
S
S
Ag(I) + X
[Cp*RhIIX]
CO2Me
F
CO2Me
CO2Me
CO2Me
Cl
F
Br
CN
I
Br
3gl
3fl
, 43%
, 50%
3hl
, 47%
3il
, 46%
EtO
CN
CN
CN
NH
RhIII Cp*
OEt
NH
S
S
S
S
S
CO2Me
CO2Me
CO2Me
X
IM1
c
3ja
3kl
, 38%
, 46%
3ll
3ml,
X
, 46%
26%
aReaction conditions: 1 (0.2 mmol, 1.0 equiv), 2a or 2l (0.6
mmol, 3.0 equiv), [Cp*Rh(MeCN)3](SbF6)2 (5.0 mol %), AgF (3.0
equiv), KOAc (0.4 equiv) and tBuOH (1.0 mL) at 100 °C for 24 h
under ambient atmosphere. Isolated yields. 1m was added
over 2 h.
S
4aa
3aa
H
EtO
S
2a
NH
RhIV Cp*
- EtOH
CN
EtO
HX
b
c
NH
RhIII
S
Cp*
IM3
S
S
Ag(0)
Ag(I)
IM2
To shed light on the reaction mechanism, kinetic isotopic effect
(KIE) experiments were conducted. Under the standard
conditions, the parallel competitive reactions of 1a and 1a-d5
with 2o were carried out, providing a KIE value of 1.54 (Scheme
4a). Meanwhile, the parallel reactions of 1a with 2n and 2n-d
gave a similar KIE value of 1.60 (Scheme 4b). These results
suggested that both C–H bond activation processes might not
be involved in the turnover-limiting step in this cross-coupling
reaction.
X = OAc, F or SbF6
Scheme 5. Proposed pathway.
We thank the financial supports from the National NSF of
China (No. 21472127 and 21772134) and the Fundamental
Research Funds for the Central Universities.
Conflicts of interest
There are no conflicts to declare.
NH
OEt
CN
H4/D4
standard conditions
+
H
H5/D5
a)
1 h
kH/kD = 1.54
S
S
1a 1a
or -d5
2n
3an 3an
or
-d4
Notes and references
1
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Interscience Publishers: London, 1970; (b) Kleemann, A.;
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Martin, S. L. Buchwald, Acc. Chem. Res. 2008, 41, 1461; (c) C.
NH
OEt
CN
standard conditions
H/D
b)
+
1 h
kH/kD = 1.60
S
S
H
1a
2n 2n
or -d
3an
Scheme 4. Kinetic isotopic effect study.
2
3
4
Based on our results and the previous reports,8,11-15
a
plausible mechanism is proposed in Scheme 5. The coordination
of the imidate group with [Cp*Rh(MeCN)3](SbF6)2 initiates the
ortho-C–H cleavage of 1a, giving a five-membered rhodacycle
species IM1.12 IM1 reacts with 2a to form IM2 via either an SEAr
or CMD mechanism.13 At this stage, IM2, a Rh(III) species, is
oxidized by Ag(I) to generate a Rh(IV) species, IM3.8,15 The
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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16 A reaction of 1a and 2a was conducted by using a
stoichiometric amount of Rh(III) catalyst without the oxidant
AgF and gave no product 3aa, excluding the direct reductive
elimination of IM2. See ESI.
4 | J. Name., 2012, 00, 1-3
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