Nickel-catalysed direct alkylation of thiophenes via double C(sp3)-H/C(sp2)-H bond cleavage: The importance of KH2PO4

Article abstract of DOI:10.1039/c7cc04252c

A Ni-catalyzed oxidative C-H/C-H cross-dehydrogenative coupling (CDC) reaction was developed for constructing various highly functionalized alkyl (aryl)-substituted thiophenes. This method employs thiophenes and aliphatic (aromatic) amides that contain an 8-aminoquinoline as a removable directing group in the presence of a silver oxidant. The approach enables the facile one-step synthesis of substituted thiophenes with high functional group compatibility via double C-H bond cleavage without affecting C-Br and C-I bonds. DFT calculations verify the importance of KH₂PO₄ as an additive for promoting C-H bond cleavage and support the involvement of a Ni(iii) species in the reaction.

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Nickel-Catalysed Direct Alkylation of Thiophenes via Double
C(sp3)-H/C(sp2)-H Bond Cleavage: The Importance of KH2PO4
Xie Wang,a,† Peipei Xie,b,† Renhua Qiu,*,a,c Longzhi Zhu,a,c Ting Liu,a You Li,a Takanori Iwasaki,c Chak-
Tong Au,a,d Xinhua Xu,a Yuanzhi Xia,*,b Shuang-Feng Yin,*,a and Nobuaki Kambec
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
A Ni-catalyzed oxidative C-H/C-H cross-dehydrogenative coupling (CDC) reaction was developed for
constructing various highly functionalized alkyl(aryl)-substituted thiophenes. This method employs
thiophenes and aliphatic(aromatic) amides that contain an 8-aminoquinoline as a removable directing
group in the presence of a sliver oxidant. The approach enables the facile one-step synthesis of substituted
thiophenes with high functional group compatibility via double C-H bond cleavage without affecting C-Br
and C-I bonds. DFT calculations verify the importance of KH2PO4 as an additive for promoting C-H bond
cleavage and support the involvement of a Ni(III) species in the reaction.
www.rsc.org/
Thiophenes and analogues thereof are ubiquitous in practical, efficient, and economical approaches. An ideal strategy to
pharmaceuticals,1 natural products,1b and functional materials.2 meeting these requirements is oxidative C-H/C-H cross-
5
(supporting information, SI).1,2
dehydrogenative coupling (CDC) between a thiophene and a
hydrocarbon as the coupling partner. Extensive studies in this vein
have been reported, and remarkable successes have been achieved
for C(sp2)-H/C(sp2)-H coupling using base metals (Co,6a Cu,6b Mn,6c
Ni,6d) and noble metals (Pd, 7 Rh,8 Ru, 9 Au10) (Scheme 1c). Oxidative
C-H/C-H oxidative dehydrocoupling
Conventional methods
cat Pd
cat. Rh, Pd etc
(c)
(a)
(b)
X
+
R M
Ar
H
H
S
S
limited to Csp2-H and noble metal
general
M = B(OR)2, ZnX, MgX, SnR3, H;
X = I, Br, OTf etc
R
C(sp3)-H/C(sp2)-H coupling has recently been recognized as
a
This work
S
n-BuLi
R-X
cat. Ni
Li
H
(d)
+
R
H
H
promising and straightforward method for introducing alkyl groups
to arenes and olefins.5 However the oxidative coupling of
thiophenes with either activated or non-activated alkanes has not
yet been accomplished. Herein we report the first example of the
S
S
S
R = alkyl, ar yl
Scheme 1. Functionalization of thiophenes
Conventional methods for the functionalization of thiophenes
include the metal-catalyzed cross-coupling of organic halides with
organometallic reagents such as Kumada coupling, Stille coupling,
and Suzuki-Miyaura coupling (Scheme 1a).3 Alternatively, lithiation
of thiophenes at low temperatures by n-BuLi followed by
nucleophilic substitution with an alkyl halide enables C(sp2)-C(sp3)
linkages to be installed (Scheme 1b).4 However, disadvantages
associated with these conventional methods include the need of
tedious, multistep procedures for preparing the starting materials,
expensive reagents, poor substrate availability, and low tolerance
towards functional groups (especially when organometallic species
such as organolithiums or organomagnesiums are involved). To
tackle these problems, considerable attention has been paid to
developing new methods for installing thiophenes via more
oxidative alkylation of thiophenes with unactivated alkanes using an
11
8-aminoquinoline (8-AQ)
as the directing group. The reaction
proceeds selectively via C(sp3)-H/C(sp2)-H CDC catalysed by a nickel
salt12 (Scheme 1d), which can be used even in cases where
thiophenes have been incorporated with a C(sp2)-X (Cl, Br, I)
bond(s). Using this approach, halothiophene products were
prepared on a gram scale and subjected to further manipulation via
palladium-catalyzed coupling with alkenes and alkynes. The present
CDC reaction can be successfully applied to the alkylation of
thiazoles and furans as well as to cross-coupling between two
heteroarenes.
As a model reaction, the cross-coupling between an aliphatic
amide 1a and thiophene (2a) was examined (Table S1 in Supporting
Information). After optimization of reaction conditions, the
oxidative C(sp3)-H/C(sp2)-H coupling took place to give 3a in 64%
yield when the reaction was conducted at 160 °C using Ni(OTf)2 as
the catalyst in the presence of Ag2CO3, MesCOOH, TBAB
(tetrabutylammonium bromide) and KH2PO4.
We found that this catalytic system was suitable for the
alkylation of a wide range of thiophenes (Table 1, 3a–3r). In
addition, not only was pivalamide tolerated, but also various N-
quinolin-8-ylamides succumb to the CDC process. It is also
noteworthy that chloro-, bromo-, and iodothiophene could
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N-Quinolin-8-ylpropanamides bearing alkyl, and/or aryl
substituents at the -position also gave the desired products in
Table 1. Substrate scopes
α
good yields (4a–4c). The reaction shows a high degree of site
selectivity, with methyl groups being preferred to methylene groups
presumably due to steric effects (4b). No evidence to indicate
C(sp2)-H bond functionalization of phenyl was observed in the
formation of 4a, c. A quaternary α-carbon is essential for efficient
C(sp3)-H bond functionalization, and unsubstituted propionamide or
isobutyramide did not participate in this reaction (4f, 4g).12d, 12e
We then attempted to apply the system to the construction of
bis(hetero)arene scaffolds (5a-5f). As expected, the reactions
proceeded exclusively at the ortho-position, giving the target
products in high yields (5a, 5b). Tri- and tetra-(hetero)arenes, which
have interesting skeletons for organic materials, were also
produced in good yields (5c-5f). Furthermore, the present
procedure worked perfectly for the site-selective functionalization
of thiazoles (6a–6e) and furans (6f, 6g). However, 1H-indole was
unreactive and N-methylindole did not give the desired products.
This new CDC reaction could be easily carried out on a gram
scale for the synthesis of alkyl-substituted 2-iodothiophene 3d (1.26
g, 58% yield) as illustrated in Scheme 2. Thus, the iodinated product
3d that was formed could be further functionalized through
palladium-catalyzed Sonogashira and Mizoroki-Heck couplings to
deliver the desired products (7, 8) in good yields of 74% and 62%,
respectively. In addition, the corresponding carboxylic acid is easy
to obtain in our previous work, which means the directing group
can be easily removed.14
Reaction conditions: 1 (0.2 mmol), 2 (0.6 mmol), Ni(OTf)2 (0.04 mmol), MesCOOH
(0.08 mmol), KH2PO4 (0.4 mmol), Ag2CO3 (0.6 mmol), TBAB (0.6 mmol) in DMSO
(0.5 mL) at 160 °C for 24 h in a 10 mL screw-capped vial. Isolated yields.
be used in the reaction without dehalogenation (3b-d). In particular,
the C-I bond in 2-iodothiophene 3d provided an opportunity for
consecutive C-C bond formation by conventional cross-coupling
(vide infra). Thiophenes bearing electron-donating groups reacted
efficiently to give 3e and 3f. Remarkably, this method was also
found to be compatible with ketone and ester groups (3g, 3h),
which often require protective groups because these carbonyl
functional groups are prone to enolate or carbonyl substitution
processes respectively under similar conditions.13 However,
thiophenes possessing an aminoethyl or cyanomethyl group did not
afford the desired products (3i, 3j), likely because of catalyst
deactivation as a result of coordination. The scope of thiophenes
was not limited to such simple scaffolds, and ring-fused
benzobthiophene (3k) and thieno-3,2-b-thiophene (3l) were also
found to be suitable substrates. Substituents at the 3-position led to
the selective cleavage at the less hindered 5-position to give 3n in
good yields. Interestingly 2,3-dibromothiophene participated in the
oxidative cross-coupling reaction exclusively at the 5-position,
giving 3o in a good yield without affecting either C-Br bond.
Regarding the synthetic application of this method, bis- and tris-
thiophenes, which often appear in organic semiconductors, were
functionalized with the pivalamide, giving 3p and 3q in only one
step without the need to prepare heteroaryl halides and/or
organometallic reagents. In addition, the 2,5-dibromothiophene
didn’t gave the C3-position substituted product in our conditions, it
could be caused by the different electron density of thiophene.
Scheme 2. Gram-scale synthesis of an alkyl-substituted iodothiophene and consecutive
transformations.
To better understand the described reactions, several
preliminary mechanistic experiments were undertaken. Kinetic
isotope effects (KIE) for both coupling partners were studied. At
first, an intermolecular competition reaction between
benzo[b]thiophene and its deuterated derivative did not give a
significant KIE value (kH/kD = 1.1), indicating that the C (sp2)-H bond
cleavage could not be the rate-determining step. Additional
competitive experiments indicate a primary KIE of 4.6, suggesting
that the C(sp3)-H cleavage is involved in the rate-determining step
(Scheme 3A). The addition of 1 equiv of a radical scavenger, such as
TEMPO or 1,4-benzoquinone, BHT, had a negligible effect on the
reaction (Scheme 3B), indicating that this CDC reaction does not
appear to proceed via radical intermediates. Furthermore, with 2-
bromothiophene without a silver salt, a C-H/C-H coupling reaction
did not occur and, instead, a C-H/C-Br coupling reaction took
place.14 In the presence of a silver salt, the CDC reaction delivered
the desired product 9 in 67% yield with the C-Br bond remaining
intact (Scheme 3C). These results clearly indicate that the presence
of a silver oxidant alters the course of the reaction, probably by
oxidizing the nickel intermediates that are produced in the catalytic
cycle. In addition, we obtained the x-ray crystal structure of product
9 to confirm that the coupling is indeed at the 2-position (see in SI).
2 | J. Name., 2012, 00, 1-3
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these two processes are almost the same (22.8 and 23.3 kcal/mol
respectively) and are similar to the barrier of the C(sp3)-H bond
scission (21.6 kcal/mol). When the ligand was changed from H2PO4
to OTf, the energies of transition states TS3 and TS4 again increased
to 30.5 and 34.9 kcal/mol, respectively (see SI). It is noted that the
incorporation of another KH2PO4 molecule in IN4 slightly reduced
the activation energy of the C(sp2)-H activation/reductive
elimination process to 20.4 and 20.9 kcal/mol, respectively (see SI).
These calculations are in accord with the proposed catalytic cycle
and suggest that phosphate anion plays important roles in the
processes for C-H bond breaking.
Although the full details are not currently known, a plausible
catalytic cycle is proposed in Figure 1. First, a Ni(II)-amide species A
is generated from NiX2 and amide 1a via C-H bond cleavage. Then,
the Ni(III) intermediate B was formed through an oxidation by Ag
salt. The electrophilic Ni(III) intermediate B reacts with thiophene
2a to generate intermediate C. Reductive elimination of
intermediate C gives the desired product 3a and Ni(I). Finally, Ni(I) is
re-oxidised to Ni(II) to complete the catalytic cycle.
A) KIE Experiment
O
O
standard conditions, 5 h
N
H
N
H(D)
S
N
H
S
N
benzo[b]thiophene
or
3k kH/kD = 1.1
[D1]-benzo[b]thiophene
(D)
H
H
(D)
H(D)
O
O
(D)H
(D)H
standard conditions
N
N
H
H
Ph Et
Ph Et
N
kH/kD = 4.6
S
N
( 19% conversion
)
1:[D3]-1 = 1:1
3:[D2]-3
(0.3 mmol)
B) Radical Trapping Experimentsa
H
standard conditons
S
O
O
N
S
N
N
NH
H
S
N
1 equiv TEMPO
69%
H
O
1 equiv 1,4-benzoquinone 72%
1 equiv BHT 17% (66%b
not found
1a
)
3a
O
Figure 1. A proposed catalytic cycle.
NHQ
C) Product Distribution
Ph
Ph
Our previous work
no [Ag]
H
S
O
72%
Ph
Ph
H
Br
N
S
H
O
N
This work
[Ag]
NHQ
H
Ph
Ph
1f
Br
S
9, 67%
Scheme 3. Mechanistic experiments (a Isolated yields of major products; b Using DMF as
solvent).
To shed lights on the details and probability of the reaction
pathways, DFT calculations (see SI for details) were carried out. The
calculated energies and geometries of stationary points are shown
in Scheme 4 (see SI for details). It was found that anion exchange
between Ni(OTf)2 and KH2PO4 is highly exergonic by 29.2 kcal/mol,
suggesting the formation of Ni(H2PO4)2 is likely and predominant in
the system (Scheme 4a). Complexation of 1a with NiX2 (X = H2PO4)
forms IN1 favourably, which undergoes N-H deprotonation via TS1
to generate intermediate IN2. Then C(sp3)-H bond scission at the β-
position proceeds by a concerted metalation deprotonation (CMD)
mechanism via transition state TS2, which has much higher energy
than TS1 and gives rise IN3 endergonically. Consequently, the
C(sp3)-H bond cleavage requires an activation barrier of 21.4
kcal/mol as indicated by the energy gap between IN1 and TS2.
Interestingly this is much lower than the activation energy of 34.5
kcal/mol that was calculated with X = OTf (see SI). This is in good
agreement with the experimental fact that the addition of KH2PO4 is
Scheme 4. Computational Results (relative free energies are in kcal/mol)
essential to achieve high yields.[15]
A possible metalation
mechanism via C(sp2)-H cleavage of thiophene with NiX2 was also
considered (Scheme 4c). Because the activation energy of this
process via TS1’ (22.1 kcal/mol) is almost the same as the barrier of
C(sp3)-H bond scission via TS2 (21.4 kcal/mol) and because
Conclusions
In summary, we report the efficient Ni-catalysed oxidative
C(sp3)-H/C(sp2)-H cross-coupling of thiophenes with alkylamides
stabilizing energy of complexation of NiX2 with 1a to form IN1 is bearing an 8-aminoquinoline unit as a directing group. This reaction
very large, metalation of thiophenes by NiX2 seems unlikely. provides a general and efficient protocol for the construction of
Metalation of thiophenes with Ni(III) complex IN4 generated by
oxidation of a Ni(II) complex IN3 by Ag(I) gives IN5 via TS3, which
then undergoes reductive elimination via TS4 to form arylated
intermediate IN6, leading to the product. The energy barriers of
C(alkyl)-C(heteroaryl) bonds using readily available alkylamides. DFT
calculations suggest that KH2PO4 represents an important additive
in each step of this reaction, and supports the involvement of a
Ni(III) species for efficient C(sp2)-H cleavage and C-C coupling. The
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protocol is also applicable to oxidative C(sp2)-H/C(sp2)-H cross-
coupling reactions as well as to the alkylation of other heteroarenes,
including thiazoles and furanes.
Li, Angew. Chem. Int. Ed. 2014, 53, 74. g) R.-J. Song, Y. Liu, Y.-
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Gao, S. Tang, W. Li, R. Shi, A. Lei, Chem. Rev. 2015, 115
,
12138.
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Acknowledgements
The authors wish to thank the National Natural Science
Foundation of China (Grant Nos. 21373003, 21676076), and
the Natural Science Foundation of Hunan Province
(2016JJ3034), and Hunan Youth Talent (2016RS3023), for
financial support. R.Q. and X.W. acknowledge financial support
7
8
for
a fellowship from CSC. The authors express their
appreciation to Prof. Li-Biao Han (AIST, Tsukuba, Japan), Prof.
Akihiro Orita (Okayama University of Science) and Prof. Gary A.
Molander (University of Pennsylvania) for helpful discussions.
C.T. Au thanks HNU for an adjunct professorship.
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4
5
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